Study On The Synthesis Of Apixaban

Apixaban, developed by Bristol-Myers Squibb and Pfizer, is an oral, highly selective, reversible,competitive and direct-acting inhibitors of Factor Xa. It is mainly used for the prevention of venous thromboembolism(VTE) formation in adult patients that had recently undergone knee or hip replacement.In 2012, it was approved for the treatment of non-valvular atrial fibrillation. It also had have a positive effect on the prevention of acute coronary syndrome(ACS) in patients with stroke.In this paper, the author reviewed lots of related literature in order to improve the synthesis of apixaban. 1-(4-Nitrophenyl) piperidin-2-one(2) was abtained via amidation and cyclization from4-nitroaniline and 5-chloro-pentanoyl chloride. 3,3-Dichloro-1-(4-nitrophenyl) piperidin-2-one(3) was prepared by the reaction of compound 2 and phosphorus pentachloride. 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridine-2(1H)- one(4) was abtained from coumpoud 3 via condensation-elimination reaction, followed by a redution using sodium sulfide to give 1-(4-aminophenyl)-3-morpholin-5,6-dihydropyridin-2(1H)- one(5). 3-morpholino-1- [4-(2-oxo-piperidin-1-yl) phenyl]-5,6-dihydropyridin-2(1H)- one(6) was preapred via amidation and cyclization of compound 5 and5-chloro-pentanoyl chloride.(Z)-2- chloro-2- [2-(4-methoxyphenyl) hydrazono] acetate(7) was obtained by the reaction of p-anisidine diazotization and ethyl 2-chloroacetoacetate.(3a S, 7aR)-1-(4-methoxyphenyl)-7a- morpholin-4-yl-7-oxo-6- [4-(2-oxo-piperidin-1-yl) phenyl]-3a, 4,5,6,7,7ahexahydro-1H- pyrazolo [3,4-c] pyridine-3-carboxylate(8) was prepared by coupling of Compound 6 andcompound 7. Elimination of compound 8 in the presence of hydrochloric acid gave1-(4-methoxyphenyl)-6-[4-(2-oxygen substituted pyridine-1-yl)phenyl]-4,5,6,7-tetrahydro-1H pyrazole pyrazole [3,4-c] pyridine 3 acid ethyl ester(9). Finally, apixaban was prepared by formamide reaction from compound 9.We made the following improvements in the apixaban specific synthesis process: The starting material 4-nitroaniline was cheap and readily available; Potassium t-butoxide was used in the preparation of compound 2 and compound 6, which was milder and safer; During the synthesis of the compound 4 and the compound 5, we used ethanol as purification solvent, which increased the yield and reduced the cost;The synthesis of the compound 8 is controlled by changing the temperature of the experiment without the presence of catalyst, which can also achieve the desired yield. The improved process in this paper is mild,convenient and suitable for industry.The Structures of the final product and its intermediates were confirmed by HPLC, 1H-NMR and13C-NMR. In the process, the total yield was up to 40%. The purity of the target compound apixaban was99.8%, which satisfied the quality standard, with a overall impurities less than 5‰ and single impurity less than 1‰. Finally, the author also studied the impurities in apixaban, which played an important role in improving the quality of API and setting quality standards of apixaban.