甲磺酸达比加群酯的合成

Synthesis of dabigatran etexilate mesylate

目的:研究和改进甲磺酸达比加群酯的合成工艺。方法:以4-甲氨基-3-硝基苯甲酸(2)和3-(吡啶-2-基氨基)丙酸乙酯(3)为原料,经酰氯化、酰胺化、中和成盐和还原制得重要中间体3-[[3-氨基-4-(甲氨基)苯甲酰基](吡啶-2-基)氨基]丙酸乙酯(5)。5再与N-(4-氰基苯基)甘氨酸经酰胺化、闭环、中和成盐、成脒、酰化,进而与甲磺酸成盐制得甲磺酸达比加群酯。结果:中间体及目标化合物经质谱、核磁共振谱、红外光谱等确证,整个工艺的总收率为33.9%。结论:本路线操作简便、成本较低、条件温和、步骤少,适合工业化生产。

Objective： To study and improve the synthesis proccess of dabigatran etexilate mesylate. Methods ： The intermediate ethyl 3- [ [ 3-amino-4- （ methylamino ） benzoyl ] （ pyridin-2-yl ） amino ] -propanoate （ 5 ） was prepared from 4-methyl amino-3-nitrobenzoie acid （2） and ethyl 3-（pyridin-2-ylamino） propanoate （3） by chlorination, amidation, neutralization and reduction. Dabigatran etexilate mesylate was synthesized from 5 and （4-cyanophenyl） glyeine by amidation, eyelization, neutralization, amidination, aeylation and salifieation with methane sulfonie acid. Results： The structures of intermediates and target compound were identified by MS and ~H-NMR. The overall yield was 33.9%. Conclusion： This improved method can be used in industrial manufacturing with the advantage of simpler purifying operation, lower cost and mild condition.