Late-stage electrosynthesis of sulfoxide metabolites from phenothiazine-based antipsychotic drugs.

Abstract

Phenothiazine (PTZ)-based antipsychotic drugs are extensively metabolised in vivo, with S-oxidation representing a major metabolic pathway. Herein, we report the application of an electrosynthetic (ES) S-oxidation strategy to three distinct classes of PTZ-based drug analogues: amino alkyl, piperidine, and piperazine-containing derivatives. The sulfoxide metabolites of the amino alkyl-containing PTZs, including chlorpromazine sulfoxide (2a, 68%), promazine sulfoxide (3a, 34%), triflupromazine sulfoxide (4a, 36%), and promethazine sulfoxide (5a, 11%), were generated under mild, constant-current conditions. For the piperidine-containing PTZs, electrooxidation of thioridazine (6) selectively afforded mesoridazine (7, 15%), while further S-oxidation of 7 at the PTZ ring system yielded the novel bis-sulfoxide 7a (3%). The piperazine-containing PTZs trifluoperazine (8) and fluphenazine (9) provided sulfoxide metabolites 8a (9%) and 9a (5%), alongside unprecedented ring-opened products 8b (1%) and 9b (2%) arising from electrochemical cleavage of the piperazine ring. Two distinct ring-opening mechanisms via decarboxylation (N-demethylation, Shono-type pathway) and via α-cleavage (neighbouring group participation) are proposed. Cyclic voltammetry confirmed successful S-oxidation through the characteristic disappearance of the first oxidation wave in all metabolite products. The methodology was further extended to thioether-containing active pharmaceutical ingredients (APIs) extracted from commercial dosage forms.