安立生坦关键中间体的合成新方法

A Novel Synthetic Route for the Key Intermediate of Ambrisentan

安立生坦(1)是一种内皮素-1受体拮抗药,2-羟基-3-甲氧基-3,3-二苯基丙酸(2)是合成1的关键中间体,本研究报道了合成2的新方法。二苯甲酮(3)与磷酰基乙酸三乙酯经Wittig-Horner反应生成3,3-二苯基丙烯酸乙酯(4)。以甲醇为溶剂,4与N-溴代丁二酰亚胺(NBS)亲电加成得到2-溴-3-甲氧基-3,3-二苯基丙酸乙酯(5)。5与乙酸酯化生成2-乙酰氧基-3-甲氧基-3,3-二苯基丙酸乙酯(6),无需分离纯化直接水解得到2,总收率75%。该工艺原料价廉易得、操作简便,避开了Darzens缩合反应,适合工业化生产。

Ambrisentan(1)is an endothelin-1 receptor antagonist.In this paper,a novel synthetic route for 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid(2),the key intermediate of 1,was reported.Ethyl 3,3-diphenylacrylate(4)was obtained from benzophenone(3)with triethyl phosphatoacetate by Wittig-Horner reaction.Ethyl 2-bromo-3-methoxy-3,3-diphenylpropanoate(5)was synthesized by electrophilic addition of 4 with NBS in methanol.Compound 5 was esterified with acetic acid to give ethyl 2-acetoxy-3-methoxy-3,3-diphenylpropanoate(6),and then without separation,6 was hydrolyzed directly to obtain 2 in a total yield of 75%.In this process,the materials are cheap and easily available,and it avoids the Darzens condensation reaction,which is suitable for industrial production.