Field of the invention:

The present invention relates to an improved process for the preparation of antifungal drug i.e., 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluoro phenyl) tetrahydro-5-(lH-1,2,4-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 compound of formula-1 represented by the following structure:

The present invention also relates to novel intermediate, which is useful in the preparation of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(lH-l,2,4-triazol-1 -ylmethyl)-3 -furanyl]methoxy]phenyi]-1 -piperazinyl]phenyl]-2-[( 1 S,2S)-1 -ethyl-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one herein referred as "Triazole derivative".

Background of the invention:

The 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-( 1H-1,2,4-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.

U.S Patent No. 5661151 (hereinafter referred to as "151") discloses several substituted tetrahydrofuran antifungal compounds, including posaconazole. This patent discloses several processes for the preparation of posaconazole.

According to one process, posaconazole is prepared by the condensation of toluene-4-sulfonic acid (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[ 1,2,4]triazol-1 -ylmethyl tetrahydro-3-furanmethyl ester with N-protected triazolone derivative in the presence of a strong base in an aprotic solvent to give a compound, which is then deprotected using hydrochloric acid in methanol followed by N-alkylation with brosylated (2S,3R) alcohol in the presence of cesium carbonate in an aprotic solvent to give hydroxy protected posaconazole, and is then deprotected to give posaconazole.

The major drawback of the above said process is that, the N-alkylation is carried out on cyclized triazolone intermediate which requires excess amount of an expensive alkylating agent, and results in a mixture of N-alkylated and O-alkylated posaconazole, necessitating laborious purification methods such as column chromatography which is a time consuming and tedious process, especially for large samples hence it is not suitable for large scale production and further results in low yields of posaconazole.
US Patent No. 5,625,064 discloses a process for the preparation of posaconazole which involves the condensation of l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1 -yl)phenyl)-1H-1,2,4-triazol-5(4H)-one with (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[ 1,2,4]triazol-1 -ylmethyl-tetrahydro-3-furanmethylester derivative in the presence of a base to give benzyl ether of posaconazole which is then deprotected either with palladium on carbon in the presence of formic acid or aqueous hydrobromic acid to form posaconazole.

The above process suffers from several drawbacks such as low yield. It was observed that condensation of unprotected hydroxyl derivative with hydrazine derivative results in low yield of the compound. Further, condensation of O-benzyl protected phenyl carbamate derivative results in the formation of impurities which requires tedious purification processes hence results in low yield. In addition, the deprotection of benzyl ether of posaconazole in the presence of formic acid does not go to completion of the reaction or requires more than 30-35 hours. This may lead to degradation of final product and may require tedious purification processes such as chromatography purification or refluxing of the product with aqueous sodium hydroxide solution for another 24 hours as reported in the prior art. On the other hand, deprotection of benzyl ether of posaconazole with aqueous hydrobromic acid results in the degradation of compound of formula 1 and also requires laborious purification methods to purify posaconazole, hence results in the loss of yield and purity.

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

Brief Description of Invention:

The first aspect of the present invention is to provide an improved process for the preparation of (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2, which comprising of the following steps:

a) Reacting the racemic methyl lactate compound of formula-8 with benzyl chloride in the presence of a suitable base in a suitable solvent to provide methyl 2-(benzyloxy)propanoate compound of formula-9,

b) hydrolyzing the compound of formula-9 in-situ with a suitable base in a suitable solvent to provide 2-(benzyloxy)propanoic acid compound of formula-10,

c) resolving the compound of formula-10 in-situ with (S)-l-phenylethanamine in a suitable solvent to provide (S)-l-phenylethanamine salt of (S)-2-(benzyloxy) propanoic acid compound of formula-10a,

d) reacting the compound of formula-10a with alcoholic solvent in presence of a suitable activating agent in a suitable solvent to provide (S)-methyl 2-(benzyloxy) propanoate compound of formula-11,

e) reducing the compound of formula-11 with a suitable reducing agent in a suitable solvent to provide (S)-2-(benzyloxy)propanal compound of formula-12,

f) reacting the compound of formula-12 in-situ with formyl hydrazine in a suitable solvent to provide (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide compound of formula-2.

The second aspect of the present invention is to provide (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid compound of formula-10a, a novel intermediate which is useful in the preparation of (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide compound of formula-2.

The third aspect of the present invention is to provide an improved process for the preparation of phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5, which comprising of reacting 4-(4-(4-aminophenyl)piperazin-l-yl)phenol compound of formula-4 with arylchloroformate in a suitable solvent.

The fourth aspect of the present invention is to provide an improved process for the preparation of pure Triazole derivative compound of formula-1, which comprising of the following steps:

a) Reacting the (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide compound of formula-2 with ethyl magnesium halide in presence of bis(trimethylsilyl) acetamide in a suitable solvent to provide N'-((2S,3S)-2-(benzyloxy)pentan-3-yl)formylhydrazide compound of formula-3,

b) reacting the compound of formula-3 in-situ with phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5 in the presence of a base in a suitable solvent to provide l-((2S,3R)-2-(benzyloxy) pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1 -yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-6,

c) condensing the compound of formula-6 with ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzene sulfonate compound of formula-13 in the presence of a base in a suitable solvent to provide 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3 -yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3 S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7,

d) debenzylating the compound of formula-7 using Pd/C in the presence of mineral acid under hydrogen pressure in a suitable solvent to provide Triazole derivative compound of formula-1,

e) optionally purifying the compound obtained in step-(d) from a suitable solvent to provide pure
compound of formula-1.

The fifth aspect of the present invention is to provide an improved process for the preparation of 4-(4-(4-(4-(((3R,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3 -yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3 S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7, comprising of condensing the l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one compound of formula-6 with ((3 S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3 -yl) methyl-4-methyl benzenesulfonate compound of formula-13 in the presence of a suitable base in a solvent to provide compound of formula-7.

The sixth aspect of the present invention is to provide an improved process for the preparation of amorphous 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7, comprising of condensing the l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxy phenyl)piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one compound of formula-6 with ((3S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3 -yl) methyl-4-methyl benzenesulfonate compound of formula-13 in the presence of a suitable base in a solvent to provide compound of formula-7, followed by quenching the reaction mixture with water and neutralizing the reaction mixture with acid to provide amorphous compound of formula-7.

Brief Description of Drawings:

Figure 1: Illustrates the PXRD pattern of isopropanol solvate crystalline form of posaconazole obtained as per the example-11.

Figure 2: Illustrates the PXRD pattern of amorphous form of compound of formula-7 obtained as per the example-12.

Detailed Description of the Invention:

As used herein the term suitable solvent selected from "alcoholic solvent" such as to methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; "ester solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, "ether solvents" such as tetrahydrofuran, diethylether, methyltert-butylether, dioxane and the like; the term "hydrocarbon solvents" such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane and the like; the term "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; the term "nitrile solvents" such as acetonitrile and the like; "ketone solvents" such as 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, POCl3, PC13 and PC15.

As used herein the term "reducing agents" refers to DIBAL-H, lithirnnaluminiurnhydride, sodiumborohydride, lithiumborohydride, NaBH3CN, 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 an improved process for the preparation of (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide compound of formula-2, comprising of the following steps: a) Reacting the racemic methyl lactate compound of formula-8 with benzyl chloride in the presence of a suitable base in a suitable solvent to provide methyl 2-(benzyloxy)propanoate compound of formula-9,

b) hydrolyzing the compound of formula-9 in-situ with aqueous base in a suitable solvent to provide 2-(benzyloxy)propanoic acid compound of formula-10,

c) resolving the compound of formula-10 in-situ with (S)-l-phenylethanamine in a suitable solvent to provide (S)-l-phenylethanamine salt of (S)-2-(benzyloxy) propanoic acid compound of formula-10a,

d) reacting the compound of formula-10a with alcoholic solvent in presence of a suitable activating agent in a suitable solvent to provide (S)-methyl 2- (benzyloxy)propanoate compound of formula-11,

e) reducing the compound of formula-11 with suitable reducing agent in a suitable solvent to provide (S)-2-(benzyloxy)propanal compound of formula-12,

f) reacting the compound of formula-12 in-situ with formyl hydrazine in a suitable solvent to provide (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2.

Wherein;
in step-a) the suitable base is inorganic base and suitable polar aprotic solvent is selected from dimethylformamide, dimethylacetamide and dimethylsulfoxide.

in step-b) the base is selected from aqueous inorganic base and the suitable solvent is selected from hydrocarbon solvents or chloro solvents.

in step-c) the suitable solvent is selected from hydrocarbon solvents.

in step-d) the suitable activating agent is thionyl chloride and the suitable solvent is selected from alcoholic solvents and polar aprotic solvents.

in step-e) the suitable reducing agent is DIBAL-H and the suitable solvent is hydrocarbon solvent.

in step-f) the suitable solvent is selected from alcoholic solvents.

In a preferred embodiment of the present invention is to provide an improved process for the preparation of (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide compound of formula-2, comprising of:

a) Reacting the racemic methyl lactate compound of formula-8 with benzyl chloride in the presence of sodiumtertiarybutoxide in dimethylformamide to provide methyl 2-(benzyloxy)propanoate compound of formula-9,

b) hydrolyzing the compound of formula-9 in-situ with aqueous sodium hydroxide in toluene to provide 2-(benzyloxy)propanoic acid compound of formula-10,

c) resolving the compound of formula-10 in-situ with (S)-phenyl ethylamine in toluene to provide (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid compound of formula-10a,

d) reacting the compound of formula-10a with methanol in presence of thionyl chloride in dimethylformamide to provide (S)-methyl 2-(benzyloxy)propanoate compound of formula-11,

e) reducing the compound of formula-11 with DIBAL-H in toluene to provide (S)-2-(benzyloxy)propanal compound of formula-12,

f) reacting the compound of formula-12 in-situ with formyl hydrazine in methanol to provide (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2.

The second aspect of the present invention is to provide (S)-l-phenylethanamine salt of (S)-2-(benzyloxy) propanoic acid compound of formula-10a, a novel intermediate compound which is useful in the preparation of (S)-N'-(2-(benzyloxy)propylidene) formylhydrazide compound of formula-2 .

The third aspect of the present invention is to provide an improved process for the preparation of phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5, which comprises of reacting 4-(4-(4-aminophenyl)piperazin-l-yl)phenol compound of formula-4 with arylchloroformate in a suitable solvent to provide phenyl 4-(4-(4-hydroxyphenyl)piperazin-1 -yl)phenylcarbamate compound of formula-5.

Wherein, the suitable arylchloroformate is phenylchloroformate and suitable solvent is polar aprotic selected from dimethylformamide, dimethylacetamide and dimethylsulfoxide, preferably dimethylformamide.

US 5,625,064 describes the process for the preparation of phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5 in the presence of a base like pyridine, which is not advisable to use in the laboratory and especially at commercial scale-up process, as it is carcinogenic in nature.

Whereas, the present invention describes the preparation of compound of formula-5 in the absence of base. Hence the present invention has improvement over the prior art.

The fourth aspect of the present invention is to provide an improved process for the preparation of pure Triazole derivative compound of formula-1, comprising of the following steps:

a) Reacting the (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2 with ethyl magnesium halide in the presence of bis(trimethylsilyl)acetamide in a suitable solvent to provide N'-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-3,

b) reacting the compound of formula-3 in-situ with phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5 in the presence of suitable base in a suitable solvent to provide l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one compound of formula-6,

c) condensing the compound of formula-6 with ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difiuorophenyl)tetrahydronaran-3-yl)methyl-4-methyl benzenesulfonate compound of formula-13,
in the presence of base in a suitable polar aprotic solvent to provide4-(4-(4-(4-(((3R,5R)-5-((l H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3 S)-2-(benzyloxy) pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7,

d) debenzylating the compound of formula-7 with Pd/C under hydrogen pressure in the presence of mineral acid in a suitable alcoholic solvent to provide Triazole derivative compound of formula-1,

e) optionally, purifying the compound obtained in step-(d) from a suitable solvent to provide pure compound of formula-1.

Wherein,
in step-a) the suitable solvent is ether solvent is selected from methyl tertiary butyl ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, preferably methyl tert-butyl ether, in step-b) the suitable base is selected from organic base and the suitable solvent is selected from ether solvents, hydrocarbon solvents and ketone solvents, preferably dioxane. in step-c) the suitable base is selected from inorganic base and the suitable solvent is selected from polar aprotic solvents, ester solvents or mixture thereof, in step-d) the suitable mineral acid is selected from hydroiodic acid, sulfuric acid and hydrochloric acid and a suitable alcoholic solvent is selected from methanol, ethanol, isopropanol and butanol. in step-e) the suitable solvent is selected from alcoholic solvent.

The present process involves in-situ reaction of the formylhydrazine derivative of formula-3 with phenylcarbamate compound of formula-5, which provides compound of formula-6 with enhanced purity as well as yield. Hence the present invention is more advantageous over the prior art processes.

US 5,625,064 disclosed a process for the deprotection of benzyl ether of posaconazole in the presence of formic acid requires 30-35 hours of time period for completion of the reaction. This may lead to degradation of final product and may require tedious purification processes such as chromatography purification. Whereas, the present invention avoids the usage of formic acid for the deprotection of compound of formula-7 and uses Pd/C and methanol for deprotection. The present invention also involves the condensation of compound of formula-6 with highly pure compound of formula-13 resulting the compound of formula-7 with high purity and yield, which inturn enhances the posaconazole compound of fomula-1 with 99.8% purity. Henceforth, the process of the present invention is more advantageous over the prior known processes.

The ((3S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl)methyl-4-methyl benzenesulfonate compound of formula-13 can be prepared by the following steps:

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

b) hydroxy methylating the compound obtained in step-(a) 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,

c) cyclizing the compound obtained in step-(b) in-situ in the presence of iodine and sodium carbonate in dichloromethane provides (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one,

d) hydrolyzing the compound obtained in step-(c) with NaOH in the presence of hydrogen peroxide in tetrahydrofuran and cyclohexane provides (3S,5R)-5-(2,4-difluorophenyl)-5-iodomethyl)tetrahydrofuran-3-carboxylic acid,

e) reducing the compound obtained in step-(d) with sodiumborohydride in the presence of BF3-etherate in tetrahydrofuran provides ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl)methanol,

f) reacting the compound obtained in step-(e) with lH-l,2,4-triazole (freebase) in the presence of sodium tertiary butoxide and dimethylaminopyridine in dimethylformamide and dichloromethane provides ((3R,5R)-5-((1H-l,2,4-triazol-l-yl)methyl)-5-(2,4-difiuorophenyl)tetrahydrofuran-3-yl)methanol,

g) reacting the compound obtained in step-(f) with p-toluenesulfonyl chloride in-situ in the presence of 4-dimethylamino pyridine in dichloromethane provides ((3 S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydro furan-3-yl) methyl-4-methyl benzenesulfonate compound of formula-13.
The fifth aspect of the present invention is to provide an improved process for the preparation of 4-(4-(4-(4-(((3R,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3 -yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3 S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7, which comprises of condensing l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxy phenyl)piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one compound of formula-6 with ((3 S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl) methyl-4-methyl benzenesulfonate compound of formula-13 in the presence of a suitable base preferably sodium hydroxide in a suitable solvent preferably dimethyl sulfoxide to provide compound of formula-7.

The prior reported processes for the preparation of compound of formula-7, involves the usage of sodium hydride (NaH) in the coupling reaction, which is pyrophoric in nature, difficult to handle and not suitable for commercial purposes. Whereas, the process of the present invention involves the usage of sodium hydroxide base and dimethyl sulfoxide solvent, which are simple, easily available and suitable for commercial scale process.

The sixth aspect of the present invention is to provide an improved process for the preparation of amorphous 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3S)- 2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7, comprising of:

a) Condensing the l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxy phenyl)piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one compound of formula-6 with ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetra hydrofuran-3-yl) methyl-4-methyl benzenesulfonate compound of formula-13 in the presence of sodium hydroxide in dimethyl sulfoxide at 45-60°C to provide the compound of formula-7,

b) quenching the reaction mixture with water,

c) neutralizing the reaction mixture with a suitable acid selected from organic acids such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluene sulfonic acid, malic acid and the like; or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like to provide amorphous compound of formula-7.

HPLC Method of Analysis for Posaconazole:
Posaconazole is analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Grace Alltima CI8,150 x 4.6mm 3μm or equivalent; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 28°C; Injection volume: 10 uL; Run time: 60 min; Diluent: Acetonitrile: water (50:50 v/v); Needle wash: Acetonitrile: water (50:50 v/v); Elution: Gradient; Mobile phase-A: Buffer Acetonitrile (90:10) v/v; Mobile phase-B: Acetonitrile: water (90:10) v/v; Buffer: 1.74 grams of potassium hydrogen phosphate in 1000 ml of water.

Adjust pH to 6.5 with diluted orthophosphoric acid and filtered through 0.45μm Nylon membrane filter paper and sonicate to degas it.

PSD Details for Posaconazole:
The particle size distribution of posaconazole compound of formual-1 is measured using the following conditions:

Instrument: Malvern Master sizer 2000; Measuring range: 0.02 to 2000 urn; Wet sample: Hydro 2000S; Dispersant: Water; Absorption Index: 0; Refractive Index of water: 1.330; Refractive Index of particle: 1.500; Stirrer speed: 2500 rpm; Obscuration range: 10-20%; Sensitivity: Normal; Measurement time: 12 seconds; Background time:

12 seconds; Internal sonication: 3 minutes; (Tip displacement-70%); Measurement repeat: 3 times at zero second interval.

HPLC Method of Analysis for Posaconazole Intermediates:
(S)-l-phenylethanamine (S)-2-(benzyloxy)propanoic acid (Formula-lOa):
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: chiral cel-OD-H 250 x 4.6mm, 5 um; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 35°C; Injection volume: 10 uL; Run time: 35 min; Diluent: Mobile phase; Needle wash: Diluent; Elution: Isocratic; Mobile phase: A mixture of 20 ml of ethanol, 980 ml of n-hexane and 1.0 ml of trifluoro acetic acid. (S)-N'-(2-(benzyloxy)propylidene)formylhydrazide (Formula-2):

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: chiralpak-IC, 250 x 4.6 mm, 5 um; Flow rate: 0.8 ml/min; Wavelength: 220 nm; Column Temperature: 35°C; Injection volume: 5 uL; Run time: 25 min; Diluent: n-hexane: Ethanol (90:10) v/v; Needle wash: Diluent; Elution: Isocratic; Mobile phase: A mixture of 100 ml of ethanol, 900 ml of n-hexane and 1.0 ml of trifluoro acetic acid.

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



Scheme-H:

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 Pb.enyl-4-(4-(4-hydroxypheny)piperazin-l-yl)phenyl carbamate (Formula
-5)

Phenyl chloroformate (139.5 g) was added to a pre-cooled solution of 4-(4-(4-aminophenyl)piperazin-l-yl)phenol compound of formula-4 (200 g) in dimethyl formamide (1400 ml) at 0-10°C over a period of 45 minutes. Temperature of the reaction mixture was raised to 25-30°C and then stirred for 3 hours at 25-30°C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the solid and washed with water. Isopropyl alcohol (600 ml) was added to the solid and the reaction mixture was heated to 60-65 °C and stirred for 1 hour at the same temperature. Further the reaction mixture was cooled to 25-30°C and then stirred for 1 hour at 25-30°C. Filtered the solid, washed with IPA and then dried to get title compound. Yield: 215 g; Purity by HPLC: 95%

Example-2: Preparation of (S)-l-phenylethanamine salt of (S)-2-(benzyloxy) propanoic acid (Formula-10a):

a) Preparation of methyl 2-(benzyloxy)propanoate (Formula-9)
To a pre-cooled solution of potassium tertiary butoxide (538.4 g) in DMF (1750 ml) at -20 to -10°C, added racemic methyl lactate compound of formula-8 (200 g) at -20 to -10°C over a period of 1 hour, followed by benzyl chloride (547 g) over a period of 1 Vi hour and the reaction mixture was stirred for 5 hours at -20 to -10°C. After completion of the reaction, the reaction mixture was quenched with water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and 10% sodium chloride solution and then distilled off the solvent from ethyl acetate layer under reduced pressure to get the title compound as a residue. The obtained residue was taken into next step without isolation.

b) Preparation of 2-(benzyloxy)propanoic acid (Formula-10)
A mixture of residue containing methyl 2-(benzyloxy)propanoate compound of formula-9 obtained in step-a) and water (1750 ml) was cooled to 0-5°C. A solution of sodium hydroxide (51.5 g) in water (375 ml) was added to reaction mixture at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. Temperature of the reaction mixture was raised to 25-30°C and stirred for 4 hours at this temperature. After completion of the reaction, extracted the reaction mixture with dichloromethane. Both dichloro methane and aqueous layers were separated and pH of aqueous layer was adjusted to 2.5 using 50% hydrochloric acid solution. Extracted the aqueous layer again with dichloro methane. Combined both the dichloro methane layers and distilled off the solvent from dichloro methane layer under reduced pressure to get the title compound as a residue. The obtained residue can be taken into next step without isolation. c) Preparation of (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid (Formula-10a)
(S)-l-phenyl ethyl amine (184.9 g) was added to a mixture of residue containing 2-(benzyloxy) propanoic acid obtained in the above step-b) and toluene (1375 ml) at 25-30°C. The reaction mixture was stirred for 6 hours at 25-30°C. Filtered the precipitated solid and washed with toluene and then dried to get the title compound. The obtained compound was recrystallized using toluene to get pure title compound. Yield: 150 g; Chiral purity: 99.0%

Example-3: Alternative process for the preparation of (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid (Formula-lOa)

a) Preparation of methyl 2-(benzyloxy)propanoate (Formula-9)
To a pre-cooled solution of racemic methyl lactate (200 g) in dimethyl formamide (400 ml) at 0-10°C, added benzyl chloride (218.8 g). Sodium tertiary butoxide (224.6 g) was added to the reaction mixture at 0-10°C over a period of 20 minutes and stirred for 6 hours at 25-35°C. After completion of the reaction, the reaction mixture was quenched with water and extracted with toluene. The toluene layer was washed with water followed by 10% sodium chloride solution. The obtained toluene layer containing title compound was taken to next step.

b) Preparation of 2-(benzyloxy)propanoic acid (Formula-10)
The toluene layer obtained in step-a) was cooled to 10-15°C and was added to a pre-cooled solution of sodium hydroxide (prepared from 61.5 g of sodium hydroxide and 350 ml of water). Temperature of reaction mixture was raised to 25-35°C and then stirred for 4 hours at 25-35°C. After completion of reaction, pH of aqueous layer was adjusted to 2.5 using 50% Hcl. The aqueous layer was extracted with toluene and washed with 10% sodium chloride solution and water. The obtained toluene layer containing title compound was taken to next step.

c) Preparation of (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid (Formula-lOa)
(S)-l-phenyl ethyl amine (184.9 g) was added to the toluene layer obtained in step-b) at 25-30°C and stirred the reaction mixture for 6 hours at 25-30°C. Filtered the precipitated solid and washed with toluene. The obtained solid was recrystallized using toluene to get pure title compound. Yield: 100 g; Chiral purity: 99.0%.

Example-4: Preparation of (S)-methyl 2-(benzyloxy)propanoate (Formula-11)
Dimethyl formamide (0.5 ml) was added to a mixture of (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid compound of formula-10a obtained in step-c) of above examples-2 & 3 (200 g) and methanol (600 ml) and the reaction mixture was cooled to 0-5°C. Thionyl chloride (58.4 ml) was slowly added to the reaction mixture at 0-5 °C over a period of 1 hour and stirred for 1 hour at 0-10°C. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloro methane. Both aqueous and dichloro methane layers were separated, dichloro methane layer was washed with 10% sodium chloride and water. Distilled off the solvent completely from dichloro methane layer to get title compound. Yield: 129 g; Chiral purity: 99.5%

Example-5: Preparation of (S)-N,-(2-(benzyloxy)propylidene)formohydrazide (Formula-2)

a) Preparation of formyl hydrazine
Hydrazine hydarte (138 g) was added slowly to a mixture of ethyl formate (200 g) and methanol (200 ml) by cooling the reaction mixture to 0-10°C. The reaction mixture was heated to 55-60°C and stirred for 24 hours at 55-60°C. Distilled off the solvent under reduced pressure. Isopropanol was added to the obtained residue. The reaction mixture was cooled to 0-5°C and stirred for 2 hours at 0-5°C. Filtered the solid, washed with isopropyl alcohol and then dried to get title compound. Yield: 140 g

b) Preparation of (S)-2-(benzyloxy)propanal (Formula-12)
A mixture of (S)-methyl 2-(benzyloxy)propanoate compound of formula-11 obtained in example-4 (100 g) and toluene (200 ml) was cooled to -75 to 70°C under nitrogen atmosphere. DIBAL (500 ml) was added to the reaction mixture and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with methanol and 30% hydrochloric acid was added to it at -75 to -70°C. Temperature of reaction mixture was raised to 25-30°C. Both organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both organic layers were combined, washed with 5% sodium bicarbonate and 10% sodium chloride solution. The organic layer containing title compound is carried for the next step without distillation.

c) Preparation of (S)-N'-(2-(benzyloxy)propylidene)formo hydrazide (Formula-2)
To a pre-cooled solution of formyl hydrazine (40.3 g) in methanol (290 ml) at 0-5°C, toluene layer containing (S)-2-(benzyloxy)propanal compound of formula-12 obtained in step-b) was added. Further, 30% hydrochloric acid was added to the reaction mixture at -75 to 70°C. Slowly raised the temperature of reaction mixture to 25-30°C and stirred for 4 hours at 25-30°C. After completion of the reaction, distilled off the solvent under reduced pressure to get title compound. Ethyl acetate (210 ml) was added to the obtained compound and stirred for 1 hour at 25-30°C. Filtered the reaction mixture to remove the unwanted solid and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure to get semi-solid. Petroleum ether (210 ml) was added to the obtained semi-solid and stirred for 2 hours at 25-30°C. Filtered the precipitated solid, washed with petroleum ether and then dried to get title compound. Yield: 67 g; Chiral purity: 99.5%

Example-6: Preparation of N'-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide (Formula-3)
A mixture of methyl tertiary butyl ether (150 ml), Mg turnings (18 g) and h (0.03 g) was heated to 40-45°C under nitrogen atmosphere and ethyl bromide (81.8 g) was added slowly to the reaction mixture for about 1 hour. The reaction mixture was further heated to 50-55°C and methyl tertiary butyl ether (60 ml) was added to it. The reaction mixture was stirred for 2 hours at 50-55°C and cooled 0-10°C. N,0-Bis trimethyl silyl acetamide (60.9 g) was added to a mixture of methyl tertiary butyl ether (150 ml) and (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2 (30 g) over a period of 45 minutes at 25-30°C and stirred for 1 hour at 25-30°C. This reaction mixture was added to the above reaction mixture at 0-10°C under nitrogen atmosphere. Temperature of the reaction mixture was raised to 25-30C and stirred for 8 hours at 25-30°C. After completion of reaction, the reaction mixture was quenched with 8% acetic acid in chilled water. The reaction mixture was stirred for 30 minutes at 25-30°C and both organic and aqueous layers were separated. The organic layer was washed with 10% sodium chloride solution and followed by water. Distilled off the solvent completely to get the title compound. The obtained compound was taken into next step without isolating the compound. Yield: 48 g

Example-7: Preparation of l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one(Formula-6)

A mixture of N'-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-3 (45.5 g) obtained in example-6, dioxane (500 ml) added phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5 (50 g) was heated to 90-100°C. Triethylamine (40 g) was added to the reaction mixture at 90-100°C over a period of 1 hour and stirred for 24 hours at 90-100°C. After completion of the reaction, the reaction mixture was cooled to 65-70°C and dichloromethane was added to the reaction mixture. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Water was added to the filtrate. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both organic layers were combined and washed with 2% sodium hydroxide solution followed by water, and then with 5% hydrochloric acid solution followed by water and 5% NaHC03 solution washing. Distilled off the solvent from organic layer under reduced pressure to get the title compound. Isopropyl alcohol (75 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30°C. The reaction mixture was stirred for 6 hours at 25-30°C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 30 g; Purity by HPLC: 98.0%

Example-8: 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-l-yl)phenyl)-l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one(Formula-7) Added l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-l-yl)phenyl)-lH-l,2,4-triazol-5(4H)-one compound of formula-6 (35 g) to a mixture of dimethylsulfoxide (350 ml) and sodium hydroxide (3.4 g) at 25-30°C and stirred for 45 minutes at 25-30°C. ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl) tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-13 (31.5 g) was added to the above reaction mixture at 25-30°C and stirred 5 hours at 25-30°C. After completion of the reaction, water was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% sodium chloride solution. Distilled off the solvent under reduced pressure to get the compound as residue. Dissolved the obtained residue in isopropanol (320 ml) at 45-50°C. Filtered the solid, washed with water and dried to get the title compound. Yield: 98%; Purity by HPLC: 95.1%

Example-9: Preparation of Posaconazole (Formula-1)
5N hydrochloric acid (72 ml) and 10% Pd-C (10 g) were added to a solution of 4-(4-(4-(4-(((3R,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl) tetrahydro furan-3 -yl)methoxy)phenyl)piperazin-1 -yl)phenyl)-1 -((2 S,3 R)-2-(benzyloxy) pentan-3 -yl)-lH-l,2,4-triazol-5(4F£)-one compound of formula-7 (42 g) in methanol (420 ml). The reaction mixture was hydrogenated for 5 hours under a hydrogen gas pressure of 4-5 kg/cm at 50°. After completion of reaction, the catalyst was filtered off and washed with methanol. pH of the filtrate was adjusted to ~7.0 using 4N sodium hydroxide. Water was added to the reaction mixture and stirred for 2 hours at 25-35°C. Filtered the separated solid and washed with water. The obtained solid was dissolved in acetone (320 ml)and stirred at reflux temperature for 30 minutes. Filtered the undissolved product and added water to the filtrate and stirred the reaction mixture for 4 hours at 25-35°C. Filtered the separated solid and washed with water. Further the solid was recrystallized from isopropyl alcohol to get the title compound. Purity by HPLC: 99%; Yield: 75.0%

Example-10: Preparation of amorphous posaconazole compound of formula-1:
A mixture of Posaconazole (100 g) and dichloro methane (500 ml) was stirred to get clear solution. The solution was filtered and the filtrate was slowly added to n-pentane (7500 ml) at 25-30°C. The resulting mixture was stirred for 2 hours at the same temperature. The compound obtained was filtered and washed with n-pentane. Dried the obtained solid to get amorphous solid. Yield: 95%.
Example-ll: Preparation of Isopropanol solvate form of Posaconazole (Formula-1)
Dissolved the posaconazole (30 g) in isopropyl alcohol (300 ml) by heating to reflux temperature. Filtered the reaction mixture, filtrate was cooled to 25-30°C and stirred for 2 hours at 25-30°C. Filtered the solid and washed with isopropyl alcohol. Dried the obtained solid for 8 hours at 60-65 °C to get the title compound. PXRD of obtained isopropanol solvate form of Posaconazole is depicted in figure-1. Yield: 75.0%

Example-12: amorphous 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-l-yl)phenyl)-l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one(Formula-7)
A solution of sodium hydroxide (9.2 g) and water (10 ml) was cooled to 25-3 5°C and added dimethyl sulfoxide (350 ml), followed by l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxy phenyl)piperazin-1 -yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (50 gms) compound of formula-6 at 25-35°C. The reaction mixture was stirred for 45 minutes at the same temperature. ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (50 gms) compound of formula-13 was added to the above reaction mixture and heated to 45-60°C. The reaction mixture was stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and neutralized with hydrochloric acid. The reaction mixture was stirred for 1 hour at 25-35°C. Filtered the solid and washed with water. Dried the solid to get the title compound. Yield: 79 g

We Claim:

1. An isopropanol solvate form of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difiuoro phenyl)tetrahydro-5-( 1H-1,2,4-triazol-1 -ylmethyl)-3-furanyl]methoxy]phenyl]-1 -piperazinyl] phenyl]-2-[( 1 S,2S)-1 -ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (designated as crystalline form-M) compound of formula-1

is characterized by its powder X-ray diffractogram having peaks at about 3.5, 6.9, 7.6, 9.8, 14.1, 14.4, 15.0, 15.7, 17.7, 19.3, 19.9, 20.3, 22.2, 22.9, 23.1 and 25.4± 0.2 degrees two-theta as illustrated in figure-1.

2. Amorphous 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-l-yl)phenyl)-l-((2S,3S)-2-(benzyloxy)pentan-3-yl)-lH-l,2,4-triazol-5(4H)-one compound of formula-7 depicted in figure-2.

3. An improved process for the preparation of amorphous 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy) phenyl)piperazin-1 -yl)phenyl)-1 -((2S,3 S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one compound of formula-7, comprising of:
a) Condensing l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1 -yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-6, with ((3 S,5R)-5-(( 1H-1,2,4-triazol-1 -yl)methyl)-5-(2,4-difluorophenyl) tetrahydro furan-3-yl)methyl-4-methyl benzenesulfonate compound of formula-13


in the presence of a suitable base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates; preferably sodium hydroxide in a suitable solvent selected from polar aprotic solvents, chloro solvents, ester solvents, ether solvents, preferably dimethylsulfoxide at 45-60°C to provide compound of formula-7,

b) quenching the reaction mixture with water,

c) neutralizing the reaction mixture with a suitable acid to provide amorphous compound of formula-7.

4. An improved process for the preparation of phenyl-4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5, comprises of reacting 4-(4-(4-aminophenyl)piperazin-l-yl)phenol compound of formula-4 with phenylchloroformate in the absence of a base in a suitable solvent selected from polar aprotic solvents, chloro solvents, ester solvents, ketone solvents, alcoholic solvents and ether solvents, preferably dimethylformamide to provide phenyl4-(4-(4-hydroxyphenyl)piperazin-1 -yl)phenylcarbamate compound of formula-5.

5. An improved process for the preparation of (S)-methyl 2-(benzyloxy)propanoate compound of formula-11, which comprising the following steps:

a) Reacting racemic methyl lactate compound of formula-8 with benzyl chloride in the presence of a suitable base selected from alkali metal alkoxides, preferably sodium tertiarybutoxide in a suitable solvent selected from polar aprotic solvents, ester solvents, chloro solvents and alcoholic solvents, preferably dimethylformamide to provide methyl 2-(benzyloxy)propanoate compound of formula-9,

b) hydrolyzing the compound of formula-9 in-situ with a suitable base selected from alkali metal hydroxides, preferably aqueous sodium hydroxide in a suitable solvent selected from hydrocarbon solvents, ester solvents, alcoholic solvents, preferably toluene to provide 2-(benzyloxy)propanoic acid compound of formula-10,

c) resolving of compound of formula-10 in-situ with (S)-l-phenylethanamine in a suitable solvent selected from hydrocarbon solvents, chloro solvents and ester solvents, preferably toluene to provide (S)-l-phenylethanamine salt of (S)-2-(benzyloxy)propanic acid compound of formula-10a,

d) reacting the compound of formula-10a with methanol in presence of thionyl chloride in a suitable solvent selected from polar aprotic solvent, preferably dimethylformamide to provide (S)-methyl 2-(benzyloxy)propanoate compound of formula-11.

6. An improved process for the preparation of l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-
(4-(4-(4-hydroxyphenyl)piperazin-1 -yl)phenyl)-1H-1,2,4-triazol-5(4H)-one
compound of formula-6, which comprises of the following steps:

a) Reacting (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2 with ethyl magnesium halide in the presence of bis(trimethylsilyl)acetamide in a suitable solvent selected from ether solvents, ester solvents, ketone solvents, preferably methyl tertiary butyl ether to provide N'-((2S,3S)-2-(benzyloxy)pentan-3-yl)formylhydrazide compound of formula-3,

b) reacting the compound of formula-3 in-situ with phenyl 4-(4-(4-hydroxyphenyl) piperazin-l-yl)phenylcarbamate compound of formula-5 in presence of an organic base in a suitable solvent selected from ether solvents, ketone solvents, hydrocarbon solvents, preferably dioxane to provide l-((2S,3R)-2-(benzyloxy) pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1 -yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-6.

7. A compound of formula:


8. An improved process for the preparation of pure Triazole derivative compound of formula-1, comprising of the following steps:

a) Reacting the (S)-N'-(2-(benzyloxy)propylidene)formohydrazide compound of formula-2 with ethyl magnesium halide in the presence of bis(trimethylsilyl)acetamide in a suitable solvent to provide N'-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-3,

b) reacting the compound of formula-3 in-situ with phenyl 4-(4-(4-hydroxyphenyl)piperazin-l-yl)phenylcarbamate compound of formula-5 in the presence of suitable base in a suitable solvent to provide l-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1 -yl)phenyl)-1H-l,2,4-triazol-5(4H)-one compound of formula-6,

c) condensing the compound of formula-6 with ((3S,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methyl benzenesulfonate compound of formula-13 in the presence of base in a suitable polar aprotic solvent to provide 4-(4-(4-(4-(((3R,5R)-5-((lH-l,2,4-triazol-l-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl) cyclo hexyl)phenyl)-1 -((2S,3S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one of compound of formula-7,

d) debenzylating the compound of formula-7 with Pd/C under hydrogen pressure in the presence of mineral acid in a suitable alcoholic solvent to provide compound of formula-1,

e) optionally, purifying the compound obtained in step-(d) from a suitable solvent to provide pure compound of formula-1.

9. The process according to claim-8 wherein, in step-a) the suitable ether solvent is selected from methyl tertiary butyl ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane. in step-b) the suitable base is selected from organic base and the suitable solvent is ether solvent selected from tetrahydrofuran, dioxane tertiarybutylmethyl ether and diethyl ether, in step-c) the suitable base is selected from inorganic base and the suitable solvent is polar aprotic solvent selected from dimethylformamide, dimethylacetamide and dimethylsulfoxde. in step-d) the suitable mineral acid is selected from hydrochloric acid, hydroiodic acid, sulfuric acid and a suitable alcoholic solvent is selected from methanol, ethanol, isopropanol and butanol. in step-e) the suitable solvent is alcoholic solvents.

10. A process for the preparation of crystalline form-M of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-( 1H-1,2,4-triazol-1 -ylmethyl)-3-furanyl]methoxy] phenyl]-1 -piperazinyl]phenyl]-2-[(l S,2S)-1 -ethyl-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-one compound of formula-1, comprising of:

a) Dissolving the compound of formula-1 in isopropanol by heating to reflux temperature,

b) filtering the reaction mixture,

c) cooling the reaction mixture,

d) stirring the reaction mixture,

e) filtering the solid and washing with isopropanol,

f) drying the solid at 60-65°C to get crystalline form-M of compound of formula-1.