Preparation of metabolites by chemical reaction: Conversion of antipsychotic phenothiazines to their sulfoxides and tertiary amino cyclic antidepressants to their N-oxide with hydrogen peroxide using titanosilicate catalyst

Abstract

The aim of this study was to establish a preparation method needed to analyze the metabolites of an analytical procedure for antipsychotic phenothiazines and tertiary amino cyclic antidepressants by chemical reaction. These drugs were oxidized to their sulfoxide and N-oxide, respectively, with hydrogen peroxide using titanosilicate as the catalyst. An acidic medium (pH 3.0) containing 20% methanol was found to be optimal for the preparation of phenothiazine sulfoxide, and an alkaline medium (pH 10.5) containing 50% methanol was optimal for the preparation of the N-oxide of tertiary amino cyclic antidepressants. Each preparative scale reaction (2 mmol) was carried out and the crystallized product of each oxide was obtained. The amount of hydrogen peroxide needed to obtain the best yields of sulfoxide was 1.3-2.0 times the molar equivalent of the phenothiazines. The purities of the prepared crystallized product of the phenothiazine sulfoxides were good except for periciazine sulfoxide. The amounts of hydrogen peroxide needed to obtain the best yields of N-oxide were 4-5 times the molar equivalent of tertiary amino cyclic antidepressants. The purities of the crystals of each N-oxide were 99.5-100%. The characteristic mass fragment ions of each prepared oxide that were distinguishable as the N-oxides from parent drug could be confirmed when the collisional energy was decreased to 10 eV. 1H- and 13C-NMR spectral data confirmed the structure of the prepared mianserin N-oxide to be 2-oxide. In conclusion, a simple and rapid preparation method for oxide metabolites of phenothiazines and tertiary amino cyclic antidepressants available as analytical standards was established.