Collect. Czech. Chem. Commun. 1990, 55, 2282-2303

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

Karel Šindelář, Jiří Jílek, Josef Pomykáček, Vladimír Valenta, Marta Hrubantová, Marie Vlková, Jiří Holubek, Emil Svátek, Miroslav Ryska, Jiřina Metyšová and Miroslav Protiva

Research Institute for Pharmacy and Biochemistry, SPOFA, 130 60 Prague 3


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.