Butenafine

UsesButenafine (Mentax) is a synthetic benzylamine antifungal agent, related structurally and pharmacologically to terbinafine. It is thought to act by inhibiting the enzyme squalene 2,3-epoxidase, resulting in decreased ergosterol and corresponding increase in squalene, with subsequent cell membrane permeability alteration and cell death. It is active against dermatophytes, yeast, and Sporothrix.

Preparation1. Using 1-naphthoic acid as a raw material, chlorination with thionyl chloride yields 1-naphthoyl chloride, which is then condensed with 1-(4-tert-butylbenzyl)-N-methylmethylamine to give N-(4-tert-butylbenzyl)-N-methyl-1-naphthoamide. This is followed by reduction with lithium aluminum hydride and salt formation to obtain butenafine hydrochloride. 2. Using p-tert-butylbenzoic acid as a raw material, chlorination with thionyl chloride yields p-tert-butylbenzoyl chloride, which is then condensed with N-methylnaphthylmethylamine to give 4-tert-butyl-N-methyl-N-(methylnaphthyl)benzamide. This is followed by reduction with lithium aluminum hydride and salt formation to obtain butenafine hydrochloride. 3. Using naphthalene as a raw material, chloromethylation synthesizes 1-chloromethylnaphthalene, which then reacts with methylamine to generate N-methylnaphthylmethylamine. This is followed by condensation with p-tert-butylbenzyl chloride and salt formation to obtain butenafine hydrochloride. 4. Starting with naphthalene, 1-chloromethylnaphthalene was prepared by chloromethylation, and then substituted with methylamine to obtain the key intermediate N-methyl-1-naphthylmethylamine hydrochloride. This was then condensed with p-tert-butylbenzyl chloride, followed by salt formation and recrystallization to obtain butenafine hydrochloride. 5. N-methyl-1-naphthylmethylamine hydrochloride (2) (41.5 g, 0.20 mol) was added to a mixture of toluene (150 ml) and 10% sodium hydroxide solution (160 g). The mixture was heated to 80 °C, and p-tert-butylbenzyl chloride (3) (40.2 g, 0.22 mol) was added dropwise with stirring over approximately 1 hour. The reaction was continued with stirring for 3 hours. The reaction was stopped, and the organic layer was separated after cooling to room temperature. The organic layer was washed with water until neutral and dried with anhydrous sodium sulfate. After filtration, the toluene was recovered, and the residue was dissolved in an appropriate amount of ethanol. The pH was adjusted to 2 with concentrated hydrochloric acid, and the solvent was recovered to obtain a white crude product (59.8 g). Recrystallization with 50% ethanol yields a white, pure product 1.

DefinitionChEBI: Trimethylamine in which hydrogen atoms attached to different methyl groups are substituted by 1-naphthyl and 4-tert-butylphenyl groups. It is an inhibitor of squalene epoxidase, an enzyme responsible for the creation of sterols needed in funga cell membranes, and is used as its hydrochloride salt for treatment of dermatological fungal infections.