DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
(2R)-2-DEOXY-2-FLUORO-2-C-METHYL-D-RIBOFURANOSE AND THEIR USE IN THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATES

INTRODUCTION
The present invention is directed towards (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compounds, their stereo isomers, salts, polymorphs and solvates thereof, processes for preparation of such (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compounds and use of the (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compounds in the preparation of phosphoramidate prodrugs of nucleosides such as Sofosbuvir.
U.S. Patent No. 7,429,572 B2 describes (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compounds, (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose nucleosides, processes for preparation, compositions and their use in treating 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 processes disclose in the prior art for the preparation of intermediates of sofosbuvir and sofosbuvir suffer from one or more drawbacks such as low purity, less yield and lengthy workup which 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 nucleoside phosphoramidate compounds including sofosbuvir and their intermediates.

SUMMARY
In the first aspect, the application provides (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose having a Formula I, their salts, stereo isomers, polymorphs and solvates thereof.

Formula I
Wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and
L is F, OMs or –OC(HN)CCl3;
In the second aspect, the application provides processes for preparation of (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose having a Formula I.
In the third aspect, the application provides use of novel (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compounds in preparation of nucleoside phosphoramidate prodrugs such as sofosbuvir.
DETAILED DESCRIPTION
A first embodiment of the application provides (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose having a Formula I, its stereo isomers, salts, polymorphs, and solvates thereof.

Formula I
Wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and
L is F, OMs or –OC(HN)CCl3.
A second embodiment of the application provides (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compound having a Formula II, its stereo isomers, salts, polymorphs, and solvates thereof.

Formula II
Wherein, R1, R2 are same as they described in the previous embodiment.
A third embodiment of the application provides (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compound having a Formula III, its stereo isomers, salts, polymorphs, and solvates thereof.

Formula III
Wherein, R1, R2 are same as they described in the previous embodiment.
A fourth embodiment of the application provides (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compound having a Formula IV, its stereo isomers, salts, polymorphs, and solvates thereof.

Formula IV
Wherein, R1, R2 are same as they described in the previous embodiment.
A fifth embodiment of the application provides the following specific nucleotide analog compounds, their stereo isomers, salts, polymorphs, and solvates thereof.

A sixth embodiment, the application provides a process for preparation of (2’R)-2’-Deoxy-2’-Fluoro-2’-C-Methyl-D-Ribofuranose having a Formula I, their stereo isomers, salts, polymorphs, and solvates thereof, which comprises one or more of the following steps:

Formula I
wherein, R1, R2 and L are same as they defined in the previous embodiment; which comprising contacting a compound of Formula V

Formula V
wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl;
with suitable reagents to substitute fluorine, mesyl or trichloroacetonitrile groups at C1 position of (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose.
The reaction can be performed in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include but are not limited to polar organic solvents such as dichloromethane, chlorobenzene, dichloroethane, chloroform, toluene, acetonitrile and terahydrofuran. The reaction is initiated at a temperature ranging from -100°C to 50°C. The reaction is then allowed to stir within the range of temperature between -100°C to 50°C for a period of about 10 minutes to 5 hours or longer.
A seventh embodiment, the application provides a process for preparation of (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compound having a Formula II, its stereo isomers, salts, polymorphs, and solvates thereof, which comprises one or more of the following steps:

Formula II
wherein, all the substituent same as defined above in Formula II of the previous embodiment; which comprising contacting a compound of Formula V;

Formula V
wherein, R1, R2 are same as they described in the previous embodiment.
with fluorinating agents comprising but not limited to Bis(2-methoxyethyl)aminosulfur Trifluoride (Deoxo-Fluor®), Diethylaminosulfur trifluoride (DAST), HF-Pyridine, 3HF.Et3N, 1,1,2,2-Tetrafluoroethyl-N,N-dimethylamine (TFEDMA), XtalFluor-E®, XtalFluor-M.
The reaction can be performed in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include but are not limited to polar organic solvents such as dichloromethane, acetonitrile, tetrahydrofuran, toluene and chloroform. The reaction is initiated at a temperature ranging from -100°C to 50°C. The reaction is then allowed to stir within the range of temperature between -100°C to 50°C for a period of about 10 minutes to 5 hours or longer.
An eighth embodiment, the application more preferably provides a process for preparation of (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compound having a Formula III, its stereo isomers, salts, polymorphs, and solvates thereof, which comprises one or more of the following steps:

Formula III
Wherein, R1, R2 are same as they described in the previous embodiment; which comprising contacting a compound of Formula V;

Formula V
Wherein, R1, R2 are same as they described in the previous embodiment.
with methanesulfonyl chloride.
The reaction can be performed in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include but are not limited to polar organic solvents such as dichloromethane, acetonitrile, tetrahydrofuran, toluene and chloroform. The reaction is initiated at a temperature ranging from -100°C to 50°C. The reaction is then allowed to stir within the range of temperature between -100°C to 50°C for a period of about 10 minutes to 5 hours or longer.
The reaction can be conducted in presence of bases including organic bases such as pyridine, triethylamine, methyl amine, imidazole, benzimidazole, histidine or inorganic bases such as NaOH, KOH, Mg(OH)2, Ca(OH)2, Na2CO3, K2CO3, NH4OH, optionally in presence phase transfer catalysts.
An ninth embodiment, the application more preferably provides a process for preparation of (2R)-2-Deoxy-2-Fluoro-2-C-Methyl-D-Ribofuranose compound having a Formula IV, its stereo isomers, salts, polymorphs, and solvates thereof, which comprises one or more of the following steps:

Formula IV
wherein, all the substituent same as defined above in Formula IV of the previous embodiment; which comprising contacting a compound of Formula V;

Formula V
Wherein, R1, R2 are same as they described in the previous embodiment.
with 2,2,2 trichloroacetonitrile.
The reaction can be performed in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include but are not limited to polar organic solvents such as dichloromethane, acetonitrile, tetrahydrofuran, toluene and chloroform. The reaction is initiated at a temperature ranging from -100°C to 50°C. The reaction is then allowed to stir within the range of temperature between -100°C to 50°C for a period of about 10 minutes to 5 hours or longer.
The reaction can be conducted in presence of a bases including organic bases such as 1,8-Diazabicycloundec-7-ene (DBU), triethylamine, pyridine, diisopropylamine and diethylamine.
If R1 is other than H, then it can be optionally converted to H by using the procedures known in the art.
A tenth embodiment, the application more preferably provides a process for preparation of nucleoside analog compound having a Formula VI which comprises one or more of the following steps;

Formula VI
wherein, R1 and R2 are defined same as in the previous embodiment; and
B is a base, which is selected from

Y is N or CH; R4, R5 and R6 are independently H, halogen (including F, Cl, Br, I), OH, OR', SH, SR', NH2, NHR', NR'2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH=CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH=CHCl, CH=CHBr and CH=CHI, lower alkynyl of C2-C6 such as C=CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R', CONH2, CONHR', CONR'2, CH=CHCO2H, CH=CHCO2R'; R' is an optionally substituted alkyl of C1-C12 (particularly when the alkyl is an amino acid residue), cycloalkyl, aryl, optionally substituted alkynyl of C2-C6, optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl.
which comprising contacting a compound of Formula I;

Formula I
Wherein, R1, R2 and L are same as they described in the previous embodiment.
wherein solvents, reagents used and conditions followed are same as in previous embodiment.
An eleventh embodiment, the application more preferably provides a process for preparation of nucleoside analog compounds having a Formula VII, their stereo isomers, salts, polymorphs, and solvates thereof, which comprises one or more of the following steps:

Formula VII

wherein, all the substituent same as defined above in Formula VII of the previous embodiment; which comprising contacting a compound of Formula II, Formula III and Formula IV;

Formula II Formula III Formula IV
wherein, all the substituent same as defined above in Formula II, Formula III and Formula IV of the previous embodiment.
wherein solvents, reagents used and conditions followed are same as in previous embodiment.
If R1 is other than H, then it can be optionally converted to H by using the procedures known in the art.
A twelfth embodiment, the application provides a process for preparation of nucleoside phosphoramidate compounds having Formula IX, their stereo isomers, salts, polymorphs, and solvates thereof, which comprises one or more of the following steps;
a) Contacting a compound of Formula X or a salt thereof

Formula X
wherein, R3 is a leaving group. X' and X'' are independently selected from H or OH. Provided when one of X' or X'' is H, then the other one is a leaving group.
with a compound of Formula VI or a salt thereof.

Formula VI
wherein, R1 is H and R2 is same as defined in the previous embodiment, to produce a compound of Formula IX.

Formula IX
wherein, R2, B are same as defined in the previous embodiment, R3 and X'' are same as defined above in the present embodiment.
b) If X'' is H or OH then displacing them with a leaving group. Preferably with a halogen.
c) contacting compound of Formula IX or salts thereof obtained from step a) with substituted or unsubstituted aminoacids or their salts provides nucleoside phosphoramidate compounds of Formula XI or 3-O-protected nucleoside phosphoramidate compounds.

Formula XI
wherein, R2, R3 and B are same as defined in the previous embodiment; A is substituted or unsubstituted amino acid.
d) If R2 is a protecting group, optionally deprotecting the 3-O-protected compound provides nucleoside phosphoramidate compounds.
wherein step a), the reaction is performed in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include but are not limited an anhydrous aromatic solvents. The reaction is initiated at a temperature ranging from -50°C to 40°C. The reaction is then allowed to stir within the range of temperature between -50°C to 40°C for a period of about 30 minutes to 3 hours or longer
wherein step b), the reaction can be conducted in a polar aprotic solvent, preferably acetonitrile, acetone, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and their combinations. The reaction can be conducted at a preferred reaction temperature range between from -50°C to 40°C.
The reaction is conducted in presence of a halogen containing organic solvent such as CCl4, CHCl3, CH2Cl2, CH3Cl, CCl3CN or their combinations to produce halogen leaving group. The same reagents can also be used as solvents in the same reaction. Any suitable solvents other than the solvents mentioned can be used in the reaction if they do not involve any reaction with the reagents.
A thirteenth embodiment, the application provides a process for preparation of sofosbuvir having Formula A, their stereo isomers, salts, polymorphs, and solvates thereof,

Formula A
which comprises one or more of the following steps;
Contacting a compound of Formula XII or a salt thereof

Formula XII
Wherein, L is a leaving group.
with a compound of Formula XIII or a salt thereof.

Formula XIII
In an embodiment of the present invention, compound of Formula XII used in the reaction can be a racemic mixture or the chirally pure at phosphorous atom. In other embodiment of the present invention, if compound of formula XII is racemic mixture, then it can be converted enatiomerically pure R and S isomers. In another embodiment of the present invention, compound of Formula XIII can be prepared by the following procedures known in the art.
The obtained compounds from Formula I to Formula XI may be further separated into pure enantiomers by following general methods known in the art such as crystallization, chromatography, use of enzymes etc.

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.
A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. 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.
The term "purified," as described herein, refers to the purity of a given compound. For example, a compound is "purified" when the given compound is a major component of the composition, i.e., at least 80% purity, at least 85% purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein "substantially pure" embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity.
As used throughout herein, the term room temperature refers to a temperature of from about 18°C to about 28°C., preferably about 20°C to about 25°C.
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 ((2R,3R,4R)-3-(benzoyloxy)-4,5-difluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate:
((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate (150 mg) and dichloromethane (3 mL) were charged into a round bottom flask under nitrogen atmosphere at 27°C. The reaction mixture was cooled to 0°C. Deoxo-fluoro (50% in THF) (0.35 mL) was added drop wise into the reaction mixture and stirred for 30 minutes at 0°C.
The obtained reaction mixture was diluted with dichloromethane (15 mL); the organic layer was washed with water (2 x 5 mL), saturated aqueous NaHCO3 solution (1 x 5 mL), and brine solution (1 x 5 mL); the organic layer was dried with Na2SO4 and evaporated under reduced pressure. The obtained crude reaction mixture of ((2R,3R,4R)-3-(benzoyloxy)-4,5-difluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate was co evaporated with dichloromethane (5 mL) and carried out to next step.
Example-2: Preparation of ((2R,3R,4R)-3-(benzoyloxy)-4,5-difluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate:
((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate (5 g) and dichloromethane (60 mL) were charged into a round bottom flask under nitrogen atmosphere at 27°C. The reaction mixture was cooled to -78°C. Diethylaminosulfur trifluoride (DAST) (3.53mL) was added drop wise into the reaction mixture and stirred for 15 minutes at the same temperature. The reaction mixture was further stirred at -78°C for 1 hour 30 minutes.
The obtained reaction mixture was diluted with dichloromethane (150 mL) and quenched with saturated aqueous NaHCO3 solution (5 mL) at -78°C. The reaction mixture was allowed to reach 27°C and stirred for 30 minutes. The organic layer was washed with water (2 x 25 mL), brine solution (1 x 25 mL), dried with Na2SO4 and evaporated under reduced pressure. The obtained crude reaction mixture of ((2R,3R,4R)-3-(benzoyloxy)-4,5-difluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate was co evaporated with dichloromethane (50 mL) and carried out next step.
Example-3: Preparation of (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate:
N-(2-((trimethylsilyl)oxy)pyrimidin-4-yl)benzamide (5.74 g) was charged into a round bottom flask under nitrogen atmosphere at 27°C. A solution of ((2R,3R,4R)-3-(benzoyloxy)-4,5-difluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate (5 g) in chlorobenzene (80 mL) was added to N-(2-((trimethylsilyl)oxy)pyrimidin-4-yl)benzamide in one portion and stirred for 10 minutes, under nitrogen atmosphere, at 27°C. SnCl4 (6.3 mL) was added into the reaction mixture and stirred at 27°C for 45 minutes. Then the reaction mixture was heated to 70°C and stirred at the same temperature for 2 hours.
NaHCO3 (26.6 g), Celite (5 g) and dichloromethane (500 mL) were charged into a 1L 2-neck round bottom flask at 27°C and cooled to 0°C. The reaction mixture was added to the cooled dichloromethane solution. The reaction mixture was quenched with water (5 mL) and stirred at 27°C for 30 minutes. The resultant reaction mixture was filtered through celite pad. The obtained residue was dissolved in dichloromethane (2 x 250 mL) and stir for 15 minutes. The combined organic layer was dried with Na2SO4 and evaporated under reduced pressure. HPLC analysis of the crude reaction mixture indicated formation a:? mixture in 1:5 ratio. For purification of the desired ? isomer, the crude product was suspended in 1:1 ratio of MeOH:IPA (80 mL) and refluxed for 30 minutes. The crude reaction mixture was cooled to 0°C. The obtained (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate was filtered through buckner funnel, washed with hexane (50 mL) and dried under vacuum for 2hours.
Yield = 3.4 grams
Example-4: Preparation of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl benzoate:
((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate (53 g) and dichloromethane (795 mL) were charged into a 2L round bottom flask under nitrogen atmosphere at 25°C. The reaction mixture was cooled to -10°C. Triethylamine (29.56 mL) and methanesulfonyl chloride (12.98 mL) were added drop wise at 0°C into the reaction mixture and stirred for 1 hour at the same temperature.
The obtained reaction mixture was diluted with dichloromethane (530 mL) and quenched with 1N HCl solution (530 mL); the organic layer was separated, washed with water (530 mL), saturated aqueous NaHCO3 solution (530 mL), and brine solution (530 mL); the organic layer was dried with anhy. Na2SO4 and evaporated under reduced pressure. The obtained crude reaction mixture of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl benzoate was carried out to next step.
Yield: 64 grams
Example-5: Preparation of (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate:
N-(2-((trimethylsilyl)oxy)pyrimidin-4-yl)benzamide (60.95 g) was charged into a round bottom flask under nitrogen atmosphere at 25°C. A solution of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)methyl benzoate (64 g) in chlorobenzene (1.02 L) was added to N-(2-((trimethylsilyl)oxy)pyrimidin-4-yl)benzamide in one portion and stirred for 5 minutes, under nitrogen atmosphere, at 25°C. SnCl4 (68.26 mL) was added into the reaction mixture and stirred at 25°C for 40 minutes. Then the reaction mixture was heated to 70°C and stirred at the same temperature for 2 hours.
NaHCO3 (284 g), Celite (32 g) and dichloromethane (1L) were charged into a 5L 3-neck round bottom flask at 25°C and cooled to 0°C. The reaction mixture was added to the cooled dichloromethane solution slowly and stirred for 5 min. The reaction mixture was quenched with water (64 mL) and stirred at 25°C for 1 hour at RT. The resultant reaction mixture was filtered through celite pad. The solid was washed with dichloromethane (2 x 250 mL). The residue was transferred to an RB flask and stirred with dichloromethane (500 mL) for 20 minutes; filtered and washed with dichloromethane (2 x 100 mL). The combined organic layer was dried with Na2SO4 (20 g) and solvent was evaporated under reduced pressure. HPLC analysis of the crude reaction mixture indicated formation a:? mixture in 1:4 ratio. For purification of the desired ? isomer, the crude product was suspended in MeOH (1 L) and heated to 90°C for 2h. The crude reaction mixture was cooled to 25°C. The obtained (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate was filtered through buckner funnel, washed with methanol (2 x 100 mL), hexane (100 mL) and dried under vacuum for 1 hour 30 minutes.
Yield = 28.5 grams
Example-6: Preparation of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-(2,2,2-trichloro-1-iminoethoxy)tetrahydrofuran-2-yl)methyl benzoate:
1,8-Diazabicycloundec-7-ene (DBU) (8 µL) was charged into the 2,2,2-trichloroacetonitrile (1 mL) under nitrogen atmosphere at 27°C. The reaction mixture was cooled to 0°C and a solution of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate (125 mg) in dichloromethane (5 mL) was slowly added drop wise into it under nitrogen atmosphere at 0°C for 5 minutes. The reaction mixture was stirred at 0°C for 30 minutes. The solvent was evaporated to obtain the crude product which was taken to next step without further purification.
Example-7: Preparation of (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate:
N-(2-((trimethylsilyl)oxy)pyrimidin-4-yl)benzamide (188 mg) was charged into a round bottom flask under nitrogen atmosphere at 27°C. A solution of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-(2,2,2-trichloro-1-iminoethoxy)tetrahydrofuran-2-yl)methyl benzoate (170 mg) in chlorobenzene (7 mL) was added to the N-(2-((trimethylsilyl)oxy)pyrimidin-4-yl)benzamide in one portion and stirred for 5 minutes, under nitrogen atmosphere, at 27°C. SnCl4 (0.15 mL) was added into the reaction mixture and stirred at 27°C for 30 minutes. Then the reaction mixture was heated to 70°C and stirred at the same temperature for 3 hours.
NaHCO3 (661 mg), Celite (200 mg) and dichloromethane (60 mL) were charged into a 1L 2-neck round bottom flask at 27°C. The reaction mixture was added to the dichloromethane solution. The reaction mixture was quenched with water (0.2 mL) and stirred at 27°C for 15 minutes. The resultant reaction mixture was filtered through celite pad. The obtained residue was dissolved in dichloromethane (2 x 15 mL) and stir for 15 minutes. The combined organic layer was washed with water (2 x 15 mL), brine solution (2 x 15 mL), dried with Na2SO4 and evaporated to get crude (2R,3R,4R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate as a/? mixture.
,CLAIMS:We Claim:
1. A compound, its salts, stereo isomers, polymorphs or solvates represented by a Formula VIII,

Formula VIII
wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and L is F, OMs or –OC(HN)CCl3.
2. The compound according to claim 1, represented by Formula h, Formula i and Formula j.

Formula h Formula i Formula j
3. A process for preparation of a compound represented by a Formula VIII, its stereo isomers, salts, polymorphs, and solvates,

Formula VIII
wherein R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and L is F, OMs or –OC(HN)CCl3; comprising: contacting a compound of Formula XII,

Formula XII
wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; with fluorinating agent, mesylation agent or trichloroacetonitrilation agent.
4. A process for preparation of a compound according to claim 3, wherein the reaction conducted in polar organic solvents selected from dichloromethane, acetonitrile, tetrahydrofuran, toluene and chloroform or .
5. A process for preparation of a compound according to claim 3, wherein the reaction conducted at a temperature ranging from -100°C to 50°C.
6. A process for preparation of a compound according to claim 3, wherein the reaction conducted in presence of organic bases selected from 1,8-Diazabicycloundec-7-ene (DBU), triethylamine, pyridine, diisopropylamine and diethylamine or .
7. A process for preparation of a compound according to claim 3, wherein the reaction conducted for a period of 10 minutes to 10 hours.
8. A process for preparation of a compound represented by a Formula XIII,

Formula XIII
wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and B is a base, which is selected from

Y is N or CH; R4, R5 and R6 are independently H, halogen (including F, Cl, Br, I), OH, OR', SH, SR', NH2, NHR', NR'2, lower alkyl of C1-C6, halogenated (F, Cl, Br, I) lower alkyl of C1-C6 such as CF3 and CH2CH2F, lower alkenyl of C2-C6 such as CH=CH2, halogenated (F, Cl, Br, I) lower alkenyl of C2-C6 such as CH=CHCl, CH=CHBr and CH=CHI, lower alkynyl of C2-C6 such as C=CH, halogenated (F, Cl, Br, I) lower alkynyl of C2-C6, lower alkoxy of C1-C6 such as CH2OH and CH2CH2OH, halogenated (F, Cl, Br, I) lower alkoxy of C1-C6, CO2H, CO2R', CONH2, CONHR', CONR'2, CH=CHCO2H, CH=CHCO2R'; R' is an optionally substituted alkyl of C1-C12 (particularly when the alkyl is an amino acid residue), cycloalkyl, aryl, optionally substituted alkynyl of C2-C6, optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl;
comprising: contacting a compound of Formula VIII,

Formula VIII
wherein, R1, R2 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl;
with a naturally occurring or modified purine or pyrimidine base.
9. A process for preparation of a compound according to claim 8, wherein the reaction conducted in solvents selected from in polar organic solvents selected from dichloromethane, acetonitrile, tetrahydrofuran, toluene and chloroform, at a temperature ranging from -100°C to 50°C, in presence of bases selected from 1,8-Diazabicycloundec-7-ene (DBU), triethylamine, pyridine, diisopropylamine and diethylamine or , and for a period of 10 minutes to 10 hours.
10. A pharmaceutical composition comprising nucleophosphoramidate compounds obtained by using the intermediates prepared according to any of the preceding claims together with one or more pharmaceutically acceptable carriers.