伏罗尼布的合成工艺研究

Study on the synthetic process of vorolanib

目的优化多靶点激酶抑制剂伏罗尼布的合成工艺。方法以{[(3S)-四氢-1H-吡咯-3-基]氨基}甲烷酸-2-甲基丙-2-基酯为起始原料,通过酰化、脱Boc保护基、酸胺缩合、Claisen-Schmidt共四步反应得到伏罗尼布。结果与结论目标化合物的结构经ESI-MS、^(1)H-NMR、^(13)C-NMR谱确证,总收率为55.3%,纯度为99.01%(HPLC)。改进后的合成方法原料易得、操作简单、产物纯度高,适合大规模工业化生产。

Vorolanib is a new generation of multi-target kinase inhibitors with a completely new chemical structure.A new synthetic route to vorolanib was designed based on the existing patent synthetic route.Vorolanib was synthesized through four steps with the final yield of 55.3%and the purity of 99.01%(HPLC).The process was investigated from the aspects of raw material selection,feed ratio,reaction temperature and the optimal conditions for each step of the reaction were determined.The structures of intermediates were confirmed by ^(1)H-NMR and ESI-MS,and the structure of vorolanib was confirmed by ^(1)H-NMR,^(13)C-NMR and ESI-MS.The optimized synthetic route has the advantages of simple operation,mild reaction conditions,high yield and purity,which is suitable for large-scale production,and provides a reference for the industrial production of vorolanib.