Journal of Pharmaceutical Research

Abstract

Flupentixol, a potent antipsychotic and antidepressant, exists in two geometric isomers, Z and E, with the Z-isomer being the therapeutically active form. The synthesis of flupentixol and related compounds often faces the challenge of controlling the stereochemistry to favor the Z-isomer. The study aimed to identify the optimal conditions for producing the Z-isomer, which is more therapeutically relevant. 2-(trifluoromethyl)-9H-thioxanthen-9-one was prepared from 2-mercaptobenzoic acid and perabromobenzotrifluoride, followed by a Grignard rearrangement to form (9-(3-dimethylamino)propyl)-2-(trifluoromethyl)-9,10aH-dihydro-8aH-thioxanthen-9-ol. The intermediate was dehydrated with various acids to produce the E and Z isomers of Flupentixol, with the product ratios subsequently analyzed using ¹H-NMR spectroscopy. The dehydration reactions yielded different E/Z isomer ratios, yields, and melting points, depending on the acid used. Hydrochloric, oxalic, and methanesulfonic acids favored the formation of the Z-isomer with E/Z ratios of 11:89, 14:86, and 12:88, respectively, while succinic acid achieved the highest yield (84.75%) with a 37:63 E/Z ratio. Maleic acid and ferrous sulfate produced intermediate ratios, and DL- and L(+)-tartaric acids gave similar results with high yields. This study revealed a novel insight into the influence of various acids on the dehydration reactions, highlighting specific acids that significantly favor the formation of the therapeutically active Z-isomer of Flupentixol with optimized yields and ratios.

Keywords: Flupentixol, Z­isomer, E­isomer, Antipsychotic drugs, ¹H­NMR, Racemic resolution