胆固醇吸收抑制剂依折麦布中2种杂质的合成

Synthesis of Two Impurities in Cholesterol Absorption Inhibitor Ezetimibe

摘要: 目的合成依折麦布原料药中的2种主要杂质。方法依折麦布(1)经氯代铬酸吡啶盐(PCC)氧化制得杂质Ⅰ；以依折麦布中间体1-(4-氟苯基)-3(R)-3-(4-氟苯基)-羟丙基-4(S)-4-(4-苄氧基)-苯基-氮杂环丁烷-2-酮(2)为原料经催化氢化反应制得杂质Ⅱ。结果所得2种杂质结构经¹H-NMR、¹³C-NMR和ESI-MS确证，纯度经HPLC检测可达98%以上。结论解决了依折麦布杂质的来源问题，为依折麦布的质量控制提供了依据。

Abstract: OBJECTIVE To synthesize two impurities(Ⅰ and Ⅱ) in ezetimibe. METHODS Impurty Ⅰwas obtained from ezetimibe(1) by oxidation using pyridinium chlorochromate(PCC), impurty Ⅱ was gained from intermediate 1-(4-fluorophenyl)-3(R)-3-(4-fluorophenyl)-hydroxypropyl-4(S)-4-(4-benzyloxy)-phenyl-azetidine-2-one(2) of ezetimibe by catalytic hydrogenation. RESULTS The structures of two impurities were verified by ¹H-NMR, ¹³C-NMR and ESI-MS. The purities were over 98% as determined by HPLC. CONCLUSION It solves the problem of impurities source and provides a basis for quality control of ezetimibe.