Study On The Synthesis Of Apixaban

As an oral direct inhibitor of factor Xa, apixaban was used for prevention of venous thromboembolic events in adult patients who have undergone elective hip or knee replacement surgery. As for the advantages of high drug safety, low possibility of drug interaction and elimination in various ways, apixaban was promised to the special crowd with liver or renal function injury. So it has great market prospect.In this paper, one dramatically improved method for the preparation of apixaban based on optimization of the reported synthetic routes was provided. According to the analyses of the experimental conditions and results, the synthetic route which can be used in industrial production for apixaban was following: 4-Nitroaniline and chloro-valeryl chloride were used as starting materials, which successively undergo acylation-cyclization, chlorination of α-carbonyl hydrogens and condensation-elimination of chloro groups to generate 3-morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one(compound 7) which was used as dipolarophiles. On the other hand,(Z)-Ethyl 2-Chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate(compound 6) as the 1,3-dipole was prepared in two steps via the diazotization of 4-methoxyaniline followed by the Japp-Klingemann reaction with ethyl 2-chloroacetoacetate. Then compound 6 was subjected to an addition-elimination sequence with compound 7 to give ethyl 6-(4-nitrophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyrid ine-3-carboxylate(nitro compound 5). Apixaban was obtained from compound 5 through reduction of nitro group, acylation, cyclization-hydrolysis and aminolysis reactions. The purity of the apixaban was over 99.8%(HPLC), and the content of a single impurity was less than 0.03%. This route has the advantages of low production cost, simple operation, no hash reaction conditions, high stability of the intermediates and high purity of products. The total yield for this route was 39.1%.The chemical structures were confirmed through IR, 1H-NMR, 13C-NMR and MS. According to the preparation demand for the crystal types of the bulk drug of apixaban, we have got one crystal type of apixaban, which has an X-ray powder diffraction pattern comprising one or more peaks at about 12.8, 13.9, 16.9, 18.4, 21.5 and 22.1 degrees 2θ.