目的 设计并合成阿哌沙班中的3个杂质。方法 以2-氯-2-[2-(4-甲氧基苯基)亚肼基]乙酸乙酯和5,6-二氢-3-(4-吗啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮为起始原料，经过环合和水解反应得到目标化合物1，化合物1分别经过水解和取代反应得到目标化合物2和3。结果 合成了目标化合物，并利用MS、¹H-NMR和¹³C-NMR确证了结构：目标化合物1～3的质量分数分别为99.3%、99.1%、99.2%。结论 3个杂质的合成和纯化为阿哌沙班的杂质研究奠定了物质基础。关键词：阿哌沙班；杂质；2-氯-2-[2-(4-甲氧基苯基)亚肼基]乙酸乙酯；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

Objective To design and synthesize three impurities in apixaban. Methods 2-Chloro-2-[2-(4-methoxyphenyl) hydrazono]acetate and 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone were used as starting materials to synthesize the target compound 1 by cyclization and hydrolysis reactions, and compound 1 was used to synthesize the target compound 2 and compound 3 by hydrolysis and substitution reactions. Results The target compounds were synthesized and characterized by MS, ¹H-NMR, and ¹³C-NMR method. And the purity detected were 99.3%, 99.1%, and 99.2%, respectively. Conclusion The synthesis and purification of three impurities lay the material base for the study of impurities in apixaban.

中华医学会医学教育研究课题资助项目（2012-SY-44）