Chinese Journal of Organic Chemistry >
Synthesis of Stable Isotope Labeled 13C4-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon
Received date: 2020-06-30
Revised date: 2020-08-15
Online published: 2020-10-12
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
Yuzhao Hu , Haiyuan Quan , Liuyang Wang , Zhinan Wang , Xiangdong Mei , Jun Nin , Dongmei She . Synthesis of Stable Isotope Labeled 13C4-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon[J]. Chinese Journal of Organic Chemistry, 2021 , 41(2) : 788 -794 . DOI: 10.6023/cjoc202006078
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