有机化学 ›› 2011, Vol. 31 ›› Issue (02): 212-215. 上一篇    下一篇

研究论文

(R)-(+)-和(S)-(-)磷酸苯并哌啉对映体的合成新方法

王晓娟1,2,郭琳琳1,3陈广威1,3徐永刚1,3郭晓1,3,徐海伟1,3刘宏民*,1,2,3   

  1. (1郑州大学新药研发中心 郑州 450001)
    (2郑州大学化学系 郑州 450001)
    (3郑州大学药学院 郑州 450001)
  • 收稿日期:2010-05-13 修回日期:2010-07-05 出版日期:2011-02-25 发布日期:2010-09-28
  • 通讯作者: 王晓娟 E-mail:juanzi409e@126.com

A New Method for Synthesis of (R)-(+)- and (S)-(-)-Benproperine Phosphate Enantiomers

Wang Xiaojuan1,2 Guo Linlin1,3 Chen Guanwei1,3 Xu Yonggang1,3 Guo Xiao1,3 Xu Haiwei1,3 Liu Hongmin*,1,2,3   

  1. (1 New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001)
    (2 Department of Chemistry, Zhengzhou University, Zhengzhou 450001)
    (3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001)
  • Received:2010-05-13 Revised:2010-07-05 Online:2011-02-25 Published:2010-09-28
  • Contact: Xiao-Juan WANG E-mail:juanzi409e@126.com

报道了(R)-和(S)-磷酸苯丙哌啉对映体的合成新方法. 以邻苄基苯酚和(S)-(+)-环氧氯丙烷为原料, 通过成醚、选择性还原开环两步反应简捷高效地制得重要中间体(R)-1-(2-苄基苯氧基)-2-丙醇(2). 中间体2与对甲苯磺酰氯酰化, 制得中间体(R)-1-(2-苄基苯氧基)-2-丙醇对甲苯磺酸酯(3), 该中间体与哌啶发生一次SN2反应直接得到(S)-(-)-苯丙哌啉, 该中间体与溴化锂和哌啶发生两次SN2反应制得(R)-(+)-苯丙哌啉. 然后它们分别与磷酸成盐制得相应的(S)-(-)-和(R)-(+)-磷酸苯丙哌啉, 其结构通过1H NMR和HRMS进行了表征. 该合成方法路线短, 反应条件温和, 易于操作, 且收率好, 适合工业化生产.

关键词: 手性药物, 苯丙哌啉, 合成, 对映体

A new and practical procedure is described for the preparation of benproperine phosphate enantiomers. Starting from the source of o-benzylphenol and (S)-(+)-epichlorohydrin, the key intermediate (R)-1-(2-benzylphenoxy) propan-2-ol (2) was prepared by etherification, selective ring opening reaction in a simple and efficient step. (R)-1-(2-Benzylphenoxy)propan-2-yl 4-methylbenzenesulfonate (3) was obtained with p-toluenesulfonate, then followed by the SN2-type reaction with piperdine furnishing (S)-(-)-benproperine, while (R)-(+)-benproperine was obtained by submitting the same tosylate to two con-secutive SN2-type reaction with LiBr and piperidine. The (S)-(-)- and (R)-(+)-benproperine phosphates were recrystallized by ethanol, respectively. And the enantiomers of benproperine phosphate were character- rized by 1H NMR and HRMS techniques. The improved method presented here features mild reaction conditions, simple operation, easy separation of product, high yield and was suitable for manufacturing in commercial scale.

Key words: chiral drug; benproperine, synthesis, enantiomer