Isotopically-labelled compounds are an essential component of the drug development process. Isotopologues enriched with stable isotopes, such as carbon-13 and deuterium, are invaluable in quantitative bioanalysis, where they can be used as internal standards for LC-MS/MS based assays. Meanwhile, radiolablled compounds provide unique access to crucial ADME data through in vivo studies, both in animals and humans. The field of isotopologue synthesis presents a unique set of challenges to synthetic chemists, who, with a limited yet highly expensive pool of labelled reagents, must efficiently incorporate either stable or radioisotopes into drug structures. Due to the frequent presence of methyl groups in drug structures, a general late-stage methylation methodology, which allows for the incorporation of both carbon and hydrogen isotopes, has been identified as a powerful transformation. While conceptually simple, generally applicable methods which utilise accesible, isotopically-enriched methylating agents, and which can be applied to late-stage intermediates, are limited. Herein, we will outline how a highly efficient, robust methodology for the methylation of aryl chlorides was identified using high throughput experimentation. In order to apply the chemistry to isotopologue synthesis, we have also developed a practically straightforward route to isotopically-labelled potassium methyltrifluoroborate – a species which had not previously been obtained as a 13/14C-enriched isotopologue. It is envisaged that this methodology will be highly applicable to the synthesis of numerous isotopologues, which has been exemplified, notably, through application to a number of drug-like scaffolds and active GSK projects.

Late-stage aromatic methylation as a tool for efficient isotope incorporation

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.