DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
STEREOSELECTIVE PREPARATION OF SOFOSBUVIR

INTRODUCTION
The present invention is directed towards a stereoselective process for the preparation of Sofosbuvir.
US7964580B2 describes processes for preparation of nucleoside phosphoramidate compounds, including sofosbuvir, their compositions and use in the treatment of a Flaviviridae infection, including hepatitis C virus, West Nile Virus, yellow fever virus, and a rhinovirus infection in a host, including animals, and especially in humans. The process described in this patent involves reaction of suitably substituted phophochloridate (racemic at phosphorous) with a nucleoside analog in the presence of anhydrous aprotic solvent such as tetrahydrofuran, dioxane in presence of a base such as N-methylimidazole, collidine, pyridine, 2,6-lutidine, 2,6-tBu-pyridine, etc. or a tertiary amine base, such as trimethylamine, diisoproylethyl amine etc. The process described herein leads to the production of nucleoside phosphoramidate prodrugs with less than 50% of the desired isomer, which requires additional purifications to get the desired isomer which enhances the number of steps and cost. This reference does not provide a particular combination of solvents and bases which provides or increases the stereo selectivity during the reaction for the production of the required Sp isomer.
US8642756B2 describes a process for preparation of deuterated sofosbuvir from phosphorochloridate and deuterated nucleoside in THF by using N-methylimidazole as a base. The obtained product is having 1:1 ratio of diastereomers.
The processes disclosed in the prior art for the preparation of nucleoside phosphoramidate compounds such as sofosbuvir suffer from drawbacks such as low stereoselectivity of desired isomer which leads to lengthy workup and it does not result in an industrially feasible process.
Hence, there is a need to provide simple, environment friendly, cost effective, industrially feasible processes for the preparation of sofosbuvir.

SUMMARY
An aspect of the invention, the application provides a stereoselective process for preparation sofosbuvir having a Formula I.

Formula I

DETAILED DESCRIPTION
An aspect of the present invention is a stereoselective process for preparation of sofosbuvir having a Formula I.

Formula I
In an embodiment, the present invention is directed to a process for preparing the compound of Formula I, which comprises reacting a chlorophosphoramidate compound of Formula II with a nucleoside compound of Formula III, in the presence of anhydrous solvents and bases, wherein the solvents can be selected from dichloromethane, 2-methyl tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine, tributylamine and their combinations, or any functional equivalent thereof and bases can be selected from tripropyl amine, tributyl amine, diisopropyl ethyl amine, and their combinations, or any functional equivalent thereof.

Formula II

Formula III
In another embodiment of the present invention, the chlorophosphoramidate compound of Formula II is dissolved in a solvent and added to the mixture of the nucleoside compound of Formula III and base.
In another embodiment of the present invention, the reaction can be performed in anhydrous solvents such as dichloromethane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine, tributylamine and their combinations, or any functional equivalent thereof.
In another embodiment of the present invention, the base can be selected from tripropyl amine, tributyl amine, diisopropyl ethyl amine, and their combinations, or any functional equivalent thereof.
In another embodiment of the present invention, the reaction can be typically initiated and conducted at a temperature range from -78°C to 40°C. The reaction can be performed for a period of 30 minutes to 24 hours. The reaction can be allowed to stir over a period of time at a temperature between about -78°C and 40°C. The solvent is removed from the reaction mixture and the product is purified by chromatography on silica gel, crystallization or other methods known in the art.
In an embodiment, use of tripropylamine, tributylamine, diisopropylethylamine or any functional equivalent bases in combination with appropriate solvents like dichloromethane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine give the desired the S-isomer at phosphorous atom as the major product.
The selection of solvent and base is very much crucial as some of the combinations may lead to the formation of undesired isomer (R-isomer) in excess level. For example, use of bases such as K2CO3 and Cs2CO3 in tetrahydrofuran produced only the ratio of isomers (Sp : Rp) 1:3.4 and 1:6 respectively. Further, as indicated above, the literature referred bases and solvents lead to the formation of about 1:1 ratio of isomers (Sp : Rp) .
In another embodiment of the present invention, stereoselectivity of desired compound such as sofosbuvir of Formula I, at phosphorous atom range starting from about 2.5:1 to 7:1.
In another embodiment of the present invention, the compound such as sofosbuvir of Formula I can be prepared by using combinations of specific solvents and specific bases as described above.
In another embodiment of the present invention, the obtained compounds from Formula I may be further purified by separating the undesired enantiomers by the known techniques such as crystallization, chromatography, use of enzymes, simulated moving bed chromatography etc.
In another embodiment of the present invention, the obtained compound of Formula I can be recrystallized by solvent & anti-solvent process wherein the solvents can be selected from dichloromethane, ethyl acetate, methanol, toluene and their functionally equivalents thereof and the anti-solvents can be selected from isopropyl ethyl ether, diisopropyl ether, heptane and methyl tertiarybutyl ether and functional equivalents thereof.
An embodiment of the present invention is directed to a process for preparation of nucleoside phosphoramidate compound of Formula IV, which comprises reacting a phosphoramidate compound of Formula V with a nucleoside compound of Formula VI, in the presence of anhydrous solvents and bases, wherein the solvents can be selected from dichloromethane, 2-methyl tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine, tributylamine and their combinations, or any functional equivalent thereof and bases can be selected from tripropyl amine, tributyl amine, diisopropyl ethyl amine, and their combinations, or any functional equivalent thereof.

Formula IV

Formula V

Formula VI
wherein,
(a) R1 is hydrogen, n-alkyl; branched alkyl, cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1')2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1')2, COR1?, and —SO2C1-6 alkyl; (R1' is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R1? is —OR' or —N(R1')2);
(b) R2 is hydrogen, C1-10 alkyl, R3a or R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, C(O)CR3aR3bNHR1, where n is 2 to 4 and R1, R3a, and R3b;
(c) R3a and R3b are (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3')2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(-NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)cCOR3?, aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano; (ii) R3a and R3b both are C1-6 alkyl; (iii) R3a and R3b together are (CH2)r so as to form a spiro ring; (iv) R3a is hydrogen and R3b and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R3b is hydrogen and R3a and R2 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R3' is independently hydrogen or C1-6 alkyl and R3? is —OR' or —N(R3')2); (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, C2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (viii) R3a is CH3, —CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H, where R3' is independently hydrogen or alkyl, which includes, but is not limited to, C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, R3? is —OR' or —N(R3')2);
(d) R4 is hydrogen, C1-10 alkyl, C1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C1-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
(e) R5 is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, i.e., —(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkyne (optionally substituted), or halogen, including F, Cl, Br, or I, with the provisos that when X is OH, base is cytosine and R6 is H, R5 cannot be N3 and when X is OH, R6 is CH3 or CH2F and B is a purine base, R5 cannot be H;
(f) R6 is H, CH3, CH2F, CHF2, CF3, F, or CN;
(g) X is H, OH, F, OMe, halogen, NH2, or N3;
(h) Y is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, OC(O)O(C1-4 alkyl), OC(O)O(C1-4 alkyl), OC(O)O(C2-4 alkynyl), OC(O)O(C2-4 alkenyl), OC1-10 haloalkyl, O(aminoacyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-18 acyl)2, wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N2, CN, one to three halogen (Cl, Br, F, I), NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4alkenyl), S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, N(C1-4 acyl)2;
The base is a naturally occurring or modified purine or pyrimidine base represented by the following structures:

wherein
Z is N or CR12;
R7, R8,R9, R10, and R11 are independently H, F, Cl, Br, I, OH, OR', SH, SR', NH2, NHR', NR'2, lower alkyl of C1-C6halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6 such as C=CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R', CONH2, CONHR', CONR'2, CH-CHCO2H, or CH-CHCO2R',
wherein R' is an optionally substituted alkyl, which includes, but is not limited to, an optionally substituted C1-20 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(O)(C1-20 alkyl), C(O)(C1-10 alkyl), or C(O)(lower alkyl) or alternatively, in the instance of NR'2, each R' comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and
R12 is H, halogen (including F, Cl, Br, I), OH, OR', SH, SR', NH2, NHR', NR'2, NO2 lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6, lower alkenyl of C2-C6, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R', CONH2, CONHR', CONR'2, CH-CHCO2H, or CH-CHCO2R'; with the proviso that when base is represented by the structure c with R11 being hydrogen, R12 is not a: (i) —C=C—H, (ii) —C-CH2, or (iii) —NO2.
X' is a suitable leaving group.
In another embodiment of the present invention, the reaction can be performed in anhydrous solvents such as dichloromethane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, acetone, methyl ethyl ketone, 1,4-dioxane, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine and their combinations, or any functional equivalent thereof.
In another embodiment of the present invention, the base can be selected from tripropyl amine, tributyl amine, diisopropyl ethyl amine, and their combinations, or any functional equivalent thereof.
In another embodiment of the present invention, the reaction can be typically initiated and conducted at a temperature range from -78°C to 40°C. The reaction can be performed for a period of 30 minutes to 24 hours. The reaction can be allowed to stir over a period of time at a temperature between about -78°C and 40°C. The solvent is removed from the reaction mixture and the product is purified by chromatography on silica gel, crystallization, or other methods known in the art.
In another embodiment of the present invention, the obtained nucleoside phosphoramidate compounds of Formula IV can be recrystallized by solvent & anti-solvent process wherein the solvents can be selected from dichloromethane, ethyl acetate, methanol, toluene and their functionally equivalents thereof and the anti-solvents can be selected from isopropyl ethyl ether, diisopropyl ether, heptane and methyl tertiarybutyl ether and functional equivalents thereof.
In another embodiment, use of tripropylamine, tributylamine, diisopropylethylamine or any functional equivalent bases in combination with appropriate solvents like dichloromethane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine give the desired the S-isomer at phosphorous atom as the major product.
The product obtained according to the present invention can be useful for the preparation of desired polymorphic forms known in the art or for the preparation of novel crystalline forms.
The product obtained according to the present invention can be useful for the preparation of novel pharmaceutically acceptable salts.

DEFINITIONS
As used herein, the term "alkyl" refers to a straight or branched saturated monovalent cyclic or acyclic hydrocarbon radical, having the number of carbon atoms vary from C1-10.
The term "aryl," as used herein, and unless otherwise specified, refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl refers to substituted or unsubstituted phenyl. The aryl group can be substituted with one or more moieties selected from among hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999. Preferably the aryl can be substituted or unsbustituted phenyl.
The term "halo," as used herein, includes chloro, bromo, iodo and fluoro.
The term "protecting group", as used herein and unless otherwise defined, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. Non-limiting examples include: C(O)-alkyl, C(O)Ph, C(O)aryl, CH3, CH2-alkyl, CH2-alkenyl, CH2Ph, CH2-aryl, CH2O-alkyl, CH2O-aryl, SO2-alkyl, SO2-aryl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trichloro-1-imine-ethanyl and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).
The term is a leaving group, such as Cl, Br, I, sulfate, acetate, tosylate, mesylate, trifluoroacetate, trifluorosulfonate, phenoxide, pentafluorophenoxide, p-NO2-phenoxide, tert-butyldimethylsilyl and levulinyl group or other commonly used leaving groups as disclosed in Advanced Organic Chemistry by March, Fourth Edition.
The term "about" (also represented by .about.) means that the recited numerical value is part of a range that varies within standard experimental error.
The phrase "pharmaceutically acceptable salt" of a compound as used herein means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, inaleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chiorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, K+, Mg2+andCa2+. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

EXAMPLES
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Example-1: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy) (phenoxy) phosphoryl) amino) propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (1.767 g) and acetone (5 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. Tripropyl amine (828 mg) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (500 mg). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 12 hours.
The reaction mixture was concentrated on rotavapour under high vacuum. The obtained crude was dissolved in 10 mL of ethyl acetate, washed with 1N HCl, saturated sodium bicarbonate, brine solution and dried over sodium sulfate. The final reaction mass was evaporated under vacuum and placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 4.3:1
Example-2: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy)(phenoxy)phosphoryl) amino)propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (587 mg) and Methylisobutyl ketone (5 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. Tripropyl amine (828 mg) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (500 mg). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 5 hours.
The reaction mixture was concentrated on rotavapour under high vacuum. The obtained crude was dissolved in 10 mL of ethyl acetate, washed with 1N HCl, saturated sodium bicarbonate, brine solution and dried over sodium sulfate. The final reaction mass was evaporated under vacuum and placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 6.6:1
Example-3: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (1.712 g) and Methyl-t-butyl ether (5 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. N,N-Diisopropylethyl amine (724 mg) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (500 mg). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 12 hours.
The reaction mixture was concentrated on rotavapour under high vacuum. The obtained crude was dissolved in 10 mL of ethyl acetate, washed with 10 mL of 10% aqueous HCl, 10 mL of brine solution, 10 mL of saturated sodium bicarbonate, 10 mL brine solution and dried over sodium sulfate. The final reaction mass was evaporated under vacuum and placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 5.8:1
Example-4: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (1.767 g) and Methyl-t-butyl ether (5 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. Tripropyl amine (828 mg) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (500 mg). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 17 hours.
The reaction mixture was concentrated on rotavapour under high vacuum. The obtained crude was dissolved in 10 mL of ethyl acetate, washed with 10% aqueous HCl, 10 mL of brine solution, 10 mL of saturated sodium bicarbonate, 10 mL brine solution and dried over sodium sulfate. The final reaction mass was evaporated under vacuum and placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 5.9:1
Example-5: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (1.767 g) and ethyl acetate (5 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. Tripropyl amine (828 mg) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (500 mg). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 17 hours.
The reaction mixture was concentrated on rotavapour under high vacuum. The obtained crude was dissolved in 15 mL of ethyl acetate, washed with 10% aqueous HCl, 10 mL of brine solution, 10 mL of saturated sodium bicarbonate, 10 mL brine solution and dried over sodium sulfate. The final reaction mass was evaporated under vacuum and placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 4.9:1
Example-6: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (8.81 g) and tetrahydrofuran (50 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. Tributyl amine (28.5 g) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (5 g). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 21 hours.
The obtained crude was dissolved in 100 mL of ethyl acetate, washed with 100 mL of 10% aqueous HCl, 100 mL of saturated sodium bicarbonate for three times, and dried over 10 g of sodium sulfate. The reaction mass was evaporated under vacuum and placed under high vacuum. The reaction mass was again dissolved in 10 mL ethyl acetate, 60 mL hexane and decanted. The final reaction mass was placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 2.8:1
Example-7: Preparation of (S)-isopropyl 2-(((S)-(((2R,3R,4R,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-11-(2H)-yl)-4-flouro-3-hydroxy-4-methyl tetrahydroxyfuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:
(2S)-isopropyl-2-((chloro(phenoxy)phophoryl)amino)propanoate (1.712 g) and Methyl-t-butyl ether (5 mL) were charged into a round bottom flask under nitrogen atmosphere at 28°C. The reaction mass was cooled to 0°C. Tripropyl amine (724 mg) was added into the reaction mass followed by the addition of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (500 mg). Temperature of the reaction mixture was raised to 28°C and allowed to maintain for 12 hours.
The reaction mixture was concentrated on rotavapour under high vacuum. The obtained crude was dissolved in 10 mL of ethyl acetate, washed with 10% aqueous HCl, 10 mL of brine solution, 10 mL of saturated sodium bicarbonate, 10 mL brine solution and dried over sodium sulfate. The final reaction mass was evaporated under vacuum and placed under high vacuum.
The ratio towards desired isomer (Sp:Rp) = 4:1
,CLAIMS:We claim:
1. A stereoselective process for preparation of sofosbuvir represented by a Formula A, its stereo isomers, salts, polymorphs, and solvates;

Formula A
comprising: contacting a compound of Formula XVIII or a salt,

Formula XVIII
wherein, L is a leaving group;
with a compound of Formula XIX or a salt.

Formula XIX
wherein the reaction is conducted in anhydrous solvents selected from dichloromethane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine, tributylamine and their combinations.
2. A process for preparation of sofosbuvir according Formula VIII of claim 1, wherein leaving group is selected from Cl, Br, I, sulfate, acetate, tosylate, mesylate, trifluoroacetate, trifluorosulfonate, phenoxide, pentafluorophenoxide, p-NO2-phenoxide, tert-butyldimethylsilyl and levulinyl group.
3. A process for preparation of sofosbuvir according to claim 1, wherein the reaction conducted in presence of a base selected from tripropyl amine, tributyl amine, diisopropyl ethyl amine.
4. A process for preparation of sofosbuvir according to claim 1, wherein the reaction conducted at a temperature selected from -78°C to 40°C.
5. A process for preparation of sofosbuvir according to claim 1, wherein the reaction conducted for a period of 30 minutes to 24 hours.
6. A pharmaceutical composition of sofosbuvir produced according to claim 1 together with one or more pharmaceutically acceptable carriers.
7. A pharmaceutical composition of sofosbuvir produced according to claim 9 for the treatment of HCV.
8. A stereoselective process for preparation of sofosbuvir represented by a Formula A, its stereo isomers, salts, polymorphs, and solvates;

Formula A
comprising: contacting a compound of Formula XX or a salt,

Formula XX
with a compound of Formula XXI or a salt.

Formula XXI
wherein the reaction is conducted in anhydrous solvents selected from dichloromethane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl-t-butyl ether, ethyl acetate, acetonitrile, cyclopentyl methylether, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, diisopropyl ethyl amine, tripropylamine, tributylamine and their combinations.