苏沃雷生关键中间体的连续流微反应合成工艺研究

Study on Continuous Flow Microreaction Synthesis of Core Intermediate of Suvorexant

采用连续流微反应器技术对苏沃雷生原料药关键中间体进行技术优化,以2-氨基-4-氯苯酚和乙基黄原酸钾为起始原料,经环化反应、卤代反应和手性拆分等反应合成苏沃雷生中间体5-氯-2-[(5R)-六氢-5-甲基-1H-1,4-二氮杂卓-1-基]苯并恶唑。同时考察了工艺流程中涉及的卤代试剂类型、缚酸剂类型、碱当量因素对相应中间体的收率和纯度的影响,确定了最佳工艺条件。产物总收率为51.8%,液相纯度达到99.2%,其结构经NMR和MS表征。该工艺适合工业化生产。

Continuous flow microreactor technology was used to optimize the technology of key intermediates of suvorexant.2-amino-4-chlorophenol and potassium ethylxanthate were used as starting materials.The intermediate 5-chloro-2-[(5R)-hexah-5-methyl-1H-1,4-diazazepine-1-yl]benzoxazole was synthesized by cyclization,halogenation and chiral resolution.At the same time,the effects of the types of halogenated reagents and acid binding agents involved in the process and the equivalent of alkali on the yield and purity of the corresponding intermediates were investigated.The optimal process conditions were determined.The total yield was 51.8%,the purity checked by HPLC was 99.2%,and the structure of the intermediates was characterized by NMR and MS.The process is suitable for industrial production.