Fluorinated tricyclic neuroleptics with prolonged action: 7-Fluoro-11-[4-(2-hydroxyethyl)piperazino]-2-isopropyl-10,11-dihydrodibenzo[b,f]thiepin

Abstract

Substitution reaction of 11-chloro-7-fluoro-2-isopropyl-10,11-dihydrodibenzo[b,f,]thiepin with 1-(2-hydroxyethyl)piperazine gave the title compound I which proved a very potent and longacting oral neuroleptic agent (isofloxythepin). Its resolution by means of dibenzoyl-(+)- and -(-)-tartaric acid led to (-)- and (+)-enantiomer out of which the former represents the neuroleptically active component. In the synthetic sequence leading to I, preparation of two key intermediates was re-elaborated using new partial sequences: 4-fluoro-2-iodobenzoic acid (XIII) from 4-fluoro-2-nitroaniline (V) via the nitrile VI and the acids VIII and XII, and [4-fluoro-2-(4-iso-propylphenylthio)phenyl]acetic acid (XVIII) from XIII via XIV and the compounds XV-XVII. The sulfoxides and N-oxides XIX-XXII were prepared as potential metabolites of isofloxythepin (I).