DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application No. 201841018197 filed on May 15, 2018.

BACKGROUND OF THE INVENTION

FIELD OF THE DISCLOSURE
The present invention relates to a process for the preparation of voxilaprevir and its intermediates.
DESCRIPTION OF THE RELATED ART
Voxilaprevir is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with sofosbuvir and velpatasvir.

Voxilaprevir is chemically named as (1aR,5S,8S,9S,10R,22aR)-5-tert-butylN-{(1R, 2R)-2-(difluoromethyl)-1-[(1-methylcyclopropanesulfonyl)carbamoyl]cyclopropyl}-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a tetradeca hydro -8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiaza cyclononadecino[11,12-b]quinoxaline-8-carboxamide and is represented by the following chemical structure:

Voxilaprevir is approved in combination with sofosbuvir and velpatasvir under the brand name of VOSEVI, marketed by Gilead Sciences.

Voxilaprevir is disclosed in U.S Patent No. 9,296 782 B2, which is hereby incorporated by reference.

The inventors of the present disclosure developed a process for the preparation of compound of formula 1 or its salt, which is a useful intermediate in the preparation of voxilaprevir.

SUMMARY OF THE DISCLOSURE
A first aspect of the present disclosure is to provide an improved process for the preparation of compound of formula 1 or its salt, which comprises:
a) reacting the compound of formula 5 with 2,2-difluoroethylamine to get compound of formula 4, which is a mixture of enantiomers and diastereomers of formulae 4a, 4b, 4c, 4d;

b) hydrolyzing the compound of formula 4 and isolating the required enantiomeric mixture of compounds of formulae 3a and 3b;

c) reacting the mixture of compounds of formulae 3a and 3b with alkylating agent to obtain a mixture of enantiomeric compounds of formulae 4a and 4b;

d) enzymatic kinetic resolution of mixture of enantiomeric compounds of formulae 4a and 4b to isolate a compound of formula 4a;

e) hydrolyzing the compound of formula 4a to get a compound of formula 3a; and

f) converting the compound of formula 3a to a compound of formula 1 or its salt.

wherein R is selected from liner or branched C1-10 alkyl;
Pg is any amine protecting group.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention relates to an improved process for the preparation of compound of formula 1, comprising the steps of:
a) reacting the compound of formula 5 with 2,2-difluoroethylamine to get compound of formula 4, which is a mixture of enantiomers and diastereomers of formulae 4a, 4b, 4c, 4d;

b) hydrolyzing the compound of formula 4 and isolating the required enantiomeric mixture of compounds of formulae 3a and 3b;

c) reacting the mixture of compounds of formulae 3a and 3b with alkylating agent to obtain a mixture of enantiomeric compounds of formulae 4a and 4b;

d) enzymatic kinetic resolution of mixture of enantiomeric compounds of formulae 4a and 4b to isolate a compound of formula 4a;

e) hydrolyzing the compound of formula 4a to get a compound of formula 3a; and

f) converting the compound of formula 3a to a compound of formula 1 or its salt.

wherein R is selected from liner or branched C1-10 alkyl;
Pg is any amine protecting group.

Yet other embodiment, the present invention relates to a process for the preparation of compound of formula 1 or its salt, comprising the steps of:
a) reacting the compound of formula 5’ with 2,2-difluoroethylamine to get compound of formula 4’, which is a mixture of enantiomers and diastereomers of formulae 4a’, 4b’, 4c’, 4d’;

b) hydrolyzing the compound of formula 4’ and isolating the required enantiomeric mixture of compounds of formulae 3a’ and 3b’;

c) reacting the mixture of compounds of formulae 3a’ and 3b’ with alkylating agent to obtain a mixture of enantiomeric compounds of formulae 4a’ and 4b’;

d) enzymatic kinetic resolution of mixture of enantiomeric compounds of formulae 4a’ and 4b’ to isolate a compound of formula 4a’;

e) hydrolyzing the compound of formula 4a’ to get a compound of formula 3a’; and

f) converting the compound of formula 3a’ to a compound of formula 1 or its salt.

Another embodiment of the present invention relates to a process for the preparation of voxilaprevir or its pharmaceutically acceptable salts using the intermediate of formula 1 or its salt.

Within the context of the present invention the enzyme used in the kinetic resolution may include, alcalase; ALK-enzyme; bacillopeptidase A; bacillopeptidase B; Bacillus subtilis alkaline proteinase bioprase; bioprase AL 15; bioprase APL 30; colistinase; subtilisin J; subtilisin S41; subtilisin Sendai; subtilisin GX; subtilisin E; subtilisin BL; genenase I; esperase; maxatase; alcalase; thermoase PC 10; protease XXVII; thermoase; superase; subtilisin DY; subtilopeptidase; SP 266; savinase 8.0L; savinase 4.0T; kazusase; protease VIII; opticlean; Bacillus subtilis alkaline proteinase; protin A 3L; savinase; savinase 16.0L; savinase 32.0 L EX; orientase 10B; protease S.

In another embodiment, the compound of formula I is prepared according to the scheme as shown in scheme-I.

Scheme-I

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
NMR Instrument details:
NMR analysis of all compounds were performed on Bruker 500 MHz Avance NMR spectrometer and the chemical shifts values are reported on ? scale in ppm, relative to TMS (? 0.00ppm).
Example 1: Preparation of L-Serine methyl ester hydrochloride

Thionyl chloride (1.1 eq.) was added dropwise to methanol (12 vol.) at 0-5 °C. To this mixture was added L-Serine portion wise (1.0 eq) at below 15 °C. The reaction mixture was warmed to 20-30 °C and then refluxed for 4 hours. Upon reaction completion, solvent was removed by distillation and the residue was mixed with methyl tert-butyl ether (7 volumes) and stirred at 20-30 °C for 2 hours. Filtered the solids and washed with methyl tert-butyl ether (2 vol.), dried the solid under vacuum at 45-50 °C for 5 hours to get pure L-Serine methyl ester hydrochloride as a white off-solid (90%).
1H NMR (500 MHz, DMSO-d6): d 5.63 (br., 1H), 4.13 (t, J = 3.5 Hz, 1H), 3.85-3.78 (m, 2H), 3.75 (s, 3H).

Example 2: Preparation of N-(tert-Butoxycarbonyl)-L-serine methyl ester

Ethyl acetate (8 vol.), BOC-anhydride (0.92 eq.) and K2CO3 (1.5 eq.) were added to a solution of L-Serine methyl ester hydrochloride (1.0 eq.) in water (8 vol.) under stirring at 20-30 °C. Stirred the reaction mixture at 20-30 °C for 24 hours. Upon reaction completion, organic layer was separated and washed the organic layer with 15% aq. NaCl solution (2 x 4 vol.). Organic layer was distilled and dried under vacuum to provide pure N-(tert-Butoxycarbonyl)-L-serine methyl ester as a pale-yellow oil (82%).
1H NMR (500 MHz, DMSO-d6): d 6.92 (d, J = 8.0 Hz, 1H), 4.88 (t, J = 6.0 Hz, 1H), 4.08-4.05 (m, 1H), 3.60-3.64 (m, 5H), 1.40 (m, 9H).

Example 3: Preparation of tert-butyl-1-(methoxycarbonyl)vinylcarbamate (5’)

To a solution of N-(tert-Butoxycarbonyl)-L-serine methyl ester (1.0 eq.) in dichloromethane (10 vol.) was added methanesulfonylchloride (1.25 eq.) followed by triethylamine (3.0 eq.) at -10 to -15 °C. After completion of addition, warmed the reaction mixture to 20-30 °C and stirred for 3 hours. Upon reaction completion, the reaction mixture cooled to 0-5 °C and adjusted the pH to 5-6 with aq. HCl. Warmed the reaction mixture to 20-30 °C, separated the layers and the organic layer washed with water (2 x 3 vol.). Silica gel (1 time) was added into the organic layer and filtered, the filtrate was distilled and dried under vacuum to provide the pure tert-butyl-1-(methoxycarbonyl)vinylcarbamate as a yellow oil (87%).

1H NMR (500 MHz, DMSO-d6): d 8.31 (s, 1H), 5.65 (br., 1H), 5.51 (s, 1H), 3.75 (s, 3H), 1.43 (s, 9H).

Example 4: Preparation of tert-butyl-1-(methoxycarbonyl)-2-(difluoromethyl) cyclopropylcarbamate (4’)

To a solution of tert-butyl-1-(methoxycarbonyl)vinylcarbamate (1.0 eq.) in CHCl3 (10 vol.) was added 2,2-difluoroethylamine (3 eq.), tert-butyl nitrite (0.5 eq.) and acetic acid (0.5 eq.) under stirring at 20-30 °C. The reaction mixture was heated to 45-50 °C and added tert-butyl nitrite (3.0 eq.) dropwise at 45-55 °C. Upon completion of addition, maintained the reaction at 45-55 °C for 60 minutes and cooled to 20-30 °C. The reaction mixture was stirred at 20-30 °C for 24 hours. The solvent was removed by distillation under vacuum at 45-50 °C to get a brown residue. The residue was suspended in toluene (2 vol.) and heated to 65-70 °C, maintained for 5 h. Upon completion of reaction, the reaction mixture was cooled to 20-30 °C, filtered and washed with toluene (1 vol.). The filtrate was distilled and dried under vacuum at 45-50 °C to get crude tert-butyl-1-(methoxycarbonyl)-2-(difluoromethyl)cyclopropyl carbamate 4’ (mixture of four isomers) as a brown oil.
1H NMR (500 MHz, DMSO-d6): (mixture of rotamers) d 7.8 (s, 0.7H), 7.7 (s, 0.3H), 7.45 (s, 0.3 H), 7.40 (0.1 H), 3.70-3.60 (m, 4.5H), 2.20-2.10 (m, 0.45H), 2.00-1.90 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.50 (m, 0.6H), 1.45-1.30 (m, 15H).

Example 5: Preparation of 1-[(tert-butoxycarbonyl)amino]-2-(difluoromethyl) cyclopropane carboxylic acid (mixture of 3a’ and 3b’)

To a solution of crude tert-butyl-1-(methoxycarbonyl)-2-(difluoromethyl)cyclopropyl carbamate (1 eq.) in THF (10 vol.) was added aq. NaOH solution (2.5 eq./1.5 vol. of water) under stirring. The reaction mixture was stirred at 20-30 °C for 12 hours. After reaction completion, solvent was removed by distillation. The residue was dissolved in water (10 vol.) and extracted the impurities with Ethyl acetate (3 x 5 vol.). The aqueous layer was acidified with aq. HCl to pH 3.5-4.0 at below 10 °C. The obtained solid material was filtered and washed with water (5 vol.). Dried the solid in an oven at 55 °C to get 1-[(tert-butoxycarbonyl)amino]-2-(difluoromethyl)cyclopropanecarboxylic acid as a pale-yellow solid (mixture of 3a’ and 3b’) (40% from 5’).
[?]D25 -0.98° (c = 0.1, MeOH); 1H NMR (500 MHz, DMSO-d6): (mixture of rotamers) d 13.1 (br, 1H), 7.69 (s, 0.7H), 7.33 (s, 0.3 H), 6.06-5.78 (m, 1H), 1.90-1.88 (m, 1H), 1.67-1.61 (m, 1H), 1.42-1.37 (m, 10H).

Example 6: Preparation of tert-Butyl-1-(methoxycarbonyl)-2-(difluoromethyl) cyclopropyl carbamate (mixture of 4a’ and 4b’)

To a solution of 1-[(tert-butoxycarbonyl)amino]-2-(difluoromethyl)cyclopropane
carboxylic acid (1 eq.) in acetone (15 vol.) was added K2CO3 (2.0 eq.) followed by methyl iodide (3.0 eq.) at 10-20 °C under stirring. The reaction mixture was stirred at 20-30 °C for 12 hours. Upon reaction completion, reaction mixture was filtered and washed with acetone (2 vol.). The filtrates were distilled under vacuum at 45-50 °C. The obtained residue was suspended in methyl tert-butyl ether (10 vol.) and washed with water (3 x 5 vol.). The organic layer was distilled and dried under vacuum to get the residue. Hexanes (4 vol.) was added to the residue and stirred for 30 minutes. The solid material was filtered and washed with hexanes (2 vol.), dried the solid under vacuum at 45-50 oC to get the tert-butyl-1-(methoxycarbonyl)-2-(difluoromethyl)cyclopropylcarbamate as a pale-yellow solid (85%) (mixture of 4a’ and 4b’);
1H-NMR (500 MHz, CDCl3) (mixture of rotamers): d 5.98-5.74 (m, 1H), 5.20, 4.94 (br., 1H), 3.77 (s, 3H), 2.03-1.98 (m, 1H), 1.89 (br., 1H), 1.58-1.54 (m, 1H), 1.45 (s, 9H).

Example 7: Preparation of tert-butyl-(1R,2R)-1-(methoxycarbonyl)-2-(difluoromethyl) cyclopropylcarbamate (4a’)

To a solution of tert-butyl-1-(methoxycarbonyl)-2-(difluoromethyl)cyclopropyl carbamate (1 eq.) in acetone (10 vol.) was added water (23 vol.). The pH of the reaction mixture was adjusted to 7.5 using aq. NaOH under stirring. To this mixture was added Alcalase 2.4 L enzyme by maintaining the pH 7.5 with the addition of 0.5M aq. NaOH solution. Reaction mixture was stirred by maintaining the pH between 7.2 and 7.7 with the addition of 0.5M aq. NaOH solution for about 35 h. Upon reaction completion, sodium bicarbonate (0.5 time) was added to the reaction mixture and extracted the product with methyl tert-butyl ether (MTBE):hexanes (2:1) mixture (2 x 15 vol.). The combined organic layers were washed with water (2 x 10 vol.). The organic layer was distilled and dried under vacuum at 45-50 °C to get tert-butyl-(1R,2R)-1-(methoxycarbonyl)-2-(difluoromethyl)cyclopropylcarbamate as a pale-yellow oil (45%).
1H NMR (500 MHz, DMSO-d6): (mixture of rotamers) d 7.80 (s, 0.7H), 7.46 (s, 0.3H), 6.05-5.77 (m, 1H), 3.68 (s, 0.9H), 3.65 (s, 2.1H), 1.99-1.94 (s, 1H), 1.74-1.65 (m, 1H), 1.44-1.35 (m, 10H).

Example 8: Preparation of (1R,2R)-1-[(tert-butoxycarbonyl)amino]-2-(difluoromethyl) cyclopropanecarboxylic acid (3a’)

To a solution of tert-butyl-(1R,2R)-1-(methoxycarbonyl)-2-(difluoromethyl) cyclopropyl carbamate (1 eq.) in methanol (7 vol.) and THF (7 vol.) was added LiOH.H2O (3.0 eq.) followed by water (1.5 vol.). The reaction mixture was stirred at 20-30 °C for 3 h. Upon reaction completion, solvent was removed by distillation under vacuum at 45-50 °C. The obtained solid was dissolved in water (10 vol.) and extracted the impurities with MTBE (5 vol.). The pH of the aqueous layer was adjusted between 2 and 3 with aq. HCl. The product was extracted with ethyl acetate (2 x 10 vol.). The combined organic layers were washed with water (5 vol.) then distilled, dried under vacuum at 45-50 °C to obtain (1R,2R)-1-[(tert-butoxycarbonyl) amino]-2-(difluoromethyl) cyclopropane carboxylic acid as an off-white solid (90%).
[?]D25 -19.8° (c = 0.1, MeOH); 1H NMR (500 MHz, DMSO-d6): (mixture of rotamers) d 13.1 (br, 1H), 7.68 (s, 0.7H), 7.32 (s, 0.3H), 6.06-5.79 (m, 1H), 1.90-1.88 (m, 1H), 1.66-1.61 (m, 1H), 1.42-1.37 (m, 10H).

Example 9: Preparation of tert-butyl-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl) sulfonyl]carbamoyl}cyclopropyl]carbamate

To a solution of (1R,2R)-1-[(tert-butoxycarbonyl)amino]-2-(difluoromethyl) cyclopropane carboxylic acid (1 eq.) in THF (10 vol.) was added CDI (2.0 eq.) at 0-5 °C and stirred for 2 hours. In another flask, charged 1-methylcyclopropanesulfonamide (1.2 eq.), tetrahydrofuran (5 vol.), DBU (1.5 eq.) and stirred for 1 h at 20-30 °C. It was added to the above reaction mixture at 0-5 °C. Reaction mass temperature was raised to 20-30 °C and stirred for 15 hours. Upon reaction completion, charged acetonitrile (4 vol.) and water (4 vol.), organic solvent from the reaction mixture was removed by distillation and pH of the mixture was adjusted approx. 3.0 with aq. acetic acid and stirred for 1 h. Filtered the solid and washed with water (10 vol.) and dried under vacuum 45-50 °C to provide tert-butyl-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl] carbamoyl}cyclopropyl]carbamate as off-white solid (75%).
1H NMR (500 MHz, DMSO-d6): (mixture of rotamers) d 11.52 (br, 1H), 7.34-7.00 (m, 1H), 5.84-5.54 (m, 1H), 2.13 (m, 1H), 1.82 (m, 1H), 1.41-1.31(m, 15 H), 0.88 (m, 2H)

Example 10: Preparation of (1R,2R)-1-Amino-2-(difluoromethyl)-N-[(1-methylcyclopropyl) sulfonyl] cyclopropanecarboxamide hydrochloride (1)

To a solution of tert-butyl-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl) sulfonyl]carbamoyl}cyclopropyl]carbamate (1 eq.) in IPA (8 vol.) was added 5N HCl in isopropyl alcohol (2 vol.) at 45-55° C and stirred for 15 hours. Upon reaction completion, solvent was distilled under vacuum up to 5 volumes and stirred at 35-45 °C for 2 hours. Reaction mixture was cooled to 10-20 °C and stirred for 2 hours, added n-Heptane (5 vol.) to the reaction mixture, stirred for 3 hours. Reaction mixture was filtered, washed with n-Heptane (3 vol.) and dried under vacuum at 50-55 oC to obtain (1R,2R)-1-Amino-2-(difluoromethyl)-N-[(1-methylcyclopropyl)sulfonyl]cyclopropanecarboxamide hydrochloride as an off-white solid (78%).
[?]D25 -20.4° (c = 0.1, MeOH); 1H NMR (500 MHz, DMSO-d6): d 9.13 (br, 2H), 6.09-5.86 (dt, J = 6.5, 1H), 5.5-4.5 (br, 2H), 2.31-2.26 (m, 1H), 1.96 (t, J= 1.4, 1H), 1.72-1.69 (m, 1H), 1.48-1.29 (m, 5H), 0.88-0.83 (m, 2H).
,CLAIMS:1. A process for the preparation of compound of formula 1 or its salt, comprising the steps of:
a) reacting the compound of formula 5 with 2,2-difluoroethylamine to get compound of formula 4, which is a mixture of enantiomers and diastereomers of formulae 4a, 4b, 4c, 4d;

b) hydrolyzing the compound of formula 4 and isolating the required enantiomeric mixture of compounds of formulae 3a and 3b;

c) reacting the mixture of compounds of formulae 3a and 3b with alkylating agent to obtain a mixture of enantiomeric compounds of formulae 4a and 4b;

d) enzymatic kinetic resolution of mixture of enantiomeric compounds of formulae 4a and 4b to isolate a compound of formula 4a;

e) hydrolyzing the compound of formula 4a to get a compound of formula 3a; and

f) converting the compound of formula 3a to a compound of formula 1 or its salt.

wherein R is selected from liner or branched C1-10 alkyl; Pg is any amine protecting group.

2. A process for the preparation of voxilaprevir or its pharmaceutically acceptable salt comprising converting the compound of formula 1 or its salt preparing as claimed in claim 1 to voxilaprevir or its pharmaceutically acceptable salt.