Stable Isotope Labeling of Pyrimidines Using a Deconstruction–Reconstruction Strategy

Incorporating stable isotopes into bioactive molecules is crucial in pharmaceutical development, particularly for metabolic studies where higher mass isotopologs of candidate compounds are required. Here we present an isotope exchange method for synthesizing isotopically enriched pyrimidines. By deconstructing pyrimidines into vinamidinium salts and reconstructing them with deuterium, 13C, and 15N-enriched amidines, we achieve high isotopic enrichment across various substitution patterns, including complex drug-like pyrimidine derivatives. The process involves a Tf2O-mediated ring-opening and ring-closing sequence to form a pyrimidinium ion, followed by cleavage to the vinamidinium salt with pyrrolidine. Cyclization with labeled amidines under basic conditions then forms the labeled pyrimidine. Additionally, we deuterated the 5-position of pyrimidines using this approach to offer further versatility in generating higher mass isotopologs.将稳定同位素（stable isotopes）引入生物活性分子，在药物研发领域至关重要，尤其在需要候选化合物高质量同位素异构体（mass isotopologs）的代谢研究中。本文报道了一种用于合成同位素富集嘧啶类化合物的同位素交换方法。我们通过将嘧啶拆解为脒鎓盐（vinamidinium salts），并以氘代、碳13（13C）及氮15（15N）富集的脒类化合物进行重构，可在多种取代模式下实现高同位素富集，涵盖结构复杂的类药嘧啶衍生物。该过程包含三氟甲磺酸酐（Tf2O）介导的开环-闭环序列以生成嘧啶鎓离子，随后与吡咯烷（pyrrolidine）反应裂解为脒鎓盐；再于碱性条件下与标记脒类化合物发生环化反应，得到同位素标记的嘧啶类产物。此外，我们还利用该方法对嘧啶的5位进行氘标记，为制备更高质量的同位素异构体提供了更多应用灵活性。