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.