Claims:
1. A process for the preparation Luliconazole (Formula I) with high yield and purity which process comprises;
a) reacting (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol (Formula III) with 4-chlorobenzene sulfonyl chloride ( Formula IV) by using a suitable base and suitable catalyst in suitable solvent under a temperature condition effective to obtain(S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride (formula II);

b) reacting 1-cyano methyl Imidazole of formula (V) with carbon disulfide in the presence of a base and in suitable solvent to form an intermediate compound represented by the structural formula (VI );

c) Insitu reacting the compound represented by structural formula (VI) with the intermediate compound of formula II in suitable solvent to obtain Luliconazole (Formula I);
d) isolating the Luliconazole (Formula I) as acid addition salt of Luliconazole (Formula I) in crystalline form by treating with suitable acid in suitable solvent at a selected temperature, with high yield and purity without attempting any additional purifications; and
e) converting the acid addition salt of Luliconazole into Luliconazole free base (Formula I) by using a suitable base in suitable solvent at selected temperature with high purity and yield.
2. The process as claimed in claim 1, wherein, the 4-chlorobenzene sulfonyl chloride (Formula IV) is used in a molar ratio of 1.0 -1.50 mole/mole of compound of formula-III.
3. The process as claimed in claim 1, wherein, the base used in step a) is either organic base selected from triethylamine, diisopropyl ethyl amine, pyridine, piperidine or an inorganic base selected from alkali metal carbonates, bicarbonates, and their hydroxides in a molar ratio of 1.0-2.0 mole/mole of compound of Formula III.
4. The process as claimed in claim 1, wherein, the catalyst used in step a) is selected from the group consisting of pyridine, 4-dimethylaminopyridine and N,N-Dialkyl anilines in a quantity ranging from 0.05 to 0.10 mole/mole of compound of Formula III.
5. The process as claimed in claim 1, wherein, the solvent in step a) is selected from group consisting of chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform; esters such as ethyl acetate, butyl acetate, isopropyl acetate: Hydrocarbons such as toluene, cyclo hexane, xylene; acetonitile, Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof.
6. The process as claimed in claim 1, wherein, the reaction of step a) can be carried out at a temperature ranging from 0 to 60°C.
7. The process as claimed in claim 1, wherein, the solvent in step b) is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, dimethyl sulfoxide, dimethylformamide or mixtures thereof.
8. The process as claimed in claim 1, wherein, the base used in step b) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, in an amount of 2.0 -5.0 mole/mole of the compound of formula-V.
9. The process as claimed in claim 1, wherein, the1-cyano methyl imidazole of the structural formula-V in step b) is used in sub molar quantity ranging from 1.0-2.0 mole/mole of the compound of formula-II.
10. The process as claimed in claim 1, wherein, the carbon disulfide used in step b) is in a quantity ranging from 1.0-2.0 mole/mole of the compound of formula-II.
11. The process as claimed in claim 1, wherein, the reaction of step b) is conducted at temperature range of 0° to 100°C.
12. The process as claimed in claim 1, wherein, the suitable acid in step d) is hydrochloric acid and suitable solvent is selected from the group consisting of C1-C4 alcohols, such as methanol, ethanol, isopropyl alcohol and butyl alcohol; ethers such as diethyl ether, petroleum ether, diisopropyl ether; esters such as ethyl acetate, butyl acetate, isopropyl acetate; Hydrocarbons such as toluene, cyclo hexane, xylene; acetonitile, acetone, methyl ethyl ketone, methyl isobutyl ketone, water or mixtures thereof.
13. The process as claimed in claim 1, wherein, the suitable base in step e) is selected from ammonium hydroxide, ammonia gas, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, triethyl amine etc.
14. The process as claimed in claim 1, wherein, the suitable solvent in step e) is selected from the group of consisting of chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform; esters such as ethyl acetate, butyl acetate, isopropyl acetate;hydrocarbons such as toluene, cyclo hexane, xylene; acetonitile, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, water or mixtures thereof.
15. The process as claimed in claim 14, wherein, the solvent is selected from water, methylene dichloride, ethyl acetate and toluene or mixtures thereof.
16. (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride(formula II),

Formula II.

, Description:Technical filed:
The present invention relates to an improved process for preparation of Luliconazole in high yield and purity involving a novel intermediate i.e., (S)- 2,4-Dichloro-alpha-(chloro methyl)benzene methanol 4-chlorosulfonyl chloride.

Background of the invention:
Luliconazole is chemically known as (R)–(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile, is an antimycolitic imidazole in the azole category.

Luliconazole ( LUZU cream, 1%) , was approved by FDA for the 2-week, once-daily treatment of interdigital tineapedis, tineacruris, and tineacorporis, caused by the organisms Trichophytonrubrum and Epidermophytonfloccosum, in patients aged 18 years and older.Luliconazole is structurally represented by the compound of formula I,

Formula - I

Luliconazole was first disclosed in WO 9702821 and, US 5900488 by Nihon Nohyaku, which explains the synthetic approach to the preparation of Luliconazole and pharmaceutical compositions comprising the same. This patent describes the synthesis of (R)–(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile as a mixture of geometrical isomers Cis and Trans. Upon further work up, the desired Trans isomer was obtained after column chromatography in very low yield.

Chinese patent CN 104151305 describes the method of converting the Z-isomer into Trans (E) isomer which is having antifungal activity. The overall reported yield of E- isomer is about 35%. Moreover, this method is not reproducible and industrially feasible.

WO2016/092478 publication discloses the process for the preparation of Luliconazole and salts thereof from the mixture of geometrical isomers. The E and Z isomers were separated by forming the acid addition salt i.e., Hydrochloride salt in different solvents and its recrystallizations were discussed. The crystallization of Luliconazole is also described. However, no yields were reported in the said publication.

WO2017/108972describes (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile HA, where HA is an acid like HCl, HBr, H2SO4, HNO3, H3PO4, Oxalic acid, Fumaric acid, citric acid, tartaric acid, acetic acid, formic acid, trifluoro acetic acid, gluconic acid, lactic acid, Malic acid, succinic acid and the process for their preparation.

The aforesaid processes though disclose the preparation of Luliconazole and its acid addition salts. However, the processes includes multiple purification steps which increases the consumption of raw materials leading to higher cost of the process, also yields are low due to multiple purifications and due to the development of undesired by products. Therefore, these processes are not environmentally feasible as well as industrially scalable.

In view of the above drawbacks, there remains a need in the art to provide an eco-friendly and economical process for preparation of Luliconazole (Formula I) in high yield and purity without any additional purification steps.

Object of the invention:
The primary objective of the present invention is to provide an eco-friendly and economically feasible process for preparation of Luliconazole (Formula I) in high yield and purity without any additional purification steps by introducing a novel intermediate i.e., (S)-2,4-Dichloro-alpha-(chloro methyl)benzene methanol 4-chlorosulfonyl chloride (Formula II).

Formula II
The other object of the invention is to provide process for the preparation of (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride.

A further objective of the present invention is to provide the use of 4-Dichloro-alpha-(chloromethyl) benzene methanol 4-chlorosulfonyl chloride in synthesis of Luliconazole.

Summary of the invention:
The present invention provides a cost-effective and industrially feasible process for the preparation of Luliconazole(Formula I) from (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol(Formula III)by introducing hither to unreported novel intermediate, viz., (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride (Formula II).

Accordingly, the present invention provides process for the preparation of Luliconazole (Formula I) with high yield and purity which process comprises;
i) reacting (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol (Formula III) with 4-chlorobenzene sulfonyl chloride ( Formula IV) by using a suitable base and suitable catalyst in suitable solvent at selected temperature to obtain(S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride (formula II);

Formula III Formula IV
ii)reacting 1-cyano methyl Imidazole of formula (V) with carbon disulfide in the presence of a base and a suitable solvent to form an intermediate represented by the structural formula (VI );

iii) insitu reacting the compound represented by structural formula (VI) with the intermediate of formula II in suitable solvent to obtain Luliconazole (Formula I);
iv) isolating the Luliconazole (Formula I) as acid addition salt of Luliconazole (Formula I) in crystalline form by treating with suitable acid in suitable solvent at selected temperature, with high yield and purity without involving any additional purifications; and
v) converting the acid addition salt of Luliconazole into Luliconazole free base (Formula I) by using a suitable base in suitable solvent at selected temperature with high purity and yield.
In another aspect the invention provides hither to unreported novel intermediate, (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride (Formula II) and a process for the synthesis of the same from (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol (Formula III).

In yet another aspect, the present invention provides process for the preparation of Luliconazole (Formula I) with high yield and purity by utilizing the novel intermediate of 4-Dichloro-alpha-(chloromethyl) benzene methanol 4-chlorosulfonyl chloride (Formula II) in the synthesis of Luliconazole.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

Accordingly, the present invention provides a cost-effective and feasible process for the preparation of Luliconazole(Formula I) from the (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol (Formula III) by introducing a novel intermediate(S)-2,4-Dichloro-alpha-(chloromethyl)benzenemethanol 4-chlorosulfonyl chloride (Formula II).

According to another embodiment, the invention provides a process for the synthesis of (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride (Formula II) from (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol (Formula III).

According to the preferred embodiment, the process for the preparation of Luliconazole (Formula I) with high yield and purity which process comprises:
i) reacting (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol (FormulaIII) with 4-chlorobenzene sulfonyl chloride ( Formula IV) by using a suitable base and suitable catalyst in suitable solvent at selected temperature to obtain (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride (formula II);

Formula III Formula IV
ii)reacting 1-cyano methyl Imidazole of formula (V) with carbon disulfide in the presence of a base and a suitable solvent to form an intermediate compound represented by the structural formula (VI );

iii) Insitu reacting the compound represented by structural formula (VI) with the novel intermediate compound of formula II in suitable solvent to obtain Luliconazole (Formula I);
iv) isolating the Luliconazole (Formula I) as acid addition salt of Luliconazole (Formula I) in crystalline form by treating with suitable acid in suitable solvent at selected temperature, with high yield and purity without involving any additional purifications; and
v) Converting the acid addition salt of Luliconazole into Luliconazole free base (Formula I) by using a suitable base in suitable solvent at selected temperature with high purity and yield.
Luliconazole (Formula I) can be obtained with high yield and purity by utilizing the novel intermediate of (S)-2,4-Dichloro-alpha-(chloromethyl) benzene methanol 4-chlorosulfonyl chloride (Formula II), according to the process of the present invention.

According to another preferred embodiment, the invention provides a process for the preparation of (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride(formula II) with high yield and purity which process comprises:
a) Reacting (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol (Formula III) with 4-chlorobenzene sulfonyl chloride (Formula IV) by using a suitable base and suitable catalyst in suitable solvent at selected temperature; and
b) isolating the (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride(formula II) with high yield and purity from reaction mass.

Accordingly, (S)-2,4-Dichloro-(alpha-chloromethyl)-benzene methanol (formula III) is reacted with 4-chlorobenzene sulfonylchloride(Formula IV) in presence of a base and catalyst in a solvent to attain 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride derivative (Formula II). The 4-chlorobenzene sulfonylchloride (Formula IV)is used in a molar ratio of 1.0 -1.50 mole/mole of formula-III. The base used in this reaction is selected from organic base such as triethylamine, diisopropyl ethyl amine, pyridine, piperidine, while the inorganic bases are selected from the group consisting of alkali metal carbonates, bicarbonates, and their hydroxides in a molar ratio of 1.0-2.0 mole/mole of Formula III. The preferred base is an organic base selected from triethylamine and pyridine. The catalyst used in this reaction is selected from pyridine, 4-dimethylaminopyridine, N,N-Dialkyl anilines in a quantity ranging from 0.05 to 0.10 mole/mole of Formula III. The preferred catalyst is 4-Dimethyl amino pyridine.
As regards the solvent usable in this reaction, any solvent may be used so long as it does not inhibit/interfere with the progress of the reaction.Thus the reaction can be carried out in a solvent selected from group consisting of chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform; esters such as ethyl acetate, butyl acetate, isopropyl acetate: Hydrocarbons such as toluene, cyclo hexane, xylene; acetonitile, Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures there of. The prefered solvents may be selected from methylene dichloride, ethyl acetate and toluene or mixtures thereof.

The reaction can be carried out at a temperature ranging from 0 to 60°C preferably at ambient temperature for a period of 1-6 hrs. After conversion of the reaction, the reaction was adjusted at a pH of 4.0-6.0 with diluted organic/inorganic acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

The (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride(formula II) thus obtained can be crystallized in the suitable solvent at suitable temperature to obtain the product with good purity.The solvent for crystallization may be selected from the group consisting of C1-C4 Alcohols, such as methanol, ethanol, isopropyl alcohol and butyl alcohol; ethers such as diethyl ether, petroleum ether, diisopropyl ether; esters such as ethyl acetate, butyl acetate, isopropyl acetate: Hydrocarbons such as toluene, cyclo hexane, xylene; acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, water or mixtures thereof, preferably, petroleum ether, isopropyl alcohol and acetonitile.

In another embodiment, Luliconazole of Formula I can be obtained by reacting 1-cyano methyl Imidazole represented by structural formula (IV) with carbon disulfide in the presence of a base and a solvent to obtainan intermediate represented by the structural formula (VI), and reacting the intermediate of formula VI insitu with a compound represented by structural formula (II).
As regards the solvent usable in this reaction, any solvent may be used so long as it does not inhibit/interfere with the progress of the reaction, and can be selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like, dimethyl sulfoxide, dimethylformamide or mixtures thereof.

The base used in this reaction can be selected from sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium Hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, etc. in quantity ranging from 2.0 -5.0 mole/mole of the structural formula-V. These can be used in the reaction either in solid or in solution form.

According to the present invention, 1-cyano methyl imidazole of the structural formula-V is used in sub molar quantity ranging from 1.0-2.0 mole/mole of the structural formula-II. Carbondisulfide used in this reaction can be in a quantity ranging from 1.0-2.0 mole/mole of the structural formula-II.

Although it is sufficient that the reaction temperature is selected in the range of 0° to 100°C., it is particularly preferable to carry out the reaction at a temperature, near room temperature. It is sufficient that the reaction time is properly selected in the range of 0.5 to 24 hours.

After completion of the conversion, the reaction mass containing Luliconazole is quenched into water followed by extraction with a suitable organic solvent selected from group consisting of chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform; esters such as Ethyl acetate, butyl acetate, Isopropyl acetate: Hydrocarbons such as Toluene, cyclohexane, xylene and distilled the organic layer under reduced pressure to recover and recycle the extraction solvent(s).

Alternatively, the obtained organic layer is acidified with the addition of suitable acid in Aqueous/suitable organic solvent media and cooled to ambient temperature to isolate the luliconazole as acid addition salt in pure form. The suitable organic solvent is selected from the group consisting of C1-C4 Alcohols, such as Methanol, ethanol, Isopropyl alcohol and butyl alcohol; ethers such as Diethyl ether, petroleum ether, diisopropyl ether; esters such as Ethyl acetate, butyl acetate, Isopropyl acetate: Hydrocarbons such as Toluene, cyclo hexane, Xylene; Acetonitile, Acetone, methyl ethyl ketone, methyl isobutyl ketone, Water or mixtures there of, preferably,Isopropyl alcohol and Acetone.

The acid that can be used for preparation of acid addition salt is Hydrochloric acid that can be used in a quantity ranging from 1.0-2.0 mole/mole of the structural formula-I.

The above described process of the present invention provides high purity acid addition salt of luliconazole of Formula I with high yield, which does not require any additional purification.

In another preferred embodiment, the invention describes the conversion of luliconazole acid addition salt into Luliconazole of structural formula I, wherein, the acid addition salt of Luliconazole is converted into its free base form by treating with suitbale base.

The suitable base that can be used in the conversion of Luliconazole may be selected from ammonium hydroxide, ammonia gas, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium Hydroxide, potassium hydroxide, potassium t-butoxide, triethyl amine etc.

The pH of the reaction mass is maintained at the range of 8-14, preferably at the range of 8-10 to obtain Luliconazole base with a purity >99% HPLC as well as chiral purity.

The solvent that can be selected from the group consisting of chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform; esters such as ethyl acetate, butyl acetate, isopropyl acetate: Hydrocarbons such as toluene, cyclo hexane, xylene; acetonitile, Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, water or mixtures thereof.The preferable solvent that can be used for the conversion of acid addition salt of Luliconazole to Luliconazole may be selected from water, methylene dichloride, ethyl acetate and toluene or mixtures thereof.

Thus the present invention provides an improved and economically feasible process for the preparation of Luliconazole with high yield and purity without any additional purification stages.

The present invention further encompasses hither to unreported novel intermediate, viz., (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chlorosulfonyl chloride(formula II), as shown below.

Formula II
This novel intermediate is further characterised by NMR.

Having thus described the present invention with reference to particular embodiments, those skilled in the art will appreciate modifications that do not depart from the spirit and scope of the disclosure. The following examples are set forth to further describe certain specific aspects and embodiments but are not intended to, and should not be construed to, be limiting in any way. The examples do not include detailed descriptions of conventional methods; as such methods are well known to those of ordinary skill in the art and are described in numerous publications.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown by way of example, for purpose of illustrative discussion of preferred embodiments of the invention, and are not limiting the scope of the invention.

Examples:
Example 1:
Process for the preparation of(S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate
100 gm of the (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol was placed in a round bottom flask and suspended in 500 ml of methylene dichloride at ambient temperature followed by the addition of triethylamine (66gm) with stirring atambient temperature. 5.0 gm of 4-dimethylamino pyridine was added to reaction mixture. Further, 111 gm of 4-chlorobenzene sulfonyl chloride was added slowly for about 30-60 minutesat 10-15°C. The reaction mass was maintained for 3-4hrs at the same temperature to complete the reaction. After completion of the reaction, the reaction mass was quenched by the addition of water (500ml) and acidified with dilute hydrochloric acid. The layers were separated and the organic layer was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent was evaporated under reduced pressure and triturated with petroleum ether (300ml). The reaction mass was stirred for 1-2 hours at 45-50° C. The mixture was cooled to ambient temperature and stirred for 1-2 hours. The formed solid was filtered off, washed with petroleum ether (100 ml) to attain 155gm of title compound with purity by HPLC is 99.2%.

1H NMR (DMSO, 300MHZ): d 4.00(1H, dd), d 4.13(1H, dd), d 5.86(1H, t), d 7.38(1H, d), d 7.40(1H,d), d 7.52(3H, d), d 7.8(2H, d)

Example 2:
Process for the preparation of (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate
100 gm of the (S)- 2,4-Dichloro-alpha-(chloromethyl)benzene methanol was placed in a round bottom flask and suspended in 600 ml of Ethyl acetate at ambient temperature followed by the addition of triethylamine (66gm) with stirring at ambient temperature. 5.0 gm of 4-dimethylamino pyridine was added to reaction mixture. Further, 111 gm of 4-chlorobenzene sulfonyl chloride was added slowly for about 30-60 minutes at 10-15°c. The reaction mass was maintained for 3-4 hrs at the same temperature to complete the reaction. After completion of the reaction, it was quenched by the addition of water (500ml) and acidified with dilute hydrochloric acid. The layers were separated and the organic layer was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent was evaporated under reduced pressure and triturated with Isopropyl alcohol (300ml). The reaction mass was stirred for 1-2 hours at 45-50° C. The mixture was cooled to ambient temperature and stirred for 1-2 hours. The formed solid was filtered off, washed with petroleum ether (100 ml) to attain 151.0 gm of title compound with purity by HPLC is 99.2%.

Example 3:
Process for the preparation of (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate
25.0 gm of the (S) -2,4-Dichloro-alpha-(chloromethyl)benzene methanol was placed in a round bottom flask and dissolved in 600 ml of Acetone followed by the addition of 1.5 gm of 4-dimethylamino pyridine at ambient temperature. Further 23gmof potassium carbonate was added slowly with stirring at ambient temperature. The reaction mass was maintained for 30 minutes at the same temperature. 28.0gm of 4-chlorobenzene sulfonyl chloride was added slowly for 30-60 minutes at 10-15°c. The reaction mass was maintained for 3-4 hrs at reflux temperature to complete the reaction. After completion of the reaction, the solvent was distilled off completely and diluted with water (500ml) and acidified with dilute hydrochloric acid. The mass was extracted with methylene dichloride and layers were separated. The organic layer thus obtained was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent was evaporated under reduced pressure and triturated with petroleum ether (300ml). The reaction mass was stirred for 1-2 hours at 45-50° C. The mixture was cooled to ambient temperature and stirred for 1-2 hours. The formed solid was filtered off, washed with petroleum ether (100 ml) to attain 37.0 gm of title compound with purity by HPLC is 99.2%.

Example 4:
Process for the preparation of (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate
100 gm of the (S)- 2,4-Dichloro-alpha-(chloro methyl)benzene methanolwas placed in a round bottom flask and suspended in 500 ml of methylene dichloride at ambient temperature followed by the addition of triethylamine (66gm) with stirring at ambient temperature. 5.0 gm of 4-dimethylamino pyridine was added to reaction mixture. Further, 111 gm of 4-chlorobenzene sulfonyl chloride was added slowly for about 30-60 minutes at 10-15°c. The reaction mass was maintained for 3-4 hrs at the same temperature to complete the reaction. After completion of the reaction, the reaction mass was quenched by the addition of water (500ml) and acidified with dilute hydrochloric acid. The layers were separated and the organic layer was subjected to washing with water. After separation of the organic layer from aqueous layer, the solvent was evaporated completely under reduced pressure. Thus obtained residual mass was proceded to further step without isolation. The weight of the obtained solid is 157gm of title compound with purity by HPLC is 99.1%.

Example 5:
Process for the preparation of (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrileHydrochloride
50.0 gm of the 1-cyano methyl Imidazole and 30.0 gm of carbon disulphide was placed in a round bottom flask and suspended in 200 ml of dimethyl sulfoxide at ambient temperature followed by the addition of powdered potassium hydroxide (33.0 gm) with stirring at cooling condition. The reaction mass was maintained for 2 hrs at cooling condition. In another flask 100.0 gm of the (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate was placed and suspended in 200 ml of dimethyl sulfoxide at ambient temperature. The reaction was maintained and added to the above prepared potassium salt undercooling condition for about 3-5 hours. The reaction mass was maintained for 3-4 hrs at ambient temperature to complete the reaction. After completion of the reaction, it was quenched by the addition of aqueous sodium chloride solution (500ml) and extracted with Ethyl acetate. The layers were separated and the organic layer was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent was evaporated under reduced pressure and acidifiedwith the addition of IPA/HCl in
in acetone media. The reaction mass was heated to reflux and maintained for 1.0 hrs. Further, the reaction mass was cooled to ambient temperature to isolate the product in pure form. The compound thus obtained was dried to attain 53.0 (85% of theoretical Yield) gm of the title compound.
HPLC purity: 99.56%; chiralpurity: 99.48% without further purifications.

Example 6:
Process for the preparation of (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrileHydrochloride
50.0 gm of the 1-cyano methyl Imidazole and 30.0 gm of carbon disulphide was placed in a round bottom flask and suspended in 200 ml of dimethyl formamide at ambient temperature followed by the addition of powdered potassium hydroxide (33.0gm) under stirring at cooling condition. The reaction mass was maintained for 2 hrs at cooling condition. In another flask 100.0 gm of the (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate was placed and suspended in 200 ml of dimethyl formamide at ambient temperature. The reaction was maintained and added to the above prepared potassium salt undercooling condition for about 3-5 hours. The reaction mass was maintained for 3-4 hrs at ambient temperature to complete the reaction. After completion of the reaction, the reaction mass was quenched by the addition of aqueous sodium chloride solution (500ml) and extracted with ethyl acetate. The layers were separated and the organic layer was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent was evaporated completely under reduced pressure and acidified with the addition of HCl in aqueous media. The reaction mass was heated to 45-50°C and maintained for 1.0 hr. Further the reaction mass was cooled to ambient temperatureto isolate the title compound in pure form. The obtained compound was dried to attain 58.0 gm of the title compound.
HPLC purity: 99.5%; chiral purity: 99.4% without further purifications.

Example 7:
Process for the preparation of (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrileHydrochloride
50.0 gm of the 1-cyano methyl Imidazole and 30.0 gm of carbon disulphide wereplaced in a round bottom flask and suspended in 200 ml of dimethyl sulfoxide at ambient temperature followed by the addition of powdered Sodium hydroxide (24.0gm) with stirring at cooling condition. The reaction mass was maintained for 2 hrs at cooling condition. 100gm of the (S)-2,4-Dichloro-alpha-(chloromethyl)benzene methanol 4-chloro benzene sulfonate was placed in a round bottom flask and suspended in 200 ml of dimethyl sulfoxide at ambient temperature. The reaction was added to the above prepared sodium salt at cooling condition for about 3-5 hours. The reaction mass was maintained for 3-4 hrs at ambient temperature to complete the reaction. After completion of the reaction, it was quenched by the addition of aqueous sodium chloride solution(500ml) and extracted with methylene dichloride. The layers were separated and the organic layer was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent was evaporated completely under reduced pressure and acidified with the addition of IPA HCl in Acetone media. The reaction mass was heated to reflux and maintained for 1.0 hrs. Further the reaction mass was cooled to ambient temperature to isolate the title compound in pure form. The obtained compound was dried to attain 56.0 gm of the title compound.
HPLC purity: 99.8%; Chiral purity: 99.7% without further purification.

Example 8:
Process for the preparation of (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile ( LULICONAZOLE )
50.0 gm of the (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile Hydrochloride was placed in a round bottom flask and suspended in 300 ml of water at ambient temperature. The pH of the reaction mass was adjusted to 8-10 with ammonium hydroxide solution at ambient temperature. The reaction was maintained for about 1.0 hr at 50°C; further cooled to ambient temperature and the reaction mass was maintained for about 1-2 hrs at ambient temperature. The reaction mass was filtered and washed with water. The obtained compound was dried to attain 44.0 gm of the title compound.
HPLC purity: 99.8%; Chiral purity : 99.8% .

Example9:
Process for the preparation of (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile ( LULICONAZOLE )
50.0 gm of the (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile Hydrochloride was placed in a round bottom flask and suspended in 300 ml of Acetone at ambient temperature. The pH of the reaction mass was adjusted to 8-10 with triethyl amine at ambient temperature. The reaction mass was maintained for about 1.0 hour at ambient temperature. Activated carbon was charged and filtered off through hyflow bed. The filtrate thus obtained was subjected to evaporation up to 80% under reduced pressure. Further, the reaction mass was cooled and maintained for overnight. The reaction mass was filtered and washed with chilled Acetone. The obtained compound was dried to attain 42.0 gm of the title compound.
HPLC purity: 99.95%;Chiral purity: 99.98%.

Example 10:
Process for the preparation of (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile ( LULICONAZOLE )
50.0 gm of the (R) –(-) (E) – [4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl acetonitrile Hydrochloride was placed in a round bottom flask and suspended in 300 ml of water and 300 ml of ethyl acetate at ambient temperature. The pH of the reaction mass was adjusted to 8-10 with sodium hydroxide solution at ambient temperature. The reaction mass was maintained for about 1.0 hour at ambient temperature. The layers were separated and the organic layer was subjected to washing with water. After separation of organic layer from aqueous layer, the solvent layer was treated with activated carbon and filtered. The filtrate thus obtained was subjected to evaporationupto 70% of the volume under reduced pressure. Further, the reaction was cooled and maintained for about 1-2 hrs. The reaction mass was filtered and washed with ethyl acetate. The compound thus obtained was dried to attain 41.0 gm of the title compound.
HPLC purity: 99.9%; Chiral purity: 99.9%.