FIELD OF THE INVENTION
The present invention relates an improved process for the purification of Luliconazole.
The present invention relates to an improved process for the purification of Luliconazole which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Luliconazole is an antifungal agent developed by Nihon Nohyaku. Luliconazole is approved by FDA in 2013. Luliconazole is marketed by Medicis Pharmaceutical Corp under the brand name LUZU. Luliconazole is chemically described as (2E)-2-[(4R)-4-(2,4-dichlorophenyl)-l,3-dithiblan-2-ylidene]-2-imidazol-l-ylacetonitrile. Its structural formula is
Formula I The molecular formula of Luliconazole is C14H9CI2N3S2 with a molecular weight of 354.28. Luliconazole is the R-enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration.
Luliconazole is disclosed in US 5,900,488, this patent also discloses the process for the preparation of Luliconazole by reacting (S)-2-bromo-l-(2,4-dichlorophenyl)ethyl methanesulfonate with potassium salt of 3,3-dimercapto imidazole intermediate to give Luliconazole. The process is shown in the scheme given below:
Scheme I:

US '488 discloses the use of silica gel chromatography technique for the purification of Luliconazole, which is highly disadvantageous at bulk level. Hence, the said process is not feasible at industrial level.
CN103012385 B discloses crystalline Form-I of Luliconazole characterized by its PXRD values.
US 9,012,484 B2 discloses a crystal composite consisting of Luliconazole and 100 to 10,000 ppm of short chain alcohol having a number of carbon atom or atoms of 1 to 4 with respect to a total amount of the crystal composite.
' The present inventors have developed an improved process for the purification of Luliconazole which results in greater efficiency than the prior art processes with higher product purity. Luliconazole prepared by the present process is free of any diastereomeric and chiral impurities.
OBJECT OF THE INVENTION
The main object of the invention is to provide a simple, cost effective, improved and robust process for the purification of Luliconazole yielding at a high yield with high purity without formation of undesired impurities such as chiral or diastereomeric impurities.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the purification of Luliconazole of Formula I
which comprises;
a. dissolving crude Luliconazole in the mixture of alcohols, L stir the reaction mass for about 30 minutes, and " isolating fte%uTe LiuliconazoleC

In a preferred aspect, the present invention provides an improved process for the purification of Luliconazole of Formula I
Formula I which comprises;
a. crystallizing the crude Luliconazole from mixture of 40% methanol and IP A, and
b. isolating the pure Luliconazole.
In another preferred aspect, the present invention provides an improved process for the purification of Luliconazole of Formula I
Formula I which comprises;
a. dissolve crude Luliconazole in mixture of 40% methanol and IP A,
b. stir the reaction mass for about 30 minutes,
c. optionally filtering the reaction mass to obtain solid,
d. added hexane or ethylacetate or their mixture, and
e. isolating the pure Luliconazole.
In yet another preferred aspect, the present invention provides an improved process for the purification of Luliconazole of Formula I

Formula I which comprises;
a. dissolve crude Luliconazole in ethyl acetate,
b. add hexane to the reaction mass,
c. cool the reaction mass,
d. filter the reaction mass,
e. crystallize the crude Luliconazole from mixture of 40% methanol and IP A, and
f. isolate the pure Luliconazole
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1: Powder X-ray diffractogram of Form-S of Luliconazole.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the purification of Luliconazole of Formula I
Formula I The inventors of the present invention has developed an improved process for the purification of Luliconazole which involves the crystallization of Luliconazole in the mixture of methanol and IPA.
In a preferred embodiment, the purification reaction is carried out in 40% mixture of methanol and IPA. The purity and yield of Luliconazole is comparatively higher when it is performed only in 40% mixture of methanol and IPA.

The purity and yield of Luliconazole was unsatisfied when the purification is carried out in other proportions of methanol and IPA mixture or other solvent mixture. Hence, the inventors of the present invention surprisingly found the present invention which is commercially feasible.
Luliconazole contains chiral center as well as double bond due to which unwanted isomers were generated during the synthesis, prior art process opted column technology to remove such impurities. However, the usage of column at industrial level highly unacceptable.
The alcohol described in the present invention can be preferably exemplified, for example, by alcohol having a straight chain or a side chain and having a number of carbon atom or atoms of 1 to 4 such as methanol, ethanol, isopropyl alcohol, and butanol [for example, methanol, ethanol, 1-propanol (propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec-butyl alcohol), 2-methyl- 1-propanol (isobutyl alcohol), and 2-methyl-2-propanol (tert-butyl alcohol)]. In particular, it is preferable to use the mixture of methanol and isopropyl alcohol.
The inventors of the present invention has developed an improved process for the purification of Luliconazole which avoids column technology and also the pure Luliconazole prepared according to the present process contains Z or SE isomer of Luliconazole less than 0.5% w/w with respect to Luliconazole as measured by HPLC.
In another preferred embodiment, the Luliconazole crystallized from mixture of methanol and IP A.
Luliconazole as prepared according to the present invention is named as crystalline Form-S which is characterized by its PXRD pattern having characteristic 29 peaks at 16.3, 21.8 & 23.3 ±20.

In a preferred embodiment crystalline Form-S of Luliconazole is further characterized by characteristic 29 peaks at 13.6, 16.3, 18.3, 21.3, 21.8, 23.3 and 25.7 ±26.
The present invention provides an improved process for the purification of Luliconazole of Formula I
which comprises;
a. dissolving crude Luliconazole in a mixture of alcohols,
b. stir the reaction mass for about 30 minutes, and
c. isolating the pure Luliconazole.
In a preferred embodiment, the present invention provides an improved process for the purification of Luliconazole of Formula I
which comprises;
a. crystallizing the crude Luliconazole from mixture of 40% methanol and IP A, and
b. isolating the pure Luliconazole.
In yet another preferred embodiment, the present invention provides an improved ■ process for the purification of Luliconazole of Formula I

which comprises;
a. dissolve crude LuJiconazole in mixture of 40% methanol and IPA,
b. stir the reaction mass for about 30 minutes,
c. optionally filtering the reaction mass to obtain solid,
d. added hexane or ethylacetate or their mixture, and
e. isolating the pure Luliconazole.
In yet another preferred embodiment, the isolation of pure Luliconazole is carried out by removal of solvent which can be carried out any known methods such as filtration, distillation, evaporation, centrifugation, spray drying, and freeze drying.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Example-1: 65g of crude Luliconazole was dissolved in mixture of 40% of methanol and
IPA (208 ml of methanol + 312 ml of IPA) at RT. Reaction mass was stirred at RT for
lOmin, temperature was raised to reflux. Reaction mas was stirred for 30 mint. Reaction mas
was cooled to RT and stirred for 2hrs. Filter the solid and washed with mixture of 40% of
methanol and IPA (26ml of methanol + 39 ml of IPA). Dried the solid under air over at 40-
45°C.
Yield: 20-25gms.
Optical purity of 99 ee%.
Example-2: 5g of crude Luliconazole was dissolved in mixture of methanol and n-butanol (25 ml of methanol + 25ml of n-butanol) at RT. Reaction mass was stirred at RT for lOmin, temperature was raised to reflux. Reaction mas was stirred for 30 mint. Reaction mas was cooled to RT and stirred for 2hrs. Filter the solid and washed with mixture of methanol and n-butanol. Dried the solid under air over at 40-45°C.

Yield: 1.5gms.
Optical purity of 99 ee%.
Example-3: 5g of crude Luliconazole was dissolved in mixture of ethanol (25 ml) and
Isopropyl alcohol (25ml) at RT. Reaction mass was stirred at RT for lOmin, temperature was
raised to reflux. Reaction mas was stirred for 30 mint. Reaction mas was cooled to RT and
stirred for 2hrs. Filter the solid and washed with mixture of ethanol and Isopropyl alcohol.
Dried the solid under air over at 40-45°C.
Yield: lgm.
Optical purity of 99 ee%.
Example-4: 5g of crude Luliconazole was dissolved in mixture of ethanol (30 ml) and n-
butanol (20ml) at RT. Reaction mass was stirred at RT for lOmin, temperature was raised to
reflux. Reaction mas was stirred for 30 mint. Reaction mas was cooled to RT and stirred for
2hrs. Filter the solid and washed with mixture of ethanol and n-butanol. Dried the solid under
air over at 40-45°C.
Yield: 0.8gm.
Optical purity of 99 ee%.
Example-5: 5g of crude Luliconazole was dissolved in mixture of ethanol (30 ml) and n-
butanol (20ml) at RT. Reaction mass was stirred at RT for lOmin, temperature was raised to
reflux. Reaction mas was stirred for 30 mint. Reaction mas was cooled to RT and stirred for
2hrs. Filter the solid and washed with mixture of ethanol and n-butanol. Dried the solid under
air over at 40-45 °C.
Yield: 0.8gm.
Optical purity of 99 ee%.
Example-6: 65g of crude Luliconazole was dissolved in mixture of 40% of methanol and IPA (208 ml of methanol + 312 ml of IP A) at RT. Reaction mass was stirred at RT for lOmin, temperature was raised to reflux. Reaction mas was stirred for 30 mint. Reaction mas was cooled to RT and stirred for 2hrs. Filter the solid and washed with mixture of 40% of methanol and IPA (26ml of methanol + 39 ml of IPA). The obtained solid was dissolved in 100ml of ethylacetate. Reaction mass was heated to reflux. Reaction mas was cooled to RT

followed by cooling to 0-5°C. 240ml of hexane was added to the reaction mass. Filter the
solid. Dried the compound.
Yield: 20gms.
Optical purity of 99 ee%.
Example-6: 65g of crude Luliconazole was dissolved in mixture of 40% of methanol and IPA (208 ml of methanol + 312 ml of IP A) at RT. Reaction mass was stirred at RT for lOmin, temperature was raised to reflux. Reaction mas was stirred for 30 mint. Reaction mas was cooled to RT and stirred for 2hrs. Filter the solid and washed with mixture of 40% of methanol and IPA (26ml of methanol + 39 ml of IPA). The obtained solid was dissolved in 100ml of ethyl acetate. Reaction mass was heated to reflux. Stirred for 30mints. Cooled to 0-5°C. Filter the solid. Dried to obtain Luliconazole. Yield: 14gms. Optical purity of 99 ee%.

We Claims:
1. An improved process for the purification of Luliconazole of Formula I
which comprises;
a. dissolving crude Luliconazole in the mixture of alcohols,
b. stir the reaction mass for about 30 minutes, and
c. isolating the pure Luliconazole.
2. An improved process according to claim 1, wherein the alcohol is selected from methanol, ethanol, isopropyl alcohol, and butanol [for example, methanol, ethanol, 1-propanol (propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec-butyl alcohol), 2-methyl- 1-propanol (isobutyl alcohol), and 2-methyl-2-propanol (leil-bulyl alcohol)]. In particular, it is preferable to use the mixture of methanol and isopropyl alcohol.
3. An improved process for the purification of Luliconazole of Formula I
which comprises;
a. crystallizing the crude Luliconazole from mixture of 40% methanol and IPA, and
b. isolating the pure Luliconazole.
4. An improved process for the purification of Luliconazole of Formula I

Formula I which comprises;
a. dissolve crude Luliconazole in mixture of 40% methanol and IPA,
b. stir the reaction mass for about 30 minutes,
c. optionally filtering the reaction mass to obtain solid,
d. added hexane or ethylacetate or their mixture, and
e. isolating the pure Luliconazole.
5. An improved process according to claim 4, wherein the alcohol is selected from methanol, ethanol, isopropyl alcohol, and butanol [for example, methanol, ethanol, 1-propanol (propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec-butyl alcohol), 2-methyl- 1-propanol (isobutyl alcohol), and 2-methyl-2-propanol (tert-butyl alcohol)]. In particular, it is preferable to use the mixture of methanol and isopropyl alcohol.
6. An improved process for the purification of Luliconazole of Formula I
Formula I which comprises;
a. dissolve crude Luliconazole in ethyl acetate,
b. add hexane to the reaction mass,
c. cool the reaction mass,
d. filter the reaction mass,
e. crystallize the crude Luliconazole from mixture of 40% methanol and IPA, and
f. isolate the pure Luliconazole.