Zhong Bo-hua
2012
Citations
0
Influential Citations
2
Citations
Journal
Chinese Journal of Medicinal Chemistry
Abstract
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.