Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
J Labelled Comp Radiopharm. 2024 Jul;67(9):314-323. doi: 10.1002/jlcr.4117. Epub 2024 Jul 14.
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-d, at an elevated temperature. Virtually, no d-d species were detected, with only traces of d-d isotopomers (< 5%) observable in the mass spectrum of pirtobrutinib-d, fulfilling requirements for stable isotope-labelled internal standard. The labelled compound-mainly consisting of isotopomers d-d 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 mol%.
在此，我们展示了一种使用简单的氘氢交换（HIE）反应对 recently approved by the FDA 的 Bruton's tyrosine kinase 抑制剂 pirtobrutinib 进行多氘标记的有效方法。使用过量 Kerr 型铱催化剂可实现极高水平的氘掺入。在高温下使用氘标记的均相溶剂氯苯-d 是实现显著氘标记的关键因素。实际上，未检测到 d-d 物种，在 pirtobrutinib-d 的质谱中仅观察到痕量的 d-d 同量异位素（<5%），满足稳定同位素标记内标物的要求。标记的化合物-主要由同位素 d-d 组成，总丰度为 82.4%-以高产率（73%）和高纯度（99%）分离。值得注意的是，首次观察到氟基团作为导向基团。观察到邻位氘的显著掺入，超过 87%。有趣的是，即使在铱催化剂负载量异常低（4.17×10-6mol%）的情况下，用于 HIE 反应的氯化溶剂也会非特异性地氘化，每个氯苯分子最多可得到 0.42 个氘。
