Tricyclic neuroleptics: Synthesis of metabolites of isofloxythepin and some related compounds

Abstract

The isofloxythepin (I) metabolite IV was synthesized via the acids IX and XI and the esters X and XII. The enamine VIII was prepared from 3-fluoro-8-(2-propyl)dibenzo[b,f]thiepin-10(11H)-one by two methods and was reduced to I. Cloflumide (II) was obtained by reaction of 2,10-dichloro-7-fluoro-10,11-dihydrodibenzo[b,f]thiepin with 3-(1-piperazinyl)propionamide and was oxidized to the sulfoxide XVI. The unsaturated analogue XVII of clopithepin (III) was prepared from 2-chlorodibenzo[b,f]thiepin-10(11H)-one by reaction with 2-bromoethanol in the presence of 4-toluenesulfonic acid in boiling benzene and by the following substitution reaction with 2-(1-piperazinyl)ethanol. An improved synthesis of 6-methyldibenzo[b,f]thiepin-10(11H)-one (XIX) was elaborated. The acid XXVII was synthesized and cyclized with polyphosphate ester. A mixture of compounds was formed from which the ketone XXXVI was isolated and processed by reaction with formamide and formic acid at 200 °C. One of the products was characterized as the formamide XXXIII and was reduced with lithium aluminium hydride to a basic product supposed to be XXXIV. A series of by-products was isolated and characterized. The enamine VIII (V⁄FB-17 156) was found to be a strong neuroleptic agent, similar to isofloxythepin (I). The enol ether XVII (V⁄FB-17 733) was characterized as a mild, practically noncataleptic neuroleptic agent.