Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (2): 788-794.DOI: 10.6023/cjoc202006078 Previous Articles     Next Articles



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-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