依折麦布有关物质的合成

Synthesis of the related substances of ezetimibe

目的合成4个依折麦布的有关物质。方法在参考依折麦布相关合成报道的基础上,以依折麦布或市售依折麦布中间体1-(4-氟苯基)-3(R)-[3-(4-氟苯基)-3-氧代丙基]-4(S)-(4-苄氧基苯基)-2-氮杂环丁烷酮、(S)-3-[5-(4-氟苯基)-5-羟基-1-氧代戊基]-4-苯基-2-口恶唑烷酮为原料,经多步反应分别制得依折麦布的4个有关物质:依折麦布的3'位羟基差向异构体3'-R-依折麦布、脱氟依折麦布,以及两个依折麦布的降解产物。结果与结论目标化合物经1H-NMR、13C-NMR及MS谱确证,纯度均大于99%。设计的合成路线方法简单、条件温和、原料易得。合成的有关物质将为依折麦布原料药质量控制研究提供物质基础。

To improve the quality control of ezetimibe,process-related impurities and the major degradation（6,7, 8,9） associated with the synthesis of ezetimibe were synthesized. Starting from the ezetimibe or commercially available intermediates, 1 - （4-fluorophenyl） - （ 3R ） - [3 - （ 4-fluorophenyl ）-3-oxopropyl ]-（4S ）-[4-（ phenylmethoxy ） phenyl ]-2-azetidinone and （ S ） -3- [5- （ 4-fluorophenyl ） -5-hydroxy-l-oxopentyl]-4-phenyl-2-oxazolidinone, the related substances of ezetirnibe were prepared based on the reported synthetic methods of ezetimibe. The structure of the related substances were confirmed by 1H-NMR,13C-NMR and MS. The reaction conditions were mild and starting materials were cheap and easy to obtain. The target compounds can be used as the related substances in the quality control. The presented studies can be also helpful for further research of ezetimibe.