The present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer and unwanted salts.
Luliconazole is chemically known as (2E)-2-[(4R)-4-(2,4-dichlorophenyl)-l,3-dithiolan-2-ylidene]-2-imidazol-l-ylacetonitrile. Luliconazole is an imidazole antifungal agent. Luliconazole is Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older. Luliconazole is marketed under the brand name Luzu®.
Luliconazole is disclosed for the first time in U.S. Pat. No. 5,900,488. This patent also discloses processes for the preparation of Luliconazole (I) by reacting compound of formula (II) with compound of formula (III) in presence of dimethyl sulfoxide (DMSO). Wherein X1 and X2 are the same or different and each represents a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogen atom and M represents an alkali metal atom.
US’488 patent exemplifies purification of Luliconazole using column chromatography followed by recrystallization using a mixture of ethyl acetate and n-hexane. The above synthesis is illustrated in the following Scheme-I

Aforesaid process for the preparation of Luliconazole 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.
WO 2016092478 discloses a process for the preparation E- isomer of Luliconazole (I)
by contacting a mixture of Luliconazole mixture (E/Z) (III) in a solvent with an
hydrochloric acid (HCl) to obtain acid addition salts of stereoisomers of Luliconazole i.e Luliconazole HCl (IV) and further it was basified to produce desired isomer of Luliconazole (I).
WO ‘478 process have several disadvantages by generating the higher amounts of solid waste and not giving the desired purity of the formula(I).
In the view of the above and there is a need to develop an efficient method that utilizes the undesired isomer. Hence, our present inventors have developed a process for the preparation of Luliconazole (I) with good yield, high purity, commercially viable and industrially applicable process by employing interconversion methodology to get a desired isomer of the formula (I).

The present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer can be obtained by the treatment of hydrobromic acid at elevated temperature in a transformation methodology.
In one aspect of the present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer, comprising the following steps:
a) treating an Luliconazole mixture (E/Z) (III) in a suitable solvent with an hydrobromic acid (HBr) at elevated temperature to obtain an E-isomer of Luliconazole hydrobromic acid (II), and
b) basifying the E- isomer of Luliconazole hydrobromic acid (II) to obtain E-isomer of Luliconazole (I).

In another aspect of the present invention provides a process for preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer, comprising the following steps:
a) reacting the compound of formula (V) with compound of formula (VI) in presence of dimethyl sulfoxide (DMSO) to obtain in-situ of Luliconazole mixture (E/Z) (III),
b) treating an in-situ of Luliconazole mixture (E/Z) (III) in a suitable solvent with hydrobromic acid (HBr) at elevated temperature to obtain an E-isomer of Luliconazole hydrobromic acid (II), and
c) basifying the E-isomer of Luliconazole hydrobromic acid (II) to obtain E-isomer of

The present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer can be obtained by the treatment of hydrobromic acid at elevated temperature in a transformation methodology.
In an embodiment of the present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer, comprising the following steps:
N'
a) treating an Luliconazole mixture (E/Z) (III) in a suitable solvent with an hydrobromic acid (HBr) at elevated temperature to obtain an E-isomer of Luliconazole hydrobromic acid (II), and
b) basifying the E- isomer of Luliconazole hydrobromic acid (II) to obtain E-isomer of Luliconazole (I).
According to the embodiment of the present invention comprises by contacting a Luliconazole mixture (E/Z) (III) in a suitable solvent with an hydrobromic acid (HBr) and the reaction is carried out at suitable temperature an about 20 to 120°C for 2 to 6 hours or till its disappearance of Z-isomer. The reaction mass was cool to 10-35ºC and stir for 2-3 hours at 10-35ºC. The resultant solid was filtered and washed with suitable solvent to obtain a wet solid; further it was basified in presence of suitable solvent and adjust pH 8-9 to obtain crude Luliconazole (I) and further it was crystallized in presence of suitable solvents to get pure Luliconazole (I).
In an embodiment of the present invention was observed, E-isomer of Luliconazole (I) was enriched, particularly when the Luliconazole hydrobromic acid is precipitated into the reaction medium. This surprising effect allows, by means of a hydrobromic acid to transform the Z-isomer into the E-isomer by the formation of the corresponding Luliconazole hydrobromic acid.

In another embodiment the present invention provides a process for preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer, comprising the following steps:
a) reacting the compound of formula (V) with compound of formula (VI) in presence of dimethyl sulfoxide (DMSO) to obtain in-situ of Luliconazole mixture (E/Z) (III),
b) treating an in-situ of Luliconazole mixture (E/Z) (III) in a suitable solvent with hydrobromic acid (HBr) at elevated temperature to obtain an E-isomer of Luliconazole hydrobromic acid (II), and
c) basifying the E-isomer of Luliconazole hydrobromic acid (II) to obtain E-isomer of Luliconazole (I).
According to the embodiment of the present invention the Luliconazole mixture (E/Z) (III) can be generated in situ through the reaction of the compound of formula (V) with compound of formula (VI) in presence of dimethyl sulfoxide (DMSO). The resulting Luliconazole mixture (E/Z) (III) is treated with hydrobromic acid at elevated emperature and further converted into Luliconazole hydrobromic acid (II) (enriched in the E-isomer). The obtained Luliconazole hydrobromic acid (II) was basified in presence of suitable base to provide Luliconazole (I)
According to the embodiment of the present invention, the reaction is carried out at suitable temperature an about 20 to 120°C for 2 to 6 hours. The reaction mass was cool to 10-35ºC and stir for 2-3 hours at 10-35ºC. The resultant solid was filtered and washed with suitable solvent to obtain a wet solid; further it was suspended in a suitable solvent, adjust at pH 8-9 with suitable base to obtain Luliconazole(I).
According to the embodiment of the present invention, the suitable solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, methanol, ethanol, isopropanol,

dichloromethane, toluene, dimethylformamide, dimethylacetamide, acetonitrile, cyclohexane, water and or mixtures thereof.
According to the embodiment of the present invention, the base or suitable base is selected from ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
According to the embodiment of the present invention, the hydrobromic acid used can be anhydrous or aqueous. In the case of an aqueous hydrobromic acid (5-48%). In the case of an anhydrous hydrobromic acid or anhydrous hydrobromic acid in acetic acid (5-33%).
In yet another embodiment of the present invention, “substantially free of Z-isomer” means that the amount of Z-isomer is not higher than 0.05%, preferably not higher than 0.1%, determined by HPLC.
The advantages of the present claimed invention are as follows:
> The present invention is to provide a simple, operation friendly process for the preparation of Luliconazole with high purity and good yield.
> The present invention process is eco-friendly, commercially viable and industrial applicable process.
> The present invention avoids column chromatography for purification.
> The present inventor has found by the treatment of hydrobromic acid at elevated temperature w.r.t transformation methodology to get pure E-isomer of Luliconazole.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0 g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs. The reaction mass was quenched into pre-chilled water upon completion of the reaction. Extracted the reaction mass with ethyl acetate and the corresponding ethyl acetate layer was treated with water. The ethyl acetate layer was dried and further treated with aqueous hydrobromic acid (70.0 ml) at 60-65oC for 4-5 hrs. The reaction mass temperature was cool to 20-25oC and stir for 2-3 hrs at 20-25oC. Filter the solid and wash with ethyl acetate.
To a suspension of wet solid in ethyl acetate was treated with aqueous ammonium hydroxide solution up to basic pH of 8-9, separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent was distil off completely under vacuum and followed by crystallization with cyclohexane to isolate the Luliconazole as an off white solid (98.0g), Yield: 84.4%, HPLC purity=99.50% (Z-isomer=0.1%).
IR (cm-1): 3077, 2194, 1583, 1550, 1461, 1302, 1101, 1060, 1045, 820, 739, 657.
1H-NMR (400 MHz, CDCl3): 7.627 (s, 1H); 7.58-7.60 (d, 1H); 7.48-7.49 (d, 1H); 7.175 (s, 1H); 7.054 (s, 1H); 5.67-5.71 (q, 1H); 3.86-3.90 (m, 1H); 3.63-3.68 (m, 1H).
Example-2:
To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0 g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs. The reaction mass was quenched into pre-chilled water upon completion of the reaction, extracted the reaction mass with ethyl acetate and the corresponding ethyl acetate layer was treated with water. The ethyl acetate layer was dried and further treated with anhydrous hydrobromic acid (70.0 ml) at 60-65oC for 4-5

hrs. The reaction mass temperature was cool to 20-25oC and stir for 2-3 hrs at same temperature. Filter the solid and wash with ethyl acetate.
To a suspension of wet solid in ethyl acetate was treated with aqueous ammonium hydroxide solution up to basic pH of 8-9, separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent was distilled out completely under vacuum and followed by crystallization with cyclohexane/ ethyl acetate to isolate the Luliconazole as an off white solid (94.0g), Yield: 81%, HPLC purity=99.50% (Z-isomer=0.05%).
Example-3:
To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0 g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs. The reaction mass was quenched into pre-chilled water upon completion of the reaction, extracted the reaction mass with ethyl acetate and the corresponding ethyl acetate layer was treated with water. The ethyl acetate layer was dried and further treated with anhydrous hydrobromic acid (70.0 ml) at 60-65oC for 4-5 hrs. The reaction mass temperature was cool to 20-25oC and stir for 2-3 hrs at same temperature. Filter the solid and wash with ethyl acetate.
To a suspension of wet solid in ethyl acetate was treated with aqueous sodium bicarbonate solution up to basic pH of 8-9, separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent completely was distilled out completely under vacuum and followed by crystallization with cyclohexane to isolate the Luliconazole as an off white solid (87.6g), Yield: 75.5%, HPLC purity=99.40% (Z-isomer=0.08%).
Example-4:
To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0 g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs. The reaction mass was quenched into pre chilled water upon

completion of the reaction. Extracted the reaction mass with ethyl acetate and the corresponding ethyl acetate layer was treated with water. The ethyl acetate layer was dried and further treated with hydrobromic acid (70.0 ml) at 60-65oC for 4-5 hrs. The reaction mass temperature was cool to 20-25oC and stir for 2-3 hrs at 20-25oC. Filter the solid and wash with ethyl acetate.
To a suspension of wet solid in ethyl acetate was treated with aqueous sodium carbonate solution up to basic pH of 8-9. Separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent was distil off completely under vacuum and followed by crystallization with cyclohexane to isolate the Luliconazole as an off white solid (93.0g), Yield: 80.0%, HPLC purity=99.60% (Z-isomer=0.1%).
Example-5:
To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0 g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs. The reaction mass was quenched into pre chilled water upon completion of the reaction. Extracted the reaction mass with ethyl acetate and the corresponding ethyl acetate layer was treated with water. The ethyl acetate layer was dried and further treated with anhydrous hydrobromic acid (70.0 ml) at 60-65oC for 4-5 hrs. The reaction mass temperature was cool to 20-25oC and stir for 2-3 hrs at 20-25oC. Filter the solid and wash with ethyl acetate.
To a suspension of wet solid in ethyl acetate was treated with aqueous sodium carbonate solution up to basic pH of 8-9. Separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent was distil off completely under vacuum and followed by crystallization with methanol/water to isolate the Luliconazole as an off white solid (84.0g), Yield: 72.4%, HPLC purity=99.65% (Z-isomer=0.07%).
Example-6:
To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0

g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs. The reaction mass was quenched into pre chilled water upon completion of the reaction. Extracted the reaction mass with ethyl acetate and the corresponding ethyl acetate layer was treated with water. The ethyl acetate layer was dried and further treated with anhydrous hydrobromic acid (70.0 ml) at 60-65oC for 4-5 hrs. The reaction mass temperature was cool to 20-25oC and stir for 2-3 hrs at 20-25oC. Filter the solid and wash with ethyl acetate.
To a suspension of wet solid in ethyl acetate was treated with aqueous sodium hydroxide solution up to basic pH of 8-9. Separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent was distil off completely under vacuum and followed by crystallization with methanol/water to isolate the Luliconazole as an off white solid (82.0g), Yield: 70.68%, HPLC purity=99.65% (Z-isomer=0.07%).
Example-7: (comparative example)
To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate (100.0 g, 0.329 mol) was added a previously prepared solution of cyanomethyl imidazole (36.0 g, 0.336 mol)/powdered potassium hydroxide (38.0 g, 0.677 mol)/ carbon disulphide (25.0 g, 0.341 mol) in Dimethyl sulfoxide (DMSO) at a temperature 15-20oC over a period of 1-2hrs.The reaction mixture was quenched in water. The reaction mixture was extracted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried and further added a solution of ethyl acetate. HCl, stirred. The reaction mixture was distilled to obtain solid. The solid was stirred in acetone, filtered and dried to get Luliconazole hydrochloride. Chiral purity: 95.0 %, HPLC Purity> 99.5%. Z: isomer content: 4.34, other undesired isomer content: 0.65
To a suspension of wet solid in ethyl acetate was treated with aqueous ammonium hydroxide solution up to basic pH of 8-9. Separated the ethyl acetate layer, the subjected ethyl acetate layer was further treated with water and followed by brine solution. The resultant solvent was distil off completely under vacuum and followed by crystallization from cyclohexane to isolate the Luliconazole as an off white solid (36.0g), Yield: 31%, HPLC purity=94.50% (Z-isomer=4.0%).

To a solution of (S)-2-chloro-1-(2,4-dichlorophenyl) ethanol (100.0g, 0.44 mol) and triethylamine (60.0g, 0.593 mol) in toluene was added methane sulfonyl chloride (70.0g, 0.611 mol) as a drop wise at a temperature below 5oC during a period of 1hr. The reaction mass was stir at 5oC for 1-2 hrs, further it was treated with water after completion of the reaction by TLC. The resultant toluene layer was treated with sodium bicarbonate solution, followed by brine solution and dried over sodium sulphate. The obtain toluene layer was distilled at below 50oC under vacuum and isolate with cyclohexane to afford (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate as an off white solid (130.0g), Yield: 97%, HPLC purity: 98.9%.
IR (cm-1): 3042, 2962, 1583, 1590, 1474, 1426, 1368, 1343, 1210, 1175, 1001, 989, 968, 954, 904, 827, 801, 780.
1H-NMR (400 MHz, DMSO-D6): 7.71-7.72 (d, 1H); 7.63-7.66 (d, 1H); 7.53-7.56 (dd, 1H); 5.99-6.02 (t, 1H); 4.05-4.06 (d, 2H); 3.22 (s, 3H).

A process for the preparation of E-isomer of Luliconazole (I) with substantially free of Z-isomer, comprising the following steps:
treating an Luliconazole mixture (E/Z) (III) in a suitable solvent with an hydrobromic acid (HBr) at elevated temperature to obtain an E-isomer of Luliconazole hydrobromic acid (II), and
basifying the E- isomer of Luliconazole hydrobromic acid (II) to obtain E-isomer of Luliconazole (I).

a) reacting the compound of formula (V) with compound of formula (VI) in presence of dimethyl sulfoxide (DMSO) to obtain in-situ of Luliconazole mixture (E/Z) (III),
b) treating an in-situ of Luliconazole mixture (E/Z) (III) in a suitable solvent with hydrobromic acid (HBr) at elevated temperature to obtain an E-isomer of Luliconazole hydrobromic acid (II), and
c) basifying the E-isomer of Luliconazole hydrobromic acid (II) to obtain E-isomer of Luliconazole (I).

3. The process as claimed in claim 1 and 2, wherein the suitable solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, dichloromethane, toluene, dimethylformamide, dimethylacetamide, acetonitrile, cyclohexane, water and or mixtures thereof.
4. The process as claimed in claim 1 and 2, wherein the base is selected from ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, trimethylamine and triethylamine.

The process as claimed in claim 1 and 2, wherein the hydrobromic acid is aqueous hydrobromic acid (5-48%), anhydrous hydrobromic acid or anhydrous hydrobromic acid in acetic acid (5-33%).

ABSTRACT
TITLE: “PROCESS FOR THE PREPARATION OF LULICONAZOLE”
The present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer and unwanted salts.
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