Methods of making HIV attachment inhibitor prodrug compound and intermediates

This non-provisional application claims the benefit of U.S. Provisional Application Ser. No. 61/437,821 filed Jan. 31, 2011.

The invention relates to methods of making prodrug compounds useful against HIV, and in particular, to methods of making the prodrug 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine, as well certain intermediates thereof, using novel alkylation, amidation, chlorination, and phosphate installation strategies. The invention also relates to the compounds obtained by the processes herein set forth.

The HIV attachment inhibitor prodrug compound identified as 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine, and having the structural formula:

has been set forth and described in U.S. Pat. No. 7,745,625, which is incorporated herein in its entirety. This compound is the phosphate prodrug of the basic compound having the structural formula:

which is set forth and described in U.S. Pat. No. 7,354,924, also incorporated herein in its entirety. Both this compound and the prodrug identified above have so far demonstrated excellent prowess against HIV.

During scale-up procedures for the production of the phosphate prodrug compound, two compounds were utilized in an alkylation process between phosphonic acid, P-(chloromethyl)-, bis(1,1-dimethylethyl) ester and 1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione. However, these compounds have proved to be difficult to process, or unstable and difficult to procure on scale. Furthermore, the yields of the alkylation reaction using these compounds has diminished as the reaction was scaled up.

What is now needed in the art are new processes for making the HIV prodrug compound 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine, as well as intermediate compounds. These new processes should utilize distinct alkylation, amidation, chlorination and phosphate installation procedures. Also needed are new compounds and intermediates which are generated as a result of the novel processes.

In a first embodiment, the invention provides a method for making the compound of Formula I:

with the chemical name 2-amino-2-(hydroxymethyl)propane-1,3-diol-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl phosphate which comprises:

(a) brominating the compound

to yield the compound

and

(b) nitrating compound 2 to yield the compound

and

(c) converting the amine group on compound 3 to a methoxy group to yield compound

and

(d) then converting compound 4 to the compound

and

(e) converting compound 5 to the compound

and

(f) forming a bicyclic structure from compound 6 to yield

and

(g) then chlorinating compound 7 to produce

and

(h) thereafter adding a triazolyl moiety to the compound 8 to yield

and

(i) converting compound 9 to the structure

and

(j) modifying compound 10 to yield the compound

and

(k) reacting compound 11 to produce the compound

and

(l) then converting the compound 12 to the compound

and

(m) then reacting the compound 13 to produce the compound

and

(n) then reacting the compound 14 to produce the compound

and

(o) then converting the compound 15 to the compound of Formula I.

In a further embodiment of the invention, there is provided a method of making the compound of Formula I:

which comprises:

(i) reacting the compound

in the presence of TMG, NMP and NaI or K 2 CO 3 , MeCN and TBAI to yield the compound.

and

(ii) reacting compound 11 with

to produce the compound

and

(iii) then converting the compound 12 to the compound

(iv) and then reacting compound 13 to produce

and

(v) then reacting the compound 14 to produce the compound

and

then converting the compound 15 to the compound of Formula I.

Also provided herein is a method for making the compound of formula (14):

which comprises:

(i) reacting the compound

to yield the compound

and

(ii) reacting compound 11 to produce the compound

and

(iii) then converting the compound 12 to the compound

(iv) and then converting compound (13) to the compound

The invention is also directed to the more general chemical transformation of converting a thio ether to the corresponding chloride using a chlorinating agent.

wherein R can be, but is not limited to alkyl, cycloalkyl, phenyl, substituted and polysubstituted phenyl rings, heteroaromatic rings, substituted and polysubstituted heteroaromatic rings. The chlorinating agent employed in this transformation can be, but is not limited to, chlorine gas, sulfuryl chloride, hexachlorethane, dichlorotriphenylphosphorane, N,N-dichloro-4-methylbenzenesulfonamide, trichloroisocyanuric acid, N-Chlorosuccinimide, 2-chloroisoindoline-1,3-dione or N-chlorosaccharin.

The invention is also directed to the novel compounds

The invention is directed to these and other important ends, hereinafter described.

The invention provides methods for the production of the compound of Formula I:

as well as certain intermediates. The overall reaction scheme may be summarized and set forth as follows:

Thus, in a first embodiment the compound

is utilized as starting material. This compound is reacted with acetic anhydride (Ac 2 O) and then bromine to produce

Next, this compound is reacted with nitric acid and sulfuric acid to produce

Thereafter, this compound is then reacted with sodium nitrite (NaNO 2 ) and trimethylsilyl chloride (TMS-Cl) in methanol (MeOH) to yield

Then this compound is reacted with

to produce

which is then reacted with a mixture of NaOMe/MeOH, CuI and NH 4 Cl in tetrahydrofuran (THF) and methyl propionate to produce

This compound is then reacted with 1% Pd/C under a hydrogen gas (H 2 ) atmosphere in ethyl acetate (EtOAc) to yield

which is further reacted with POCl 3 to produce

This resultant compound is in turn reacted with three (3) equivalents of

in 4-Me-2-pentanol to produce

This compound is then reacted with

in iPrMgC1 and THF to get

Next, this compound is reacted with

and tetramethylguanidine (TMG) in N-methylpyrrolidone (NMP) or K 2 CO 3 in MeCN to obtain

This compound is then reacted with

in Ti(OnBu) 4 and MeTHF to yield

Next, this compound is chlorinated using chlorine gas (Cl 2 ) to yield

Next, this compound is reacted with dichloromethane (DCM) in water to produce

This compound is then further reacted with

to obtain

Finally, there is a further reaction with acetone in water, and then tromethamine to produce the prodrug

In a further embodiment of the invention, the compound of Formula I above is produced utilizing

as a starting material. This compound may be synthesized according to the procedures detailed above, or may be obtained according to the processes set forth and described in U.S. 20060293304, 28 Dec. 2006, which is incorporated herein by reference in its entirety.

In this embodiment,

is first reacted with

in the presence of TMG, NMP and NaI or K 2 CO 3 , MeCN and TBAI to yield the compound

Next, this compound is reacted with

to produce the compound

This compound is then converted to the compound

using chlorine (Cl 2 ) gas. Thereafter, this compound is converted to

using dichloromethane in water. This compound is then reacted to produce the compound

using

and finally, this compound is then converted to the compound of Formula I with acetone in water, and then tromethamine.

In a further embodiment of the invention, the compound of formula (14) is made using the compound of formula (10) as starting material. This process involves reacting the compound

to yield the compound

and then reacting compound 11 to produce the compound

Next, compound 12 is converted to the compound

Thereafter, compound 13 is converted to the compound

Compounds 11, 12, 13 and 14 thus constitute further embodiments of the invention.

The following Example sets forth a preferred method of the invention, but should not be construed as limiting the scope thereof:

In this Example, the compound

was used as the starting material. (see U.S. 20060293304, 28 Dec. 2006 for producing Compound 10). Below is the summary of the procedure for converting compound 10 to compound 11:

Analytical data: m.p. 127.0-128.8° C. 1 H-NMR (Acetic Acid, d 4 ) (δ, ppm): 9.01 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.5 Hz, 2H), 5.60 (s, 2H), 4.10 (s, 3H), 3.95 (s, 3H), 2.58 (s, 3H). 13 C-NMR (Acetic Acid, d 4 ) (δ, ppm): 181.4, 165.1, 162.0, 152.1, 147.4, 142.7, 136.3 (3C), 130.6, 130.4 (2C), 129.9, 127.9, 126.8, 122.8, 114.3, 57.3, 56.7, 53.3, 13.3. HRMS: Calcd for C 21 H 19 O 4 N 5 CIS [M+1] + 472.0841 found 472.0841. Elemental Analysis: C, 53.44; H, 3.84; N, 14.84, S, 6.79, Cl, 7.51. found: C, 53.53; H, 3.55; N, 14.63, S, 6.98, Cl, 7.73.

The process was then continued as follows, with a summary of the conversion of compound 11 to compound 12 set forth below:

Analytical Data: m.p. 162° C. 1 H-NMR (CDCl 3 ) (8, ppm): 2.54 (s, 3H), 3.52 (bs, 4H), 3.74 (bs, 4H), 4.08 (s, 3H), 5.52 (s, 2H), 6.96 (d, J=8.2 Hz, 2H), 7.2 (d, J=8.8 Hz, 2H), 7.44 (bs, 5H), 7.62 (s, 1H), 7.91 (s, 1H), 8.62 (s, 1H): 13 C-NMR (CDCl 3 ) (8, ppm): 13.91, 41.6, 45.9, 56.5, 56.8, 114.3, 122.3, 125.1, 126.7, 127.0, 128.64, 129.5, 129.6, 129.8, 130.2, 134.9, 135.2, 135.7, 140.8, 145.5, 150.6, 161.9, 165.9, 170.6, 184.4; HRMS; cacld for C 31 H 29 ClN 7 O 4 S [M+1] + : 630.1685; found: 630.1688. Elemental Analysis: C, 59.09; H, 4.47; N, 15.56, S, 5.08, Cl, 5.62. found: C, 59.05; H, 4.28; N, 15.57, S, 5.07, Cl, 5.66.

The process was then continued as follows, with a summary of the process for the conversion of compound 12 to compound 14 set forth below:

A reaction vessel was purged with inert gas. All steps were performed under inert gas protection.

The vessel was then charged with 5 L of dichloromethane at 20-25° C. Next, 1.00 kg of the compound of formula 12 was added to the vessel to produce a colorless solution. The solution was then cooled to 0° C. (−3 to 3° C.), followed by the subsurface addition of 113 g chlorine. An orange solution was formed and the reaction was noted to be exothermic. The temperature was kept near 0° C. (−3 to 3° C.).

A sample was taken for high pressure liquid chromatography (HPLC) monitoring, and additional chlorine charges were added as necessary.

Upon reaction completion, solution was warmed to 15° C.

A solution of isopropanol (1.0 eq.) and 10 L of acetone were prepared. 5 vol % of this solution was added to the vessel over about 30 minutes to produce a thin yellow suspension. After a 30 min age, the remaining 95 vol % of the isopropanol/acetone solution was added over 2 h to produce a white suspension. This addition was slightly exothermic and some cooling was necessary (T max =25° C.). Slurry was aged at 20° C. and HPLC was utilized to monitor the crystallization progress.

Product 13 was then filtered, and washed with 5 L of 2:1 (v:v) acetone:dichloromethane, followed by 2.5 L of acetone.

Product 13 could then either be dried at a maximum temperature of 50° C. until reaching constant weight or the wet cake taken forward to product 3.

For the isolation of 13, yield was 0.78 kg (88%) as white crystals.

For the isolation of 14, a second reaction vessel was purged with inert gas.

The vessel was then charged with 5 L of dichloromethane at 20-25° C. Next, about 1.10 kg of the wet cake compound of formula 13a was added to the vessel to produce a white suspension, followed by the addition of 5 L water. A biphasic solution formed and the temperature was kept near 22° C. (20 to 25° C.).

A phase-split was conducted, and the lower, product-rich organic layer was then charged with 1.5 L ethyl acetate under constant-volume distillation conditions (pressure=400 mbar). The resulting solution was then seeded with 13b, and aged for 30 min. 9-12 L of additional ethyl acetate were then added under constant-volume distillation conditions (pressure down to <100 mbar).

Slurry was aged at 20° C. and HPLC was utilized to monitor the crystallization progress.

Product 14 was then filtered, and washed with 4 L of ethyl acetate.

Product 14 was then dried at a maximum temperature of 50° C. until reaching constant weight.

For the isolation of 14, yield was 0.70 kg (85%) as white crystals.

Analytical data for 13: m.p. 121° C. 1 H-NMR (d7-DMF) (δ, ppm): 11.17 (br s, 1H), 9.18 (s, 1H), 8.88 (s, 1H), 8.19 (s, 1H), 7.52-7.54 (m, 5H), 6.44 (s, 2H), 4.19 (s, 3H), 3.67-3.84 (m, 8H), 2.55 (s, 3H); 13 C-NMR (d7-DMF) (δ, ppm): 185.4, 169.9, 166.2, 161.3, 151.1, 146.6, 142.3, 136.1, 129.9, 129.5, 128.6, 127.3, 127.2, 124.7, 123.4, 116.1, 57.7, 56.9, 45.9, 41.7, 13.1; HRMS calcd for C 25 H 25 ClH 7 O 4 [M-Cl] + : 522.1578 found 522.1648. Elemental analysis: C, 53.77; H, 4.51; N, 17.55, Cl, 12.69. found: C, 53.05; H, 4.68; N, 17.20, Cl, 12.56.

Analytical data for 14: m.p. 211° C. 1 H-NMR (CDCl 3 ) (δ, ppm): 8.59 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.41 (s, 5H), 6.09 (s, 2H), 4.04 (s, 3H), 3.40-4.00 (m, 8H), 2.51 (s, 3H); 13 C-NMR (CDCl 3 ) (δ, ppm): 184.4, 170.6, 165.7, 162.1, 150.6, 145.6, 140.8, 134.8, 130.1, 129.6, 128.6, 127.0, 126.7, 125.1, 122.9, 116.1, 57.1, 56.8, 45.9, 41.7, 13.9; HRMS: calcd for C 25 H 25 ClH 7 O 4 [M+H] + :522.1578, found 522.1653. Elemental analysis: C, 57.52; H, 4.64; N, 18.78, Cl, 6.79. found C, 57.26; H, 4.60; N, 18.44, Cl 7.14.

The process was then continued as follows, with a summary of the process for the conversion of compound 14 to compound 15 set forth below:

A reaction vessel was purged with inert gas. All steps were performed under inert gas protection.

The vessel was then charged with 3 L of dichloromethane at 20-25° C. Next, 1.00 kg of the compound of formula 14, 0.20 kg of tetraethylammonium bromide (0.50 eq.) and 0.5 L dichloromethane were added to the vessel to produce a colorless solution. The solution was then warmed to 35° C. (33 to 37° C.), and charged with 0.57 kg of di-tert-butyl potassium phosphate (1.2 eq.) in 4×0.3 eq. portions over 1 h, followed by 0.5 L dichloromethane. A yellow suspension formed and the reaction was warmed to 40° C. (38 to 42° C.).

A sample was taken for high pressure liquid chromatography (HPLC) monitoring, and additional di-tert-butyl potassium phosphate was added if necessary.

Upon reaction completion, suspension was cooled to 20° C.

The vessel was then charged with 5 L water and the resulting biphasic solution was kept near 20° C. (18 to 22° C.).

A phase-split was conducted, and the lower, product-rich organic layer was then charged with 5 L of 20:1 (v:v) tert-butylmethyl ether:isopropanol. The solution was then seeded with compound 15, and aged for 30 min. 11 L of additional 20:1 (v:v) tert-butylmethyl ether:isopropanol was then added over 3 h.

Slurry was aged at 20° C. and HPLC was utilized to monitor the crystallization progress.

Compound 15 was then filtered, and washed with 5 L of 4:1 (v:v) [20:1 (v:v) tert-butylmethyl ether:isopropanol]: dichloromethane, followed by 5 L of tert-butylmethyl ether.

Compound 15 was then dried at a maximum temperature of 50° C. until reaching constant weight.

For the isolation of compound 15, yield was 1.13 kg (85%) as white crystals.

Analytical data for 2: m.p. 198° C. 1 H-NMR (CDCl 3 ) (δ, ppm): 8.51 (s, 3H), 8.17 (s, 3H), 7.88 (s, 3H), 7.39 (m, 5H), 5.92 (d, J=14 Hz, 2H), 4.03 (s, 3H), 3.30-3.80 (m, 8H), 2.47 (s, 3H), 1.25 (s, 18H); 13 C-NMR (CDCl 3 ) (6, ppm): 184.6, 170.5, 166.8, 161.4, 150.7, 145.3, 141.8, 134.9, 130.1, 129.5, 128.5, 127.5, 127.0, 124.6, 122.6, 115.1, 83.7 (d, J=7.4 Hz), 73.55 (d, J=6.6 Hz), 56.8, 45.9, 41.6, 29.5 (d, J=4.4 Hz), 13.8; 31 P-NMR (CDCl 3 ) (δ, ppm): −10.0; HRMS: calcd for C33H43N7O8P [M+H] + : 696.2832 found 696.2885. Elemental analysis: C, 56.97; H, 6.08; N, 14.09. found C, 57.00; H, 6.04; N, 14.13.

The above process may then be continued as herein set forth in the description to yield the compound of Formula I.

The compound of Formula I, once synthesized, may be utilized in compositions to treat HIV infection as set forth and described in U.S. Pat. Nos. 7,745,625, 7,354,924 and 7,776,863, by way of non-limiting examples.

The foregoing description is merely illustrative and should not be understood to limit the scope or underlying principles of the invention in any way. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.