Points of Interest in the Chemistry of the Levomepromazine Drug Substance: Recycling of Undesired Enantiomer, Identification of New Phenothiazine Dimers, Synthesis of a Pharmacopeial Impurity, and an Unexpected Rearrangement

Abstract

As a traditional manufacturer of drug substance levomepromazine maleate, we were interested in the elaboration of an optimized process that uses the undesired enantiomer dextromepromazine, a waste product from the production of levomepromazine, to recover the starting material 2-methoxyphenothiazine. In 2-methoxyphenothiazine samples, two new dimertype impurities have been detected and these have also been synthesized. One of these dimers was used for the preparation of the pharmacopeial standard Imp. D, on the synthesis and characterization of which the literature is surprisingly silent. During the attempted synthesis of another pharmacopeial impurity (Imp. E), similarly unknown in the literature, an unexpected rearrangement was discovered. Its possible mechanism is also discussed below.