高等学校化学学报 ›› 2017, Vol. 38 ›› Issue (2): 200-205.doi: 10.7503/cjcu20160742

• 有机化学 • 上一篇    下一篇

γ-分泌酶抑制剂(LY411575)的合成工艺研究

郭宏垚1, 李冬1(), 雷雄1, 张旭1, 许人军2, 王锋1, 李稳宏1   

  1. 1. 西北大学化工学院, 西安 710069
    2. 西安市轻工业研究所, 西安 710001
  • 收稿日期:2016-10-25 出版日期:2017-02-10 发布日期:2017-01-06
  • 作者简介:联系人简介: 李 冬, 男, 博士, 副教授, 主要从事化工研究. E-mail: lidong@nwu.edu.cn
  • 基金资助:
    陕西省青年科技新星(批准号: 2016KJXX-32)资助

Synthesis Process Research of γ-Secretase Inhibitors(LY411575)

GUO Hongyao1, LI Dong1,*(), LEI Xiong1, ZHANG Xu1, XU Renjun2, WANG Feng1, LI Wenhong1   

  1. 1. School of Chemical Engineering, Northwest University, Xi’an 710069, China
    2. Xi’an Institute of Light Industry, Xi’an 710001, China
  • Received:2016-10-25 Online:2017-02-10 Published:2017-01-06
  • Contact: LI Dong E-mail:lidong@nwu.edu.cn
  • Supported by:
    † Supported by the Shaanxi Province Youth New-Star Plan of Science and Technology, China(No.2016KJXX-32).

摘要:

γ-分泌酶抑制剂(LY411575)的合成路线进行改进, 新合成路线下该化合物的总收率为35%, 比文献方法提高了16%; 对关键中间体提前进行了手性拆分, 从而使在制备最终产品的后3步反应中用到的原料减少了50%, 降低了反应成本和最终产品的纯化难度. 另外, 对拆分过程中的主要因子进行了单因素实验, 考察了各因素对产品的e.e.值和反应收率的影响. 获得了最佳反应条件: D-(+)-二对甲基苯甲酰酒石酸为拆分试剂, 甲醇作溶剂, 加热到回流溶解, 加入的溶剂量为每g底物12 mL, 从回流降到室温所用时间控制在120 min, 拆分的收率为40%, e.e.值为99%.

关键词: 阿尔茨海默病, γ-分泌酶, 关键中间体, 抑制剂

Abstract:

The original synthetic route of gamma secretase inhibitors(LY411575) was improved, the yield of 35% was achieved which increased by 16% compared with the traditional process. Meanwhile, key interme-diates were resolved by chiral acid in advance so that the consumption of raw materials in latter three steps of synthetic process was decreased by 50%. The method contributed to decrease the reaction cost and the difficulty of product purification. In addition, the single-factor experiment was conducted for main factors affected the resolving process to study the influence of various factors on the e.e. value and the yield of products. The optimal reaction condition was obtained as follows: D-(+)-2 methyl benzoyl tartaric acid as the resolution agent, methanol as the solvent, heated to reflux for dissolution, the solvent of 12 mL per gram substrate, the time from the initial temperature of reflux to room temperature controlled in 120 min, the resolution yield of 40% and the e.e. value of 99%.

Key words: Alzheimer’s disease(AD), γ-Secretase, Key intermediate, Inhibitor

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