ジルチアゼム (ヘルベッサー^®) の改良合成法

抄録

An efficient method for preparation of diltiazem hydrochloride, a representive calcium antagonist widely used for the treatment of ischemic heart disease all over the world, is described.
In the reaction of 2-nitrothiophenol (1) with trans-3-phenylglycidic esters (2) carrying various substituents on the benzene ring, both reactivity and stereoselectivity of the oxirane ring-opening of the glycidates were markedly influenced by the electronic nature of the substituents. As a result of our investigation on the catalytic effect of various Lewis acids in the reaction of 2a with 1, tin compounds were found to be effective catalysts for the cis-opening and readily produced the threo-nitro ester (3a), a key intermediate for the synthesis of diltiazem.
Isolation of the crystalline complex from the reaction of 1 with SnCl₄ and its efficient catalytic activity similar to that of SnCl₄ suggest that the transition state involves co-cordination of tin derivatives both with 1 and the epoxy oxygen of 2a to result in highly specific cis-opening.