TECHNICAL FIELD

The invention relates to a process for preparation of itraconazole. More particularly  invention relates to an improved process for preparation of Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro -2-(1-methyl- propyl)-3H-l 2 4-triazol-3-one  commonly known as itraconazole and represented by compound of formula-A. The improved process of the invention comprises condensation of hydroxyl derivative with mesylate derivative or tosyl derivative in a biphasic organic/water medium or in aqueous medium.

BACK GROUND OF THE INVENTION

Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one  commonly known as itraconazole  a broad-spectrum antifungal agent is a heterocyclic triazole derivative and can be used through different routes of administration like oral  parenteral or topical. The first itraconazole compound was disclosed by Janssen Pharmaceuticals in U.S. Pat. No.4 267 179.

US Patent No. 5 998 413 discloses the synthesis of itraconazole and four cis isomeric forms of itraconazole and a process of synthesizing the same by condensing Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate and 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one in DMF or N N-Dimethyl acetamide and in presence of a base such as sodium or potassium hydroxide. This patent also discloses purification of itraconazole in methanol.

WO2011/121594 A1 discloses a process for the preparation of itraconazole which comprises condensing Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one in the presence of DMSO  DMF  dimethyl acetamide and a base like sodium hydroxide  potassium hydroxide  sodium carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate  potassium tert-butoxide  triethyl amine and diisopropyl amine. This patent also disclosed the purification of itraconazole in a mixture of dimethylformamide  acetone and methanol.

Therefore  as described above  various efforts of preparation and purification of itraconazole have been made in the prior art which comprise condensing Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one to prepare itraconazole.

However  methods disclosed in the prior art have limitations for large scale industrial use such as the itraconazole produced by the disclosed methods has comparatively high amount of impurities therefore  these methods require several purification steps  the quantity of effluents is comparatively high and the product yield is less  making the prior art methods complicated  costly and time taking.

OBJECTS OF THE INVENTION

Primary object of the invention is to provide an improved process for preparation of Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy] phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (itraconazole).

Another object of the invention is to provide a process for preparation of itraconazole with enhanced product yield and purity.

Another object of the invention is to provide a process for preparation of itraconazole with low effluent and less purification steps.

A further object of the invention is to provide a cost effective and simplified process for preparation of itraconazole.

SUMMARY OF THE INVENTION

Accordingly  there is provided an improved process for preparation of Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperaz-inyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (itraconazole) represented by compound of formula-A.

The process comprises condensation of hydroxyl derivative (compound C) with mesylate derivative (compound B) or tosyl derivative (compound E) in a biphasic medium or in aqueous medium  followed by slurrying and purification of the crude product to obtain purified itraconazole compound of formula-A.

The itraconazole compound of formula-A can be prepared in four possible stereo isomeric cis forms by the process of the invention.

In one embodiment  the invention provides a process for preparation of pure itraconazole of formula-A in a biphasic medium comprising:

a). condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) in presence of a base and a phase transfer catalyst (PTC) in an inert organic solvent in a biphasic condition (inert organic solvent + water) to obtain wet title compound;

b). slurrying the wet title compound obtained above in methanol or in a mixture of methanol and dimethylformamide (DMF) to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4 -dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (compound D);

c). Purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-yl methyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl -propyl)-3H-l 2 4-triazol-3-one obtained above in the presence of halogenated hydrocarbons and an alcoholic solvent to obtained pure itraconazole compound of formula-A.

In another embodiment  the invention provides a process for preparation of pure itraconazole of formula-A in an aqueous medium comprising:

a). condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) in presence of a base and a phase transfer catalyst (PTC) in aqueous medium without using any organic solvent in the reaction to get the title compound;

b). slurrying the wet title compound obtained above in methanol or in a mixture of methanol and dimethylformamide (DMF) to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (compound D);

c). purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-meth yl-propyl)-3H-l 2 4-triazol-3-one obtained above in the presence of halogenated hydro carbons and an alcoholic solvent to obtained pure itraconazole compound of formula-A.

In another embodiment  the invention provides a process for preparation of pure itraconazole of formula-A in an organic medium comprising:

a). condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperzinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) in presence of a base and a phase transfer catalyst (PTC) in an inert organic solvent to obtain wet title compound;

b). slurring the wet title compound obtained above in methanol or in a mixture of methanol and dimethylformamide (DMF) to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (compound D);

c). purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-meth yl-propyl)-3H-l 2 4-triazol-3-one obtained above in the presence of halogenated hydro carbons and an alcoholic solvent to obtained pure itraconazole compound of formula-A.

The process is represented in below scheme:

Wherein  mesylate derivative (compound B) in the above scheme can be replaced with tosyl derivative (compound E) represented below-

Compound E
DETAILED DESCRIPTION OF THE INVENTION
Detailed embodiments of the present invention are disclosed hereinafter in following paragraphs. However  it is to be understood that the disclosed embodiments are merely exemplary of the invention  which can be embodied in various forms. Therefore  specific structural and functional details disclosed herein are not to be interpreted as limiting  but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Further  the terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention.

An improved process for preparation of Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-meth yl-propyl)-3H-l 2 4-triazol-3-one (itraconazole) represented by compound of formula-A is described hereinafter in following paragraphs.

The process comprises condensation of hydroxyl derivative (compound C) with mesylate derivative (compound B) or tosyl derivative (compound E) in a biphasic medium or in aqueous medium  followed by slurrying and purification of the crude product to obtain purified itraconazole compound of formula-A.

The invention provides a process wherein four possible stereo isomeric cis forms of the itraconazole depicted by compound of formula-A can be prepared.

The process is represented in below scheme and described hereinafter in following paragraphs.

Wherein  mesylate derivative (compound B) in the above scheme can be replaced with tosyl derivative (compound E) represented below-

Compound E
The process comprises condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzene sulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl] phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one (compound C) to obtain wet title compound-A. Slurry of the obtained wet compound is made in aqueous  organic or biphasic (aqueous/organic) medium to obtain crude compound D. The crude compound is then purified to obtain pure itraconazole.

In one embodiment  the invention provides a process for preparation of pure itraconazole of formula-A in a biphasic medium comprising:

a). condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) in the presence of a base and a phase transfer catalyst (PTC) in an inert solvent in a biphasic condition (inert organic solvent + water) to obtain wet title compound;

b). slurrying the wet title compound obtained above in methanol or in a mixture of methanol and dimethylformamide (DMF) to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (compound D);

c). purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-yl methyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl -propyl)-3H-l 2 4-triazol-3-one obtained above in the presence of halogenated hydrocarbons and an alcoholic solvent to obtain pure itraconazole compound of formula-A.

In another embodiment  the invention provides a process for preparation of pure itraconazole of formula-A in an aqueous medium comprising:

a). condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) in presence of a base and a phase transfer catalyst (PTC) in an aqueous medium without using any organic solvent in the reaction to get the title compound;

b). slurring the wet title compound obtained above in methanol or in a mixture of methanol and dimethylformamide (DMF) to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4 -dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (compound D);

c). purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-yl methyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl -propyl)-3H-l 2 4-triazol-3-one obtained above in the presence of halogenated hydrocarbons and an alcoholic solvent to obtain pure itraconazole compound of formula-A.

In another embodiment  the invention provides a process for preparation of pure itraconazole of formula-A in an inert organic medium comprising:

a). condensation of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) in presence of a base and a phase transfer catalyst (PTC) in an inert organic solvent to obtain wet title compound;

b). slurrying the wet title compound obtained above in methanol or in a mixture of methanol and dimethylformamide (DMF) to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl -propyl)-3H-l 2 4-triazol-3-one (compound D);

c). purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-yl methyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl -propyl)-3H-l 2 4-triazol-3-one obtained above in the presence of halogenated hydrocarbons and an alcoholic solvent to obtain pure itraconazole compound of formula-A.

The phase transfer catalyst (PTC) in any or all the processes described above may be selected from tetra butyl ammonium bromide (TBAB)  benzyl trimethyl ammonium chloride and hexadecyltributyl phosphonium bromide  and the like.

In one preferred embodiment of the invention  the phase transfer catalyst is tetra butyl ammonium bromide (TBAB). The catalyst (TBAB) may be used in an amount of 0.015 to 0.062 equivalents per equivalent of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one.

The base in any or all the processes described above may be selected from sodium hydroxide  sodium hydride  potassium hydroxide  sodium carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate  potassium tert-butoxide  triethyl amine  diisopropyl amine and the like.

In one preferred embodiment of the invention  the base is sodium hydroxide.

The base is used in an amount of 0.75 to 1.5 equivalents per equivalents of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one.

The inert organic solvent in any or all the processes described above may be selected from inert solvents such as toluene  xylene  n-hexane  n-heptane  cyclohexane and the like.

In one preferred embodiment of the invention  the inert solvent is toluene.

The halogenated hydrocarbons in any or all the processes described above may be selected from methylenedichloride  ethylene dichloride  chloroform and the like.
In one preferred embodiment of the invention  the halogenated hydrocarbon is methylenedichloride.

The alcoholic solvents for purification may be selected from methanol  ethanol and propanol and the like.

In one preferred embodiment of the invention  the alcoholic solvent used for purification is methanol.

The condensation step in any or all the processes described above may be conducted at a temperature of about 700C to 1000C.

In one preferred embodiment of the invention  the reaction is carried out at a temperature in between 85-900C. In an exemplary embodiment the condensation reaction is carried out for a period of 2-3 hours at temperature between 85-900C.

In one embodiment of the invention  when condensation reaction is performed in biphasic medium  after completion of the condensation reaction at temperature about 85-900C  the water and inert organic solvent layer are separated at the same temperature.

The inert organic solvent layer is slowly cooled to 25-300 and solid precipitates are obtained in the reaction mixture. The precipitated solid is filtered and washed with fresh toluene to get the wet title compound.

The wet compound may be slurred either in methanol or in a mixture of methanol and dimethylformamide (DMF) combination to obtain crude itraconazole compound of formula (D).

In an exemplary embodiment of the invention  the purification in any or all the processes described above is done with halogenated hydrocarbon  activated carbon and alcoholic solvent at 25-650 C to obtain pure cis-itraconazole of formula-A.

It was observed that 4-[4-[4-[4[[cis-2-(2 4-dichlorophenyl)-2-(4H-1 2 4]triazol-4-ylmethyl)-1 3-dioxolan-4-yl]methoxy]-phenyl]piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2 4-dihydro-3H-1 2 4-triazol-3-one was generated as impurity-B when condensation reaction was performed in strong basic conditions at higher temperatures (reflux temp) and when more than 1.10 equivalents of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl] methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) per 1.0 equivalent of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) were used. Impurity-B formation was identified using High Performance Liquid Chromatography (HPLC).
The formation of this impurity-B may be avoided by using 1.06 to 1.10 mole ratio of methanesulfonic acid Cis-2-(2 4-dichlorophenyl)-2-[1 2 4]-triazol-1-ylmethyl-[1 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) per 1.0 mole ratio of 2-sec-Butyl-4-{4-[4-(4-hydroxyphenyl)-piperazin-1-yl]phenyl}-2 4-dihydro-[1 2 4]triazol-3-one (compound C) in the final condensation step.

If more than 1.10 mole equivalents of Cis-mesylate or tosyl derivative were used in the condensation reaction  the impurity–B percentage was more than 0.1% in the final API. Due to this  to remove the impurity-B in the final API need more slurry was required in a combination of methanol and DMF.

Whereas  if less than 1.06 mole equivalents of Cis-mesylate or tosyl derivative were used in the process to reduce the impurity-B  some of the 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C) remains unreacted in the reaction medium. The unreacted compound-C also leads to the impurity in the final API.

Therefore  it was observed the most suitable range of Cis-2-(2 4-dichlorophenyl)-2-[1 2 4]-triazol-1-ylmethyl-[1 3-dioxolan-4-yl]methyl methanesulfonate (compound B) or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E) to obtain the purest form of itraconazole with minimum impurity is 1.06 to 1.10 mole equivalents of compound B or compound E per 1.0 mole equivalents of 2-sec-Butyl-4-{4-[4-(4-hydroxyphenyl)-piperazin-1-yl]phenyl}-2 4-dihydro-[1 2 4]triazol-3-one (compound C).

The compound Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (itraconazole) obtained as impurity B  represented by formula-1 was removed from the final compound by slurring in a mixture of DMF/methanol or DMF to reach the API specification.

The invention is further described in following examples  which are mere exemplary  and not limiting to the scope of the claims.

Example: 1

Preparation of crude itraconazole in biphasic medium:
100.0g (0.254mmol) of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one and TBAB (5.0g  0.015mmol) were dissolved in toluene (750.0 mL) and sodium hydroxide solution (30.0g in 100.0 mL of water) was added drop wise over a period of 30-40 minutes at 25-300 C and reaction mixture was stirred for 30 minutes at same temperature. Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (110.0g  0.269 mmol) was added in the reaction mixture and the reaction mixture was slowly heated to 85-900C in water bath for 2-3 hours. The progress of the reaction was monitored either by TLC (or) HPLC. After completion of the reaction  aqueous layer was separated at 85-900 C and organic layer was cooled to 25-300C. While cooling the organic layer  solid product precipitated from the reaction mass. The precipitated compound was filtered and washed with methanol (60.0 mL). The obtained wet compound was slurred in a mixture of methanol (400.0 mL) and DMF (100.0 mL) to get the crude itraconazole.
Dry weight: 172.0 g.

Example: 2

Preparation of crude itraconazole in an aqueous medium:
40.0g (0.101mmol) of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one and TBAB (2.0 g  0.006 mmol) was dissolved in lye solution (12.0 g NaOH in 120.0 ml of purified water) and stirred at 25-300C for 30 minutes. Then Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (44.0g  0.107mmol) was added and the reaction mixture was slowly heated to 85-900 C in water bath for 2-3 hours. The progress of the reaction was monitored either by TLC (or) HPLC. After completion of reaction  reaction mass was cooled to 25-300C  and the precipitated compound was filtered. The filtered compound was washed with methanol (100.0 mL). Obtained wet compound was slurred either in methanol (200.0 mL) (or) in a mixture of methanol (100.0 mL) and DMF (100.0 mL) to get crude itraconazole.
Dry weight: 69.0 g.

Example-3

Preparation of crude itraconazole in an aqueous medium:
40.0g (0.101mmol) of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one and TBAB (2.0 g  0.006 mmol) was dissolved in lye solution (12.0 g NaOH in 120.0 ml of purified water) and stirred at 25-300C for 30 minutes. Then Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (46.0g  0.112mmol) was added and the reaction mixture was slowly heated to 85-900 C in water bath for 2-3 hours. The progress of the reaction was monitored either by TLC (or) HPLC. After completion of reaction  reaction mass was cooled to 25-300C  and the precipitated compound was filtered. The filtered compound was washed with methanol (100.0 mL). Obtained wet compound was slurred in a mixture of methanol (100.0 mL) and DMF (100.0 mL) to get crude itraconazole.
Dry weight: 67.0 g

Example: 4

Preparation of crude itraconazole in biphasic medium:
5.0g (0.0127mmol) of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one and TBAB (0.25g  0.0007mmol) were dissolved in toluene (37.5 mL) and sodium hydroxide solution (1.5g in 5.0 mL of water) was added drop wise over a period of 5-10 minutes at 25-300 C and reaction mixture was stirred for 30 minutes at same temperature. 6.46g  (0.0133mmol) of ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate was added in the reaction mixture and the reaction mixture was slowly heated to 85-900C in water bath for 3-4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction  aqueous layer was separated at 85-900 C and organic layer was cooled to 25-300C. While cooling the organic layer  solid product precipitated from the reaction mass. The precipitated compound was filtered and washed with methanol (60.0 mL). The obtained wet compound was slurred in a mixture of methanol (400.0 mL) and DMF (100.0 mL) to get the crude itraconazole.
Dry weight: 6.5 g.

Example: 5

Preparation of crude itraconazole in an aqueous medium:
5.0g (0.0127mmol) of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one and TBAB (0.25g 0.0007mmol) was dissolved in lye solution (1.5 g of NaOH in 15.0 ml of purified water) and stirred at 25-300C for 30 minutes. 6.46g  (0.0133mmol) of ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate was added and the reaction mixture was slowly heated to 85-900 C in water bath for 3-5 hours. The progress of the reaction was monitored by TLC. After completion of reaction  reaction mass was slowly cooled to 25-300C  and the precipitated compound was filtered. The filtered compound was washed with methanol (8.0 mL). Obtained wet compound was slurred in a mixture of methanol (10.0 mL) and DMF (10.0 mL) to get crude itraconazole.
Dry weight: 6.7 g.

Example-6

Purification of Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H -l 2 4-triazol-3-one

Crude itraconazole (172.0g) obtained from example 1 was dissolved in methylene dichloride (500.0 mL) at room temperature and activated carbon (4.0 g) was added in the reaction mass. The reaction mass was stirred for 10-20 minutes and filtered through hyflow bed and washed with methylenedichloride (60.0 mL). The filtered methylenedichloride was completely distilled under vacuum below 45-500C and co-distilled with methanol (200.0 mL). Fresh methanol (600.0 mL) was added and heated to 50-550C  then cooled to 25-300C and maintained at this temperature for 30-40 minutes. Solid product was filtered and washed with methanol (80.0 mL). The obtained product was dried at 60-700C to get pure cis-itraconazole.
Dry Weight: 168.0 g

We claim:
1. A process for preparation of Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl- propyl)-3H-l 2 4-triazol-3-one (itraconazole) of formula-A:

Comprising:
a). condensing Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate (compound B)

or  ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate (Compound E)

(E)

with 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C)

to obtain a wet compound;

b). slurrying the wet compound obtained in step (a) in an organic solvent to obtain crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl- propyl)-3H-l 2 4-triazol-3-one (compound D);

c). Purifying the crude Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-yl methyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl -propyl)-3H-l 2 4-triazol-3-one obtained above with a halogenated hydrocarbon compound in an alcoholic solvent to obtain pure itraconazole compound of formula-A.

2. A process as claimed in claim 1  wherein said condensation is done in presence of a base and a phase transfer catalyst (PTC) in a solvent.

3. A process as claimed in claim 2  wherein said base is selected from sodium hydroxide  sodium hydride  potassium hydroxide  sodium carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate  potassium tert-butoxide  triethyl amine and diisopropyl amine.

4. A process as claimed in claim 2  wherein said phase transfer catalyst (PTC) is selected from tetra butyl ammonium bromide (TBAB)  benzyltrimethylammonium chloride and hexadecyltributyl phosphonium bromide.

5. A process as claimed in claim 2  wherein said solvent is an inert organic solvent.

6. A process as claimed in claim 2  wherein said solvent is water.

7. A process as claimed in claim 2  wherein said solvent is a biphasic mixture of inert organic solvent and water.

8. A process as claimed in claims 5 or 7  wherein said inert organic solvent is selected from toluene  xylene  n-hexane  n-heptane and cyclohexane.

9. A process as claimed in claim 1  wherein said organic solvent for slurrying is methanol  or dimethylformamide (DMF) or a mixture of methanol and dimethylformamide (DMF).

10. A process as claimed in claim 1  wherein said halogenated hydrocarbon is selected from methylenedichloride  ethylene dichloride and chloroform.

11. A process as claimed in claim 1  wherein said alcoholic solvent used in purification is selected from methanol  ethanol and isopropanol.

12. A process as claimed in claim 1  wherein said purification is done with halogenated hydrocarbon  activated carbon and alcoholic solvent.

13. A process as claimed in claim 1  wherein 0.015 to 0.062 equivalents of said phase transfer catalyst (PTC) are used per 1.0 equivalent of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methyl propyl)-3H-1 2 4-triazol-3-one.

14. A process as claimed in claim 1  wherein in condensation step  1.06 to 1.10 mole equivalents of Cis-[2-(2 4-dichlorophenyl)-2-(lH-l 2 4-triazol-l-yl-methyl)-l 3-dioxolan-4-yl]methyl methanesulfonate or ((2S 4S)-2-((1H-1 2 4-Triazol-1-yl)methyl)-2-(2 4-dichlorophenyl)-1 3-dioxolan-4-yl)methyl-4-methyl-benzenesulfonate are used per 1.0 mole equivalents of 2-sec-Butyl-4-{4-[4-(4-hydroxyphenyl)-piperazin-1-yl]phenyl}-2 4-dihydro-[1 2 4]triazol-3-one.

15. A process as claimed in claim 3  wherein said base in condensation step is used in an amount of 0.75 to 1.5 equivalents per equivalent of 2 4-dihydro-4-[4-[4-[(4-hydroxyphenyl)-1-piperazinyl]phenyl]2-(1-methylpropyl)-3H-1 2 4-triazol-3-one (compound C).

16. A Cis-4-[4-[4-[4-[[2-(2 4-Dichlorophenyl)-2-(1H-1 2 4-triazol-1-ylmethyl)-1 3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2 4-dihydro-2-(1-methyl-propyl)-3H-l 2 4-triazol-3-one (itraconazole) compound of formula-A obtained from the process as claimed in claim 1.

Dated this the 30th day of May 2012.

Afzal Hasan
of HASAN AND SINGH
IN/PA-1328