Collection of Czechoslovak Chemical Communications - digital archive 

Abstract

Reaction of ketone IX with 4-tetrahydrothiopyranylmagnesium bromide and the following dehydration with thionyl chloride afforded the sulfide III which was transformed to the methiodide II (sulfonium analogue of pizotifen). Similar sequence starting from the ketone XXIV and concluded by dehydration of the alcohol XX, cleavage of the enol ether, and by treatment with methyl iodide resulted in the formation of the sulfonium analogue of ketotifen (V). Three modified routes leading to ketotifen (IV) are being described. The chirality of ketotifen was proven by ¹H NMR spectroscopy with the help of the optically active NMR shift reagent. The resolution of racemic ketotifen (IV) was achieved by crystallization of salts with optically active O,O'-diacyltartaric acids and homogeneous enantiomers were obtained. The X-ray crystallographic analysis of (+)-IV (-)-O,O'-di(p-toluoyl)-(R)-tartarate led to the three-dimensional structure of the molecule of (+)-ketotifen which enabled to determine its absolute configuration to be (R). One of the products of bromination of the ketone IX, the following methanolysis and dehydrobromination, identified as XXVII, was transformed by reaction with 1-methyl-4-piperidylmagnesium chloride, by the following acid-catalyzed dehydration, and cleavage of the enol ether to the 2-bromo derivative of ketotifen XXXIV. (R) (+)-Ketotifen (IV) was found to be the more active ketotifen enantiomer but the stereoselectivity of its action is only a partial one. The 2-bromo derivative of ketotifen (XXXIV) is much less active than ketotifen in the line of antihistamine activity.