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    卡马替尼中间体1-(2-氯-1-羟基-3-(6-喹啉基)丙基)-2,5-吡咯烷二酮的合成工艺研究

    Synthesis Process of 1-(2-Chloro-1-hydroxy-3-(6-quinolineyl)propyl)-2,5-pyrrolidinedione, an Intermediate of Capmatinib

      摘要
    • 摘要:
      目的  探索卡马替尼中间体1-(2-氯-1-羟基-3-(6-喹啉基)丙基)-2,5-吡咯烷二酮的合成及优化。
      方法 考察以6-溴喹啉和丙烯醛缩二乙醇为反应底物经过Heck偶联反应，加氢还原，盐酸水解，氯代反应，最终得到关键中间体1-(2-氯-1-羟基-3-(6-喹啉基)丙基)-2,5-吡咯烷二酮的相关因素。通过对温度，溶剂，催化剂等的变化，提高反应收率和产品纯度。
      结果 目标产物结构经过LC-MS和1H NMR验证正确，产品纯度98.8%，总收率61.6%。
      结论 优化后，收率明显提升，原料廉价易得，为工业化合成研究提供有价值的参考。

       

      Abstract:
      OBJECTIVE  To explore the synthesis and optimization of 1-(2-chloro-1-hydroxy-3-(6-quinolinyl)propyl)-2,5-pyrrolidinedione, an intermediate of capmatinib.
      METHODS This study investigated the factors influencing the preparation of the key intermediate 1-(2-chloro-1-hydroxy-3-(6-quinolinyl)propyl)-2,5-pyrrolidinedione from 6-bromoquinoline and acrolein diethyl acetal via Heck coupling, hydrogenation, hydrochloric acid hydrolysis, and chlorination. Reaction parameters including temperature, solvent, and catalyst were optimized to improve the reaction yield and product purity.
      RESULTS The structure of the target product was verified by LC-MS and 1H NMR, the purity of the product was 98.8%, and the total yield was 61.6%.
      CONCLUSION After optimization, the yield is significantly improved, and the raw materials are cheap and easy to obtain, which is more suitable for industrial production.

       

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