Easy-to-Implement Hydrogen Isotope Exchange for the Labeling of N-Heterocycles, Alkylkamines, Benzylic Scaffolds, and Pharmaceuticals

Facilitating access to deuterated and tritiated complex molecules is of paramount importance due to the fundamental role of isotopically labeled compounds in drug discovery and development. Deuterated analogues of drugs are extensively used as internal standards for quantification purposes or as active pharmaceutical ingredients, whereas tritiated drugs are essential for preclinical ADME studies. In this report, we describe the labeling of prevalent substructures in FDA-approved drugs such as azines, indoles, alkylamine moieties, or benzylic carbons by the in situ generation of Rh nanopartides able to catalyze both C(sp(2))-H and C(sp(3))-H activation processes. In this easy-to-implement labeling process, Rh nanocatalysts are formed by decomposition of a commercially available rhodium dimer under a deuterium or tritium gas atmosphere (1 bar or less), using the substrate itself as a surface ligand to control the aggregation state of the resulting metallic clusters. It is noteworthy that the size of the nanopartides observed is surprisingly independent of the substrate used and is homogeneous, as evidenced by transmission electron microscopy experiments. This method has been successfully applied to the one-step synthesis of (1) deuterated pharmaceuticals usable as internal standards for MS quantification and (2) tritiated drug analogues with very high molar activities (up to 113 Ci/mmol).

Automated summary

This report describes a simple labeling process using in situ generated Rh nanopartides to label common substructures in drugs. The size of the observed nanopartides is independent of the substrate used and is consistently distributed. The method has been successfully applied to the one-step synthesis of deuterated pharmaceuticals and tritiated drug analogues with high molar activities.