阿哌沙班的中试合成工艺研究

Study on Scale Synthetic Process of Apixaban

本文进行了抗凝血药物阿哌沙班的中试合成工艺研究。以关键中间体5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮(A)和2-氯-2-[2-(4-甲氧基苯基)亚肼基]乙酸乙酯(B)为起始原料,两者经[1+3]偶极环加成反应生成阿哌沙班乙酯(C),C经酰胺化反应即可制得阿哌沙班粗品,粗品经两次重结晶后制得阿哌沙班成品,总收率为35.7%,纯度达99.93%。以上制得的阿哌沙班经XRPD及固体核磁分析确定为N-1晶型,稳定性试验中未见降解杂质产生。本路线具有原料方便易得、反应条件温和、产品收率高、纯度理想的优点,适合工业化生产。

This article conducted a scale synthetic process study of anticoagulant drug Apixaban.Using 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1)-Piperidinyl)phenyl]-2(1H)-pyridone(A)and 2-chloro-2-[2-(4-methoxyphenyl)hydrazino]ethyl acetate(B)as starting materials,ethyl apixaban(C)was generated via[1+3]dipolar cycloaddition reaction.Amidation reaction of C provided crude apixaban.After recrystallization for two times,final product was obtained in overall yield of 35.66%with HPLC purity of 99.93%.The crystal form of apixaban was confirmed to be crystal form N-1 via solid NMR and XRPD analysis.Above synthetic route was characterized with commercially available starting materials,mild reaction conditions,final product with high yield and ideal purity which was suitable for scale-up production.