1-苄基-5-氧代-3-吡咯烷甲酸是制备抗老年痴呆药奈拉西坦的重要中间体,奈拉西坦可改善脑能量代谢和神经传递功能,对脑内胆碱能系统机能障碍有明显改善作用。
医药
路线1:
- 步骤:将1-苄基-5-氧代-3-吡咯烷羧酸甲酯(2.00g,8.57mmol)溶于甲醇(10ml)和四氢呋喃(10ml)的混合溶剂中,加入2N氢氧化锂水溶液(8.6ml),加热回流20分钟;反应完成后,冰冷却,用硫酸氢钾水溶液酸化,乙酸乙酯萃取,浓缩萃取液,经乙酸乙酯/己烷再浆化洗涤、干燥,得目标产物(1.83g,97%)。
- 条件:With lithium hydroxide In tetrahydrofuran; methanol; water for 0.33 h; Heating / reflux
- 产率:97%
- 参考文献:[1] Patent: EP1403255, 2004, A1. Location in patent: Page 78 [2] Journal of Medicinal Chemistry, 1997, vol. 40, #15, p. 2374 - 2385 [3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, #1, p. 377 - 379 [4] European Journal of Organic Chemistry, 2005, #4, p. 673 - 682 [5] Patent: WO2006/123725, 2006, A1. Location in patent: Page/Page column 64-65
路线2:
- 步骤:将衣康酸(18g,0.138mol)和苄胺(14.8g,0.138mol)于反应瓶中,N2保护下,升温至130℃,熔化后搅拌反应2.5h;停止加热,冷却至100℃时加入10%NaOH溶液200ml,冷至室温,水层用乙酸乙酯洗涤,用10%盐酸溶液滴加至水层pH=1-2,过滤,水洗至pH约为6,得白色颗粒状固体25.1g。
- 条件:at 130℃; for 2.50 h; Inert atmosphere
- 产率:82.9%
- 参考文献:[1] Journal of Organic Chemistry, 2010, vol. 75, #11, p. 3766 - 3774 [2] Journal of Fluorine Chemistry, 2010, vol. 131, #2, p. 224 - 228 [3] Patent: CN104447733, 2016, B. Location in patent: Paragraph 0055; 0056; 0057 [4] Chemical and Pharmaceutical Bulletin, 2004, vol. 52, #1, p. 63 - 73 [5] Patent: EP1180513, 2002, A1. Location in patent: Referential example 44 [6] Journal of the American Chemical Society, 1950, vol. 72, p. 1415 [7] Molecules, 2005, vol. 10, #2, p. 367 - 375