摘要/Abstract

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


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