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

l,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...

Synthesis of Stable Isotope Labeled13C4-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon

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 of¹³C-labeled 1,4-dihydropyridine.A method was described for the synthesis of¹³C4-1,4-dihydropyridines in this article.Using¹³C2-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 give¹³C2-N-acetylimidazole.Then,the sodium salt of 1,2,3,4-¹³C4-acetoacetylimidazole was synthesized from¹³C2-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-acetylacetic esters were aminated by ammonium carbamate to give 1,2,3,4-¹³C4-3-aminocrotonates.Subsequently,5,6-position and its substituent carbon-labeled¹³C4-nitrandipine,¹³C4-amlodipine besylate and¹³C4-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 with¹³C isotope.And it meets the independent synthesis requirements of stable isotope internal standards for the consistency evaluation of generic drugs in China.