FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation Sofosbuvirof Formula (I).

BACKGROUND OF THE INVENTION

(S)-isopropyl-2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydr opyrimidin-l(2H)-yl)-4- fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phen oxy)phosphorylamino) propanoateor Sofosbuvir is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

Sofosbuvir was approved by USFDA in 2013 and is marketed under the brand name Sovaldi ^® . It is indicated for the treatment for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sovaldi ^® , efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Sofosbuvir is marketed in a crystalline free base form.Itis a white to off-white crystalline solid with the empirical formula C22H29FN309P and a molecular weight of 529.45 Daltons. It is highly soluble compound and possessing solubility of > 2 mg/mL across the pH range of 2-7.7 at 37°C. As per the EMEA scientific discussion "Sofosbuvir is chiral molecule and possesses 6 stereogenic centers which are well controlled by the synthetic process and the specifications of raw materials. The absolute and relative configuration of these chiral centers was established by single crystal X-ray crystallography. Eight polymorphic forms of Sofosbuvir have been observed and the manufacturing process consistently produces Sofosbuvir as the most thermodynamically stable polymorphic form, containing a small amount of a metastable form which were determined to be pharmaceutically equivalent as per ICH Q6A (decision tree #4). Other polymorphic forms are excluded by the manufacturing process and their absence is confirmed by DSC "

Sofosbuviris specifically disclosed in US 7,964,580.The process disclosed for the preparation of Sofosbuviris delineated below:

HO yr ne _Bz 0 j. BzO

ΝΗ,/MeOH

Sofosbuvir

This patent discloses a process for the preparation of Sofosbuvir by using the chloro as an activating group. This patent has not provided any insight about the impurity concern as well as disclosure of any purity and their levels in the final product.The process was found to be cumbersome and involves the formation of many impurities. Further, the use of intermediate- 2 in the synthesis of Sofosbuvir yields the final API in poor yield, which was about20%. In view of this, it is necessary to develop a process resulting in the product, which is complying with the 1CH requirements of quality parameters besides industrially viable process.

Ross et al in US 8,735,569 disclose a process for the preparation of Sofosbuvir by protecting the hydroxyl group with pentafluoro phenol. The process is as disclosed below:

The present inventors found that the overall yield appears to be only 35-40% to get the desired isomer. This patent has not disclosed any generalized impurities formed during the process development. This patent has also not disclosed the content of total impurities formed in the final active pharmaceutical ingredient (API).

Deshpande Milind et al in US20140309189 disclosed process for the preparation of Sofosbuvir using various protecting groups selected from an arylhydroxyl or aryl sulfhydryl, R -LH where L is S or O, and R is an optionally substituted aryl, heteroaryl, or heterocycloalkyl group such as phenyl, pyrrole, pyridyl, pyridinyl, or indole, or alternatively R-LH can be an N-hydroxyimide such as N-hydroxysuccinimide or N-hydroxyphthalimide, and in certain embodiment -LH is

The proposed protecting groups results in the formation of byproducts due to incomplete conversion and results in significantly lower yield and quality. Further, it is observed that, after completion of the reaction, it is very difficult to remove the process related impurities and involves cumbersome workup to remove these impurities. The present inventors observed that the use of theses protecting groups is very difficult in large scale synthesis.

In view of the above it is pertinent to note that there is a need to develop new process for the preparation of Sofosbuvir having further improved yield, physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel process for the preparation of Sofosbuvir, which may further improve the characteristics of drug Sofosbuvirand in developing the substantially pure Sofosbuvir.

Exploring new process for developing a stable and pure form of Sofosbuvir, which are amenable to scale up for pharmaceutically active useful compoundsin the preparation of Sofosbuvirmay thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility. Hence, inventors of the present application report a process for the preparation of a stable and substantially pure form of Sofosbuvir, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

The present invention provides an improved process for the preparation of substantially pure Sofosbuvir, wherein substantially pure material having a purity of greater than 99.5% by HPLC and meeting the quality of ICH guidelines. Sofosbuvirobtained by the process of the present invention is non-hygroscopic and chemically stable and has good dissolution properties.

In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of substantially pure Sofosbuvir, which is industrially feasible process, with the use of neither industrial friendly solvents, which nor involves tedious work up and hazardous handling steps. OBJECTIVE OF THE INVENTION

The main objective of the invention relates to a process for the preparation of Sofosbuvir.

Yet another objective of the invention relates to a process for the preparation of substantially pure Sofosbuvir.

Yet another objectiveof the invention relates a process for the preparation of Sofosbuvir, which is free of process related impurities. SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Sofosbuvir of Formula

(I)comprising the steps of - a) reacting dihalophenyl phosphate (II) with an amino ester or a salt of amino ester (III) to form a compound of Formula (IV);

wherein X is CI, Br, I

b) reacting compound of Fonnula (IV) with an oxime derivative of Formula (V) to from an intermediate of Formula (VI);

c) preparation of Sofosbuvir:

i. reacting compound of Formula (VI) with a nucleoside of formula (VII) in resence of base; or

ii. reacting compound of Formula (VI) with a secondary hydroxy protected nucleoside of formula (VIII) in presence of base, followed by deprotection; and

d) optionally, purifying the Sofosbuvir using a solvent.

The present invention further relates to a process for the preparation of Sofosbuvir comprises of

i. reacting compound of Formula (VI) with a nucleoside of formula (VII) in presence of base; or

ii. reacting compound of Formula (VI) with a secondary hydroxy protected nucleoside of formula (VIII) in presence of base;

The present invention further relates to ula (VI)

wherein Rl and R2 are same or different selected from H, -CN, -COOMe, COOEt, -Ph, -p- Nitro Phenyl, 2,6-dichloro-3-fluro phenyl, -COMe,amino, deuterium, hydroxy, (Ci-C ₆ )alkyl, (CrC ₆ )alkoxy, halo, (C ₁ -C ₆ )acyl, (C!-C6)alkylamino, amino( (Ci-C ₆ )alkyl, (Ci-C6)alkoxy- CO— NH, (C,-C ₆ )alkylamino-CO— (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) alkynyl, (Ci-C ₆ )alkylamino, amino(C ₁ -C ₆ )alkyl, hydroxy( (C,-C ₆ )acyloxy( (Q- C ₆ )alkyl, nitro, cyano(C _! -C6)alkyl, halo(Ci-C ₆ )alkyl, nitro(Ci-C ₆ )alkyl, trifluoromethyl, trifluoromethyl(Ci-C6)alkyl, (Ci-C6)acylamino, (C ₁ -C6)acylamino(Ci-C ₆ )alkyl, (Q- C ₆ )alkoxy(Ci-C ₆ )acylamino, amino(Ci-C ₆ )acyl, amino(Ci-C ₆ )acyl((Ci-C ₆ )alkyl, (Q- C ₆ )alkylamino( (C C ₆ )acyl, ((Ci-C ₆ )alkyl) ₂ amino(C,-C ₆ )acyl, CO— O— R'where R' is hydrogen or (C ₁ -C ₆ )alkyl,benzyl,alkyl aryl, alkyl hertocyclicor any electron withdrawing groups.

The present invention further relates to Sofosbuvir having a purity of greater than 99.5% DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Sofosbuvir of Formula (I) comprising the steps of reacting dihalo phenyl phosphate (II) with an amino ester or a salt of amino ester (III) to form a compound of Formula (IV) in presence of a solvent selected from alcohol (Cl-4) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from -20°C to 50°C for a period of 20 minutes to 1 hour to provide an intermediate of Formula (IV), which may be isolated. The present inventors found that the compound of formula (IV) is unstable if it is isolated. Hence, it is preferred not to isolate. The obtained compound of Formula (IV) is dissolved in a solvent selected fromalcohol (Cl-4) or Ketones (C3-6) or organic solvents (Cl -8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from -20°C to 50°C for a period of 1 hour to 3 hours under nitrogen atmosphere, then the mixture of oxime derivative of Formula (V) elected from and not limited to

HO

HO. HO HO.

N

N N N

EtOOC CN EtOOC COOEt MeOOC COOMe

MeOOC COOEt .

COOEt

MeOC V ^0H

in presence of base selected frominorganic such as Magnesium ditertiatybutoxide,tert- butylmagnesiumchloride sodium tertiary butoxide, potassium tertiary butoxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide; or organic bases, such as triethylamine, diisoproylethylamine, tributyl amine, Ν,Ν-dimethyl aniline, pyridine, N- methylmorpholine, DBN, DBU; was added to the above reaction mass at -20 to -5°C over a period of 1 hour to 2 hours, and allowed the reaction mass to reach the temperature around 25-30°C, concentrated the reaction mass and methyl tertiary butyl ether was added to the residue and stirred the solution for 5-10min, filter the solution to remove unwanted salts and concentrated the solution to obtain compound of Formula (VI), wherein Rl and R2 are same or different selected from H, -CN, -COOMe, COOEt, -Ph, -p-Nitro Phenyl, 2,6-dichloro-3- fluro phenyl, -COMe,amino, deuterium, hydroxy, (Ci-C6)alkyl, (Ci-C ₆ )alkoxy, halo, (d- C ₆ )acyl, amino( (Cj-C ₆ )alkyl, (d-C ₆ )alkoxy-CO— NH, (Q- C ₆ )alkylamino-CO— , (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) alkynyl, (Ci-C ₆ )alkylamino, amino(C C ₆ )alkyl, hydroxy( (C,-C ₆ )alkyl, (C, -C6)alkoxy(Cj-C6)alkyl, (Ci-C ₆ )acyloxy( (Ci-C ₆ )alkyl, nitro, cyano(Ci-C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, nitro(Ci-C ₆ )alkyl, trifluoromethyl, trifluoromethyl(C _r C ₆ )alkyl, (C C ₆ )acylamino, (C]-C ₆ )acylamino(Ci-C ₆ )alkyl, (Cj- C ₆ )alkoxy(Ci-C ₆ )acylamino, aminoiC C^acyl, amino(Ci-C ₆ )acyl((Ci-C ₆ )alkyl, (Ci- C ₆ )alkylamino( (C _r C ₆ )acyl, ((CrC ₆ )alkyl) ₂ amino(C,-C ₆ )acyl, CO— O— R'where R' is hydrogen or (Ci-C6)alkyl,benzyl,alkyl aryl, alkyl hertocyclicor any electron withdrawing groups. Preparation of Sofosbuvir involves two different processes. One of the process comprises of reacting a compound of Formula (Vl)with a nucleoside of formula (VII) in presence of base selected frominorganic such as Magnesium ditertiatybutoxide,tertbutylmagnesium chloridesodium tertiary butoxide, potassium tertiary butoxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide; or organic bases, such as triethylamine, diisoproylethylamine, tributyl amine, Ν,Ν-dimethyl aniline, pyridine, N-methylmorpholine, DBN, DBU; and a solvent selected from alcohol (CI -4) or Ketones (C3-6) or organic solvents (CI -8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from 20 to 50°C over a period of 12 hour to 20 hours. pH of the reaction mass was adjusted and extracted the organic layer with an organic solvent to provide Sofosbuvir. The second process comprises of reacting a compound of Formula (Vl)with a secondary hydroxy protected nucleoside of formula (VIII), wherein Z is a hydroxyl protecting group selected from acetyl, benzyl, benzoyl, levulinoyl;in presence of base selected frominorganic such as Magnesium ditertiatybutoxide,tert butyl magnesium chloride sodium tertiary butoxide, potassium tertiary butoxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide; or organic bases, such as triethylamine, diisoproylethylamine, tributyl amine, Ν,Ν-dimethyl aniline, pyridine, N-methylmorpholine, DBN, DBU; and a solvent selected from alcohol (CI -4) or Ketones (C3-6) or organic solvents (CI -8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from 20 to 50°C over a period of 12 hour to 20 hours. pH of the reaction mass was adjusted and extracted the organic layer with an organic solvent to provide protected Sofosbuvir, followed by deprotection of hydroxyl group yields Sofosbuvir.

The prior art publications discloses a use of tertiary butyl magnesium chloride catalyzed reagents, which leads to the formation of process related impurities, and is carried out for further steps results in the formation of Sofosbuvir having the corresponding un-reacted impurities. The Sofosbuvir obtained as per the prior-art process does not meet the requirements of ICH guidelines. Extra purification is required to remove these process related impurities, which is cumbersome and the yield of the product is also comparatively low with respect to the present invention. However, the present inventors surprisingly found that the use of base in the condensation step leads to the formation of pure condensed material, which leads to the formation of highly pure Sofosbuvir free of process related impurities, which is novel and inventive and does not involve any extra purification for the as preparation of pure Sofosbuvir. The present inventors surprisingly found that the use of Magnesium di-tertiary butoxidein present invention in the condensation step leads to completion of the reaction and minimizes the formation of process related impurities as well as side products as disclosed in the prior art, which finally leads to the formation of Sofosbuvir, which is free of process related impurities and having a purity of greater than 99.5% (By HPLC).

Further, the present inventors found that the use of Magnesium di-tertiary butoxide in the condensation step leads to the formation of desired isomer more than 50%. The present invention further relates to compou of Formula (VI)

wherein Rl and R2 are same or different selected from H, -CN, -COOMe, COOEt, -Ph, -p- Nitro Phenyl, 2,6-dichloro-3-fluro phenyl, -COMe,amino, deuterium, hydroxy, (Cj-C )alkyl, (Ci-C ₆ )alkoxy, halo, (Ci-C ₆ )acyl, (Ci-C6)alkylamino, amino( (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy- CO— NH, (C _r C ₆ )alkylamino-CO— , (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ ) alkynyl, (C C ₆ )alkylamino, amino(Ci-C ₆ )alkyl, hydroxy( (C _r C ₆ )alkyl, (Ci-C ₆ )alkoxy(Ci-C ₆ )alkyl, (Ci-C ₆ )acyloxy( (d- C ₆ )alkyl, nitro, cyano(Ci-C ₆ )alkyl, halo(CrC ₆ )alkyl, nitro(Ci-C ₆ )alkyl, trifluoromethyl, trifluoromethyl(Ci-C6)alkyl, (C ₁ -C ₆ )acylamino, (Ci-C ₆ )acylamino(Ci-C ₆ )alkyl, (Ci- C6)alkoxy(C]-C ₆ )acylamino, amino(C ₁ -C ₆ )acyl, (Cj- C ₆ )alkylamino( (Ci-C ₆ )acyl, ((Ci-C ₆ )alkyl) ₂ amino(C ₁ -C ₆ )acyl, CO— O— R'where R' is hydrogen or (Ci-C ₆ )alkyl,benzyl,alkyl aryl, alkyl hertocyclicor any electron withdrawing groups. The present inventors found that the use of these intermediates in the preparation of Sofosbuvir yields highly purified material with a purity of greater than 99.5%.

The Sofosbuvir of the compound of the formula (I) obtained from the above stage may be purified by treating the compound of the formula (I) or a reaction mixture or a solvated form thereof is treated with an acid selected from methane sulphonic acid, sulphuric acid, trifluoro- methanesulphonic acid, difluoromethanesulphonic acid, dichloroacetic acid, glucornic acid, gluconic acid, Ferulate, glycols and glycol ethers; to form a salt of the compound of the formula (I) which precipitates from the solution containing the solvated compound of the formula (I), the salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the pure form of compound of the formula (I), preferably at a temperature of from 15° C. to 45° C, most preferably from 25° C. to 35° C. If required, repeat again the acidification followed by basification to obtained desired purity, which is greater than 99.5 %.

Further, the purification of Sofosbuvir of formula (I)may be purified by dissolving compound of the formula (I) in a solvent selected from solvent selected from alcohol (CI -3) or Ketones (C3-6) or organic solvents (CI -8 alkanes, dimethyl formamide) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof. Reaction mass was heated to reflux temperature, filtered the material and washed with the solvent toyieldhighly pure Sofosbuvir.

The obtained pure Sofosbuvir was analyzed, if it is not matching with the desired purity; again repeat the process by treating the Sofosbuvir with acid to prepare the corresponding salt, followed by treating with an alkali solution to obtain substantially pure Sofosbuvir having a purity of greater than 99.5% and meeting the ICH guidelines.

Another embodiment of the present invention relates to substantially pure Sofosbuvir having a purity of greater than 99.5 %, wherein substantially pure Sofosbuvir is having an impurity profile meeting the ICH guidelines.

Another embodiment of the present invention relates to substantially pure Sofosbuvir having a purity of greater than 99.5 %, wherein substantially pure Sofosbuvir contains the process related impurities within the limits of ICH guidelines. The process related impurities that appear in the impurity profile of the Sofosbuvir(I) may be substantially removed by the process of the present invention resulting in the formation of substantially Sofosbuvir(I), which meets the ICH guidelines.

The Sofosbuvir obtained as per the present process is found devoid of any other process related impurities and is adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-85°C for a time ranging from 5 to 10 hours depending upon the physical attributes of the end product obtained i.e. Pure Sofosbuvir, which is obtained according to the present invention is having purity greater than 99.5%.

In another embodiment of the present invention the substantially pure Sofosbuvir obtained by the processes of the present application may be taken as such in crystalline/ noncrystalline form for manufacture of solid dosage forms like tablets, capsules and/or for manufacture of oral liquids.

In another embodiment, the substantially pure Sofosbuviror its acid addition saltobtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with the substantially pure Sofosbuviror its acid addition salt, while retaining the crystalline nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising substantially pure Sofosbuvir or its acid addition saltobtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, di-calcium phosphate, tri-calcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like. Pharmaceutically acceptable excipients used in the compositions derived from substantially pure Sofosbuvir or its acid addition saltof the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation. The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

Example-1

Preparation of 2-[Ethyl 2-iminoxyl, 2--cyanoacetate)-Phenoxy-phosphoryIamino] propionic acid isopropyl ester (±)

Phenyldichlorophosphate(8.05 g, 0.038 mol) and methylene dichloride (50 ml) are charged in to the reaction vessel at 25-30 °C under nitrogen atmosphere. L-Alanine isopropyl ester(5.0 g, 0.038mol) in methylene dichloride (50ml) were slowly added at -10 to -15°C under stirring. The reaction mixture was stirred for 2 hours at -10 to -5 °C. A solution of ethyl 2-cyano-2-(hydroxyimino)acetate (5.4g, 0.038mol) and triethylamine (8.09g,0.08mol) in dichloromethane (50mL) was added drop wise over a period of 45min-lh at -10 to -15°C. The reaction mixture was stirred for 2 hours at -10 to -5°C.The temperature of the reaction mixture was raised to 25-30°C under stirring. The reaction mixture filtered and filtrate concentrated to residue under vacuum. Methyl tertiary butyl ether (50 ml) was added to the residue and stirred for 10 minutes. Filtered the solution and concentrate to yield the title product.

Yield: 14.0 g Example-2

Preparation of compound of Formula (VI) using Ethyl, 2-cyanoacetate Oxime

Isopropyl L-alanine ester (20g) solution in Dichloromethane (512mL)was added drop wise to the solution of Dichloro phenyl phosphate (32.2g) in Dichloromethane (200. OmL) at -10 to - 15°C under nitrogen atmosphere. Stirred the reaction mass at the same temperature for 2h then the mixture of Ethyl cyanoacetate Oxime (21.70g) and Triethyl amine(32.38g) in Dichloromethane(200.0mL) was added to the above reaction mass at -10 to -15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(200.0mL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with 200. OmL of MTBE and concentrated the solution to afford title product.

Yield: 52.0 g

Example-3

Preparation of compound of Formula (Vl)using Benzophenone Oxime

Isopropyl L-alanine ester (3.0g)solution in Dichloromethane (30.0mL)was added drop wise to the solution ofDichloro phenyl phosphate (4.83g) in Dichloromethane (30.0mL) at -10 to - 15°C under nitrogen atmosphere.Stirred the reaction mass at the same temperature for 2h then the mixture of BenzophenoneOxime (4.5 lg) and Triethylamine (4.8g) in Dichloromethane (30. OmL) was added to the above reaction mass at -10 to -15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(30.0mL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with 30. OmL of MTBE and concentrated the solution to yield title product. Yield: 9.0 g

ExampIe-4

Preparation of compound of Formula (VI) using2,6dichloro3-fIuoroacetophenone oxime:

Isopropyl L-alanine ester (0.5g) solution in Dichloromethane(5.0mL) was added drop wise to the solution of Dichloro phenyl phosphate (0.805g) in Dichloromethane (5. OmL) at -10 to - 15°C under nitrogen atmosphere. Stirred the reaction mass at the same temperature for 2h then the mixture of2,6-Dichloro3-fluoro acetophenone Oxime (0.847g) and Triethylamine (0.809g) in Dichloromethane (5. OmL) was added to the above reaction mass at -10 to - 15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(5.0mL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with S.OniL of MTBE and concentrated the solution to get title product.

Yield: 1.5 g

Example-5

Preparation of compound of Formula (Vl)using Nitro Benz aldehyde Oxime:

Isopropyl alanine ester (0.6g) solution in Dichloromethane (6.0mL) was added drop wise to the solution of Dichloro phenyl phosphate (0.966g) in Dichloromethane (6.0mL) at -10 to - 15°C under nitrogen atmosphere. Stirred the reaction mass at the same temperature for 2h then the mixture of NitrobenzaldehydeOxime (0.760g) and Triethylamine (0.97g) in Dichloromethane (6.0mL) was added to the above reaction mass at -10 to -15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(lO.OmL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with lO.OmL of MTBE and concentrated the solution to yield title product

Yield: 2.1 g

Example-6

Preparation of compound of Formula (Vl)using MalononitrileOxime:

Isopropyl alanine ester (2g) solution in Dichloromethane (20mL) was added drop wise to the solution of Dichloro phenyl phosphate (3.2g) in Dichloromethane (20.0mL) at -10 to -15°C under nitrogen atmosphere. Stirred the reaction mass at the same temperature for 2h then the mixture of MalononitrileOxime (1.45g) and Triethylamine (3.2g) in Dichloromethane (20.0mL) was added to the above reaction mass at -10 to -15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(20.0mL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with 20.0mL of MTBE and concentrated the solution to yield title product Yield: 5.0 g

Example-7

Preparation of compound of Formula (VI)using Diethyl malonateOxime:

Isopropyl alanine ester (2g) solution in Dichloromethane (lO.OmL) was added drop wise to the solution ofDichloro phenyl phosphate (3.2g) in Dichloromethane (20.0mL) at -10 to - 15°C under nitrogen atmosphere. Stirred the reaction mass at the same temperature for 2h then the mixture of Diethyl malonateOxime (2.8g) and Triethylamine (3.2g) in Dichloromethane (20.0mL) was added to the above reaction mass at -10 to -15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(20.0mL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with 20.0mL of MTBE and concentrated the solution to yield title product

Yield: 5.0 g

Example-')

Preparation of compound of Formula (VI) using Ethyl acetoacetateOxime:

Isopropyl alanine ester (5.0g) solution in Dichloromethane(50.0mL) was added drop wise to the solution of Dichloro phenyl phosphate (8.05g) in Dichloromethane (50.0mL) at -10 to - 15°C under nitrogen atmosphere, stirred the reaction mass at the same temperature for 2h then the mixture of Ethyl acetoacetate Oxime (6.08g) and Triethylamine (8.08g) in Dichloromethane (50.0mL) was added to the above reaction mass at -10 to -15°Cover the period of 85min. and allowed the reaction to 25-30°C, concentrated the reaction mass and added MTBE(lOO.OmL) to the residue and stirred for 5-10min then filter the solution to remove unwanted salts and repeated the same with lOO.OmL of MTBE and concentrated the solution to yield title product

Yield: 11.2 g

Example-9

Preparation of Sofosbuvir

Magnesium tert-butoxide (8.6g, 0.050) was added to the solution of 2'-deoxy-2 ^, -fluoro-2'- methyluridine(6.3g, 0.0243mol) in THF(126ml) at 25-30°C and maintained the reaction 30min at 25-30°C . Formula- VI derived from ethyl cyanoacetateoxime (10. Og) in THF (31.5ml) was added to the reaction mass drop wise over the period of 30min at 0-5°C, allowed to 25-30°c and maintained for overnight. Quenched the reaction mass with 2N HC1 solution (70.0mL)at 10-15°C, separated two layers and extracted aqueous layer with ethyl acetate (31.5mL) and THF layer was concentrated and dissolved the residue in ethyl acetate (252mL). Combined two ethyl acetate layers and washed with 5% sodium carbonate solution ,5% brine solution successively and dried over sodium sulphate and filtered and concentrated to give3.5g of crude product stage-II (Sofosbuvir). Crude product was purified with dichloromethane(37.8mL) and MTBE(18.9mL) stilted for 12h. Filtered the precipitated solid and dried to afford title product.

Yield: 0.6g

Chromatographic Purity (ByHPLC): >99.5 %

ExampIe-10

Preparation of Sofosbuvir

t-butyl magnesium chloride (75.0 ml, 1.7M in THF) was added drop wise to the solution of 2 ^, -deoxy-2'-fluoro-2'-methyluridine(15.8g) in THF(316.0ml) at 0-5°C over a period of 40- 45min under nitrogen atmosphere. Allowed reaction mass to 25-30°C and maintained for 30min at 25-30°C. Formula- VI derived from ethyl cyanoacetateoxime (25. Og) in THF (79.0ml) was added to the reaction mass drop wise over the period of 30min at 0-5°C, allowed to 25-30°c and maintained for overnight. Quenched the reaction mass with 2NHCL(158.0mL) by adjusting pH to2.5 at 10-15°C, separated two layers and extracted aqueous layer with ethyl acetate (79.0mL) and THF layer was concentrated and dissolved the residue in ethyl acetate(632. OmL). Combined two ethyl acetate layers and washed with brine solution(316.0mL) then added 5% sodium carbonate solution(316.0mL) at 10-15°C and agitated the reaction mixture for 10-15min at 20-25°C repeated this operation as thrice of times, then separated two layers then adjusted pH of the organic layer to 6.5-7.0 by adding IN HCl(1.5mL) at 10-15°C,organic layers and washed the brine solution(316.0mL) as twice of times followed by activated charcoal(1.5g) treatment and filtered through celite bed .Filtrate was concentrated to obtainsofosbuvir.

Yield: 14.0 g While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.