Study On The Synthetic Process Of Betrixaban

Thrombotic disease is a disease of serious harm to people’s health, which has become the main cause of death and disability in our and western countries. According to the world health organization statistics, 17 million people died from various kinds of disease of thrombotic disease every year. Betrixaban is a new generation of oral anticoagulants which is a factor Xa inhibitors. It has a broad application prospects and is developed in phase III clinical trial stage by Portola Pharmaceuticals in the United States.In order to develop a new synthetic route applied in betrixaban production, one new synthetic route was designed and optimized in this paper on the basis of the literatures according to the design and Selection principle of pharmaceutical process.5-Methoxy-2-nitro benzoic acid was reacted with oxalyl chloride to get the corresponding acyl chloride at room temperature and N-(5-chloro-2-pyridinyl)-5-methoxy-2-nitrobenzamide was obtained from the acyl chloride and 2-amino-5-chlorine pyridine at room temperature. After reduced by Fe powder, the reduction product was reacted with 4-cyanobenzoic acid to generate N-(5-chloro-2-pyridinyl)-2-[(4-cyanobenzoyl)amino]-5-methoxy benzamide in presence of CDI(N,N’-Carbonyldiimidazole). The corresponding imidoate was synthesized in hydrogen chloride/methanol and ethyl acetate solution and hydrochloride was prepared from the imidoate reacting with dimethylamine. The free betrixaban was produced after neutralization by sodium carbonate and which was reacted with maleic acid in ethanol/water solution to obtain the target product-betrixaban maleate.The final product was synthesized upto a total yield of 19.63% and the purity was >99.5% determined by HPLC. The synthetic process is easy to operate with achieving high yield and purity. The method is simple and can be easily controlled with less waste, the starting matirals were easily got and suitable for industrial production.The chemical structures of intermediates and betrixaban have been characterized by infrared spectrum, 1H-NMR and 13C-NMR.