Applications of Lewis acids for the efficient syntheses of diltiazem, cephems, and taxoids.
An efficient method is described for preparation of diltiazem hydrochloride (Herbesser(R)), a marketed calcium antagonist widely used for the treatment of ischemic heart disease. 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-t), a key intermediate for the synthesis of diltiazem. Isolation of the crystalline complex from the reaction of 1 and SnCl(4); and its efficient catalytic activity similar to that of SnCl(4) suggests that the transition state involves co-coordination of tin derivatives both with 1 and the epoxy oxygen of 2a to result in highly specific cis-opening. We have also amplified this chemistry into other fields, leading to applications in the syntheses of cephem and taxoid templates.
Hashiyama
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Medicinal Chemistry Department, Discovery Research Laboratory Tanabe Seiyaku Co. Ltd., 2-2-50, Kawagishi, Toda, Saitama, 335-8505, Japan.
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry*; D002121:Calcium Channel Blockers / Q000737:chemistry*; D002384:Catalysis; D002513:Cephamycins / Q000737:chemistry*; D004110:Diltiazem / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D017239:Paclitaxel / Q000737:chemistry*
D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D002513:Cephamycins; D004110:Diltiazem; D017239:Paclitaxel