Direct Multi‐Deuterium Labelling of Pirtobrutinib

Abstract

Herein, we demonstrate an efficient method for multi‐deuterium labelling of pirtobrutinib—a Bruton's tyrosine kinase inhibitor recently approved by the FDA—using a straightforward hydrogen isotope exchange (HIE) reaction. A remarkably high level of deuterium incorporation was achieved using an excess of a Kerr‐type iridium catalyst. The key factor in the significant deuterium labelling was the decision to employ a deuterium uniformly labelled solvent, chlorobenzene‐d5, at an elevated temperature. Virtually, no d0–d3 species were detected, with only traces of d4–d5 isotopomers (< 5%) observable in the mass spectrum of pirtobrutinib‐d8, fulfilling requirements for stable isotope‐labelled internal standard. The labelled compound—mainly consisting of isotopomers d6–d9 at 82.4% of the total abundance—was isolated in a high yield (73%) and purity (99%). Noteworthy, fluorine group acting as a directing group was observed for the first time. Significant incorporation of deuterium in ortho‐positions, exceeding 87%, was observed. Interestingly, chlorinated solvent used in the HIE reactions was non‐specifically deuterated yielding up to 0.42 deuterium per chlorobenzene molecule even at an exceptionally low iridium catalyst loading of 4.17 × 10–2 mol%.