Amine compound and pharmaceutical use thereof

2-amino-2-{2-[3-cyano-4-(3-phenylpropoxy)phenyl]ethyl}propane-1,3-diol hydrochloride

(1-1) Synthesis of 5-bromo-2-(3-phenylpropoxy)benzonitrile (Compound 1-1)

3-Phenylpropanol (2.17 g) was dissolved in N,N-dimethylformamide (32 ml), and sodium hydride (60%, 0.638 g) was added at room temperature. After stirring for 1 hr, 5-bromo-2-fluorobenzonitrile (1.60 g) was added, and the mixture was further stirred at 40-50° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (2.30 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.13-2.20(2H, m), 2.85(2H, t, J=7.6 Hz), 4.03(2H, t, J=6.4 Hz), 6.78(1H, d, J=8.8 Hz), 7.19-7.22(3H, m), 7.27-7.30(2H, m), 7.57(1H, dd, J=8.8, 2.4 Hz), 7.66(1H, d, J=2.4 Hz).

(1-2) Synthesis of (5-{2-[3-cyano-4-(3-phenylpropoxy)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 1-2)

Compound 1-1 (0.720 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (0.634 g) synthesized according to the known method (e.g., Tetrahedron vol.57 (2001) pages 6531-6538), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.050 g), bis(acetonitrile)palladium(II) dichloride (0.009 g) and cesium carbonate (0.855 g) were stirred in acetonitrile (8.7 ml) at 70° C. for 7 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give (5-{2-[3-cyano-4-(3-phenylpropoxy)phenyl]ethynyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a pale-brown solid. This solid was dissolved in ethyl acetate (5 ml), 10% palladium carbon (containing water about 50%, 0.044 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The solution was filtered, and the filtrate was concentrated to give the object product (0.408 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.92-1.96(2H, m), 2.12-2.18(2H, m), 2.49-2.53(2H, m), 2.85(2H, t, J=7.2 Hz), 3.68(2H, d, J=11.2 Hz), 3.86(2H, d, J=11.2 Hz), 4.01(2H, t, J=6.4 Hz), 4.97(1H, s), 6.80(1H, d, J=8.8 Hz), 7.17-7.22(3H, m), 7.25-7.31(3H, m), 7.35(1H, d, J=2.0 Hz).

(1-3) Synthesis of 2-amino-2-{2-[3-cyano-4-(3-phenylpropoxy)phenyl]ethyl}propane-1,3-diol hydrochloride (Compound 1-3)

Compound 1-2 (0.408 g) was dissolved in a mixed solvent of ethanol (3 ml) and tetrahydrofuran (2 ml), p-toluenesulfonic acid monohydrate (0.028 g) was added, and the mixture was stirred at room temperature for 4.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give a compound deprotected acetal of compound 1-2 as an oil. To the obtained oil was added hydrogen chloride-containing dioxane (4 mol/l, 2 ml), and the mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration, and dried to give the object product (0.104 g) as a white powder.

MS(ESI)m/z: 355[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78 (2H, m), 2.03-2.08(2H, m), 2.54-2.61(2H, m), 2.76(2H, t, J=7.6 Hz), 3.51(4H, d, J=4.8 Hz), 4.09(2H, t, J=6.0 Hz), 5.37(2H, t, J=4.8 Hz), 7.15-7.22(4H, m), 7.27-7.30(2H, m), 7.48(1H, d, J=8.8 Hz), 7.56(1H, s), 7.85(3H, brs).

2-amino-2-{2-[3-cyano-4-(4-phenylbutoxy)phenyl]ethyl}propane-1,3-diol hydrochloride

(2-1) Synthesis of 5-bromo-2-(4-phenylbutoxy)benzonitrile (Compound 2-1)

4-Phenylbutanol (0.834 g) was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60%, 0.638 g) was added. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (0.640 g) was added, and the mixture was further stirred at 40-50° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (1.04 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.81-1.89(4H, m), 2.70(2H, t, J=6.8 Hz), 4.04(2H, t, J=6.0 Hz), 6. 80(1H, d, J=9.2 Hz), 7.16-7.20(3H, m), 7.26-7.30(2H, m), 7.58(1H, dd, J=8.8, 2.4 Hz), 7.64(1H, d, J=2.4 Hz).

(2-2) Synthesis of (5-{2-[3-cyano-4-(4-phenylbutoxy)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 2-2)

Compound 2-1 (0.544 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (0.459 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.36 g), bis(acetonitrile)palladium(II) dichloride (0.007 g) and cesium carbonate (0.538 g) were stirred in acetonitrile (8.3 ml) at 70-80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give (5-{2-[3-cyano-4-(4-phenylbutoxy)phenyl]ethynyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester as a yellow oil. This oil was dissolved in ethyl acetate (6 ml), 10% palladium carbon (containing water about 50%, 0.080 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hr. The solution was filtered, and the filtrate was concentrated to give the object product (0.519 g) as a pale-yellow powder.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.43(3H, s), 1.46(9H, s), 1.84-1.86(4H, m), 1.91-1.96(2H, m), 2.48-2.53(2H, m), 2.69(2H, t, J=6.8 Hz), 3.67(2H, d, J=11.6 Hz), 3.86(2H, d, J=11.6 Hz), 4.03(2H, t, J=5.6 Hz), 4.97(1H, s), 6.82(1H, d, J=8.8 Hz), 7.15-7.21(3H, m), 7.26-7.29(2H, m), 7.30(1H, dd, J=8.8, 2.0 Hz), 7.34(1H, d, J=2.0 Hz).

(2-3) Synthesis of 2-amino-2-{2-[3-cyano-4-(4-phenylbutoxy)phenyl]ethyl}propane-1,3-diol hydrochloride (Compound 2-3)

Compound 2-2 (0.519 g) was dissolved in a mixed solvent of ethanol (5 ml) and tetrahydrofuran (4 ml), p-toluenesulfonic acid monohydrate (0.035 g) was added, and the mixture was stirred at room temperature for 3.5 hr, and further at 50-60° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give a compound deprotected acetal of compound 2-2 as an oil. To the obtained oil was added hydrogen chloride-containing dioxane (4 mol/l, 2 ml), and the mixture was stirred at room temperature for 8 hr. The precipitate was collected by filtration, and dried to give the object product (0.164 g) as a black-brown powder.

MS(ESI)m/z: 369[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(6H, m), 2.54-2.59(2H, m), 2.65(2H, t, J=6.8 Hz), 3.51(4H, d, J=5.2 Hz), 4.10-4.14(2H, m), 5.36(2H, t, J=5.2 Hz), 7.15-7.22(4H, m), 7.27(1H, m), 7.28(1H, d, J=8.8 Hz), 7.48(1H, dd, J=8.8, 2.0 Hz), 7.54(1H, d, J=2.0 Hz), 7.82(3H, brs).

2-amino-2-{2-[4-(4-cyclohexylbutoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(3-1) Synthesis of 4′-methoxy-3′-trifluoromethylacetophenone (Compound 3-1)

To a solution of 4′-fluoro-3′-trifluoromethylacetophenone (25.0 g) in N,N-dimethylformamide (70 ml) was added under ice-cooling sodium methoxide (7.21 g), and the mixture was stirred under ice-cooling for 2 hr and further at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (24.3 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 2.59(3H, s), 3.99(3H, s), 7.06(1H, d, J=8.7 Hz), 8.14(1H, dd, J=2.1, 8.7 Hz), 8.19(1H, d, J=2.1 Hz).

(3-2) Synthesis of 4′-methoxy-3′-trifluoromethylphenacylbromide (Compound 3-2)

To a solution of compound 3-1 (24.3 g) in acetic acid (120 ml) was added pyridinium tribromide (90%, 39.6 g), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 1M aqueous sodium hydroxide solution, saturated ammonium chloride and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (34.2 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 4.01(3H, s), 4.39(2H, s), 7.09(1H, d,

J=8.7 Hz), 8.18(1H, dd, J=2.2, 8.7 Hz), 8.23(1H, d, J=1.9 Hz).

(3-3) Synthesis of 2-acetamide-2-[2-(4-methoxy-3-trifluoromethylphenyl)-2-oxoethyl]malonic acid diethyl ester (Compound 3-3)

To a solution of diethyl 2-acetamidomalonate (20.1 g) in N,N-dimethylformamide (100 ml) was added under ice-cooling sodium hydride (60%, 4.07 g) in two portions, and the mixture was stirred for 30 min. A solution of compound 3-2 (33.0 g) in N,N-dimethylformamide (50 ml) was added to this solution, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (31.8 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.25(6H, t, J=7.1 Hz), 1.97(3H, s), 3.98(3H, s), 4.22(2H, s), 4.27(4H, dq, J=2.4, 7.1 Hz), 7.05(1H, d, J=8.7 Hz), 7.09(1H, brs), 8.13(1H, dd, J=2.2, 8.7 Hz), 8.20(1H, d, J=2.0 Hz).

(3-4) Synthesis of 2-acetamide-2-[2-(4-methoxy-3-trifluoromethylphenyl)ethyl]malonic acid diethyl ester (Compound 3-4)

To a solution of compound 3-3 (31.5 g) in trifluoroacetic acid (230 ml) was added triethylsilane (116 ml), and the mixture was stirred at 70° C. for 13 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound and a mixture of the starting material as a yellow oil. To a solution of this oil in trifluoroacetic acid (230 ml) was added triethylsilane (116ml), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give the object product (7.91 g) as a white powder. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the object product (4.29 g). The combined yield was 12.2 g.

1 H-NMR(CDCl 3 ) δ (ppm): 1.25(6H, t, J=7.2 Hz), 2.02(3H, s), 2.44-2.48(2H, m), 2.62-2.68(2H, m), 3.87(3H, s), 4.15-4.27(4H, m), 6.78(1H, brs), 6.90(1H, d, J=8.4 Hz), 7.27(1H, dd, J=2.0, 8.4 Hz), 7.32(1H, d, J=2.0 Hz).

(3-5) Synthesis of N-[1,1-bis(hydroxymethyl)-3-(4-methoxy-3-trifluoromethylphenyl)propyl]acetamide (Compound 3-5)

To a solution of compound 3-4 (12.2 g) in ethanol (200 ml) and water (40 ml) was added calcium chloride (6.46 g) and dissolved. To this mixture was added under ice-cooling sodium borohydride (4.40 g) in two portions, and the mixture was stirred under ice-cooling for 3 hr, and further at room temperature for 20 hr. To the reaction mixture was added under ice-cooling 1M hydrochloric acid (300 ml), the mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.88 g) as white foams.

1 H-NMR(CDCl 3 ) δ (ppm): 1.92-1.96(2H, m), 2.02(3H, s), 2.60-2.64(2H, m), 3.57(2H, brs), 3.64(2H, brd, J=11.6 Hz), 3.85(2H, brd, J=11.6 Hz), 3.87(3H, s), 5.94(1H, brs), 6.92(1H, d, J=8.5 Hz), 7.32(1H, dd, J=1.9, 8.5 Hz), 7.37(1H, d, J=1.9 Hz).

(3-6) Synthesis of [3-(4-hydroxy-3-trifluoromethylphenyl)-1,1-bis(hydroxymethyl)propyl]carbamic acid t-butyl ester (Compound 3-6)

To a solution of compound 3-5 (9.70 g) in methylene chloride (90 ml) was added dropwise 1M methylene chloride solution (116 ml) of tribromide boron at −70° C. The mixture was heated to 0° C. with stirring over 1 hr, and further stirred under ice-cooling for 2 hr. To the reaction mixture was gradually added under ice-cooling methanol (200 ml), and the mixture was concentrated under reduced pressure. To a solution of the obtained residue in ethanol (50 ml) was added concentrated hydrochloric acid (50 ml), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to a solution of the obtained residue and N,N-diisopropylethylamine (12.6 ml) in methanol (80 ml) was added under ice-cooling di-t-butyl-dicarbonate (6.94 g), and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (500 ml), and the mixture was concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (2.15 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.46(9H, s), 1.84-1.89(2H, m), 2.57-2.61(2H, m), 3.26(2H, brs), 3.66(2H, dd, J=5.9, 11.4 Hz), 3.87(2H, dd, J=5.2, 11.4 Hz), 5.04(1H, brs), 5.58(1H, brs), 6.87(1H, d, J=8.4 Hz), 7.23(1H, dd, J=1.8, 8.4 Hz), 7.30(1H, d, J=1.8 Hz).

(3-7) Synthesis of 4-bromobutylcyclohexane (Compound 3-7)

4-Cyclohexyl-1-butanol (5.00 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (9.15 g) and N-bromosuccinimide (6.21 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (6.30 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.80-0.96(2H, m), 1.10-1.35(6H, m), 1.38-1.49(2H, m), 1.60-1.77(5H, m), 1.82-1.92(2H, quint, J=7.0 Hz), 3.41(2H, t, J=7.0 Hz).

(3-8) Synthesis of {3-[4-(4-cyclohexylbutoxy)-3-trifluoromethylphenyl]-1,1-bis(hydroxymethyl)propyl}carbamic acid t-butyl ester (Compound 3-8)

Compound 3-6 (360 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (262 mg) and compound 3-7 (250 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (520 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.81-0.94(2H, m), 1.10-1.50(6H, m), 1.40-1.50(2H, m), 1.45(9H, s), 1.61-1.82(7H, m), 1.83-1.89(2H, m), 2.57-2.62(2H, m), 3.24(2H, brs), 3.62-3.68(2H, m), 3.85-3.90(2H, m), 4.00(2H, t, J=6.4 Hz), 5.02(1H, brs), 6.89(1H, J=8.4 Hz), 7.25-7.29(1H, m), 7.36(1H, d, J=1.8 Hz).

(3-9) Synthesis of 2-amino-2-{2-[4-(4-cyclohexylbutoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 3-9)

Compound 3-8 (520 mg) was dissolved in methylene chloride (5 ml), hydrogen chloride-containing dioxane (4 mol/l 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (410 mg) as a white powder.

MS(ESI)m/z: 418[M+H]

1 H-NMR(CD 3 0D) S (ppm): 0.88-0.99(2H, m), 1.15-1.31(6H, m), 1.46-1.55(2H, m), 1.60-1.81(7H, m), 1.90-1.96(2H, m), 2.63-2.69(2H, m), 3.69(4H, s), 4.04(2H, t, J=6.1 Hz), 7.07(1H, d, J=8.5 Hz), 7.39-7.45(2H, m).

2-amino-2-{2-[4-(4-phenylbutoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(4-1) Synthesis of {1,1-bis(hydroxymethyl)-3-[4-(4-phenylbutoxy)-3-trifluoromethylphenyl]propyl}carbamic acid t-butyl ester (Compound 4-1)

Compound 3-6 (350 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (255 mg) and 4-phenylbutylbromide (235 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (490 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.45(9H, s), 1.81-1.90(6H, m), 2.57-2.62(2H, m), 2.64-2.70(2H, m), 3.24(2H, brs), 3.63-3.68(2H, m). 3.84-3.90(2H, m), 4.00(2H, t, J=6.4 Hz), 5.02(1H, brs), 6.87(1H, d, J=8.5 Hz), 7.15-7.19(3H, m), 7.24-7.31(3H, m), 7.36(1H, brs).

(4-2) Synthesis of 2-amino-2-{2-[4-(4-phenylbutoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 4-2)

Compound 4-1 (490 mg) was dissolved in methylene chloride (7 ml), hydrogen chloride-containing dioxane (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 12 hr stirred for. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (370 mg) as a white powder.

MS(ESI)m/z: 412[M+H]

1 H-NMR(CD 3 OD) δ (ppm): 1.79-1.84(4H, m), 1.90-1.95(2H, m), 2.64-2.72(4H, m), 3.69(4H, s), 4.06(2H, t, J=5.4 Hz), 7.06(1H, d, J=8.5 Hz), 7.12-7.21(3H, m), 7.22-7.29(2H, m), 7.40(1H, d, J=8.5 Hz), 7.45(1H, brs).

2-amino-2-{2-[4-(5-phenylpentyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(5-1) Synthesis of {1,1-bis(hydroxymethyl)-3-[4-(5-phenylpentyloxy)-3-trifluoromethylphenyl]propyl}carbamic acid t-butyl ester (Compound 5-1)

Compound 3-6 (380 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (277 mg) and 5-phenylpentylbromide (281 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.45(911, s), 1.45-1.59(2H, m), 1.60-1.72(2H, m), 1.79-1.91(4H, m), 2.57-2.68(4H, m), 3.25(2H, brs), 3.63-3.68(2H, m), 3.84-3.90(2H, m), 4.00(2H, t, J=6.4 Hz), 5.02(1H, brs), 6.88(1H, d, J=8.5 Hz), 7.15-7.19(3H, m), 7.24-7.31(3H, m), 7.36(1H, brs).

(5-2) Synthesis of 2-amino-2-{2-[4-(5-phenylpentyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 5-2)

Compound 5-1 (560 mg) was dissolved in methylene chloride (5 ml), hydrogen chloride-containing dioxane (4 mol/l 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (410 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(CD 3 OD) δ (ppm): 1.48-1.60(2H, m), 1.64-1.75(2H, m), 1.78-1.88(2H, m), 1.92-1.96(2H, m), 2.60-2.71(4H, m), 3.68(4H, s), 4.04(2H, t, J=6.2 Hz), 7.06(1H, d, J=8.4 Hz), 7.12-7.20(3H, m), 7.22-7.27(2H, m), 7.41(1H, d, J=8.4 Hz), 7.45(1H, d, J=1.7 Hz).

2-amino-2-{2-[4-(3-benzyloxybenzyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(6-1) Synthesis of 3-benzyloxybenzylbromide (Compound 6-1)

3-Benzyloxybenzyl alcohol (5.00 g) was dissolved in methylene chloride (70 ml), triphenylphosphine (6.52 g) and N-bromosuccinimide (4.43 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.75 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 4.46(2H, s), 5.07(2H, s), 6.89-6.93(1H, m), 6.98-7.03(2H, m), 7.22-7.28(1H, m), 7.32-7.38(5H, m).

(6-2) Synthesis of (5-{2-[4-(3-benzyloxybenzyloxy)-3-trifluoromethylphenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 6-2)

Reference Example compound 2-6 (510 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 6-1 (396 mg) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (810 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.92-1.98(2H, m), 2.51-2.57(2H, m), 3.69(2H, d, J=11.7 Hz). 3.89(2H, d, J=11.7 Hz), 4.98(1H, brs), 5.07(2H, s), 5.13(2H, s), 6.91(1H, d, J=8.6 Hz), 6.92(1H, d, J=8.0 Hz), 7.05(1H, d, J=7.5 Hz), 7.09(1H, s), 7.24-7.48(8H, m).

(6-3) Synthesis of 2-amino-{2-(2-[4-(3-benzyloxybenzyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 6-3)

Compound 6-2 (810 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (620 mg) as a white powder.

MS(ESI)m/z: 476[M+H]

1 H-NMR(CD 3 OD) δ (ppm): 1.88-1.93(2H, m), 2.63-2.68(2H, m), 3.67(4H, s), 5.08(2H, s), 5.18(2H, s), 6.93(1H, dd, J=8.4, 2.4 Hz), 7.02(1H, d, J=7.6 Hz), 7.09(1H, brs), 7.12(1H, d, J=8.4 Hz), 7.25-7.44(7H, m), 7.49(1H, d, 1.9 Hz).

2-amino-2-{2-[4-(3-phenoxybenzyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(7-1) Synthesis of (2,2-dimethyl-5-{2-[4-(3-phenoxybenzyloxy)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 7-1)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and 3-phenoxybenzylchloride (0.271 ml) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (850 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s). 1.93-1.98(2H, m), 2.51-2.56(2H, m), 3.69(2H, d, J=11.6 Hz), 3.89(2H, d, J=11.6 Hz), 4.98(1H, brs), 5.11(2H, s), 6.89-7.18(8H, s), 7.24-7.40(4H, m).

(7-2) Synthesis of 2-amino-2-{2-[4-(3-phenoxybenzyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 7-2)

Compound 7-1 (850 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (603 mg) as a white powder.

MS(ESI)m/z: 462[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.89-1.94(2H, m), 2.63-2.69(2H, m), 3.68(4H, s), 5.18(2H, s), 6.90-6.99(3H, m), 7.06-7.20(4H, m), 7.31-7.38(3H, m), 7.41(1H, dd, J=8.4, 1.8 Hz), 7.48(1H, d, J=1.8 Hz).

2-amino-2-{2-[4-(3-phenylpropoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(8-1) Synthesis of (2,2-dimethyl-5-{2-[4-(3-phenylpropoxy)-3-trifluoromethylphenyl]ethyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 8-1)

Reference Example compound 2-6 (540 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (533 mg) and 3-phenylpropylbromide (0.235 ml) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.09-2.15(2H, m), 2.51-2.56(2H, m), 2.83(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.6 Hz), 3.89(2H, d, J=11.6 Hz), 3.99(2H, t, J=6.0 Hz), 4.98(1H, brs), 6.83(1H, d, J=8.5 Hz), 7.18-7.22(3H, m), 7.24-7.31(3H, m), 7.37(1H, d, J=2.0 Hz).

(8-2) Synthesis of 2-amino-2-{2-[4-(3-phenylpropoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 8-2)

Compound 8-1 (740 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.

MS(ESI)m/z: 398[M+H]

1 H-NMR(CD 3 OD) δ (ppm): 1.90-1.95(2H, m), 2.04-2.12(2H, m), 2.63-2.68(2H, m), 2.81(2H, t, J=7.4 Hz), 3.68(4H, s), 4.01(2H, t, J=6.0 Hz), 7.23(1H, d, J=8.5 Hz), 7.12-7.28(5H, m), 7.40(1H, dd, J=8.5, 1.6 Hz), 7.48(1H, d, J=1.6 Hz).

2-amino-2-{2-[4-(3-cyclohexylpropoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(9-1) Synthesis of 3-bromopropylcyclohexane (Compound 9-1)

3-Cyclohexyl-1-propanol (5.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (10.2 g) and N-bromosuccinimide (6.90 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (7.17 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.81-0.96(2H, m), 1.10-1.45(6H, m), 1.60-1.78(5H, m), 1.82-1.92(2H, quint, J=7.0 Hz), 3.39(2H, t,

J=7.0 Hz).

(9-2) Synthesis of (5-{2-[4-(3-cyclohexylpropyl)-3-trifluoromethylphenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 9-2)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 9-1 (293 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.81-0.95(2H, m), 1.10-1.39(7H, m), 1.42(3H, s), 1.44(3H, m), 1.47(9H, s), 1.61-1.84(6H, m), 1.91-1.98(2H, m), 2.51-2.57(2H, m), 3.68(2H, d, J=11.7 Hz), 3.87(2H, d, J=11.7 Hz), 3.98(2H, t, J=6.4 Hz), 4.98(1H, brs), 6.87(1H, d, J=8.5 Hz), 7.25-7.28(1H, m), 7.34(1H, d, J=1.9 Hz).

(9-3) Synthesis of 2-amino-2-{2-[4-(3-cyclohexylpropoxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 9-3)

Compound 9-2 (760 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (525 mg) as a white powder. MS(ESI)m/z: 404[M+H]

1 H-NMR(CD 3 OD) δ (ppm): 0.88-0.98(2H, m), 1.15-1.33(4H, m), 1.34-1.41(2H, m), 1.61-1.83(7H, m), 1.89-1.96(2H, m), 2.63-2.68(2H, m), 3.68(4H, s), 4.03(2H, t, J=6.2 Hz), 7.07(1H, d, J=8.4 Hz), 7.41(1H, dd, J=8.4, 1.7 Hz), 7.45(1H, d, J=1.7 Hz).

2-amino-2-(2-{4-[3-(4-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(10-1) Synthesis of 1-(3-bromopropyl)-4-methoxybenzene (Compound 10-1)

3-(4-Methoxyphenyl)-1-propanol (5.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (8.86 g) and N-bromosuccinimide (5.94 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:1-3:1) to give the object product (990 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.14(2H, quint, J=6.5 Hz), 2.72(2H, t, J=7.2 Hz), 3.38(2H, t, J=6.5 Hz), 3.78(3H, s), 6.84(2H, d, J=8.6 Hz), 7.11(2H, d, J=8.6 Hz).

(10-2) Synthesis of [5-(2-{4-[3-(4-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 10-2)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 10-1 (327 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (730 mg) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.09(2H, m), 2.51-2.64(2H, m), 2.77(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.78(3H, s), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=6.0 Hz), 4.98(1H, brs), 6.81-6.85(3H, m), 7.11(2H, d, J=8.6 Hz), 7.24-7.26(111, m), 7.36(111, d, J=1.8 Hz).

(10-3) Synthesis of 2-amino-2-(2-{4-[3-(4-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 10-3)

Compound 10-2 (730 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (550 mg) as a white powder.

MS(ESI)m/z: 428[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.80(2H, m), 1.91-2.02(2H, m), 2.57-2.63(2H, m), 2.68(2H, t, J=7.4 Hz), 3.50(4H, brs), 3.71(3H, s), 4.03(2H, t, J=5.8 Hz), 5.34(2H, brs), 6.84(2H, d, J=8.2 Hz), 7.10(2H, d, J=8.2 Hz), 7.15(1H, d, J=8.4 Hz), 7.43(1H, d, J=8.4 Hz), 7.47(1H, brs), 7.68(3H, brs).

2-amino-2-(2-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}ethyl)propane-1,3-diol hydrochloride

(11-1) Synthesis of 3-(4-trifluoromethylphenyl)-1-propanol (Compound 11-1)

4-Trifluoromethylcinnamic acid (10.0 g) was dissolved in methanol (20 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (5.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a colorless powder (10.5 g). The colorless powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane•tetrahydrofuran solution (1 mol/l, 59.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 16 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.53 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.54(1H, brs), 1.87-1.94(2H, m), 2.78(2H, t, J=7.7 Hz), 3.68(2H, t, J=6.3 Hz), 7.31(2H, d, J=8.0 Hz), 7.54(2H, d, J=8.0 Hz).

(11-2) Synthesis of 1-(3-bromopropyl)-4-trifluoromethylbenzene (Compound 11-2)

Compound 11-1 (9.53 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (13.3 g) and N-bromosuccinimide (8.97 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (200 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (10.1 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.18(2H, quint, J=7.4 Hz), 2.85(2H, t, J=7.4 Hz), 3.39(2H, t, J=6.4 Hz), 7.32(2H, d, J=8.0 Hz), 7.55(2H, d, J=8.0 Hz).

(11-3) Synthesis of [2,2-dimethyl-5-(2-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 11-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 11-2 (382 mg) were added, and the mixture was stirred at 80° C. for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (800 mg) as a pale-yellow solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.99(2H, m), 2.10-2.18(2H, m), 2.51-2.57(2H, m), 2.90(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.83(1H, d, J=8.5 Hz), 7.25-7.32(3H, m), 7.38(1H, d, J=1.6 Hz), 7.53(2H, d, J=8.1 Hz).

(11-4) Synthesis of 2-amino-2-(2-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}ethyl)propane-1,3-diol hydrochloride (Compound 11-4)

Compound 11-3 (800 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (592 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.79(2H, m), 2.02-2.08(2H, m), 2.58-2.64(2H, m), 2.84(2H, t, J=7.5 Hz), 3.52(4H, d, J=4-6 Hz), 4.06(2H, t, J=6.1 Hz), 5.36(2H, t, J=4.8 Hz), 7.17(1H, d, J=8.5 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.2 Hz), 7.78(3H, brs).

2-amino-2-(2-{3-trifluoromethyl-4-[3-(3-trifluoromethylphenyl)propoxy]phenyl}ethyl)propane-1,3-diol hydrochloride

(12-1) Synthesis of 3-(3-trifluoromethylphenyl)-1-propanol (Compound 12-1)

3-Trifluoromethylcinnamic acid (10.0 g) was dissolved in methanol (50 ml) and tetrahydrofuran (30 ml), 10% palladium carbon (5.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 11 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a white powder (10.4 g). The white powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane•tetrahydrofuran solution (1 mol/l, 60.2 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 16 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.00 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.56(1H, brs), 1.87-1.95(2H, m), 2.78(2H, t, J=7.5 Hz), 3.69(2H, t, J=6.4 Hz), 7.38-7.48(4H, m).

(12-2) Synthesis of 1-(3-bromopropyl)-3-trifluoromethylbenzene (Compound 12-2)

Compound 12-1 (9.00 g) was dissolved in methylene chloride (80 ml), triphenylphosphine (12.8 g) and N-bromosuccinimide (8.63 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (200 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (8.59 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.17-2.23(2H, m), 2.85(2H, t, J=7.5 Hz), 3.40(2H, t, J=6.4 Hz), 7.38-7.49(4H, m).

(12-3) Synthesis of [2,2-dimethyl-5-(2-{3-trifluoromethyl-4-[3-(3-trifluoromethylphenyl)propoxy]phenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 12-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 12-2 (382 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (810 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 1.99-2.15(2H, m), 2.51-2.57(2H, m), 2.90(2H, t, J=7.6 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.99(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.84(1H, d, J=8.4 Hz), 7.25-7.28(1H, m), 7.35-7.40(3H, m), 7.45(2H, brs).

(12-4) Synthesis of 2-amino-2-(2-{3-trifluoromethyl-4-[3-(3-trifluoromethylphenyl)propoxy]phenyl}ethyl)propane-1,3-diol hydrochloride (Compound 12-4)

Compound 12-3 (810 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.71-1.76(2H, m), 2.04-2.08(2H, m), 2.57-2.62(2H, m), 2.85(2H, t, J=7.5 Hz), 3.49(4H, brs), 4.05(2H, t, J=6.0 Hz), 5.29(2H, brs), 7.16(1H, d, J=8.5 Hz), 7.43(1H, d, J=8.5 Hz), 7.47(1H, d, J=1.5 Hz), 7.50-7.58(4H, m).

2-amino-2-(2-{4-[3-(4-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(13-1) Synthesis of 3-(4-methylphenyl)-1-propanol (Compound 13-1)

To a suspension of lithium aluminum hydride (585 mg) and tetrahydrofuran (50 ml) was added dropwise a solution of 4-methylcinnamic acid (1.00 g) in tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a colorless oil (1.05 g). The colorless oil was dissolved in ethyl acetate (30 ml), 10% palladium carbon (200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (690 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.22(1H, brs), 1.84-1.92(2H, m), 2.31(3H, s), 2.67(2H, t, J=7.5 Hz), 3.67(2H, t, J=6.1 Hz), 7.09(4H, s).

(13-2) Synthesis of 1-(3-bromopropyl)-4-methylbenzene (Compound 13-2)

Compound 13-1 (690 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.33 g) and N-bromosuccinimide (899 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (830 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.11-2.18(2H, m), 2.32(3H, s), 2.74(2H, t, J=7.5 Hz), 3:67(2H, t, J=6.6 Hz), 7.07-7.11(4H, m).

(13-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(4-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 13-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 13-2 (305 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42 (3H, s), 1.44 (3H, s), 1.47 (9H, s), 1.93-1.98(2H, m), 2.07-2.14(2H, m), 2.31(3H, s), 2.51-2.57(2H, m), 2.78(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=6.1 Hz), 4.98(1H, brs), 6.83(1H, d, J=8.5 Hz), 7.09(4H, brs), 7.23-7.26(1H, m), 7.36(1H, d, J=2.0 Hz).

(13-4) Synthesis of 2-amino-2-(2-{4-[3-(4-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 13-4)

Compound 13-3 (790 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.

MS(ESI)m/z: 412[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 1.96-2.04(2H, m), 2.25(3H, s), 2.58-2.63(2H, m), 2.69(2H, t, J=7.5 Hz), 3.51(4H, d, J=3.3 Hz), 4.03(2H, t, J=5.9 Hz), 5.35(2H, brs), 7.08(4H, s), 7.15(1H, d, J=8.7 Hz), 7.43(1H, d, J=8.7 Hz), 7.47(1H, brs), 25 7.71(3H, brs).

2-amino-2-(2-{4-[3-(2-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(14-1) Synthesis of 3-(2-methylphenyl)-1-propanol (Compound 14-1)

To a suspension of lithium aluminum hydride (1.74 g) and tetrahydrofuran (100 ml) was added dropwise a solution of 2-methylcinnamic acid (3.00 g) in tetrahydrofuran (30 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 4.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a yellow oil (3.17 g). The yellow oil was dissolved in ethyl acetate (30 ml), 10% palladium carbon (500 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give the object product (3.10 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, brs), 1.84-1.90(2H, m), 2.32(3H, s), 2.70(2H, t, J=7.8 Hz), 3.72(2H, t, J=6.2 Hz), 7.08-7.20(4H, m).

(14-2) Synthesis of 1-(3-bromopropyl)-2-methylbenzene (Compound 14-2)

Compound 14-1 (3.10 g) was dissolved in methylene chloride (70 ml), triphenylphosphine (5.28 g) and N-bromosuccinimide (3.58 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.67 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.09-2.17(2H, m), 2.32(3H, s), 2.77(2H, t, J=7.8 Hz), 3.72(2H, t, J=6.4 Hz), 7.11-7.17(4H, m).

(14-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(2-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 14-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 14-2 (305 mg) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (750 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.94-1.98(2H, m), 2.03-2.11(2H, m), 2.32(3H, s), 2.52-2.57(2H, m), 2.83(2H, t, J=7.6 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.03(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.86(1H, d, J=8.5 Hz), 7.09-7.16(4H, m), 7.28(1H, d, J=2.0 Hz), 7.37(1H, d, J=2.0 Hz).

(14-4) Synthesis of 2-amino-2-(2-{4-[3-(2-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 14-4)

Compound 14-3 (750 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.

MS(ESI)m/z: 412[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.67-1.73(2H, m), 1.85-1.90(2H, m), 2.18(3H, s), 2.52-2.57(2H, m), 2.67(2H, t, J=7.8 Hz), 3.45(4H, d, J=4.3 Hz), 4.02(2H, t, J=5.8 Hz), 5.30(2H, t, J=4.6 Hz), 6.99-7.08(4H, m), 7.10(1H, d, J=8.4 Hz), 7.37(1H, d, J=8.4 Hz), 7.41(1H, d, J=1.7 Hz), 7.74(3H, brs).

2-amino-2-(2-{4-[3-(3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(15-1) Synthesis of 3-(3-methylphenyl)-1-propanol (Compound 15-1)

To a suspension of lithium aluminum hydride (1.75 g) and tetrahydrofuran (100 ml) was added dropwise a solution of 3-methylcinnamic acid (3.00 g) in tetrahydrofuran (30 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a yellow oil (2.97 g). The yellow oil was dissolved in ethyl acetate (30 ml), 10% palladium carbon (500 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the object product (1.88 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, brs), 1.85-1.93(2H, m), 2.33(3H, s), 2.67(2H, t, J=7.5 Hz), 3.72(2H, t, J=6.4 Hz), 6.99-7.02(3H, m), 7.18(1H, t, J=7.5 Hz).

(15-2) Synthesis of 1-(3-bromopropyl)-3-methylbenzene (Compound 15-2)

Compound 15-1 (1.88 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.64 g) and N-bromosuccinimide (2.46 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:1) to give the object product (2.25 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.09-2.17(2H, m), 2.33(3H, s), 2.74(2H, t, J=7.4 Hz), 3.40(2H, t, J=6.5 Hz), 6.98-7.03(3H, m), 7.18(1H, t, J=7.4 Hz).

(15-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 15-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 15-2 (305 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (720 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.05-2.12(2H, m), 2.32(3H, s), 2.51-2.57(2H, m), 2.78(2H, t, J=7.6 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, J=11.7 Hz), 3.99(2H, t, J=6.0 Hz), 4.97(1H, brs), 6.84(1H, J=8.5 Hz), 6.98-7.01(3H, m), 7.17(1H, t, J=7.4 Hz), 7.23-7.26(1H, m), 7.36(1H, d, J=1.7 Hz).

(15-4) Synthesis of 2-amino-2-(2-{4-[3-(3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 15-4)

Compound 15-3 (720 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.

MS(ESI)m/z: 412[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 1.97-2.03(2H, m), 2.26(3H, s), 2.58-2.63(2H, m), 2.70(2H, t, J=7.5 Hz), 3.51(4H, d, J=3.9 Hz), 4.04(2H, t, J=6.1 Hz), 5.34(2H, brs), 6.96-7.01(3H, m), 7.16(2H, t, J=7.5 Hz), 7.43(1H, d, J=8.6 Hz), 7.47(1H, d, J=1.6 Hz), 7.69(3H, brs).

2-amino-2-(2-{4-[3-(3-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(16-1) Synthesis of 3-(3-methoxyphenyl)-1-propanol (Compound 16-1)

To a suspension of lithium aluminum hydride (1.60 g) and tetrahydrofuran (80 ml) was added dropwise a solution of 3-methoxycinnamic acid (3.00 g) in tetrahydrofuran (30 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a yellow oil (2.75 g). The yellow oil was dissolved in ethyl acetate (30 ml), 10% palladium carbon (800 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3-1:4) to give the object product (2.00 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, brs), 1.86-1.93(2H, m), 2.69(2H, t, J=7.6 Hz), 3.68(2H, t, J=6.4 Hz), 3.80(3H, s), 6.72-6.75(2H, m), 6.80(1H, d, J=7.6 Hz), 7.18(1H, t, J=7.6 Hz).

(16-2) Synthesis of 1-(3-bromopropyl)-3-methoxybenzene (Compound 16-2)

Compound 16-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.58 g) and N-bromosuccinimide (2.40 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.07 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.13-2.20(2H, m), 2.76(2H, t, J=7.4 Hz), 3.40(2H, t, J=6.6 Hz), 3.80(3H, s), 6.74-6.70(3H, m), 7.18-7.23(1H, m).

(16-3) Synthesis of [5-(2-{4-[3-(3-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 16-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 16-2 (328 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (800 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.08-2.12(2H, m), 2.51-2.56(2H, m), 2.81(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.76(3H, s), 3.89(2H, d, J=11.7 Hz), 3.99(2H, t, J=6.0 Hz), 4.98(1H, brs), 6.72-6.84(4H, m), 7.19(1H, t, J=7.5 Hz), 7.24(1H, d, J=1.8 Hz), 7.36(1H, d, J=1.8 Hz).

(16-4) Synthesis of 2-amino-2-(2-{4-[3-(3-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 16-4)

Compound 16-3 (800 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.

MS(ESI)m/z: 428[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 1.99-2.05(2H, m), 2.57-2.63(2H, m), 2.72(2H, t, J=7.4 Hz), 3.51(4H, d, J=4.8 Hz), 3.69(3H, s), 4.03(2H, t, J=6.1 Hz), 5.34(2H, t, J=4.8 Hz), 6.73-6.78(3H, m), 7.14-7.22(2H, m), 7.43(1H, d, J=8.7 Hz), 7.47(1H, brs), 7.69(3H, brs).

2-amino-2-(2-{4-[3-(2-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(17-1) Synthesis of 3-(2-methoxyphenyl)-1-propanol (Compound 17-1)

To a suspension of lithium aluminum hydride (1.60 g) and tetrahydrofuran (70 ml) was added dropwise a solution of 2-methoxycinnamic acid (3 g) in tetrahydrofuran (30 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a colorless oil (2.95 g). The colorless oil was dissolved in ethyl acetate (30 ml), 10% palladium carbon (700 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to give the object product (2.00 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, brs), 1.81-1.89(2H, m), 2.73(2H, t, J=7.3 Hz), 3.60(2H, brs), 3.84(3H, s), 6.85-6.92(2H, m), 7.13-7.21(2H, m).

(17-2) Synthesis of 1-(3-bromopropyl)-2-methoxybenzene (Compound 17-2)

Compound 17-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.58 g) and N-bromosuccinimide (2.40 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.24 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.11-2.18(2H, m), 2.76(2H, t, J=7.3 Hz), 3.40(2H, t, J=6.9 Hz), 3.82(3H, s), 6.83-6.90(2H, m), 7.13-7.22(2H, m).

(17-3) Synthesis of [5-(2-{4-[3-(2-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 17-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 17-2 (328 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (780 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.06-2.10(2H, m), 2.51-2.56(2H, m), 2.81(2H, t, J=7.4 Hz), 3.69(2H, d, J=11.7 Hz), 3.80(3H, s), 3.89(2H, d, J=11.7 Hz), 3.99(2H, t, J=6.0 Hz), 4.98(1H, brs), 6.83-6.88(3H, m), 7.13(1H, d, J=7.0 Hz), 7.18(1H, t, J=7.8 Hz), 7.24(1H, brs), 7.36(1H, d, J=1.4 Hz).

(17-4) Synthesis of 2-amino-2-(2-{4-[3-(2-methoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 17-4)

Compound 17-3 (780 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.

MS(ESI)m/z: 428[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.94-2.04(2H, m), 2.57-2.64(2H, m), 2.72(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.3 Hz), 3.75(3H, s), 4.04(2H, t, J=6.0 Hz), 5.36(2H, brs), 6.85(1H, t, J=7.3 Hz), 6.95(1H, d, J=8.2 Hz), 7.08(1H, d, J=7.3 Hz), 7.13-7.18(2H, m), 7.43(1H, d, J=8.5 Hz), 7.47(1H, brs), 7.77(3H, brs).

2-amino-2-(2-{4-[3-(3,4-dimethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(18-1) Synthesis of 3-(3,4-dimethoxyphenyl)-1-propanol (Compound 18-1)

To a suspension of lithium aluminum hydride (1.37 g) and tetrahydrofuran (70 ml) was added dropwise a solution of 3,4-dimethoxycinnamic acid (3.00 g) in tetrahydrofuran (30 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a colorless oil (2.96 g). The colorless oil was dissolved in ethyl acetate (50 ml), 10% palladium carbon (1.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:3) to give the object product (2.00 g) as a pale-yellow oil.

1H-NMR(CDCl 3 ) δ (ppm): 1.21-1.25(1H, m), 1.84-1.92(2H, m), 2.66(2H, t, J=7.8 Hz), 3.69(2H, q, J=6.1 Hz), 3.86(3H, s), 3.87(3H, s), 6.73-6.75(2H, m), 6.78-6.81(1H, m).

(18-2) Synthesis of 1-(3-bromopropyl)-3,4-dimethoxybenzene (Compound 18-2)

Compound 18-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (2.97 g) and N-bromosuccinimide (1.99 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-3:1) to give the object product (2.17 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.11-2.18(2H, m), 2.73(2H, t, J=7.3 Hz), 3.40(2H, t, J=6.5 Hz), 3.86(3H, s), 3.88(3H, s), 6.72-6.75(2H, m), 6.79-6.81(1H, m).

(18-3) Synthesis of [5-(2-{4-[3-(3,4-dimethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 18-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 18-2 (371 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.00 g) as a pale-yellow solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.05-2.10(2H, m), 2.51-2.56(2H, m), 2.78(2H, t, J=7.3 Hz), 3.69(2H, d, J=11.7 Hz), 3.79(3H, s), 3.84-3.90(5H, m), 3.97(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.71-6.75(2H, m), 6.77-6.84(2H, m), 7.24-7.26(1H, m), 7.37(1H, d, J=1.6 Hz).

(18-4) Synthesis of 2-amino-2-(2-{4-[3-(3,4-dimethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 18-4)

Compound 18-3 (1.00 g) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (580 mg) as a pale-yellow powder.

MS(ESI)m/z: 458[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 1.97-2.04(2H, m), 2.57-2.64(2H, m), 2.68(2H, t, J=7.3 Hz), 3.52(4H, d, J=4.7 Hz), 3.66(3H, s), 3.70(3H, s), 4.02(2H, t, J=6.0 Hz), 5.36(2H, t, J=4.7 Hz), 6.69(1H, dd, J=8.4, 1.5 Hz), 6.76(1H, d, J=1.5 Hz), 6.84(1H, d, J=8.0 Hz), 7.15(1H, d, J=8.4 Hz), 7.43(1H, d, J=8.4 Hz), 7.47(1H, s), 7.76(3H, brs).

2-amino-2-(2-{4-[3-(2,4-dimethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(19-1) Synthesis of 3-(2,4-dimethoxyphenyl)-1-propanol (Compound 19-1)

To a suspension of lithium aluminum hydride (2.28 g) and tetrahydrofuran (100 ml) was added dropwise a solution of 2,4-dimethoxycinnamic acid (5.00 g) in tetrahydrofuran (50 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 2 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated to give a yellow oil (4.30 g). The a yellow oil was dissolved in ethyl acetate (50 ml), 10% palladium carbon (1.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to give the object product (2.68 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.54(1H, brs), 1.77-1.85(2H, m), 2.65(2H, t, J=7.3 Hz), 3.59(2H, q, J=6.2 Hz), 3.81(3H, s), 3.83(3H, s), 6.42-6.47(2H, m), 7.04(1H, d, J=7.9 Hz).

(19-2) Synthesis of 1-(3-bromopropyl)-2,4-dimethoxybenzene (Compound 19-2)

Compound 19-1 (2.68 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.99 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to give the object product (2.71 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.07-2.14(2H, m), 2.69(2H, t, J=7.2 Hz), 3.39(2H, t, J=6.7 Hz), 3.79(6H, s), 6.40-6.45(2H, m), 7.04(1H, d, J=8.0 Hz).

(19-3) Synthesis of [5-(2-{4-[3-(2,4-dimethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 19-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 19-2 (371 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (930 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.02-2.06(2H, m), 2.51-2.56(2H, m), 2.74(2H, t, J=7.4 Hz), 3.69(2H, d, J=11.8 Hz), 3.77(3H, s), 3.79(3H, s), 3.87-3.90(2H, m), 3.97(2H, t, J=6.1 Hz), 4.98(1H, brs), 6.39(1H, dd, J=8.1, 2.3 Hz), 6.44(1H, d, J=2.3 Hz), 6.84(1H, d, J=8.5 Hz), 7.01(1H, d, J=8.1 Hz), 7.24-7.26(1H, m), 7.36(1H, d, J=1.8 Hz).

(19-4) Synthesis of 2-amino-2-(2-{4-[3-(2,4-dimethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 19-4)

Compound 19-3 (930 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, and the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml). The precipitate was collected by filtration and dried to give the object product (460 mg) as a white powder.

MS(ESI)m/z: 458[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.79-1.84(2H, m), 1.96-2.00(2H, m), 2.64-2.72(4H, m), 3.57(4H, d, J=4.1 Hz), 3.78(3H, s), 3.79(3H, s), 4.07(2H, t, J=6.1 Hz), 5.40(2H, brs), 6.48(1H, dd, J=8.1, 2.3 Hz), 6.58(1H, d, J=2.3 Hz), 7.03(1H, d, J=8.1 Hz), 7.19(1H, d, J=8.5 Hz), 7.49(1H, d, J=8.5 Hz), 7.52(1H, s), 7.75(3H, brs).

2-amino-2-(2-{4-[3-(4-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(20-1) Synthesis of 3-(4-fluorophenyl)-1-propanol (Compound 20-1)

4-Fluorocinnamic acid (10.0 g) was dissolved in methanol (10 ml) and tetrahydrofuran (100 ml), 10% palladium carbon (2.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a colorless powder (10.2 g). The colorless powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 72.2 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 2 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.39 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.22-1.25(1H, m), 1.83-1.91(2H, m), 2.69(2H, t, J=7.6 Hz), 3.67(2H, q, J=6.1 Hz), 6.94-6.99(2H, m), 7.13-7.17(2H, m).

(20-2) Synthesis of 1-(3-bromopropyl)-4-fluorobenzene (Compound 20-2)

Compound 20-1 (9.39 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (8.58 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. To the reaction mixture was slowly added water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.93 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.18(2H, m), 2.76(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.5 Hz), 6.98(2H, t, J=8.3 Hz), 7.15(2H, t, J=6.5 Hz).

(20-3) Synthesis of [5-(2-{4-[3-(4-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 20-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 20-2 (310 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (720 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.11(2H, m), 2.52-2.56(2H, m), 2.80(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=5.9 Hz), 4.97(1H, brs), 6.83(1H, d, J=8.5 Hz), 6.93-6.98(2H, m), 7.12-7.16(2H, m), 7.25-7.27(1H, m), 7.37(1H, d, J=1.9 Hz).

(20-4) Synthesis of 2-amino-2-(2-{4-[3-(4-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 20-4)

Compound 20-3 (720 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (523 mg) as a white powder.

MS(ESI)m/z: 416[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.98-2.05(2H, m), 2.59-2.64(2H, m), 2.74(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.7 Hz), 4.04(2H, t, J=6.1 Hz), 5.37(2H, t, J=4.7 Hz), 7.07-7.17(3H, m), 7.20-7.24(2H, m), 7.44(1H, dd, J=8.5, 1.7 Hz),7.47(1H, brs), 7.80(3H, brs).

2-amino-2-(2-{4-[3-(3,4-methylenedioxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(21-1) Synthesis of 3-(3,4-methylenedioxyphenyl)-1-propanol (Compound 21-1)

3,4-Methylenedioxycinnamic acid (10.0 g) was dissolved in methanol (30 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (2.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a colorless powder (9.88 g). The colorless powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 61.1 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 12 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.72 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.21-1.26(1H, m), 1.82-1.89(2H, m), 2.64(2H, t, J=7.6 Hz), 3.67(2H, q, J=6.0 Hz), 5.92(2H, s), 6.63-6.66(1H, m), 6.69-6.74(2H, m).

(21-2) Synthesis of 1-(3-bromopropyl)-3,4-methylenedioxybenzene (Compound 21-2)

Compound 21-1 (9.72 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (5.27 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 6.5 hr. To the reaction mixture was slowly added water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.05 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.08-2.15(2H, m), 2.70(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.5 Hz), 5.92(2H, s), 6.63-6.69(2H, m), 6.74(1H, d, J=7.8 Hz).

(21-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3,4-methylenedioxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 21-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 21-2 (388 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (860 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.09(2H, m), 2.51-2.56(2H, m), 2.75(2H, t, J=7.4 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=5.9 Hz), 4.97(1H, brs), 5.91(2H, s), 6.62-6.73(3H, m), 6.83(1H, d, J=8.5 Hz), 7.25-7.26(1H, m), 7.36(1H, J=1.8 Hz).

(21-4) Synthesis of 2-amino-2-(2-{4-[3-(3,4-methylenedioxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 21-4)

Compound 21-3 (860 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (570 mg) as a white powder.

MS(ESI)m/z: 442[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.70-1.75(2H, m), 1.91-1.99(2H, m), 2.54-2.59(2H, m), 2.62(2H, t, J=7.4 Hz), 3.47(4H, d, J=4.7 Hz), 3.98(2H, t, J=6.1 Hz), 5.32(2H, t, J=4.7 Hz), 5.91(2H, s), 6.59(1H, dd, J=7.8, 1.3 Hz), 6.73-6.77(2H, m), 7.11(1H, d, J=8.5 Hz),7.37-7.43(2H, m), 7.70(3H, brs).

2-amino-2-(2-{4-[3-(2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(22-1) Synthesis of 3-(2-fluorophenyl)-1-propanol (Compound 22-1)

2-Fluorocinnamic acid (10.0 g) was dissolved in methanol (20 ml) and tetrahydrofuran (30 ml), 10% palladium carbon (5.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a white powder (10.3 g). The white powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 78.3 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 1.5 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (8.68 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.52-1.58(1H, m), 1.85-1.92(2H, m), 2.75(2H, t, J=7.6 Hz), 3.68(2H, t, J=6.3 Hz), 6.98-7.08(2H, m), 7.14-7.20(2H, m).

(22-2) Synthesis of 1-(3-bromopropyl)-2-fluorobenzene (Compound 22-2)

Compound 22-1 (8.68 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (6.35 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. To the reaction mixture was slowly added water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.00 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.13-2.21(2H, m), 2.81(2H, t, J=7.4 Hz), 3.40(2H, t, J=6.6 Hz), 6.99-7.08(2H, m), 7.16-7.23(2H, m).

(22-3) Synthesis of [5-(2-{4-[3-(2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 22-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 22-2 (310 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.09-2.15(2H, m), 2.51-2.56(2H, m), 2.86(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.00(2H, t, J=6.1 Hz), 4.97(1H, brs), 6.84(1H, d, J=8.5 Hz), 6.98-7.05(2H, m), 7.16-7.19(2H, m), 7.27(1H, brs), 7.37(1H, brs).

(22-4) Synthesis of 2-amino-2-(2-{4-[3-(2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 22-4)

Compound 22-3 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.

MS(ESI)m/z: 416[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.71-1.75(2H, m), 1.95-1.99(2H, m), 2.55-2.60(2H, m), 2.75(2H, t, J=7.6 Hz), 3.48(4H, d, J=4.5 Hz), 4.04(2H, t, J=5.9 Hz), 5.33(2H, t, J=4.5 Hz), 7.07-7.13(3H, m), 7.21-7.25(2H, m),7.40(1H, d, J=8.6 Hz), 7.44(1H, brs), 7.73(3H, brs).

2-amino-2-(2-{4-[3-(3-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(23-1) Synthesis of 3-(3-fluorophenyl)-1-propanol (Compound 23-1)

3-Fluorocinnamic acid (10.0 g) was dissolved in methanol (20 ml) and tetrahydrofuran (30 ml), 10% palladium carbon (3.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a yellow powder (10.6 g). The yellow powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane tetrahydrofuran solution (1 mol/1, 78.3 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 4 hr. To the reaction mixture was added water, 1 mol/1 aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (10.0 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.25(1H, brs), 1.85-1.93(2H, m), 2.72(2H, t, J=7.6 Hz), 3.68(2H, t, J=6.4 Hz), 6.86-6.92(2H, m), 6.97(1H, d, J=7.5 Hz), 7.20-7.25(1H, m).

(23-2) Synthesis of 1-(3-bromopropyl)-3-fluorobenzene (Compound 23-2)

Compound 23-1 (10.0 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (17.5 g) and N-bromosuccinimide (11.8 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (11.1 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.12-2.20(2H, m), 2.78(2H, t, J=7.3 Hz), 3.39(2H, t, J=6.4 Hz), 6.88-6.92(2H, m), 6.98(1H, d, J=7.6 Hz), 7.22-7.28(1H, m).

(23-3) Synthesis of [5-(2-{4-[3-(3-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 23-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 23-2 (310 mg) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (700 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.08-2.14(2H, m), 2.52-2.56(2H, m), 2.83(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=5.9 Hz), 4.97(1H, brs), 6.83(1H, d, J=8.4 Hz), 6.88-6.92(2H, m), 6.97(1H, d, J=7.6 Hz), 7.20-7.27(2H, m), 7.37(1H, brs).

(23-4) Synthesis of 2-amino-2-(2-{4-[3-(3-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 23-4)

Compound 23-3 (700 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (525 mg) as a white powder.

MS(ESI)m/z: 416[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.00-2.08(2H, m), 2.58-2.63(2H, m), 2.77(2H, t, J=7.5 Hz), 3.51(4H, d, J=4.8 Hz), 4.04(2H, t, J=6.1 Hz), 5.36(2H, t, J=4.8 Hz), 7.01-7.05(3H, m), 7.16(1H, d, J=8.5 Hz),7.29-7.33(1H, m), 7.44(1H, d, J=8.5 Hz), 7.47(1H, brs), 7.75(3H, brs).

2-amino-2-(2-{3-trifluoromethyl-4-[3-(2-trifluoromethylphenyl)propoxy]phenyl}ethyl)propane-1,3-diol hydrochloride

(24-1) Synthesis of 3-(2-trifluoromethylphenyl)-1-propanol (Compound 24-1)

2-Trifluoromethylcinnamic acid (5.43 g) was dissolved in methanol (30 ml) and tetrahydrofuran (30 ml), 10% palladium carbon (2.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a white powder (5.8 g). The white powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 32.4 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 18 hr. To the reaction mixture were added water and 1 mol/l aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.07 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.55(1H, brs), 1.86-1.94(2H, m), 2.88(2H, t, J=7.9 Hz), 3.73(2H, t, J=6.3 Hz), 7.29(1H, t, J=7.8 Hz), 7.36(1H, d, J=7.8 Hz), 7.47(1H, d, J=7.8 Hz), 7.47(1H, d, J=7.8 Hz).

(24-2) Synthesis of 1-(3-bromopropyl)-2-trifluoromethylbenzene (Compound 24-2)

Compound 24-1 (5.07 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (7.24 g) and N-bromosuccinimide (4.86 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 4.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (5.32 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.14-2.21(2H, m), 2.95(2H, t, J=7.7 Hz), 3.45(2H, t, J=6.6 Hz), 7.29-7.36(2H, m), 7.48(1H, t, J=7.6 Hz), 7.63(1H, d, J=7.6 Hz).

(24-3) Synthesis of [2,2-dimethyl-5-(2-{3-trifluoromethyl-4-[3-(2-trifluoromethylphenyl)propoxy]phenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 24-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 24-2 (382 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (800 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.94-1.99(2H, m), 2.11-2.14(2H, m), 2.52-2.57(2H, m), 3.00(2H, t, J=7.8 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.05(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.87(1H, d, J=8.5 Hz), 7.29(2H, t, J=7.3 Hz), 7.34-7.38(2H, m), 7.46(1H, t, J=7.6 Hz), 7.62(1H, d, J=7.6 Hz).

(24-4) Synthesis of 2-amino-2-(2-{3-trifluoromethyl-4-[3-(2-trifluoromethylphenyl)propoxy]phenyl}ethyl)propane-1,3-diol hydrochloride (Compound 24-4)

Compound 24-3 (800 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.75-1.80(2H, m), 2.00-2.05(2H, m), 2.59-2.64(2H, m), 2.94(2H, t, J=7.8 Hz), 3.52(4H, d, J=4.9 Hz), 4.15(2H, t, J=5.8 Hz), 5.37(2H, t, J=4.9 Hz), 7.19(1H, t, J=8.5 Hz), 7.42-7.52(4H, m),7.62(1H, t, J=7.7 Hz), 7.68(1H, J=7.7 Hz), 7.77(3H, brs).

2-amino-2-(2-{4-[3-(3-chlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(25-1) Synthesis of 3-(3-chlorophenyl)-1-propanol (Compound 25-1)

3-(3-Chlorophenyl)propionic acid (5.00 g) was dissolved in tetrahydrofuran (100 ml), a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 34.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 15 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (3.48 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.56(1H, brs), 1.84-1.92(2H, m), 2.70(2H, t, J=7.7 Hz), 3.67(2H, t, J=6.4 Hz), 7.06-7.16(1H, m), 7.18-7.23(3H, m).

(25-2) Synthesis of 1-(3-bromopropyl)-3-chlorobenzene (Compound 25-2)

Compound 25-1 (1.00 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (1.71 g) and N-bromosuccinimide (1.15 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (970 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.12-2.19(2H, m), 2.76(2H, t, J=7.4 Hz), 3.39(2H, t, J=6.5 Hz), 7.08(1H, d, J=7.0 Hz), 7.18-7.24(3H, m).

(25-3) Synthesis of [5-(2-{4-[3-(3-chlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 25-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 25-2 (333 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (760 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.45(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.07-2.12(2H, m), 2.52-2.56(2H, m), 2.81(2H, t, J=7.6 Hz), 3.69(2H, d, J=11.6 Hz), 3.89(2H, d, J=11.6 Hz), 3.98(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.84(1H, d, J=8.4 Hz), 7.07(1H, t, J=7.1 Hz), 7.15-7.22(3H, m), 7.27(1H, brs), 7.37(1H, d, J=1.8 Hz).

(25-4) Synthesis of 2-amino-2-(2-{4-[3-(3-chlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 25-4)

Compound 25-3 (760 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.

MS(ESI)m/z: 432[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.80(2H, m), 2.00-2.06(2H, m), 2.59-2.63(2H, m), 2.75(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.9 Hz), 4.04(2H, t, J=6.0 Hz), 5.37(2H, t, J=4.9 Hz), 7.17(2H, d, J=8.2 Hz), 7.24-7.32(3H, m), 7.44(1H, d, J=8.9 Hz), 7.48(1H, brs), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(4-chlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(26-1) Synthesis of 1-(3-bromopropyl)-4-chlorobenzene (Compound 26-1)

3-(4-Chlorophenyl)-1-propanol (1.00 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.66 g) and N-bromosuccinimide (1.11 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 6 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.18(2H, m), 2.76(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.5 Hz), 7.13(2H, d, J=8.3 Hz), 7.31-7.35(2H, m).

(26-2) Synthesis of 2-amino-2-(2-{4-[3-(4-chlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 26-2)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 26-1 (334 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a yellow oil (860 mg). The yellow oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (130 mg) as a white powder.

MS(ESI)m/z: 432[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.97-2.05(2H, m), 2.58-2.63(2H, m), 2.74(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.8 Hz), 4.03(2H, t, J=6.0 Hz), 5.37(2H, t, J=4.8 Hz), 7.16(1H, d, J=8.5 Hz), 7.22(2H, d, J=8.2 Hz), 7.34(2H, d, J=8.2 Hz), 7.43(1H, d, J=8.3 Hz), 7.47(1H, brs), 7.78(3H, brs).

2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride

(27-1) Synthesis of (2-hydroxy-1-hydroxymethyl-1-methyl)ethylcarbamic acid t-butyl ester (Compound 27-1)

2-Amino-2-methyl-1,3-propanediol hydrochloride (14.0 g) was dissolved in methanol (200 ml), N,N-diisopropylethylamine (46.3 ml) and di-t-butyl-dicarbonate (43.7 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 40 min and further at room temperature for 27 hr. To the reaction mixture was added 1M aqueous sodium hydroxide solution (100 ml) under ice-cooling, the mixture was stirred for 40 min, and methanol was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (25.3 g) as a white powder.

1 H-NMR(CDCl 3 ) δ (ppm): 1.17(3H, s), 1.44(9H, s), 3.45(2H, brs), 3.62(2H, dd, J=7.1, 11.3 Hz), 3.78(2H, dd, J=5.4, 11.3 Hz), 4.96(1H, brs).

(27-2) Synthesis of (1-hydroxymethyl-2-methoxymethoxy-1-methyl)ethylcarbamic acid t-butyl ester (Compound 27-2)

To a solution of compound 27-1 (25.3 g) in methylene chloride (300 ml) were added N,N-diisopropylethylamine (26.8 ml) and methoxymethylchloride (11.6 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min and further at room temperature for 22 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (14.2 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(3H, s), 1.44(9H, s), 3.38(3H, s), 3.57(1H, d, J=9.7 Hz), 3.61(1H, dd, J=7.8, 11.5 Hz), 3.66(1H, J=9.7 Hz), 3.71(1H, dd, J=5.0, 11.5 Hz), 3.91(1H, brs), 4.64(2H, s), 5.10(1H, brs).

(27-3) Synthesis of (1-formyl-2-methoxymethoxy-1-methyl)ethylcarbamic acid t-butyl ester (Compound 27-3)

To a mixed solution of compound 27-2 (14.2 g) and sodium bromide (5.86 g) in toluene (100 ml), ethyl acetate (100 ml) and water (20 ml) were added 2,2,6,6-tetramethylpiperidine 1-oxyl and free radical (178 mg) under ice-cooling, and then 10% aqueous sodium hypochlorite solution (46.7 g) and a solution of sodium hydrogen carbonate (13.8 g) in water (150 ml) were added dropwise over 1.5 hr. The mixture was further stirred under ice-cooling for 1.5 hr. The organic layer was partitioned, washed with water and saturated-brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (13.1 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.39(3H, s), 1.45(9H, s), 3.34(3H, s), 3.75(2H, s), 4.60(2H, s), 5.39(1H, brs), 9.51(1H, s).

(27-4) Synthesis of [3-(4-hydroxy-3-trifluoromethylphenyl)-1-(methoxymethoxy)methyl-1-methyl]propylcarbamic acid t-butyl ester (Compound 27-4)

Reference Example compound 2-5 (21.8 g) was suspended in tetrahydrofuran (200 ml), potassium t-butoxide (4.35 g) was added under ice-cooling, and the mixture was stirred for 1 hr. To the mixed solution was added a solution of compound 27-3 (4.80 g) in tetrahydrofuran (40 ml), and the mixture was stirred under ice-cooling for 1.5 hr, and at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give [3-(4-benzyloxy-3-trifluoromethylphenyl)-1-(methoxymethoxy)methyl-1-methyl]allylcarbamic acid t-butyl ester (8.45 g) as a colorless oil. The geometric isomer ratio of the obtained compound was (E:Z=3:7). To a solution of the oil in 1,4-dioxane (150 ml) was added 10% palladium carbon (containing water about 50%, 845 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered through celite and concentrated to give the object product (6.92 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(3H, s), 1.45(9H, s), 1.88-1.95(1H, m), 2.00-2.08(1H, m), 2.52-2.60(2H, m), 3.38(3H, s), 3.47(1H, d, J=9.5 Hz), 3.65(1H, d, J=9.5 Hz), 4.65(2H, s), 4.78(1H, brs), 5.98(1H, brs), 6.85(1H, d, J=8.4 Hz), 7.18(1H, dd, J=1.5, 8.4 Hz), 7.29(1H, d, J=1.5 Hz).

(27-5) Synthesis of (1-(methoxymethoxy)methyl-1-methyl-3-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl})propylcarbamic acid t-butyl ester (Compound 27-5)

To a solution of compound 27-4 (480 mg) in N,N-dimethylformamide (1 ml) were added potassium carbonate (488 mg) and compound 11-2 (378 mg), and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (700 mg) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(3H, s), 1.45(9H, s), 1.88-1.99(1H, m), 2.00-2.21(3H, m), 2.58(2H, t, J=8.5 Hz), 2.88-2.92(2H, m), 3.38(3H, s), 3.48(1H, d, J=9.5 Hz), 3.64(1H, d, J=9.5 Hz), 3.98(2H, t, J=5.4 Hz), 4.64(2H, s), 4.72(1H, brs), 6.83(1H, d, J=8.2 Hz), 7.25-7.32(2H, m), 7.38(1H, brs), 7.52-7.57(3H, m).

(27-6) Synthesis of 2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride (Compound 27-6)

To a solution of compound 27-5 (400 mg) in ethanol (15 ml) was added concentrated hydrochloric acid (1.5 ml), and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to give the object product (440 mg) as a pale-red powder.

MS(ESI)m/z: 450[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.21(3H, s), 1.70-1.85(2H, m), 2.02-2.10(2H, m), 2.62(2H, t, J=8.7 Hz), 2.84(2H, t, J=7.5 Hz), 3.41(1H, dd, J=4.8, 11.2 Hz), 3.48(1H, dd, J=4.8, 11.2 Hz), 4.06(2H, t, J=6.0 Hz), 5.50(1H, t, J=5.0 Hz), 7.17(1H, d, J=8.5 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.0 Hz), 7.90(3H, brs).

(S)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride

(28-1) Synthesis of (S)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol (Compound 28-1-1) and (R)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol (Compound 28-1-2)

To a solution of compound 27-5 (1.90 g) in ethanol (15 ml) was added concentrated hydrochloric acid (1.5 ml), and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, chloroform (50 ml) and 1M aqueous sodium hydroxide solution (50 ml) were added, and the mixture was stirred at 50° C. for 1 hr. The mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a mixture (1.24 g) of compound 28-1-1 and compound 28-1-2. The mixture (1.24 g) was separated by HPLC using CHIRALPAK (registered trade mark) AD-H (hexane/ethanol/isopropylamine) to give both enantiomers as colorless oil. The primary peak with a shorter retention time was S-configuration (0.41 g, compound 28-1-1), and the secondary peak with a longer retention time was R-configuration (0.53 g, compound 28-1-2).

(28-2) Synthesis of (S)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride (Compound 28-2)

Compound 28-1-1 (0.41 g) was dissolved in methanol (5 ml) and methylene chloride (10 ml), hydrogen chloride-containing ether (1 mol/l, 15 ml) was added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and dried to give the object product (424 mg) as a white powder.

MS(ESI)m/z: 450[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.21(3H, s), 1.71-1.86(2H, m), 2.02-2.11(2H, m), 2.62(2H, t, J=8.7 Hz), 2.84(2H, t, J=7.5 Hz), 3.41(1H, dd, J=5.3, 11.3 Hz), 3.48(1H, dd, J=5.3, 11.3 Hz), 4.06(2H, t, J=6.0 Hz), 5.53(1H, t, J=5.2 Hz), 7.17(1H, d, J=8.5 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.1 Hz), 7.91(3H, brs).

(R)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride

(29-1) Synthesis of (R)-2-amino-2-methyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride (Compound 29-1)

Compound 28-1-2 (0.53 g) was dissolved in methanol (5 ml) and methylene chloride (10 ml), hydrogen chloride-containing ether (1 mol/l, 15 ml) was added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and dried to give the object product (427 mg) as a white powder.

MS(ESI)m/z: 450[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.20(3H, s), 1.71-1.84(2H, m), 2.01-2.10(2H, m), 2.61(2H, t, J=8.7 Hz), 2.84(2H, t, J=7.5 Hz), 3.40(1H, dd, J=5.2, 11.5 Hz), 3.48(1H, dd, J=5.2, 11.5 Hz), 4.06(2H, t, J=6.0 Hz), 5.53(1H, t, J=5.2 Hz), 7.17(1H, d, J=8.6 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.0 Hz), 7.86(3H, brs).

2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride

(30-1) Synthesis of [1,1-bis(hydroxymethyl)propyl]carbamic acid t-butyl ester (Compound 30-1)

To a solution of 2-amino-2-ethyl-1,3-propanediol (22.0 g) and N,N-diisopropylethylamine (64.3 ml) in methanol (500 ml) was added di-t-butyl-dicarbonate (60.5 g) under ice-cooling, and the mixture was stirred under ice-cooling for 40 min and further at room temperature for 16 hr. To the reaction mixture was added 1M aqueous sodium hydroxide solution (184 ml) under ice-cooling, and the mixture was stirred for 40 min, and methanol was removed under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (41.0 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.90(3H, t, J=7.5 Hz), 1.45(9H, s), 1.59(2H, q, J=7.5 Hz), 3.45(2H, brs), 3.60(2H, dd, J=6.9, 11.6 Hz), 3.84(2H, dd, J=4.8, 11.6 Hz), 4.89(1H, brs).

(30-2) Synthesis of [1-hydroxymethyl-1-(methoxymethoxy)methyl]propylcarbamic acid t-butyl ester (Compound 30-2)

To a solution of compound 30-1 (41.0 g) in methylene chloride (400 ml) were added, N,N-diisopropylethylamine (40.7 ml) and methoxymethylchloride (17.6 ml) were added under ice-cooling, and the mixture was stirred under ice-cooling for 40 min and further at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the object product (21.3 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.89(3H, t, J=7.5 Hz), 1.44(9H, s), 1.55-1.62(1H, m), 1.75-1.84(1H, m), 3.38(3H, s), 3.49(1H, d, J=9.8 Hz), 3.68(2H, d, J=6.6 Hz), 3.74(1H, d, J=9.8 Hz), 4.04(1H, brs), 4.63(2H, s), 5.05(1H, brs).

(30-3) Synthesis of [1-formyl-1-(methoxymethoxy)methyl]propylcarbamic acid t-butyl ester (Compound 30-3)

To a mixed solution of compound 30-2 (21.3 g) and sodium bromide (8.32 g) in toluene (170 ml), ethyl acetate (170 ml) and water (30 ml) were added 2,2,6,6-tetramethylpiperidine 1-oxyl, free radical (253 mg), and then 10% aqueous sodium hypochlorite solution (66.3 g) and a solution of sodium hydrogen carbonate (19.6 g) in water (200 ml) was added dropwise over 1.5 hr. The mixture was further stirred under ice-cooling for 1.5 hr, a solution of 10% aqueous sodium hypochlorite solution (22.1 g) and sodium hydrogen carbonate (6.53 g) in water (67 ml) was added dropwise over 30 min, and the mixture was further stirred for 30 min. The organic layer was partitioned, and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (22.0 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.81(3H, t, J=7.5 Hz), 1.45(9H, s), 1.74-1.83(1H, m), 2.04-2.11(1H, m), 3.32(3H, s), 3.81(1H, d, J=10.0 Hz), 4.03(1H, d, J=10.0 Hz), 4.59(2H, s), 5.37(1H, brs), 9.39(1H, s).

(30-4) Synthesis of [1-ethyl-3-(4-hydroxy-3-trifluoromethylphenyl)-1-(methoxymethoxy)methyl]propylcarbamic acid t-butyl ester (Compound 30-4)

Reference Example compound 2-5 (26.3 g) was suspended in tetrahydrofuran (120 ml), potassium t-butoxide (5.24 g) was added under ice-cooling, and the mixture was stirred for 50 min. To the mixed solution was added a solution of compound 30-3 (6.10 g) in tetrahydrofuran (80 ml), and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give [1-ethyl-3-(4-benzyloxy-3-trifluoromethylphenyl)-1-(methoxymethoxy)methyl]allylcarbamic acid t-butyl ester (10.3 g) as a colorless oil. The geometric isomer ratio of the obtained compound was (E:Z=1:2.8). To a solution of this oil in 1,4-dioxane (200 ml) was added 10% palladium carbon (containing water about 50%, 2 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated to give the object product (8.67 g) as a white powder.

1 H-NMR(CDCl 3 ) δ (ppm): 0.89(3H, t, J=7.5 Hz), 1.45(9H, s), 1.65-1.74(1H, m), 1.76-1.86(1H, m), 1.93-1.97(2H, m), 2.52-2.56(2H, m), 3.39(3H, s), 3.57(1H, d, J=9.7 Hz), 3.63(1H, d, J=9.7 Hz), 4.64(3H, m), 5.85(1H, brs), 6.85(1H, d, J=8.3 Hz), 7.20(1H, brd, J=8.3 Hz), 7.29(1H, d, J=1.4 Hz).

(30-5) Synthesis of [1-ethyl-1-(methoxymethoxy)methyl-3-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}]propylcarbamic acid t-butyl ester (Compound 30-5)

To a solution of compound 30-4 (500 mg) in N,N-dimethylformamide (10 ml) were added potassium carbonate (492 mg) and compound 11-2 (381 mg), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.90(3H, t, J=7.4 Hz), 1.45(9H, s), 1.68-1.88(2H, m), 1.92-1.99(2H, m), 2.10-2.16(2H, m), 2.53-2.58(2H, m), 2.90(2H, t, J=7.4 Hz), 3.38(3H, s), 3.57(1H, d, J=9.8 Hz), 3.63(1H, d, J=9.8 Hz), 3.98(2H, t, J=5.8 Hz), 4.60(1H, brs), 4.64(2H, s), 6.83(1H, d, J=8.4 Hz), 7.25-7.32(3H, m), 7.38(1H, brs), 7.52-7.56(2H, m).

(30-6) Synthesis of 2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride (Compound 30-6)

To a solution of compound 30-5 (740 mg) in ethanol (15 ml) was added concentrated hydrochloric acid (1.5 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (550 mg) as a white powder.

MS(ESI)m/z: 464[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.90(3H, t, J=7.4 Hz), 1.58-1.69(2H, m), 1.70-1.79(2H, m), 2.01-2.10(2H, m), 2.56-2.62(2H, m), 2.84(2H, t, J=7.5 Hz), 3.47(2H, brs), 4.06(2H, t, J=5.9 Hz), 5.45(1H, brs), 7.17(1H, d, J=8.5 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.0 Hz), 7.80(3H, brs).

(S)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride

(31-1) Synthesis of (S)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol (Compound 31-1-1) and (R)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol (Compound 31-1-2)

To a solution of compound 30-5 (1.64 g) in ethanol (20 ml) was added concentrated hydrochloric acid (3.0 ml), and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, chloroform (50 ml) and 1M aqueous sodium hydroxide solution (50 ml) were added, and the mixture was stirred at 50° C. for 1 hr. The mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a mixture (1.18 g) of compound 31-1-1 and compound 31-1-2. The mixture (1.18 g) was separated by HPLC using CHIRALPAK (registered trade mark) AD-H (hexane/ethanol/isopropylamine) to give both enantiomers as colorless oil. The primary peak with a shorter retention time was S-configuration (0.36 g, compound 31-1-1), and the secondary peak with a longer retention time was R-configuration (0.36 g, compound 31-1-2).

(31-2) Synthesis of (S)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride (Compound 31-2)

Compound 31-1-1 (0.36 g) was dissolved in methanol (5 ml) and methylene chloride (10 ml), hydrogen chloride-containing ether (1 mol/l, 15 ml) was added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and dried to give the object product (370 mg) as a white powder.

MS(ESI)m/z: 464[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.90(3H, t, J=7.5 Hz), 1.58-1.68(2H, m), 1.70-1.78(2H, m), 2.04-2.10(2H, m), 2.56-2.62(2H, m), 2.84(2H, t, J=7.5 Hz), 3.47(2H, brs), 4.06(2H, t, J=6.0 Hz), 5.48(1H, brs), 7.17(1H, d, J=8.5 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.0 Hz), 7.81(3H, brs).

(R)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride

(32-1) Synthesis of (R)-2-amino-2-ethyl-4-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)propoxy]phenyl}butanol hydrochloride (Compound 32-1)

Compound 31-1-2 (0.36 g) was dissolved in methanol (5 ml) and methylene chloride (10 ml), hydrogen chloride-containing ether (1 mol/l, 15 ml) was added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration and dried to give the object product (370 mg) as a white powder.

MS(ESI)m/z: 464 [M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.90(3H, t, J=7.5 Hz), 1.58-1.68(2H, m), 1.70-1.78(2H, m), 2.02-2.09(2H, m), 2.54-2.61(2H, m), 2.84(2H, t, J=7.5 Hz), 3.47(2H, brs), 4.06(2H, t, J=6.0 Hz), 5.48(1H, brs), 7.17(1H, d, J=8.5 Hz), 7.42-7.48(4H, m), 7.65(2H, d, J=8.1 Hz), 7.79(3H, brs).

2-amino-2-(2-{4-[2-(4-methylphenyl)ethoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(33-1) Synthesis of 2-(4-methylphenyl)-1-ethanol (Compound 33-1)

To a suspension of lithium aluminum hydride (1.40 g) and tetrahydrofuran (40 ml) was added dropwise a solution of 4-methylphenylmethyl acetate ester (5.00 g) in tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. To the reaction solution was slowly added dropwise a saturated aqueous sodium sulfate solution to quench the reaction, the solution was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (3.96 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.35(1H, t, J=5.9 Hz), 2.33(3H, s), 2.83(2H, t, J=6.5 Hz), 3.84(2H, q, J=6.3 Hz), 7.12(4H, s).

(33-2) Synthesis of [2,2-dimethyl-5-(2-{4-[2-(4-methylphenyl)ethoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 33-2)

Triphenylphosphine (632 mg) was dissolved in tetrahydrofuran (10 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.28 ml), compound 33-1 (324 mg) and Reference Example compound 2-6 (500 mg) were added, and the mixture was stirred at room temperature for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to give the object product (820 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.92-1.97(2H, m), 2.33(3H, s), 2.50-2.56(2H, m), 3.07(2H, t, J=7.0 Hz), 3.68(2H, d, J=11.7 Hz), 3.83-3.90(2H, m), 4.16(2H, t, J=6.9 Hz), 4.98(1H, brs), 6.85(1H, d, J=8.4 Hz), 7.09-7.20(4H, m), 7.23-7.26(1H, m), 7.34(1H, d, J=1.8 Hz).

(33-3) Synthesis of 2-amino-2-(2-{4-[2-(4-methylphenyl)ethoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 33-3)

Compound 33-2 (820 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. 90 mg from the white powder was purified by HPLC, and hydrogen chloride-containing ether (1 mol/l, 10 ml) was added the obtained residue to give hydrochloride. The precipitate was collected by filtration and dried to give the object product (75 mg) as a white powder.

MS(ESI)m/z: 398 [M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.72-1.77(2H, m), 2.26(3H, s), 2.56-2.63(2H, m), 2.98(2H, t, J=6.6 Hz), 3.51(4H, d, J=4.8 Hz), 4.23(2H, t, J=6.6 Hz), 5.39(2H, brs), 7.10(2H, d, J=7.8 Hz), 7.20(3H, d, J=7.8 Hz), 7.41-7.45(2H, m), 7.80(3H, brs).

2-(2-{4-[2-(4-acetylphenyl)ethoxy]-3-trifluoromethylphenyl}ethyl)-2-aminopropane-1,3-diol hydrochloride

(34-1) Synthesis of 4-acetylphenethylacetate (Compound 34-1)

To a solution of aluminum chloride (20.8 g) and 1,2-dichloroethane (100 ml) was added acetyl chloride (7.39 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. A solution of phenethylacetate (8.54 g) in 1,2-dichloroethane (50 ml) was added dropwise under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. To the reaction solution was slowly added dropwise ice-cooled water to quench the reaction, and the mixture was extracted with methylene chloride. The organic layer was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1) to give the object product (8.65 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.03(3H, s), 2.60(3H, s), 3.00(2H, t, J=6.8 Hz), 4.31(2H, t, J=6.8 Hz), 7.32(2H, d, J=7.7 Hz), 7.91(2H, d, J=7.7 Hz).

(34-2) Synthesis of 4-acetylphenethyl alcohol (Compound 34-2)

To a solution of compound 34-1 (3.65 g) in tetrahydrofuran (30 ml) were added 1M aqueous sodium hydroxide solution (40 ml) and methanol (20 ml), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-1:3) to give the object product (2.73 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.39(1H, t, J=5.6 Hz), 2.60(3H, s), 2.94(2H, t, J=6.5 Hz), 3.88-3.93(2H, m), 7.34(2H, d, J=8.1 Hz), 7.92(2H, d, J=8.1 Hz).

(34-3) Synthesis of 2-(2-{4-[2-(4-acetylphenyl)ethoxy]-3-trifluoromethylphenyl}ethyl)-2-aminopropane-1,3-diol hydrochloride (Compound 34-3)

Triphenylphosphine (632 mg) was dissolved in tetrahydrofuran (10 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.28 ml), compound 34-2 (391 mg) and Reference Example compound 2-6 (500 mg) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethanol (15 ml) was added concentrated hydrochloric acid (1.5 ml), and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (206 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.72-1.77(2H, m), 2.56(3H, s), 2.56-2.63(2H, m), 3.12(2H, t, J=6.3 Hz), 3.51(4H, d, J=4.8 Hz), 4.31(2H, t, J=6.3 Hz), 5.39(2H, brs), 7.21(1H, d, J=8.8 Hz), 7.43-7.48(4H, m), 7.82(3H, brs), 7.89(2H, d, J=8.0 Hz).

2-amino-2-(2-{4-[3-(3,5-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(35-1) Synthesis of 3-(3,5-dichlorophenyl)-2-propyne-1-ol (Compound 35-1)

A mixture of 3,5-dichloroiodobenzene (2.50 g), copper(I) iodide (34.9 mg), triphenylphosphine (120 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (189 mg), propargyl alcohol (0.596 ml), diisopropylethylamine (6.38 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 4 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-80:20) to give the object product (1.73 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.68(1H, t, J=6.3 Hz), 4.49(2H, d, J=6.3 Hz), 7.31-7.33(3H, m).

(35-2) Synthesis of 3-(3,5-dichlorophenyl)-1-propanol (Compound 35-2)

A suspension of compound 35-1 (1.73 g) and chlorotris(triphenylphosphine)rhodium(I) (1.00 g) in toluene (90 ml) was stirred under a hydrogen atmosphere at 60° C. for 10 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (1.22 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.31(1H, brs), 1.83-1.90(2H, m), 2.68(2H, t, J=7.7 Hz), 3.65-3.69(2H, m), 7.09(2H, d, J=1.7 Hz), 7.20(1H, t, J=1.8 Hz).

(35-3) Synthesis of 1-(3-bromopropyl)-3,5-dichlorobenzene (Compound 35-3)

Compound 35-2 (1.23 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.75 g) and N-bromosuccinimide (1.17 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.13-2.17(2H, m), 2.75(2H, t, J=7.2 Hz), 3.39(2H, t, J=6.3 Hz), 7.09(2H, s), 7.22(1H, s).

(35-4) Synthesis of [5-(2-{4-[3-(3,5-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 35-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 35-3 (383 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.94-1.99(2H, m), 2.01-2.11(2H, m), 2.52-2.57(2H, m), 2.77-2.82(2H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.99(2H, t, J=5.6 Hz), 4.99(1H, brs), 6.84(1H, d, J=8.5 Hz), 7.09(2H, brs), 7.20(1H, brs), 7.26-7.29(1H, m), 7.38(1H, brs).

(35-5) Synthesis of 2-amino-2-(2-{4-[3-(3,5-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 35-5)

Compound 35-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (590 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.81(2H, m), 2.01-2.09(2H, m), 2.58-2.63(2H, m), 2.76(2H, t, J=7.5 Hz), 3.52(4H, d, J=5.0 Hz), 4.04(2H, t, J=6.1 Hz), 5.39(2H, t, J=5.0 Hz), 7.17(1H, d, J=8.6 Hz), 7.27(1H, s), 7.28(1H, s), 7.42-7.45(2H, m), 7.48(1H, brs), 7.80(3H, brs).

2-amino-2-(2-{4-[3-(3,5-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(36-1) Synthesis of 3-(3,5-dimethylphenyl)-2-propyne-1-ol (Compound 36-1)

A mixture of 1-iodo-3,5-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 10 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (2.39 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.65(1H, t, J=6.1 Hz), 2.28(6H, s), 4.48(2H, d, J=6.2 Hz), 6.96(1H, brs), 7.07(2H, brs).

(36-2) Synthesis of 3-(3,5-dimethylphenyl)-1-propanol (Compound 36-2)

A solution of compound 36-1 (2.39 g) and 10% palladium carbon (0.50 g) in 1,4-dioxane (40 ml) was stirred under a hydrogen atmosphere at room temperature for 22 hr. The reaction mixture was filtered through celite and concentrated to give the object product (2.37 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, brs), 1.84-1.91(2H, m), 2.29(6H, s), 2.63(2H, t, J=7.7 Hz), 3.68(2H, t, J=6.3 Hz), 6.82-6.83(3H, m).

(36-3) Synthesis of 1-(3-bromopropyl)-3,5-dimethylbenzene (Compound 36-3)

Compound 36-2 (2.36 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.19 g) and N-bromosuccinimide (2.81 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.82 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.12-2.18(2H, m), 2.29(6H, s), 2.69(2H, t, J=7.3 Hz), 3.40(2H, t, J=6.6 Hz), 6.81(2H, s), 6.85(1H, s).

(36-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3,5-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 36-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 36-3 (325 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (750 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.03-2.12(2H, m), 2.28(6H, s), 2.51-2.56(2H, m), 2.72-2.76(2H, m), 3.69(2H, d, J=11.8 Hz), 3.89(2H, d, J=11.8 Hz), 3.99(2H, t, J=6.1 Hz), 4.99(1H, brs), 6.82-6.85(4H, m), 7.25-7.27(1H, m), 7.36(1H, brs).

(36-5) Synthesis of 2-amino-2-(2-{4-[3-(3,5-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 36-5)

Compound 36-4 (750 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.96-2.04(2H, m), 2.51(6H, s), 2.58-2.63(2H, m), 2.66(2H, t, J=7.4 Hz), 3.51(4H, d, J=6.0 Hz), 4.04(2H, t, J=6.0 Hz), 5.39(2H, t, J=4.8 Hz), 6.79-6.81(3H, m), 7.16(1H, d, J=8.5 Hz), 7.44(1H, d, J=8.5 Hz), 7.48(1H, brs), 7.79(3H, brs).

2-amino-2-(2-{4-[3-(3,4-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(37-1) Synthesis of 3-(3,4-dimethylphenyl)-2-propyne-1-ol (Compound 37-1)

A mixture of 1-iodo-3,4-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.12 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.64(1H, t, J=6.2 Hz), 2.23(3H, s), 2.26(3H, s), 4.48(2H, d, J=6.0 Hz), 7.07(1H, d, J=7.7 Hz), 7.18(1H, d, J=7.7 Hz), 7.22(1H, s).

(37-2) Synthesis of 3-(3,4-dimethylphenyl)-1-propanol (Compound 37-2)

A solution of compound 37-1 (2.12 g) and 10% palladium carbon (1.00 g) in 1,4-dioxane (100 ml) was stirred under a hydrogen atmosphere at room temperature for 16 hr. The reaction mixture was filtered through celite and concentrated to give the object product (2.11 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.84-1.91(2H, m), 2.23(3H, s), 2.24(3H, s), 2.64(2H, t, J=7.7 Hz), 3.68(2H, t, J=6.4 Hz), 6.94(1H, d, J=7.6 Hz), 6.80(1H, s), 7.05(1H, d, J=7.6 Hz).

(37-3) Synthesis of 1-(3-bromopropyl)-3,4-dimethylbenzene (Compound 37-3)

Compound 37-2 (1.95 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.46 g) and N-bromosuccinimide (2.33 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.20 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.18(2H, m), 2.23(3H, s), 2.24(3H, s), 2.71(2H, t, J=7.3 Hz), 3.40(2H, t, J=6.6 Hz), 6.93(1H, d, J=7.5 Hz), 6.96(1H, s), 7.06(1H, d, J=7.5 Hz).

(37-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3,4-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 37-4)

Reference Example compound 2-6 (432 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (427 mg) and compound 37-3 (281 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (640 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.12(2H, m), 2.23(6H, s), 2.51-2.56(2H, m), 2.73-2.77(2H, m), 3.69(2H, d, J=11.8 Hz), 3.89(2H, d, J=11.8 Hz), 3.99(2H, t, J=6.1 Hz), 4.99(1H, brs), 6.84(1H, d, J=8.5 Hz), 6.93(1H, d, J=7.5 Hz), 6.97(1H, s), 7.04(1H, d, J=7.5 Hz), 7.24-7.26(1H, m), 7.36(1H, d, J=1.9 Hz).

(37-5) Synthesis of 2-amino-2-(2-{4-[3-(3,4-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 37-5)

Compound 37-4 (640 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (470 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.95-2.02(2H, m), 2.17(6H, s), 2.58-2.63(2H, m), 2.66(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.8 Hz), 4.03(2H, t, J=6.1 Hz), 5.39(2H, t, J=5.1 Hz), 6.89(1H, d, J=7.3 Hz), 6.96(1H, s), 7.02(1H, d, J=7.7 Hz), 7.15(1H, d, J=8.5 Hz), 7.43(1H, d, J=8.5 Hz), 7.48(1H, d, J=1.4 Hz), 7.80(3H, brs).

2-amino-2-(2-{4-[3-(3,4-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(38-1) Synthesis of 3-(3,4-dichlorophenyl)-2-propyne-1-ol (Compound 38-1)

A mixture of 3,4-dichloroiodobenzene (5.00 g), copper(I) iodide (69.8 mg), triphenylphosphine (240 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg), propargyl alcohol (1.19 ml), diisopropylethylamine (12.8 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (3.21 g) as a pale-brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.65(1H, t, J=6.2 Hz), 4.49(2H, J=6.2 Hz), 7.26(1H, dd, J=1.6, 8.4 Hz), 7.39(1H, d, J=8.4 Hz), 7.52(1H, d, J=1.6 Hz).

(38-2) Synthesis of 3-(3,4-dichlorophenyl)-1-propanol (Compound 38-2)

A suspension of Compound 38-1 (3.21 g) and chlorotris(triphenylphosphine)rhodium(I) (1.60 g) in toluene (100 ml) was stirred under a hydrogen atmosphere at 60° C. for 10 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.83 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.33(1H, brs), 1.83-1.90(2H, m), 2.68(2H, t, J=7.7 Hz), 3.67(2H, t, J=6.3 Hz), 7.04(1H, dd, J=8.1, 1.8 Hz), 7.29(1H, d, J=1.8 Hz), 7.34(1H, d, J=8.1 Hz).

(38-3) Synthesis of 1-(3-bromopropyl)-3,4-dichlorobenzene (Compound 38-3)

Compound 38-2 (2.82 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.02 g) and N-bromosuccinimide (2.71 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.42 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.18(2H, m), 2.75(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.5 Hz), 7.04(1H, dd, J=8.3, 1.9 Hz), 7.30(1H, d, 1.9 Hz), 7.36(1H, d, J=8.3 Hz).

(38-4) Synthesis of [5-(2-{4-[3-(3,4-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 38-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 38-3 (383 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-2.05(2H, m), 2.04-2.12(2H, m), 2.52-2.56(2H, m), 2.80(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=5.8 Hz), 5.00(1H, brs), 6.83(1H, d, J=8.4 Hz), 7.03(1H, dd, J=8.4, 1.9 Hz), 7.28-7.30(2H, m), 7.33(1H, d, J=8.2 Hz), 7.37-7.38(1H, m).

(38-5) Synthesis of 2-amino-2-(2-{4-[3-(3,4-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 38-5)

Compound 38-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (590 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.79(2H, m), 1.99-2.08(2H, m), 2.58-2.63(2H, m), 2.75(2H, t, J=7.5 Hz), 3.51(4H, d, J=4.5 Hz), 4.04(2H, t, J=6.0 Hz), 5.39(2H, t, J=4.8 Hz), 7.17(1H, d, J=8.6 Hz), 7.20(1H, dd, J=8.4, 1.9 Hz), 7.44(1H, d, J=8.6 Hz), 7.47-7.49(2H, m), 7.54(1H, d, J=8.4 Hz), 7.76(3H, brs).

2-amino-2-(2-{4-[3-(4-ethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(39-1) Synthesis of 3-(4-ethylphenyl)-2-propyne-1-ol (Compound 39-1)

A mixture of 4-ethyliodobenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 12 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.10 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.23(3H, t, J=7.6 Hz), 1.65(1H, t, J=6.0 Hz), 2.64(2H, q, J=7.6 Hz), 4.49(2H, d, J=5.9 Hz), 7.15(2H, d, J=7.6 Hz), 7.36(2H, d, J=7.6 Hz).

(39-2) Synthesis of 3-(4-ethylphenyl)-1-propanol (Compound 39-2)

A solution of compound 39-1 (2.10 g) and 10% palladium carbon (1.00 g) in 1,4-dioxane (80 ml) was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction mixture was filtered through celite and concentrated to give the object product (1.98 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.22(3H, t, J=7.6 Hz), 1.29(1H, brs), 1.85-1.92(2H, m), 2.62(2H, q, J=7.6 Hz), 2.68(2H, t, J=7.7 Hz), 3.68(2H, t, J=6.4 Hz), 7.12(4H, s).

(39-3) Synthesis of 1-(3-bromopropyl)-4-ethylbenzene (Compound 39-3)

Compound 39-2 (1.97 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.35 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.26 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.22(3H, t, J=7.5 Hz), 2.10-2.18(2H, m), 2.62(2H, q, J=7.5 Hz), 2.75(2H, t, J=7.3 Hz), 3.40(2H, t, J=6.5 Hz), 7.10-7.13(4H, m).

(39-4) Synthesis of [5-(2-{4-[3-(4-ethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 39-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 39-3 (325 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (770 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.20-1.28(3H, m), 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.13(2H, m), 2.51-2.56(2H, m), 2.58-2.64(2H, m), 2.77-2.81(2H, m), 3.69(2H, d, J=11.8 Hz), 3.89(2H, d, J=11.8 Hz), 3.98(2H, t, J=6.1 Hz), 4.99(1H, brs), 6.84(1H, d, J=8.5 Hz), 7.11(4H, s), 7.24-7.26(1H, m), 7.36(1H, d, J=1.6 Hz).

(39-5) Synthesis of 2-amino-2-(2-{4-[3-(4-ethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 39-5)

Compound 39-4 (770 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.51(3H, t, J=7.8 Hz), 1.74-1.78(2H, m), 1.98-2.06(2H, m), 2.55(2H, q, J=7.8 Hz), 2.58-2.64(2H, m), 2.70(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.6 Hz), 4.03(2H, t, J=6.0 Hz), 5.40(2H, t, J=4.8 Hz), 7.08-7.16(5H, s), 7.44(1H, d, J=8.5 Hz), 7.48(1H, d, J=1.6 Hz), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(3-bromophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(40-1) Synthesis of 3-(3-bromophenyl)-2-propyne-1-ol (Compound 40-1)

A mixture of 3-bromoiodobenzene (5.00 g), copper(I) iodide (67.4 mg), triphenylphosphine (232 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (366 mg), propargyl alcohol (1.15 ml), diisopropylethylamine (12.3 ml) and tetrahydrofuran (90 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-70:30) to give the object product (3.42 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.67(1H, t, J=6.2 Hz), 4.50(2H, d, J=6.2 Hz), 7.19(1H, t, J=7.9 Hz), 7.36(1H, d, J=7.8 Hz), 7.46(1H, d, J=7.8 Hz), 7.59(1H, t, J=1.7 Hz).

(40-2) Synthesis of 3-(3-bromophenyl)-1-propanol (Compound 40-2)

A suspension of compound 40-1 (3.42 g) and chlorotris(triphenylphosphine)rhodium(I) (1.70 g) in toluene (130 ml) was stirred under a hydrogen atmosphere at 60° C. for 9 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (2.79 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, t, J=4.4 Hz), 1.84-1.91(2H, m), 2.69(2H, t, J=7.7 Hz), 3.65-3.69(2H, m), 7.11-7.14(1H, m), 7.16(1H, t, J=7.7 Hz), 7.31-7.34(1H, m), 7.36(1H, brs).

(40-3) Synthesis of 3-bromo-1-(3-bromopropyl)benzene (Compound 40-3)

Compound 40-2 (2.78 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.72 g) and N-bromosuccinimide (2.53 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.34 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.12-2.19(2H, m), 2.76(2H, t, J=7.3 Hz), 3.39(2H, t, J=6.5 Hz), 7.12-7.18(2H, m), 7.33-7.35(2H, m).

(40-4) Synthesis of [5-(2-{4-[3-(3-bromophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 40-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 40-3 (479 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (980 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.07-2.12(2H, m), 2.51-2.56(2H, m), 2.78-2.82(2H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=5.9 Hz), 4.99(1H, brs), 6.84(1H, d, J=8.5 Hz), 7.12-7.17(2H, m), 7.26-7.28(1H, m), 7.30-7.34(3H, m).

(40-5) Synthesis of 2-amino-2-(2-{4-[3-(3-bromophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 40-5)

Compound 40-4 (980 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (590 mg) as a white powder.

MS(ESI)m/z: 476, 478[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.00-2.06(2H, m), 2.58-2.63(2H, m), 2.75(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.5 Hz), 4.04(2H, t, J=6.0 Hz), 5.40(2H, t, J=4.9 Hz), 7.15-7.28(3H, m), 7.38-7.46(3H, m), 7.48(1H, brs), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(4-bromophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(41-1) Synthesis of 3-(4-bromophenyl)-2-propyne-1-ol (Compound 41-1)

A mixture of 4-bromoiodobenzene (8.00 g), copper(I) iodide (108 mg), triphenylphosphine (372 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (586 mg), propargyl alcohol (1.84 ml), diisopropylethylamine (19.7 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 13 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (4.34 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.64(1H, t, J=6.2 Hz), 4.48(2H, d, J=6.2 Hz), 7.30(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz).

(41-2) Synthesis of 3-(4-bromophenyl)-1-propanol (Compound 41-2)

A suspension of compound 41-1 (4.34 g) and chlorotris(triphenylphosphine)rhodium(I) (2.50 g) in toluene (170 ml) was stirred under a hydrogen atmosphere at 60° C. for 7 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-70:30) to give the object product (3.62 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.83-1.90(2H, m), 2.67(2H, t, J=7.7 Hz), 3.67(2H, t, J=6.3 Hz), 7.08(2H, d, J=8.2 Hz), 7.40(2H, d, J=8.2 Hz).

(41-3) Synthesis of 4-bromo-1-(3-bromopropyl)benzene (Compound 41-3)

Compound 41-2 (3.63 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (4.88 g) and N-bromosuccinimide (3.31 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.87 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.17(2H, m), 2.74(2H, t, J=7.4 Hz), 3.38(2H, t, J=6.5 Hz), 7.08(2H, d, J=8.3 Hz), 7.41(2H, dd, J=8.3, 1.9 Hz).

(41-4) Synthesis of [5-(2-{4-[3-(4-bromophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 41-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 41-3 (447 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (820 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.06-2.10(2H, m), 2.51-2.56(2H, m), 2.77-2.81(2H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.96(2H, t, J=6.0 Hz), 5.00(1H, brs), 6.83(1H, d, J=8.5 Hz), 7.05-7.09(2H, m), 7.24-7.27(1H, m), 7.36-7.43(3H, m).

(41-5) Synthesis of 2-amino-2-(2-{4-[3-(4-bromophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 41-5)

Compound 41-4 (820 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.

MS(ESI)m/z: 476, 478[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.97-2.04(2H, m), 2.58-2.63(2H, m), 2.75(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.7 Hz), 4.03(2H, t, J=6.0 Hz), 5.39(2H, t, J=4.9 Hz), 7.14-7.18(3H, m), 7.42-7.48(4H, m), 7.83(3H, brs).

2-amino-2-(2-{4-[3-(4-methoxy-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(42-1) Synthesis of 1-(4-methoxy-3-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 42-1)

A mixture of 4-bromo-2-methylanisole (3.02 g), cesium carbonate (12.7 g), 2-(2-propynyloxy)tetrahydropyran (3.16 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (429 mg), bis(acetonitrile)palladium(II) dichloride (77.8 mg) and acetonitrile (100 ml) was stirred at 80° C. for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give the object product (1.76 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.54-1.70(4H, m), 1.73-1.90(2H, m), 2.17(3H, s), 3.54-3.59(1H, m), 3.83(3H, s), 3.85-3.92(1H, m), 4.44(1H, d, J=15.6 Hz), 4.50(1H, d, J=15.6 Hz), 4.90(1H, t, J=3.4 Hz), 6.74(1H, d, J=8.2 Hz), 7.24(1H, s), 7.28(1H, dd, J=1.7, 8.2 Hz).

(42-2) Synthesis of 1-(4-methoxy-3-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 42-2)

A solution of compound 42-1 (1.76 g) and 10% palladium carbon (0.90 g) in 1,4-dioxane (25 ml) was stirred under a hydrogen atmosphere at room temperature for 5 hr. The reaction mixture was filtered through celite and concentrated to give the object product (1.78 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.51-1.61(4H, m), 1.70-1.76(1H, m), 1.81-1.92(3H, m), 2.19(3H, s), 2.55-2.68(2H, m), 3.40(1H, dt, J=9.9, 6.4 Hz), 3.47-3.53(1H, m), 3.76(1H, dt, J=9.6, 6.5 Hz), 3.80(3H, s), 3.85-3.91(1H, m), 4.58(1H, t, J=3.6 Hz), 6.73-6.76(1H, m), 6.97-6.99(2H, m).

(42-3) Synthesis of 3-(4-methoxy-3-methylphenyl)-1-propanol (Compound 42-3)

A solution of compound 42-2 (1.78 g) and p-toluenesulfonic acid monohydrate (17.0 mg) in methanol (100 ml) was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (1.03 g) as a pale-yellow solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, brs), 1.83-1.90(2H, m), 2.20(3H, s), 2.62(2H, t, J=7.6 Hz), 3.67(2H, t, J=6.4 Hz), 3.81(3H, s), 6.75(1H, d, J=8.8 Hz), 6.97-6.99(2H, m).

(42-4) Synthesis of 1-(3-bromopropyl)-4-methoxy-3-methylbenzene (Compound 42-4)

Compound 42-3 (860 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.39 g) and N-bromosuccinimide (0.934 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (800 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.09-2.16(2H, m), 2.20(3H, s), 2.68(2H, t, J=7.3 Hz), 3.39(2H, t, J=6.5 Hz), 3.81(3H, s), 6.75(1H, d, J=8.0 Hz), 6.96-6.99(2H, m).

(42-5) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(4-methoxy-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 42-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 42-4 (348 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (810 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.03-2.12(2H, m), 2.19(3H, s), 2.51-2.55(2H, m), 2.71-2.75(2H, m), 3.69(2H, d, J=11.7 Hz), 3.80(3H, s), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=6.1 Hz), 4.99(1H, brs), 6.72-6.76(1H, m), 6.84(1H, d, J=8.5 Hz), 6.96-6.99(2H, m), 7.24-7.26(1H, m), 7.36(1H, d, J=1.6 Hz).

(42-6) Synthesis of 2-amino-2-(2-{4-[3-(4-methoxy-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 42-6)

Compound 42-5 (810 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (570 mg) as a white powder.

MS(ESI)m/z: 442[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 1.95-2.00(2H, m), 2.10(3H, s), 2.58-2.66(4H, m), 3.52(4H, d, J=4.5 Hz), 3.73(3H, s), 4.02(2H, t, J=6.0 Hz), 5.39(2H, t, J=4.9 Hz), 6.80-6.83(1H, m), 6.94-6.96(2H, m), 7.15(1H, d, J=8.6 Hz), 7.43(1H, d, J=8.6 Hz), 7.48(1H, d, J=1.4 Hz), 7.80(3H, brs).

2-amino-2-(2-{4-[2-(4-ethylphenyl) ethoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(43-1) Synthesis of 4-ethylphenethylacetate (Compound 43-1)

To a solution of compound 34-1 (5.00 g) in methylene chloride (20 ml) were added trifluoroacetic acid (20 ml) and triethylsilane (12 ml), and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=30:1-10:1) to give the object product (5.32 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.22(3H, t, J=7.5 Hz), 2.04(3H, s), 2.63(2H, q, J=7.5 Hz), 2.90(2H, t, J=7.0 Hz), 4.26(2H, t, J=7.0 Hz), 7.14(4H, s).

(43-2) Synthesis of 4-ethylphenethyl alcohol (Compound 43-2)

To a solution of compound 43-1 (5.32 g) in tetrahydrofuran (30 ml) were added 1M aqueous sodium hydroxide solution (40 ml) and methanol (30 ml), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the object product (3.35 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.21-1.26(3H, m), 1.37(1H, t, J=5.9 Hz), 2.60-2.66(2H, m), 2.85(2H, t, J=6.5 Hz), 3.85(2H, q, J=6.3 Hz), 7.15(4H, s).

(43-3) Synthesis of 2-amino-2-(2-{4-[2-(4-ethylphenyl)ethoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 43-3)

Triphenylphosphine (632 mg) was dissolved in tetrahydrofuran (10 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.28 ml), compound 43-2 (356 mg) and Reference Example compound 2-6 (500 mg) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethanol (15 ml) was added concentrated hydrochloric acid (1.5 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (360 mg) as a white powder.

MS(ESI)m/z: 412[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.15(3H, t, J=7.4 Hz), 1.73-1.78(2H, m), 2.50-2.62(4H, m), 2.99(2H, t, J=6.5 Hz), 3.51(4H, d, J=4.7 Hz), 4.23(2H, t, J=6.8 Hz), 5.39(2H, t, J=4.9 Hz), 7.13(2H, d, J=7.8 Hz), 7.18-7.23(3H, m), 7.42-7.45(2H, m), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(4-fluoro-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(44-1) Synthesis of 1-(4-fluoro-3-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 44-1)

A mixture of 5-bromo-2-fluorotoluene (10.0 g), cesium carbonate (45.0 g), 2-(2-propynyloxy)tetrahydropyran (11.2 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.51 g), bis(acetonitrile)palladium(II) dichloride (274 mg) and acetonitrile (300 ml) was stirred at 85° C. for 10 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (8.08 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.53-1.70(4H, m), 1.73-1.90(2H, m), 2.24(3H, d, J=1.4 Hz), 3.54-3.59(1H, m), 3.86-3.92(1H, m), 4.43(1H, d, J=15.8 Hz), 4.49(1H, d, J=15.8 Hz), 4.89(1H, t, J=3.4 Hz), 6.93(1H, t, J=8.9 Hz), 7.23-7.30(2H, m).

(44-2) Synthesis of 1-(4-fluoro-3-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 44-2)

A solution of compound 44-1 (8.08 g) and 10% palladium carbon (2.02 g) in 1,4-dioxane (150 ml) was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated to give the object product (8.07 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.51-1.63(4H, m), 1.70-1.76(1H, m), 1.80-1.92(3H, m), 2.24(3H, d, J=1.4 Hz), 2.58-2.70(2H, m), 3.39(1H, dt, J=9.6, 6.6 Hz), 3.47-3.53(1H, m), 3.76(1H, dt, J=9.5, 6.7 Hz), 3.84-3.90(1H, m), 4.57(1H, t, J=3.5 Hz), 6.89(1H, t, J=8.9 Hz), 6.94-7.01(2H, m).

(44-3) Synthesis of 3-(4-fluoro-3-methylphenyl)-1-propanol (Compound 44-3)

A solution of compound 44-2 (8.07 g) and p-toluenesulfonic acid monohydrate (15.0 mg) in methanol (120 ml) was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (5.48 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.82-1.89(2H, m), 2.25(3H, d, J=1.4 Hz), 2.64(2H, t, J=7.6 Hz), 3.67(2H, t, J=6.2 Hz), 6.90(1H, t, J=8.9 Hz), 6.94-7.01(2H, m).

(44-4) Synthesis of 1-(3-bromopropyl)-4-fluoro-3-methylbenzene (Compound 44-4)

Compound 44-3 (5.47 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (9.39 g) and N-bromosuccinimide (6.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.10 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.09-2.16(2H, m), 2.25(3H, d, J=1.5 Hz), 2.71(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.4 Hz), 6.88-7.00(3H, m).

(44-5) Synthesis of [5-(2-{4-[3-(4-fluoro-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 44-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 44-4 (331 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (800 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.12(2H, m), 2.23(3H, d, J=1.7 Hz), 2.51-2.56(2H, m), 2.75(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.88(2H, d, J=11.7 Hz), 3.97(2H, t, J=6.0 Hz), 4.99(1H, brs), 6.82-7.00(4H, m), 7.25-7.26(1H, m), 7.37(1H, d, J=1.9 Hz).

(44-6) Synthesis of 2-amino-2-(2-{4-[3-(4-fluoro-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 44-6)

Compound 44-5 (800 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.

MS(ESI)m/z: 430[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 1.97-2.03(2H, m), 2.19(3H, brs), 2.58-2.63(2H, m), 2.69(2H, t, J=7.5 Hz), 3.51(4H, d, J=4.2 Hz), 4.03(2H, t, J=6.0 Hz), 5.38(2H, brs), 7.01-7.03(2H, m), 7.10(1H, d, J=7.4 Hz), 7.16(1H, d, J=8.6 Hz), 7.44(1H, d, J=8.6 Hz), 7.48(1H, brs), 7.76(3H, brs).

2-amino-2-(2-{4-[3-(2-fluoro-5-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(45-1) Synthesis of 1-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 45-1)

A mixture of 3-bromo-4-fluorotoluene (10.0 g), cesium carbonate (45.0 g), 2-(2-propynyloxy)tetrahydropyran (11.2 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.51 g), bis(acetonitrile)palladium(II) dichloride (274 mg) and acetonitrile (250 ml) was stirred at 90° C. for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-95:5) to give the object product (8.32 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.52-1.70(4H, m), 1.74-1.90(2H, m), 2.29(3H, s), 3.55-3.59(1H, m), 3.87-3.92(1H, m), 4.49(1H, d, J=15.8 Hz), 4.53(1H, d, J=15.8 Hz), 4.92(1H, t, J=3.4 Hz), 6.94(1H, t, J=8.8 Hz), 7.06-7.10(1H, m), 7.24(1H, dd, J=2.0, 6.6 Hz).

(45-2) Synthesis of 1-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 45-2)

A solution of compound 45-1 (8.32 g) and 10% palladium carbon (2.00 g) in 1,4-dioxane (40 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hr. The reaction mixture was filtered through celite and concentrated to give the object product (8.32 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.51-1.63(4H, m), 1.70-1.76(1H, m), 1.80-1.94(3H, m), 2.28(3H, s), 2.63-2.76(2H, m), 3.40(1H, dt, J=9.6, 6.6 Hz), 3.47-3.53(1H, m), 3.78(1H, dt, J=9.6, 6.6 Hz), 3.85-3.90(1H, m), 4.58(1H, t, J=3.5 Hz), 6.87(1H, t, J=9.0 Hz), 6.92-6.96(1H, m), 7.00(1H, dd, J=1.6, 7.4 Hz).

(45-3) Synthesis of 3-(2-fluoro-5-methylphenyl)-1-propanol (Compound 45-3)

A solution of compound 45-2 (8.32 g) and p-toluenesulfonic acid monohydrate (20.0 mg) in methanol (200 ml) was stirred at room temperature for 14 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (5.53 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(1H, t, J=4.5 Hz), 1.84-1.91(2H, m), 2.29(3H, s), 2.70(2H, t, J=7.6 Hz), 3.65-3.69(2H, m), 6.86-6.91(1H, m), 6.94-6.96(1H, m), 6.98-7.00(1H, m).

(45-4) Synthesis of 1-(3-bromopropyl)-2-fluoro-5-methylbenzene (Compound 45-4)

Compound 45-3 (5.54 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (9.49 g) and N-bromosuccinimide (6.44 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.78 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.12-2.19(2H, m), 2.29(3H, s), 2.76(2H, t, J=7.4 Hz), 3.41(2H, t, J=6.6 Hz), 6.87-6.92(1H, m), 6.95-7.00(2H, m).

(45-5) Synthesis of [5-(2-{4-[3-(2-fluoro-5-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 45-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 45-4 (331 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (640 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.13(2H, m), 2.26(3H, s), 2.51-2.56(2H, m), 2.80(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, J=11.7 Hz), 4.00(2H, t, J=6.1 Hz), 4.99(1H, brs), 6.84-6.90(2H, m), 6.93-6.98(2H, m), 7.25-7.26(1H, m), 7.37(1H, d, J=1.8 Hz).

(45-6) Synthesis of 2-amino-2-(2-{4-[3-(2-fluoro-5-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 45-6)

Compound 45-5 (640 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (480 mg) as a white powder.

MS(ESI)m/z: 430[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.97-2.01(2H, m), 2.24(3H, s), 2.59-2.64(2H, m), 2.71-2.76(2H, m), 3.52(4H, J=4.4 Hz), 4.08(2H, t, J=5.9 Hz), 5.40(2H, t, J=4.8 Hz), 7.00-7.08(3H, m), 7.17(1H, d, J=8.5 Hz), 7.45(1H, d, J=8.5 Hz), 7.48(1H, brs), 7.83(3H, brs).

2-amino-2-(2-{4-[3-(2-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(46-1) Synthesis of 3-(2-thienyl)-2-propyne-1-ol (Compound 46-1)

A mixture of 2-iodothiophene(5.00 g), copper(I) iodide (91 mg), triphenylphosphine (315 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (497 mg), propargyl alcohol (1.54 ml), diisopropylethylamine (16.6 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 20 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (1.45 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.66(1H, t, J=6.2 Hz), 4.51(2H, d, J=6.1 Hz), 6.96-6.99(1H, m), 7.21-7.22(1H, m), 7.27(1H, s).

(46-2) Synthesis of 3-(2-thienyl)-1-propanol (Compound 46-2)

A solution of compound 46-1 (1.45 g) and 10% palladium carbon (1.00 g) in ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature for 23 hr The reaction mixture was filtered through celite and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the object product (1.29 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.31(1H, brs), 1.91-1.99(2H, m), 2.95(2H, t, J=7.6 Hz), 3.71(2H, brs), 6.81(1H, d, J=2.8 Hz), 6.91-6.93(1H, m), 7.11-7.13(1H, m).

(46-3) Synthesis of 2-(3-bromopropyl)thiophene (Compound 46-3)

Compound 46-2 (1.29 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.62 g) and N-bromosuccinimide (1.76 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (760 mg) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.17-2.25(2H, m), 3.02(2H, t, J=7.2 Hz), 3.43(2H, t, J=6.5 Hz), 6.84(1H, d, J=2.9 Hz), 6.92-6.94(1H, m), 7.13-7.15(1H, m).

(46-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(2-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 46-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 46-3 (293 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.10-2.21(2H, m), 2.51-2.56(2H, m), 3.06(2H, t, J=7.3 Hz), 3.69(2H, d, J=11.8 Hz), 3.89(2H, d, J=11.8 Hz), 4.02(2H, t, J=5.9 Hz), 4.99(1H, brs), 6.80(1H, d, J=3.0 Hz), 6.85(1H, d, J=8.5 Hz), 6.91(1H, dd, J=5.1, 3.5 Hz), 7.12(1H, J=5.8 Hz), 7.26-7.27(1H, m), 7.36(1H, brd, J=1.4 Hz).

(46-5) Synthesis of 2-amino-2-(2-{4-[3-(2-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 46-5)

Compound 46-4 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (360 mg) as a white powder.

MS(ESI)m/z: 404[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.02-2.08(2H, m), 2.59-2.63(2H, m), 2.96(2H, t, J=7.3 Hz), 3.52(4H, d, J=4.6 Hz), 4.08(2H, t, J=5.9 Hz), 5.39(2H, t, J=4.9 Hz), 6.85(1H, d, J=3.0 Hz), 6.93-6.95(1H, m), 7.17(1H, d, J=8.6 Hz), 7.31-7.33(1H, m), 7.44(1H, d, J=8.6 Hz), 7.48(1H, s), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(3-ethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(47-1) Synthesis of 1-(3-ethylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 47-1)

A mixture of 1-bromo-3-ethylbenzene (9.79 g), cesium carbonate (45.0 g), 2-(2-propynyloxy)tetrahydropyran (11.2 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.51 g), bis(acetonitrile)palladium(II) dichloride (274 mg) and acetonitrile (300 ml) was stirred at 90° C. for 10 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-95:5) to give the object product (5.25 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.22(3H, t, J=7.5 Hz), 1.53-1.71(4H, m), 1.74-1.91(2H, m), 2.62(2H, q, J=7.5 Hz), 3.54-3.60(1H, m), 3.87-3.92(1H, m), 4.46(1H, d, J=15.7 Hz), 4.51(1H, d, J=15.7 Hz), 4.91(1H, t, J=3.4 Hz), 7.14-7.16(1H, m), 7.22(1H, t, J=7.5 Hz), 7.26-7.28(1H, m), 7.30(1H, brs).

(47-2) Synthesis of 1-(3-ethylphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 47-2)

A solution of compound 47-1 (5.25 g) and 10% palladium carbon (1.06 g) in 1,4-dioxane (120 ml) was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction mixture was filtered through celite and concentrated to give the object product (5.31 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.23(3H, t, J=7.5 Hz), 1.51-1.63(4H, m), 1.69-1.76(1H, m), 1.81-1.88(1H, m), 1.93(2H, quint, J=7.1 Hz), 2.62(2H, q, J=7.6 Hz), 2.63-2.75(2H, m), 3.41(1H, dt, J=9.7, 6.6 Hz), 3.47-3.53(1H, m), 3.78(1H, dt, J=9.8, 6.5 Hz), 3.85-3.91(1H, m), 4.58(1H, t, J=3.6 Hz), 7.00-7.04(3H, m), 7.20(1H, t, J=7.4 Hz).

(47-3) Synthesis of 3-(3-ethylphenyl)-1-propanol (Compound 47-3)

A solution of compound 47-2 (5.31 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (100 ml) was stirred at room temperature for 21 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (3.53 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.23(3H, t, J=7.5 Hz), 1.28(1H, brs), 1.86-1.94(2H, m), 2.63(2H, q, J=7.6 Hz), 2.69(2H, t, J=7.7 Hz), 3.68(2H, m), 7.01-7.04(3H, m), 7.19-7.23(1H, m).

(47-4) Synthesis of 1-(3-bromopropyl)-3-ethylbenzene (Compound 47-4)

Compound 47-3 (3.53 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (6.19 g) and N-bromosuccinimide (4.20 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (4.29 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.23(3H, t, J=7.5 Hz), 2.14-2.20(2H, m), 2.63(2H, q, J=7.5 Hz), 2.75(2H, t, J=7.4 Hz), 3.40(2H, t, J=6.6 Hz), 7.00-7.05(3H, m), 7.21(1H, t, J=7.4 Hz).

(47-5) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3-ethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 47-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 47-4 (325 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.20(3H, t, J=7.7 Hz), 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.99(2H, m), 2.08-2.12(2H, m), 2.51-2.56(2H, m), 2.61(2H, q, J=7.7 Hz), 2.80(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.99(2H, t, J=6.0 Hz), 4.98(1H, brs), 6.84(1H, d, J=8.4 Hz), 7.00-7.03(3H, m), 7.20(1H, t, J=7.7 Hz), 7.24-7.26(1H, m), 7.37(1H, J=1.9 Hz).

(47-6) Synthesis of 2-amino-2-(2-{4-[3-(3-ethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 47-6)

Compound 47-5 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (570 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.13(3H, t, J=7.5 Hz), 1.74-1.79(2H, m), 1.98-2.02(2H, m), 2.50-2.63(4H, m), 2.71(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.3 Hz), 4.03(2H, t, J=6.1 Hz), 5.39(2H, brs), 6.98-7.02(3H, m), 7.14-7.20(2H, m), 7.44(1H, d, J=8.6 Hz), 7.48(1H, s), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(5-methyl-2-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(48-1) Synthesis of 3-(5-methyl-2-thienyl)-2-propyne-1-ol (Compound 48-1)

A mixture of 2-iodo-5-methylthiophene (5.00 g), copper(I) iodide (82 mg), triphenylphosphine (286 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (445 mg), propargyl alcohol (1.91 ml), diisopropylethylamine (15.1 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 20 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (1.48 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.64(1H, t, J=6.2 Hz), 2.46(3H, s), 4.49(2H, d, J=6.1 Hz), 6.62(1H, d, J=4.2 Hz), 7.02(1H, d, J=3.6 Hz).

(48-2) Synthesis of 3-(5-methyl-2-thienyl)-1-propanol (Compound 48-2)

A solution of compound 48-1 (1.48 g) and 10% palladium carbon (1.00 g) in ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature for 6 hr. The reaction mixture was filtered through celite and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the object product (1.23 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.87-2.05(2H, m), 2.43(3H, s), 2.85(2H, t, J=7.5 Hz), 3.67-3.73(2H, m), 6.55(1H, d, J=2.8 Hz)6.58(1H, d, J=3.2 Hz).

(48-3) Synthesis of 2-(3-bromopropyl)-5-methylthiophene (Compound 48-3)

Compound 48-2 (1.23 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.27 g) and N-bromosuccinimide (1.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (650 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.13-2.20(2H, m), 2.43(3H, s), 2.92(2H, t, J=7.2 Hz), 3.43(2H, t, J=6.4 Hz), 6.55(1H, d, J=2.6 Hz), 6.60(1H, d, J=3.4 Hz).

(48-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(5-methyl-2-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 48-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 48-3 (313 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (710 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.09-2.19(2H, m), 2.42(3H, s), 2.51-2.56(2H, m), 2.97(2H, t, J=7.3 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.02(2H, t, J=5.9 Hz), 4.99(1H, brs), 6.53(1H, J=2.7 Hz), 6.56(1H, d, J=3.2 Hz), 6.85(1H, d, J=8.5 Hz), 7.25-7.26(1H, m), 7.36(1H, d, J=1.6 Hz).

(48-5) Synthesis of 2-amino-2-(2-{4-[3-(5-methyl-2-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 48-5)

Compound 48-4 (710 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (480 mg) as a white powder.

MS(ESI)m/z: 418[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.98-2.04(2H, m), 2.37(3H, s), 2.59-2.64(2H, m), 2.87(2H, t, J=7.4 Hz), 3.52(4H, d, J=4.6 Hz), 4.07(2H, t, J=6.0 Hz), 5.40(2H, t, J=4.9 Hz), 6.59(2H, s), 7.16(1H, d, J=8.6 Hz), 7.45(1H, d, J=8.6 Hz), 7.48(1H, s), 7.85(3H, brs).

2-amino-2-(2-{4-[3-(2,3-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(49-1) Synthesis of 3-(2,3-dimethylphenyl)-2-propyne-1-ol (Compound 49-1)

A mixture of 1-iodo-2,3-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 19 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-70:30) to give the object product (1.91 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.66(1H, t, J=6.2 Hz), 2.27(3H, s), 2.38(3H, s), 4.54(2H, d, J=6.2 Hz), 7.04(1H, t, J=7.6 Hz), 7.11(1H, d, J=7.4 Hz), 7.28(1H, d, J=7.6 Hz).

(49-2) Synthesis of 3-(2,3-dimethylphenyl)-1-propanol (Compound 49-2)

A solution of compound 49-1 (1.91 g) and 10% palladium carbon (0.95 g) in 1,4-dioxane (80 ml) was stirred under a hydrogen atmosphere at room temperature for 15 hr. The reaction mixture was filtered through celite and concentrated to give the object product (1.93 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.29(1H, t, J=5.0 Hz), 1.80-1.88(2H, m), 2.22(3H, s), 2.28(3H, s), 2.71-2.74(2H, m), 3.69-3.73(2H, m), 6.99-7.06(3H, m).

(49-3) Synthesis of 1-(3-bromopropyl)-2,3-dimethylbenzene (Compound 49-3)

Compound 49-2 (1.83 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.25 g) and N-bromosuccinimide (2.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.12 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.96-2.03(2H, m), 2.16(3H, s), 2.22(3H, s), 2.71(2H, t, J=7.8 Hz), 3.55(2H, t, J=6.5 Hz), 6.97-7.00(3H, m).

(49-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(2,3-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 49-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 49-3 (325 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (670 mg) as a white solid.

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.32(3H, s), 1.33(3H, s), 1.40(9H, s), 1.88-1.95(4H, m), 2.15(3H, s), 2.22(3H, s), 2.45-2.50(2H, m), 2.72-2.78(2H, m), 3.66(2H, d, J=11.6 Hz), 3.88(2H, d, J=11.3 Hz), 4.07(2H, t, J=5.7 Hz), 6.65(1H, brs), 6.94-7.01(3H, m), 7.14(1H, d, J=8.4 Hz), 7.37-7.40(1H, m), 7.40(1H, s).

(49-5) Synthesis of 2-amino-2-(2-{4-[3-(2,3-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 49-5)

Compound 49-4 (670 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (490 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.75-1.79(2H, m), 1.89-1.96(2H, m), 2.16(3H, s), 2.22(3H, s), 2.58-2.63(2H, m), 2.76(2H, t, J=7.6 Hz), 3.52(4H, d, J=5.1 Hz), 4.08(2H, t, J=5.8 Hz), 5.40(2H, t, J=5.0 Hz), 6.94-6.99(3H, m), 7.17(1H, d, J=8.5 Hz), 7.44(1H, d, J=8.6 Hz), 7.48(1H, s), 7.82(3H, brs).

2-amino-2-[2-(4-{3-[3,5-bis(trifluoromethyl)phenyl]propoxyl}-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride

(50-1) Synthesis of 3-[3,5-bis(trifluoromethyl)phenyl]-2-propyne-1-ol (Compound 50-1)

A mixture of 1-iodo-3,5-bis(trifluoromethyl)benzene (5.00 g), copper(I) iodide (56.0 mg), triphenylphosphine (193 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (304 mg), propargyl alcohol (0.954 ml), diisopropylethylamine (10.2 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 6 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.81 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.76(1H, t, J=6.3 Hz), 4.53(2H, d, J=6.2 Hz), 7.82(1H, brs), 7.87(2H, brs).

(50-2) Synthesis of 3-[3,5-bis(trifluoromethyl)phenyl]-1-propanol (Compound 50-2)

A solution of compound 50-1 (3.81 g) and 10% palladium carbon (1.50 g) in 1,4-dioxane (60 ml) was stirred under a hydrogen atmosphere at room temperature for 20 hr. The reaction mixture was filtered through celite and concentrated to give the object product (3.47 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.36(1H, brs), 1.90-1.97(2H, m), 2.87(2H, t, J=7.8 Hz), 3.71(2H, t, J=6.2 Hz), 7.66(2H, brs), 7.72(1H, brs).

(50-3) Synthesis of 1-(3-bromopropyl)-3,5-bis(trifluoromethyl)benzene (Compound 50-3)

Compound 50-2 (3.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.73 g) and N-bromosuccinimide (2.5 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.27 g) as a yellow oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.18(2H, quint, J=6.8 Hz), 2.92(2H, t, J=7.9 Hz), 3.53(2H, t, J=6.8 Hz), 7.93(1H, s), 7.98(2H, s).

(50-4) Synthesis of 2-amino-2-[2-(4-{3-[3,5-bis(trifluoromethyl)phenyl]propoxy}-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride (Compound 50-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 50-3 (480 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained pale-yellow oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (630 mg) as a white powder.

MS(ESI)m/z: 534[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 2.10-2.13(2H, m), 2.57-2.61(2H, m), 2.95(2H, t, J=7.4 Hz), 3.51(4H, d, J=5.1 Hz), 4.05(2H, t, J=6.0 Hz), 5.39(2H, t, J=5.0 Hz), 7.17(1H, d, J=8.4 Hz), 7.43(1H, d, J=8.6 Hz), 7.47(1H, s), 7.77(3H, brs), 7.92(3H, s).

2-amino-2-{2-[3-difluoromethyl-4-(3-phenylpropoxy)phenyl]ethyl}propane-1,3-diol hydrochloride

(51-1) Synthesis of 2-benzyloxy-5-bromobenzaldehyde (Compound 51-1)

To a suspension of 5-bromosalicylaldehyde (25.0 g) and potassium carbonate (51.4 g) in N,N-dimethylformamide (250 ml) was added benzyl bromide (15.4 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 40 min, and further at room temperature for 15 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with 0.1M aqueous sodium hydroxide solution and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in hexane (200 ml) and collected by filtration to give the object product (32.7 g) as a pale-yellow powder.

1 H-NMR(CDCl 3 ) δ (ppm): 5.19(2H, s), 6.95(1H, d, J=8.8 Hz), 7.34-7.43(5H, m), 7.61(1H, dd, J=2.8, 8.8 Hz), 7.95(1H, d, J=2.8 Hz), 10.46(1H, s).

(51-2) Synthesis of 1-benzyloxy-4-bromo-2-difluoromethylbenzene (Compound 51-2)

To a solution of compound 51-1 (2.70 g) in methylene chloride (5 ml) was added a solution of diethylaminosulfur trifluoride (DAST, 1.66 g) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 21 hr. The reaction mixture was added to water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography to give the object product (2.16 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 5.11(2H, s), 6.86(1H, d, J=9.1 Hz), 6.95(1H, t, J=55.3 Hz), 7.33-7.42(5H, m), 7.49(1H, dd, J=1.6, 9.8 Hz), 7.69(1H, d, J=1.9 Hz).

(51-3) Synthesis of {5-[(4-benzyloxy-3-difluoromethylphenyl)ethynyl]-2,2-dimethyl-1,3-dioxan-5-yl}carbamic acid t-butyl ester (Compound 51-3)

Compound 51-2 (9.48 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (7.34 g) synthesized according to the known method (e.g., Tetrahedron vol. 57 (2001) 15 pages 6531-6538), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (868 mg), bis(acetonitrile)palladium(II) dichloride (157 mg) and cesium carbonate (25.6 g) were stirred in acetonitrile (200 ml) at 80° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (11.1 g) as a pale-brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.45(3H, s), 1.48(9H, s), 1.50(3H, s), 4.03(2H, d, J=11.2 Hz), 4.10(2H, d, J=11.2 Hz), 5.13(2H, s), 5.20(1H, brs), 6.91(1H, d, J=8.6 Hz), 6.94(1H, t, J=55.4 Hz), 7.33-7.40(5H, m), 7.46(1H, d, J=8.6 Hz), 7.65(1H, s).

(51-4) Synthesis of {5-[2-(3-difluoromethyl-4-hydroxyphenyl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}carbamic acid t-butyl ester (Compound 51-4)

Compound 51-3 (11.1 g) was dissolved in 1,4-dioxane (250 ml), 10% palladium carbon (3.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The residue was suspended in a mixed solution of diisopropyl ether and hexane and collected by filtration to give the object product (8.17 g) as a white powder.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.92-1.96(2H, m), 2.50-2.54(2H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 5.03(1H, brs), 5.57(1H, brs), 6.77(1H, d, J=8.4 Hz), 6.84(1H, t, J=55.5 Hz), 7.12(1H, d, J=8.4 Hz), 7.23(1H, s).

(51-5) Synthesis of 2-amino-2-{2-[3-difluoromethyl-4-(3-phenylpropoxy)phenyl]ethyl}propane-1,3-diol hydrochloride (Compound 51-5)

Compound 51-4 (600 mg) was dissolved in N,N-dimethylformamide (10 ml), sodium hydride (66 mg) and 3-phenylpropylbromide (0.272 ml) were added, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethanol (15 ml) was added concentrated hydrochloric acid (1.5 ml), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 10 ml), and the precipitate was collected by filtration and dried to give the object product (98 mg) as a white powder.

MS(ESI)m/z: 380[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 2.00-2.08(2H, m), 2.56-2.62(2H, m), 2.75(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.8 Hz), 4.01(2H, t, J=6.1 Hz), 5.39(2H, J=4.6 Hz), 7.04(1H, d, J=8.6 Hz), 7.06(1H, t, J=51.9 Hz), 7.15-7.25(3H, m), 7.26-7.33(3H, m), 7.37(1H, brs), 7.79(3H, brs).

2-amino-2-(2-{5-[3-(4-trifluoromethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(52-1) Synthesis of 3-(4-trifluoromethoxyphenyl)-2-propyne-1-ol (Compound 52-1)

A mixture of 1-iodo-4-(trifluoromethoxy)benzene (5.00 g), copper(I) iodide (66.3 mg), triphenylphosphine (228 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (360 mg), propargyl alcohol (1.13 ml), diisopropylethylamine (12.1 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 21 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.46 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.73(1H, t, J=6.1 Hz), 4.50(2H, d, J=6.4 Hz), 7.16(2H, d, J=8.2 Hz), 7.46(2H, d, J=8.6 Hz).

(52-2) Synthesis of 3-(4-trifluoromethoxyphenyl)-1-propanol (Compound 52-2)

A solution of compound 52-1 (3.46 g) and 10% palladium carbon (0.80 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered through celite and concentrated to give the object product (3.33 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.29(1H, brs), 1.85-1.92(2H, m), 2.72(2H, t, J=7.8 Hz), 3.68(2H, t, J=6.3 Hz), 7.13(2H, d, J=8.2 Hz), 7.21(2H, d, J=8.6 Hz).

(52-3) Synthesis of 1-(3-bromopropyl)-4-trifluoromethoxybenzene (Compound 52-3)

Compound 52-2 (3.33 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (4.35 g) and N-bromosuccinimide (2.95 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.39 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.12-2.19(2H, m), 2.79(2H, t, J=7.4 Hz), 3.39(2H, t, J=6.5 Hz), 7.14(2H, d, J=8.3 Hz), 7.22(2H, d, J=8.6 Hz).

(52-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(4-trifluoromethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 52-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 52-3 (405 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.05-2.13(2H, m), 2.52-2.56(2H, m), 2.84(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=5.9 Hz), 4.99(1H, brs), 6.84(1H, d, J=8.5 Hz), 7.10-7.14(2H, m), 7.19-7.22(2H, m), 7.26-7.28(1H, m), 7.37(1H, d, J=1.6 Hz).

(52-5) Synthesis of 2-amino-2-(2-{4-[3-(4-trifluoromethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 52-5)

Compound 52-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (600 mg) as a white powder.

MS(ESI)m/z: 482[M+H]

1 H-NMR(DMSO-d 3 ) δ (ppm): 1.74-1.80(2H, m), 1.98-2.07(2H, m), 2.59-2.64(2H, m), 2.78(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.6 Hz), 4.05(2H, t, J=6.1 Hz), 5.40(2H, t, J=5.0 Hz), 7.17(1H, d, J=8.5 Hz), 7.26-7.34(4H, m), 7.45(1H, d, J=8.5 Hz), 7.48(1H, brs), 7.85(3H, brs).

2-amino-2-(2-{4-[3-(3,4-difluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(53-1) Synthesis of 3-(3,4-difluorophenyl)-2-propyne-1-ol (Compound 53-1)

A mixture of 3,4-difluoroiodobenzene (5.00 g), copper(I) iodide (79.4 mg), triphenylphosphine (273 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (432 mg), propargyl alcohol (1.35 ml), diisopropylethylamine (14.5 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.25 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.69(1H, t, J=6.2 Hz), 4.48(2H, d, J=6.2 Hz), 7.10(1H, dt, J=10.0, 8.2 Hz), 7.16-7.19(1H, m), 7.22-7.27(1H, m).

(53-2) Synthesis of 3-(3,4-difluorophenyl)-1-propanol (Compound 53-2)

A solution of compound 53-1 (3.25 g) and 10% palladium carbon (0.75 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction mixture was filtered through celite and concentrated to give the object product (3.12 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.83-1.90(2H, m), 2.68(2H, t, J=7.7 Hz), 3.64-3.68(2H, m), 6.88-6.91(1H, m), 6.97-7.03(1H, m), 7.06(1H, dt, J=10.5, 8.2 Hz).

(53-3) Synthesis of 1-(3-bromopropyl)-3,4-difluorobenzene (Compound 53-3)

Compound 53-2 (3.11 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (5.21 g) and N-bromosuccinimide (3.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.6 g) as a yellow oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.06-2.13(2H, m), 2.71(2H, t, J=7.8 Hz), 3.50(2H, t, J=6.7 Hz), 7.05-7.08(1H, m), 7.28-7.34(2H, m).

(53-4) Synthesis of 2-amino-2-(2-{4-[3-(3,4-difluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 53-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 53-3 (340 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained colorless oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (475 mg) as a white powder.

MS(ESI)m/z: 434[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.99-2.06(2H, m), 2.59-2.63(2H, m), 2.74(2H, t, J=7.4 Hz), 3.52(4H, d, J=5.2 Hz), 4.04(2H, t, J=6.1 Hz), 5.40(2H, t, J=5.2 Hz), 7.01-7.04(1H, m), 7.17(1H, d, J=8.5 Hz), 7.26-7.37(2H, m), 7.44(1H, d, J=8.6 Hz), 7.48(1H, d, J=1.4 Hz), 7.87(3H, brs).

2-amino-2-(2-{4-[3-(3-chloro-2-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(54-1) Synthesis of 3-(3-chloro-2-methylphenyl)-2-propyne-1-ol (Compound 54-1)

A mixture of 2-chloro-6-iodotoluene (5.00 g), copper(I) iodide (75.4 mg), triphenylphosphine (260 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (410 mg), propargyl alcohol (1.29 ml), diisopropylethylamine (13.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (2.58 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.74(1H, t, J=5.6 Hz), 2.50(3H, s), 4.54(2H, d, J=5.6 Hz), 7.07(1H, t, J=7.9 Hz), 7.31-7.33(2H, m).

(54-2) Synthesis of 3-(3-chloro-2-methylphenyl)-1-propanol (Compound 54-2)

A suspension of Compound 54-1 (2.58 g) and chlorotris(triphenylphosphine)rhodium(I) (1.50 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 60° C. for 11 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.11 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(1H, brs), 1.80-1.87(2H, m), 2.36(3H, s), 2.75(2H, t, J=7.8 Hz), 3.70(2H, t, J=6.4 Hz), 7.02-7.07(2H, m), 7.20-7.24(1H, m).

(54-3) Synthesis of 1-(3-bromopropyl)-3-chloro-2-methylbenzene (Compound 54-3)

Compound 54-2 (2.10 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.30 g) and N-bromosuccinimide (2.23 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.56 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.99-2.06(2H, m), 2.32(3H, s), 2.77(2H, t, J=7.8 Hz), 3.56(2H, t, J=6.5 Hz), 7.14-7.15(2H, m), 7.26-7.30(1H, m).

(54-4) Synthesis of 2-amino-2-(2-{4-[3-(3-chloro-2-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 54-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 54-3 (355 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (535 mg) as a white powder.

MS(ESI)m/z: 446[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.92-1.98(2H, m), 2.31(3H, s), 2.58-2.63(2H, m), 2.82(2H, t, J=7.6 Hz), 3.52(4H, d, J=5.2 Hz), 4.09(2H, t, J=5.8 Hz), 5.40(2H, t, J=5.2 Hz), 7.13(1H, s), 7.14(1H, d, J=3.6 Hz), 7.18(1H, d, J=8.6 Hz), 7.28(1H, q, J=3.2 Hz), 7.45(1H, d, J=8.6 Hz), 7.48(1H, s), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(3-chloro-4-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(55-1) Synthesis of 3-(3-chloro-4-methylphenyl)-2-propyne-1-ol (Compound 55-1)

A mixture of 2-chloro-4-iodotoluene (5.00 g), copper(I) iodide (75.4 mg), triphenylphosphine (260 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (410 mg), propargyl alcohol (1.29 ml), diisopropylethylamine (13.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (2.80 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.65(1H, t, J=6.2 Hz), 2.37(3H, s), 4.48(2H, d, J=6.2 Hz), 7.16(1H, d, J=7.9 Hz), 7.22(1H, d, J=7.9 Hz), 7.42(1H, d, J=1.2 Hz).

(55-2) Synthesis of 3-(3-chloro-4-methylphenyl)-1-propanol (Compound 55-2)

A suspension of compound 55-1 (2.80 g) and chlorotris(triphenylphosphine)rhodium(I) (1.50 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 60° C. for 11 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-75:25) to give the object product (2.35 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.29(1H, brs), 1.83-1.90(2H, m), 2.33(3H, s), 2.66(2H, t, J=7.7 Hz), 3.67(2H, t, J=6.2 Hz), 6.99(1H, dd, J=1.2, 7.8 Hz), 7.13(1H, d, J=7.8 Hz), 7.18(1H, d, J=1.2 Hz).

(55-3) Synthesis of 1-(3-bromopropyl)-3-chloro-4-methylbenzene (Compound 55-3)

Compound 55-2 (2.34 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.66 g) and N-bromosuccinimide (2.48 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.04-2.11(2H, m), 2.28(3H, s), 2.67(2H, t, J=7.8 Hz), 3.48(2H, t, J=6.6 Hz), 7.09(1H, dd, J=7.8, 1.8 Hz), 7.26(1H, d, J=7.8 Hz), 7.27(1H, s).

(55-4) Synthesis of 2-amino-2-(2-{4-[3-(3-chloro-4-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 55-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 55-3 (355 mg) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained colorless oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (458 mg) as a white powder.

MS(ESI)m/z: 446[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 1.97-2.04(2H, m), 2.28(3H, s), 2.57-2.62(2H, m), 2.71(2H, t, J=7.6 Hz), 3.51(4H, d, J=5.0 Hz), 4.02(2H, t, J=6.1 Hz), 5.39(2H, t, J=5.0 Hz), 7.06(1H, d, J=7.8 Hz), 7.16(1H, d, J=8.5 Hz), 7.24(1H, s), 7.25(1H, d, J=8.1 Hz), 7.43(1H, d, J=8.5 Hz), 7.47(1H, d, J=1.5 Hz), 7.78(3H, brs).

2-amino-2-(2-{4-[3-(1-indanon-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(56-1) Synthesis of 1-(1-indanon-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 56-1)

A mixture of 5-bromo-1-indanone (10.0 g), cesium carbonate (40.3 g), 2-(2-propynyloxy)tetrahydropyran (10.0 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.40 g), bis(acetonitrile)palladium(II) dichloride (246 mg) and acetonitrile (200 ml) was stirred at 90° C. for 6 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (7.87 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.53-1.91(6H, m), 2.69-2.72(2H, m), 3.12(2H, t, J=6.0 Hz), 3.55-3.60(1H, m), 3.86-3.93(1H, m), 4.48(1H, d, J=15.9 Hz), 4.55(1H, d, J=15.9 Hz), 4.90(1H, t, J=3.3 Hz), 7.43(1H, d, J=7.9 Hz), 7.55(1H, s), 7.69(1H, d, J=7.9 Hz).

(56-2) Synthesis of 3-(1-indanon-5-yl)-1-propanol (Compound 56-2)

A solution of compound 56-1 (7.87 g) and 10% palladium carbon (3.00 g) in ethyl acetate (50 ml) was stirred under a hydrogen atmosphere at room temperature for 12 hr. The reaction mixture was filtered through celite and concentrated. The residue was purified by silica gel column chromatography to give 1-(1-indanon-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (6.24 g) as a yellow oil. A solution of 2.02 g of the yellow oil and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (30 ml) was stirred at room temperature for 6 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:4) to give the object product (1.15 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.32(1H, t, J=5.1 Hz), 1.89-1.96(2H, m), 2.67-2.70(2H, m), 2.81(2H, t, J=7.6 Hz), 3.09-3.13(2H, m), 3.67-3.72(2H, m), 7.22(1H, d, J=7.9 Hz), 7.31(1H, s), 7.69(1H, d, J=7.9 Hz).

(56-3) Synthesis of 5-(3-bromopropyl)-1-indanone (Compound 56-3)

Compound 56-2 (1.15 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.74 g) and N-bromosuccinimide (1.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (430 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.16-2.24(2H, m), 2.67-2.73(2H, m), 2.87(2H, t, J=7.4 Hz), 3.12(2H, t, J=5.9 Hz), 3.40(2H, t, J=6.5 Hz), 7.22(1H, d, J=7.9 Hz), 7.31(1H, s), 7.70(1H, d, J=7.9 Hz).

(56-4) Synthesis of [5-(2-{4-[3-(1-indanon-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 56-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 56-3 (430 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (840 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.99(2H, m), 2.12-2.17(2H, m), 2.52-2.57(2H, m), 2.66-2.71(2H, m), 2.92(2H, t, J=7.5 Hz), 3.08-3.14(2H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.00(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.84(1H, d, J=8.5 Hz), 7.21(1H, d, J=7.8 Hz), 7.26-7.30(1H, m), 7.31(1H, s), 7.38(1H, d, J=1.4 Hz), 7.68(1H, d, J=7.8 Hz).

(56-5) Synthesis of 2-amino-2-(2-{4-[3-(1-indanon-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 56-5)

Compound 56-4 (840 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (410 mg) as a white powder.

MS(ESI)m/z: 452[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.04-2.08(2H, m), 2.59-2.63(4H, m), 2.85(2H, t, J=7.5 Hz), 3.06(2H, t, J=5.8 Hz), 3.52(4H, d, J=4.6 Hz), 4.07(2H, t, J=6.0 Hz), 5.39(2H, t, J=4.9 Hz), 7.17(1H, d, J=8.6 Hz), 7.26(1H, d, J=7.8 Hz), 7.41-7.48(3H, m), 7.56(1H, d, J=7.8 Hz), 7.78(3H, brs).

2-amino-2-(2-{4-[3-(2-chloro-5-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(57-1) Synthesis of 3-(2-chloro-5-trifluoromethylphenyl)-2-propyne-1-ol (Compound 57-1)

A mixture of 4-chloro-3-iodobenzotrifluoride (10.0 g), copper(I) iodide (124 mg), triphenylphosphine (428 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (675 mg), propargyl alcohol (2.12 ml), diisopropylethylamine (22.6 ml) and tetrahydrofuran (180 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (7.63 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.73(1H, t, J=6.3 Hz), 4.57(2H, d, J=6.3 Hz), 7.50(1H, dd, J=1.7, 8.5 Hz), 7.53(1H, d, J=8.5 Hz), 7.74(1H, d, J=1.7 Hz).

(57-2) Synthesis of 3-(2-chloro-5-trifluoromethylphenyl)-1-propanol (Compound 57-2)

A suspension of compound 57-1 (7.63 g) and chlorotris(triphenylphosphine)rhodium(I) (2.00 g) in toluene (100 ml) was stirred under a hydrogen atmosphere at 60° C. for 10 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-70:30) to give the object product (6.33 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.37(1H, brs), 1.88-1.95(2H, m), 2.90(2H, t, J=7.8 Hz), 3.72(2H, brs), 7.41(1H, dd, J=1.7, 8.3 Hz), 7.46(1H, d, J=8.3 Hz), 7.51(1H, d, J=1.7 Hz).

(57-3) Synthesis of 1-(3-bromopropyl)-2-chloro-5-trifluoromethylbenzene (Compound 57-3)

Compound 57-2 (6.32 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (7.64 g) and N-bromosuccinimide (5.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (7.53 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.16-2.24(2H, m), 2.96(2H, t, J=7.5 Hz), 3.44(2H, t, J=6.4 Hz), 7.41-7.51(3H, m).

(57-4) Synthesis of [5-(2-{4-[3-(2-chloro-5-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 57-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 57-3 (431 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (870 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.93-1.99(2H, m), 2.10-2.17(2H, m), 2.52-2.57(2H, m), 3.10(2H, t, J=7.6 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.03(2H, t, J=5.9 Hz), 5.00(1H, brs), 6.86(1H, d, J=8.4 Hz), 7.26-7.29(1H, m), 7.37-7.48(4H, m).

(57-5) Synthesis of 2-amino-2-(2-{4-[3-(2-chloro-5-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 57-5)

Compound 57-4 (870 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (630 mg) as a white powder.

MS(ESI)m/z: 500[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.75-1.80(2H, m), 2.03-2.08(2H, m), 2.60-2.64(2H, m), 2.96(2H, t, J=7.5 Hz), 3.53(4H, d, J=4.0 Hz), 4.10(2H, t, J=5.7 Hz), 5.41(2H, brs), 7.18(1H, d, J=8.5 Hz), 7.46(1H, d, J=8.5 Hz), 7.49(1H, s), 7.60-7.70(3H, m), 7.86(3H, brs).

2-amino-2-(2-{4-[3-(3-trifluoromethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(58-1) Synthesis of 3-(3-trifluoromethoxyphenyl)-2-propyne-1-ol (Compound 58-1)

A mixture of 1-iodo-3-(trifluoromethoxy)benzene (5.00 g), copper(I) iodide (66.3 mg), triphenylphosphine (228 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (360 mg), propargyl alcohol (1.13 ml), diisopropylethylamine (12.1 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.28 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.71(1H, t, J=6.2 Hz), 4.51(2H, d, J=6.2 Hz), 7.18-7.20(1H, m), 7.29(1H, brs), 7.34(1H, t, J=7.6 Hz), 7.36-7.38(1H, m).

(58-2) Synthesis of 3-(3-trifluoromethoxyphenyl)-1-propanol (Compound 58-2)

A solution of compound 58-1 (3.28 g) and 10% palladium carbon (0.75 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction mixture was filtered through celite and concentrated to give the object product (3.17 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.30(1H, brs), 1.86-1.93(2H, m), 2.74(2H, t, J=7.8 Hz), 3.68(2H, t, J=6.0 Hz), 7.04-7.06(2H, m), 7.13(1H, d, J=7.6 Hz), 7.28-7.32(1H, m).

(58-3) Synthesis of 1-(3-bromopropyl)-3-trifluoromethoxybenzene (Compound 58-3)

Compound 58-2 (3.15 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.13 g) and N-bromosuccinimide (2.79 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.54 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.13-2.20(2H, m), 2.80(2H, t, J=7.4 Hz), 3.39(2H, t, J=6.4 Hz), 7.05-7.08(2H, m), 7.14(1H, d, J=7.7 Hz), 7.31(1H, t, J=7.7 Hz).

(58-4) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3-trifluoromethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 58-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 58-3 (405 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.08-2.15(2H, m), 2.52-2.57(2H, m), 2.86(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.8 Hz), 3.89(2H, d, J=11.8 Hz), 3.98(2H, t, J=5.9 Hz), 4.99(1H, brs), 6.83(1H, d, J=8.4 Hz), 7.03-7.05(2H, m), 7.13(1H, d, J=7.8 Hz), 7.25-7.31(2H, m), 7.37(1H, d, J=1.8 Hz).

(58-5) Synthesis of 2-amino-2-(2-{4-[3-(3-trifluoromethoxyphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 58-5)

Compound 58-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed, with diethyl ether to give the object product (590 mg) as a white powder.

MS(ESI)m/z: 482[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.01-2.08(2H, m), 2.59-2.64(2H, m), 2.80(2H, t, J=7.4 Hz), 3.52(4H, d, J=4.6 Hz), 4.04(2H, t, J=6.1 Hz), 5.40(2H, t, J=5.0 Hz), 7.14-7.19(3H, m), 7.25(1H, d, J=7.6 Hz), 7.40-7.45(2H, m), 7.48(1H, d, J=1.3 Hz), 7.84(3H, brs).

2-amino-2-(2-{4-[3-(2-naphthyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(59-1) Synthesis of 3-(2-naphthyl)-1-propanol (Compound 59-1)

3-(2-Naphthyl)acrylic acid (5.00 g) was dissolved in methanol (30 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (2.40 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a pale-yellow solid (4.86 g). The pale-yellow solid was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 27.0 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 18 hr. To the reaction mixture was added water, and 1M aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.33 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.26(1H, t, J=7.1 Hz), 1.95-2.02(2H, m), 2.88(2H, t, J=7.6 Hz), 3.71(2H, t, J=6.5 Hz), 7.35(1H, dd, J=8.3, 1.3 Hz), 7.39-7.47(2H, m), 7.64(1H, s), 7.76-7.81(3H, m).

(59-2) Synthesis of 2-(3-bromopropyl)naphthalene (Compound 59-2)

Compound 59-1 (4.33 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (6.69 g) and N-bromosuccinimide (4.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 21 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (4.95 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.22-2.30(2H, m), 2.95(2H, t, J=7.3 Hz), 3.43(2H, t, J=6.5 Hz), 7.34(1H, dd, J=8.5, 1.3 Hz), 7.41-7.48(2H, m), 7.65(1H, s), 7.77-7.82(3H, m).

(59-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(2-naphthyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 59-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 59-2 (356 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (500 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.16-2.24(2H, m), 2.51-2.56(2H, m), 3.00(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.01(2H, t, J=6.0 Hz), 4.99(1H, brs), 6.83(1H, d, J=8.5 Hz), 7.24(1H, brd, J=1.8 Hz), 7.33-7.40(2H, m), 7.41-7.46(2H, m), 7.63(1H, brs), 7.74-7.81(3H, m).

(59-4) Synthesis of 2-amino-2-(2-{4-[3-(2-naphthyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 59-4)

Compound 59-3 (500 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (400 mg) as a white powder.

MS(ESI)m/z: 448[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 2.09-2.18(2H, m), 2.57-2.62(2H, m), 2.92(2H, t, J=7.5 Hz), 3.51(4H, d, J=4.2 Hz), 4.09(2H, t, J=6.1 Hz), 5.36(2H, brs), 7.17(1H, d, J=8.6 Hz), 7.38-7.49(5H, m), 7.70(4H, brs), 7.81-7.87(3H, m).

2-amino-2-(2-{4-[3-(2,3-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(60-1) Synthesis of 3-(2,3-dichlorophenyl)-2-propyne-1-ol (Compound 60-1)

A mixture of 2,3-dichloroiodobenzene (5.00 g), copper(I) iodide (69.8 mg), triphenylphosphine (240 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg), propargyl alcohol (1.19 ml), diisopropylethylamine (12.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.12 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.75(1H, t, J=6.3 Hz), 4.56(2H, d, J=6.3 Hz), 7.15(1H, t, J=7.9 Hz), 7.39(1H, dd, J=7.9, 1.3 Hz), 7.42(1H, dd, J=8.4, 1.3 Hz).

(60-2) Synthesis of 3-(2,3-dichlorophenyl)-1-propanol (Compound 60-2)

A suspension of compound 60-1 (3.12 g) and chlorotris(triphenylphosphine)rhodium(I) (1.80 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 60° C. for 10 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.66 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.35(1H, brs), 1.86-1.93(2H, m), 2.86-2.90(2H, m), 3.70(2H, t, J=6.3 Hz), 7.12(1H, t, J=7.3 Hz), 7.16(1H, dd, J=7.6, 2.2 Hz), 7.32(1H, dd, J=7.6, 2.2 Hz).

(60-3) Synthesis of 1-(3-bromopropyl)-2,3-dichlorobenzene (Compound 60-3)

Compound 60-2 (2.67 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.76 g) and N-bromosuccinimide (2.55 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.25 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.15-2.22(2H, m), 2.95(2H, t, J=7.5 Hz), 3.42(2H, t, J=6.5 Hz), 7.11-7.19(2H, m), 7.33-7.36(1H, m).

(60-4) Synthesis of [5-(2-{4-[3-(2,3-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 60-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 60-3 (383 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (770 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.94-1.98(2H, m), 2.10-2.19(2H, m), 2.52-2.57(2H, m), 3.00(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.00(2H, t, J=5.9 Hz), 4.98(1H, brs), 6.85(1H, d, J=8.5 Hz), 7.07-7.19(2H, m), 7.25-7.36(2H, m), 7.38(1H, d, J=1.6 Hz).

(60-5) Synthesis of 2-amino-2-(2-{4-[3-(2,3-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 60-5)

Compound 60-4 (770 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.99-2.05(2H, m), 2.58-2.63(2H, m), 2.94(2H, t, J=7.6 Hz), 3.52(4H, d, J=4.2 Hz), 4.10(2H, t, J=5.8 Hz), 5.39(2H, t, J=4.6 Hz), 7.18(1H, d, J=8.6 Hz), 7.31(2H, d, J=4.8 Hz), 7.45(1H, d, J=8.6 Hz), 7.48-7.52(2H, m), 7.75(3H, brs).

2-amino-2-(2-{4-[3-(3-chloro-4-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(61-1) Synthesis of 3-(3-chloro-4-fluorophenyl)-2-propyne-1-ol (Compound 61-1)

A mixture of 3-chloro-4-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.20 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.66(1H, t, J=6.2 Hz), 4.48(2H, d, J=6.2 Hz), 7.09(1H, t, J=8.7 Hz), 7.29-7.33(1H, m), 7.49(1H, dd, J=2.1, 7.0 Hz).

(61-2) Synthesis of 3-(3-chloro-4-fluorophenyl)-1-propanol (Compound 61-2)

A suspension of Compound 61-1 (3.20 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (70 ml) was stirred under a hydrogen atmosphere at 65° C. for 10 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-75:25) to give the object product (2.47 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.32(1H, brs), 1.82-1.90(2H, m), 2.68(2H, t, J=7.7 Hz), 3.67(2H, t, J=6.3 Hz), 7.04-7.06(2H, m), 7.23(1H, d, J=7.4 Hz).

(61-3) Synthesis of 1-(3-bromopropyl)-3-chloro-4-fluorobenzene (Compound 61-3)

Compound 61-2 (2.47 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (3.78 g) and N-bromosuccinimide (2.56 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.06 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.17(2H, m), 2.75(2H, t, J=7.4 Hz), 3.38(2H, t, J=6.4 Hz), 7.05-7.07(2H, m), 7.23(1H, d, J=7.1 Hz).

(61-4) Synthesis of [5-(2-{4-[3-(3-chloro-4-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 61-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 61-3 (360 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.94-1.98(2H, m), 2.05-2.14(2H, m), 2.52-2.57(2H, m), 2.79(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=5.8 Hz), 4.99(1H, brs), 6.84(1H, d, J=8.5 Hz), 7.02-7.07(2H, m), 7.22(1H, d, J=7.4 Hz), 7.25-7.28(1H, m), 7.37(1H, d, J=1.6 Hz).

(61-5) Synthesis of 2-amino-2-(2-{4-[3-(3-chloro-4-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 61-5)

Compound 61-4 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (520 mg) as a white powder.

MS(ESI)m/z: 450[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.98-2.05(2H, m), 2.58-2.63(2H, m), 2.74(2H, t, J=7.5 Hz), 3.52(4H, d, J=5.2 Hz), 4.03(2H, t, J=6.0 Hz), 5.40(2H, t, J=5.1 Hz), 7.17(1H, d, J=8.7 Hz), 7.18-7.22(1H, m), 7.32(1H, t, J=8.7 Hz), 7.40-7.46(2H, m), 7.47(1H, brs), 7.86(3H, brs).

2-amino-2-(2-{4-[3-(2,5-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(62-1) Synthesis of 3-(2,5-dimethylphenyl)-2-propyne-1-ol (Compound 62-1)

A mixture of 1-iodo-2,5-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.70 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.64(1H, t, J=6.2 Hz), 2.28(3H, s), 2.38(3H, s), 4.53(2H, d, J=6.2 Hz), 7.03(1H, dd, J=1.0, 7.8 Hz), 7.08(1H, d, J=7.8 Hz), 7.23(1H, s).

(62-2) Synthesis of 3-(2,5-dimethylphenyl)-1-propanol (Compound 62-2)

A solution of compound 62-1 (1.70 g) and 10% palladium carbon (0.50 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated to give the object product (1.69 g) as a dark-green oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.30(1H, brs), 1.81-1.88(2H, m), 2.27(3H, s), 2.29(3H, s), 2.64-2.68(2H, m), 3.70-3.72(2H, m), 6.92(1H, d, J=7.6 Hz), 6.97(1H, s), 7.03(1H, d, J=7.6 Hz).

(62-3) Synthesis of 1-(3-bromopropyl)-2,5-dimethylbenzene (Compound 62-3)

Compound 62-2 (1.64 g) was dissolved in methylene chloride (33 ml), triphenylphosphine (2.90 g) and N-bromosuccinimide (1.95 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.97 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.98-2.05(2H, m), 2.21(3H, s), 2.23(3H, s), 2.65(2H, t, J=7.9 Hz), 3.56(2H, t, J=6.4 Hz), 6.90(1H, d, J=7.5 Hz), 6.95(1H, s), 7.02(1H, d, J=7.6 Hz).

(62-4) Synthesis of 2-amino-2-(2-{4-[3-(2,5-dimethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 62-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 62-3 (330 mg) were added, and the mixture was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (440 mg) as a white powder.

MS(ESI)m/z: 426[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.75-1.79(2H, m), 1.90-1.96(2H, m), 2.20(3H, s), 2.21(3H, s), 2.59-2.63(2H, m), 2.69(2H, t, J=7.7 Hz), 3.52(4H, d, J=5.1 Hz), 4.09(2H, t, J=5.8 Hz), 5.40(2H, t, J=5.2 Hz), 6.89(1H, d, J=7.5 Hz), 6.94(1H, s), 7.01(1H, d, J=7.6 Hz), 7.18(1H, d, J=8.6 Hz), 7.45(1H, d, J=8.6 Hz), 7.48(1H, s), 7.84(3H, brs).

2-amino-2-(2-{4-[3-(3-chloro-2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(63-1) Synthesis of 3-(3-chloro-2-fluorophenyl)-2-propyne-1-ol (Compound 63-1)

A mixture of 3-chloro-2-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (90 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.15 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.73(1H, t, J=6.3 Hz), 4.54(2H, d, J=6.3 Hz), 7.04(1H, t, J=7.8 Hz), 7.31-7.39(2H, m).

(63-2) Synthesis of 3-(3-chloro-2-fluorophenyl)-1-propanol (Compound 63-2)

A suspension of Compound 63-1 (3.15 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (90 ml) was stirred under a hydrogen atmosphere at 60° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.48 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.36(1H, brs), 1.88(2H, quint, J=7.0 Hz), 2.77(2H, t, J=7.9 Hz), 3.68(2H, t, J=6.3 Hz), 7.00(1H, t, J=7.9 Hz), 7.09-7.13(1H, m), 7.22-7.26(1H, m).

(63-3) Synthesis of 1-(3-bromopropyl)-3-chloro-2-fluorobenzene (Compound 63-3)

Compound 63-2 (2.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.80 g) and N-bromosuccinimide (2.57 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.06-2.13(2H, m), 2.79(2H, t, J=7.8 Hz), 3.54(2H, t, J=6.4 Hz), 7.17(1H, t, J=8.0 Hz), 7.30(1H, dd, J=7.5, 1.0 Hz), 7.44(1H, dd, J=8.1, 1.4 Hz).

(63-4) Synthesis of 2-amino-2-(2-{4-[3-(3-chloro-2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 63-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 63-3 (330 mg) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (467 mg) as a white powder.

MS(ESI)m/z: 450[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.75-1.79(2H, m), 1.99-2.05(2H, m), 2.59-2.63(2H, m), 2.83(2H, t, J=7.7 Hz), 3.52(4H, d, J=5.2 Hz), 4.08(2H, t, J=5.9 Hz), 5.41(2H, t, J=5.1 Hz), 7.14-7.18(2H, m), 7.26(1H, dd, J=7.8, 1.2 Hz), 7.41-7.46(2H, m), 7.48(1H, s), 7.85(3H, brs).

2-amino-2-(2-{4-[3-(5-chloro-2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(64-1) Synthesis of 3-(5-chloro-2-fluorophenyl)-2-propyne-1-ol (Compound 64-1)

A mixture of 5-chloro-2-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.82 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.71(1H, t, J=6.3 Hz), 4.53(2H, d, J=6.3 Hz), 7.02(1H, t, J=8.7 Hz), 7.25-7.29(1H, m), 7.41(1H, dd, J=2.8, 6.2 Hz).

(64-2) Synthesis of 3-(5-chloro-2-fluorophenyl)-1-propanol (Compound 64-2)

A suspension of compound 64-1 (2.81 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (90 ml) was stirred under a hydrogen atmosphere at 60° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.31 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.36(1H, brs), 1.84-1.91(2H, m), 2.72(2H, t, J=7.7 Hz), 3.68(2H, t, J=6.3 Hz), 6.95(1H, t, J=9.0 Hz), 7.12-7.16(1H, m), 7.19(1H, dd, J=2.6, 6.5 Hz).

(64-3) Synthesis of 1-(3-bromopropyl)-5-chloro-2-fluorobenzene (Compound 64-3)

Compound 64-2 (2.28 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.70 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.05-2.12(2H, m), 2.74(2H, t, J=7.8 Hz), 3.53(2H, t, J=6.4 Hz), 7.22(1H, t, J=9.0 Hz), 7.32(1H, ddd, J=8.6, 4.4, 2.7 Hz), 7.41(1H, dd, J=6.4, 2.7 Hz).

(64-4) Synthesis of 2-amino-2-(2-{4-[3-(5-chloro-2-fluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 64-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 64-3 (360 mg) were added, and the mixture was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (478 mg) as a white powder.

MS(ESI)m/z: 450[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.98-2.05(2H, m), 2.58-2.63(2H, m), 2.78(2H, t, J=7.8 Hz), 3.52(4H, d, J=5.0 Hz), 4.08(2H, t, J=5.8 Hz), 5.40(2H, t, J=5.0 Hz), 7.16-7.23(2H, m), 7.32(1H, ddd, J=8.6, 4.4, 2.7 Hz), 7.36(1H, dd, J=6.5, 2.7 Hz), 7.44(1H, d, J=8.6 Hz), 7.47(1H, s), 7.83(3H, brs).

2-amino-2-(2-{4-[3-(2,4-difluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(65-1) Synthesis of 3-(2,4-difluorophenyl)-2-propyne-1-ol (Compound 65-1)

A mixture of 2,4-difluoroiodobenzene (5.00 g), copper(I) iodide (79.4 mg), triphenylphosphine (273 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (432 mg), propargyl alcohol (1.35 ml), diisopropylethylamine (14.5 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.03 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.71(1H, t, J=6.2 Hz), 4.52(2H, d, J=6.2 Hz), 6.81-6.88(2H, m), 7.39-7.45(1H, m).

(65-2) Synthesis of 3-(2,4-difluorophenyl)-1-propanol (Compound 65-2)

A solution of compound 65-1 (1.03 g) and 10% palladium carbon (0.50 g) in 1,4-dioxane (60 ml) was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated to give the object product (0.99 g) as a dark-green oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.32(1H, brs), 1.85(2H, quint, J=7.0 Hz), 2.71(2H, t, J=7.6 Hz), 3.67(2H, t, J=6.1 Hz), 6.75-6.83(2H, m), 7.13-7.19(1H, m).

(65-3) Synthesis of 1-(3-bromopropyl)-2,4-difluorobenzene (Compound 65-3)

Compound 65-2 (940 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (1.58 g) and N-bromosuccinimide (1.07 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.03 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.17(2H, m), 2.78(2H, t, J=7.4 Hz), 3.39(2H, t, J=6.6 Hz), 6.75-6.83(2H, m), 7.14-7.21(1H, m).

(65-4) Synthesis of [5-(2-{4-[3-(2,4-difluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 65-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 65-3 (336 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (730 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.05-2.11(2H, m), 2.52-2.57(2H, m), 2.82(2H, t, J=7.4 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=5.9 Hz), 4.99(1H, brs ) , 6.75-6.81(2H, m), 6.84(1H, d, J=8.5 Hz), 7.12-7.18(1H, m), 7.26-7.28(1H, m), 7.37(1H, d, J=1.8 Hz).

(65-5) Synthesis of 2-amino-2-(2-{4-[3-(2,4-difluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 65-5)

Compound 65-4 (730 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (480 mg) as a white powder.

MS(ESI)m/z: 434[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.97-2.01(2H, m), 2.58-2.63(2H, m), 2.76(2H, t, J=7.5 Hz), 3.52(4H, d, J=5.0 Hz), 4.06(2H, t, J=5.9 Hz), 5.39(2H, t, J=5.0 Hz), 7.02(1H, td, J=8.5, 2.4 Hz), 7.15-7.20(2H, m), 7.28-7.34(1H, m), 7.44(1H, d, J=8.5 Hz), 7.48(1H, d, J=1.5 Hz), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(2,5-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(66-1) Synthesis of 3-(2,5-dichlorophenyl)-2-propyne-1-ol (Compound 66-1)

A mixture of 2,5-dichloroiodobenzene (5.00 g), copper(I) iodide (69.8 mg), triphenylphosphine (240 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg), propargyl alcohol (1.19 ml), diisopropylethylamine (12.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.38 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.74(1H, t, J=6.3 Hz), 4.55(2H, d, J=6.3 Hz), 7.23(1H, dd, J=2.3, 8.6 Hz), 7.32(1H, d, J=8.6 Hz), 7.46(1H, d, J=2.3 Hz).

(66-2) Synthesis of 3-(2,5-dichlorophenyl)-1-propanol (Compound 66-2)

A suspension of compound 66-1 (3.38 g) and chlorotris(triphenylphosphine)rhodium(I) (1.80 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 60° C. for 10 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.74 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.36(1H, brs), 1.85-1.92(2H, m), 2.81(2H, t, J=7.8 Hz), 3.70(2H, t, J=6.2 Hz), 7.12(1H, dd, J=2.5, 8.6 Hz), 7.24(1H, d, J=2.5 Hz), 7.27(1H, d, J=8.6 Hz).

(66-3) Synthesis of 1-(3-chloropropyl)-2,5-dichlorobenzene (Compound 66-3)

Compound 66-2 (1.73 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.43 g) and N-chlorosuccinimide (1.24 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.76 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.05-2.13(2H, m), 2.87(2H, t, J=7.4 Hz), 3.56(2H, t, J=6.5 Hz), 7.12-7.16(1H, m), 7.23-7.29(2H, m).

(66-4) Synthesis of [5-(2-{4-[3-(2,5-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 66-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 66-3 (320 mg) were added, and the mixture was stirred at 80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a pale-yellow solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.94-1.98(2H, m), 2.04-2.13(2H, m), 2.52-2.57(2H, m), 2.89-2.94(2H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.03(2H, t, J=5.9 Hz), 4.99(1H, brs), 6.86(1H, d, J=8.5 Hz), 7.13(1H, td, J=8.5, 2.4 Hz), 7.21-7.29(3H, m), 7.38(1H, d, J=1.8 Hz).

(66-5) Synthesis of 2-amino-2-(2-{4-[3-(2,5-dichlorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 66-5)

Compound 66-4 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (500 mg) as a white powder.

MS(ESI)m/z: 466[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.98-2.06(2H, m), 2.58-2.63(2H, m), 2.87(2H, t, J=7.7 Hz), 3.52(4H, d, J=5.0 Hz), 4.10(2H, t, J=5.9 Hz), 5.40(2H, t, J=5.1 Hz), 7.19(1H, d, J=8.5 Hz), 7.32(1H, dd, J=8.5, 2.7 Hz), 7.41-7.80(4H, m), 7.83(3H, brs).

2-amino-2-(2-{4-[3-(4-chloro-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(67-1) Synthesis of 3-(4-chloro-3-methylphenyl)-2-propyne-1-ol (Compound 67-1)

A mixture of 2-chloro-5-iodotoluene (5.00 g), copper(I) iodide (75.4 mg), triphenylphosphine (260 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (410 mg), propargyl alcohol (1.29 ml), diisopropylethylamine (13.8 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.08 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.65(1H, t, J=6.1 Hz), 2.34(3H, s), 4.48(2H, d, J=6.1 Hz), 7.19(1H, dd, J=1.5, 8.3 Hz), 7.27(1H, d, J=8.3 Hz), 7.31(1H, d, J=1.5 Hz).

(67-2) Synthesis of 3-(4-chloro-3-methylphenyl)-1-propanol (Compound 67-2)

A suspension of Compound 67-1 (3.08 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (70 ml) was stirred under a hydrogen atmosphere at 65° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-75:25) to give the object product (2.49 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.83-1.90(2H, m), 2.34(3H, s), 2.65(2H, t, J=7.7 Hz), 3.67(2H, t, J=6.3 Hz), 6.96(1H, dd, J=1.6, 8.2 Hz), 7.06(1H, d, J=1.6 Hz), 7.24(1H, d, J=8.2 Hz).

(67-3) Synthesis of 1-(3-bromopropyl)-4-chloro-3-methylbenzene (Compound 67-3)

Compound 67-2 (2.49 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.90 g) and N-bromosuccinimide (2.64 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.99 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.05-2.11(2H, m), 2.30(3H, s), 2.66(2H, t, J=7.8 Hz), 3.50(2H, t, J=6.6 Hz), 7.06(1H, dd, J=8.0, 1.8 Hz), 7.20(1H, d, J=1.3 Hz), 7.31(1H, d, J=8.0 Hz).

(67-4) Synthesis of 2-amino-2-(2-{4-[3-(4-chloro-3-methylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 67-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 67-3 (355 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained pale-white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (433 mg) as a white powder.

MS(ESI)m/z: 446[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 1.97-2.04(2H, m), 2.28(3H, s), 2.62-2.58(2H, m), 2.70(2H, t, J=7.6 Hz), 3.52(4H, d, J=5.2 Hz), 4.04(2H, t, J=6.1 Hz), 5.40(2H, t, J=5.2 Hz), 7.03(1H, dd, J=8.3, 1.9 Hz), 7.16(1H, d, J=8.6 Hz), 7.18(1H, s), 7.31(1H, d, J=8.0 Hz), 7.43(1H, d, J=8.5 Hz), 7.47(1H, d, J=1.8 Hz), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(3-fluoro-4-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(68-1) Synthesis of 3-(3-fluoro-4-trifluoromethylphenyl)-2-propyne-1-ol (Compound 68-1)

A mixture of 2-fluoro-4-iodobenzotrifluoride (5.00 g), copper(I) iodide (65.5 mg), triphenylphosphine (226 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (356 mg), propargyl alcohol (1.12 ml), diisopropylethylamine (12.0 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.08 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.73(1H, t, J=6.2 Hz), 4.52(2H, d, J=6.2 Hz), 7.25(1H, d, J=10.0 Hz), 7.30(1H, d, J=8.2 Hz), 7.55(1H, t, J=7.7 Hz).

(68-2) Synthesis of 3-(3-fluoro-4-trifluoromethylphenyl)-1-propanol (Compound 68-2)

A solution of compound 68-1 (3.08 g) and 10% palladium carbon (1.50 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 8 hr. The reaction mixture was filtered through celite and concentrated to give the object product (2.83 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(1H, brs), 1.86-1.93(2H, m), 2.78(2H, t, J=7.8 Hz), 3.69(2H, t, J=6.2 Hz), 7.03-7.08(2H, m), 7.51(1H, t, J=7.7 Hz).

(68-3) Synthesis of 1-(3-bromopropyl)-3-fluoro-4-trifluoromethylbenzene (Compound 68-3)

Compound 68-2 (2.83 g) was dissolved in methylene chloride (42 ml), triphenylphosphine (3.67 g) and N-bromosuccinimide (2.56 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.87 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.11-2.18(2H, m), 2.82(2H, t, J=7.8 Hz), 3.53(2H, t, J=6.8 Hz), 7.29(1H, d, J=8.0 Hz), 7.41(1H, d, J=12.1 Hz), 7.70(1H, t, J=8.0 Hz).

(68-4) Synthesis of 2-amino-2-(2-{4-[3-(3-fluoro-4-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 68-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 68-3 (410 mg) were added, and the mixture was stirred at 80° C. for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (458 mg) as a white powder.

MS(ESI)m/z: 484[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.04-2.11(2H, m), 2.58-2.62(2H, m), 2.85(2H, t, J=7.6 Hz), 3.52(4H, d, J=5.1 Hz), 4.06(2H, t, J=6.1 Hz), 5.40(2H, t, J=5.1 Hz), 7.18(1H, d, J=8.5 Hz), 7.25(1H, d, J=8.0 Hz), 7.38(1H, d, J=12.2 Hz), 7.44(1H, d, J=8.5 Hz), 7.48(1H, s), 7.70(1H, t, J=8.0 Hz), 7.83(3H, brs).

2-amino-2-(2-{4-[3-(4-fluoro-3-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(69-1) Synthesis of 3-(4-fluoro-3-trifluoromethylphenyl)-2-propyne-1-ol (Compound 69-1)

A mixture of 2-fluoro-5-iodobenzotrifluoride (5.00 g), copper(I) iodide (65.5 mg), triphenylphosphine (226 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (356 mg), propargyl alcohol (1.12 ml), diisopropylethylamine (12.0 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.26 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.69(1H, t, J=6.2 Hz), 4.50(2H, d, J=6.2 Hz), 7.16(1H, t, J=9.3 Hz), 7.58-7.62(1H, m), 7.69(1H, dd, J=1.4, 6.8 Hz).

(69-2) Synthesis of 3-(4-fluoro-3-trifluoromethylphenyl)-1-propanol (Compound 69-2)

A solution of compound 69-1 (3.26 g) and 10% palladium carbon (1.50 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 8 hr. The reaction mixture was filtered through celite and concentrated to give the object product (3.01 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.33(1H, brs), 1.85-1.92(2H, m), 2.75(2H, t, J=7.8 Hz), 3.68(2H, t, J=6.2 Hz), 7.09-7.13(1H, m), 7.34-7.38(1H, m), 7.41-7.43(1H, m).

(69-3) Synthesis of 1-(3-bromopropyl)-4-fluoro-3-trifluoromethylbenzene (Compound 69-3)

Compound 69-2 (3.05 g) was dissolved in methylene chloride (46 ml), triphenylphosphine (4.00 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.86 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.08-2.15(2H, m), 2.79(2H, t, J=7.8 Hz), 3.51(2H, t, J=6.5 Hz), 7.43(1H, dd, J=10.5, 8.4 Hz), 7.59-7.64(2H, m).

(69-4) Synthesis of 2-amino-2-(2-{4-[3-(4-fluoro-3-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 69-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 69-3 (410 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (467 mg) as a white powder.

MS(ESI)m/z: 484[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.02-2.08(2H, m), 2.54-2.62(2H, m), 2.82(2H, t, J=7.6 Hz), 3.52(4H, d, J=5.2 Hz), 4.04(2H, t, J=6.1 Hz), 5.40(2H, t, J=5.2 Hz), 7.17(1H, d, J=8.6 Hz), 7.40-7.45(2H, m), 7.47(1H, d, J=1.8 Hz), 7.56-7.59(2H, m), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(2,3,4-trifluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(70-1) Synthesis of 3-(2,3,4-trifluorophenyl)-2-propyne-1-ol (Compound 70-1)

A mixture of 2,3,4-trifluoroiodobenzene (5.00 g), copper(I) iodide (73.9 mg), triphenylphosphine (254 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (402 mg), propargyl alcohol (1.26 ml), diisopropylethylamine (13.5 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 17 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue 5 was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.14 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.73(1H, t, J=6.3 Hz), 4.53(2H, d, J=6.3 Hz), 6.90-6.97(1H, m), 7.13-7.19(1H, m).

(70-2) Synthesis of 3-(2,3,4-trifluorophenyl)-1-propanol (Compound 70-2)

A solution of compound 70-1 (3.14 g) and 10% palladium carbon (1.50 g) in 1.4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated to give the object product (2.88 g) as a dark-green oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(1H, brs), 1.83-1.90(2H, m), 2.74(2H, t, J=7.6 Hz), 3.68(2H, t, J=6.2 Hz), 6.85-6.94(2H, m).

(70-3) Synthesis of 1-(3-bromopropyl)-2,3,4-trifluorobenzene (Compound 70-3)

Compound 70-2 (2.90 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (4.40 g) and N-bromosuccinimide (2.99 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.14 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.11-2.18(2H, m), 2.81(2H, t, J=7.3 Hz), 3.39(2H, t, J=6.4 Hz), 6.88-6.94(2H, m).

(70-4) Synthesis of [5-(2-{4-[3-(2,3,4-trifluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 70-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 70-3 (362 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (700 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.07-2.12(2H, m), 2.52-2.56(2H, m), 2.86(2H, t, J=7.4 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=5.8 Hz), 4.99(1H, brs), 6.82-6.89(3H, m), 7.26-7.28(1H, m), 7.37(1H, d, J=1.8 Hz).

(70-5) Synthesis of 2-amino-2-(2-{4-[3-(2,3,4-trifluorophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 70-5)

Compound 70-4 (700 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (520 mg) as a white powder.

MS(ESI)m/z: 452[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.97-2.05(2H, m), 2.58-2.63(2H, m), 2.80(2H, t, J=7.5 Hz), 3.52(4H, d, J=5.2 Hz), 4.07(2H, t, J=5.8 Hz), 5.40(2H, t, J=5.1 Hz), 7.12-7.18(2H, m), 7.24-7.26(1H, m), 7.45(1H, d, J=8.6 Hz), 7.47(1H, s), 7.85(3H, brs).

2-amino-2-(2-{4-[3-(2-chloro-4-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(71-1) Synthesis of 3-(2-chloro-4-trifluoromethylphenyl)-2-propyne-1-ol (Compound 71-1)

A mixture of 3-chloro-4-iodobenzotrifluoride (5.00 g), copper(I) iodide (62.1 mg), triphenylphosphine (214 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (337 mg), propargyl alcohol (1.06 ml), diisopropylethylamine (11.4 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 17 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.05 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.74(1H, t, J=6.3 Hz), 4.58(2H, d, J=6.3 Hz), 7.48(1H, d, J=8.5 Hz), 7.59(1H, d, J=8.1 Hz), 7.67(1H, s).

(71-2) Synthesis of 3-(2-chloro-4-trifluoromethylphenyl)-1-propanol (Compound 71-2)

A suspension of Compound 71-1 (3.05 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 65° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-70:30) to give the object product (2.52 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.35(1H, t, J=4.8 Hz), 1.87-1.94(2H, m), 2.90(2H, t, J=7.8 Hz), 3.71(2H, q, J=5.6 Hz), 7.37(1H, d, J=8.0 Hz), 7.45(1H, d, J=8.0 Hz), 7.62(1H, s).

(71-3) Synthesis of 1-(3-bromopropyl)-2-chloro-4-trifluoromethylbenzene (Compound 71-3)

Compound 71-2 (2.48 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.00 g) and N-bromosuccinimide (2.03 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 16 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.79 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.16-2.23(2H, m), 2.97(2H, t, J=7.5 Hz), 3.43(2H, t, J=6.4 Hz), 7.39(1H, d, J=8.0 Hz), 7.46(1H, d, J=8.0 Hz), 7.62(1H, s).

(71-4) Synthesis of [5-(2-{4-[3-(2-chloro-4-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 71-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 71-3 (431 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (790 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.93-1.99(2H, m), 2.12-2.23(2H, m), 2.52-2.57(2H, m), 3.02(2H, brt, J=6.6 Hz), 3.70(2H, d, J=11.6 Hz), 3.89(2H, d, J=11.6 Hz), 4.02(2H, brs), 5.00(1H, brs), 6.85(1H, d, J=8.4 Hz), 7.26-7.28(1H, m), 7.33-7.45(3H, m), 7.64(1H, brs).

(71-5) Synthesis of 2-amino-2-(2-{4-[3-(2-chloro-4-trifluoromethylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 71-5)

Compound 71-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.

MS(ESI)m/z: 500[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.02-2.08(2H, m), 2.58-2.63(2H, m), 3.06(2H, t, J=7.7 Hz), 3.52(4H, d, J=5.0 Hz), 4.12(2H, t, J=5.8 Hz), 5.40(2H, t, J=5.1 Hz), 7.19(1H, J=8.5 Hz), 7.45(1H, d, J=8.5 Hz), 7.48(1H, s), 7.57(1H, d, J=8.0 Hz), 7.68(1H, d, J=7.5 Hz), 7.77-7.89(4H, m).

2-amino-2-(2-{4-[3-(4-cyanophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(72-1) Synthesis of 3-(4-cyanophenyl)-2-propyne-1-ol (Compound 72-1)

A mixture of 4-iodobenzonitrile (10.0 g), copper(I) iodide (166 mg), triphenylphosphine (572 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (904 mg), propargyl alcohol (2.83 ml), diisopropylethylamine (30.5 ml) and tetrahydrofuran (170 ml) was stirred at room temperature for 23 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-67:33) to give the object product (5.79 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.72(1H, t, J=6.2 Hz), 4.53(2H, d, J=6.2 Hz), 7.52(2H, d, J=8.2 Hz), 7.61(2H, d, J=8.2 Hz).

(72-2) Synthesis of 3-(4-cyanophenyl)-1-propanol (Compound 72-2)

A suspension of Compound 72-1 (5.79 g) and chlorotris(triphenylphosphine)rhodium(I) (5.00 g) in toluene (150 ml) was stirred under a hydrogen atmosphere at 65° C. for 15 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-50:50) to give the object product (4.20 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.36(1H, brs), 1.86-1.93(2H, m), 2.79(2H, t, J=7.8 Hz), 3.68(2H, t, J=6.2 Hz), 7.31(2H, d, J=8.2 Hz), 7.58(2H, d, J=8.2 Hz).

(72-3) Synthesis of 1-(3-bromopropyl)-4-cyanobenzene (Compound 72-3)

Compound 72-2 (4.22 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (7.58 g) and N-bromosuccinimide (5.14 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (5.37 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.14-2.21(2H, m), 2.86(2H, t, J=7.5 Hz), 3.39(2H, t, J=6.5 Hz), 7.32(2H, d, J=8.2 Hz), 7.60(2H, d, J=8.2 Hz).

(72-4) Synthesis of [5-(2-{4-[3-(4-cyanophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 72-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 72-3 (321 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (750 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.94-1.98(2H, m), 2.04-2.13(2H, m), 2.52-2.57(2H, m), 2.91(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=5.8 Hz), 5.00(1H, brs), 6.86(1H, d, J=8.5 Hz), 7.27-7.32(3H, m), 7.38(1H, d, J=1.8 Hz), 7.56-7.60(2H, m).

(72-5) Synthesis of 2-amino-2-(2-{4-[3-(4-cyanophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 72-5)

Compound 72-4 (750 mg) was dissolved in a mixed solvent of ethanol (10 ml) and methanol (10 ml), p-toluenesulfonic acid monohydrate (0.041 g) was added, and the mixture was stirred at room temperature for 4.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in methylene chloride (15 ml) was added hydrogen chloride containing dioxane (4 mol/l, 5 ml), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (390 mg) as a white powder.

MS(ESI)m/z: 423[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.02-2.06(2H, m), 2.58-2.63(2H, m), 2.83(2H, t, J=7.5 Hz), 3.52(4H, d, J=5.2 Hz), 4.03(2H, t, J=6.1 Hz), 5.36(2H, t, J=5.1 Hz), 7.17(1H, d, J=8.6 Hz), 7.40-7.48(4H, m), 7.76(2H, d, J=8.0 Hz), 7.84(3H, brs).

2-amino-2-(2-{4-[3-(1-naphthyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(73-1) Synthesis of 3-(1-naphthyl)-1-propanol (Compound 73-1)

3-(1-Naphthyl) acrylic acid (5.00 g) was dissolved in methanol (30 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (2.40 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 13 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a white solid (5.00 g. The white solid was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 27.4 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 18 hr. To the reaction mixture was added water, and 1M aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (4.70 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.32(1H, brs), 2.00-2.07(2H, m), 3.19(2H, t, J=7.5 Hz), 3.73-3.78(2H, m), 7.34-7.42(2H, m), 7.47-7.52(2H, m), 7.72(1H, d, J=8.2 Hz), 7.84-7.87(1H, m), 8.07(1H, d, J=8.2 Hz).

(73-2) Synthesis of 1-(3-bromopropyl)naphthalene (Compound 73-2)

Compound 73-1 (4.70 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (7.13 g) and N-bromosuccinimide (4.84 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (5.67 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.27-2.34(2H, m), 3.26(2H, t, J=7.4 Hz), 3.47(2H, t, J=6.5 Hz), 7.35-7.43(2H, m), 7.46-7.55(2H, m), 7.74(1H, d, J=7.8 Hz), 7.87(1H, d, J=7.8 Hz), 8.05(1H, d, J=8.3 Hz).

(73-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(1-naphthyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 73-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 73-2 (356 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (620 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.94-1.99(2H, m), 2.22-2.28(2H, m), 2.53-2.57(2H, m), 3.31(2H, t, J=7.6 Hz), 3.70(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.06(2H, t, J=5.7 Hz), 5.00(1H, brs), 6.85(1H, d, J=8.5 Hz), 7.25-7.28(1H, m), 7.32-7.40(3H, m), 7.45-7.53(2H, m), 7.72(1H, d, J=7.9 Hz), 7.84-7.87(1H, m), 8.12(1H, d, J=7.9 Hz).

(73-4) Synthesis of 2-amino-2-(2-{4-[3-(1-naphthyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 73-4)

Compound 73-3 (620 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (490 mg) as a white powder.

MS(ESI)m/z: 448[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.76-1.80(2H, m), 2.09-2.14(2H, m), 2.60-2.65(2H, m), 3.21-3.25(2H, m), 3.53(4H, d, J=5.1 Hz), 4.15(2H, t, J=5.8 Hz), 5.42(2H, t, J=5.1 Hz), 7.19(1H, d, J=8.6 Hz), 7.36(1H, d, J=6.7 Hz), 7.41-7.47(2H, m), 7.50-7.54(3H, m), 7.79(1H, d, J=8.2 Hz), 7.87(3H, brs), 7.92-7.94(1H, m), 8.10-8.13(1H, m).

2-amino-2-(2-{4-[3-(morpholin-4-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol dihydrochloride

(74-1) Synthesis of 2-amino-2-(2-{4-[3-(morpholin-4-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol dihydrochloride (Compound 74-1)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.27 ml), 4-(3-hydroxypropyl)morpholine (0.347 ml) and Reference Example compound 2-6 (500 mg) were added, and the mixture was stirred at room temperature for 4.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated and 500 mg of the obtained residue (1 g) was purified by HPLC. The obtained residue was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 5 ml), and the precipitate was collected by filtration and dried to give the object product (80 mg) as a white powder.

MS (ESI)m/z: 407[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.18-2.29(2H, m), 2.60-2.66(2H, m), 3.00-3.11(2H, m), 3.12-3.20(2H, m), 3.34-3.44(2H, m), 3.52(4H, s), 3.80-3.86(2H, m), 3.97(2H, J=11.3 Hz), 4.18(2H, t, J=6.0 Hz), 5.41(2H, brs), 7.22(1H, J=9.2 Hz), 7.47-7.49(2H, m), 7.90(3H, brs), 11.3(1H, brs).

2-amino-2-(2-{4-[3-(3-cyanophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(75-1) Synthesis of 3-(3-cyanophenyl)-2-propyne-1-ol (Compound 75-1)

A mixture of 3-iodobenzonitrile (10.0 g), copper(I) iodide (166 mg), triphenylphosphine (572 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (904 mg), propargyl alcohol (2.83 ml), diisopropylethylamine (30.5 ml) and tetrahydrofuran (170 ml) was stirred at room temperature for 23 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-67:33) to give the object product (5.59 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.76(1H, t, J=6.2 Hz), 4.51(2H, d, J=6.2 Hz), 7.44(1H, t, J=7.8 Hz), 7.61(1H, d, J=7.8 Hz), 7.65(1H, d, J=7.8 Hz), 7.71(1H, s).

(75-2) Synthesis of 3-(3-cyanophenyl)-1-propanol (Compound 75-2)

A suspension of compound 75-1 (5.59 g) and chlorotris(triphenylphosphine)rhodium(I) (5.00 g) in toluene (110 ml) was stirred under a hydrogen atmosphere at 65° C. for 15 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-50:50) to give the object product (4.24 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.41(1H, brs), 1.86-1.93(2H, m), 2.77(2H, t, J=7.8 Hz), 3.68(2H, t, J=6.3 Hz), 7.37-7.41(1H, m), 7.44-7.46(1H, m), 7.49-7.50(2H, m).

(75-3) Synthesis of 1-(3-bromopropyl)-3-cyanobenzene (Compound 75-3)

Compound 75-2 (4.45 g) was dissolved in methylene chloride (95 ml), triphenylphosphine (8.13 g) and N-bromosuccinimide (5.51 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the object product (5.44 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 2.09-2.16(2H, m), 2.77(2H, t, J=7.8 Hz), 3.51(2H, t, J=6.8 Hz), 7.51(1H, t, J=7.6 Hz), 7.59(1H, d, J=7.8 Hz), 7.68(1H, d, J=7.5 Hz), 7.72(1H, s).

(75-4) Synthesis of [3-{4-[3-(3-cyanophenyl)propoxy]-3-trifluoromethylphenyl}-1,1-bis(hydroxymethyl)propyl]carbamic acid t-butyl ester (Compound 75-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 75-3 (320 mg) were added, and the mixture was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained white solid was dissolved in a mixed solvent of ethanol (6 ml) and methanol (4 ml), p-toluenesulfonic acid monohydrate (41 mg) was added, and the mixture was stirred at room temperature for 7 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (480 mg) as a white solid.

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.62(9H, s), 2.01-2.05(2H, m), 2.21-2.30(2H, m), 3.03(2H, t, J=7.8 Hz), 3.65(2H, dd, J=10.6, 5.6 Hz), 3.74(2H, dd, J=10.6, 5.6 Hz), 4.24-4.28(2H, m), 4.84(2H, t, J=5.8 Hz), 6.28(1H, brs), 7.36(1H, d, J=8.5 Hz), 7.60(1H, d, J=8.5 Hz), 7.63(1H, s), 7.72(1H, t, J=7.7 Hz), 7.78(1H, d, J=7.8 Hz), 7.89(1H, d, J=7.3 Hz), 7.92(1H, s).

(75-5) Synthesis of 2-amino-2-(2-{4-[3-(3-cyanophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 75-5)

To compound 75-4 (100 mg) was added hydrogen chloride-containing dioxane (4 mol/2 ml), and the mixture was stirred at room temperature for 2 hr. The precipitate was collected by filtration, and dried to give the object product (70 mg) as a white powder.

MS(ESI)m/z: 423[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.02-2.09(2H, m), 2.57-2.62(2H, m), 2.80(2H, t, J=7.8 Hz), 3.51(4H, d, J=5.0 Hz), 4.05(2H, t, J=6.2 Hz), 5.39(2H, t, J=5.2 Hz), 7.17(1H, d, J=8.5 Hz), 7.44(1H, d, J=8.6 Hz), 7.47-7.49(1H, m), 7.51(1H, d, J=7.5 Hz), 7.56(1H, d, J=7.8 Hz), 7.67-7.69(2H, m), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(2,3-dihydrobenzofuran-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(76-1) Synthesis of 3-(2,3-dihydrobenzofuran-5-yl)-1-propanol (Compound 76-1)

3-(2,3-Dihydrobenzofuran-5-yl)propionic acid (2.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 11.5 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 16 hr. Water was added to the reaction mixture, and 1M aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (1.91 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.21-1.26(1H, m), 1.82-1.89(2H, m), 2.63(2H, t, J=7.6 Hz), 3.18(2H, t, J=8.6 Hz), 3.65(2H, q, J=6.2 Hz), 4.54(2H, t, J=8.7 Hz), 6.71(1H, d, J=8.2 Hz), 6.93(1H, d, J=7.7 Hz), 7.03(1H, brs).

(76-2) Synthesis of 5-(3-bromopropyl)-2,3-dihydrobenzofuran (Compound 76-2)

Compound 76-1 (1.91 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.97 g) and N-bromosuccinimide (2.01 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (2.31 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.08-2.16(2H, m), 2.70(2H, t, J=7.3 Hz), 3.18(2H, t, J=8.7 Hz), 3.39(2H, t, J=6.5 Hz), 4.55(2H, t, J=8.7 Hz), 6.71(1H, d, J=8.0 Hz), 6.92(1H, d, J=8.0 Hz), 7.03(1H, brs).

(76-3) Synthesis of [5-(2-{4-[3-(2,3-dihydrobenzofuran-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 76-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 76-2 (345 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.14(2H, m), 2.51-2.56(2H, m), 2.75(2H, t, J=7.5 Hz), 3.17(2H, t, J=8.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.98(2H, t, J=6.0 Hz), 4.51-4.57(2H, m), 4.99(1H, brs), 6.69(1H, d, J=8.0 Hz), 6.85(1H, d, J=8.5 Hz), 6.92(1H, d, J=8.0 Hz), 7.03(1H, brs), 7.24-7.27(1H, m), 7.36(1H, brd, J=1.7 Hz).

(76-4) Synthesis of 2-amino-2-(2-{4-[3-(2,3-dihydrobenzofuran-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 76-4)

Compound 76-3 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (500 mg) as a white powder.

MS(ESI)m/z: 440[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.92-1.99(2H, m), 2.59-2.67(4H, m), 3.12(2H, t, J=8.6 Hz), 3.52(4H, brs), 4.03(2H, t, J=5.8 Hz), 4.47(2H, t, J=8.6 Hz), 5.40(2H, brs), 6.65(1H, d, J=8.2 Hz), 6.87(1H, d, J=8.2 Hz), 7.05(1H, brs), 7.15(1H, d, J=8.6 Hz), 7.44(1H, d, J=8.6 Hz), 7.48(1H, brs), 7.84(3H, brs).

2-amino-2-(2-{4-[3-(biphenyl-4-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(77-1) Synthesis of 3-(4-biphenyl)-2-propyne-1-ol (Compound 77-1)

A mixture of 4-iodobiphenyl (5.00 g), copper(I) iodide (68.0 mg), triphenylphosphine (234 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (370 mg), propargyl alcohol (1.16 ml), diisopropylethylamine (12.4 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 17 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-60:40) to give the object product (3.88 g) as a brown solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.65(1H, t, J=6.2 Hz), 4.53(2H, d, J=6.2 Hz), 7.34-7.38(1H, m), 7.45(2H, t, J=7.7 Hz), 7.50-7.52(2H, m), 7.55-7.57(2H, m), 7.58-7.60(2H, m).

(77-2) Synthesis of 3-(4-biphenyl)-1-propanol (Compound 77-2)

A solution of compound 77-1 (3.88 g) and 10% palladium carbon (1.94 g) in 1,4-dioxane (120 ml) was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-60:40) to give the object product (2.09 g) as a white powder.

1 H-NMR(CDCl 3 ) δ (ppm): 1.29(1H, t, J=4.9 Hz), 1.90-1.98(2H, m), 2.76(2H, t, J=7.7 Hz), 3.72(2H, q, J=5.9 Hz), 7.28(2H, d, J=8.0 Hz), 7.31-7.35(1H, m), 7.43(2H, t, J=7.7 Hz), 7.52-7.54(2H, m), 7.57-7.59(2H, m).

(77-3) Synthesis of 4-(3-bromopropyl)biphenyl (Compound 77-3)

Compound 77-2 (2.02 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.75 g) and N-bromosuccinimide (1.87 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 20 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.40 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.17-2.24(2H, m), 2.82(2H, t, J=7.4 Hz), 3.43(2H, t, J=6.5 Hz), 7.25-7.29(3H, m), 7.31-7.35(1H, m), 7.43(1H, t, J=7.7 Hz), 7.52-7.54(2H, m), 7.57-7.59(2H, m).

(77-4) Synthesis of [5-(2-{4-[3-(biphenyl-4-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 77-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 77-3 (394 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (870 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.13-2.16(2H, m), 2.52-2.57(2H, m), 2.88(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.02(2H, t, J=5.9 Hz), 5.00(1H, brs), 6.85(1H, d, J=8.5 Hz), 7.24-7.29(3H, m), 7.30-7.40(2H, m), 7.41-7.45(2H, m), 7.50-7.54(2H, m), 7.57-7.59(2H, m).

(77-5) Synthesis of 2-amino-2-(2-{4-[3-(biphenyl-4-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 77-5)

Compound 77-4 (870 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.

MS(ESI)m/z: 474[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.75-1.80(2H, m), 2.02-2.09(2H, m), 2.59-2.64(2H, m), 2.80(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.7 Hz), 4.08(2H, t, J=5.9 Hz), 5.40(2H, t, J=5.0 Hz), 7.18(1H, d, J=8.6 Hz), 7.30(2H, d, J=8.2 Hz), 7.34(1H, t, J=7.5 Hz), 7.24-7.47(3H, m), 7.49(1H, brs), 7.59(2H, d, J=8.2 Hz), 7.64(2H, d, J=7.5 Hz), 7.85(3H, brs).

2-amino-2-(2-{4-[2-(2-naphthyl)ethoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(78-1) Synthesis of 2-amino-2-(2-{4-[2-(2-naphthyl)ethoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 78-1)

Triphenylphosphine (1.25 g) was dissolved in tetrahydrofuran (20 ml), diisopropyl azodicarboxylate (40% toluene solution, 2.51 ml), 2-naphthaleneethanol (838 mg) and Reference Example compound 2-6 (1.00 g) were added, and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2.0 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (790 mg) as a white powder.

MS(ESI)m/z: 434[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.72-1.77(2H, m), 2.57-2.61(2H, m), 3.20(2H, t, J=6.5 Hz), 3.50(4H, d, J=4.5 Hz), 4.37(2H, t, J=6.5 Hz), 5.37(2H, t, J=4.9 Hz), 7.24(1H, d, J=8.4 Hz), 7.43-7.51(5H, m), 7.77(3H, brs), 7.81-7.89(4H, m).

2-amino-2-(2-{4-[3-(biphenyl-3-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(79-1) Synthesis of 1-(3-biphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 79-1)

A mixture of 3-bromobiphenyl (5.00 g), cesium carbonate (18.2 g), 2-(2-propynyloxy)tetrahydropyran (4.53 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (615 mg), bis(acetonitrile)palladium(II) dichloride (111 mg) and acetonitrile (90 ml) was stirred at 90° C. for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.90 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.53-1.72(4H, m), 1.75-1.91(2H, m), 3.55-3.61(1H, m), 3.88-3.93(1H, m), 4.49(1H, d, J=15.7 Hz), 4.54(1H, d, J=15.7 Hz), 4.92(1H, t, J=3.4 Hz), 7.34-7.40(2H, m), 7.42-7.46(3H, m), 7.53-7.58(3H, m), 7.69-7.70(1H, m).

(79-2) Synthesis of 1-(3-biphenyl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 79-2)

A solution of compound 79-1 (1.90 g) and 10% palladium carbon (0.95 g) in 1,4-dioxane (40 ml) was stirred under a hydrogen atmosphere at room temperature for 15 hr. The reaction mixture was filtered through celite and concentrated to give the object product (1.94 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.50-1.64(4H, m), 1.70-1.77(1H, m), 1.81-1.89(1H, m), 1.98(2H, quint, J=7.2 Hz), 2.72-2.84(2H, m), 3.41-3.53(2H, m), 3.81(1H, dt, J=9.8, 6.5 Hz), 3.85-3.91(1H, m), 4.59(1H, t, J=3.6 Hz), 7.18-7.20(1H, m), 7.31-7.37(2H, m), 7.41-7.45(4H, m), 7.58-7.60(2H, m).

(79-3) Synthesis of 3-(3-biphenyl)-1-propanol (Compound 79-3)

A solution of compound 79-2 (1.94 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (20 ml) was stirred at room temperature for 17 hr. To the reaction mixture was added triethylamine (0.10 ml), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-70:30) to give the object product (1.24 g) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.34(1H, brs), 1.91-1.99(2H, m), 2.78(2H, t, J=7.7 Hz), 3.71(2H, t, J=6.4 Hz), 7.19-7.20(1H, m), 7.32-7.38(2H, m), 7.42-7.46(4H, m), 7.58-7.60(2H, m).

(79-4) Synthesis of 3-(3-bromopropyl)biphenyl (Compound 79-4)

Compound 79-3 (1.23 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.67 g) and N-bromosuccinimide (1.13 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.49 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.18-2.26(2H, m), 2.85(2H, t, J=7.3 Hz), 3.43(2H, t, J=6.5 Hz), 7.19(1H, d, J=7.5 Hz), 7.33-7.39(2H, m), 7.42-7.46(4H, m), 7.57-7.60(2H, m).

(79-5) Synthesis of [5-(2-{4-[3-(biphenyl-3-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 79-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 79-4 (394 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (810 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.14-2.18(2H, m), 2.51-2.56(2H, m), 2.90(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.02(2H, t, J=5.9 Hz), 5.00(1H, brs), 6.85(1H, d, J=8.5 Hz), 7.19(1H, d, J=7.4 Hz), 7.24-7.27(1H, m), 7.33-7.40(2H, m), 7.41-7.46(5H, m), 7.53-7.60(2H, m).

(79-6) Synthesis of 2-amino-2-(2-{4-[3-(biphenyl-3-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 79-6)

Compound 79-5 (810 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (530 mg) as a white powder.

MS(ESI)m/z: 474[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.04-2.12(2H, m), 2.59-2.63(2H, m), 2.83(2H, t, J=7.4 Hz), 3.52(4H, d, J=4.6 Hz), 4.07(2H, t, J=5.9 Hz), 5.40(2H, t, J=4.9 Hz), 7.18(2H, t, J=9.0 Hz), 7.33-7.49(8H, m), 7.58(2H, d, J=7.4 Hz), 7.78(3H, brs).

2-amino-2-(2-{4-[3-(benzothiophen-3-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(80-1) Synthesis of 1-(3-benzothienyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 80-1)

A mixture of 3-bromobenzothiophene(5.00 g), cesium carbonate (20.0 g), 2-(2-propynyloxy)tetrahydropyran (4.96 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (672 mg), bis(acetonitrile)palladium(II) dichloride (122 mg) and acetonitrile (100 ml) was stirred at 90° C. for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.19 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.52-1.73(4H, m), 1.76-1.92(2H, m), 3.57-3.62(1H, m), 3.90-3.95(1H, m), 4.57(1H, d, J=15.8 Hz), 4.59(1H, d, J=15.8 Hz), 4.97(1H, t, J=3.4 Hz), 7.39(1H, t, J=7.3 Hz), 7.42-7.46(1H, m), 7.63(1H, s), 7.84(1H, d, J=7.8 Hz), 7.95(1H, d, J=8.0 Hz).

(80-2) Synthesis of 1-(3-benzothienyl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 80-2)

A solution of compound 80-1 (2.19 g) and 10% palladium carbon (1.10 g) in 1,4-dioxane (70 ml) was stirred under a hydrogen atmosphere at room temperature for 9 hr. The reaction mixture was filtered through celite and concentrated to give the object product (2.04 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.51-1.65(4H, m), 1.71-1.78(1H, m), 1.82-1.90(1H, m), 2.06(2H, quint, J=7.0 Hz), 2.89-3.02(2H, m), 3.46-3.54(2H, m), 3.83-3.92(2H, m), 4.59-4.61(1H, m), 7.11(1H, s), 7.32-7.40(2H, m), 7.76-7.78(1H, m), 7.86(1H, d, J=8.2 Hz).

(80-3) Synthesis of 3-(3-benzothienyl)-1-propanol (Compound 80-3)

A solution of compound 80-2 (2.04 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (80 ml) was stirred at room temperature for 20 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (1.48 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.37(1H, brs), 2.03(2H, quint, J=7.0 Hz), 2.96(2H, t, J=7.6 Hz), 3.75(2H, t, J=5.7 Hz), 7.12(1H, s), 7.32-7.41(2H, m), 7.77(1H, dd, J=1.2, 7.3 Hz), 7.86(1H, dd, J=1.2, 7.3 Hz).

(80-4) Synthesis of 3-(3-bromopropyl)benzothiophene (Compound 80-4)

Compound 80-3 (1.46 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.19 g) and N-bromosuccinimide (1.49 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.64 g) as a pale-yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.25-2.33(2H, m), 3.05(2H, t, J=7.3 Hz), 3.47(2H, t, J=6.4 Hz), 7.16(1H, s), 7.33-7.42(2H, m), 7.77(1H, d, J=7.5 Hz), 7.87(1H, dd, J=7.5, 1.0 Hz).

(80-5) Synthesis of [5-(2-{4-[3-(benzothiophen-3-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 80-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 80-4 (365 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (800 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.48(9H, s), 1.93-1.98(2H, m), 2.21-2.27(2H, m), 2.52-2.57(2H, m), 3.09(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.05(2H, t, J=5.8 Hz), 5.00(1H, brs), 6.85(1H, d, J=8.5 Hz), 7.11(1H, brs), 7.24-7.28(1H, m), 7.33-7.40(3H, m), 7.77-7.80(1H, m), 7.84-7.87(1H, m).

(80-6) Synthesis of 2-amino-2-(2-{4-[3-(benzothiophen-3-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 80-6)

Compound 80-5 (800 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.

MS(ESI)m/z: 454[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.11-2.18(2H, m), 2.59-2.64(2H, m), 3.00(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.4 Hz), 4.16(2H, t, J=5.9 Hz), 5.40(2H, t, J=4.7 Hz), 7.19(1H, t, J=8.5 Hz), 7.35-7.40(2H, m), 7.41-7.46(2H, m), 7.49(1H, brs), 7.78-7.87(4H, m), 7.97-8.00(1H, m).

2-amino-2-(2-{4-[3-(4-cyclopropylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(81-1) Synthesis of [5-(2-{4-[3-(4-cyclopropylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 81-1)

Compound 41-4 (500 mg) was dissolved in tetrahydrofuran (1.6 ml), tripotassium phosphate (430 mg), palladium acetate (9.0 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (17 mg), cyclopropylboronic acid (85 mg) and water (40 μl) were added, and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (440 mg) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.57-0.62(2H, m), 0.87-0.92(2H, m), 1.31(3H, s), 1.32(3H, s), 1.40(9H, s), 1.82-1.87(1H, m), 1.91-1.99(4H, m), 2.44-2.50(2H, m), 2.68(2H, t, J=7.2 Hz), 3.66(2H, d, J=11.5 Hz), 3.88(2H, d, J=11.1 Hz), 4.01(2H, t, J=5.4 Hz), 6.66(1H, brs), 6.98(2H, d, J=7.5 Hz), 7.06(2H, d, J=7.7 Hz), 7.12(1H, d, J=8.1 Hz), 7.36-7.39(2H, m).

(81-2) Synthesis of 2-amino-2-(2-{4-[3-(4-cyclopropylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 81-2)

Compound 81-1 (440 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (300 mg) as a white powder.

MS(ESI)m/z: 438[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.61(2H, dd, J=9.6, 5.4 Hz), 0.90(2H, dd, J=13.1, 5.4 Hz), 1.74-1.78(2H, m), 1.86(1H, ddd, J=13.4, 9.0, 5.4 Hz), 1.98(2H, quint, J=6.8 Hz), 2.58-2.62(2H, m), 2.68(2H, t, J=7.4 Hz), 3.52(4H, d, J=4.7 Hz), 4.02(2H, t, J=5.8 Hz), 5.40(2H, t, J=4.7 Hz), 6.98(2H, d, J=7.8 Hz), 7.06(2H, d, J=7.8 Hz), 7.15(1H, d, J=8.6 Hz), 7.43(1H, d, J=8.7 Hz), 7.48(1H, s), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(indan-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (82-1) Synthesis of 3-(indan-5-yl)propanol (Compound 82-1)

Compound 56-2 (4.20 g) was dissolved in tetrahydrofuran (100 ml), and lithium borohydride (1.33 g) was added under ice-cooling. The mixture was warmed to room temperature and stirred at 80° C. for 5 hr. The reaction mixture was added to (1M hydrogen chloride-containing dioxane:diisopropyl alcohol=1:3, 50 ml), and the mixture was stirred at 50° C. for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 ml), p-toluenesulfonic acid monohydrate (0.040 g) was added, and the mixture was stirred at 50° C. for 24 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.41 g) as a colorless oil. The obtained object product contained 3-(3H-inden-5-yl)propanol in about 40%.

1 H-NMR(CDCl 3 ) δ (ppm): 1.23-1.29(1H, m), 1.85-1.94(2H, m), 2.02-2.10(2H, m), 2.65-2.70(2H, m), 2.85-2.90(4H, m), 3.66-3.70(2H, m), 6.97(1H, d, J=7.3 Hz), 7.08(1H, brs), 7.32(1H, d, J=7.8 Hz).

(82-2) Synthesis of 5-(3-bromopropyl)indane (Compound 82-2)

The compound (1.41 g) obtained in Example (82-1) was dissolved in methylene chloride (30 ml), triphenylphosphine (2.31 g) and N-bromosuccinimide (1.57 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (700 mg) as a colorless oil. The obtained compound contained 5-(3-bromopropyl)-3H-inden in about 40%.

1 H-NMR(CDCl 3 ) δ (ppm): 2.02-2.08(2H, m), 2.10-2.19(2H, m), 2.74(2H, t, J=7.3 Hz), 2.81-2.90(4H, m), 3.38-3.42(2H, m), 6.96(1H, d, J=7.6 Hz), 7.07(1H, brs), 7.15(1H, d, J=7.6 Hz).

(82-3) Synthesis of 2-amino-2-(2-{4-[3-(indan-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 82-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylfonnamide (10 ml), potassium carbonate (494 mg) and the compound (342 mg) obtained in Example (82-2) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was dissolved in methanol (20 ml), 10% palladium carbon (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hr. The reaction container was purged with nitrogen, and the solution was filtered. The filtrate was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.

MS(ESI)m/z: 438[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.94-2.01(4H, m), 2.59-2.63(2H, m), 2.69(2H, t, J=7.5 Hz), 2.77-2.82(4H, m), 3.52(4H, d, J=4.9 Hz), 4.03(2H, t, J=6.0 Hz), 5.40(2H, t, J=5.0 Hz), 6.92(1H, d, J=7.6 Hz), 7.05(1H, brs), 7.10-7.17(2H, m), 7.44(1H, d, J=8.6 Hz), 7.48(1H, brs), 7.86(3H, brs).

2-amino-2-(2-{4-[3-(2-methyl-4-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(83-1) Synthesis of 1-(2-methylthiophen-4-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 83-1)

A mixture of 4-bromo-2-methylthiophene(5.00 g), cesium carbonate (23.9 g), 2-(2-propynyloxy)tetrahydropyran (5.96 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (806 mg), bis(acetonitrile)palladium(II) dichloride (147 mg) and acetonitrile (90 ml) was stirred at 90° C. for 11 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (1.48 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.53-1.69(4H, m), 1.72-1.89(2H, m), 2.44(3H, s), 3.53-3.58(1H, m), 3.85-3.91(1H, m), 4.43(1H, d, J=15.8 Hz), 4.47(1H, d, J=15.8 Hz), 4.88(1H, t, J=3.3 Hz), 6.76(1H, s), 7.21(1H, s).

(83-2) Synthesis of 1-(2-methylthiophen-4-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propane (Compound 83-2)

A solution of compound 83-1 (1.48 g) and 10% palladium carbon (0.75 g) in 1,4-dioxane (40 ml) was stirred under a hydrogen atmosphere at room temperature for 15 hr. The reaction mixture was filtered through celite and concentrated to give the object product (1.47 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.51-1.62(4H, m), 1.69-1.76(1H, m), 1.80-1.93(3H, m), 2.45(3H, s), 2.61-2.67(2H, m), 3.41(1H, dt, J=9.9, 6.4 Hz), 3.47-3.53(1H, m), 3.77(1H, dt, J=9.8, 6.5 Hz), 3.84-3.90(1H, m), 4.57-4.58(1H, m), 6.61(1H, s), 6.68(1H, s).

(83-3) Synthesis of 1-(2-methylthiophen-4-yl)-1-propanol (Compound 83-3)

A solution of compound 83-2 (1.47 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (20 ml) was stirred at room temperature for 17 hr. Triethylamine (0.10 ml) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-70:30) to give the object product (0.73 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.29(1H, brs), 1.83-1.90(2H, m), 2.45(3H, s), 2.64(2H, t, J=7.6 Hz), 3.68(2H, t, J=6.3 Hz), 6.61(1H, s), 6.69(1H, s).

(83-4) Synthesis of 4-(3-bromopropyl)-2-methylthiophene (Compound 83-4)

Compound 83-3 (720 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.33 g) and N-bromosuccinimide (0.902 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (840 mg) as a colorless oil. The obtained object product contained 2-bromo-3-(3-bromopropyl)-5-methylthiophene in about 15%.

1 H-NMR(CDCl 3 ) δ (ppm): 2.09-2.16(2H, m), 2.45(3H, s), 2.70(2H, t, J=7.2 Hz), 3.39-3.42(2H, m), 6.60(1H, s), 6.72(1H, s).

(83-5) Synthesis of 2-amino-2-(2-{4-[3-(2-methyl-4-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 83-5)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and the compound (313 mg) obtained in Example (83-4) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 ml), p-toluenesulfonic acid monohydrate (0.041 g) was added, and the mixture was stirred at room temperature for 12.5 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in methylene chloride (15 ml) was added hydrogen chloride containing dioxane (4 mol/l, 5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was separated by HPLC using NOVApack (registered trade mark) HR C18 (0.05% trifluoroacetic acid-water/acetonitrile), a main component peak (primary peak with a shorter retention time) was collected and the obtained residue was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (260 mg) as a white powder.

MS(ESI)m/z: 418[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.96-2.02(2H, m), 2.39(3H, s), 2.59-2.67(4H, m), 3.52(4H, d, J=4.6 Hz), 4.05(2H, t, J=6.1 Hz), 5.40(2H, t, J=4.9 Hz), 6.68(1H, s), 6.85(1H, s), 7.16(1H, d, J=8.5 Hz), 7.46(1H, d, J=8.5 Hz), 7.48(1H, d, J=1.7 Hz), 7.85(3H, brs).

2-amino-2-(2-{4-[3-(2-bromo-5-methyl-3-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(84-1) Synthesis of 2-amino-2-(2-{4-[3-(2-bromo-5-methyl-3-thienyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 84-1)

In the purification by HPLC in Example (83-5), a sub-component peak (secondary peak with a longer retention time) was collected and the obtained residue was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 10 ml), and the precipitate was collected by filtration and dried to give the object product (40 mg) as a pale-yellow powder.

MS(ESI)m/z: 496, 498[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.72-1.77(2H, m), 1.91-1.99(2H, m), 2.45(3H, s), 2.54-2.67(4H, m), 3.50(4H, d, J=4.4 Hz), 4.06(2H, t, J=5.9 Hz), 5.36(2H, brs), 6.67(1H, s), 7.17(1H, d, J=8.6 Hz), 7.44(1H, d, J=8.6 Hz), 7.47(1H, brs), 7.65(3H, brs).

2-amino-2-(2-{4-[3-(3-cyclopropylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(85-1) Synthesis of [5-(2-{4-[3-(3-cyclopropylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 85-1)

Compound 40-4 (400 mg) was dissolved in tetrahydrofuran (1.3 ml), tripotassium phosphate (350 mg), palladium acetate (7.2 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13 mg) and cyclopropylboronic acid (80 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water (30 μl) was added, and the mixture was further stirred for 5.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (330 mg) as a white solid.

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.56(2H, ddd, J=6.1, 4.8, 4.2 Hz), 0.88(2H, ddd, J=8.4, 6.4, 4.1 Hz), 1.31(3H, s), 1.33(3H, s), 1.40(9H, s), 1.80-1.87(1H, m), 1.91-2.02(4H, m), 2.45-2.50(2H, m), 2.69(2H, t, J=7.5 Hz), 3.66(2H, d, J=11.6 Hz), 3.88(2H, d, J=11.3 Hz), 4.00(2H, t, J=6.1 Hz), 6.66(1H, brs), 6.87(1H, s), 6.87(1H, d, J=7.4 Hz), 6.94(1H, d, J=7.4 Hz), 7.11-7.16(2H, m), 7.37(1H, d, J=8.6 Hz), 7.40(1H, s).

(85-2) Synthesis of 2-amino-2-(2-{4-[3-(3-cyclopropylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 85-2)

Compound 85-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (168 mg) as a white powder.

MS(ESI)m/z: 438[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 0.57(2H, ddd, J=6.5, 5.2, 4.3 Hz), 0.89(2H, ddd, J=8.4, 6.5, 4.3 Hz), 1.76-1.79(2H, m), 1.81-1.88(1H, m), 1.99(2H, quint, J=6.4 Hz), 2.58-2.63(2H, m), 2.69(2H, t, J=7.4 Hz), 3.52(4H, d, J=5.2 Hz), 4.01(2H, t, J=6.0 Hz), 5.40(2H, t, J=5.2 Hz), 6.87(1H, s), 6.88(1H, d, J=7.8 Hz), 6.94(1H, d, J=7.4 Hz), 7.12-7.16(2H, m), 7.43(1H, d, J=8.6 Hz), 7.48(1H, d, J=1.8 Hz), 7.84(3H, brs).

2-amino-2-{2-[4-(3-phenylallyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride

(86-1) Synthesis of 2-amino-2-{2-[4-(3-phenylallyloxy)-3-trifluoromethylphenyl]ethyl}propane-1,3-diol hydrochloride (Compound 86-1)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (4 ml), azodicarboxylic acid diisopropyl ester (40% toluene solution, 1.25 ml) and cinnamyl alcohol (320 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Reference Example compound 2-6 (500 mg) was added, and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate). The obtained colorless oil was dissolved in ethanol (10 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (139 mg) as a white powder.

MS(ESI)m/z: 396[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.59-2.63(2H, m), 3.52(4H, d, J=5.1 Hz), 4.85(2H, d, J=5.4 Hz), 5.40(2H, t, J=5.2 Hz), 6.48(1H, dt, J=16.0, 5.6 Hz), 6.78(1H, d, J=16.1 Hz), 7.27-7.30(2H, m), 7.36(2H, t, J=7.8 Hz), 7.46-7.49(4H, m), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(2,2-difluoro-1,3-benzodioxol-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(87-1) Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne (Compound 87-1)

A mixture of 5-bromo-2,2-difluoro-1,3-benzodioxole (10.0 g), cesium carbonate (35.0 g), 2-(2-propynyloxy)tetrahydropyran (8.90 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.24 g), bis(acetonitrile)palladium(II) dichloride (219 mg) and acetonitrile (100 ml) was stirred at 90° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (6.53 g) as a brown oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.54-1.69(4H, m), 1.73-1.90(2H, m), 3.55-3.59(1H, m), 3.85-3.91(1H, m), 4.43(1H, d, J=15.7 Hz), 4.51(1H, d, J=15.7 Hz), 4.87(1H, t, J=3.3 Hz), 6.99(1H, d, J=8.5 Hz), 7.14(1H, d, J=1.3 Hz), 7.29(1H, dd, J=8.5, 1.3 Hz).

(87-2) Synthesis of 2,2-difluoro-5-(3-hydroxypropyl)-1,3-benzodioxole (Compound 87-2)

A solution of compound 87-1 (6.53 g) and 10% palladium carbon (3.00 g) in ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature for 14 hr. The reaction mixture was filtered through celite and concentrated. To a solution of the obtained residue in methanol (30 ml) was added p-toluenesulfonic acid monohydrate (30.0 mg), and the mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (3.54 g) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.24-1.28(1H, m), 1.82-1.90(2H, m), 2.72(2H, t, J=7.7 Hz), 3.65-3.69(2H, m), 6.87-6.92(2H, m), 6.96(1H, d, J=8.0 Hz).

(87-3) Synthesis of 5-(3-bromopropyl)-2,2-difluoro-1,3-benzodioxole (Compound 87-3)

Compound 87-2 (3.54 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (4.73 g) and N-bromosuccinimide (3.21 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (4.10 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.17(2H, m), 2.78(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.3 Hz), 6.88-6.92(2H, m), 6.97(1H, d, J=8.0 Hz).

(87-4) Synthesis of [5-(2-{4-[3-(2,2-difluoro-1,3-benzodioxol-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-2,2-dimethyl-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 87-4)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (493 mg) and compound 87-3 (399 mg) were added, and the mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (770 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.09(2H, m), 2.52-2.56(2H, m), 2.83(2H, t, J=7.4 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.96(2H, t, J=5.8 Hz), 4.99(1H, brs), 6.82-6.96(4H, m), 7.26-7.28(1H, m), 7.37(1H, d, J=1.9 Hz).

(87-5) Synthesis of 2-amino-2-(2-{4-[3-(2,2-difluoro-1,3-benzodioxol-5-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 87-5)

Compound 87-4 (870 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.

MS(ESI)m/z: 478[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.73-1.78(2H, m), 2.00-2.04(2H, m), 2.58-2.63(2H, m), 2.77(2H, t, J=7.4 Hz), 3.51(4H, d, J=4.1 Hz), 4.03(2H, t, J=5.8 Hz), 5.39(2H, brs), 7.01(1H, d, J=8.2 Hz), 7.17(1H, d, J=8.5 Hz), 7.29-7.31(2H, m), 7.44(1H, d, J=8.5 Hz), 7.48(1H, brs), 7.80(3H, brs).

2-amino-2-(2-{4-[3-(4-chlorophenyl)allyloxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(88-1) Synthesis of 3-(4-chlorophenyl)-2-propene-1-ol (Compound 88-1)

3-(4-Chlorophenyl)methyl acrylate ester (2.00 g) was dissolved in methylene chloride (100 ml), 1M diisobutylaluminum hydride/toluene solution (20 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature. Aluminum salt was collected by filtration through celite, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (1.33 g) as a white powder.

1 H-NMR(DMSO-d 6 ) δ (ppm): 4.11(2H, td, J=4.7, 1.2 Hz), 4.91(1H, t, J=5.5 Hz), 6.41(1H, dt, J=16.0, 4.7 Hz), 6.55(1H, d, J=16.0 Hz), 7.37(2H, d, J=8.5 Hz), 7.45(2H, d, J=8.5 Hz).

(88-2) Synthesis of 2-amino-2-(2-{4-[3-(4-chlorophenyl)allyloxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 88-2)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (4 ml), azodicarboxylic acid diisopropyl ester (40% toluene solution, 1.25 ml) and compound 88-1 (400 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Reference Example compound 2-6 (500 mg) was added, and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate). The obtained pale-yellow oil was dissolved in ethanol (10 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (94 mg) as a white powder.

MS(ESI)m/z: 430[M+H]

1 H-NMR (DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.58-2.63(2H, m), 3.51(4H, d, J=5.0 Hz), 4.84(2H, d, J=5.2 Hz), 5.40(2H, t, J=5.2 Hz), 6.52(1H, dt, J=16.2, 5.5 Hz), 6.76(1H, d, J=15.9 Hz), 7.27(1H, d, J=8.5 Hz), 7.41(2H, d, J=8.5 Hz), 7.46-7.51(2H, m), 7.51(2H, d, J=8.5 Hz), 7.81(3H, brs).

2-amino-2-(2-{4-[3-(3-chlorophenyl)allyloxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(89-1) Synthesis of 3-(3-chlorophenyl)-2-propene-1-ol (Compound 89-1)

3-(3-Chlorophenyl)acrylic acid (5.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained pale-yellow powder was dissolved in methylene chloride (130 ml), 1M diisobutylaluminum hydride/toluene solution (52 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature. Aluminum salt was collected by filtration through celite, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (3.29 g) as a yellow oil.

1 H-NMR (DMSO-d 6 ) δ (ppm): 4.11-4.14(2H, m), 4.93(1H, t, J=5.4 Hz), 6.47(1H, dt, J=16.0, 4.5 Hz), 6.55(1H, d, J=16.0 Hz), 7.27(1H, dt, J=7.8, 1.5 Hz), 7.34(1H, t, J=7.8 Hz), 7.40(1H, dt, J=7.7, 1.5 Hz), 7.50(1H, t, J=1.7 Hz).

(89-2) Synthesis of 2-amino-2-(2-{4-[3-(3-chlorophenyl)allyloxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 89-2)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (8 ml), azodicarboxylic acid diisopropyl ester (40% toluene solution, 1.25 ml) and compound 89-1 (400 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Reference Example compound 2-6 (500 mg) was added, and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate). The obtained yellow oil was dissolved in ethanol (25 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (287 mg) as a white powder.

MS(ESI)m/z: 430[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.59-2.63(2H, m), 3.51(4H, d, J=5.1 Hz), 4.85(2H, d, J=5.3 Hz), 5.40(2H, t, J=5.1 Hz), 6.60(1H, dt, J=16.2, 5.4 Hz), 6.76(1H, d, J=16.0 Hz), 7.27(1H, d, J=8.5 Hz), 7.34(1H, d, J=7.9 Hz), 7.38(1H, t, J=7.8 Hz), 7.43-7.49(3H, m), 7.57(1H, s), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(4-fluorophenyl)allyloxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(90-1) Synthesis of 3-(4-fluorophenyl)-2-propene-1-ol (Compound 90-1)

3-(4-Fluorophenyl)acrylic acid (5.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 3.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white powder was dissolved in tetrahydrofuran (110 ml), 1M diisobutylaluminum hydride/toluene solution (55 ml) was added dropwise at −78° C., and the mixture was stirred at it was at −78° C. for 1 Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature. Aluminum salt was collected by filtration through celite, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with water and hexane to give the object product (3.82 g) as a white powder.

1 H-NMR(DMSO-d 6 ) δ (ppm): 4.10(2H, td, J=5.4, 1.4 Hz), 4.88(1H, t, J=5.4 Hz), 6.33(1H, dt, J=15.8, 5.2 Hz), 6.54(1H, d, J=15.9 Hz), 7.15(2H, d, J=8.7 Hz), 7.47(2H, dd, J=8.6, 5.6 Hz).

(90-2) Synthesis of 2-amino-2-(2-{4-[3-(4-fluorophenyl)allyloxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 90-2)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (8 ml), azodicarboxylic acid diisopropyl ester (40% toluene solution, 1.25 ml) and compound 90-1 (360 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Reference Example compound 2-6 (500 mg) was added, and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate). The obtained colorless oil was dissolved in ethanol (25 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (203 mg) as a white powder.

MS(ESI)m/z: 414[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.58-2.63(2H, m), 3.51(4H, d, J=5.0 Hz), 4.83(2H, d, J=5.6 Hz), 5.40(2H, t, J=5.0 Hz), 6.44(1H, dt, J=16.0, 5.6 Hz), 6.77(1H, d, J=16.0 Hz), 7.18(2H, t, J=8.7 Hz), 7.28(1H, d, J=8.5 Hz), 7.46(1H, d, J=8.7 Hz), 7.49(1H, s), 7.53(2H, dd, J=8.6, 5.7 Hz), 7.80(3H, brs).

2-amino-2-(2-{3-trifluoromethyl-4-[3-(3-trifluoromethylphenyl)allyloxy]phenyl}ethyl)propane-1,3-diol hydrochloride

(91-1) Synthesis of 3-(3-trifluoromethylphenyl)-2-propene-1-ol (Compound 91-1)

3-(3-Trifluoromethylphenyl)acrylic acid (3.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 5.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white powder was dissolved in tetrahydrofuran (40 ml), 1M diisobutylaluminum hydride/toluene solution (26 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 2 hr. Saturated Rochelle salt water, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (2.0 g) as a colorless oil.

1 H-NMR(DMSO-d 6 ) δ (ppm): 4.15(2H, td, J=4.9, 0.9 Hz), 4.96(1H, t, J=5.5 Hz), 6.57(1H, dt, J=16.0, 4.6 Hz), 6.67(1H, d, J=15.9 Hz), 7.55-7.67(2H, m), 7.75(2H, s).

(91-2) Synthesis of 2-amino-2-(2-{3-trifluoromethyl-4-[3-(3-trifluoromethylphenyl)allyloxy]phenyl}ethyl)propane-1,3-diol hydrochloride (Compound 91-2)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (12 ml), azodicarboxylic acid diisopropyl ester (40% toluene solution, 1.25 ml) and compound 91-1 (480 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Reference Example compound 2-6 (500 mg) was added, and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate). The obtained colorless oil was dissolved in ethanol (10 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (76 mg) as a white powder.

MS(ESI)m/z: 464[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.59-2.63(2H, m), 3.52(4H, d, J=5.1 Hz), 4.87(2H, d, J=5.0 Hz), 5.39(2H, t, J=5.1 Hz), 6.69(1H, dt, J=16.1, 5.2 Hz), 6.86(1H, d, J=16.1 Hz), 7.29(1H, d, J=8.5 Hz), 7.47(1H, d, J=8.6 Hz), 7.50(1H, s), 7.57-7.65(2H, m), 7.80(3H, brs), 7.82(2H, brs).

2-amino-2-(2-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)allyloxy]phenyl}ethyl)propane-1,3-diol hydrochloride

(92-1) Synthesis of 3-(4-trifluoromethylphenyl)-2-propene-1-ol (Compound 92-1)

3-(4-Trifluoromethylphenyl)acrylic acid (3.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 3.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained white powder was dissolved in tetrahydrofuran (40 ml), 1M diisobutylaluminum hydride/toluene solution (34 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 1 hr. Saturated Rochelle salt water, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (2.64 g) as a white powder.

1 H-NMR(DMSO-d 6 ) δ (ppm): 4.17(2H, t, J=4.4 Hz), 4.99(1H, t, J=5.4 Hz), 6.57(1H, dt, J=16.1, 4.4 Hz), 6.66(1H, d, J=16.2 Hz), 7.64(2H, d, J=8.8 Hz), 7.67(2H, d, J=8.8 Hz).

(92-2) Synthesis of 2-amino-2-(2-{3-trifluoromethyl-4-[3-(4-trifluoromethylphenyl)allyloxy]phenyl}ethyl)propane-1,3-diol hydrochloride (Compound 92-2)

Triphenylphosphine (625 mg) was dissolved in tetrahydrofuran (12 ml), azodicarboxylic acid diisopropyl ester (40% toluene solution, 1.25 ml) and compound 92-1 (480 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 min. Reference Example compound 2-6 (500 mg) was added, and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate). The obtained colorless oil was dissolved in ethanol (15 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (423 mg) as a white powder.

MS(ESI)m/z: 464[M+H]

1 H-NMR (DMSO-d 6 ) δ (ppm): 1.74-1.78(2H, m), 2.59-2.63(2H, m), 3.51(4H, d, J=4.7 Hz), 4.89(2H, d, J=5.1 Hz), 5.37(2H, t, J=4.8 Hz), 6.67(1H, dt, J=16.1, 5.1 Hz), 6.86(1H, d, J=16.2 Hz), 7.28(1H, d, J=8.5 Hz), 7.47(1H, d, J=8.6 Hz), 7.49(1H, s), 7.68-5 7.72(7H, m).

(E)-2-amino-2-(2-{4-[3-(3-methylphenyl)propoxy]-3-trifluoromethylphenyl}vinyl)propane-1,3-diol hydrochloride

(93-1) Synthesis of 4-benzyloxy-3-trifluoromethylbenzoic acid (Compound 93-1)

To a solution of potassium t-butoxide (27.5 g) in N,N-dimethylformamide (120 ml) was added dropwise a solution of benzyl alcohol (15.9 ml) in N,N-dimethylformamide (60 ml) over min. The mixture was stirred for 30 min, and a solution of 4-fluoro-3-trifluoromethylbenzoic acid (20.0 g) in N,N-dimethylformamide (90 ml) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and further at 50° C. for 1 hr. The reaction mixture was added to ice water, and acidified with 1M hydrochloric acid (300 ml). The precipitated solid was collected by filtration, and washed with water and then hexane to give the object product (28.2 g) as a white powder.

1 H-NMR(CDCl 3 ) δ (ppm): 5.29(2H, s), 7.10(1H, d, J=8.7 Hz), 7.33-7.37(1H, m), 7.39-7.45(4H, m), 8.22(1H, dd, J=2.0, 8.7 Hz), 8.36(1H, d, J=2.0 Hz).

(93-2) Synthesis of 4-benzyloxy-3-trifluoromethylbenzyl alcohol (Compound 93-2)

To a solution of compound 93-1 (28.2 g) in toluene (400 ml) was added dropwise a solution of a 70% toluene solution (15.9 ml) of bis(2-methoxyethoxy)aluminum sodium hydride in toluene (80 ml) over 15 min under ice-cooling. Further, under ice-cooling, a solution of a 70% toluene solution (79.3 ml) of bis(2-methoxyethoxy)aluminum sodium hydride in toluene (80 ml) was added dropwise over 15 min. The reaction mixture was stirred at room temperature for 2 hr, at 30° C. for 1 hr and further at 40° C. for 1 hr. The reaction mixture was ice-cooled, a solution of sodium hydroxide (90 g) in water (270 ml) was added dropwise, and the mixture was extracted with toluene. The organic layer was washed with a solution of sodium hydroxide (90 g) in water (270 ml) and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (26.6 g) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.67(1H, t, J=5.9 Hz), 4.66(2H, d, J=5.9 Hz), 5.20(2H, s), 7.02(1H, d, J=8.5 Hz), 7.30-7.34(1H, m), 7.37-7.40(2H, m), 7.43-7.47(3H, m), 7.61(1H, d, J=1.8 Hz).

(93-3) Synthesis of 4-hydroxy-3-trifluoromethylbenzyl alcohol (Compound 93-3)

A solution of compound 93-2 (26.6 g) and 10% palladium carbon (5.00 g) in 1,4-dioxane (250 ml) was stirred under a hydrogen atmosphere at room temperature for 5 hr. The reaction mixture was filtered through celite and concentrated to give the object product (18.8 g) as a white solid.

1 H-NMR (DMSO-d 6 ) δ (ppm): 4.41(2H, s), 5.16(1H, brs), 6.97(1H, d, J=8.4 Hz), 7.37(1H, dd, J=1.6, 8.4 Hz), 7.44(1H, d, J=1.6 Hz), 10.40(1H, brs).

(93-4) Synthesis of 3-trifluoromethyl-4-[(2-trimethylsilylethoxy)methoxy]benzyl alcohol (Compound 93-4)

To a solution of compound 93-3 (18.8 g) in N,N-dimethylformamide (120 ml), potassium carbonate (40.6 g) and 2-(trimethylsilyl)ethoxymethyl chloride (19.1 ml) were added under ice-cooling, and the mixture was stirred under ice-cooling for 4 hr and further at room temperature for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (28.5 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.01(9H, s), 0.92-0.99(2H, m), 1.69(1H, brs), 3.74-3.80(2H, m), 4.68(2H, s), 5.32(2H, s), 7.24(1H, d, J=8.5 Hz), 7.48(1H, dd, J=1.6, 8.4 Hz), 7.59(1H, d, J=1.6 Hz).

(93-5) Synthesis of 3-trifluoromethyl-4-[(2-trimethylsilylethoxy)methoxy]benzyl chloride (Compound 93-5)

Compound 93-4 (28.5 g) was dissolved in methylene chloride (450 ml), 1-chloro-N,N,2-trimethyl-1-propenylamine (12.9 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was diluted with methylene chloride (200 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-90:10) to give the object product (14.5 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.01(9H, s), 0.92-0.97(2H, m), 3.75-3.79(2H, m), 4.57(2H, s), 5.32(2H, s), 7.24(1H, d, J=8.6 Hz), 7.50(1H, dd, J=2.1, 8.6 Hz), 7.60(1H, d, J=2.0 Hz).

(93-6) Synthesis of {3-trifluoromethyl-4-[(2-trimethylsilylethoxy)methoxy]benzyl}phosphonic acid dimethyl (Compound 93-6)

To a mixture of compound 93-5 (14.4 g), tetrabutylammonium iodide (17.2 g), cesium carbonate (15.1 g) and N,N-dimethylformamide (40 ml) was added dimethyl phosphite (4.26 ml) under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-25:75) to give the object product (10.4 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.01(9H, s), 0.92-0.96(2H, m), 3.13(2H, d, J=21.4 Hz), 3.70(6H, d, J=10.7 Hz), 3.75-3.79(2H, m), 5.30(2H, s), 7.21(1H, d, J=8.6 Hz), 7.40-7.43(1H, m), 7.46-7.47(1H, m).

(93-7) Synthesis of (E)-[2,2-dimethyl-5-(2-{3-trifluoromethyl-4-[(2-trimethylsilylethoxy)methoxy]phenyl}vinyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 93-7)

To a solution of t-butoxy potassium (7.88 g) in tetrahydrofuran (170 ml) was added dropwise a solution of compound 93-6 (10.4 g) and Reference Example compound 1-2 (8.45 g) in tetrahydrofuran (150 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr, and further at room temperature for 4 hr. The reaction mixture was added to an aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-75:25) to give the object product (10.9 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 0.01(9H, s), 0.91-0.95(2H, m), 1.45(9H, s), 1.47(3H, s), 1.49(3H, s), 3.74-3.79(2H, m), 3.90(2H, d, J=11.5 Hz), 3.97(2H, d, J=11.5 Hz), 5.22(1H, brs), 5.30(2H, s), 6.13(1H, d, J=16.4 Hz), 6.49(1H, d, J=16.4 Hz), 7.18(1H, d, J=8.6 Hz), 7.45(1H, dd, J=1.8, 8.6 Hz), 7.56(1H, d, J=1.6 Hz).

(93-8) Synthesis of (E)-{5-[2-(4-hydroxy-3-trifluoromethylphenyl)vinyl]-2,2-dimethyl-1,3-dioxan-5-yl}carbamic acid t-butyl ester (Compound 93-8)

A mixture of compound 93-7 (10.9 g) and a solution (199 ml) of tetrabutylammonium fluoride in 1M tetrahydrofuran was stirred at 50° C. for 19 hr. The reaction mixture was added to brine, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was suspended in diisopropyl ether (20 ml) and hexane (200 ml), and the solid was collected by filtration, and washed with hexane to give the object product (6.11 g) as a white powder.

1 H-NMR(CDCl 3 ) δ (ppm): 1.47(3H, s), 1.49(12H, s), 3.88(2H, d, J=11.6 Hz), 3.92(2H, d, J=11.6 Hz), 5.44(1H, brs), 5.93(1H, d, J=16.4 Hz), 6.35(1H, d, J=16.4 Hz), 6.64(1H, d, J=7.6 Hz), 6.97(1H, brs), 7.31(1H, s).

(93-9) Synthesis of (E)-[2,2-dimethyl-5-(2-{4-[3-(3-methylphenyl)propoxy]-3-trifluoromethylphenyl}vinyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 93-9)

Compound 93-8 (400 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (397 mg) and compound 15-2 (246 mg) were added, and the mixture was stirred at 50° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.45(9H, s), 1.47(3H, s), 1.49(3H, s), 2.07-2.14(2H, m), 2.32(3H, s), 2.79(2H, t, J=7.5 Hz), 3.90(2H, d, J=11.4 Hz), 3.96-4.03(4H, m), 5.22(1H, brs), 6.11(1H, d, J=16.4 Hz), 6.48(1H, d, J=16.4 Hz), 6.87(1H, d, J=8.6 Hz), 6.98-7.02(3H, m), 7.17(1H, t, J=7.4 Hz), 7.43(1H, dd, J=8.6, 1.7 Hz), 7.57(1H, d, J=1.7 Hz).

(93-10) Synthesis of (E)-2-amino-2-(2-{4-[3-(3-methylphenyl)propoxy]-3-trifluoromethylphenyl}vinyl)propane-1,3-diol hydrochloride (Compound 93-10)

Compound 93-9 (560 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (370 mg) as a white powder.

MS(ESI)m/z: 393

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.98-2.05(2H, m), 2.26(3H, s), 2.71(2H, t, J=7.5 Hz), 3.59-3.67(4H, m), 4.09(2H, t, J=6.1 Hz), 5.47(2H, t, J=5.4 Hz), 6.24(1H, d, J=16.6 Hz), 6.70(1H, d, J=16.6 Hz), 6.96-7.01(3H, m), 7.17(1H, t, J=7.4 Hz), 7.24(1H, d, J=8.6 Hz), 7.63(1H, dd, J=8.6, 1.6 Hz), 7.66(1H, brs), 8.05(3H, brs).

2-amino-2-(2-{4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(94-1) Synthesis of 1-(3-hydroxypropyl)-1,2,3,4-tetrahydronaphthalene (Compound 94-1)

(3-Benzyloxypropyl)triphenylphosphoniumbromide (1.00 g) was dissolved in tetrahydrofuran (10 ml), sodium hydride (162 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. α-Tetralone (1.36 ml) was added to the reaction mixture, and the mixture was stirred at 75° C. for 48 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethyl acetate (10 ml) was added 10% palladium carbon (200 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the object product (140 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.24(1H, brs), 1.60-1.80(6H, m), 1.81-1.89(2H, m), 2.73-2.80(3H, m), 3.68(2H, brs), 7.04-7.10(3H, m), 7.11-7.13(1H, m).

(94-2) Synthesis of 1-(3-bromopropyl)-1,2,3,4-tetrahydronaphthalene (Compound 94-2)

Compound 94-1 (140 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (212 mg) and N-bromosuccinimide (144 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature 16 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (190 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.68-1.79(2H, m), 1.80-1.90(4H, m), 1.91-2.02(2H, m), 2.70-2.82(3H, m), 3.40-3.47(2H, m), 7.05-7.18(4H, m).

(94-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 94-3)

Reference Example compound 2-6 (282 mg) was dissolved in N,N-dimethylformamide (7 ml), potassium carbonate (278 mg) and compound 94-2 (190 mg) were added, and the mixture was stirred at 80° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (400 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.42(3H, s), 1.44(3H, s), 1.47(9H, s), 1.69-1.77(3H, m), 1.82-1.97(7H, m), 2.51-2.56(2H, m), 2.74-2.78(2H, m), 2.79-2.88(1H, m), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.03(2H, t, J=5.6 Hz), 4.99(1H, brs), 6.87(1H, d, J=8.5 Hz), 7.04-7.14(3H, m), 7.19(1H, brd, J=7.2 Hz), 7.26-7.28(1H, m), 7.35(1H, brd, J=1.8 Hz).

(94-4) Synthesis of 2-amino-2-(2-{4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 94-4)

Compound 94-3 (400 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (270 mg) as a white powder.

MS(ESI)m/z: 452[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.60-1.71(3H, m), 1.72-1.86(7H, m), 2.58-2.62(2H, m), 2.63-2.72(2H, m), 2.78(1H, brs), 3.51(4H, d, J=4.7 Hz), 4.11(2H, brs), 5.40(2H, t, J=5.0 Hz), 7.02-7.10(3H, m), 7.13-7.20(2H, m), 7.43-7.47(2H, m), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(3-nitrophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(95-1) Synthesis of 3-(3-nitrophenyl)-1-propanol (Compound 95-1)

3-(3-Nitrophenyl)propionic acid (1.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 7.25 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and further at room temperature for 2.5 hr. Water was added to the reaction mixture, and 1 mol/1 aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the object product (220 mg) as a yellow oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.31(1H, t, J=5.0 Hz), 1.90-1.97(2H, m), 2.85(2H, t, J=7.8 Hz), 3.71(2H, q, J=6.1 Hz), 7.46(1H, t, J=7.8 Hz), 7.55(1H, d, J=7.5 Hz), 8.05-8.08(2H, m).

(95-2) Synthesis of 1-(3-bromopropyl)-3-nitrobenzene (Compound 95-2)

Compound 95-1 (220 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (350 mg) and N-bromosuccinimide (238 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (30 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (280 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.18-2.25(2H, m), 2.92(2H, t, J=7.5 Hz), 3.41(2H, t, J=6.4 Hz), 7.45-7.50(1H, m), 7.55(1H, d, J=7.7 Hz), 8.08-8.10(2H, m).

(95-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(3-nitrophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 95-3)

Reference Example compound 2-6 (437 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (431 mg) and compound 95-2 (280 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (587 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H. s), 1.44(3H, s), 1.48(9H, s), 1.94-1.98(2H, m), 2.08-2.19(2H, m), 2.52-2.57(2H, m), 2.96(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 4.00(2H, t, J=5.9 Hz), 5.00(1H, brs), 6.84(1H, d, J=8.4 Hz), 7.26-7.28(1H, m), 7.38(1H, brd, J=1.5 Hz), 7.45(1H, t, J=7.8 Hz), 7.54(1H, d, J=7.3 Hz), 8.05-8.08(2H, m).

(95-4) Synthesis of 2-amino-2-(2-{4-[3-(3-nitrophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 95-4)

Compound 95-3 (587 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (430 mg) as a white powder.

MS(ESI)m/z: 443[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.06-2.12(2H, m), 2.58-2.63(2H, m), 2.89(2H, t, J=7.5 Hz), 3.52(4H, d, J=4.9 Hz), 4.07(2H, t, J=6.0 Hz), 5.40(2H, t, J=5.0 Hz), 7.18(1H, d, J=8.6 Hz), 7.44(1H, d, J=8.6 Hz), 7.48(1H, brd, J=1.8 Hz), 7.60(1H, t, J=8.3 Hz), 7.69(1H, d, J=7.6 Hz), 7.82(3H, brs), 8.06-8.08(2H, m).

2-amino-2-(2-{4-[3-(4-methylthiophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(96-1) Synthesis of 3-(4-methylthiophenyl)-1-propanol (Compound 96-1)

3-(4-Methylsulfanylphenyl)propionic acid (1.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 6.42 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and further at room temperature for 1 hr. Water was added to the reaction mixture, and 1 mol/l aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the object product (940 mg) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 1.28(1H, brs), 1.85-1.89(2H, m), 2.47(3H, s), 2.68(2H, t, J=7.7 Hz), 3.67(2H, brt, J=6.0 Hz), 7.13(2H, d, J=8.2 Hz), 7.19-7.22(2H, m).

(96-2) Synthesis of 1-(3-bromopropyl)-4-methylthiobenzene (Compound 96-2)

Compound 96-1 (940 mg) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.43 g) and N-bromosuccinimide (966 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 18 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (1.13 g) as a colorless oil.

1 H-NMR(CDCl 3 ) δ (ppm): 2.10-2.18(2H, m), 2.47(3H, s), 2.74(2H, t, J=7.3 Hz), 3.38(2H, t, J=6.6 Hz), 7.13(2H, d, J=8.2 Hz), 7.19-7.22(2H, m).

(96-3) Synthesis of [2,2-dimethyl-5-(2-{4-[3-(4-methylthiophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)-1,3-dioxan-5-yl]carbamic acid t-butyl ester (Compound 96-3)

Reference Example compound 2-6 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and compound 96-2 (351 mg) were added, and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (740 mg) as a white solid.

1 H-NMR(CDCl 3 ) δ (ppm): 1.43(3H, s), 1.44(3H, s), 1.47(9H, s), 1.93-1.98(2H, m), 2.04-2.12(2H, m), 2.52(3H, s), 2.53-2.56(2H, m), 2.79(2H, t, J=7.5 Hz), 3.69(2H, d, J=11.7 Hz), 3.89(2H, d, J=11.7 Hz), 3.97(2H, t, J=6.0 Hz), 4.99(1H, brs), 6.83(1H, d, J=8.5 Hz), 7.12(2H, d, J=8.3 Hz), 7.18-7.22(2H, m), 7.25-7.26(1H, m), 7.36(1H, s).

(96-4) Synthesis of 2-amino-2-(2-{4-[3-(4-methylthiophenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 96-4)

Compound 96-3 (587 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (490 mg) as a white powder.

MS(ESI)m/z: 444[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 1.97-2.02(2H, m), 2.44(3H, s), 2.58-2.63(2H, m), 2.71(2H, t, J=7.4 Hz), 3.52(4H, d, J=4.6 Hz), 4.03(2H, t, J=6.0 Hz), 5.40(2H, t, J=4.9 Hz), 7.13-7.20(5H, m), 7.44(1H, d, J=8.5 Hz), 7.48(1H, brs), 7.82(3H, brs).

2-amino-2-(2-{4-[3-(4-methanesulfinylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(97-1) Synthesis of 2-amino-2-(2-{4-[3-(4-methanesulfinylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 97-1)

Compound 96-3 (720 mg) was dissolved in methylene chloride (20 ml), m-chloroperbenzoic acid (containing 25% water, 293 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 20 hr. m-Chloroperbenzoic acid (containing 25% water, 234 mg) was further added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was separated by HPLC using capcellpac (registered trade mark) UG80 (0.05% trifluoroacetic acid-water/0.05% trifluoroacetic acid-acetonitrile), and the residue obtained by collecting a peak with a shorter retention time (primary peak) was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 10 ml), and the precipitate was collected by filtration and dried to give the object product (75 mg) as a white powder.

MS (ESI)m/z: 460[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.02-2.10(2H, m), 2.59-2.64(2H, m), 2.72(3H, s), 2.82(2H, t, J=7.5 Hz), 3.52(4H, d, J=5.2 Hz), 4.07(2H, t, J=6.0 Hz), 5.41(2H, t, J=5.2 Hz), 7.13-7.20(1H, m), 7.40-7.48(4H, m), 7.61(2H, d, J=8.0 Hz), 7.86(3H, brs).

2-amino-2-(2-{4-[3-(4-methanesulfonylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride

(98-1) Synthesis of 2-amino-2-(2-{4-[3-(4-methanesulfonylphenyl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol hydrochloride (Compound 98-1)

In the purification by HPLC in Example (97-1), the residue obtained by collecting a peak with a longer retention time (secondary peak) was converted to hydrochloride by the addition of hydrogen chloride containing ether (1 mol/l, 10 ml), and the precipitate was collected by filtration and dried to give the object product (95 mg) as a pale-yellow powder.

MS(ESI)m/z: 476[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.74-1.79(2H, m), 2.03-2.10(2H, m), 2.59-2.64(2H, m), 2.86(2H, t, J=7.5 Hz), 3.19(3H, s), 3.52(4H, d, J=5.0 Hz), 4.07(2H, t, J=6.0 Hz), 5.41(2H, t, J=5.0 Hz), 7.18(1H, d, J=8.5 Hz), 7.43-7.50(4H, m), 7.85(2H, d, J=8.3 Hz), 7.87(3H, brs).

2-amino-2-(2-{4-[3-(piperidin-1-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol dihydrochloride

(99-1) Synthesis of 2-amino-2-(2-{4-[3-(piperidin-1-yl)propoxy]-3-trifluoromethylphenyl}ethyl)propane-1,3-diol dihydrochloride (Compound 99-1)

Triphenylphosphine (750 mg) was dissolved in tetrahydrofuran (30 ml), diisopropyl azodicarboxylate (40% toluene solution, 1.51 ml), 1-piperidinepropanol (0.447 ml) and Reference Example compound 2-6 (600 mg) were added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated and the obtained oil was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (580 mg) as a white powder.

MS(ESI)m/z: 405[M+H]

1 H-NMR(DMSO-d 6 ) δ (ppm): 1.32-1.48(1H, m), 1.74-1.82(7H, m), 2.17-2.24(2H, m), 2.60-2.65(2H, m), 2.82-2.92(2H, m), 3.08-3.14(2H, m), 3.35-3.42(2H, m), 3.52(4H, s), 4.17(2H, t, J=6.0 Hz), 5.42(2H, brs), 7.22(1H, d, J=9.1 Hz), 7.47-7.49(2H, m), 7.91(3H, brs), 10.5(1H, brs).

(E)-2-amino-2-{2-[4-(3-phenylpropoxy)-3-trifluoromethylphenyl]vinyl}propane-1,3-diol hydrochloride

(100-1) Synthesis of (E)-(2,2-dimethyl-5-{2-[4-(3-phenylpropoxy)-3-trifluoromethylphenyl]vinyl}-1,3-dioxan-5-yl)carbamic acid t-butyl ester (Compound 100-1)

Compound 93-8 (400 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (397 mg) and 3-phenylpropylbromide (0.175 ml) were added, and the mixture was stirred at 50° C. for 2 hr, and at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a color