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

关键词:  卡马替尼  工艺优化  合成  中间体

Key words:  capmatinib  process optimization  Synthesis  Intermediates

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 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-吡咯烷二酮的因素的考察。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1HNMR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:

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 6-bromoquinoline and acrolein diethanol were used as reaction substrates to obtain the target compounds through Heck coupling reaction, hydroreduction, hydrochloric acid hydrolysis and chlorination reaction. The reaction conditions and parameters were optimized, and the optimization conditions were as follows: n (6-bromoquinoline): n (acrolein diethanol): n (bistriphenylphosphine palladium dichloride) = 1.00:1.75:0.10 in Heck reaction, the reaction temperature was 80 °C, and the solvent was DMF; In the hydroreduction reaction, m (compound 1): m (palladium-carbon)=1.00:0.10, and the reaction solvent is THF; In the hydrolysis reaction, n (compound 2): n (4N hydrochloric acid) = 1.00: 5.00, the reaction temperature is 0 °C, and the solvent is ethyl acetate; In the chlorination reaction, n (compound 3): n (NCS): n (L-proline): n (benzoic acid) = 1.00: 1.05: 0.20: 0.20, the reaction solvent is dichloromethane, and the temperature is 0 °C. RESULTS The structure of the target product was verified by LC-MS and 1HNMR, 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. Keywords: capmatinib; process optimization; synthesis; intermediates