目的 設(shè)計(jì)并合成阿哌沙班中的3個(gè)雜質(zhì)。方法 以2-氯-2-[2-(4-甲氧基苯基)亞肼基]乙酸乙酯和5,6-二氫-3-(4-嗎啉基)-1-[4-(2-氧代-1-哌啶基)苯基]-2(1H)-吡啶酮為起始原料，經(jīng)過(guò)環(huán)合和水解反應(yīng)得到目標(biāo)化合物1，化合物1分別經(jīng)過(guò)水解和取代反應(yīng)得到目標(biāo)化合物2和3。結(jié)果 合成了目標(biāo)化合物，并利用MS、¹H-NMR和¹³C-NMR確證了結(jié)構(gòu)：目標(biāo)化合物1～3的質(zhì)量分?jǐn)?shù)分別為99.3%、99.1%、99.2%。結(jié)論 3個(gè)雜質(zhì)的合成和純化為阿哌沙班的雜質(zhì)研究奠定了物質(zhì)基礎(chǔ)。關(guān)鍵詞：阿哌沙班；雜質(zhì)；2-氯-2-[2-(4-甲氧基苯基)亞肼基]乙酸乙酯；5,6-二氫-3-(4-嗎啉基)-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.

中華醫(yī)學(xué)會(huì)醫(yī)學(xué)教育研究課題資助項(xiàng)目（2012-SY-44）