Fenticonazole

Originator

Lomexin,Effik

Uses

Isotope labelled Fenticonazole Nitrate broad spectrum antimycotic; also active as antibacterial. Antifungal (topical).

Uses

Antifungal.

Definition

ChEBI: 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole is a member of the class of imidazoles that carries a 2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl group at position 1. It is a member of imidazoles, a dichlorobenzene, an ether and an aryl sulfide.

Indications

Topical treatment of mycoses of the skin induced or sustained by fungi such as dermatophytes and yeasts. In addition, fenticonazole is indicated for therapy of vulvovaginal mycoses caused by Candida species and Candida (Torulopsis) glabrata.

Manufacturing Process

1-(2',4'-Dichlorophenyl)-2-chloroethanol:
49.5 g of sodium borohydride were added slowly and in small parts to a suspension of 233 g of 1-(1'-hydroxy-2'-chloroethyl)-2,4-dichlorobenzene in 1 liter of methanol stirred at room temperature. The solution thus obtained was stirred at room temperature for a further two hours, and it was then poured into 1 liter of 5 N hydrochloric acid cooled with ice. After extraction with ethyl acetate or chloroform, the extract was washed with water, with 1 N sodium hydroxide, then again with water until neutrality, and finally with a saturated sodium chloride solution. The extract was dried, the solvent evaporated off and 220 g of an oil were obtained. The oil solidified on standing and the solid 1-(2',4'-dichlorophenyl)-2-chloro-ethanol melted at 48-51°C.
1-(2',4'-Dichlorophenyl)-2-(N-imidazolyl)ethanol:
30 g of sodium were added to a solution of 88.5 g of imidazole in 600 ml of methanol; the solvent was then evaporated off. The residue was dissolved in 300 ml of dimethylformamide and heated to 115-120°C. To the solution so obtained was added, dropwise and under stirring, a solution of 225 g of 1- (2',4'-dichlorophenyl)-2-chloroethanol in 400 ml of dimethylformamide. The mixture was heated to 115-120°C and maintained at that temperature for 20 min and, after subsequent cooling to 40°C, 2500 ml of iced water were added under vigorous stirring. The product precipitated under stirring over a period of about two hours, the upper liquid was then decanted off, a further 2500 ml of water were added and, after standing, the whole was filtered. The precipitate thus obtained was dried and crystallized from toluene. 170 g of the 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)ethanol, melting at 134-135°C, was obtained.
METHOD 1:
A solution of 2.57 g of 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)ethanol in 10 ml of hexamethylphosphoramide was dropped at 25°C into a suspension of 0.52 g of sodium hydride (50% in oil) in 5 ml of hexamethylphosphoramide. When hydrogen emission was over, the salification was completed by heating for 1 hour at 50°C. After cooling to 25°C, 2.58 g of 1-chloromethyl-4- phenylthiobenzene were added. The temperature was raised to 50°C and maintained at that temperature for 12 hours. At the end of the reaction, the mixture was poured into 200 ml of water, the product was extracted with diethyl ether, the solvent was evaporated off and the residue was purified twice on a silica gel column, using ethyl acetate as eluant and testing the various fractions by TLC. The solvent was evaporated off the middle fractions to give 2.4 g of the 1-[2,4-dichloro-beta-[[p-(phenylthio)benzyl]oxy] phenethyl]imidazole as a yellowish oil, showing a single spot on TLC.
METHOD 2:
0.66 g of sodium hydride (50% in oil) were added at 20-30°C and under nitrogen atmosphere to 3.86 g of 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl) ethanol in 15 ml of dimethylsulphoxide (dried on calcium hydride). The mixture was heated under stirring at 50-60°C until gas emission was over. After cooling to 20-25°C, 0.5 g of potassium iodide were added and slowly a solution of 3.51 g of 1-chloromethyl-4-phenylthiobenzene in 4 ml of dimethylsulphoxide was dropped in. The mixture was stirred at 20-25°C until addition of the 1-chloromethyl-4-phenylthiobenzene was over. The mixture was then poured into 150 ml of water and extracted with diethyl ether. To the etheric solution, after drying on anhydrous sodium sulphate, was added excess 4 N nitric acid solution in diethyl ether: the desired product precipitated as nitrate, an oil which solidified on standing. After standing for 20 hours, the etheric liquid was decanted off and the residue was crystallized from ethanol. The nitrate thus obtained, not completely pure, was dissolved in water and excess sodium carbonate was added in order to liberate the base which was then extracted with ethyl acetate. The base, obtained by filtration, was purified on a silica gel column using ethyl acetate as eluant. The combined fractions containing the desired product were evaporated to dryness. The residue was dissolved in diethyl ether, again transformed into the nitrate and crystallized from ethanol. Yield: 3.1 g of a white crystalline powder, melting at 136°C; λmax 252 nm (methanol).

Therapeutic Function

Antifungal

Side effects

Local irritations such as itching and burning sensations and allergic reactions may occur in rare cases and are mainly due to the galenic formulation.

Solubility in organics

Solubility at 20 ?C: water < 0.1 mg/mL, diethyl ether < 0.1 mg/mL, ethanol 30 mg/mL, methanol 100 mg/mL, chloroform 300 mg/mL, DMF 600 mg/mL.