瑞帕利辛的不对称合成工艺研究

Study on asymmetric synthesis process of repertaxin

目的优化瑞帕利辛的不对称合成工艺。方法以异丁芬酸(2)为起始原料,通过Evans辅基诱导的不对称烷基化反应引入手性中心,得到重要中间体(R)-4-苄基-3-[(R)-2-(4-异丁基苯基)丙酰基]噁唑烷-2-酮(4),再经水解以及酰胺化反应得到瑞帕利辛。结果与结论目标化合物结构经^(1)H-NMR、^(13)C-NMR和HR-ESI-MS确证,总收率为42.0%(以异丁芬酸计),纯度大于99.1%,光学纯度大于97.9%。该工艺路线原料易得、收率较高、操作简单、成本较低,并经百克级放大验证。

Repertaxin,as an anti-tumor adjuvant drug,plays an important role in clinical application.However,most of the reported synthetic methods for this drug were highly costed and difficult to operate due to the requirements for chiral resolution.Herein,we rationally designed an asymmetric synthesis strategy for repertaxin based on the Evans cofactor and achieved the target product through four linear steps with 42.0%overall yield.This method has the advantages of low cost,simple operation,convenient separation,and no column chromatography involved,which is suitable for the hundred-gram scale synthesis.