Field of the Invention:
The present invention provides novel processes for the preparation of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4^
methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate represented by the following structural formula-1.
Background of the Invention:
(S)-isopropyl 2-((S)-(((2R,3R54R,5R)-5-(2s4-dioxo-354-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoiylamino) propanoate, commonly known as Sofosbuvir is used for hepatitis C virus (HCV) infection. Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-a-fluoro-P-C-methyluridine-5'-triphosphate. It was discovered at Pharmasset and developed by Gilead Sciences. Sofosbuvir got approval both in US and Europe and currently marketed under the brand name Sovaldi.
US7964580B2 discloses nucleoside phosphoramidate prodrugs such as (S)-isopropyl 2-((S)-(((2R3R,4R,5R)-5-(2,4-dioxo-^
methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate and process for their preparation.
Still, there is a significant need in the art to develop improved/novel process for the preparation of (S)-isopropyl 2-((S)-(((2R33R,4R,5R)-5-(234-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoryl amino)propanoate.
US8618076B2 assigned to Gilead Pharmasset has described six crystalline polymorphs namely crystalline form-1, form-2, form-3, form-4, form-5 & form-6 and an amorphous form of (S)-isopropyl 2-((S)-(((2R,3R,4RJ5R)-5-(2,4-dioxo-3,4-dihydro

pyrimidin-1 (2H)-yl)-4-fluoro-3-hydros phosphoryl amino)propanoate.
Still, there is a significant need in the art to develop novel polymorphic form of the said compound which may have advantageous physical properties such as free flowability, greater stability and greater bioavailability.
Brief description of the invention:
The first aspect of the present invention is to provide novel process for the preparation of (S)-isopropyl. 2-((S)-(((2R,3R54R,5R)-5-(2)4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoryl amino)propanoate compound of formula-1.
The second aspect of the present invention is to provide another novel process for the preparation of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2J4-dioxo-334-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoryl amino)propanoate compound of formula-1.
The third aspect of the present invention is to provide novel crystalline polymorph of (S)-isopropyl 2-((S)-(((2R,3R^
3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1.
The fourth aspect of the present invention is to provide process for the preparation of novel crystalline polymorph of (S)-isopropyl 2-((S)-(((2R,3R?4RJ5R)-5-(2,4-dioxo-3J4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1.
The fifth aspect of the present invention is to provide a process for the preparation of l-((2R,3RJ4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl) pyrimidine-2,4(lHs3H)-dione compound of formula-3.
Brief description of the Drawings:
Figure-1: Illustrates the PXRD pattern of novel crystalline form-M of (S)-isopropyl 2-((S)-
(((2R,3R,4R55R)-5-(234-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyl
tetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate (Formula-1).

Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane- 1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the aforementioned solvents.
The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methyl imidazole, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-

ene(DBN), N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or their mixtures.
The term "suitable acid" used in the present invention refers to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, alkyl/aryl sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
The term "alkyl magnesium halides" used in the present invention refers to a class of compounds represented by the general formula R'MgX, wherein R' represents Ci-Ce straight chain or branched chain alkyl, alkenyl and C5-C10 substituted/unsubstituted aryl groups. Those groups includes but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, substituted or unsubstituted phenyl and the like; 'X' represents halogen such as CI, Br, and I.
In the present invention, the separation of diastereomers can be carried out by crystallization from a suitable solvent or by using chromatography techniques such as high performance liquid chromatography (HPLC), column chromatography, preparative HPLC, supercritical fluid chromatography (SFC), chiral column chromatography and the like. The diastereomers separation process is not limited to the above mentioned techniques. This can also be done by using any conventional techniques known in the art.
The first aspect of the present invention provides novel process for the preparation of (S)-isopropyl2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-^ 3-hydroxy-4-methyltetrahydrofliran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1, comprising of;
a) Tritylation of L-cysteine or its acid-addition salt by treating it with a suitable tritylating agent in a suitable solvent optionally in presence of a suitable base to provide (R)-2-amino-3-(tritylthio)propanoic acid compound of formula-5 or its acid-addition salt,

b) esterification of compound of formula-5 or its salt by reacting it with isopropyl alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide (R)-isopropyl 2-amino-3-(tritylthio)propanoate compound of formula-6 or its acid-addition salt,
c) reacting the compound of formula-6 or its salt with compound of general formula-7 in presence of a suitable base in a suitable solvent followed by reacting the obtained compound with compound of general formula R-OH in presence of a suitable base in a suitable solvent to provide compound of general formula-8,
d) separating the diastereomers form the compound of general formula-8 to provide compound of general formula-2,
e) reacting the compound of general formula-2 with l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lHJ3H)-dione compound of formula-3 in presence of alkyl magnesium halide or a suitable base in a suitable solvent to provide (R)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy) (phenoxy)phosphorylamino)-3-(tritylthio)propanoate compound of formula-9,
f) treating the compound of formula-9 with Raney Ni in a suitable solvent to provide compound of formula-1,
g) optionally purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.
Wherein, in step-a) the suitable tritylating agent is selected from trityl chloride, p-methoxybenzyl trityl ether and the like;
in step-b) the suitable esterification catalyst is selected from conc.FhSO^ thionyl chloride, oxalyl chloride and the like;
in step-a), step-c) and step-e) the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
in step-a) to step-g) wherever necessary the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixture.

Alternatively, compound of formula-9 is deprotected by treating it with a suitable trityl deprotecting agent in a suitable solvent to provide (R)-isopropyl 2-((S)-(((2R,3R,4R35R)-5-(2,4-dioxo-3)4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hyd tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)-3-mercaptopropanoate compound of formula-10 followed by treating the compound of formula-10 with Raney Ni in a suitable solvent to provide compound of formula-1.
Wherein, the suitable trityl deprotecting agent is selected from acids such as HC1, formic acid, acetic acid, trifluoroacetic acid, Lewis acids or the detritylation can be done by hydrogenolysis; the suitable solvent is same as defined above in first aspect.
The l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydro furan-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 utilized in step-e) of the first aspect of the present invention can be synthesized by any of the processes known in the art.
Alternatively, in the above process compound of general formula-7 is reacted with compound of general formula R-OH in presence of a suitable base in a suitable solvent followed by reaction of the obtained compound with (R)-isopropyl 2-amino-3-(tritylthio)propanoate compound of formula-6 or its acid-addition salt in presence of a suitable base in a suitable solvent to provide the compound of general formula-8.
Wherein, the suitable base and the suitable solvent are same as defined above in step-c) of the first aspect of the present invention.
In another embodiment of the present invention compound of formula-1 is prepared
as follows;
a) Reacting the compound of general formula-8 with l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 in presence of alkyl magnesium halide or a suitable base in a suitable solvent to provide (2R)-isopropyl 2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy) (phenoxy)phosphorylamino)-3-(tritylthio)propanoate compound of formula-15,

b) treating the compound of formula-15 with Raney Ni in a suitable solvent to provide (2S)-isopropyl 2-((((2R)3R)4R,5R>5-(2J4-dioxo-334-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate compound of formula-16,
c) separating the diastereomers from the compound of formula-16 to provide compound of formula-1.
Wherein, in step-a) the suitable base is same as defined in step-e) of the first aspect of the present invention;
in step-a) & step-b) the suitable solvent is same as defined in step-a) of the first aspect of the present invention.
The second aspect of the present invention provides another novel process for the preparation of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoryl amino)propanoate compound of formula-1, comprising of;
a) Esterification of (2R,2,R)-3,3'-disulfanediylbis(2-aminopropanoic acid) compound of formula-11 with isopropyl alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) compound of formula-12,
b) reacting the compound of formula-12 with compound of general formula-7 in presence of a suitable base in a suitable solvent followed by reacting the obtained compound with compound of general formula R-OH in presence of a suitable base in a suitable solvent to provide compound of general formula-13,
c) separating the diastereomers form the compound of general formula-13 to provide compound of general formula-4,
d) reacting the compound of general formula-4 with l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 in presence of alkyl magnesium halide or a suitable base in a suitable solvent to provide compound of formula-14,

e) treating the compound of formula-14 with Raney Ni in a suitable solvent to provide compound of formula-1,
f) optionally purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.
Wherein, in step-a) the suitable esterification catalyst is same as defined in step-b) of the first aspect of the present invention;
in step-b) & step-d) the suitable base is same as defined in step-c) of the first aspect of the present invention;
in step-a) to step-f) wherever necessary, the suitable solvent is same as defined in first aspect of the present invention.
Alternatively, in the above process compound of general formula-7 is reacted with compound of general formula R-OH in presence of a suitable base in a suitable solvent followed by reaction of the obtained compound with (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) compound of formula-12 in presence of a suitable base in a suitable solvent provides the compound of general formula-13.
An embodiment of the present invention provides alternate process for the preparation of (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) compound of formula-12, comprising of; a) Reacting the (2R,2'R)-3,3'-disulfanediylbis(2-aminopropanoic acid) compound of
formula-11 with a suitable amine protecting agent under suitable conditions to provide
compound of general formula-23,
wherein, T3" represents amine protecting group; b) reacting the compound of general formula-23 with isopropyl alcohol to provide compound of general formula-24,

c) deprotecting the compound of general formula-24 by treating it with a suitable amine deprotecting agent to provide (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-amino propanoate) compound of formula-12 or its salt.
Wherein, in step-a) the amine protecting group (N-protecting group) is selected from but not limited to tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA) group and the like;
The suitable amine protecting agent is selected such that it is capable of protecting the nitrogen atom of the amine group with any of the above mentioned amine protecting groups. Suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzoic anhydride, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like; the amine protection step can be carried out optionally in presence of a suitable base or a suitable acid in a suitable solvent as defined above based on the type of the protecting group to be incorporated;
In step-b) the reaction is carried out in presence of a suitable coupling agent optionally in presence of a suitable base and/or a suitable solvent. Wherein the suitable coupling agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1), N,N-carbonyldiimidazole (CDI), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), 4-

methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1 -yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1 -hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-1 -yl)-N,N,N\N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS); the suitable base is selected from organic bases, inorganic bases or their mixtures;
In step-c) the suitable deprotecting agent is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(Ci-C6)alkylsilanes, tri(C i -C6)alkylsilyl halides and the like;
In step-a) to step-c) the suitable solvent is selected from but not limited to alcohol solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, nitrile solvents, polar solvents, polar-aprotic solvents, ketone solvents or their mixtures.
The (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) compound of formula-12 or its salt obtained by the above process is converted into compound of formula-1 according to the above described processes.
In another embodiment of the present invention compound of formula-1 is prepared
as follows;
a) Reacting the compound of general formula-13 with l-((2R,3Rs4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 in presence of alkyl magnesium halide or a suitable base in a suitable solvent to provide compound of formula-17,

b) treating thexompound of formula-17 with Raney Ni in a suitable solvent to provide (2S)-isopropyl 2-((((2R3R,4RJ5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate compound of formula-16,
c) separating the diastereomers from the compound of formula-16 to provide compound of formula-1.
Wherein, in step-a) the suitable base is same as defined in step-e) of the first aspect of the present invention;
in step-a) & step-b) the suitable solvent is same as defined in step-a) of the first aspect of the present invention.
The third aspect of the present invention provides novel crystalline polymorph of (S)-isopropyl 2-((S)-(((2R,3R,4R35R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1. The said novel polymorph is herein after designated as crystalline form-M and it is characterized by X-Ray powder diffraction pattern having peaks at 8.0, 10.3, 12.4, 13.4, 16.1, 16.7, 17.1, 19.3, 20.0, 20.8, 21.3, 24.3, 25.3, 27.1 ± 0.2° of 20 values. The crystalline form-M of compound of formula-1 of the present invention is further characterized by its PXRD pattern as illustrated in figure-1.
The crystalline form-M of the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-1 is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula-1 present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as conventional pharmaceutical excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.

The fourth aspect of the present invention provides process for the preparation of novel crystalline polymorph (herein designated as crystalline form-M) of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-d^
methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1, comprising of;
a) Adding a suitable solvent or mixture of solvents to compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering and drying the solid to provide crystalline form-M of compound of formula-1.
Wherein, in step-a) the suitable solvent is selected from hydrocarbon solvents, ester solvents, ether solvents, acetic acid or their mixture;
In step-b) the suitable temperature is ranging from 35°C to reflux temperature of the solvent used; In step-c) the suitable temperature is ranging from 20°C to -20°C.
One embodiment of the present invention provides a process for the preparation of novel crystalline form-M of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy) phosphorylamino)propanoate compound of formula-1, comprising of;
a) Adding a mixture of n-heptane and n-butyl acetate to compound of formula-1,
b) heating the reaction mixture to 60-65°C,
c) slowly cooling the reaction mixture to 0-5°C,
d) filtering and drying the solid to provide crystalline form-M of compound of formula-1.
Another embodiment of the present invention provides a process for the preparation of novel crystalline form-M of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1, comprising of;
a) Adding a mixture of n-heptane, methyl tert.butyl ether and acetic acid to compound of formula-1,
b) heating the reaction mixture to 65-70°C,

c) slowly cooling the reaction mixture to 0-5°C,
d) filtering and drying the solid to provide crystalline form-M of compound of formula-1.
The compound of formula-1 utilized in step-a) of the fourth aspect of the present invention can be obtained by any of the processes known in the art or it can be obtained by the process as described in the present invention.
The fifth embodiment of the present invention provides a process for the preparation of l-((2R)3R)4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl) pyrimidine-2,4(lH,3H)-dione compound of formula-3, comprising of;
a) Halogenation of compound of general formula-18 by treating it with a suitable halogenating agent in a suitable solvent optionally in presence of a suitable phase transfer catalyst to provide compound of general formula-19,
b) reacting the compound of general formula-19 with 2,4-dimethoxypyrimidine compound of formula-20 optionally in presence of a suitable solvent to provide compound of general formula-21,
c) hydrolyzing the compound of general formula-21 in presence of a suitable acid optionally in presence of a suitable solvent to provide compound of general formula-22,
d) deprotecting the compound of general formula-22 to provide compound of formula-3.
Wherein, in step-a) the suitable halogenating agent is selected from Ch, Br2, I2, SOG2, SOBr2, SO2CI2, S02Br2, CCI4, CBr^ N-chlorosuccinimide, N-bromosuccinimide and the like; the suitable phase transfer catalyst is selected from tetraalkyl/aryl ammonium halides, tetraalkyl/aryl ammonium hydroxides and the like; and the reaction can be carried out optionally in presence of a suitable catalyst such as triphenylphosphine;
In step-c) the suitable acid is hydrochloric acid, sulfuric acid and the like;
In step-a) to step-c) the suitable solvent is same as defined in step-a) of first aspect.
In the present invention, the suitable O-protecting group 'Pi' & c?2* is selected from but not limited to benzyloxycarbonyl (Cbz), acyl group such as acetyl (Ac), benzoyl (Bz); benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA) group and the like.

The suitable O-protecting agent is selected such that it is capable of protecting the oxygen atom with any of the above mentioned amine protecting groups.
Suitable O-protecting agent is selected from but not limited to benzyl chloroformate, acetyl chloride, acetic anhydride, benzoyl halides, benzoic anhydride, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like.
In step-d), the deprotection of compound of general formula-22 is carried out based on the type of the protecting group employed. The said deprotection step is performed by treating the compound of general formula-22 with a suitable deprotecting agent selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid and the like; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(Ci-C6)alkylsilanes, tri(Ci-C6)alkylsilyl halides and the like.
The compound of formula-18 used in the present invention can be prepared by any of process known in the art.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Exam pie-1: Preparation of L-Cysteine hydrochloride
A mixture of L-Cysteine (2 gm) and toluene (10 ml) was cooled to 0-5°C and stirred the reaction mixture for 10 min at the same temperature under nitrogen atmosphere. Ethyl acetate-HCl (2 ml) was added to the reaction mixture at 0-5°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with toluene and dried the material to get the title compound. Yield: 2.0 gm.
Example-2: Preparation of (R)-2-amino-3-(tritylthio)propanoic acid hydrochloride salt (Formula-5a)
A mixture of L-cysteine hydrochloride (2 gm) and N,N-dimethylformamide (8 ml) was stirred for 5 min at 25-30°C. Trityl chloride (3.1 gm) was added to the reaction mixture at 25-30°C and stirred for 48 hrs at the same temperature. Slowly poured the reaction mixture into aqueous sodium acetate solution at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the solid and washed with water. Acetone (30 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with acetone and dried the material to get the title compound. Yield: 3.6 gm.
Example-3: Preparation of (R)-isopropyl 2-amino-3-(tritylthio)propanoate hydrochloride salt (Formula-6a)
A mixture of (R)-2-amino-3-(tritylthio)propanoic acid hydrochloride salt compound of formula-5a (5 gm) and isopropyl alcohol (50 ml) was cooled to -15°C to -10°C and stirred the reaction mixture for 10 min at the same temperature under nitrogen atmosphere. Thionyl chloride (2 ml) was added to the reaction mixture at -15°C to -10°C and stirred for 10 min at the same temperature. Slowly heated the reaction mixture to 75-80°C and stirred for 3 hrs at

the same temperature. Thionyl chloride (0.5 ml) was added to the reaction mixture at 75-80°C and stirred for 214 hrs at the same temperature. Distilled off the reaction mixture under reduced pressure. Slowly heated the reaction mixture to 120-125°C and stirred for 15 min under reduced pressure. Reduced the temperature of the reaction mixture to 40-45°C and co-distilled the reaction mixture with dichloromethane to get the title compound. Yield: 5.9 gm.
Example-4: Preparation of (2R)-isopropyl 2-((4-nitrophenoxy)(phenoxy) phosphorylamino)-3-(tritylthio)propanoate (FormuIa-8a)
Phenyl dichlorophosphate (2.8 gm) followed by triethylamine (4.4 ml) were slowly added to a pre-cooled mixture of (R)-isopropyl 2-amino-3-(tritylthio)propanoate hydrochloride salt compound of formula-6a (5 gm) and dichloromethane (75 ml) at -20°C to -15°C under nitrogen atmosphere and stirred the reaction mixture for 60 min at the same temperature. Raised the temperature of the reaction mixture to -10°C to -5°C and stirred for 70 min at the same temperature. p-Nitro phenol (1.7 gm), dichloromethane (25 ml) and triethylamine (2 ml) were added to the reaction mixture at -10°C to -5°C and stirred for 6 hrs at the same temperature. Distilled the reaction mixture under reduced pressure and co-distilled with ethyl acetate. Cooled the reaction mixture to 25-30°C and ethyl acetate was added. Further cooled the reaction mixture to 0-5°C and stirred for 40 min at the same temperature. Filtered the reaction mixture and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tert.butyl ether. 20 ml of methyl tert.butyl ether was added to the obtained compound at 25-30°C and stirred for 40 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried to get the title compound. Yield: 3.0 gm.
Example-5: Preparation of (2R)-isopropyI 2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)-3-(tritylthio)propanoate (Formula-15)
2M tert-butyl magnesium chloride solution (3.7 ml) was slowly added to a pre-cooled mixture of l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydro furan-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 (1.0 gm), tetrahydrofuran

(15 ml) and N-methyl pyrrolidone (1 ml) at 15-20°C and stirred the reaction mixture for 15 min at the same temperature under nitrogen atmosphere. A solution of (2R)-isopropyl 2-((4-nitrophenoxy)(phenoxy)phosphorylamino)-3-(tritylthio)propanoate compound of formula-8a (4.7 gm) in tetrahydrofuran (40 ml) was slowly added to the reaction mixture at 15-20°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 hrs at the same temperature. Slowly quenched the reaction mixture with aqueous ammonium chloride solution at 25-30°C and stirred for 10 min at the same temperature. Ethyl acetate was added to the reaction mixture and stirred for 10 min. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium carbonate solution
*
followed by with aqueous sodium chloride solution. Distilled off the solvent completely from
the organic layer and co-distilled with dichloromethane, ethyl acetate followed by with
cyclohexane to get the title compound as a solid.
Yield: 2.2 gm.
ExampIe-6: Preparation of (2S)-isopropyI 2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-
dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-
yl)methoxy)(phenoxy)phosphorylamino)propanoate (Formula-16)
Raney Ni (8.0 gm) was added to a mixture of (2R)-isopropyl 2-((((2R,3R,4R,5R)-5-(2J4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)-3-(tritylthio)propanoate compound of formula-15 (1.7 gm) and methanol (80 ml) in an autoclave vessel at 25-30°C under nitrogen atmosphere. Flushed the reaction mixture with hydrogen gas. 3-4 Kg/cm2 hydrogen gas pressure was applied to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Released the hydrogen gas from the autoclave vessel. Filtered the reaction mixture through hyflow bed and washed with methanol under nitrogen atmosphere. Distilled off the solvent completely from the filtrate under reduced pressure. The obtained compound is isolated from the reaction mixture by column chromatography by using ethyl acetate in cyclohexane as eluent.
Example-7: Preparation of crystalline form-M of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)« 5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydro furan-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate (Formula-1)

A mixture of n-heptane (30 ml) and n-butyl acetate (0.2 ml) was added to (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-d%^
hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propa^ compound of formula-1 (500 mg) at 25-30°C. Slowly heated the reaction mixture to 55-60°C and stirred for 1 hr at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Further cooled the reaction mixture slowly to 0-5°C and stirred for 10 min at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound.
The PXRD pattern of the obtained compound is shown in figure-1. Yield: 350.0 mg.
Example-8: Preparation of crystalline form-M of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyItetrahydro furan-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate (Formula-1)
A mixture of acetic acid (0.5 ml), methyl tert-butyl ether (50 ml) and n-heptane (25 ml) was added to (S)-isopropyl 2-((S)-(((2R,3R,4R35R)-5-(2,4-dioxo-334-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoryl amino)propanoate compound of formula-1 (500 mg) at 25-30°C. Slowly heated the reaction mixture to 60-65°C and stirred for 1 hr at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 4 hrs at the same temperature. Filtered the solid and dried to get the title compound.
The PXRD pattern of the obtained compound is shown in figure-1. Yield: 180.0 mg.
Example-9: Preparation of (R)-2-amino-3-(tritylthio)propanoic acid hydrochloride (Formula-5a)
Ethyl acetate-HCl (25 ml) was added to a pre-cooled mixture of L-cysteine (25 gm) and toluene (125 ml) at 0-5°C under nitrogen atmosphere and stirred the reaction mixture for 90 min at the same temperature. Filtered the solid, washed with toluene and dried the material. N,N-dimethylformamide (100 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 5 min at the same temperature. Trityl chloride (38.9 gm)

was added to the reaction mixture and stirred for 48 hrs at the same temperature. Slowly poured the reaction mixture into 10% aqueous sodium acetate solution at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the solid, washed with water and then suck dried the material. Acetone (375 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 45 min at the same temperature. Slowly cooled the reaction mixture to 0-5°C and stirred for 1 hr at same temperature. Filtered the solid, washed with acetone and dried to provide title compound. Yield: 45.0 gm.
Example-10: Preparation of (R)-isopropyl 2-amino-3-(tritylthio)propanoate hydrochloride salt (Formula-6a)
Thionyl chloride (2 ml) was added to a pre-cooled mixture of (R)-2-amino-3-(tritylthio)propanoic acid hydrochloride salt compound of formula-5a (5 gm) and isopropyl alcohol (50 ml) at -10°C to -15°C under nitrogen atmosphere and stirred the reaction mixture for 10 min at the. same temperature. Raised the temperature of the reaction mixture to 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 3 hrs at the same temperature. Thionyl chloride (0.5 ml) was added to the reaction mixture at 75-80°C and stirred for 2XA hrs at the same temperature. Heated the reaction mixture to 120-125°C. Distilled the reaction mixture under reduced pressure and stirred the reaction mixture for 15 min at 120-125°C under reduced pressure. Cooled the reaction mixture to 40-45°C. Co-distilled the reaction mixture with dichloromethane and cooled the reaction mixture to 25-30°C to provide the title compound. Yield: 4.75 gm.
Example-11: Preparation of (2R)-isopropyl 2-((4-nitrophenoxy)(phenoxy)phosphoryl amino)-3-(tritylthio)propanoate (Formula-8a)
Phenyl dichlorophosphate (2.8 gm) and triethylamine (4.4 ml) were added to a pre-cooled mixture of (R)-isopropyl 2-amino-3-(tritylthio)propanoate hydrochloride compound of formula-6a (5 gm) and dichloromethane (75 ml) at -15°C to -20°C and stirred the reaction mixture for 1 hr at the same temperature. Raised the temperature of the reaction mixture to -5°C to -10°C and stirred the reaction mixture for 60 min at the same temperature. Dichloromethane (25 ml) and p-nitrophenol (1.7 gm) were added to the reaction mixture. Triethylamine (1.9 ml) was slowly added to the reaction mixture at -5°C to -10°C and stirred

the reaction mixture for 6 hrs at the same temperature. Distilled the reaction mixture under reduced pressure and co-distilled with ethyl acetate under reduced pressure. Cooled the reaction mixture to 25-30°C and ethyl acetate (60 ml) was added. Further cooled the reaction mixture to 0-5°C and stirred for 40 min at the same temperature. Filtered the reaction mixture and washed with ethyl acetate. Distilled off the solvent completely from the organic layer and co-distilled with methyl tert.butyl ether. 20 ml of methyl tert.butyl ether was added to the 0 obtained compound at 25-30°C and stirred the reaction mixture for 40 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and then dried the material to provide the title compound. Yield: 5.0 gm.
Example-12: Preparation of (2R)-isopropyl 2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy)(pheno\y)phosphorylamino)-3-(trityIthio)propanoate (Formula-15)
2M tert.butyl magnesium chloride solution (3.6 ml) was slowly added to a pre-cooled mixture of l-((2R53R,4R55R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydro furan-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 (1 gm), tetrahydrofuran (15 ml) and N-methylpyrrolidone (1 ml) at 15-20°C under nitrogen atmosphere and stirred the reaction mixture for 15 min at the same temperature. A solution of (2R)-isopropyl 2-((4-nitrophenoxy)(phenoxy) phosphorylamino)-3-(tritylthio)propanoate compound of formula-8a (4.7 gm) in tetrahydrofuran (40 ml) was slowly added to the reaction mixture at 15-20°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 hrs at the same temperature. Slowly quenched the reaction mixture using aqueous ammonium chloride solution at 25-30°C and stirred the reaction mixture for 10 min. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred the reaction mixture for 10 min. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium carbonate solution followed by with aqueous sodium chloride solution. Dried the organic layer over sodium sulfate, distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with dichloromethane, ethyl acetate followed by with cyclohexane to provide the title compound. Yield: 1.0 gm.

Example-13: Preparation of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy)-(phenoxy)phosphorylamino)propanoate (Formula-1)
Raney Ni (8 gm) was added to a mixture of (2R)-isopropyl 2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro pyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)-3-(tritylthio)propanoate compound of formula-15 (1.7 gm) and methanol (80 ml) in an autoclave vessel at 25-30°C under nitrogen atmosphere. Flushed the reaction mixture with hydrogen gas. 3-4 Kg/cm2 hydrogen gas pressure was applied to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Released the hydrogen gas from the autoclave vessel. Filtered the reaction mixture through hyflow bed and washed with methanol under nitrogen atmosphere. Distilled off the solvent completely from the filtrate under reduced pressure. The obtained compound is isolated from the reaction mixture by column chromatography by using ethyl acetate in cyclohexane as eluent. Yield: 0.89 gm.
Example-14: Preparation of (6R,HR)-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-diazahe\adecane-6,ll-dicarboxylic acid (Formula-23a)
10% Aqueous sodium hydroxide solution (500 ml) was added to a mixture of L-cystine (100 gm) and tetrahydrofuran (1000 ml) at 25-30°C and cooled the reaction mixture to 0-5°C. Di tert.butyl dicarbonate (272 gm) was slowly added to the reaction mixture at 0-5°C and stirred the reaction mixture for 22 hrs at the same temperature. Filtered the reaction mixture and washed with tetrahydrofuran. Methyl tert.butyl ether (500 ml) was added to the filtrate and stirred the reaction mixture for 10 min. Both the organic and aqueous layers were separated, acidified the aqueous layer by using 10% aqueous citric acid solution and stirred the reaction mixture for 30 min. Filtered the precipitated solid, washed with water and dried the material to provide the title compound. Yield: 130.0 gm.
Example-15: Preparation of (6R,llR)-diisopropyl-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-diazahexadecane-6,ll-dicarboxylate (Formuia-24a)

A solution of dicyclohexylcarbodiimide (70.2 gm) in dichloromethane (200 ml) was added to a mixture of (6R,11R)-2,2J5J5-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-diazahexadecane-6,ll-dicarboxylic acid compound of formula-23a (50 gm), dimethylamino pyridine (2.49 gm), isopropyl alcohol (50 ml) in dichloromethane (500 ml) at 25-30°C and . stirred the reaction mixture for 22 hrs at the same temperature. The reaction mixture was filtered and washed with dichloromethane. Concentrated the filtrate, methyl tert.butyl ether (250 ml) was added and stirred the reaction mixture for 30 min. Filtered the reaction mixture and concentrated the filtrate to provide the title compound. Yield: 55.0 gm.
Example-16: Preparation of (2R,2'R)-isopropyl 3,3'-disulfanediyIbis(2-amino propanoate) dihydrochloride (Formula-12a)
Methanolic HC1 (750 ml) was added to (6R,llR)-diisopropyl-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-diazahexadecane-6,11 -dicarboxylate compound of formula-24a (50 gm) at 25-30°C and stirred the reaction mixture for 24 hrs at the same temperature. Concentrated the reaction mixture, ethyl acetate (200 ml) was added and stirred the reaction mixture for 2 hrs. Filtered the solid, washed with ethyl acetate and then dried the material to provide the title compound. Yield: 35.0 gm. Example-17: Preparation of compound of formula-4a
Triethylamine (5.7 gm) was added to a mixture of (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) dihydrochloride compound of formula-12a (5 gm), phenylphosphorodichloridate (6.3 gm) in dichloromethane (75 ml) at -78°C and stirred the reaction mixture for 1 hr at the same temperature. Raised the temperature of the reaction mixture to 0-5°C and 4-nitrophenol (3.5 gm) followed by triethylamine (3.2 gm) were added to it. The resulting reaction mixture was stirred for 6 hrs at 0-5°C and quenched with water. Both the organic and aqueous layers were separated and washed the organic layer with water. The organic layer was dried and concentrated. The obtained compound was purified by column chromatography using cyclohexane:ethyl acetate (90:10) and then concentrated to provide the title compound. Yield: 7.0 gm. Example-18: Preparation of compound of formula-14

2M tert.butyl magnesium chloride solution (3.6 ml) was slowly added to a pre-cooled mixture of l-((2R?3R34R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydro furan-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3 (1 gm), tetrahydrofuran (15 ml) and N-methylpyrrolidone (1 ml) at 15-20°C under nitrogen atmosphere and stirred the reaction mixture for 15 min at the same temperature. A solution of compound of formula-4a SOA 3E (6 gm) in tetrahydrofuran (40 ml) was slowly added to the reaction mixture at 15-20°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 hrs at the same temperature. Slowly quenched the reaction mixture using aqueous ammonium chloride solution at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with 5% aqueous sodium carbonate solution followed by with 10% aqueous sodium chloride solution. Dried the organic layer over sodium sulfate. Distilled off the solvent from the organic layer under reduced pressure, co-distilled with dichloromethane, ethyl acetate followed by with cyclohexane and then dried the material to provide the title compound. Yield: 3.0 gm. Example-19: Preparation of compound of formula-1
Raney Ni (8 gm) was added to a mixture of compound of formula-14 (2 gm) and methanol (80 ml) at 25-30°C in an autoclave vessel under nitrogen atmosphere. Flushed the reaction mixture with hydrogen gas. 3-4 Kg/cm2 hydrogen gas pressure was applied to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Released the hydrogen gas from the autoclave vessel. Flushed the reaction mixture with nitrogen gas. Filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure. The obtained compound was isolated by column chromatography using ethyl acetate/cyclohexane. Yield: 0.75 gm.

We Claim:
1. Novel process for the preparation of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3 -hydroxy-4-methyltetrahydrofuran-2-yl) methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1, comprising; a) Tritylation of L-cysteine or its acid-addition salt by treating it with a suitable tritylating agent in a suitable solvent optionally in presence of a suitable base to provide (R)-2-amino-3-(tritylthio)propanoic acid compound of formula-5 or its acid-addition salt,
b) esterification of compound of formula-5 or its salt by reacting it with isopropyl alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide (R)-isopropyl 2-amino-3-(tritylthio)propanoate compound of formula-6 or its acid-addition salt,
c) reacting the compound of formula-6 or its salt with compound of general formula-7
wherein, 'X' represents halogen;
in presence of a suitable base in a suitable solvent followed by reacting the obtained compound with compound of general formula R-OH in presence of a suitable base in a suitable solvent to provide compound of general formula-8,

wherein, 'R' represents aliphatic groups such as alkylsulfonyl; substituted or unsubstituted arylsulfonyl, camphorsulfonyl; aromatic groups selected from unsubstituted or mono, di or trisubstituted aryl/aralkyl groups; substituted or unsubstituted 1-naphthyl, 2-naphthyl, 7-azabenzotriazole-l-yl, 1-benzotriazolyl, 2,5-pyrrolidinedione-1-yl groups; d) separating the diastereomers from the compound of general formula-8 to provide compound of general formula-2,
e) reacting the compound of general formula-2 with l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione compound of formula-3
in presence of alkyl magnesium halide or a suitable base in a suitable solvent to provide (R)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy) phosphorylamino)-3-(tritylthio)propanoate compound of formula-9,

f) treating the compound of formula-9 with Raney Ni in a suitable solvent to provide compound of formula-1,
g) optionally purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.
2. The process according to claim 1, wherein,
in step-a) the suitable tritylating agent is selected from trityl chloride, p-methoxybenzyl trityl ether and the like;
in step-b) the suitable esterification catalyst is selected from conc.IfeSO^ thionyl chloride, oxalyl chloride and the like;
in step-a), step-c) and step-e) the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilieon bases or their mixtures;
in step-a) to step-g) wherever necessary the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixture.
3. Novel process for the preparation of (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-
3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)
methoxy)-(phenoxy)phosphoryl amino)propanoate compound of formula-1, comprising;
a) Esterification of (2R,2'R)-3,3'-disulfanediylbis(2-aminopropanoic acid) compound of
formula-11

with isopropyl alcohol in presence of a suitable esterification catalyst optionally in presence of a suitable solvent to provide (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) compound of formula-12,
b) reacting the compound of formula-12 with compound of general formula-7 in presence of a suitable base in a suitable solvent followed by reacting the obtained compound with compound of general formula R-OH in presence of a suitable base in a suitable solvent to provide compound of general formula-13,
wherein, 'R' is as defined above; c) separating the diastereomers form the compound of general formula-13 to provide compound of general formula-4,

d) reacting the compound of general formula-4 with l-((2R,3R,4R55R)-3-fluoro-4-hydroxy-5^(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lHJ3H)-dione compound of formula-3 in presence of alkyl magnesium halide or a suitable base in a suitable solvent to provide compound of formula-14,
e) treating the compound of formula-14 with Raney Ni in a suitable solvent to provide compound of formula-1,
f) optionally purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.
4. The process according to claim 3, wherein,
in step-a) the suitable esterification catalyst is same as defined in step-b) of the first aspect of the present invention;
in step-b) & step-d) the suitable base is same as defined in step-c) of the first aspect of the present invention;
in step-a) to step-f) wherever necessary, the suitable solvent is same as defined in first aspect of the present invention.

5. A process for the preparation of (2R,2'R)-isopropyl 3,3 '-disulfanediylbis(2-aminopropanoate) compound of formula-12 or its salt, comprising of; a) Reacting the (2R,2,R)-3,3,-disulfanediylbis(2-aminopropanoic acid) compound of
formula-11 with a suitable amine protecting agent under suitable conditions to
provide compound of general formula-23,
wherein, T3" represents amine protecting group; b) reacting the compound of general formula-23 with isopropyl alcohol to provide compound of general formula-24,
.1. UltllUlU ^* ■
c) deprotecting the compound of general formula-24 by treating it with a suitable amine deprotecting agent to provide (2R,2'R)-isopropyl 3,3 '-disulfanediylbis(2-amino propanoate) compound of formula-12 or its salt.
6. The process according to claim 5, wherein,
in step-a) the amine protecting agent is selected from di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbpnyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzoic anhydride, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride; the amine protection step can be carried out optionally in presence of a suitable base or a suitable acid in a suitable solvent;

In step-b) the reaction is carried out in presence of a suitable coupling agent optionally in presence of a suitable base and/or a suitable solvent;
In step-c) the suitable deprotecting agent is selected from acids, bases and hydrogenating agents;
In step-a) to step-c) the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, nitrile solvents, polar solvents, polar-aprotic solvents, ketone solvents or their mixtures.
7. A process for the preparation of (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-
aminopropanoate) dihydrochloride compound of formula-12a, comprising of;
a) Reacting the (2R,2'R)-3,3'-disulfanediylbis(2-aminopropanoic acid) compound of
formula-11 with di tert.butyl dicarbonate in presence of aqueous sodium hydroxide in
tetrahydrofuran to provide (6R, 11 R)-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-
8,9-dithia-5,12-diazahexadecane-6,ll-dicarboxylic acid compound of formula-23a,
b) reacting the compound of formula-23a with isopropyl alcohol in presence of dicyclohexylcarbodiimide and dimethylaminopyridine in dichloromethane to provide (6R, 11 R)-diisopropyl-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-di azahexadecane-6,ll-dicarboxylate compound of formula-24a,
c) deprotecting the compound of formula-24a by treating it with methanolic HC1 to provide (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) dihydrochloride compound of formula-12a.

8. A process according to any of the preceding claims 5 to 7, wherein the (2R,2'R)-isopropyl 3,3'-disulfanediylbis(2-aminopropanoate) compound of formula-12 or its hydrochloride salt is converted into compound of formula-1 according to process described in claim 3.
9. A process for the preparation of crystalline form-M of (S)-isopropyl 2-((S)-(((2Rs3RJ4R)5R)-5-(234-dioxo-3J4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound of formula-1, comprising of;

a) Adding n-heptane and n-butyl acetate to compound of formula-1,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering and drying the solid to provide crystalline form-M of formula-1.
10. A process for the preparation of crystalline form-M of (S)-isopropyl 2-((S)-
(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-
methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate compound
of formula-1, comprising of;
a) Adding n-heptane, methyl tert.butyl ether and acetic acid to compound of formula-1,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering and drying the solid to provide crystalline form-M of formula-1.