Collect. Czech. Chem. Commun. 1984, 49, 1021-1038

Analogues of the neuroleptic agent isobutaclamol: Stereoisomeric 3b,4,5,6,7,9,9a,10-octahydro-[1]benzothiepino[2,3,4-ed]pyrido[2,1-a]isoquinolin-5-ols and some related compounds

Karel Šindelář, Jiří Holubek, Miroslav Ryska, Emil Svátek, Antonín Dlabač, Martin Valchář and Miroslav Protiva

Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3


10,11-Dihydrodibenzo[b,f]thiepin-10-carbonitrile (XVI) was reduced with aluminium hydride to the primary amine XVII which was formylated with acetic formic anhydride. The formamide derivative was cyclized by the Bischler-Napieralski reaction to the condensed dihydroisoquinoline XX. Addition of methyl vinyl ketone to the hydrochloride of compound XX at 100 °C gave a mixture of the stereoisomeric 3b,4,5,6,7,9,9a,10-octahydro[1]benzothiepino[2,3,4-ed]pyrido[2,1-a]isoquinolin-5-ones (XIII) which was separated by chromatography to the major 3b,9a-cis isomer XIIIb and the minor 3b,9a-trans isomer XIIIa to which the configuration was assigned on the basis of analogy. Reactions of both ketones with tert-butylmagnesium chloride and isopropyllithium led to mixtures whose chromatographic separation afforded the tertiary alcohols XIa, XIb, XIIa and XIIb mostly in low yields. In most cases the main products were the secondary alcohols XIV and apparently also the pinacols XXIII, formed by reduction. An attempt at preparing similar [1]benzothiopyrano[2,3,4-ed]pyrido[1,2-a]isoquinoline derivatives was discontinued because of an anomalous result of cyclization of compound XXVII. Compound XIa, being a 15-thia analogue of isobutaclamol (VI) displayed a high affinity to dopamine receptors in striatum of the rat brain which confirms the correctness of the assignment of relative configuration on C(3b) and C(9a).