Modified syntheses of 2-(methylthio)-10-(2-(1-methyl-2-piperidinyl)ethyl)phenothiazine (thioridazine) and 1-(3-(2-(methylsulfonyl)-10-phenothiazinyl)propyl)-piperidine-4-carboxamide (metopimazine)

Abstract

Modified syntheses of the title compounds used the enhanced reactivity of the aromatic fluorine atom in exchange reactions and proceeded via fluorinated intermediates. 2-(2-Fluorophenylthio)-5-(methylthio)nitrobenzene (III) was synthesized, reduced to the amine IV which was alkylated with 2-(2-chloroethyl)-1-methylpiperidine to compound VI. This was cyclized with sodium hydride in dimethyl sulfoxide to thioridazine (I) in excellent yield. The last two steps could be combined and thioridazine resulted from IV in one step. Synthesis of metopimazine (II) started similarly from 4-(2-fluorophenylthio)-3-nitrophenyl methyl sulfone (XII) which was reduced to the amine XIV and cyclized to 2-(methylsulfonyl)phenothiazine (XVII). Alkylation of XIV with 1-(3-chloropropyl)piperidine-4-carboxamide (X) proceeded with simultaneous cyclization and afforded metopimazine (II).