FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"PROCESS FOR PREPARATION OF SOFOSBUVTR"
Glenmark Pharmaceuticals Limited;
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered office at
Glenmark House, HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala, Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of sofosbuvir and intermediates
thereof.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) is a heterogeneous RNA virus, with 6 known genotypes and numerous subtypes.
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma. According to WHO estimate, 130-170 million people are chronically infected worldwide with hepatitis C virus (HCV) and 3-4 million people are infected with HCV every year.
Sofosbuvir, 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-2yl)rnethoxy)-(phenoxy)phosphorylamino)propanoate, is represented by compound of Formula la.

Sofosbuvir is currently marketed in United States under the trade name SOVALDI® as tablets (400 mg) for oral administration. SOVALDI® 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.
Various intermediates and processes for preparation of sofosbuvir are disclosed in United States Patent Nos 8642756 and US8618076. Presently, we have developed a novel process and novel intermediates for the preparation of sofosbuvir or salts thereof.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula II or a stereoisomer thereof or a mixture or salt thereof,


wherein P* is a chiral phosphorus atom, and wherein
(a) W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally substituted benzyl or the optionally substituted trityl may have one or more substituents selected from the group G;
(b) L is selected from the group consisting of halo, mesylate, tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate, nonaflate and ORa, wherein Ra is selected from the group consisting of H, C1-C8 alkyl, acyl, aryl, alkaryl, heteroaryl, trityl, and a group of formula Y;

wherein if aryl is phenyl then the phenyl is substituted with one or more substituents selected
from the group G;
wherein each alkyl, acyl, aryl, alkaryl, trityl or heteroaryl is independently optionally substituted
with one or more substituents selected from the group G; and wherein G is C1-C8alkyl,C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(O)2OR, -C(O)OR, or -C(0)R; wherein R is H orC1-C8alkyl
comprising deprotecting a compound of Formula II-a-1 or salt thereof
The present invention provides a process for the preparation of Sofosbuvir, a compound of formula la or pharmaceutically acceptable salt thereof



wherein W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally substituted benzyl or optionally substituted trityl may have one or more substituents selected from the group G wherein G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR or -C(0)R; wherein R is H or C1-C8 alkyl.
DETAILED DESCRIPTION OF THE INVENTION
The term "P*" means that phosphorus atom is chiral and that it has a corresponding Cahn-Ingold-Prelog designation of "R" or "S". It is contemplated that compounds of present invention include racemic mixtures of all stereoisomers, enantiomers or diastereoisomers.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
The term "halo" refers to halogen consisting of chlorine, bromine, iodine or fluorine.
The term "C1-C8 alkyl" refers a straight or branched chain, saturated, monovalent hydrocarbon residue containing 1-8 carbon atoms. Examples of C1-C8 alkyl group includes but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like. The C1-C8 alkyl may be unsubstituted or substituted with a group G wherein G is C1-C8alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR or -C(0)R; wherein R is H or C1-C8 alkyl
The term "acyl" refers to a substituent containing carbonyl moiety and includes groups like acetyl, propionyl, benzoyl and the like; preferably the term acyl refers to acetyl. The acyl group may be unsubstituted or substituted with a group G. For example substituted acyl includes trifluoroacetyl and the like.
The term "aryl" refers to an aromatic hydrocarbon radical derived by the removal of one hydrogen from a single carbon atom of a parent aromatic system containing 1-20 carbon atoms. Examples of aryl group includes but not limited to phenyl, biphenyl, naphthyl and the like. The aryl group may be unsubstituted

or substituted at one or more position with a group G. For example substituted aryl includes p-nitrophenyl, pentafluorophenyl, and the like.
The term "alkaryl" refers to an alkyl group with an aryl substituent, for example benzyl and the like.
The term "heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Examples of heteroaryl includes but not limited to pyridinyl, pyrrolyl, oxazolyl, indolyl, purinyl, furanyl, thienyl, isoxazolyl, pyrazolyl and the like.
The term "C1-C8 alkoxy" refers to a group having formula -0-(C1-C8 alkyl), in whichC1-C8 alkyl group is, as defined above, is attached to parent molecule via an oxygen atom. Examples of C1-C8 alkoxy group includes but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.
Whenever a compound described herein is substituted with one or more groups, then it should be understood that the groups may be same or different.
The present invention provides a compound of formula II or a stereoisomer thereof or a mixture or salt thereof,

wherein P* is a chiral phosphorus atom, and wherein
(a) W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally
substituted benzyl or the optionally substituted trityl may have one or more substituents selected from
the group G;
(b) L is selected from the group consisting of halo, mesylate, tosylate, brosylate, nosylate, triflate,
camphorsulphonate, tresylate, nonaflate and ORa, wherein Ra is selected from the group consisting of
H, C1-C8 alkyl, acyl, aryl, alkaryl, heteroaryl, trityl, and a group of formula Y;


wherein if aryl is phenyl then the phenyl is substituted with one or more substituents selected from the
group G;
wherein each alkyl, acyl, aryl, alkaryl, trityl or heteroaryl is independently optionally substituted with
one or more substituents selected from the group G; and wherein G is C1-C8alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR, or -C(0)R; wherein R is H or C,.Cg alkyl-
In one embodiment the present invention provides a compound formula IIa orIIib

wherein W and L are as defined above.
In one embodiment the present invention provides a compound of formula II or a stereoisomer thereof or a mixture or salt thereof, wherein P* is a chiral phosphorus atom, and wherein
(a) W is an optionally substituted benzyl wherein the optionally substituted benzyl may have one or more substituents selected from the group G;
(b) L is selected from the group consisting of halo, mesylate, tosylate, camphorsulphonate and ORa, wherein Ra is selected from the group consisting of H, aryl and a group of formula Y;

wherein if aryl is phenyl then the phenyl is substituted with one or more substituents selected from the
group G; wherein G is C1-C8alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR or -C(0)R; wherein R is H or C1-C8 alkyl.
In one embodiment, the present invention provides a compound of formula II, as represented above or stereoisomer thereof or mixture or salt thereof, wherein W is an optionally substituted benzyl; wherein the

optionally substituted benzyl may have one or more substituents selected from the group G, wherein G is C1-C8alkyl, C1-C8alkoxy, nitro, halo or amino and L is ORa, wherein Ra is a group of formula Y.
In one embodiment the present invention provides a compound of formula IIa or IIb or salt thereof, wherein
(a) W is an optionally substituted benzyl; wherein the optionally substituted benzyl may have one or more substituents selected from the group G; and
(b) L is selected from group consisting of halo, mesylate, tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate, nonaflate and ORa, wherein Ra is selected from the group consisting of H, substituted aryl, trityl and a group of formula Y;

wherein the substituted aryl has one or more substituents selected from the group G; wherein G is C1-C8 alkyl,C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR, or -C(0)R; wherein R is H or C1-C8 alkyl.
In one embodiment, the present invention provides a compound of formula IIa or IIb or salt thereof wherein W is an optionally substituted benzyl; wherein the optionally substituted benzyl may have one or more substituents selected from the group G and L is ORa and wherein Ra is a group of formula Y represented by compounds of formula II-a-1 and II-b-1. Preferably the substituent on the benzyl group is methoxy.

II-a-1 II-b-1
In one embodiment, the present invention provides a compound of formula II-a-1 or salt thereof wherein W is benzyl

In one embodiment, the present invention provides a compound of formula IIa or IIb or salt thereof W is an optionally substituted benzyl as defined above and L is OH.
In one embodiment, the present invention provides a compound of formula IIa or IIb or salt thereof wherein W is optionally substituted benzyl as defined above and L is ORa, wherein Ra is a substituted aryl; wherein substituted aryl may have one or more substituents selected from the group G.
In one embodiment, the present invention provides a compound of formula IIa or IIb or salt thereof W is an optionally substituted benzyl as defined above and L is selected from mesylate, tosylate, brosylate, nosy late, triflate, camphorsulphonate, tresylate, nonaflate or the like.
In one embodiment the present invention provides a compound of formula IIa or IIb or salt thereof wherein W is an optionally substituted benzyl as defined above and L is ORa, wherein Ra is a substituted phenyl; wherein the substituted phenyl may have one or more substituents selected from the group G. Preferably halo or nitro.
In one embodiment, the present invention provides a compound of formula IIa or IIb, wherein Ra is p-nitrophenyl or pentafluorophenyl represented by compounds of formula II-a-2, II-b-2, II-a-3 and II-b-3 respectively,

or pharmaceutical acceptable salt thereof; wherein W is an optionally substituted benzyl; wherein optionally substituted benzyl may have one or more substituents selected from the group G. Preferably G is methoxy.

In one embodiment, the present invention provides a compound of formula II-a-2 or II-a-3, wherein W is benzyl.

comprising deprotecting a compound of Formula II-a-1 or salt thereof;

In one embodiment, the present invention provides a process for the preparation of Sofosbuvir, a compound of formula la or pharmaceutical acceptable salt thereof
wherein W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally substituted benzyl or optionally substituted trityl may have one or more substituents selected from the group G wherein G is C1-C8 alkyl, C1-C8alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR or -C(0)R; wherein R is H or C1-C8 alkyl.
In one embodiment, W is optionally substituted benzyl and G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo or amino; preferably methoxy.
In one embodiment, the deprotection of compound of formula II-a-1 may be carried out by hydrogenolysis, oxidative cleavage, acidic cleavage or by other commonly used methods for N-benzyl or N-trityl deprotection.
The hydrogenolysis of compound of formula II-a-1 may be performed in the presence of a catalyst. The catalyst used may include metal catalysts such as platinum on carbon, palladium on carbon

and the like; palladium hydroxide on carbon; platinum hydroxide on carbon; platinum oxide or Raney nickel.
In one embodiment, the present invention provides a process for the preparation of Sofosbuvir, a compound of formula la or pharmaceutically acceptable salt thereof comprising deprotecting a compound of Formula II-a-1 or salt thereof wherein W is benzyl.
In one embodiment, the deprotection of compound of formula II-a-1 or salt thereof wherein W is benzyl may be carried out by hydrogenolysis.
The present invention provides a process for preparation of compound of Formula II-a-1 comprising contacting a compound of Formula IIa or salt thereof

wherein W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally substituted benzyl or optionally substituted trityl may have one or more substituents selected from the group G; L is selected from the group consisting of halo, mesylate, tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate, nonaflate and ORa, wherein Ra is selected from the group consisting of H, C1-C8 alkyl, acyl, aryl, alkaryl, heteroaryl and trityl; wherein if aryl is phenyl then the phenyl is substituted with group G; wherein each alkyl, acyl, aryl, alkaryl, trityl or heteroaryl is independently optionally substituted with one or more substituents selected from the group G; and wherein the group G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)20R, -C(0)OR, or -C(0)R; wherein R is H or C1-C8 alkyl; with a compound of Formula VII or salt thereof.
In one embodiment of the process of the present invention W is an optionally substituted benzyl; wherein the optionally substituted benzyl may have one or more substituents selected from the group G; L is selected from group consisting of halo, mesylate, tosylate, and ORa, wherein Ra is selected from the group consisting of H, substituted aryl and trityl; wherein the substituted aryl has one or more substituents selected from the group G. Preferably the substituted aryl is p-nitrophenyl, or pentafluorophenyl.

The reaction of compound of formula IIa with a compound of formula VII may be carried out in presence of a base. The base may be selected from the group consisting of Grignard reagents like methyl magnesium bromide, t-butyl magnesium chloride and the like, alkali metal hydroxides like sodium hydroxide, potassium hydroxide and the like, alkoxides like sodium methoxide, sodium ethoxide, sodium hexamethyldisilazane, DBU, DBN, alkali metal carbonates like sodium carbonate, potassium carbonate and the like.
In one embodiment, the present invention provides a process for the preparation of a compound of formula IIa as described above, comprising (a) providing a compound of formula II; and

(b) isolating the compound of formula IIa, by diastereoselective crystallization of compound of formula II; wherein W and L are as defined above.
The diastereoselective crystallization may be carried out by crystallization from a solvent or mixture of solvents. The solvent may be selected from the group consisting of acetone, methanol, butanol, propanol, dimethylsulfoxide, dimethylformamide, dioxane, ethanol, isopropyl alcohol, water, ethyl acetate, heptane, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, 2,2,2-trifluoroethanol, tetrahydrofuran, toluene, diisopropyl ether.
In one embodiment the diastereoselective crystallization may be carried out by dissolving the compound of formula II in a solvent and adding an antisolvent to crystallize out the compound of formula Ha.
In one embodiment, the present invention provides a process for preparing a compound of formula II, wherein W is as defined above and L is halo, represented by compound of formula II-a-4 wherein X is halo.

comprising treating a compound of formula III with a compound of formula IV wherein X is halo.

In one embodiment, the present invention provides a process for preparing a compound of formula II; wherein W is as defined above and L is OH, represented by compound of formula II-a-5 comprising reacting a compound of formula II -a-4 with water.

In one embodiment, the present invention provides a process for preparing a compound of formula II; wherein L is ORa; wherein Ra is substituted aryl, by a method comprising activating the hydroxyl group of compound of formula II-a-5 and then reacting it with substituted aryl alcohol.
In one embodiment, the present invention provides a process for preparing a compound of formula II-a-2 comprising reacting a compound of formula II-a-5, wherein W is optionally substituted benzyl with 4-nitrophenol.
In one embodiment, the present invention provides a process for preparing a compound of formula II-a-3 comprising reacting a compound of formula II-a-5, wherein W is optionally substituted benzyl with pentafluorophenol.
In one embodiment, the present invention provides a process for preparing a compound of formula II; wherein L is ORa; wherein Ra is substituted aryl, by a method comprising reacting II-a-4 with substituted aryl alcohol.
In one embodiment, the present invention provides a process for preparing a compound of formula II-a when L is selected from mesylate, tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate or nonaflate; by a process comprising treating compound of II-a-5 with corresponding sulfonyl halide.

In one embodiment, present invention provides a process for the preparation of compound of formula lb or pharmaceutically acceptable salt thereof comprising deprotecting a compound of Formula II-b-1 or salt thereof;

In one embodiment, the present invention provides a process for the preparation of compound of formula III, wherein W is optionally substituted benzyl by reacting L- alanine isopropyl ester or salt thereof with an optionally substituted benzaldehyde.
In one embodiment, sofosbuvir, a compound of formula la may be crystallized from a suitable solvent or mixture of solvents selected from the group consisting of acetone, methanol, butanol, propanol, dimethylsulfoxide, dimethylformamide, dioxane, ethanol, isopropyl alcohol, water, ethyl acetate, heptane, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, 2,2,2-trifluoroethanol, tetrahydrofuran, toluene.
In one embodiment, sofosbuvir, a compound of formula la may be crystallized from a mixture of isopropyl alcohol and water.
In one embodiment the present invention provides solvates of sofosbuvir, a compound of formula la with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, isobutyl acetate, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethylformamide or dimethyl sulfoxide or mixtures thereof.
In one embodiment the present invention provides process for the preparation of amorphous Form of sofosbuvir, a compound of formula la the process comprising:
(a) dissolving sofosbuvir in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and
(b) removing the solvent from the solution obtained in (a).

In one embodiment the present invention provides process for the preparation of amorphous Form of sofosbuvir, a compound of formula la the process comprising:
(a) dissolving solvate of sofosbuvir in a solvent or mixture of solvents or aqueous mixtures thereof to provide a solution; and
(b) removing the solvent from the solution obtained in (a).
The removal of solvent in (b) is carried out by distilling out the solvent, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
In one embodiment, the present invention provides a process for the preparation of sofosbuvir, compound of formula la comprising reacting compound of formula VIII with a compound capable of introducing an isopropyl moiety, for example isopropyl alcohol optionally in the presence of an activating agent.

In one embodiment, the present invention provides a process for the preparation of compound of formula VIII comprising hydrolyzing a compound of formula IX, wherein Rl is selected from the group consisting of optionally substituted benzyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, pentyl; wherein the substituent on benzyl is present at one or more positions and selected from the group G, as described supra.

In one embodiment, the present invention provides a process for the preparation of compound of formula VIII comprising hydrolyzing a compound of formula IX, wherein Rl is benzyl.

In one embodiment, the present invention provides a process for the preparation of compound of formula IX, comprising reacting a compound of formula X, wherein Rl is selected from the group consisting of optionally substituted benzyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, pentyl; wherein substituent on benzyl is selected from the group G, as described supra and R2 is a substituent at one or more positions on the phenyl ring selected from the group consisting of C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH with a compound of formula VII.

In one embodiment, the present invention provides a process for the preparation of compound of formula IX, wherein R1 is benzyl comprising reacting a compound of formula X, wherein R1 is benzyl and R2 is a substituent at one or more positions on the phenyl ring selected from nitro and halo. Preferably R2 is 4-nitro or pentafluoro group.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

Examples
Example-1: N-benzyl L-alanine isopropyl ester
A mixture of L- alanine isopropyl ester hydrochloride 10 g in methanol (100ml) and triethyl amine (7.24 gm) was stirred for 5 min. 9.5 g of benzaldehyde was charged and the reaction mass was stirred for 120 min. The reaction mass was cooled to 0°C and 3.42 g of sodium borohydride was added slowly and the resulting reaction mass was stirred for 60 to 120 min at 0-5°C. After completion of reaction, 100 ml water and 100 ml ethyl acetate was added to the reaction mass. The reaction mass was stirred, and layer was separated. The organic layer was washed with 20% sodium chloride solution. The organic layer was distilled & degassed to give an oily mass.
ExampLe-2: Propan-2-yl (2S)-2-{benzyl [(S)-(4-nitrophenoxy)(phenoxy)phosphoryl] amino} propanoate
In a 100 ml RBF 10 ml THF, 1.96 g of phosphorus oxychloride and 1.0 g of phenol was charged and the reaction mixture was cooled to -70°C. 1.29g of triethyl amine was added and the reaction mass temperature was maintained below -50°C. The reaction mass was stirred for 60min, and 2.2g of N-benzyl L-alanine isopropyl ester was charged and 2.75g of triethyl amine was added maintaining the reaction mass temperature below -50°C. The reaction mass was stirred for 60min and 1.45g of p-nitrophenol and 1.29g of triethyl amine was added maintaining the reaction mass temperature below -50°C. The reaction mass was stirred for 60 min and the temperature was raised to 25-30°C and 20 ml water and 20 ethyl acetate was added. The layers were separated and the organic layer was washed with water and then distilled and degassed. To the degassed mass 10 ml of diisopropyl ether was charged and stirred the mass for 60 min & the solid obtained was filtered to yield Propan-2-yl (25)-2-{benzyl [(S)-(4-nitrophenoxy)(phenoxy)phosphoryl]amino}propanoate.
Example -3: N-benzyl Sofosbuvir
In 100 ml RBF 1.0 g of l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl) pyrimidine-2,4(lH,3H)-dione 10 ml of THF and 2.0 gm of Propan-2-yl (25)-2-{benzyl [(S)-(4-nitrophenoxy)(phenoxy)phosphoryl]amino}propanoate were taken. The reaction mass was cooled to 0-5°C add 5.0 ml of 2M t-butyl magnesium chloride was added and the reaction mixture was stirred for 60-120 min. 20 ml water and 20ml ethyl acetate were charged to the reaction mixture and the layers were separated. The organic layer was washed with 10% ammonium chloride solution. The organic layer was separated and washed with water. The organic layer was distilled and degassed to give the title compound.

Ex-4: Sofosbuvir
In a par bottle 5.0 gm of N-benzyl Sofosbuvir, 50 ml of methanol and 0.5 gm of 10% Pd/C were charged. 5.0 kg/cm2 hydrogen pressure was applied and the reaction was monitored by TLC. After completion of reaction the catalyst was removed by filtration and the filtrate was distilled and degassed. To degassed mass MDC was charged and stirred overnight and the solid obtained was filtered. To the obtained solid 15 ml IPA and 15 ml of water was added and the solid precipitated out was filtered and dried to yield Sofosbuvir.

WE CLAIM;
1. A compound of formula II or a stereoisomer thereof or a mixture or salt thereof,

wherein P* is a chiral phosphorus atom, and wherein
(a) W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally substituted benzyl or the optionally substituted trityl may have one or more substituents selected from the group G;
(b) L is selected from the group consisting of halo, mesylate, tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate, nonaflate and ORa, wherein Ra is selected from the group consisting of H, C1-C8alkyl, acyl, aryl, alkaryl, heteroaryl, trityl, and a group of formula Y;

wherein if aryl is phenyl then the phenyl is substituted with one or more substituents selected
from the group G;
wherein each alkyl, acyl, aryl, alkaryl, trityl or heteroaryl is independently optionally substituted
with one or more substituents selected from the group G; and wherein G is C1-C8alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)20R, -C(0)OR, or -C(0)R; wherein R is H or d. C8 alkyl.

wherein W and L are as defined in claim 1.
2. A compound as claimed in claim 1, or salt thereof represented by formula IIa or IIb

3. A compound as claimed in claim 2, or salt thereof wherein L is ORa and wherein Ra is a group of formula Y

and W is as defined in claim 1. 4. A compound as claimed in claim 2, wherein
(a) W is optionally substituted benzyl; wherein the optionally substituted benzyl may have one or more substituents selected from the group G; and
(b) L is selected from group consisting of halo, mesylate, tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate, nonaflate and ORa, wherein Ra is selected from the group consisting of H, substituted aryl, trityl and a group of formula Y;

wherein the substituted aryl has one or more substituents selected from the group G; wherein G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR, or -C(O)R; wherein R is H or C1-C8 alkyl.
5. A compound as claimed in claim 4 or a salt thereof wherein W is as defined in claim 4 and L is ORa wherein Ra is substituted aryl.
6. A compound as claimed in claim 5 or a salt thereof wherein the substituted aryl is p-nitrophenyl, or pentafluorophenyl.
7. A process for the preparation of Sofosbuvir, a compound of formula la or pharmaceutically acceptable salt thereof



comprising deprotecting a compound of Formula II-a-1 or salt thereof
wherein W is an optionally substituted benzyl or an optionally substituted trityl wherein the optionally substituted benzyl or optionally substituted trityl may have one or more substituents selected from the group G wherein G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR, -C(0)OR or -C(0)R; wherein R is H or C1-C8 alkyl.

with a compound of Formula VII or salt thereof

8. A process as claimed in claim 7, wherein the compound of Formula II-a-1 is obtained by a method comprising contacting a compound of Formula IIa or salt thereof;

wherein W is as defined in claim 7 ; L is selected from the group consisting of halo, mesylate,
tosylate, brosylate, nosylate, triflate, camphorsulphonate, tresylate, nonaflate and ORa, wherein
Ra is selected from the group consisting of H, C1-C8 alkyl, acyl, aryl, alkaryl, heteroaryl and
trityl;
wherein if aryl is phenyl then the phenyl is substituted with group G; wherein each alkyl, acyl,
aryl, alkaryl, trityl or heteroaryl is independently optionally substituted with one or more
substituents selected from the group G; and
wherein the group G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)2OR,
-C(0)OR, or -C(0)R; wherein R is H or C1-C8 alkyl.
9. A process as claimed in claim 8,wherein W is optionally substituted benzyl; wherein the
optionally substituted benzyl may have one or more substituents selected from the group G; L is
selected from group consisting of halo, mesylate, tosylate, and ORa, wherein Ra is selected from
the group consisting of H, substituted aryl and trityl; wherein the substituted aryl has one or more
substituents selected from the group G;
wherein G is C1-C8 alkyl, C1-C8 alkoxy, nitro, halo, cyano, amino, -N3, OH, -S(0)20R, -C(0)OR or -C(0)R; wherein R is H or C1-C8alkyl.
10. A process as claimed in claim 9 wherein the substituted aryl is p-nitrophenyl, or .
pentafluorophenyl.