ジルチアゼム(ヘルベッサー(R))の改良合成法
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概要
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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. <BR>In the reaction of 2-nitrothiophenol (1) with <I>trans</I>-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 <I>cis</I>-opening and readily produced the <I>threo</I>-nitro ester (3a), a key intermediate for the synthesis of diltiazem.<BR>Isolation of the crystalline complex from the reaction of 1 with SnCl<SUB>4</SUB> and its efficient catalytic activity similar to that of SnCl<SUB>4</SUB> 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 <I>cis</I>-opening.
- 社団法人 有機合成化学協会の論文
- 1999-05-01