4-fluoro-3-oxocarboxylic esters and process for producing the same

Synthesis of methyl 4-fluoro-3-oxopentanoate

To a liquor in which 1.31 g of 62.8% sodium hydride was suspended in 10 ml of tetrahydrofuran was added dropwise a mixed solution comprising 2.00 g of methyl 2-fluoropropionate and 2.10 g of methyl acetate over 10 minutes, and the mixture was then heated at 30 to 35° C. for 4 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 2.57 g of methyl 4-fluoro-3-oxopentanoate was formed (yield: 92%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 2.03 g of methyl 4-fluoro-3-oxopentanoate.

Boiling point: 80 to 81° C./24 to 25 mmHg

Mass analysis value: CI-MS m/e=149 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.47 to 1.60 (3H, m), 3.66 to 3.67 (1.7H, d), 3.76 to 3.77 (3H, d), 4.87 to 5.12 (1H, m), 5.33 (0.15H, s), 11.80 to 12.00 (0.15H, bs)

According to 1 H-NMR analysis, it could be confirmed to exist a keto-enol form.

Synthesis of methyl 4-fluoro-3-oxopentanoate

To a liquor in which 2.32 g of powder sodium methoxide was suspended in 10 ml of tetrahydrofuran was added dropwise a mixed solution comprising 2.00 g of methyl 2-fluoropropionate and 2.80 g of methyl acetate over 10 minutes, and the mixture was then heated at 50 to 60° C. for 5 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 2.36 g of methyl 4-fluoro-3-oxopentanoate was formed (yield: 84%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 1.86 g of methyl 4-fluoro-3-oxopentanoate.

Synthesis of ethyl 4-fluoro-3-oxopentanoate

To a liquor in which 1.28 g of 62.8% sodium hydride was suspended in 10 ml of tetrahydrofuran was added dropwise a mixed solution comprising 2.00 g of ethyl 2-fluoropropionate and 1.91 g of ethyl acetate over 10 minutes, and the mixture was then heated at 35 to 40° C. for 4 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 2.35 g of ethyl 4-fluoro-3-oxopentanoate was formed (yield: 87%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 1.73 g of ethyl 4-fluoro-3-oxopentanoate.

Boiling point: 38 to 41° C./2 mmHg

Mass analysis value: CI-MS m/e=163 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.26 to 1.32 (3H, m), 1.47 to 1.60 (3H, m), 3.63 to 3.64 (1.72H, d), 4.18 to 4.26 (2H, m), 4.86 to 5.12 (1H, m), 5.31 (0.14H, s), 12.02 (0.14H, s)

According to 1 H-NMR analysis, it could be confirmed to exist a keto-enol form.

Synthesis of methyl and ethyl 4-fluoro-3-oxopentanoates

To a liquor in which 1.26 g of 63.7% sodium hydride was suspended in 10 ml of tetrahydrofuran was added dropwise a mixed solution comprising 2.00 g of ethyl 2-fluoropropionate and 1.86 g of methyl acetate over 10 minutes, and the mixture was then heated at 30 to 35° C. for 4 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 1.43 g (yield: 58%) of methyl 4-fluoro-3-oxopentanoate and 0.95 g (yield: 35%) of ethyl 4-fluoro-3-oxopentanoate were formed (total yield: 93%).

Synthesis of butyl 4-fluoro-3-oxopentanoate

To a liquor in which 15.41 g of 63.7% sodium hydride was suspended in 150 ml of tetrahydrofuran was added dropwise a mixed solution comprising 29.86 g of butyl 2-fluoropropionate and 35.31 g of butyl acetate over 90 minutes, and the mixture was then heated at 45 to 55° C. for 6 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 23.79 g of butyl 4-fluoro-3-oxopentanoate was formed (yield: 62%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 20.00 g of butyl 4-fluoro-3-oxopentanoate.

Boiling point: 92 to 95° C./7 to 8 mmHg

Mass analysis value: CI-MS m/e=191 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 0.91 to 0.97 (3H, m), 1.31 to 1.69 (7H, m), 3.63 to 3.65 (1.7H, m), 4.13 to 4.19 (2H, m), 4.86 to 5.12 (1H, m), 5.32 (0.15H, s), 11.70 to 12.30 (0.15H, bs)

According to 1 H-NMR analysis, it could be confirmed to exist a keto-enol form.

Synthesis of ethyl 4-fluoro-4-methyl-3-oxopentanoate

To a liquor in which 13.11 g of 63.7% sodium hydride was suspended in 115 ml of tetrahydrofuran was added dropwise a mixed solution comprising 23.02 g of ethyl 2-fluoro-2-methylpropionate and 22.85 g of ethyl acetate over 75 minutes, and the mixture was then heated at 35 to 45° C. for 4 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 23.75 g of ethyl 4-fluoro-4-methyl-3-oxopentanoate was formed (yield: 78%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 21.42 g of ethyl 4-fluoro-4-methyl-3-oxopentanoate.

Boiling point: 65 to 70° C./10 mmHg

Mass analysis value: CI-MS m/e=177 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.24 to 1.33 (3H, m), 1.43 to 1.67 (6H, m), 3.65 to 3.67 (1.8H, d), 4.17 to 4.25 (2H, m), 5.35 (0.1H, s), 11.90 to 12.40 (0.1H, bs)

According to 1 H-NMR analysis, it could be confirmed to exist a keto-enol form.

Synthesis of ethyl 4-fluoro-3-oxo-4-phenylbutanoate

To a liquor in which 0.75 g of 63.7% sodium hydride was suspended in 10 ml of tetrahydrofuran was added dropwise a mixed solution comprising 1.81 g of ethyl α-fluoro-phenylacetate and 1.32 g of ethyl acetate over 10 minutes, and the mixture was then heated at 35 to 40° C. for 3 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 1.63 g of ethyl 4-fluoro-3-oxo-4-phenylbutanoate was formed (yield: 73%).

This organic layer was concentrated under reduced pressure, and the concentrate was isolated by silica gel column chromatography (Wako gel C-200, eluted by hexane:ethyl acetate=8:2) to obtain 1.46 g of ethyl 4-fluoro-3-oxo-4-phenylbutanoate.

Mass analysis value: CI-MS m/e=225 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.21 to 1.33 (3H, m), 3.51 to 3.70 (1.6H, m), 4.13 to 4.26 (2H, m), 5.48 (0.2H, s), 5.70 to 5.93 (1H, dd), 7.40 (5H, s), 12.02 (0.2H, s)

According to 1 H-NMR analysis, it could be confirmed to exist a keto-enol form.

Synthesis of ethyl 4-fluoro-3-oxooctanoate

To a liquor in which 2.38 g of 63.7% sodium hydride was suspended in 28 ml of tetrahydrofuran was added dropwise a mixed solution comprising 5.59 g of ethyl 2-fluoro-hexanoate and 4.16 g of ethyl acetate over 40 minutes, and the mixture was then heated at 45 to 50° C. for 2 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 3.87 g of ethyl 4-fluoro-3-oxooctanoate was formed (yield: 55%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 3.17 g of ethyl 4-fluoro-3-oxooctanoate.

Boiling point: 73 to 75° C./3 to 4 mmHg

Mass analysis value: CI-MS m/e=205 (m+1)

1 H-NMR (CDC 3 ) δ (ppm): 0.90 to 0.95 (3H, m), 1.26 to 1.53 (7H, m), 1.74 to 1.96 (2H, m), 3.57 to 3.69 (1.84H, m), 4.19 to 4.25 (2H, m), 4.76 to 5.03 (1H, m), 5.30 (0.08H, s), 11.80 to 12.20 (0.08H, bs)

According to 1 H-NMR analysis, it could be confirmed to exist a keto-enol form.

Synthesis of ethyl 4-fluoro-2-methyl-3-oxopentanoate

To a liquor in which 3.13 g of 63.7% sodium hydride was suspended in 25 ml of tetrahydrofuran was added dropwise a mixed solution comprising 5.02 g of ethyl 2-fluoropropionate and 6.40 g of ethyl propionate over 30 minutes, and the mixture was then heated at 40 to 45° C. for 2 hours.

After completion of the reaction, the mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid and the liquids were separated. The organic layer was quantitated by the gas chromatography internal standard method to find out that 5.27 g of ethyl 4-fluoro-2-methyl-3-oxopentanoate was formed (yield: 72%).

This organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 2.25 g of ethyl 4-fluoro-2-methyl-3-oxopentanoate.

Boiling point: 82 to 83° C./17 to 18 mmHg

Mass analysis value: CI-MS m/e=177 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.25 to 1.29 (3H, m), 1.35 to 1.39 (3H, m), 1.46 to 1.62 (3H, m), 3.83 to 3.89 (1H, m), 4.17 to 4.25 (2H, m), 4.91 to 5.17 (1H, m)

Reference Example 1

Synthesis of 6-(1-fluoroethyl)-4-pyrimidone

To a solution in which 9.33 g of methyl 4-fluoro-3-oxopentanoate dissolved in 115 ml of methanol were successively added 36.5 g of a 28% sodium methoxide methanol solution, and 9.84 g of formamidine acetate at room temperature, and then, the mixture was stirred at 40° C. for 12 hours.

Moreover, 0.66 g of formamidine acetate was additionally added and the mixture was stirred at 50° C. for 2 hours. Then, the mixture was cooled to 10° C. or lower, and a mixture comprising 9.51 g of conc. sulfuric acid and 8.5 g of water was added to the above mixture.

After stirring at 50° C. for 30 minutes, insoluble materials were filtered off, and the filtrate was quantitated by the liquid chromatography internal standard method to find out that 7.99 g of 6-(1-fluoroethyl)-4-pyrimidone was formed (yield: 89.2%).

The filtrate was concentrated under reduced pressure, and the concentrated solution was recrystallized from 40 ml of isopropanol to obtain 5.82 g of 6-(1-fluoroethyl)-4-pyrimidone.

Melting point: 170 to 171.50° C.

Mass analysis value: CI-MS m/e=143 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.60 to 1.67 (3H, dd), 5.34 to 5.47 (1H, dq), 6.62 to 6.63 (1H, t), 8.13 (1H, s), 13.3 (1H, br)

Reference Example 2

Synthesis of 5-chloro-6-(1-fluoroethyl)-4-pyrimidone

Sulfuryl chloride (2.45 g) was added to a solution in which 1.29 g of 6-(1-fluoroethyl)-4-pyrimidone dissolved in 15 ml of N,N-dimethylformamide, and the mixture was stirred at 50° C. for 3 hours.

When the reaction mixture was quantitated by the liquid chromatography internal standard method, 1.52 g of 5-chloro-6-(1-fluoroethyl)-4-pyrimidone was found to be formed (yield: 95.0%).

The reaction mixture was concentrated under reduced pressure and the concentrated solution was recrystallized from 3 ml of isopropanol to obtain 1.32 g of 5-chloro-6-(1-fluoroethyl)-4-pyrimidone.

Melting point: 190 to 191° C.

Mass analysis value: CI-MS m/e=177 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.49 to 1.60 (3H, dd), 5.76 to 6.00 (1H, dq), 8.27 (1H, s), 13.15 (1H, br)

Reference Example 3

Synthesis of 4,5-dichloro-6-(1-fluoroethyl)pyrimidine

To a liquor in which 1.00 g of 5-chloro-6-(1-fluoroethyl)-4-pyrimidone was suspended in 10 ml of 1,2-dichloro-ethane were added one drop of N,N-dimethylformamide and 0.81 g of thionyl chloride, and the mixture was refluxed for 2 hours.

The reaction mixture was washed with 10 ml of water, and the organic layer was quantitated by the liquid chromatography internal standard method to find out that 1.09 g of 4,5-dichloro-6-(1-fluoroethyl)pyrimidinewas formed (yield: 98%).

The organic layer was concentrated under reduced pressure, and distilled under reduced pressure to obtain 0.76 g of 4,5-dichloro-6-(1-fluoroethyl)pyrimidine.

Boiling point: 84 to 88° C./5 mmHg

Mass analysis value: CI-MS m/e=195 (m+1)

1 H-NMR (CDCl 3 ) δ (ppm): 1.66 to 1.78 (3H, dd), 5.89 to 6.14 (1H, dq), 8.92 (1H, s)

Utilizability in Industry

The novel 4-fluoro-3-oxocarboxylates of the present invention are an important synthetic intermediate for aminopyrimidine derivatives useful as an insecticide, acaricide, fungicide or nematocide.