FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF LULICONAZOLE"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivli (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of (2E)-[(4R)-4-(2,4-Dichlorophenyl)-l,3-dithiolan-2-ylidene](lH-imidazol-l-yl)acetonitrile represented by formula (I), commonly known as Luliconazole.
The process provides Luliconazole in higher yield and purity compared to the previously known processes.

BACKGROUND OF THE INVENTION
Luliconazole is an imidazole antifungal drug and is used as a topical cream for treatment of fungal infections of the skin.
U.S. Patent No. 5,900,488, hereinafter referred to as '488 patent, describes a method of preparation of Luliconazole by reacting compound of formula (B) with compound of formula (D), wherein X1 and X may be same or different and may be selected from a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogen atom; and M is an alkali metal.

The '488 patent exemplifies purification of Luliconazole using column chromatography followed by recrystallization using a mixture of ethylacetate and n-hexane. Column

chromatography, used for purification, makes the process more tedious, time consuming and commercially unviable.
The '488 patent also describes in example l-(b) a process for preparation of compound of formula (B) wherein, Xi is methanesulfonyloxy and X is bromine. The compound of formula (B) prepared therein is not purified before reacting with dithiolate, hence leading to lower purity levels of the compound of formula (B). Lower purity of compound of formula (B) may lead to lower purity levels in Luliconazole.
The process for preparation of Luliconazole described in the above patent suffers from the drawbacks like low purity levels of Luliconazole and/or intermediates thereof and use of a tedious process like column chromatography for purification.
Japanese Patent No. JPS6293204 discloses method for preparation of luliconazole of formula (I). The process involves reaction between l-(cyanomethyl)imidazole with CS2 in the presence of a base followed by cyclocondensation with XCHRCH2X (X = halo, MeSO3, p-MeC6H4SO3). Specifically, a mixture of 0.005 mol 1-(cyanomethyl)imidazole and 0.005 mol CS2 in dimethyl sulfate was allowed to react for 1 hr in the presence of powdered KOH and 0.006 g BrCH2CHBrCH2CHMe2 was added drop wise.
Chinese Publication No. 103044192 discloses preparation of luliconazole intermediate namely 2,4-dichloro-l-[(lS)-l,2-dichloroethyl]-benzene of formula (i) by reducing 2-chloro-l-(2,4-dichlorophenyl)-ethanone of formula (ii) to get 2-chloro-l-(2,4-dichlorophenyl) ethanol of formula (iii) followed by chlorination with oxalyl chloride to obtain 2,4-dichloro-l-(l,2-dichloroethyl) benzene.


Overall, the processes for preparation of Luliconazole and its intermediates described in various prior arts are not suitable for large scale production due to drawbacks discussed above. Therefore, there is a need for a simple, efficient and commercially viable process for preparation of Luliconazole and/or intermediates thereof with higher purity levels.
The present invention provides such an improved process for the preparation of Luliconazole and/or intermediates thereof, avoiding the above drawbacks.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of Luliconazole, a compound of formula (I), comprising

(a) converting (S)-l-(2,4-dichlorophenyl)-2-haloethanol, a compound of formula (A), to a compound of formula (B), wherein X1 is selected from the group consisting of methanesulfonyloxy, benzenesulfonyloxy and p-toulenesulfonyloxy; and X is a halogen;

(b) purifying a compound of formula (B) prepared in step (a);
(c) reacting cyanomethyl imidazole of formula (C) with carbon disulfide to prepare a dithiolate of formula (D), wherein M is an alkali metal; and


(d) reacting a compound of formula (B) obtained in step (b) with the dithiolate of formula (D) obtained in step (c) to prepare Luliconazole of formula (I), wherein Xi, X and M are as defined above.

Another object of the present invention is to provide an improved process for preparation of the Luliconazole intermediate represented by a compound of formula (B) from (S)-l-(2,4-dichlorophenyl)-2-halooethanol, a compound of formula (A), with higher purity levels.
Another object of the present invention is to provide an improved process for preparation of highly purified Luliconazole while avoiding the use of column chromatography.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of Luliconazole, a compound of formula (I), comprising

(a) converting (S)-l-(2,4-dichlorophenyl)-2-haloethanol, a compound of formula (A), to a compound of formula (B) wherein, Xi is selected from the group consisting

of methanesulfonyloxy, benzenesulfonyloxy and toulenesulfonyloxy; and X is a halogen;
(b) purifying a compound of formula (B) prepared in step
(a);
(c) reacting cyanomethyl imidazole of formula (C) with carbon disulfide to prepare a
dithiolate of formula (D), wherein M is an alkali metal; and
(d) reacting a compound of formula (B) obtained in step (b) with the dithiolate of formula (D) obtained in step (c) to prepare Luliconazole of formula (I), wherein Xi, X and M are as defined above.

from the group consisting of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.
In one embodiment, step (a) comprises converting the compound of formula (A) to a compound of formula (B) wherein, X1 is methanesulfonyloxy and X is chloro, by reacting the compound of formula (A) with methanesulfonyl chloride.
In one embodiment, the compound of formula (B) wherein, X1 is methanesulfonyloxy and X is chloro is (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate and represented by formula (Bl)

Step (a) may be performed in the presence of a suitable base and a suitable solvent.
The suitable base includes organic and inorganic bases. An organic base used includes, but is not limited, to primary, secondary or tertiary amines such as methylamine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine and the like. Inorganic base used, includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, caesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. Preferably, the base used in step (a) an organic amine, more preferably triethylamine.
The suitable solvent used in step (a) includes, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-

butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water; or mixtures thereof. Preferably the solvent selected a haloalkane, more preferably dichloromethane.
The reaction in step (a) may be carried out at a temperature of about 0°C to about 20°C optionally, under stirring. Preferably the reaction may be carried out at a temperature of about 0°C to about 15°C, more preferably at about 0°C to about 10°C. The temperature conditions of step (a) play an important role in the purity level of compound of formula (B). Such reaction conditions were unknown heretofore.
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-haloethanol, a compound of formula (A), with a sulfonic acid halide at a temperature of about 0°C to about 20°C, to obtain a compound of formula (B). In one embodiment, the sulfonic acid halide may be selected from the group consisting of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.

In one embodiment the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-haloethanol of formula (A) with a sulfonic acid halide at a temperature of about 0°C to about 20°C, in presence of triethylamine as base and dichloromethane as solvent, to obtain a compound of formula (B). In one embodiment, the sulfonic acid halide may be selected from the group consisting of methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride.

In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol of formula (Al) with methanesulfonyl chloride to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl).

In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol of formula (Al) with methanesulfonyl chloride in presence of triethylamine as base and dichloromethane as solvent, to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl).
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compound of formula (Al), with methanesulfonyl chloride, under stirring for about 1.5 - 3.5 hrs, at a temperature of about 0°C to about 10°C in presence of dichloromethane as solvent and triethylamine as base to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl).

After completion of the reaction in step (a), suitable work up may be performed, as known to a skilled artisan, to isolate the compound of formula (B) before purification. In one embodiment, water was added to the reaction mixture after completion of the

reaction and organic solvent layer, preferably dichloromethane layer, was separated and washed with water and dried. The product may be isolated by distillation of the solvent to get residue which may be further purified.
In one embodiment, the product obtained in step (a) may be purified by techniques known in the art such as crystallization, fractional crystallization, liquid-liquid extraction and the like.
The process exemplified in US'488 patent doesn't show purification of compound of formula (B). The present invention involves purification of compound of formula (B) in step (b) before further reaction.
In one embodiment, step (b) provides purification of the compound of formula (B), obtained in step (a) wherein X and X1 are as defined above, by a process comprising crystallization from a suitable solvent. The suitable solvent for purification includes, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; esters such as methyl acetate, ethyl acetate and the like; hydrocarbons such as hexane, cyclohexane, xylene and the like; water; or mixtures thereof. Preferably, the solvent selected for purification may be an alcohol, more preferably isopropanol.
In one embodiment, the purification in step (b) may involve dissolving compound of formula (B), obtained in step (a) wherein X and X1 are as defined above, in a suitable solvent preferably under heating followed by cooling the solution so obtained. The suitable solvent are as defined above. The step of dissolving the compound of formula (B), wherein X and Xi are as defined above, may be performed under heating, optionally under stirring, at a temperature of about 40°C to about 80°C, preferably at a temperature of about 50°C to about 70°C. The step of cooling the solution obtained upon dissolution of compound of formula (B) in a suitable solvent may involve cooling to about room temperature or to a temperature lower than room temperature, preferably cooling to a temperature of about 0°C to about 15°C.

In one embodiment, the present invention provides a process for purification of compound of formula (B), wherein X and X1 are as defined above, comprising crystallization from an alcohol, preferably isopropanol.
In one embodiment, the present invention provides a process for purification of compound of formula (B), wherein X and X1 are as defined above, comprising dissolving the compound of formula (B) in an alcohol at a temperature of about 50°C to about 70°C, followed by cooling to a temperature of about 0°C to about 15°C.
In one embodiment, the present invention provides a process for purification of (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate of formula (Bl) comprising crystallization from an alcohol, preferably isopropanol.
In one embodiment, the present invention provides a process for purification of compound of formula (Bl) comprising dissolving the compound of formula (Bl) in an alcohol at a temperature of about 50°C to about 70°C, followed by cooling to a temperature of about 0°C to about 15°C.
In one embodiment, the purification in step (b) involves dissolving compound of formula (B), obtained in step (a), in isopropanol, preferably under heating, followed by cooling the solution so obtained. The step of dissolving the compound of formula (B), wherein X and Xi are as defined above, may be performed under heating, under stirring, at a temperature of about 40°C to about 80°C, preferably at a temperature of about 50°C to about 70°C. The solution obtained may be cooled to about room temperature or to a temperature lower than room temperature, preferably cooling to a temperature of about 0°C to about 15°C for about 60-90 min. The solid is then isolated by techniques known in the art, like filtration. The wet cake obtained is washed with isopropanol and dried to obtain purified compound of formula (B).
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I) comprising,

(a) reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compound of formula (Al), with methanesulfonyl chloride at a temperature of about 5°C to 10°C to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl), in presence of dichloromethane as solvent; and

(b) purifying the obtained compound of formula (Bl) using an alcohol.
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I) comprising,
(a) reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compound of formula (Al), with methanesulfonyl chloride at a temperature of about 5°C to 10°C to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl), in presence of dichloromethane as solvent; and

(b) purifying the obtained compound of formula (Bl) using isopropanol.
The step of purification in step (b) leads to preparation of compound of formula (B) with improved purity levels, heretofore unknown.
Step (c), as described above, comprises reacting cyanomethyl imidazole of formula (C) with carbon disulfide to prepare a dithiolate of formula (D), wherein M is an alkali metal.


In one embodiment, M in compound of formula (D) may be Li, Na or K.
Step (c), as described above, may be performed in the presence of a suitable base and a suitable solvent.
The suitable base includes organic and inorganic bases. An organic base used includes, but is not limited, to primary, secondary or tertiary amines such as methylamine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine and the like. Inorganic base used, includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, caesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. Preferably, the base used in step (b) is an alkali metal hydroxide, more preferably potassium hydroxide.
The suitable solvent used in step (c) includes, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone and the like; water; or mixtures thereof. Preferably, the solvent selected is dimethyl sulfoxide.
The reaction in step (c) may be carried out at a temperature of about 5°C to about 30°C, optionally under stirring. The reaction may be carried out for a period of about 1.5-4 hrs. Preferably, the reaction may be carried out at a temperature of about 10°C to about 25°C for a period of about 2.5 - 3.5 hrs.

In one embodiment the present invention provides a process for the preparation of Luliconazole, a compund of formula (I) comprising reacting cyanomethyl imidazole of formula (C) with carbon disulfide in presence of a solvent and a base, to prepare a compound of formula (D) wherein M is an alkali metal.

In one embodiment the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting cyanomethyl imidazole of formula (C) with carbon disulfide in presence of dimethyl sulfoxide as solvent and potassium hydroxide as base, to prepare a compound of formula (D) wherein M is K.
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting cyanomethyl imidazole of formula (C) with carbon disulfide at a temperature of about 15°C to about 20°C, under stirring, for a period of about 2 - 4 hrs in presence of dimethyl sulfoxide as solvent and potassium hydroxide as base, to obtain dithiolate of formula (D) wherein M is K.
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I) comprising,
(a) reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compund of formula (Al), with methanesulfonyl chloride at a temperature of about 5°C to 10°C to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl), in presence of dichloromethane as solvent;


(b) purifying the obtained compound of formula (Bl) using an alcohol; and
(c) reacting cyanomethyl imidazole of formula (C) with carbon disulfide in
dimethylsulfoxide as solvent to prepare a dithiolate of formula (D), wherein M is K.

After the completion of reaction in step (c), suitable work up may be performed, as known to a skilled artisan to isolate the compound of formula (D) before purification.
In one embodiment, the compound of formula (D) obtained in step (c) may be purified by techniques known in the art such as crystallization, fractional crystallization, liquid-liquid extraction and the like.
In one embodiment, the dithiolate of formula (D) may not be isolated before further treatment with compound of formula (B) in step (d). In one embodiment, the reaction mixture comprising dithiolate, after completion of reaction in step (c), is used for further reaction with compound of formula (B) in step (d).
Step (d), as described above, may be performed by reacting compound of formula (B), obtained in step (b) and compound of formula (D) obtained in step (c) presence of a suitable solvent, wherein X, Xi and M are as defined above.


The suitable solvent used in step (d) includes, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone and the like; water or mixtures thereof. Preferably, the solvent selected is dimethyl sulfoxide.
The reaction in step (d) may be carried out at a temperature in the range of about 5°C to about 30°C, optionally under stirring. The reaction may be carried out for a period of about 1 - 5 hours. Preferably the reaction may be carried out at a temperature of about 10°C to about 25°C, optionally under stirring, for a period of about 1.5 - 4.5 hours, more preferably the reaction may be carried out at a temperature of about 15°C to about 20°C for a period of about 1-4 hours.

In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting a compound of formula (B) with dithiolate of formula (D) in dimethylsulfoxide as solvent at a temperature of about 15°C to about 30°C, for a period of about 1 - 5 hours, wherein X, X1 and M are as defined above.

In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl), with dithiolate of formula (D) in dimethylsulfoxide as solvent at a temperature of about 15°C to about 30°C, for a period of about 1 - 5 hours.
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl) with dithiolate of formula (D) in dimethylsulfoxide as solvent at a temperature of about 15°C to about 25°C, under stirring, for a period of about 1 - 3 hours.
In one embodiment, the present invention provides a process for the preparation of Luliconazole, a compound of formula (I) comprising,
(a) reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compound of formula (Al), with methanesulfonyl chloride at a temperature of about 5°C to 10°C to obtain (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl), in presence of dichloromethane as solvent;

(b) purifying the obtained compound of formula (Bl) using an alcohol;
(c) reacting cyanomethyl imidazole of formula (C) with carbon disulfide to prepare a dithiolate of formula (D), wherein M is K; and


(d) reacting compound of formula (Bl), obtained in step (b) and compound of formula (D) obtained in step (c) in dimethylsulfoxide as solvent, wherein X, Xi and M are as defined above.
After the completion of the reaction in step (d), suitable work up may be performed, as known to a skilled artisan to isolate Luliconazole of formula (I), before further purification. In one embodiment, after completion of reaction in step (c), the reaction mixture was quenched with chilled water, followed by extraction with a suitable solvent. The suitable solvent used is as defined above. Preferably, the solvent used is ethylacetate. The organic layer, preferably ethylacetate layer, was washed with water and brine. The product was isolated by techniques known in the art, preferably by distillation of the solvent. The residue obtained was added to a suitable solvent. The suitable solvent used is as defined above. Preferably, the solvent used is a mixture of ethyl acetate and n-hexane, and heated to a temperature of about 50°C to about 70°C under stirring for about 30-60 min. The mixture obtained was cooled to about 20°C to about 30°C, under stirring, for about 2-6 hrs. The mixture was further cooled to about 10 - 15°C. The mixture was further heated to a temperature of about 30°C to about 40°C for about 30-60 min. The product was isolated by filtration and washed with a suitable solvent. The suitable solvent used is as defined above. Preferably, the solvent used is a mixture of ethyl acetate and n-hexane, followed by drying to obtain Luliconazole.
The isolation procedure for Luliconazole, described above, leads to crude Luliconazole.
The expression "crude Luliconazole" means Luliconazole containing from about 20% w/w to 30% w/w of undesired Z isomer of Luliconazole with respect to Luliconazole as measure by HPLC.

The US'488 patent, as discussed above, exemplifies use of column chromatography for purification of Luliconazole. The present invention avoids use of tedious and commercially unviable process like column chromatography.
In one embodiment, the present invention provides a process for purification of Luliconazole comprising crystallizing crude Luliconazole from a suitable solvent at a suitable temperature.
The suitable solvent for purification includes, but is not limited alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; hydrocarbons such as hexane, cyclohexane, xylene and the like; esters such as methyl acetate, ethyl acetate and the like; or mixtures thereof. Preferably the solvent selected for purification may be an alcohol, more preferably isopropanol.
Purification of crude Luliconazole may be carried out at a temperature of about 30°C to about 80°C, optionally under stirring. Preferably, the reaction may be carried out at a temperature of about 35°C to about 75°C, more preferably at a temperature of about 38°C to about 65°C.
In one embodiment, purification of crude Luliconazole comprises treating crude Luliconazole with a suitable solvent at a temperature of about 50°C to about 80°C, optionally under stirring, to provide a clear solution. The solution so obtained may be cooled, optionally under stirring, to a temperature of about 15°C to about 40°C, preferably to about 30°C to about 40°C, for about 60 - 120 min.
In one embodiment, the present invention provides a process for purification of Luliconazole comprising crystallizing crude Luliconazole from isopropanol at a suitable temperature.
In one embodiment, purification of crude Luliconazole comprises crystallizing crude Luliconazole from isopropanol which comprises, treating crude Luliconazole with isopropanol at a temperature of about 55°C to about 75°C, under stirring, to obtain a clear solution. The solution so obtained may be cooled, under stirring, to a temperature of about 20°C to about 40°C.

In one embodiment, purification of crude Luliconazole comprises treating crude Luliconazole with isopropanol at a temperature of about 55°C to about 75°C, under stirring, to obtain a clear solution. The solution so obtained may be cooled, under stirring, to a temperature of about 25°C to about 30°C. The solution so obtained, may be heated again to a temperature of about 35°C to about 40°C. The product obtained may be filtered hot, washed with isopropanol and dried.
Luliconazole so obtained may be further treated with isopropanol, optionally under stirring, at a temperature of about 55°C to about 75°C to obtain a suspension which may be cooled to a temperature of about 30°C to about 50°C, optionally under stirring, for 1 -2 hrs. The product obtained is filtered, washed with isopropanol and dried.
In one embodiment, the process of purification of Luliconazole, as described above, may be repeated.
The Luliconazole obtained after crystallization/s from isopropanol, as described above, contains less than about 20% w/w to 30% w/w of undesired Z isomer of Luliconazole with respect to Luliconazole as measure by HPLC. In one embodiment, Luliconazole obtained after crystallization/s from isopropanol, contains less than about 15 % w/w, preferably less than about 5 % w/w, of undesired Z isomer of Luliconazole with respect to Luliconazole as measure by HPLC. In one embodiment, Luliconazole obtained after crystallization/s from isopropanol, contains less than about 1 % w/w of undesired Z isomer of Luliconazole with respect to Luliconazole as measure by HPLC.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.

Example-1: Preparation of (S)-l-(2,4-dichIorophenyl)-2-chloroethyl
methanesulfonate
A clear solution (6.0 L) of (S)-l-(2,4-dichlorophenyl)-2-chloroethanol (1.0 kg, 4.43 moles) in dichloromethanol was cooled to about 10°C and triethyl amine (0.9 kg, 8.86 moles) was added to it. The reaction mixture was stirred, followed by addition of methanesulfonyl chloride (0.762 kg, 6.65 moles). The reaction mixture was stirred at about 5°C to 10°C. After completion of reaction, water (5.0 L) was added and the reaction mixture was stirred to separate dichloromethane layer. The aqueous layer was washed with dichloromethane (1.0 L). Both dichloromethane layers obtained were then combined and washed with water, dried over the sodium sulphate and distilled to obtain solid residue compound.
Example-2: Purification of (S)-l-(2,4-dichlorophenyl)-2-chloroethyl
methanesulfonate
The solid residue obtained in Example-1 was added to isopropanol (4.0 L), heated at 60°C to 70°C under stirring to obtain a clear solution. The obtained solution was cooled to about 10°C, stirred and filtered. The solid obtained was washed with chilled isopropanol (2.0 L) and dried under vacuum to obtain the titled compound (1.10 kg ;Yield: 82%) with HPLC purity more than 98.0%
Example-3: Preparation of (R)-(-)-(E)-4-(2,4-dichlorophenyl)-l,3-dithiolan-2-ylidene-l-imidazolyl acetonitrile (Luliconazole crude)
To a stirred suspension of powdered potassium hydroxide (0.660 kg, 10.01 moles) and dimethyl sulfoxide (4.4 L) a mixture of cyanomethyl imidazole (0.438 kg, 4.09 moles) and carbon disulfide (0.372 kg, 1.35 moles) in dimethyl sulfoxide (2.2 L) was slowly added at 15° to 20°C. The reaction was maintained at 15° to 20°C to obtain dithiolate solution. The obtained dithiolate solution was slowly added to a solution of (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate (1.1 kg, 3.62 moles) and dimethyl sulfoxide (3.3 L) at 15° to 20°C. The reaction mixture was then stirred and quenched by adding ice-water (22.0 L); followed by extraction with ethyl acetate. The ethyl acetate

layer was further washed with water and brine (8.8 L) and was distilled out completely to get residue. A mixture of ethyl acetate (1.76 L) and hexane (1.21 L) was added to the residue and the mixture was heated at 60°C to 70°C under stirring. The reaction mixture was then cooled to about 25°C to 30°C, further cooled to about 10°C under stirring. The mixture was further heated to about 35°C to 40°C. The solid obtained was then washed with 50% ethyl acetate and hexane (1.10 L) mixture and dried at 50° to 55° under vacuum to get title compound (0.870 kg, 68.0 % yield) with HPLC purity of more than 60.0% and Z-isomer content of about 20 - 30% as measured by HPLC.
Example-4: Purification of Luliconazole crude
Luliconazole crude (0.650 kg) obtained in Example-3 was suspended in isopropanol (5.2 L). and the suspension was heated at about 60°C to 70°C to get clear solution. The clear solution was then cooled at 25°C to 30°C under stirring, again heated at 35°C to 40°C and stirred. The product was filtered, washed with isopropanol and dried under vacuum to get Luliconazole (0.450 kg, 69.2%) with HPLC purity of more than 85.0% and Z-Isomer content of less than about 10% as measured by HPLC.
Example-5: Re-purification of Luliconazole
Luliconazole obtained in Example-4 (0.450 kg) was suspended in isopropanol (1.80 L) and heated at 60°C to 70°C. The mixture was then cooled to about 35°C to 40°C under stirring and stirred. The product obtained was filtered, washed with isopropanol and dried under vacuum to get highly pure Luliconazole (0.33 kg, 70.3 % yield) with HPLC purity of more than 99.0% and Z-Isomer content of less than 1.0% as measured by HPLC. (M.P. 149.2 - 150.8°C)

We claim:
1. A process for preparation of Luliconazole, a compund of formula (I), comprising

(a) converting (S)-l-(2,4-dichlorophenyl)-2-haloethanol, a compund of formula (A), to a compound of formula (B), wherein, Xi is selected from the group consisting of methanesulfonyloxy, benzenesulfonyloxy and toulenesulfonyloxy; and X is a halogen;

(b) purifying the compound of formula (B) prepared in step (a);
(c) reacting cyanomethyl imidazole of formula (C) with carbon disulfide to prepare a dithiolate of formula (D), wherein M is an alkali metal; and

(d) reacting a compound of formula (B) obtained in step (a) with the dithiolate of formula (D) obtained in step (b) to prepare Luliconazole of formula (I), wherein Xi, X and M are as defined above.

A process according to claim 1, wherein in compound of formula (B), Xi is methanesulfonyloxy, X is chloro and M is K.
3. A process according to claim 1, wherein the purification in step (b) comprises crystallization from an alcohol.
4. A process according to claim 3, wherein the alcohol is selected from the group consisting methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and n-pentanol.
5. A process for preparation of (S)-l-(2,4-dichlorophenyl)-2-chloroethyl methanesulfonate, a compound of formula (Bl), comprising reacting (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compound of formula (Al), with methanesulfonyl chloride at a temperature of about 0°C to about 20°C.

6. A process according to claim 5, wherein the reaction between (S)-l-(2,4-dichlorophenyl)-2-chloroethanol, a compound of formula (Al), and methanesulfonyl chloride is performed at temperature of about 0°C to about 15°C.
7. A process for purification of Luliconazole comprising crystallizing crude Luliconazole from an alcoholic solvent.

8. A process according to claim 7, wherein an alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and n-pentanol.