WO2009141837A2

WO2009141837A2 - Process for preparing posaconazole and intermediates thereof

Info

Publication number: WO2009141837A2
Application number: PCT/IN2009/000292
Authority: WO
Inventors: Venkateswaran Srinivasan Chidambaram; Atchuta Kishore Miryala; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2008-05-21
Filing date: 2009-05-19
Publication date: 2009-11-26
Also published as: WO2009141837A3

Abstract

The present invention relates to an industrially advantageous process for the preparation of tetrahydrofuran antifungals preferably posaconazole of formula I. The present invention further relates to improved processes for preparing key and novel intermediates useful in the preparation of posaconazole. The present invention further relates to improved processes for preparing the compound of formula II, a key intermediate in the preparation of posaconazole.

Description

Process for Preparing Posaconazole And Intermediates Thereof

FIELD OF THE INVENTION

The present invention relates to an industrially advantageous process for the preparation of tetrahydrofuran antifungals, in particular, posaconazole of formula I.

O_H ^CIi3

Formula I

The present invention further provides a process for the preparation of compound of formula II,

Formula II a key intermediate in the preparation of posaconazole.

The present invention further provides novel intermediates useful for the preparation of posaconazole.

BACKGROUND OF THE INVENTION

Posaconazole of formula I, chemically known as (2R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5- (l,2,4-triazol-l-ylmethyl)-tetrahydrofuran-3-ylmethoxy]-phenyl]piperazin-l-yl]phenyl]-2-[l(S)- ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H- 1 ,2,4-triazol-3-one,

Formula I is an antifungal agent which is used against a wide range of fungal pathogens, including both yeasts and molds.

U.S. Patent No. 5,661,151 (herein referred to as '151) discloses several substituted tetrahydrofuran antifungal compounds, including posaconazole. The patent discloses several processes for the preparation of posaconazole.

According to one process, posaconazole is prepared by condensation of toluene-4-sulfonic acid (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[l,2,4]triazol-l-ylmethyl-tetrahydro-3-furanmethyl ester with TV-protected triazolone derivative of following formula,

wherein SEM is 2-(trimethyl)silylethoxymethyl group in presence of a strong base in an aprotic solvent to give the compound of following formula,

wherein SEM is as defined above which is then deprotected using hydrochloric acid in methanol followed by iV-alkylation with brosylated (2S,3R) alcohol of the following formula,

wherein R represents hydroxyl protecting group (R = SEM, benzyloxymethyl), in presence of strong base in an aprotic solvent to give hydroxy protected posaconazole which is then deprotected using hydrochloric acid in methanol to give posaconazole of formula I, which is purified by column chromatography.

In an alternative process, ' 151 discloses the preparation of posaconazole by condensing (3R-cis)-

N-4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(lH-l,2,4-triazol-l-yl)methyl)-furan-3- yl]methoxy]-phenyl]-l-piperazinyl]-phenyl]-carbamic acid phenyl ester of following formula,

with hydrazine hydrate in dioxane followed by cyclization in the presence of formamidine acetate in dimethylformamide to give a cyclized intermediate of following formula,

which is further JV-alkylated with brosylated (2S,3R) alcohol of formula,

wherein R represents hydroxyl protecting group (R = SEM, benzyloxymethyl), in 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 processes disclosed above is that iV-alkylation is carried out on cyclized triazolone intermediate which requires a large excess of expensive alkylating agent, and results in a mixture of iV-alkylated and 6>~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.

In a still another methodology, "151 discloses a process for preparing posaconazole by reacting (3R-cis)-N-4-[4-[4-[[5-(2,4-difluoroρhenyl)tetrahydro-5-(lH-l,2,4-triazol-l-yl)methyl)-furan-3- yl]methoxy] -phenyl] -1-piperazinyl] -phenyl] -carbamic acid phenyl ester with 2-[3-(2S, 3S)-2- (benzyloxy)pentyl] formic acid hydrazide in the presence of 1-8-diaza bicyclo [5.4.0]undec-7-ene under heating to give benzyl ether of posaconazole of formula,

which on hydrogenolysis with palladium on carbon and formic acid in methanol affords posaconazole which is further purified on preparative thin layer chromatography. US patent No. 5,403,937 discloses a process for the preparation of key intermediate of posaconazole, specifically toluene-4-sulfonic acid 5-(2,4-difluoro-phenyl)-5-[l,2,4]triazol-l- ylmethyl-tetrahydro-furan-3-ylmethyl ester as depicted below:

The process disclosed in US patent 5,403,937 involves the use of n-butyl lithium during the preparation of oxazolidinone lithium salt, which is very expensive and extremely flammable. The process requires column chromatography purification at- different stages to purify the intermediates which is tedious and lengthy process. The above drawbacks make the process unviable on commercial scale

U.S. Patent No. 5,625,064 (^Λ064) discloses a process for the preparation of posaconazole which involves the condensation of compound of formula II,

with (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4-triazol-l-yl)methyl]-tetrahydro-3-furan methyl ester derivative of following formula,

wherein OB represents a suitable leaving group selected from p-chlorobenzenesulfonyl, p- toluenesulfonyl, methanesulfonyl in the presence of 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 starting compound of formula II is prepared by the method as depicted in the following scheme:

wherein R represents H, CH₃, C₆H₅CH₂

The above process suffers from several drawbacks such as low yields in the condensation step of phenyl carbamate intermediate and hydrazine derivative. We have observed that condensation of unprotected hydroxyl derivative with hydrazine derivative results in low yield of the compound of formula II due to less solubility of hydroxyl compound in most of the solvents. Further, condensation of O-benzyl protected phenyl carbamate derivative with hydrazine derivative results in formation of impurities which further requires tedious purification processes hence resulting in low yields. In addition, the deprotection of benzyl ether of posaconazole in the presence of formic acid does not go to completion or requires even more than 30-35 hours. This may lead to the degradation of the final product and may require tedious purification processes such as chromatographic 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 degradation of the compound of formula I necessitating laborious purification methods to purify posaconazole, hence resulting in loss of yield and purity.

In view of the above, there is thus 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 long reaction time, use of hazardous reagent, stringent reaction conditions, low yields and tedious purifications. OBJECT OF THE INVENTION

One principle object of the invention is to provide a process for the preparation of highly pure posaconazole in high yield and reduced time cycle.

Another object of the present invention is to provide a cost effective, efficient, and industrially viable process for the preparation of posaconazole avoiding stringent reaction conditions. Another object of the present invention is to provide a process for the preparation of pure posaconazole wherein purification by column chromatography is avoided. Still another object of the present invention is to provide a process for the preparation of key intermediate of formula II in good yields using novel intermediates. Still another object of the present invention is to provide novel intermediates, process for the preparation thereof.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for the preparation of highly pure posaconazole of formula I

Formula I from a compound of formula II.

Formula II which comprises: a. debenzylating compound of formula II, using mineral acid in the presence of noble metal catalyst, in an organic solvent, under hydrogen gas pressure to prepare compound of formula

III;

Formula III b. condensing the resulting compound of formula III with compound of formula IV,

Formula IV wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl, p- toluenesulfonyl, methanesulfonyl and the like in the presence of suitable base in an organic solvent; c. isolating posaconazole; and d. optionally purifying posaconazole.

Another aspect of the present invention is to provide a process for the preparation of compound of formula II which comprises : a. acylating 4- [4-(4-nitro-phenyl)-piperazin- 1 -yl] -phenol with a reagent of formula R' C(O)X, wherein R ' represents straight, branched, substituted or unsubstituted Ci-Cg alkyl or substituted or unsubstituted phenyl and X represents halogen, to give a compound of formula V;

Formula V b. reducing the compound of formula V using a noble metal catalyst, in an organic solvent, under hydrogen gas pressure to give novel amine derivative of formula VI;

Formula VI wherein R ' is as defined above c. condensing the compound of formula VI with substituted or unsubstituted phenyl chloroformate in the presence of a tertiary amine base in a suitable solvent to afford a novel and key intermediate of formula VII;

Formula VII wherein R ' is as defined above and R " is independently selected from the group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH_∑, CN, acetoxy, N(CH₃)₂, phenyl, phenoxy, benzyl, benzyloxy, NO₂, CHO, CHsCH(OH), acetyl, ethylene dioxy d. reacting the compound of formula VII with a hydrazine derivative of formula VIII;

Formula VIII wherein Z is selected from -CHO; or -C(O)OC(CH₃) ₃; or -C(O)OCH₂C₆H₅ in the presence of tertiary amine base in an inert solvent to afford the compound of formula

IX; and

Formula IX wherein R ' is as defined above e. hydrolyzing the compound of formula IX using a base to afford the compound of formula II. Still another aspect of the present invention is to provide novel intermediates of formulae V, VI, VII and IX, preparation thereof and conversion thereof to posaconazole.

Another aspect of the present invention provides a process for the preparation of posaconazole of formula I comprises: a. reacting 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid of formula X,

Formula X with methyltriphenylphosphonium bromide in the presence of sodium hexamethyldisilazane and a base to afford a compound of formula XI;

Formula XI b. purifying the compound of formula XI with C₁-C₇ hydrocarbon solvent; c. reacting the compound of formula XI with chiral auxiliary in the presence of an activating agent, tertiary amine base and 4-dimethylamino pyridine in an inert solvent to afford a compound of formula XII;

Formula XII wherein Q* represents a chiral auxiliary d. treating the compound of formula XII with 1,3,5-trioxane in the presence of titanium tetrachloride, titanium isopropoxide and a tertiary amine base to afford a compound of formula XIII;

Formula XIII wherein Q* is as defined above e. halocyclizing the compound of formula XIII in the presence of suitable halogen, an amine base in an inert solvent to afford a compound of formula XIV;

Formula XIV wherein X is selected from halogen such as iodo, chloro, bromo and the like and Q* is as defined above f. purifying the compound of formula XIV with C₁-C₄ linear or branched alcoholic solvents, C₂-Cs linear or branched ethers and mixtures thereof; g. reducing the compound of formula XIV with a suitable reducing agent in an organic solvent to afford compound of formula XV;

Formula XV wherein X is as defined above h. condensing the compound of formula XV with alkali metal triazole in the presence of 1,3- dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone in polar aprotic solvent such as N,N- dimethylformamide and the like to afford a compound of formula XVI; Formula XVI i. reacting the compound of formula XVI with a reagent having a suitable leaving group in the presence of a base in a suitable solvent to afford a compound of formula IV;

Formula IV wherein OB is as defined above j. purifying compound of formula IV by recrystallization from an organic solvent selected from ethers, C₁-C₄ alcohols, C₃-C₇ linear, branched and cyclic alkanes or mixtures thereof; and k. converting the compound of formula IV to posaconazole.

Yet another aspect of the present invention is to provide an improved process for the preparation of highly pure posaconazole of formula I, which comprises: a. debenzylating the benzyl ether of posaconazole of formula XVII,

Formula XVII using a mineral acid in presence of a noble metal catalyst in an organic solvent, under hydrogen pressure, at a temperature of 20 °C to 80 °C; b. isolating posaconazole; and c. optionally purifying posaconazole.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides processes for the preparation of posaconazole of formula I.

According to the one aspect, the present invention provides a process for the preparation of posaconazole of formula I from a compound of formula II. In one aspect, the compound of formula II is debenzyled first and thereafter the resulting debenzylated compound of formula III is condensed with compound of formula IV. In another aspect, the compound of formula II is condensed with compound of formula IV first and thereafter the resulting compound is debenzylated to afford posaconazole. Typically, debenzylation of the compound of formula II is carried out using mineral acid in an organic solvent, in the presence of a noble metal catalyst employing hydrogen gas pressure. Generally, hydrogen gas is applied at a pressure of about 2 kg/cm² to 8 kg/cm². Preferably, the hydrogen pressure applied is about 3 kg/cm² to 6 kg/cm². Noble metal catalyst may be selected from Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably the noble metal catalyst is palladium on carbon. Mineral acid can be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, preferably hydrochloric acid. Organic solvent may be selected from alcoholic solvent such as C₁-C₄ alcohols, dimethylformamide,dimethylsulfoxide, preferably methanol, ethanol, propanol, n-butanol, isopropanol, dimethylsulfoxide and more preferably methanol is employed.

The debenzylation reaction is usually conducted at a temperature of about 20 °C to 80 ⁰C. Preferably, the temperature is maintained during reaction is about 40 °C to about 60 ⁰C for a period of about 1 to 5 hours. The completion of reaction may be monitored by TLC or HPLC. After completion of reaction, reaction mixture is filtered to remove the catalyst. Solvent is distilled out and the resulting residue is further dissolved in suitable aliphatic esters such as ethyl acetate and further stirred for 1 to 2 hours at the reflux temperature of the solvent to afford debenzylated compound of formula III. Thereafter, the resulting debenzylated compound of formula III is condensed with compound of formula IV in the presence of a base in an organic solvent, at temperature of about 30 ⁰C to the reflux temperature of the solvent to afford posaconazole of formula I.

Base can be selected from an alkali or alkaline earth metal hydroxide, hydrides or carbonates, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydride, lithium hydride, potassium hydride and the like, sodium carbonate, potassium carbonate, calcium carbonate, and the like. Organic solvent can be selected from polar aprotic or protic solvent preferably methanol, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, and the like or mixture thereof.

Preferably the condensation reaction is carried out in the presence of sodium hydroxide in a suitable solvent selected from isopropyl alcohol or dimethylsulfoxide at a temperature of about 30 °C to 80 °C. Normally the condensation reaction is completed 3 to 15 hours. After the completion of the reaction, the reaction mixture is cooled and diluted with water and stirred for the sufficient time to precipitate posaconazole of formula I, which is then isolated by filtration. According to another aspect, the present invention provides a process for the preparation of compound of formula II. The compound of formula II can be prepared by initially acetylating 4-[4-(4-nitro-phenyl)- piperazin-l-yl]-phenol with a reagent of formula R⁵C(O)X, wherein R ' and X are as defined above to give a novel compound of formula V, which further represents a part of the invention. Although other suitable reagents capable of acylating such as inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester can equally be employed. Preferably acetyl chloride or acetic anhydride can be used. Acylation is carried out in the presence of tertiary amine base such as triethylamine in halogenated organic solvent such as dichloromethane at ambient temperature with stirring for a period of about 3-6 hours. Progress of the reaction can be monitored by HPLC or TLC. After completion of the reaction the solvent is removed by methods known in art like evaporation, distillation and the like to afford a compound of formula V.

The compound of formula V is further reduced using a noble metal catalyst, in an organic solvent, under hydrogen pressure to give novel amine derivative of formula VI, which further represents a part of the invention. Noble metal catalyst may be selected from platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably the noble metal catalyst is palladium on carbon. Hydrogen gas is applied at a pressure of about 1 kg/cm² to about 3 kg/cm². Organic solvent is selected from polar aprotic or polar protic solvent in combination with water; preferably a mixture of tetrahydrofuran and water is used. Reaction is preferably performed at ambient temperature. In an alternate process, 4- [4-(4-nitro-phenyl)-piperazin-l-yl] -phenol is first reduced using a noble metal catalyst, in an organic solvent, under hydrogen pressure, and then it is acetylated to give compound of formula VI.

The compound of formula VI is further condensed with substituted or unsubstituted phenyl chloroformate in the presence of a tertiary amine base such as triethylamine in a suitable solvent to afford a novel and key intermediate of formula VII, further represents a part of the invention. The condensation reaction is performed at a temperature of about 0 ⁰C to about 10 °C. Solvent can be selected from polar aprotic solvent, a non polar solvent or mixtures thereof, preferably N,7V-dimethylformamide, toluene or mixture thereof is used. In an alternate process, compound of formula VII can also be prepared by the condensation of 4- [4-(4-amino-phenyl)-piperazin-l-yl] -phenol with substituted or unsubstituted phenyl chloroformate derivative followed by acylation with a reagent of formula R⁵C(O)X. Thereafter compound of formula VII is converted to compound of formula II thorough novel intermediate of formula IX. Typically, the compound of formula VII is condensed with hydrazine derivative of general formula VIII in the presence of tertiary amine base in an inert solvent to afford the novel and key intermediate of formula IX, which further represents a part of the invention. Preferably, compound of formula VII and hydrazine derivative of formula VIII is suspended in an inert solvent in the presence of a suitable base. Base can be selected from tertiary amine base such as triethylamine. Solvent can be selected from 1,2-dimethoxyethane, diethyl ether or tetrahydrofuran preferably 1,2-dimethoxyethane. The resulting suspension is refluxed at about 60 ⁰C to about 100 °C for a period of 20-30 hours then an aromatic hydrocarbon solvent such as hexane, toluene or xylene is added preferably toluene is added. The resulting suspension is further refluxed at about 90 °C to about 120 °C for a period of 20-30 hours preferably till reaction completion. The product is isolated preferably by distillation of the solvent to give compound of formula IX in high yield and purity. It is advantageous to use O-acylated derivative of formula VII during condensation with hydrazine derivative as the solubility of O-acylated compound of formula VII is better in most of the solvent as compared^' to the O-alkylated phenyl carbamte derivatives as disclosed in the prior art and hence results in better yields. Further, hydrolysis of O-acylated compound can be carried out under mild reaction conditions. The compound of formula IX is further hydrolyzed to compound of formula II using suitable base. The process comprises of dissolving the compound of formula IX in a suitable alcoholic solvent selected from C₁-C₄ alcohols, preferably methanol, ethanol, propanol, n-butanol, isopropanol or tertiary butanol and the like. The reaction mass is then treated with an aqueous solution of alkali metal hydroxide base preferably sodium hydroxide at a temperature of below 15 ⁰C for time sufficient to convert to compound of formula II. The resulting mixture is then neutralized with aqueous acidic solution preferably with IN hydrochloric acid solution. The compound of formula II is then extracted with halogenated hydrocarbon solvent such as dichloromethane by layer separation method. The compound of formula II is finally crystallized in ethereal solvent preferably in methyl tert-butyl ether in high yield and purity. The compound of formula II is further converted into posaconazole by the processes known in prior art or as disclosed in present invention.

The key intermediate of formula IV may be procured from commercial source or prepared by the processes well known in art such as US patent No. 5,403,937 and Tetrahedron Letters, vol.37, No.32, pp 5657-5660 (1996) with modification which are reported herein for reference. Typically, compound of formula IV can be prepared by initially reacting 4-(2,4-difluoro-phenyl)- 4-oxo-butyric acid compound of formula X under wittig reaction conditions to give compound of formula XL

Preferably, a solution of methyltriphenylphosphonium bromide, sodium hexamethyldisilazane and base preferably alkali metal hydride in a suitable solvent selected from polar aprotic solvent is prepared at ambient temperature, followed by stirring the reaction mass at a temperature of about 40 °C to 55 °C. The reaction mass is then cooled to a temperature of below 0 ⁰C and is added to the solution of compound of formula X in polar aprotic solvent at temperature about -75 ⁰C to -80 ⁰C. Alkali metal hydride base can be selected from sodium hydride, lithium hydride, potassium hydride and the like, most preferably sodium hydride. Polar aprotic solvent can be selected from 1,4-dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide and mixtures thereof, preferably polar aprotic solvent is tetrahydrofuran. The reaction mass is then heated to a temperature of 60-80 °C with stirring for 8-14 hours. Completion of reaction may be monitored by TLC or HPLC and after completion of the reaction, mixture is cooled to 10-20 ⁰C and quenched with an alcoholic solvent preferably methanol. The resulting mixtμre is then treated with an aqueous solution of citric acid optionally with hydrochloric acid and extracted with aliphatic esters preferably with ethyl acetate to remove side products present as impurities. The crude product so formed is further purified by treatment with suitable aqueous base like potassium hydroxide, sodium hydroxide and the like to prepare base addition salt of compound of formula XI followed by neutralization of the salt with dilute mineral acid such as hydrochloric acid in the presence of C₁-C₇ hydrocarbon solvent to extract the product in organic layer to yield compound of formula XI in high yield and purity. C₁-C₇ hydrocarbon solvent is selected from n-pentane, n-hexane, n-heptane and the like, preferably n- hexane. It has been found that using alkali metal hydride base such as sodium hydride in combination with sodium hexamethyldisilazane facilitates easy isolation of the product from the reaction mass as compared to the prior art processes.

The compound of formula XI is then treated with known activating agents such as oxalyl chloride, thionyl chloride, carbonylditriazole or oxalylditriazole, pivaloyl chloride etc., preferably pivaloyl chloride, in the presence of tertiary amine base such as triethylamine in an inert solvent such as, dichloromethane, tetrahydrofuran and the like to afford activated intermediate. The activated intermediate is then treated insitu with a chiral auxiliary in the presence of base like 4-dimethyl amino pyridine in an inert solvent such as N₁N- dimethylformamide, iV,N-dimethylacetamide, dimethylsulfoxide or mixtures thereof at ambient temperature to afford a compound of formula XII. Preferably the chiral auxiliary used is (R)-benzyl-2-oxazolidinone. The reaction mixture is heated to a temperature of about 35-55 °C, more preferably at about 45-50 ⁰C and further stirred for a period of about 3-6 hours. Completion of the reaction may be monitored by TLC or HPLC. After completion of reaction, reaction mixture is cooled and quenched with a suitable quenching agent. Suitable quenching agent may be selected from ammonium chloride, inorganic acids selected from sulfuric acid, hydrochloride acid, and the like or organic acid selected from acetic acid, formic acid, benzoic acid, and the like or any other reagent selected from ketones such as acetone, ethylmethyl ketone, methylisobutyl ketone.

The present invention is advantageous as it teaches the direct use of chiral auxiliary in presence of 4-dimethyl amino pyridine without converting it to its lithium salt using highly inflammable and expensive n-butyl lithium as disclosed in prior art.

Compound of formula XII is then converted to compound of formula XIII by treating the compound of formula XII with titanium tetrachloride and titanium isopropoxide in the presence of halogenated solvent selected from chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane and the like, preferably dichloromethane at a temperature of below 0 °C. To the resulting solution a tertiary amine base such as triethylamine, diisopropylethylamine, preferably triethyl amine is added at a temperature of about -5 to 0 °C to prepare metal enolates of compound of formula XII. Metal enolates of compound of formula XII is further treated insitu with a solution of 1,3,5-trioxane in halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane and the like, preferably dichloromethane at -5 to 0 °C. Preferably a solution of 1,3,5-trioxane in a halogenated solvent is added to the solution of metal enolate of compound of formula XII. It is advantageous to add another lot of titanium tetra chloride after the addition 1,3,5-trioxane solution.

Completion of the reaction may be monitored by TLC. After completion of reaction, reaction mixture is quenched with a suitable quenching agent like aqueous ammonium chloride to give compound of formula XIII.

In the present invention, the compound of formula XIII is further halocyclized to give compound of formula XIV. Preferably compound of formula XIII is dissolved in an inert solvent selected from polar aprotic solvent such as acetonitrile, acetone, tetrahydrofuran, 2-methyl- tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof and treated with halogen such as iodine, chlorine, bromine and the like, preferably with iodine in the presence of an amine base such as pyridine while maintaining the temperature at about -5 to 5°C. The temperature of reaction mass is maintained at ambient temperature for a time sufficient to form compound of formula XIV. After completion of reaction, reaction mixture is quenched with a suitable quenching agent and further extracted with a non polar solvent such as an ethereal solvent preferably diisopropyl ether.

Compound of formula XIV is then recrystallized using suitable solvent selected from ethereal solvents such as diisopropyl ether, t-butyl methyl ether, and the like; C₁-C₄ linear and branched alcoholic solvents such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol and the like or mixtures thereof. Preferably diisopropyl ether, ethanol or a combination thereof is used. Compound of formula XIV is then reduced to compound of formula XV using a hydride reducing agent in the presence of polar protic and aprotic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof, preferably ethanol, tetrahydrofuran and mixture thereof is employed. The reaction is preferably performed at a temperature of -5 to 0 ⁰C. Completion of reaction may be monitored by TLC. Thereafter the reaction mixture is quenched with a suitable quenching agent and further extracted with a non polar solvent such as an ethereal solvent preferably diisopropyl ether to afford compound of formula XV. Compound of formula XV is further condensed with alkali metal triazole preferably 1,2,4- sodium triazole in presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-ρyrimidinone in polar aprotic solvent such as N,N-dimethylformamide at a temperature of 90-110°C for time sufficient to convert to compound of formula XVI.

The hydroxyl group of compound of formula XVI is further converted to a suitable leaving group to give compound of formula IV. Preferably compound of formula XVI is dissolved in an inert solvent followed by addition of an amine base such as 4-dimethyl amino pyridine, pyridine, triethylamine preferably 4-dimethyl amino pyridine at ambient temperature. Solvent can be selected from halogenated hydrocarbons such as carbon tetrachloride, chloroform, tetrachloroethene, trichloroethene, dichloroethene, 1,1- dichloroethene, 1,3-dichloropropene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4- dichlorobenzene, 3-chlorotoluene, dichloromethane; aliphatic esters such as ethyl acetate; tetrahydrofuran, toluene and mixtures thereof, preferably dichloromethane is used. The reaction mass is cooled to -5 to 10 °C preferably 0 to 5 ⁰C and treated with a reagent having suitable leaving group such as p-chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and the like, preferably p-chlorobenzene sulfonyl chloride. The reaction mass is stirred for sufficient time preferably till reaction completion at ambient temperature.

Compound of formula IV can further be crystallized using suitable solvent selected from ethers such as diisopropyl ether, t-butyl methyl ether, and the like; C₁-C₄ alcohols such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol and the like; C₃-C₇ linear, branched and cyclic alkanes or mixtures thereof in high purity, without the need to use column chromatography as reported in prior art. Most preferably solvent of crystallization is ethanol. According to another aspect, posaconazole of formula I is prepared by the condensation of compound of formula II with compound of formula IV to afford benzyl ether of posaconazole of formula XVII, which is further debenzylated to afford posaconazole. Particularly, the compound of formula II is condensed with the compound of formula IV in the presence of base in an organic solvent, at temperature of about 30 °C to the reflux temperature of organic solvent to afford compound of formula XVII, which is then debenzylated to posaconazole. Base can be selected from an alkali or alkaline earth metal hydroxide, hydrides or carbonates, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydride, lithium hydride, potassium hydride and the like, sodium carbonate, potassium carbonate, calcium carbonate, and the like. Organic solvent can be selected from polar aprotic or protic solvent preferably methanol, ethanol, isopropanol, dimethylformarnide, dimethylsulfoxide, and the like or mixture thereof. One another aspect of the present invention relates to an improved process for the preparation of posaconazole of formula I, by debenzylating . benzyl ether of posaconazole of formula XVII using a noble metal catalyst in the presence of mineral acid in an organic solvent, under hydrogen pressure, at a temperature of 20-80⁰C. Noble metal catalyst may be selected from Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably the noble metal catalyst is palladium on carbon. Mineral acid can be selected from hydrochloric acid, hydrobromic acid; hydroiodic acid, sulfuric acid, more preferably hydrochloric acid, hydrobromic acid and most preferably hydrochloric acid. Organic solvent may be selected from alcoholic solvent such as C₁-C₄ branched or linear aliphatic alcohols, dimethylformamide, dimethylsulfoxide, more preferably organic solvent is methanol, ethanol, propanol, n-butanol, isopropanol, dimethylsulfoxide and most preferably the organic solvent is methanol. Preferably, the reaction is performed at a hydrogen gas pressure of about 2 kg/cm to 8 kg/cm , preferably the hydrogen gas pressure is about 3 kg/cm² to 6 kg/cm². The reaction is conducted at a temperature of about 20 °C to 80 °C, preferably at a temperature of about 40 °C to 60 ⁰C for a period of 3 to 7 hours.

The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, reaction mixture is filtered to remove the catalyst. The solvent is distilled out and the resulting residue is further dissolved in a suitable alcoholic solvent. The suitable alcoholic solvent may be selected from C₁- C₄ branched or linear aliphatic alcohols, more preferably methanol, ethanol, propanol, n-butanol, isopropanol, tertiary butanol and the like and most preferably tertiary butanol. Thereafter, the reaction mass is treated with a base preferably sodium hydroxide in an amount sufficient to adjust the pH of the reaction mixture, preferably, to about 6 to about 7 to isolate the posaconazole of formula I in high yield and purity. Use of mineral acid during hydrogenation reaction is advantageous because reaction is completed in lesser time as compared to the prior art processes and hence degradation of product and impurity formation is reduced.

The starting compound that is benzyl ether of posaconazole of compound of formula XVII may be prepared by the process reported in the prior art such as U.S. Patent No. 5,625,064 etc or by the processes of the present invention.

Posaconazole thus prepared by the processes described in the present invention may further be purified by recrystallization using the solvent selected from C₁-C₄ linear or branched alcoholic solvents such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol, acetonitrile, acetone, water and mixtures thereof, preferably methanol.

Wherever required the intermediates and final compound posaconazole can be treated with activated charcoal or silica gel to improve the color and quality of the material. Isolation and purification of the compounds and intermediates described can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the aspects discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery. EXAMPLES Example 1: Preparation of 2-(2(S)-benzyloxy-l(S)-ethyl-propyl)-4~{4-[4-(4-hydroxy- phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one a) Preparation of acetic acid 4- [4-(4-nitro-phenyl)-piperazin-l-yI] -phenyl ester: To a stirred suspension of 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenol (5Og), triethylamine (34.34g) in dichloromethane (500ml), acetyl chloride (16.Og) was added slowly at 10 . The temperature of the resulting mixture was raised to ambient temperature and stirred for 4-5 hours. After completion of reaction (monitored by TLC), the reaction mixture was washed with water (250ml) and brine (250ml). Organic layer was separated and evaporated to obtain 50g of title compound having purity of 98.0% by HPLC. b) Preparation of acetic acid 4-[4-(4-amino-phenyl)-piperazin-l-yl]-phenyl ester: A stirred suspension of acetic acid 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenyl ester (5Og) in tetrahydrofuran (1500ml) and water (50ml) was hydrogenated for 1-2 hours under a hydrogen pressure of 2 kg/cm² at ambient temperature in the presence of palladium on carbon (5%, 5.Og). After completion of hydrogenation (monitored by TLC)₅ the catalyst was filtered off and solvent was evaporated to obtain 43g of the title compound having purity of 98.0% by HPLC. c) Preparation of 2-(2(S)-benzyloxy-l(S)-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)- piperazin-l-yI]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one: To a stirred mixture of acetic acid 4- [4-(4-amino-phenyl)-piperazin-l-yl] -phenyl ester (43g), triethylamine (28g) in toluene (860ml) and N,iV-dimethylformamide (86ml), phenyl chloroformate (26g) was added at 0 °C-10 ⁰C. The resulting mixture was warmed to ambient temperature and stirred for 5-6 hours. To the resulting mixture 2-[3-(2S, 3S)-2-(benzyloxy)pentyl]formic acid hydrazide (43 g) was added and further stirred for 24-30 hours at 80 ⁰C-IOO °C. After completion of reaction (monitored by TLC), solvent was distilled and residue was dissolved in methanol (430ml). The solution was cooled to 0 ⁰C-IO ⁰C. The pH of the cooled solution was adjusted to 8-9 with aqueous sodium hydroxide (10%w/v) and further stirred for 30 minutes. The pH of the resulting mixture was again adjusted to 6-7 with hydrochloric acid (IN) and the product was extracted with dichloromethane (2x400ml). The organic layer was separated and subsequently washed with saturated solution of sodium bicarbonate (400ml) and brine (400ml). The organic layer was treated with activated , charcoal, solvent was distilled off and the title compound was crystallized in methyl tert-butyl ether to obtain 64.Og of the title compound having purity of 97.0% by HPLC. Example 2: Preparation of acetic acid 4-[4-(4-phenoxycarbonyIamino-phenyl)-piperazin-l- yl]-phenyl ester

Method A: To a solution of 4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl-carbamic acid phenyl ester (40g) and triethylamine (4Ig) in ΛζiV-dimethylformamide (400ml), acetylchloride (24.2g) was added at 0 °C-10 ⁰C. The resulting mixture was warmed to ambient temperature and stirred for 4-5 hours. After completion of reaction (monitored by TLC)₅ the reaction mixture was quenched with ice water (1200ml) and filtered to obtain 42.Og of the title compound having purity of 98.0% by HPLC.

Method B: To a suspension of acetic acid 4- [4-(4-amino-phenyl)-piperazin-l-yl] -phenyl ester (5g), triethylamine (3.2g) in toluene (100ml) and ΛζN-dimethylformamide (10ml), phenyl chloroformate (2.52g) was added at 10 ⁰C. The resulting mixture was stirred for 6-8 hours at same temperature and filtered to obtain 6.5g of the title compound having purity of 95.0% by HPLC.

Example 3: Preparation of 2-(2(S)-benzyloxy-l(S)-ethyl-propyl)~4-{4-[4-(4-hydroxy~ phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one To a stirred suspension of acetic acid 4-[4-(4-phenoxycarbonylamino-phenyl)-piperazin-l-yl]~ phenyl ester (2Og) in 1,2-dimethoxyethane (300ml), 2-[3-(2S,3S)-2-(benzyloxy)pentyl]formic acid hydrazide (14.7g) and triethylamine (5g) were added at ambient temperature. The resulting suspension was heated to 80 °C and stirred for 24 hours. To the resulting mixture toluene (300ml) was added and stirred for a period of 24 hours at 100 ⁰C-I lO ⁰C. After completion of reaction (monitored by TLC), solvent was removed by distillation and the resulting residue was dissolved in methanol (200ml) and the solution was cooled to 0 °C-10 ⁰C. The pH of the cooled solution was adjusted to 9-10 with aqueous sodium hydroxide (10% w/v) and further stirred. The pH of the resulting mixture was again adjusted to 6-7 with IN solution of hydrochloric acid and product was extracted with dichloromethane (2x400ml). The organic layer was separated and subsequently washed with saturated solution of sodium bicarbonate (300ml) and brine (300ml). The organic layer was treated with activated charcoal, distilled and the title compound is crystallized in methyl tert-butyl ether to obtain 22g of the title compound having purity of 98.0% by HPLC.

Example 4: Preparation of (-)-(5R-cis)-5-(2,4-difluoro-phenyl)-5-[(lH-l,2,4-triazole-l- yl)methyl]-tetrahyro-3-furanmethanol-4-chlorobenzene sulphonate a) Preparation of 4-(2,4-difluoro-phenyl)-pent-4-enoic acid: To a stirred suspension of methyltriphenylphosphonium bromide (668g) in tetrahydrofuran (1400ml), solution of sodium hexamethyldisilazane (35%, 850ml) in tetrahydrofuran was added at 20-30 ⁰C under nitrogen atmosphere. To the resulting suspension sodium hydride (35g) was added at 20-30 ⁰C. The resulting mixture was further stirred for 90 minutes at 45-50 ⁰C. The solution was cooled to -78 ⁰C and a solution of 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid (200 g) in tetrahydrofuran (600 ml) was added and stirring was continued for 1-2 hours at 0 ⁰C. The reaction mixture was slowly heated to 65-75 ⁰C and further stirred for 10-12 hours at the same temperature. After completion of reaction (monitored by TLC), the reaction was cooled to 10-20 ⁰C and quenched with methanol. The resulting mixture is diluted with an aqueous solution of citric acid and further stirred for 30 to 60 minutes. The so-formed mixture was extracted with ethyl acetate (1500ml). The organic layer was separated and distilled off to obtain an oily mass which was treated with aqueous potassium hydroxide (16% w/w) to adjust pH of reaction mass to 10-11. The aqueous layer was washed with dichloromethane (2x 1000ml) and ethyl acetate (1000ml) and thereafter treated with 5N hydrochloric acid to adjust pH of reaction mixture to 2-3. The resulting product was extracted with hexane (2x1500ml) and the combined organic layer was washed with brine. The solvent was removed to provide 16Og of the title compound as a white solid having purity of 99.0% by HPLC. b) Preparation of (4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-pent-4-enoyl]-oxazolidin-2-one: To a stirred solution 4-(2,4-difluorophenyl)-pent-4-enoic acid (150g) in dichloromethane (1500ml), triethylamine (146.6 g) was added at ambient temperature. The reaction mixture was cooled to 10 ⁰C and pivaloyl chloride (85 ml) was added dropwise raising the temperature to 20- 25 °C and stirred at the same temperature for 90 minutes. To the resulting solution (R)-benzyl-2- oxazolidinone (110.4g) and a mixture of 4-dimethyl amino pyridine (35.Ig) in N,N- dimethylformamide (56.1ml) was added at ambient temperature. The resulting mixture was warmed to 45-50 °C and stirred for 4-5 hours at the same temperature. After completion of reaction (monitored by TLC), reaction mass was cooled and quenched with sulfuric acid (2%, 500 ml). The organic layer was separated and subsequently washed with hydrochloric acid (IN, 500 ml) and sodium hydroxide (2 N, 500 ml). The organic layer was separated and distilled off to obtain a residue which was further treated with a mixture of activated carbon, silica gel in diisopropyl ether, stirred for 30 minutes and filtered. The solvent was removed to obtain 21Og of the title compound having purity of 98.0% by HPLC. c) Preparation of (-)(2R)-(4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-2-hydroxymethyl-pent-4- enoyl]-oxazolidin-2-one: To a stirred solution of (4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-pent- 4-enoyl]-oxazolidin-2-one (21Og) in dichloromethane (1730 ml), titanium tetrachloride (108 ml) followed by titanium isopropoxide (159 ml) was added drop wise at -5 to 0 ⁰C. To the resulting solution triethylamine (114g) was added slowly in 60 minutes while maintaining the temperature at 0 °C, the mixture was heated at 14-15 ⁰C and further stirred for 60 minutes. The reaction mixture was cooled to 0 °C and a solution of 1,3,5-trioxane (103 g) in dichloromethane (250ml) was added at same temperature. To the resulting mixture titanium tetrachloride (171ml) was added while maintaining the temperature below -10 ⁰C and further stirred to obtain a clear solution. After completion of reaction (monitored by TLC), reaction mass was quenched with aqueous ammonium chloride solution. The organic layer was separated and washed with saturated ammonium chloride solution then treated with activated carbon and silica gel. The organic layer was filtered and solvent was removed to obtain 24 Ig of the title compound. d) Preparation of (-)(5R-cis)-(4R)-4-benzyl-3-[5-(2,4-difluorophenyl)-5-(iodomethyl)tetra hydro-furan-3-carbonyl]~oxazolidin-2-one: To a stirred solution of (-)(2R)-(4R)-4-benzyl~3- [4-(2,4-difluorophenyl)-2-hydroxymethyl-pent-4-enoyl]-oxazolidin-2-one (24Ig) in acetonitrile (2410 ml), iodine pellets (346 g) were added at ambient temperature. To the resulting mixture pyridine (108 ml) was added dropwise in 60 minutes while maintaining the temperature at 0 ⁰C, the reaction mixture was heated to ambient temperature and stirred for 5 hours. After completion of reaction (monitored by TLC), reaction mass was cooled and quenched with of sodium thiosulfate (35%w/v, 2000 ml). The product was extracted with diisopropyl ether (1800ml) and subsequently washed with demineralized water (1000ml) and hydrochloric acid (IN, 1000 ml). The organic layer was separated and dried over sodium sulfate. The solvent was evaporated to obtain a solid residue. The solid residue was dissolved in ethanol (720ml) and stirred for 5 hours. The resulting mixture was cooled, filtered and washed the compound with ethanol to obtain lOOg of the title compound as a white solid having purity of 99.0% by HPLC. e) Preparation of (-)(5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furan methanol: To a stirred solution of (-)(5R-cis)-(4R)-4-benzyl-3-[5-(2,4-difluorophenyi)-5- (iodomethyl)tetrahydro-furan-3-carbonyl]-oxazolidin-2-one (10Og) in tetrahydrofuran (700 ml) and ethanol (300ml), lithium borohydride (458 ml) was added_^dropwise for a period of one hour at -5 to 0 °C. The resulting slurry was stirred for 2-3 hours at the same temperature. After completion of reaction (monitored by TLC), reaction mass was cooled and quenched with saturated ammonium chloride solution. The product was extracted with diisopropyl ether (2x500ml) and subsequently washed with demineralized water (500ml) and brine. The organic layer was separated and solvent was evaporated to provide a solid residue. The solid residue was dissolved in diisopropyl ether (550ml) and stirred for 1 hour at 0 ⁰C and thereafter filtered. The solvent was evaporated to obtain 7Og of the title compound as a white solid having purity of 97.0% by HPLC. f) Preparation of (-)-(5R-cis)-5-(2,4-difluoro-phenyl)-5-[(lH-l,2,4-triazole-l-yl) methyl]- tetrahyro-3-furanmethanoI: To a solution of (-)(5R-cis)-5-(2,4-difluorophenyl)-5- (iodomethyl)tetrahydiO-3-furanmethanol (7Og) in ΛζiV-dimethylformamide (700 ml), 1,2,4- sodium triazole (9Og) and l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (17.7 ml) were added at ambient temperature. The resulting mixture was heated to 100 °C and stirred for 24 hours. After completion of reaction (monitored by TLC),the reaction mass was cooled and quenched with demineralized water. The product was extracted with dichloromethane (2x500ml). The organic layer was treated with 6N hydrochloric acid (400 ml). The layers were separated and pH of the aqueous layer is adjusted to 8-9 with aqueous sodium hydroxide (50% w/v). The product from aqueous layer was extracted with ethyl acetate (2x500ml) and subsequently organic layer was washed with brine and dried over sodium sulfate. The solvent was removed to obtain 42g of the title compound. g) Preparation of (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4-triazole-l-yI)methyI]- tetrahyro-3-furanmethanol-4-chlorobenzene sulphonate: To a solution of (-)-(5R-cis)-5-(2,4- difluorophenyl)-5-[(lH-l,2,4-triazole-l-yl) methyl] -tetrahyro-3-furanmethanol (42g) in dichloromethane (420ml), 4-dimethylamino pyridine (30g) was added. The reaction mixture was cooled to 0 °C and 4-chlorobenzenesulfonylchloride (44.77g) was added while maintaining the temperature at 0-5 °C. The resulting mixture was stirred for 3 hours at ambient temperature. After completion of reaction (monitored by TLC), reaction mass was washed with (2x300ml) of 5N solution of hydrochloric acid and saturated solution of sodium bicarbonate (300ml). The organic layer was separated and dried over sodium sulfate. The solvent was evaporated and the residue was dissolved in ethanol (300ml) and stirred for 4 hours. The resulting mixture was cooled, filtered and washed with ethanol to obtain 33.6g of the title compound as a white solid having purity of 99.90% by HPLC. Example 5: Preparation of posaconazole a) Preparation of (lS)-(2S)-2-(l-ethyI-2-hydroxy-propyl)-4-{4-[4-(4-hydroxy-phenyl)- piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one: 2-(2(S)-Benzyloxy-l-ethyl-propyl)- 4- {4-[4-(4-hydroxy-phenyl)-piperazin- 1 -yl] -phenyl} -2,4-dihydro- [ 1 ,2,4]triazol-3-one (3 Og) was taken in 5N hydrochloric acid (60 ml) in methanol (300ml), and was hydrogenated for 2-3 hours under a hydrogen pressure of 4 kg/cm² at 50 °C in the presence of palladium on carbon (10%, 3g). After completion of reaction (monitored by TLC), the catalyst was filtered off and catalyst was washed with methanol (60 ml). The combined filtrate was concentrated and the resulting mass was dissolved in ethyl acetate (600ml) and refluxed for 1 hour. The resulting mixture was cooled, filtered to obtain 26g of the title compound having purity of 98.0% by HPLC. b) Preparation of posaconazole: To a stirred solution of (lS)-(2S)-2-(l-ethyl-2-hydroxy-. propyl)-4- {4- [4-(4-hydroxy-phenyl)-piperazin- 1 -yl] -phenyl} -2,4-dihydro- [ 1 ,2,4]triazol-3 -one obtained above in dimethylsulfoxide (140ml), a solution of sodium hydroxide (5.15g) in water was added at ambient temperature and stirred for 15 minutes. The reaction mixture was cooled to 10 ⁰C and (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4-triazole-l-yl)methyl]-tetrahyro-3- furanmethanol-4-chlorobenzenesulphonate (30.0 g) was added. The temperature of the reaction mass was raised to 35-40 °C with stirring for 10-12 hours. To the resulting solution, water was added dropwise and further stirred for 60 minutes. The resulting mixture was filtered to obtain 36.4 g of the crude title compound as a white solid having purity of 97.0% by HPLC. The crude posaconazole was taken in methanol (360ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (50ml) and dried to obtain 32g of the title compound having purity of 99.5% by HPLC.

Example 6: Preparation of posaconazole a) Preparation of (lS)-(2S)-2-(l-ethyl-2-hydroxy~propyl)-4-{4-[4-(4-hydroxy-phenyl)- piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one: (lS)-(2S)-2-(2-benzyloxy-l-ethyl- propyl)-4- {4- [4-(4-hydroxy-phenyl)-piperazin- 1 -yl]-ρhenyl} -2,4-dihydro-[ 1 ,2,4]triazole-3 -one (6.5g) was taken in 5N hydrochloric acid (13ml) in methanol (65ml) and was hydrogenated for 2-3 hours under a hydrogen gas pressure of 4 kg/cm² at 50 °C in the presence of palladium on carbon (10%, 0.65g). After completion of reaction (monitored by TLC), the catalyst was filtered off and washed with methanol (15ml). The combined filtrate was concentrated to obtain .a residue. Residue was dissolved in ethyl acetate (65ml) and refluxed for 1 hour. The resulting mixture was cooled, filtered to obtain 5.3g of the title compound as a white solid having purity of 98.0% by HPLC. b) Preparation of posaconazole: To a stirred solution of (lS)-(2S)-2-(l-ethyl-2-hydroxy- propyl)-4- {4- [4-(4-hydroxy-phenyl)-piperazin- 1 -yl] -phenyl} -2,4-dihydro-[ 1 ,2,4]triazol-3 -one (5g) in isopropyl alcohol (50ml), a solution of sodium hydroxide (1.44g) in water was added at ambient temperature and stirred for 15 minutes. To the resulting mixture (-)-(5R-cis)-5-(2,4- difluoro-phenyl)-5 - [( 1 H- 1 ,2,4-triazole- 1 -yl)methyl] -tetrahyro-3 -furanmethanol-4-chloro- benzene sulphonate (6.5g) was added, raising the temperature to 70-80 °C and stirred at the same temperature for 6-7 hours. The resulting mixture was cooled, filtered to obtain 7.5g of the title compound as a white solid having purity of 97.0% by HPLC.

Purification: The crude posaconazole (7.5g) was taken in methanol (75ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (15ml) and dried to obtain 6g of posaconazole having purity of 99.5% by HPLC. Example 7: Preparation of benzyl ether of posaconazole

To a stirred solution of (lS)-(2S)-2-(2-benzyloxy-l-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)- piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazole-3-one (1Og) in dimethylsulfoxide (100ml), a solution of sodium hydroxide (1.3g) in water (5ml) was added at ambient temperature and stirred for 15 minutes. To the resulting mixture (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4- triazole-1-yl) methyl] -tetrahyro-3 -furanmethanol-4-chlorobenzene sulphonate (10.0 g) was added, raising the temperature to 35-45° C and stirred at the same temperature for 10-12 hours. To the resulting solution water was added and stirred for 60 minutes. The resulting mixture was filtered to obtain 12.5g of the title compound having purity of 97.0% by HPLC. Example 8: Preparation of posaconazole Benzyl ether of posaconazole (12.5g) was taken in 5N hydrochloric acid (25ml) in methanol (125ml), and was hydrogenated for 4-5 hours under a hydrogen gas pressure of 4 kg/cm² at 50 °C in the presence of palladium on carbon (10%, 1.2g). After completion of hydrogenation (monitored by TLC), the catalyst was filtered off and washed with methanol (25ml). The combined filtrate was concentrated to obtain a residue. Residue was dissolved in tert. butanol (250ml) and pH of the reaction mixture was adjusted to 6-7 with 4N sodium hydroxide solution to give 1Og of crude title compound having purity of 93.5% by HPLC.

Purification: Crude posaconazole obtained above was taken in methanol (100ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (20ml) and dried at 50 °C to obtain 7g of the title compound having purity of 99.5% by HPLC.

Claims

WE CLAIM

1. A process for the preparation of highly pure posaconazole of formula I,

Formula I which comprises: a), debenzylating compound of formula II,

Formula II using mineral acid in an organic solvent in the presence of noble metal catalyst under hydrogen gas pressure to prepare compound of formula III;

Formula III b). condensing the compound of formula III with compound of formula IV,

Formula IV wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl, p- toluenesulfonyl, methanesulfonyl and the like . in the presence of suitable base and organic solvent; c). isolating posaconazole; and d). optionally purifying posaconazole.

2. The process according to claim 1, wherein in step a) the mineral acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid and the like.

3. The process according to claim 1, wherein in step a) noble metal catalyst is selected from platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide and the like.

4. The process according to claim 1, wherein in steps a) and b), the organic solvent is selected from C₁-C₄ branched or linear aliphatic alcohols, dimethylformamide, dimethylsulfoxide or a mixture thereof.

5. The process according to claim 1, wherein in step b), the base is selected from alkali or alkaline earth metal hydroxides, hydrides- or carbonates like sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, calcium carbonate.

6. A process for the preparation of a compound of formula II, comprises: a. acetylating 4- [4-(4-nitro-phenyl)-piperazin-l-yl] -phenol with a reagent of formula R⁵C(O)X, wherein R ' represents straight, branched, substituted or unsubstituted Cj-Cg alkyl or substituted or unsubstituted phenyl and X represents halogen, to give compound of formula V;

Formula V wherein R ' is as defined above b. reducing compound of formula V using a noble metal catalyst in an organic solvent, under hydrogen pressure to give amine derivative of formula VI;

Formula VI wherein R ' is as defined above c. condensing compound of formula VI with substituted or unsubstituted phenyl chloroformate in the presence of a tertiary amine base such as triethylamine in a suitable solvent to afford a novel and key intermediate of formula VII;

Formula VII wherein R ' is as defined above and R " is independently selected from the group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, acetoxy, N(CHs)₂, phenyl, phenoxy, benzyl, benzyloxy, NO₂, CHO, CHiCH(OH), acetyl, ethylene dioxy and the like d. reacting the compound of formula VII with a compound of formula VIII,

Formula VIII wherein Z is selected from -CHO; or -C(O)OC(CH₃) ₃; or -C(O)OCH₂C₆H₅ in the presence of tertiary amine base in an inert solvent to afford the compound of formula IX; and

Formula IX wherein R ' is as defined above e. hydrolyzing the compound of formula IX using a base to afford the compound of formula

II.

7. The process according to claim 6, wherein in step b) noble metal catalyst is selected from platinum, palladium, rhodium, ruthenium and the like; organic solvent is selected from polar aprotic or polar protic solvent in combination with water.

8. The process according to claim 6, wherein in step c) suitable solvent is selected from polar aprotic solvent, a non polar solvent like ΛζiV-dimethylformamide, toluene or mixture thereof.

9. The process according to claim 6, wherein in step d) solvent is selected from 2- dimethoxyethane, diethyl ether or tetrahydrofuran.

10. The process according to claim 6, wherein in step e) base is alkali metal hydroxide.

11. A process for the preparation of posaconazole of formula I , comprises: a. preparing compound of formula II according to claim 6; and b. converting compound of formula II to posaconazole of formula I.

12. A compound of formula VI,

Formula VI wherein R' represents straight, branched, substituted or unsubstituted Ci-Ce alkyl or substituted or unsubstituted phenyl.

13. A compound of formula VII,

Formula VII wherein R ' represents straight, branched, substituted or unsubstituted Ci-Ce alkyl or substituted or unsubstituted phenyl and R" is independently selected from the group consisting of H, lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH₂, CN, acetoxy, N(CHs)₂, phenyl, phenoxy, benzyl, benzyloxy, NO₂, CHO, CHiCH(OH), acetyl, ethylene dioxy.

14. A compound of formula IX,

Formula IX wherein R ' represents straight, branched, substituted or unsubstituted Ci-Ce alkyl or substituted or unsubstituted phenyl.

15. A process for the preparation of posaconazole of formula I which comprises: a. reacting 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid of formula X₅

Formula XIV wherein Q* is as defined above and X is selected from halogen such as iodo, chloro, bromo and the like f. purifying the compound of formula XIV with C₁-C₄ linear or branched alcoholic solvents, C₂-C₈ linear or branched ethers and mixtures thereof; g. reducing the compound of formula XIV with suitable reducing agent in an organic solvent to afford compound of formula XV;

Formula XV wherein X is as defined above h. condensing the compound of formula XV with alkali metal triazole in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone in polar aprotic solvent such as N₁N- dimethylformamide and the like to afford a compound of formula XVI;

Formula XVI i. reacting the compound of formula XVI with a reagent having a suitable leaving group in a suitable solvent in presence of a base to afford a compound of formula IV;

Formula IV wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl, p- toluenesulfonyl, methanesulfonyl and the like j. purifying the compound of formula IV; and k. converting the compound of formula IV to posaconazole.

16. The process according to claim 15, wherein in step a) base is alkali metal hydride such as sodium hydride, lithium hydride, potassium hydride and the like.

17. The process according to claim 15, wherein in step c) activating agent is selected from oxalyl chloride, thionyl chloride, carbonylditriazole or oxalylditriazole, pivaloyl chloride and the like; and tertiary amine base is triethylamine and the like.

18. The process according to claim 15, wherein in step c) inert solvent is selected from N₁N- dimethylformamide, N,iV-dimethylacetamide, dimethylsulfoxide or mixture thereof.

19. The process according to claim 15, wherein in step d) tertiary amine base such as triethylamine, diisopropylamine and the like.

20. The process according to claim 15, wherein in step e), amine base is pyridine and the like.

21. The process according to claim 15, wherein in step e), suitable inert solvent is selected from acetonitrile, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof.

22. The process according to claim 15, wherein in step g), reducing agent is selected from hydride reducing agent; and organic solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof.

23. The process according to claim 15, wherein step i) reagent is selected from p- chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and the like and base is selected from 4-dimethyl amino pyridine, pyridine or triethylamine.

24. The process according to claim 15, wherein in step i), solvent is selected from halogenated hydrocarbons, aliphatic esters; tetrahydrofuran, toluene and mixtures thereof.

25. The process according to claim 15, wherein in step j) purification is carried out by recrystallization from solvent selected from ethers, C₁-C₄ alcohols, C₃-C₇ linear, branched and cyclic alkanes or mixtures thereof.

26. A process for the preparation of posaconazole of formula I which comprises: a), debenzylating the benzyl ether of posaconazole of formula XVII,

Formula XVII using mineral acid in an organic solvent in the presence of a noble metal catalyst under hydrogen gas pressure to prepare posaconazole; b). optionally purifying posaconazole; and c). isolating highly pure posaconazole there from.

27. The process according to claim 26, wherein step a) the mineral acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; noble metal catalyst is Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper- chromium oxide, etc., and the like; and organic solvent is selected from C₁-C₄ branched or linear aliphatic alcohols, dimethylformamide, dimethylsulfoxide or a mixture thereof.

28. The process according to claim 26, wherein in step b) purification is carried out by recrystallization using suitable solvent selected from C₁-C₄ alcohol such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol, acetonitrile, acetone, water and mixtures thereof.