替米沙坦关键中间体的新合成路线

本研究设计了替米沙坦关键中间体2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑(1)的新合成路线。正丁腈(2)与甲醇或乙醇在氯化氢作用下反应得到正丁基亚胺酯(3)的盐酸盐,经碱化得到游离的3,再与4-氨基-3-甲基苯甲酸(4)反应得到4-丁脒基-3-甲基苯甲酸(5)。5与次氯酸钠反应生成中间过渡产物,然后直接在氢氧化钠作用下关环生成2-正丙基-4-甲基苯并咪唑-6-羧酸(6)。6与N-甲基邻苯二胺盐酸盐(7)脱水缩合生成1。该路线采用了2次叠缩工艺,简化了生产操作,总收率高达79%(以4计)。

A New Synthetic Route for the Key Intermediate of Telmisartan

A new synthetic route of 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole(1),the key intermediate of telmisartan,was reported.n-Butyronitrile(2)reacted with MeOH or EtOH in the presence of HCl gas to give the hydrochloride salt of n-butylimide ester(3),which was followed by alkalization to obtain the free base 3.4-Amino-3-methylbenzoic acid(4)reacted with 3 to give 4-butyrimidamido-3-methylbenzoic acid(5).Compound 5 reacted with NaClO to form an intermediate transition product,which was directly cyclized in the presence of NaOH to obtain 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid(6).Compound 6 and N-methyl-1,2-benzenediamine dihydrochloride(7)were condensed to give 1.The telescoping was used twice in this process,which simplified the operation,and the total yield of this new route was 79%(based on 4).