Field of the invention:

The present invention relates to a process for the preparation of ((3S,5R)-5-((lH-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3 -yl)methyl-4-methyl benzenesulfonate compound of formula-1 via novel intermediates. The compound of formula-1 is useful as a key intermediate for the preparation of Triazole Antifungal drug represented by the following structure:

Background of the invention:

The 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluoro phenyl)tetrahydro-5-(lH-l,2,4-triazol-1 -ylmethyl)-3-furanyl]methoxy]phenyl]-1 -piperazinyl]phenyl]-2-[( 1 S,2S)-1 -ethyl-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one is commonly known as posaconazole, an antifungal agent which is used against a wide range of fungal pathogens, including both yeast and molds.

US Patent No. 5,403,937 discloses a process for the preparation of key intermediate of posaconazole, specifically ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate. The process involves the usage of n-butyllithium during the preparation of oxazolidinone lithium salt, which is extremely flammable. The process requires column chromatographic purification at different stages to purify the intermediates which is tedious and lengthy process. The above said drawbacks make the process unviable on commercial scale.

In view of the above, there is an obvious need to find an efficient and industrially advantageous process for the synthesis of above said key intermediate of posaconazole which overcomes the problems associated with the prior art such as prolonged reaction time, low yields and tedious purifications.

Advantages of the present invention:

1. Avoids the usage of pyridine which is carcinogenic in nature and cannot be used on commercial scale.

2. Removing the 4-phenyIoxazolidin-2-one bi-product formed during the reaction, to give high yield and pure intermediate compound of formula-7.

3. Provides process for the preparation of highly pure novel intermediates, which improves the yield in subsequent steps.

4. Reducing the reaction time and avoiding tedious purification processes like column chromatography etc.

Brief Description of Invention:

The first aspect of the present invention is to provide an improved process for the preparation of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7, comprising of the following steps:

a) Reacting the 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in presence of activating agent and a suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence of a suitable base and suitable catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyi oxazolidin-2-one compound of formula-5,

c) cyclizing the compound of formula-5 in-situ in the presence of iodine and a suitable base in a suitable solvent to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 with a suitable base in the presence of a suitable catalyst in a suitable solvent to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7.

The second aspect of the present invention is to provide a novel process for the preparation of (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5, comprising of:

a) Reacting 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in presence of a suitable activating agent and a suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence of a base and a suitable catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5 as residue, which is optionally isolated as a solid from a suitable solvent.

The third aspect of the present invention is to provide a novel process for the preparation of ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl) methanol compound of formula-8, comprising of:

a) Hydrolyzing the (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 with a suitable base in the presence of suitable catalyst in a suitable solvent to provide (3S,5R)-5-(2,4-difluorophenyI)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7,

b) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydro furan-3-yl)methanol compound of
formula-8.

The fourth aspect of the present invention is to provide an improved process for the preparation of ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetra hydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-1, which comprising of the following steps:
a) Reacting the 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formuia-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of a suitable activating agent and a suitable base in a suitable solvent to provide (R)-3- (4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence of a suitable base and a suitable catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyI oxazolidin-2-one compound of formula-5,

c) cyclizing the compound of formula-5 in-situ in the presence of iodine and a suitable base in a suitable solvent to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 in the presence of a suitable base and a catalyst in a suitable solvent to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7,

e) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-yl)methanol compound of formula-8,

f) reacting the compound of formula-8 with lH-l,2,4-triazole in the presence of a suitable base in a suitable solvent to provide ((3R,5R)-5-((lH-l,2,4-triazol-l-yl) methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol compound of formula-9,

g) reacting the compound of formula-9 in-situ with tosyl chloride in the presence of a suitable base in a suitable solvent to provide ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-methyl benzene sulfonate compound of formula-1.

The fifth aspect of the present invention is to provide novel intermediates which are useful in the preparation of triazole derivative compound of formula-1, comprising of the following:

a) (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyI oxazolidin-2-one compound of formula-5,

c) (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7.

Detailed Description of the Invention:

As used herein the term "alcoholic solvent" refers to methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; "ester solvents" refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, "ether solvents" like tetrahydrofuran, diethylether, methyltert-butylether, dioxane and the like; the term "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane, n-pentane and the like; the term "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "polar aprotic solvents" refers to dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; the term "nitrile solvents" refers to acetonitrile and the like; "ketone solvents" refers to acetone, methyl isobutyl ketone and the like.

As used herein the term "base" is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine and the like.

As used herein the term "base" is selected from aqueous inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates.

As used herein the term "activating agent" refers to thionyl chloride, oxalyl chloride, pivaloyl chloride, carbonylditriazole, oxalylditriazole, POCI3, PCI3, PCI5 and SO2CI2.

As used herein the term "reducing agents" refers to DIBAL-H, lithiumaluminiumhydride, sodiumborohydride, lithiumborohydride, NaBHsCN,
sodiumborohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or
borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN.

The first aspect of the present invention is to provide a novel process for the preparation of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7, comprising of the following steps:

a) Reacting 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of a suitable activating agent and suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyl oxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence of a base and a suitable catalyst in a suitable solvent to provide (R)-3- ((S)-4-(2,4-difluorophenyl)-2-hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin- 2-one compound of formula-5,

c) cyclizing the compound of formula-5 in-situ in the presence of iodine and a suitable base in a suitable solvent to provide (R)-3-((3S,5R)-5-(2,4- difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 with a suitable base in the presence of a suitable catalyst in a suitable solvent to provide (3S,5R)-5-(2,4-difluorophenyl)-5- (iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7

Wherein;
in step-a) suitable activating agent is selected from thionyl chloride, oxalyl chloride, pivaloyl chloride, carbonylditriazole, oxalylditriazole, POCI3, PCI3, PCl5 and SO2CI2; the suitable base is selected from organic base such as triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine; and the suitable solvent is selected from chloro solvents, polar aprotic solvents, alcoholic solvents and mixture thereof

in step-b) the suitable base is selected from organic bases such as triethylamine,tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine; and the suitable solvent is selected from chloro solvents.

ketone solvents, ester solvents and mixture thereof and the suitable catalyst is TiCl4.

in step-c) the suitable base is selected from inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; and the suitable solvent is selected from chloro solvents, ether solvents, alcoholic solvents and mixture thereof.

in step-d) the suitable catalyst is preferably hydrogen peroxide and the suitable base is selected from inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and the suitable solvent is selected from ether solvents, ketone solvents and hydrocarbon solvents.

In a preferred embodiment of the present invention is to provide a novel process for the preparation of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuran-3-carboxylic acid compound of formula-7, comprising of the following steps:

a) Reacting the 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of fonnula-3 in the presence of pivaloyl chloride, 4-dimethylaminopyridine and triethylamine in a mixture of dimethylformamide and dichloromethane to provide (R)-3-(4-(2,4-difluoro phenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 using 1,3,5-trioxane in the presence of titanium tetrachloride and diisopropylethylamine in dichloromethane provides (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5,

c) cyclizing the compound of formula-5 in-situ in the presence of iodine and sodium carbonate in a mixture of tetrahydrofuran, methyl tertiarybutyl ether and isopropanol to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 with NaOH in the presence of hydrogen peroxide in tetrahydrofuran and cyclohexane to provide (3S,5R)-5-(2,4-difluoro phenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7.

The mole ratio of hydrogen peroxide used in step-d) of the above aspect is in between 1.0:2.0, preferably between 1.0:1.80, most preferably between 1.0:1.75 with respect to the compound of formula-6.

US 5,403,937 disclosed the usage of base like pyridine in step-a) and step-c) of the above aspect. As pyridine is carcinogenic in nature hence is not advisable for the commercial scale-up process. Whereas, the present process uses bases like 4-dimethylamino pyridine in step a) and sodium carbonate in step-c) respectively which are safer and easy to handle in the laboratory as well as in the commercial scale-up process. Hence the present process is advantageous over the prior art process.

The second aspect of the present invention is to provide a novel process for the preparation of (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5, comprising of:

a) Reacting 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of a suitable activating agent and suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence of a base and a suitable catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5 as residue, which is optionally isolated as solid from a suitable solvent.

wherein, the suitable solvent used for the isolation of compound of formula-5 in step-(b) is alcohol solvent, preferably isopropyl alcohol.

In a preferred embodiment of the present invention is to provide a novel process for the preparation of (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5, comprising of:

a) Reacting the 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of pivaloyl chloride, 4-dimethylaminopyridine and triethylamine in dimethylformamide and dichloromethane to provide (R)-3-(4-(2,4-difluoro phenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4, b) hydroxy methylating the compound of formula-4 using 1,3,5-trioxane in the presence of titanium tetrachloride and diisopropylethylamine in dichloromethane provides (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5 as residue, which is isolated as a solid from isopropyl alcohol.

The third aspect of the present invention is to provide a process for the preparation of ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl) methanol compound of formula- 8 , comprising of:
a) Hydrolyzing the (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydro furan-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 with a suitable base in the presence of a catalyst in a suitable solvent to provide (3S,5R)-5-(2,4- difluorophenyl)-5-(iodomethyl) tetrahydro furan-3-carboxylic acid compound of formula-7,

b) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuran-3-yl)methanol compound of formula-8.

wherein;
in step-a) the suitable catalyst is preferably hydrogen peroxide and the suitable base is selected from inorganic bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and the suitable solvent is selected from ether solvents, ketone solvents, hydrocarbon solvents and polar solvents or mixtures thereof

in step-b) the suitable reducing agent is selected from DIBAL-H,lithiumaluminiumhydride, sodiumborohydride, lithiumborohydride, NaBH3CN, sodiumborohydride/BF3 -etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminiumchloride, sodiumborohydride/iodine and 9-BBN and the suitable solvent is selected from ether solvent, ester solvents, hydrocarbon solvents and ketone solvents.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-yl)methanol compound of formula-8, which comprising of the following steps:

a) Hydrolyzing the compound of formula-6 with sodium hydroxide in the presence of hydrogen peroxide in tetrahydrofuran to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7,

b) reducing the compound of formula-7 with sodiumborohydride in the presence of BFs-etherate in tetrahydrofuran to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl)methanol compound of formula-8.

US 5,403,937 describes the reduction of compound of formula-6 using lithium chloride/sodiumborohydride to provide the compound of formula-8 with lower purity. The obtained compound contains impurities and 4-benzyloxazolidin-2one as a bi-product, which requires tedious purification process to get the pure compound.

In the process of the present invention, compound of formula-6 is hydrolyzed in the presence of suitable base and a catalyst to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuran-3-carboxylic acid compound of formula-7 with enhanced percentage of yield and purity. Further the compound of formula-7 is reduced in the presence of sodiumborohydride/BF3-etherate to provide compound of formula-8 without the formation of 4-phenyloxazolidin-2-one as a bi-product, which results in the increase in the yield and purity of compound of formula-8. Hence the process of the present invention is more advantageous over the prior art process.

The fourth aspect of the present invention is to provide a novel process for the preparation of ((3 S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetra hydrofuran-3-yl)methyl 4-

methylbenzenesulfonate compound of formula-1, which comprising the following steps:

a) Reacting the 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of suitable activating agent and a suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence a base and a suitable catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyl oxazolidin-2-one compound of formula-5,

c) cyclizing the compound of formula-5 in-situ in the presence of iodine and a suitable base in a suitable solvent to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyl oxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 with a suitable base in the presence of a suitable catalyst in a suitable solvent to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7,

e) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-yl)methanol compound of formula-8,

f) reacting the compound of formula-8 with lH-l,2,4-triazole (free base) in the presence of a suitable base in a suitable solvent to provide ((3R,5R)-5-((lH-1,2,4-triazol-1 -yl)methyl)-5-(2,4-ifluorophenyl)tetrahydrofiiran-3 -yl)methanol compound of formula-9,

g) reacting the compound of formula-9 in-situ with p-toluenesulfonyl chloride in the presence of a
suitable base in a suitable solvent to provide ((3S,5R)-5-((lH-l,2,4-triazol-1 -yl) methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-methyl benzene sulfonate compound of formula-1.

Wherein;
The reagents, catalysts, solvents and bases used in step-(a) to step-(d) of the present aspect is same as defined in first aspect of the present invention;

in step-e) the suitable reducing agent is selected from DIBAL-H, lithium aluminium hydride, sodiumborohydride, lithiumborohydride, NaBHsCN, sodium boro hydride/BFs-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminiumchloride, sodiumborohydride/iodine and 9-BBN; and the suitable solvent is selected from ether solvent, ester solvents, hydrocarbon solvents and ketone solvents.

in step-f) the suitable base is selected from inorganic base or organic base as defined above and the suitable solvent is selected from polar aprotic solvents, chloro solvents, alcoholic solvents and hydrocarbon solvents or mixture thereof.

in step-g) the suitable base is selected from organic base as defined above and the suitable solvent is selected from chloro solvents, alcoholic solvents and hydrocarbon solvents

In a preferred embodiment of the present invention provide a novel process for the preparation of ((3S,5R)-5-((lH-l,2,4-triazol-l-yl) methyl)-5-(2,4-difluorophenyl) tetrahydrofiiran-3-yl)methyl 4-methyl benzenesulfonate compound of formula-1, comprising of the following steps:

a) Reacting the 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of pivaloyl chloride, DMAP and TEA in a mixture of dimethylformamide and dichloromethane to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 using 1,3,5-trioxane in the presence of titanium tetrachloride and diisopropylethylamine in dichloromethane provides (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5,

c) cyclizing the compound of formula-5 in-situ in the presence of iodine and sodium carbonate in dichloromethane to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 with NaOH in the presence of hydrogen peroxide in tetrahydrofuran and cyclohexane to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7.

e) reducing the compound of formula-7 with sodiumborohydride in the presence of BFs-etherate in tetrahydrofuran to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl)methanol compound of formula-8,

f) reacting the compound of formula-8 with lH-l,2,4-triazole (freebase) in the presence of sodium tertiary butoxide and dimethylaminopyridine in dimethylformamide and dichloromethane to provide ((3R,5R)-5-((lH-1,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol compound of formula-9,

g) reacting the compound of formula-9 with p-toluenesulfonyl chloride in-situ in the presence of 4-dimethylamino pyridine in dichloromethane to provide ((3S,5R)-5-((1H-1,2,4-triazoi-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl) methyl-4-methyi benzenesulfonate compound of formula-1.

US 5,403,937 disclosed the process for the preparation of compound of formula-9, which involves reacting the compound of formula-8 with sodium triazole and DMPU to provide compound of formula-9.

As sodium triazole is unstable and is prepared at the time of the reaction. And the usage of DMPU reagent in the reaction takes longer time for the completion of the reaction and thereby the compoxmd of formula-9 is formed with low yield with DMPU as impurity, hence it requires tedious purification process to get the pure compound of formula-9.

The present invention is carried out by reacting the compound of formula-8 with triazole (free base), in the presence of base like 4-dimethylaminopyridine, due to which the reaction completes in short period of time and the product formed with enhanced yield as well as purity. Hence the present process has improvement over the prior art process.
US 5,403,937 also disclosed the usage of base like pyridine in step-g) which is not advisable to be use in the laboratory process and especially at commercial scale-up process, as it is carcinogenic in nature.
The process of the present invention involves the usage of base like 4-dimethylaminopyridine, which is safer and easy to use in the laboratory as well as in the commercial scale-up process.

The fifth aspect of the present invention is to provide novel intermediate compounds which are useful in the preparation of anti-fungal drug of compound of formula-1. The said novel intermediates include:

a) (R)-3 -(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4;
b) (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5;
c) (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyl oxazolidin-2-one compound of formula-6;
d) (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7.

Method of Analysis for Posaconazole Intermediates:
Related substances of the Posaconazole intermediates were analyzed by HPLC using the following conditions:

(R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyl oxazolidin-2-one (Formula-5):
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: kromosil-C18 125 x 4.6mm, 3 μm, 5 μm or equivalent; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 10 μL; Rim time: 45 min; Diluent: Water: Acetonitrile (1:1) v/v; Needle wash: Diluent; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile:water (90:10) v/v; Buffer: 1 ml of ortho phosphoric acid in 1000 ml of Milli-Q-water, mix well and filter through 0.22 μm Nylon membrane filter paper. (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one (Formula-6):

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Chiral pak-IC 250 x 4.6 mm,'3μm, 5 μm ; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 10 μL; Run time: 40 min; Diluent: n-Hexane: IPA: THF (80:20:1) v/v; Needle wash: Diluent;

Elution: Gradient; Mobile phase-A: n-Hexane: IPA: THF (90:10:1); Mobile phase-B: Isopropyl alcohol (100%).

(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid (Formula-7):
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: kromosil-C18 125 x 4.6mm, 3μm, 5 μm or equivalent; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 10 μL; Run time: 45 min; Diluent: Acetonitrile:Water (50:50) v/v; Needle wash: Diluent; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Water (90:10%) v/v; Buffer: 1 ml of ortho phosphoric acid in (85%) 1000 ml of Milli-Q-water and filter through 0.45 |im Nylon membrane filter paper.

The process of the present invention is schematically represented as below:


The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Example-1: Preparation of 4-(2,4-difluorophenyl)peiit-4-enoic acid (Formula-2)
To a mixture of 4-(2,4-difluorophenyl)-4-oxobutanoic acid (100 g) and toluene (1000 ml), added methyl triphenylphosphine iodide (377.5 g) and sodium tertiary butoxide (183 g) at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 6-8 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture for about 15 mmutes and both organic and aqueous layers were separated. pH of aqueous layer was adjusted to 11 using 50% hydrochloric acid. Extracted the aqueous layer with toluene and washed the aqueous layer with dichloromethane. pH of the aqueous layer was further adjusted to 2.5 using 50% HCl and the reaction mixture was stirred for 45 minutes. Filtered the obtained solid, washed with water and then dried to obtain get title compound. Cyclohexane (500 ml) was added to the obtained solid and heated to 45-50°C.

Carbon (10 g) was added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture and washed with hot cyclohexane. Distilled off half of the solvent under reduced pressure. Cooled the reaction mixture to 10-15°C and stirred for 60 minutes at the same temperature. Filtered the solid and washed with chilled cyclohexane and dried to get the title compound. Yield: 65.75 g

£xample-2: Preparation of (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyl oxazolidin-2-one

(Formula-4)
To a solution of 4-(2,4-difluorophenyl)pent-4-enoic acid compound of fonnula-2 (100 g) in dichloromethane (800 ml), added triethylamine (97.4 g) at 25-30°C over a period of 45 minutes and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 10-15°C and added pivaloyl chloride (63 g) to the reaction mixture over a period of 45 minutes.

Temperature of the reaction mixture was raised to 25-30°C and the reaction mixture was stirred for 2 hours at 25-30°C. After completion of the reaction, added (R)-4-phenyloxazolidin-2-one compound of formula-3 (69 g), 4-dimethylamino pyridine (21 g), dimethyl formamide (37 ml) and

followed by dichioromethane (200 ml) to the above reaction mixture. Heated the reaction mixture to 45°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C. 2% sulfuric acid was added to the reaction mixture and stirred for 15 minutes. Both organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and isopropyl alcohol was added to the obtained residue at 25-30°C and stirred for 15 minutes at the same temperature. The reaction mixture was cooled to 0-10°C and then stirred for 1 V-i hour at the same temperature. Filtered the obtained solid, washed with chilled isopropyl alcohol and then dried to get title compound.

Yield: 95 g; purity by HPLC: 98.24, 0.17 (R-POZ), 0.73 (SMI); Melting range: 50-55°C.

Example-3: Preparation of (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one(Formula-6) Step-a): Preparation of (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl) pent-4- enoyl)-4-phenyloxazolidin-2-one(Formula-5)
Titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichioromethane) was added to a pre-cooled solution of (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of fonnula-4 (100 g) in dichloro methane (1000 ml) at -20 to -10°C over a period of 45 minutes vmder nitrogen atmosphere and the reaction mixture was stirred for 40 minutes at -20 to -10°C. A trioxane solution (prepared from 52.94 g of trioxane and 150 ml of dichloro methane) was added to the reaction mixture over a period of 45 minutes at -20 to -10°C and followed by titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichloro methane) over a period of 45 minutes at -20 to -10°C. Temperature of the reaction mixture was raised to -5 to 0°C and stirred for 2 hours at -5 to 0°C. After completion of the reaction, the reaction mixture was added to 10% ammonium chloride at 10-15°C. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloro methane. Both the dichloro methane layers were combined and washed with water followed by 10% sodium chloride solution. The obtained dichloro methane layer (containing the title compound) was taken to the next step without isolating the title compound.

Step-b): Preparation of (R)-3-((3S,5R)-5-(2,4-difluorophenyI)-5-(iodomethyl)tetra hydrofuran -3-carbonyl)-4-phenyloxazolidin-2-one(Formula-6)
To the above obtained dichloromethane layer containing (R)-3-((S)-4-(2,4-difluoro phenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formuia-5, added sodium carbonate (59.4 g) followed by iodine (177.8 g) and the reaction mixture was stirred for 3 hours at 25-35°C. After completion of the reaction, the reaction mixture was quenched with 30% hypo solution and the reaction mixture was extracted with methyl tertiary butyl ether. Both organic and aqueous layers were separated and the organic layer was washed with 30% hypo solution, followed by 10% sodium chloride solution.

Distilled off the solvent completely from the organic layer. Isopropanol (600 ml) was added to the concentrated organic layer and the reaction mixture was stirred for 1 V 2 hour at 25-30°C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 65 g; Chiral purity: 99.5% Example-4: Preparation of (R)-3-((S)-4-(2,4-difluorophenyi)-2-(hydroxymethyl) pent-4-enoyl)-4-phenyloxazolidin-2-one(Formula-5)

Titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichloromethane) was added to a pre-cooled solution of compound of formula-4 (100 g) in dichloro methane (1000 ml) at -20 to -10°C over a period of 45 minutes under nitrogen atmosphere and the reaction mixture was stirred for 40 minutes at -20 to -10°C. A trioxane solution was added to the reaction mixture over a period of 45 minutes at -20 to -10°C and followed by titanium chloride solution over a period of 45 minutes at -20 to -10°C. Temperature of the reaction mixture was raised to -5 to 0°C and stirred for 2 hours at -5 to 0°C. After completion of the reaction, distilled off the solvent from the reaction mixture to obtain a residue. Isopropyl alcohol was added to the obtained residue and stirred for 3 hours at 25-30°C. Filtered the solid and washed with isopropyl alcohol. Dried the solid to get the title compound. Yield: 81 g.

Example-5: Preparation of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-carboxylic acid (Formula-7)
Sodium hydroxide solution (prepared from 17.7 g of sodium hydroxide and 390 ml of water) was added to a pre-cooled solution of hydrogen peroxide (30 ml), water (65 ml) and tetrahydrofuran (390 ml) at 0-10°C over a period of 60 minutes, followed by a solution of (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 (130 g) in tetrahydro furan (390 ml) over a period of 60 minutes at 0-10°C and the reaction mixture was stirred for 30 minutes at 0-10°C. Further temperature of the reaction mixture was raised to 25-30°C and then stirred for 2 hours at 25-30°C. After completion of the reaction, the reaction mixture was quenched with 10% sodium sulphite solution and the reaction mixture was washed with toluene. Both organic and aqueous layers were separated, pH of aqueous layer was adjusted to 10.5 using 50% HCl and then washed with dichloromethane. Further pH of aqueous layer was again adjusted to 4.5 using 50% HCl. The aqueous layer was extracted with methyl tertiary butyl ether and distilled off the solvent and then co-distilled with cyclohexane. Cyclohexane (190 ml) was added to the reaction mixture and stirred for 2 hours at 25-30°C. Filtered the solid, washed with cyclohexane and then dried to get title compound. Yield: 65 g; MR: 80-87°C.

£xample-6: Preparation of ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl) tetrahydrofuraii-3-yl)methanoI(Formula-8)
A solution of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7 (150 g) in tetrahydrofuran (750 ml) was added to a pre-cooled solution of sodium borohydride (45.2 g) in tetrahydrofiiran (750 ml) over a period of 60 minutes at 0-5°C, followed by sodium borohydride (172.2 g) over a period of 60 minutes at 0-5°C. Temperature of the reaction mixture was raised to 25-30°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with chilled hydrochloric acid. Both organic and aqueous layers were separated and the aqueous layers was extracted with ethyl acetate. Both the organic layers were combined, washed with water followed by 10% sodiimi chloride solution and then distilled off the solvent to get the title compound as a residue. Yield: 140 g; purity byHPLC:98.5%.

Example-?: Preparation of ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (Formula-1) Step-a): Preparation of ((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methanol(FormuIa-9)

Added 4-dimethylaminopyridine (8.61 g) and sodium tertiary butoxide (339 g) to a mixture of dimethylformamide (2500 mi) and 1,2,4-triazole (243.6 g) and stirred the reaction mixture for 30-45 minutes at 25-35°C. ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyI)tetrahydrofuran-3-yl)methanol compound of formula-8 (250 g) was added to the reaction mixture. The reaction mixture was heated to 100-110°C and stirred for 18 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35°C and then poured into water. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloro methane. The combined dichloro methane layers was treated with 50% Hcl followed by 50% sodium hydroxide. Both organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by sodium chloride solution and then distilled to get title compound as a residue. The obtained residue containing the title compound of formula-9 was taken to next step without isolation. Step-b): Preparation of ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl) tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (Formula-1)

Dichloromethane (1250 ml) was added to the obtained residue obtained in step-a) at 25-30°C and the reaction mixture was cooled to 0-5°C. Dimethylamino pyridine (8.61 g) was added to the reaction mixture, and followed by p-toluene sulfonyl chloride (121.1 g) at 0-5°C and stirred the reaction mixture for 1 hour at 0-5°C. Temperature of the reaction mixture was raised to 25-30°C and stirred for 10 hours at 25-30°C. After completion of the reaction, the reaction mixture was quenched with water. Extracted the aqueous layer with dichloromethane and washed the dichloromethane layer with water followed by 10% sodium chloride solution. Distilled off the solvent completely fi-om dichloromethane layer to get the crude title compound. To the obtained compound pet.ether (625 ml) and followed by isopropyl alcohol (62.5 ml) were added and the reaction mixture was stirred for 2 hours at 25-30°C to obtain a solid. The obtained solid was recrystallized using isopropyl alcohol (625 ml) to get pure title compound. Yield: 75 grams; purity by HPLC: 98.5 %.

The above prepared compound of formula-I can be used as a key intermediate in the preparation of Triazole Antifungal drug, preferably in posaconazole.

We Claim:

1. An improved process for the preparation of (3S,5R)-5-(2,4-difluorophenyl)-5-iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7,

comprising of the following steps:

a) Reacting 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3

in presence of a suitable activating agent and a suitable base in a suitable solvent to provide (R)-3 -(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in presence of a base and a catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5,


c) cyclizing the compound of formula-5 in-situ in presence of iodine and a suitable base in a suitable solvent to provide (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3 -carbonyl)-4-phenyloxazolidin-2-one compound of formula-6,

d) hydrolyzing the compound of formula-6 with a suitable base in presence of hydrogen peroxide in a suitable solvent to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7.

2. A process according to claim 1, wherein,
in step-a) the suitable activating agent is selected from thionyl chloride, oxalyl chloride, pivaloyl chloride, carbonylditriazole, oxalylditriazole, POCI3, PCI3, PCI5 and SO2CI2, preferably pivaloyl chloride; the suitable organic base is selected from triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine, preferably triethylamine and 4-dimethylaminopyridine; and the suitable solvent is selected from chloro solvents, ester solvents, ketone solvents, polar aprotic solvents and alcoholic solvents, preferably dichloromethane, dimethylformamide and isopropanol and mixture thereof, in step-b) the suitable base is selected from organic base such as triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and

diisopropylethyl amine, preferably diisopropylethylamine; and suitable catalyst is titanium tetrachloride, and the suitable solvent is selected from chloro solvent, ketone solvents, ester solvents, ether solvents and alcoholic solvents, preferably dichloromethane.

in step-c) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, preferably sodium carbonate; and the suitable solvent is selected from ether solvents, chloro solvents, alcoholic solvents and ester solvents, preferably methyl tertiarybutyl ether, dichloromethane and isopropanol and mixture thereof.

in step-d) the suitable base is selected from organic base such as triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine and inorganic base such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, preferably sodium hydroxide; and the suitable solvent is selected from ether solvents, ester solvents, ketone solvents and hydrocarbon solvents preferably tetrahydrofuran and cyclohexane.

3. A process according to claim-1, wherein the mole ratio of hydrogen peroxide used in
step-(d) is in between 1.0:2.0, preferably between 1.0:1.80, more preferably between 1.0:1.75 with respect to the compound of formula-6.

4. A process for the preparation of (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxyl
methyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5, comprising of:

a) Reacting 4-(2,4-difluorophenyl)pent-4-enoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in the presence of a suitable activating agent and suitable base in a suitable solvent to provide (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4,

b) hydroxy methylating the compound of formula-4 with 1,3,5-trioxane in the presence of a base and a suitable catalyst in a suitable solvent to provide (R)-3-((S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-5 as residue, which is optionally isolated as solid from a suitable solvent.

5. An improved process for the preparation of ((3S,5R)-5-((lH-l,2,4-triazol-l-yl) methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl4-methylbenzene sulfonate compound of formula-1, which comprising of the following steps:

a) Hydrolyzing the (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 in presence of a suitable base and hydrogen peroxide in a suitable solvent to provide (3S,5R)- 5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylicacid compound of formula-7,

b) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-yl)methanol compound of formula-8,

c) reacting the compound of formula-8 with triazole (free base) in presence of a suitable base in a suitable solvent to provide ((3R,5R)-5-((lH-l,2,4-triazol-l- yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol compound of formula-9,

d) reacting the compound of formula-9 with tosyl chloride in presence of a suitable base in a suitable solvent to provide ((3S , 5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3 -yl)methyl 4- methylbenzenesulfonate compound of formula-1.

6. A process according to claim 5, wherein,
in step-a) the suitable base is selected from inorganic base such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, preferably sodium hydroxide; and the suitable solvent is selected from ether solvents, ester solvents and ketone solvents; preferably tetrahydrofuran and methyl tertiary butyl ether.

in step-b) the suitable reducing agent is selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithiumborohydride, NaBH3CN, sodiumborohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminiumchloride, sodiumborohydride/iodine and 9-BBN; and the suitable solvent is selected from ether solvents, ester solvents and ketone solvents; preferably tetrahydrofuran and ethyl acetate.

in step-c) the suitable base is selected from organic base refers to triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine (or) inorganic base is selected from alkali metal carbonates, alkali metal hydroxide, alkali metal bicarbonates, alkali metal alkoxides, preferably dimethylaminopyridine (or) sodium tertiarybutoxide; and the suitable solvent is selected from polar aprotic solvents, chloro solvents, ester solvents, ketone solvents; preferably dimethylformamide, dichloromethane and ethyl acetate.

in step-d) the suitable base is selected from organic base such as triethylamine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine, preferably dimethylaminopyridine; and the suitable solvent is selected from chloro solvents, alcoholic solvents, hydrocarbon solvents; preferably petroleum ether, isopropanol and dichloromethane.

7. An improved process for the preparation of ((3R,5R)-5-(2,4-difluorophenyl)-5-
(iodomethyl)tetrahydrofuran-3-yi)methanol compound of formula-8, which comprises of the following steps;

Hydrolyzing the (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-carbonyl)-
4-phenyloxazolidin-2-one compound of formula-6 in presence of a suitable base selected from inorganic base such as alkali metal hydroxide and hydrogen peroxide in a suitable solvent selected from ether solvents, ester solvents and ketone solvents, preferably tetrahydrofiiran and methyl tertiarybutyl ether or mixture thereof to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7,

b) reducing the compound of formula-7 with a suitable reducing agent selected from DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithiumborohydride, NaBHsCN, sodiumborohydride/BFs-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminiumchloride, sodiumborohydride/iodine and 9-BBN in a suitable solvent selected from ether solvents, ester solvents and ketone solvents, preferably tetrahydrofuran and ethyl acetate to provide ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-yl)methanol compound of formula-8.

8. An improved process for the preparation of (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carboxylic acid compound of formula-7, comprising of hydrolyzing the (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro furan-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 with NaOH in the presence of hydrogen peroxide in tetrahydrofiiran and cyclohexane to provide (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofiiran-3-carboxylic acid compound of formula-7.

9. (3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyI)tetrahydrofuran-3-carboxyIic acid compound of formula-7 isolated as a solid.