Stable Isotope Labeling of Pyrimidines Using a Deconstruction-Reconstruction Strategy.

Authors

Benjamin J H Uhlenbruck, Andrew McNally

Published in

Journal of the American Chemical Society. Sep 17, 2025. Epub Sep 17, 2025.

Abstract

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.

PMID:
40963094
Bibliographic data and abstract were imported from PubMed on 18 Sep 2025.

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