甲磺酸达比加群酯的合成

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。

Synthesis of dabigatran etexilate mesylate

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-nitrobenzoic 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) glycine by amidation,cyclization,neutralization,amidination,acylation and salification with methane sulfonic acid.Results: The structures of intermediates and target compound were identified by MS and 1H-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.