阿戈美拉汀合成工艺研究-化学工程专业论文.docx

万方数据 万方数据 摘 要 阿戈美拉汀是一种新型的褪黑激素类抗抑郁药,兼具有 5-HT2C 受体拮抗作 用，既可以模拟褪黑激素的作用，又具有较为独特的作用方式，可使昼夜节律已 被破坏的动物模型重新恢复其昼夜节律同步。本品最早由法国 Servier 公司开发， 于 2009 年 2 月 19 日得到 EMEA 批准并在欧盟上市，临床主要用于治疗中度至 重度抑郁症，安全性状况良好且停药后不易复发，是治疗生理节律紊乱性疾病非 常具有前途的候选药物。 本文在检索、分析阿戈美拉汀多种文献资料的基础上，自行设计了一条含 4 步反应的合成路线。经对所设计路线展开实际的小试研究，考察、确定了每步反 应中温度、时间、溶剂、精制方法等关键节点的控制方法，尤其是在第三步合成 阿戈美拉汀粗品的过程中，将氢化、乙酰化两个反应一步完成，简便、环保、高 收率的得到目标产品，路线总收率达到 52.1%；并通过紫外、红外、核磁、质谱 等方法确证成品结构正确；继而，针对每一步反应相关杂质进行了系统、深入的 分析，确定了较为完善的质量控制方法。 关键词：阿戈美拉汀；抗抑郁药；合成工艺；杂质；质量控制 ABSTRACT Agomelatine is an agonist of melatonin receptors and an antagonist of the serotonin 5-HT2C receptor, It works in two ways, by stimulating the MT1 and MT2 receptors, which are normally activated by melatonin, and also by blocking the 5-HT2C receptors, which are normally activated by the neurotransmitter 5-hydroxytryptamine (also called serotonin). Agomelatine was first authorised in the EU in February 2009. It is now marketed in all EU countries. It is believed to help relieve the symptoms of depression. It might also help to normalise the patient’s sleep patterns. In this study, on the basis of analysis and assessment of several synthesis routes of agomelatine that had been reported, we designed an efficient, and productive process that consist of 4 steps. After laboratory experiment of the route we designed, we studied the temperature, time, solvent, and purification of each step. Critical control points were concluded. We combine the hydrogenation and acetylation steps into one step in step 3, so that we got the target compound in total yield 52.1%. The structure had been confirmed by UV, IR, NMR, MS. We also studied the relevant impurities which occurred in the process, and developed a robust quality control method. Keywords: Agomelatine, antidepressant，synthetic process，impurities, quality control 目 录 HYPERLINK \l _bookmark0 前 言............................................................................................................................1 HYPERLINK \l _bookm