阿齐沙坦的合成工艺优化

Improved synthetic process of azilsartan

目的改进阿齐沙坦合成中的硝基还原反应工艺。方法以2-{[(2-氰基联苯-4-基)甲基]氨基}-3-硝基苯甲酸乙酯(SM1)为起始原料,以甲酸铵为供氢体,经催化转移氢化,还原得到3-氨基-2-[(2-氰基联苯-4-基)甲基]氨基苯甲酸乙酯(AQ-1),AQ-1与原碳酸四乙酯环化得到2-乙氧基-1-{[(2′-氰基联苯-4-基)甲基]苯并咪唑}-7-羧酸乙酯(AQ-2),AQ-2依次经过肟化、CDI环合和酯基水解,共计5步反应得到阿齐沙坦。结果目标产物结构经1H-NMR、13C-NMR、MS谱和元素分析确证,硝基还原反应收率由74.5%提高至90.6%。结论新工艺反应进程快、易操作,且有较好的反应选择性,避开了污染大、压力高等落后工艺,具有较高的商业化价值。

Objective To improve the nitro reduction process in the synthesis of azilsartan.Methods Using ethyl(2-ethoxy-1-benzimidazole)-7-carboxylate(SM1)as starting material,ethyl-3-amino-2-[(2′-cyanoiphenyl-4-yl)methyl]-amino benzoate(AQ-1)was synthesized by catalytic transfer hydrogenation with ammonium formate as hydrogen donor,followed by cyclization with tetraethyl orthocarbonate to obtain ethyl-2-ethoxy-1-[[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole]-7-carboxylate(AQ-2).Finally,azilsartan(AQST)was synthesized by oximation,cyclization of CDI and ester hydrolysis.Results The structure of the product was verified by^1H-NMR/^(13)C-NMR/MS and elemental analysis.The yield of nitro reduction was increased from 74.5%to 90.6%.Conclusion The new process has the advantages of fast reaction,easy operation and good selectivity,which avoids heavy pollution and high pressure.The improved synthetic process has high industrialization prospect.