“PREPARATION OF FENTICONAZOLE NITRATE”
FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of Fenticonazole nitrate of Formula (I) with commercially viable and industrial applicable process.
BACKGROUND OF THE INVENTION:
Fenticonazole nitrate is a drug chemically known as 1-[2-(2,4-dichlorophenyl)-2-[[4-(phenylthio)phenyl]methoxy]ethyl]-1H-Imidazole nitrate of formula (I) with a molecular formula C24H20Cl2N2OS.HNO3. It is an imidazole antifungal drug, used locally as the nitrate in the treatment of vulvovaginal candidiasis. It is active against a range of organisms including dermatophyte pathogens, Malassezia furfur, and Candida albicans.
Fenticonazole nitrate (I) was first described in US 4,221,803 and its process for the preparation of Fenticonazole nitrate (I) comprising 1-chloroacetyl-2,4-dichloro-benzene (VI) by reduction of the keto group using sodium borohydride and condensed with imidazole (VIII) to obtain 1-(2’,4’-dichlorophenyl)-2-(N-imidazolyl)-ethanol (V). The compound of formula (V) is reacted with (4-

(chloromethyl)phenyl)(phenyl)sulfane (IV) and followed by treated with nitric acid to get Fenticonazole nitrate (I).which is depicted in the scheme-I given below.
CN 102180835 Bdiscloses a process for the preparation of Fenticonazole nitrate (I) by reacting 2,4,2'-Trichloroacetophenoneis (VI)reacted with imidazole (VIII), which is followed by reduced in presence of potassium borohydride to get 1-(2’,4’-dichlorophenyl)-2-(N-imidazolyl)-ethanol (V); further it is reacted with (4-(chloromethyl)phenyl)(phenyl)sulfane (IV) in presence of Phase transfer catalyst (PTC) and followed by reacted with nitric acid to obtain Fenticonazole nitrate (I).

The major disadvantage with the above prior art processescauses for unwanted impurities and that leads to lower yield. Hence the said prior art processes are not industrial viable.
The present invention has advantages over the prior art processes, which are industrially friendly by preparing Fenticonazole hydrochloride and further it is hydrolysis to remove unwanted impuritiesby producinghigh purity and good yield of Fenticonazole and then it is treated with nitric acid to give Fenticonazolenitrate. Similarly, the present invention involves simple steps which are commonly adopted in industrial scale.
The present invention involves the use of commercially available and less expensive compare to prior art process in the preparation of Fenticonazole nitrate.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Fenticonazole nitrate in terms of good yield and purity.
In an aspect of the present invention relates to aprocess for the preparation of Fenticonazole nitrate of formula (I), which comprises reacting
a) (4-(phenylthio)phenyl)methanol (III) converts into (4-(chloromethyl)phenyl) (phenyl)sulfane (IV) in presence of chlorinating agent,
b) (4-(chloromethyl)phenyl)(phenyl) sulfane (IV) is reacted with 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (V) in presence inorganic base/ Isopropyl alcohol / HClto get Fenticonazole hydrochloride(Ia),
c) hydrolysis of Fenticonazole hydrochloride(Ia) with alkali base, and
d) further reacted with nitric acid to get Fenticonazole nitrate (I).
The above synthetic process is illustrated by the following Scheme:

DETAILEDDESCRIPTION OF THE INVENTION
The present invention relates to aprocess for the preparation of Fenticonazole nitrate
by using Fenticonazole hydrochloride.The present invention is also
providescommercially viable and industrially applicable process for the preparation of Fenticonazole nitrate
An embodiment of the present invention provides aprocess for the preparation of Fenticonazole nitrate of formula (I), which comprises
a) (4-(phenylthio)phenyl)methanol (III) converts into (4-(chloromethyl)phenyl)(phenyl) sulfane (IV) in presence of chlorinating agent,
b) (4-(chloromethyl)phenyl)(phenyl) sulfane (IV) is reacted with 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (V) in presence inorganic base/ isopropyl alcohol / HCl to get Fenticonazole hydrochloride (Ia),
c) hydrolysis of Fenticonazole hydrochloride (Ia) with alkali base, and
d) further reacted with nitric acid to get Fenticonazole nitrate (I).
According to an embodiment of the present invention, wherein (4-(phenylthio)phenyl)methanol (III) converts into (4-(chloromethyl)phenyl)(phenyl) sulfane (IV) in presence of chlorinating agent and organic solvent at room

temperature and maintain it for 5-10 hrs, preferably 25 to 30°C for 6-8 hours.The compound of formula (IV) is reacted with 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (V) in presence of phase transfer catalyst (PTC), organic solvent and inorganic base followed by reacted with IPA.HCl at ambient temperature under adjust pH to 1-5 preferably at 25-30°Cunder pH 1-2 and stir for 60 minutes. The resultant solid was filtered to obtain Fenticonazole hydrochloride (Ia) and followed by hydrolysis in presence of alkali base; further it is reacted with nitric acid in presence of solvent at below 10˚C and stir for 30 min to obtain Fenticonazole nitrate (I).
In an embodiment of the present invention, the suitable chlorinating agent is selected from thionyl chloride, calcium hypochlorite, lithium hypochlorite, sodium hypochlorite,phosphoryl chloride, phosphorus pentachloride, chlorine gas and hydrochloric acid gas. Most preferably hydrochloride gas.
According to an embodiments of the present invention, the suitable alkali base is selected fromsodium hydroxide, potassium hydroxide and lithium hydroxide, etc. preferably sodium hydroxide.
According to an embodiments of the present invention, the phase transfer catalyst is selected fromTetra-butylammonium bromide (TBAB), Tetrabutylammonium hydroxide, Tetrabutylammonium fluoride, Tetrabutylammonium tribromide, Tetramethylammonium chloride, Tetramethylammonium hydroxide and Tetramethyl ammonium penta fluoroxenate. Preferably Tetra-butylammonium bromide (TBAB).
According to an embodimentsof the present invention, the suitable organic solvents are selected from hydrocarbon solvents such as toluene, xylene, cyclohexane and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof; ketones such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; and amides such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide and the like or mixture of solvents thereof.

Advantages of the present invention:
1. The present invention is a simple, mild, facile, operation friendly, commercially viable and industrially applicable process.
2. The reaction sequence of the present invention is carried out in a less spanof time with high purity and less impurity profile.
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.
Experimental procedure:
Example: 1
Process for the preparation of 4-phenylthiobenzylchloride:
Charge toluene (400ml), 4-phenyl thiobenzyl alcohol (100gm) into the R.B flask at 25-30˚C and pass dry hydrochloride gas (~200gm) to the reaction mixture at 25-30˚C for 3-4 hrs, maintain it for 6-8 hrs. The resultant mixture was added purified water (200 ml), stir the mixture for 10 min and settled for 20 min. to separate the layers. Take toluene layer into the flask and wash with 5% sodium bi carbonate solution(200 ml), and further it was washed with purified water (400ml). The obtain toluene layer was distilled out under reduced pressure at below 60˚C to get a title compound.
Example: 2
Process for the preparation of 4-phenylthiobenzylchloride:
Charge toluene (400 ml), 4-phenyl thiobenzyl alcohol (100 gm) into the R.B flask at 25-30˚C and pass chlorine gas to the reaction mixture at 25-30˚C for 3-4 hrs, maintain it for 6-8 hrs. Theresultant mixture was added purified water (200 ml), stir the mixture

for 10 min and settled for 20 min. to separate the layers. Take toluene layer into the flask and wash with 5% sodium bi carbonate solution (200 ml),and further it was washed with purified water (400ml). The obtain toluene layer was distilled out under reduced pressure at below 60˚C to get a title compound.
Example: 3 Process for the preparation of 4-phenylthiobenzylchloride:
Charge toluene (400 ml), 4-phenyl thiobenzyl alcohol (100 gm) into the R.B flask at 25-30˚C and slowly add thionyl chloride to the reaction mixture at 25-30˚C and heat to 50-60˚C, maintain it for 6-8 hrs. The resultant mixture was added to purified water (200 ml), stir the mixture for 10 min and settled for 20 min. to separate the layers. Take toluene layer into the flask and wash with 5% sodium bi carbonate solution (200 ml), and further it was washed with purified water (400 ml). The obtain toluene layer was distilled out under reduced pressure at below 60˚C to get a title compound.
Example: 4
Process for the preparation of Fenticonazole hydrochloride:
Take a clean and dry the R.B flask, charge toluene (650 ml), added2,4-dichlorophenyl-2-1H imidazole-1-yl ethanol (120 gm) and sodium hydroxide solution (63.0 gm dissolve 63.0ml of purified water) at below 40˚C.The reaction mixture was cooled to 25-30˚C, added tetra butyl ammonium bromide (20.0 gm) at 25-30˚C, stir the mixture for 6-8 hrs at 25-30˚C and then slowly added 4-phenylthiobenzylchloride (100.0 gm) over a period of 2-3 hrs and maintain the mixture for 12-15 hrs at 25-30˚C. The completion of the reaction (checked by TLC), added purified water (400ml) into the reaction mixture, stir the mixture for 15min and settlethe mixture for 10min to separate the layers. Take toluene layer and wash with sodium chloride solution (200ml), followed by wash with purified water (400ml). The obtain toluenelayer was adjust pH to 1.0 to 2.0 with isopropanol hydrochloride solution at 25-30˚C and then resultant isopropanol was distilled out under reduced pressure at below 80˚C; Further it allows to cool the mixture to 10-15˚C and stir for 60 min. The resultant solid was filtered, washed with toluene (50ml) /purified water (500ml) and dried at 60-65˚C for 8-10 hrs to obtain a title compound

Dry wt: - 200.0 gm
Example: 5
Process for the preparation of Fenticonazole nitrate:
Take a clean and dry R.B flask, charge purified water (400ml),ethyl acetate (400ml) and Fenticonazole hydrochloride (200 gm) were added at 25-30˚C. The reaction mixture was cooled to 0-5˚C, adjust the reaction mixture pH 9.0 to 10.0 with 10% sodium hydroxide solution and stir for 10 min to separate layers. Theethyl acetate layer was washed with brine solution (200 ml) and purified water (200ml). Theethyl acetate layer was slowly adjust pH 1.0-2.0 with aqueous nitric acid (~60-70%) at below 10˚C and stir for 30min at same temperature. The obtainsolid was washed with purified water (400ml) and ethyl acetate (100ml). The resultant solid was filtered and dried at 50-60˚C for 6-8 hrs to obtain title compound.

WE CLAIM:
1. An improved process for the preparation of Fenticonazole nitrate of formula (I), which comprises
a) (4-(phenylthio)phenyl)methanol (III) converts into (4-(chloromethyl)phenyl)(phenyl) sulfane (IV) in presence of chlorinating agent,
b) (4-(chloromethyl)phenyl)(phenyl) sulfane (IV) is reacted with 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (V) in presence inorganic base/ Isopropyl alcohol / HCl to get Fenticonazole hydrochloride (Ia),
c) hydrolysis of Fenticonazole hydrochloride (Ia) with alkali base, and
d) further reacted with nitric acid to get Fenticonazole nitrate (I).
2. The process as claimed in claim 1, the chlorinating agent is selected from thionyl chloride, calcium hypochlorite, lithium hypochlorite, sodium hypochlorite, phosphoryl chloride, phosphorus pentachloride chlorine gas and hydrochloric acid gas. Most preferably hydrochloride gas.

3. The process as claimed in claim 1, the organic solvent is selected from the group consisting of toluene, ethyl acetate, dimethyl formamide, methanol, ethanol, isopropyl alcohol and dichloromethane.
4. The process as claimed in claim 1, the suitable alkali base is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide. Preferably sodium hydroxide.
5. The process as claimed in claim 1, the phase transfer catalyst is selected from Tetra-butyl ammonium bromide (TBAB), Tetra butyl ammonium hydroxide, Tetra butyl ammonium fluoride, Tetra butyl ammonium tribromide, Tetra methyl ammonium chloride, Tetra methyl ammonium hydroxide and Tetra methyl ammonium penta fluoroxenate. Preferably Tetra-butyl ammonium bromide (TBAB).