The Synthesis And Crystallization Research Of The New Oral Anticoagulant Apixaban

Thromboembolic diseases are a major health problem.This article first summarized the mechanism of coagulation,the targets of anticoagulation and the progresses on anticoagulants.Apixaban,1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide,is one of the new oral anticoagulants(NOACs)which was developed by BMS-Pfizer.The trade name of apixaban is Eliqus.The dosage form of this agent is tablet.It’s target is Factor Xa.Factor Xa plays a key role in haemostasis,it occupies a central role in the blood coagulation intrinsic and extrinsic pathway and it can be activated through either the intrinsic or the extrinsic pathway.As a Factor Xa inhibitor,apixaban exerts anticoagulant effect by blocking the generation of thrombin from prothrombin.Apixaban had been approved by FDA in 2012 for prevention of stroke or systemic thromboembolism in patients with non-valvular artrial fibrillation(AF).Later,it was approved for the treatment of deep venous thrombosis(DVT)and pulmonary embolism(PE)in patients with hip or knee replacement.Compared with other traditional anticoagulants,such as vitamin K antagonists,it was convenient,effective and safe.Due to the good application prospects,the study on its synthetic method is of great importance.Through accessing the relevant literatures,summarizing the advantages and disadvantages of reported synthetic routes,We selected p-anisidine as starting material.And then,followed with diazotization reaction,Japp-Klingemann reaction,[3+2]cyclic addition and amidation of ester,Apixaban generated.This route avoided using expensive reagents,and can be used in industrial scale.The results showed that the yield and quality of product was improved by optimizing the conditions of each step.The total yield of this route was improved to 69.4%from 40.5%with the purity over 99.8%.This article also did a research on crystallization form of apixaban,and got the pharmaceutical crystal.All the products were characterized by 1H-NMR,MS and their structure were confirmed.Crystallization form was characterized by XRPD and TGA-DSC.