奥斯替尼甲磺酸盐合成工艺改进

Process Improvement for Synthesis of Osimertinib Mesylate

摘要:

以3-（2-氯嘧啶-4-基）-1-甲基吲哚为原料，经取代、缩合、还原和酰胺化以及成盐4步反应，得到目标化合物奥斯替尼甲磺酸盐，总收率为41.9%。通过单因素实验对每步反应的关键参数进行了优化，得到一条快速、高效的合成路线。在还原和酰胺化反应过程中采用“一锅法”不仅简化了操作步骤,同时解决了中间产物不稳定难于分离纯制的问题，由Ⅴ合成Osimertinib的收率也由文献的33%提升到61%。此外，在该过程中以廉价的丙烯酸代替丙烯酰氯，不仅降低了成本，并且反应条件更加温和、易于操作。 关键词:奥斯替尼甲磺酸盐；EGFR抑制剂；工艺改进；“一锅法”；医药与日化原料

Abstract:

Osimertinib mesylate in a total yield of 41.9% was obtained via four steps of substitution, condensation, reduction and amidation, and salt formation with 3-(2-chloropyrimidin-4-yl)-1-methylindole as raw material. The key parameters of each step were optimized by single factor experiment and a fast and efficient synthetic route was obtained. The “one-pot method” used in the process of reduction and amidation not only simplifies the operation steps, but also solves the problem that the intermediate product is unstable and difficult to separate and purify. And the yield of osimertinib from Ⅴ reached 61%, higher than that reported in the literature (33%). Besides, in this process, acryloyl chloride was replaced by cheap acrylic acid, which not only reduced costs, but also made the reaction conditions milder and easier to operate.