达比加群酯的合成工艺改进

Improved synthesis of dabigatran etexilate

目的改进达比加群酯的合成工艺,提高反应收率并简化操作。方法以4-甲胺基-3-硝基苯甲酸为原料,与3-(吡啶-2-基氨基)丙酸乙酯缩合后,经催化氢化、酰胺化后闭环、成脒、与氯甲酸正己酯反应得到达比加群酯。结果与结论目标化合物的结构经核磁共振氢谱、质谱确证。改进后的合成方法与原工艺相比,环境友好,收率提高了16.4%,总收率为33.75%(以4-甲胺基-3-硝基苯甲酸计)。

Dabigatran etexilate,an oral direct thrombin inhibitor（DTI）,is an effective drug for thromboembolic diseases.A new economical and environmental friendly synthetic method was developed.Firstly,4-（methylamino）-3-nitrobenzoic acid was reacted with ethyl 3-（pyridin-2-ylamino）propanoate（2） under the catalysis of 2-chloro-1-methylpyridinium iodide（CMPI） to give ethyl 3-[4-（methylamino）-3-nitro-N-（pyridin-2-yl）benzamido] propanoate（4）,4 was reduced to get ethyl 3-[3-amino-4-（methylamino）-N-（pyridin-2-yl）benzamido] propanoate（5）,then 5 was reacted with 2-（4-cyanophenylamino）acetic acid（6） to get ethyl 3-{2-[（4-cyanophenylamino）methyl]-1-methyl-N-（pyridin-2-yl）-1H-benzoimidazole-5-carboxamido}propanoate（7）,7 was reacted with hydroxylamine hydrochloride then reduced in the presence of HCOONH4 and Pd/C to get ethyl 3-{2-[（4-carbamimidoyl-phenylamino）methyl]-1-methyl-N-（pyridin-2-yl）-1H-benzoimidazole-5-carboxamido}propanoate（8）,finally,8 was reacted with hexyl carbonochloridate（9） to afford dabigatran etexilate（1）.The overall yield was about 33.75%,which increased by 16.4% based on 4-（methylamino）-3-nitrobenzoic acid.The chemical structure of dabigatran etexilate was characte-rized by MS,1H-NMR.Compared with the original synthetic process,the new route is facile and suitable for industrialized production with lower pollution and higher yield.