DESC:Field of the Invention:
The present invention relates to a novel process for the preparation of Sofosbuvir and its intermediates.

Background of the Invention:
Sofosbuvir (formerly PSI-7977 or GS-7977) is an approved drug for the treatment of hepatitis
C. It was discovered at Pharmasset and then acquired for development by Gilead Sciences.
Sofosbuvir is chemically known as (S)-isopropyl-2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate of Formula (I).

Formula 1

US 7964580 (‘580) is directed towards novel nucleoside phosphoramidate prodrug for the treatment of hepatitis C virus infection. ‘580 patent discloses Sofosbuvir and process for preparation of Sofosbuvir.
Process for preparation of Sofosbuvir as per ‘580 patent involve reaction of compound of formula 4” with a nucleoside 5’

Compound 4” nucleoside 5’
Wherein X’ is a leaving group, such as Cl, Br, I, tosylate, mesylate, trifluoroacetate, trifluroslfonate, pentafluorophenoxide, p-NO2-phenoxide etc.

PCT publication no. WO 2010/135569 A1 discloses various processes for the preparation of
Sofosbuvir and its intermediates.

Summary of Invention:
In one aspect the present invention provides a novel process for the preparation of Sofosbuvir.
In another aspect the present invention provides a novel process for preparation of compound of formula 3:

Formula 3
Wherein R is a protecting group, non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, C2H5-,CH2-alkyl, CH2-alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene)..

Detail Description of the Invention:
There is always a need for alternative preparative routes, which for example, use reagents, solvents that are less expensive, and/or easier to handle, consume smaller amounts of reagents and solvents, provide a higher yield of product, involve fewer steps, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.
In one embodiment, there is provided a novel process for the preparation of Sofosbuvir. The process comprises:
a) reacting a compound of formula 2 or salt thereof with a compound of formula 4 or salt thereof to obtain compound of formula 3 or salt thereof.

b) deprotection of compound of formula 3 or salt thereof to obtain Sofosbuvir.

wherein R is a protecting group, non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, C2H5-,CH2-alkyl, CH2-alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

The reaction of step (a) can be carried out in the presence of a Grignard reagent and a solvent.

The Grignard reagent for the reaction of step (a) can be alkyl magnesium halide such as Butylmagnesiumchloride (BuMgCl), Butylmagnesiumbromide (BuMgBr), tertiary-butylmagnesiumchloride-(tert-BuMgCl), tertiary-butylmagnesiumbromide (tert-BuMgBr) or the like.
The solvent for the reaction of step (a) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step (a) is carried out at a temperature of about 0°C to about 100°C, preferably at about 5°C to about 50°C.

The deprotection reaction of step (b) can be done under acidic conditions by using aqueous hydrochloric acid or the like.

The reaction of step (b) can be carried out in presence a solvent.

The solvents for the reaction of step (b) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methanol.

The reaction of step (b) is carried out at a temperature of about 10°C to about 100°C, preferably at about 25°C to about 50°C.

In another embodiment, there is provided a novel process for preparation of compound formula 3 or salt thereof, the process comprises:
a) reacting compound of a formula 2 or salt thereof with compound of formula 4 or salt thereof to obtain compound of formula 3 or salt thereof.

Wherein,

R is a protecting group, non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, C2H5-,CH2-alkyl, CH2-alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

The reaction of step (a) can be carried out in the presence of a Grignard reagent and a solvent.

The Grignard reagent for the reaction of step (a) can be alkyl magnesium halide such as Butylmagnesiumchloride (BuMgCl), Butylmagnesiumbromide (BuMgBr), tertiary-butylmagnesiumchloride-(tert-BuMgCl), tertiary-butylmagnesiumbromide (tert-BuMgBr) or the like.

The solvents for the reaction of step (a) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.
The a process for preparation of compound formula 3 is carried out at a temperature of about 0°C to about 100°C, preferably at about 5°C to about 50°C.

The intermediate of formula 2 can be prepared according to the disclosed methods in the prior art.

The invention is explained in its best way by examples herein given below. It will be apparent to those skilled in the art that the various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. The examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

Example-1
Process for preparation of compound of formula 4 (isopropyl 2-((((3-nitro-5-(trifluoromethyl)pyridine-2-yl)oxy)(phenoxy)phosphoryl)amino)propanoate ):

Anhydrous dichloromethane (DCM) 700ml was charged in round bottom flask flushed with nitrogen. The flask was cooled to -60° to -70°C in a dry ice acetone bath. Phenyl phosphodichloridate (76.04 gm) was added in one portion in the flask at -65°C. Solution of L-alanine isopropyl ester hydrochloride (60.56 gm) in DCM (50 ml) was added to the reaction mass. Solution of triethylamine (72.44gm) in DCM (50ml) was added to the reaction mass over a course of 60 minutes, while maintaining internal temperature below -70°C throughout the addition. The resulting white slurry was agitated for additional 60 minutes. Then the temperature of reaction mass was raised to room temperature. Reaction mass was stirred for 60 min & TLC was checked. Reaction mass was filtered and rinsed with anhydrous dichloromethane (2 X100 mL). The filtrate was concentrate under vacuum to 20 V and reaction mass was filtered, washed with DCM (15ml). The filtrate was transferred to RBF. The reaction mass was cooled to 0°-10°C. A solution of 2-hydroxy-3-nitro-5-(trifluoromethyl) pyridine (15.gm) in DCM (100ml) & triethyl amine (21.89gm) was added to the reaction mass. Temperature of reaction mass was raised to 20-30°C. Reaction mass was stirred overnight. Reaction was monitored using TLC. After completion, the reaction mass was filtered and washed with DCM (30ml). Filtrate was washed with water (150 ml x 2). Organic layer was concentrated under vacuum and degased. Diisopropyl ether (200ml) was charged to reaction mass and reaction mass was stirred for 15 minutes , filtered and washed with methyl ter-butyl ether (MTBE 30ml). Filtrate was concentrated under vacuum and dried. (8.68gm, MP-12.5°-131.5°C). Obtained compound was characterized by Mass, NMR & IR. 1H NMR (DMSO-d6) d 1.07 -1.27 (m, 9H), 4.04-4.11(m, 1H), 4.73-4.79(m, 1H), 6.76-7.43 (m, 5H), 9.00-9.02 (d, 2H); MS, m/e 478 (M+1) +; FTIR, 1203, 1409, 1580, 1732, 3217.

Example 2:
Process for the coupling of isopropyl 2-((((3-nitro-5-(trifluoromethyl)pyridine-2-yl)oxy)(phenoxy)phosphoryl)amino)propanoate with 4-ethoxy-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)one:

A solution of 4-ethoxy-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one (10gm.) in 250 ml tetrahydrofuran and acetonitrile (1:1) was cooled to 5-10°C. Tert-butylmagnesium chloride (36.5ml, 2M solution in THF) was added dropwise to the above reaction mass. Following the addition, the reaction mixture was stirred for 30 min at5-10°C. A solution of isopropyl 2-((((3-nitro-5-(trifluromethyl)pyridine-2-yl)oxy)phenoxy)phosphoryl)amino)propanoate (19.87gm) in tetrahydrofuran (100ml) was added to the reaction mass at ambient temperature at 5-10°C. Reaction mass was stirred till reaction was complete. After completion of reaction, reaction mass was quenched by saturated aqueous ammonium chloride solution (35m in 100ml) at 5-10°C. Reaction mass was stirred and temperature of reaction mass was raised to room temperature. Reaction mass was concentrated under vacuum and degassed. Ethyl acetate(100ml) and water (100ml) were added to reaction mass, stirred and organic layer was separated. The separated organic layer was washed with 15% aqueous K2CO3 solution (2x 50ml).Organic layer was distilled, the oily residue thus obtained was dissolved in dichloromethane, filtered and concentrated under vacuum. Obtained product was purified by column chromatography and characterized with Mass, NMR & FTIR.
1H NMR (CdCl3) d 1.13 -1.34 (m, 15H), 3.7-3.85.11(m, 2H), 4.04-4.06(m, 1H), 4.27-4.38 (m, 4H), 4.82-4.88 (m, 1H), 5.88-6.12(m,4H), 7.17-7.24 (m,3H), 7.35-7.39 (m,2H), 7.87-7.89(m,1H); MS, m/e 558 (M+1) +; FTIR, 1086,1210,1657,1738,3400.

Example 3 Preparation of Sofosbuvir

Compound obtained from ex.2 (8.5 gm) was dissolved in methanol (85ml). The solution was cooled to 5-10°C. 10% dil. HCl (13ml) was added drop wise to reaction mass at 5-10°C. The reaction mass was stirred at 5-10°C until reaction was complete. Reaction mass was distilled under vacuum & degassed. Ethyl acetate (180ml) and water (50ml) were added to the reaction mass. Layers were separated; organic layer was washed with 15% NaHCO3 solution and water. Organic layer was separated and distilled under vacuum. Dichloromethane (DCM, 17ml) was charged to the residue. Diisopropyl ether (DIPE, 34ml) was added slowly to the reaction mass. Reaction mass was stirred overnight a t20-25°C, filtered, washed with DCM & DIPE (1:2). Solid was dried under vacuum at 50-55°C. Obtained product was characterized with mass & NMR.
,CLAIMS:1. A process for the preparation of Sofosbuvir comprising:
a) reacting a compound of formula 2 or salt thereof with a compound of formula 4 or salt thereof to obtain a compound of formula 3 or salt thereof.

and
R is a protecting group.
b) deprotection of the compound of formula 3 or salt thereof to obtain Sofosbuvir;

2. The process according to claim 1, wherein protecting group is selected from the group consisting of: -C(O)-alkyl, -C(O)Ph, -C(O)aryl, -CH3, -C2H5-, -CH2-alkyl, -CH2-alkenyl, -CH2Ph, -CH2-aryl, -CH2O-alkyl, -CH2O-aryl, -SO2-alkyl, -SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

3. The process according to claim 1, wherein the reaction of step (a) is carried out in presence of a Grignard reagent and a solvent.

4. The process according to claim 3, wherein the reaction in step (a) is performed in the presence of a solvent selected from the group consisting of aromatic hydrocarbons chlorinated hydrocarbons; alcohols; ethers; and polar aprotic solvents

5. The process according to claim 4 wherein the reaction in step (a) is performed in the presence of a solvent selected from toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, methanol, ethanol, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, and acetonitrile or mixtures thereof.

6. The process according to claim 3, wherein the reaction in step (a) is performed in the presence of a Grignard reagent selected from the group consisting of butylmagnesiumchloride(BuMgCl), butylmagnesiumbromide (BuMgBr), tertiary-butylmagnesiumchloride (tert-BuMgCl), and tertiary-butylmagnesiumbromide (tert-BuMgBr).

7. The process according to claim 1, wherein the deprotection step (b) is performed under acidic conditions.

8. A process for the preparation of a compound of formula 3 or salt thereof comprising reacting a compound of formula 2 or salt thereof with a compound of formula 4 or salt thereof:

wherein
;
and

R is a protecting group.

9. The process according to claim 8, wherein protecting group is selected from the group consisting of: -C(O)-alkyl, -C(O)Ph, -C(O)aryl, -CH3, -C2H5-, -CH2-alkyl, -CH2-alkenyl, -CH2Ph, -CH2-aryl, -CH2O-alkyl, -CH2O-aryl, -SO2-alkyl, -SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

10. The process according to claim 8, wherein the reaction of step (a) can be carried out in presence of a Grignard reagent and a solvent.

11. The process according to claim 10, wherein the reaction is performed in the presence of a solvent selected from hydrocarbons; chlorinated hydrocarbons; alcohols; ethers; and polar aprotic solvents.

12. The process according to claim 11,wherein the reaction in step (a) is performed in the presence of a solvent selected from toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, methanol, ethanol, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone and acetonitrile or mixtures thereof.

13. The process according to claim 8, wherein the reaction in step (a) is performed in the presence of a Grignard reagent selected from the group consisting of butylmagnesiumchloride (BuMgCl), butylmagnesiumbromide (BuMgBr), tertiary-butylmagnesiumchloride (tert-BuMgCl), and tertiary-butylmagnesiumbromide (tert-BuMgBr).