有机化学 ›› 2021, Vol. 41 ›› Issue (2): 788-794.DOI: 10.6023/cjoc202006078 上一篇    下一篇

研究论文

稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成

胡宇钊a, 全海源a,b, 王留洋a, 王智楠a, 梅向东a, 宁君, 折冬梅a,*()   

  1. a 中国农业科学院植物保护研究所 北京 100193
    b 中国化工集团曙光橡胶工业研究设计院有限公司 广西桂林 541000
  • 收稿日期:2020-06-30 修回日期:2020-08-15 发布日期:2020-10-12
  • 通讯作者: 折冬梅
  • 作者简介:
    * Corresponding author. E-mail:
    † 共同第一作者(These authors contributed equally to this work).
  • 基金资助:
    国家重点研究发展计划(2016YFD0200201); 国家自然科学基金(31772175); 国家自然科学基金(31621064)

Synthesis of Stable Isotope Labeled 13C4-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon

Yuzhao Hua, Haiyuan Quana,b, Liuyang Wanga, Zhinan Wanga, Xiangdong Meia, Jun Nin, Dongmei Shea,*()   

  1. a Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193
    b Shuguang Rubber Industry Research & Design Institute, Guilin, Guangxi 541000
  • Received:2020-06-30 Revised:2020-08-15 Published:2020-10-12
  • Contact: Dongmei She
  • Supported by:
    the National Key Research and Development Program of China(2016YFD0200201); the National Natural Science Foundation of China(31772175); the National Natural Science Foundation of China(31621064)

1,4-二氢吡啶结构是许多生物活性物以及药物分子的重要骨架,同时也是非常重要的有机合成中间体。当前并没有一种适用的方法用于13C标记1,4-二氢吡啶的合成. 提供了一种13C标记1,4-二氢吡啶的合成方法以13C2-乙酸钠为标记原料, 经磷酸酸化得到13C2-乙酸, 羰基二咪唑酰化13C2-乙酸得到13C2-N-乙酰咪唑, 随后在咪唑钠的作用下进行克莱森缩合反应获得1,2,3,4-13C4-乙酰乙酰咪唑的钠盐, 经乙酸酸化得到1,2,3,4-13C4-乙酰乙酰咪唑, 再通过与醇进行酯化得到1,2,3,4-13C4-乙酰乙酸酯, 1,2,3,4-13C4-乙酰乙酸酯经氨基甲酸铵氨化得到1,2,3,4-13C4-3-氨基丁烯酸酯。随后采用Hantzsch改进法合成了5,6-位及其取代基碳标记的13C4-尼群地平、13C4-苯磺酸氨氯地平和13C4-马来酸氨氯地平. 该方法操作简单, 反应条件温和且产率高, 为1,4-二氢吡啶的5,6-位及其取代基引入13C同位素标记合成提供了新的思路,满足中国仿制药物一致性评价的稳定同位素内标自主合成需求。

关键词: 1,4-二氢吡啶, 乙酰乙酸酯, 同位素, 合成

1,4-Dihydropyridines are important central motifs that are abundant in many biologically active molecules and drug molecules, as well as versatile building blocks for organic synthesis. Currently, there is no suitable method for the synthesis of 13C-labeled 1,4-dihydropyridine. A method was described for the synthesis of 13C4-1, 4-dihydropyridines in this article. Using 13C2-sodium acetate as the raw material for labeling, 13C4-acetoacetates were obtained by phosphoric acid acidification, 13C2-Acetic acid was acylated with N,N-carbonyldiimidazole to give 13C2-N-acetylimidazole. Then, the sodium salt of 1,2,3,4-13C4-acetoacetylimidazole was synthesized from 13C2-N-acetylimidazole by Claisen condensation under the catalysis of sodium imidazolate. The sodium salt of 1,2,3,4-13C4-acetoacetylimidazole was acidified with acetic acid to obtain 1,2,3,4-13C4-acetoacetylimidazole, and then esterified with alcohol to obtain 1,2,3,4-13C4-acetylacetic esters. 1,2,3,4-13C4-acety- lacetic esters were aminated by ammonium carbamate to give 1,2,3,4-13C4-3-aminocrotonates. Subsequently, 5,6-position and its substituent carbon-labeled 13C4-nitrandipine, 13C4-amlodipine besylate and 13C4-amlodipine maleate were synthesized using Hantzsch modified method. The method has simple operation, mild reaction conditions, and high yield. This study provides a new idea for the introduction of 1,4-dihydropyridine which 5,6-position and its substituents are labeled with 13C isotope. And it meets the independent synthesis requirements of stable isotope internal standards for the consistency evaluation of generic drugs in China.

Key words: 1,4-dihydropyridines, acetylacetic esters, isotope, synthesis