千克级芳构化-还原“一锅煮”制备阿戈美拉汀

One-pot aromatization-reduction preparation of agomelatine at kilogram scale

摘要:

以7-甲氧基四氢萘-1-酮（Ⅱ）为起始原料，在庚酸和苄胺催化下，与氰乙酸缩合得到(7-甲氧基-3,4-二氢-1-萘基)乙腈（Ⅲ）；然后以5%Pd/C（Pd质量分数为5%）为催化剂，丙烯酸烯丙酯（Ⅶ）为氢受体，化合物Ⅲ经芳构化-还原“一锅煮”先制备了(7-甲氧基-1-萘基)乙腈（Ⅳ），不需分离直接加入甲酸铵为氢供体，制备了(7-甲氧基-1-萘基)乙胺（Ⅴ）。芳构化反应优化条件为：Pd/C用量为5%(以Ⅲ物质的量计)、n(Ⅲ)∶n(Ⅶ)=1.0∶1.1、回流反应时间4 h，转化率为100%，选择性为92.12%；还原反应优化条件为：n(Ⅲ)∶n(甲酸铵)=1.0∶4.0、反应温度70 ℃、反应时间2 h，收率为83.35%。最后，化合物Ⅴ与盐酸反应制得(7-甲氧基-1-萘基)乙胺盐酸盐（Ⅵ），Ⅵ与乙酰氯反应得到阿戈美拉汀（I），反应总收率为64.60%。并用1HNMR、13CNMR、MS、FTIR对产物结构进行表征，该工艺经千克级放大实验，反应总收率为60.68%，产物纯度为99.91%。

Abstract:

7-methoxytetralone(Ⅱ)was selected as staring material, condensation with cyanoacetic acid catalyzed by heptanoic acid and benzylamine to obtain (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (III).The aromatization-reduction“one-pot” preparation of (7-methoxy-1-naphthyl)ethylamine(Ⅴ) was performed by aromatization of Ⅲ using allyl acrylate(Ⅶ) as hydrogen acceptor under 5%Pd/C(5%Pd mass fraction) to obtain (7-methoxy-1-naphthyl)acetonitrile(Ⅳ),followed by transfer hydrogenation using ammonium formate as the hydrogen donor. The optimized conditions were: aromatization, the amount of 5%Pd/C , n(Ⅲ)∶n(Ⅶ)=1.0∶1.1, and the reaction time was 4.0 h. reduction reaction, n(Ⅲ)∶n(HCO2NH4 )=1.0∶4.0, the reaction temperature was 70 °C, the reaction time was 2.0 h. V reacts with hydrochloric acid to obtain Ⅵ, and the reaction of VI with acetyl chloride obtain agomelatine (I) in 64.70% total yield. The product and intermediates were characterized by 1HNMR, 13CNMR, MS, and FTIR .The process was scaled up on a kilogram scale with an overall yield of 60.70% and a purity of 99.91%.