PLK1 抑制剂 Onvansertib 关键中间体合成工艺的改进

文章在 Onvansertib 原研合成路线的基础上, 对其重要中间体 N-(2-(三氟甲氧基)-5-(4-甲基哌嗪-1-基)-苯基)胍(化合物 3)的合成工艺进行了优化设计, 对反应溶剂、溶剂浓度、物料摩尔比、反应温度和时间等参数进行了筛选, 根据实验结果得到最佳的合成工艺条件如下: 以 6 mol/L 的盐酸溶液作为溶剂, 反应原料氰胺和 2-(三氟甲氧基)-5-(4-甲基哌嗪-1-基)苯胺的摩尔比为 10:1, 在 95 ℃ 下搅拌反应 1.0 h。在该工艺条件下产物的收率可以达到 92.7%。优化后的工艺反应条件温和、操作便捷, 为工业化生产提供了一个全新的思路。

Based on the original synthesis route of Onvansertib, the synthesis process of N-(2-(trifluoromethoxy)-5-(4-methylpiperazin-1-yl)-phenyl)guanidine(compound 3), a key intermediate of Onvansertib, was optimized. This process focused on the screening of reaction solvent, solvent concentration, molar ratio of materials, reaction temperature and time. The optimal synthesis process conditions for this step were obtained: 6 mol/L hydrochloric acid solution was used as solvent, the molar ratio of the reaction raw material cyanamide and 2-(trifluoromethoxy)-5-(4-methylpiperazin-1-yl)aniline was 10:1, and the reaction was stirred for 1.0 h at 95 °C, with a yield of the product of 92.7%. The optimized process has mild reaction conditions, convenient operation, which provides a new idea for industrial production.