达比加群酯的合成工艺改进

Improved Synthesis of Dabigatran Etexilate

摘要:

以3-[[2-[(4-氰基苯胺基)甲基]-1-甲基-1H-苯并咪唑-5-羰基](吡啶-2-基)氨基]丙酸乙酯为起始原料，采用氯化锌Lewis酸催化进行Pinner 反应，将氰基醇解，再氨解得到脒化产物，然后经过酰化反应制得达比加群酯，目标产物在乙酸乙酯中重结晶，收率78%，纯度可达到99.31%。最终产物结构通过IR、1H NMR及ESI-MS 进行了表征。探讨了中间体Ⅱ、Ⅲ和目标化合物达比加群酯Ⅳ合成工艺的影响因素，优化后反应总收率为53.6%。

Abstract:

The dabigatran etexilate(Ⅳ) was synthesized from Ethyl 3-(2-(((4-cyanophenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate by Pinner reaction and Acylation Reaction. The structure was confirmed by IR, 1H NMR and ESI-MS. The influencing factors of intermediate Ⅱ, Ⅲ and target compound dabigatran etexilate (Ⅳ) in the synthetic reactions were investigated. The optimized overall yield was 53.6%, which was superior to literature.