Tritium hydrogen‐isotope exchange with electron‐poor tertiary benzenesulfonamide moiety; application in late‐stage labeling of T0901317

Abstract

The multifunctional radioligand [3H]T0901317 ([3H]1) has been employed as a powerful autoradiographic tool to target several receptors, such as liver X, farnesoid X, and retinoic acid‐related orphan receptor alpha and gamma subtypes at nanomolar concentrations. Although [3H]1 is commercially available and its synthesis via tritiodebromination has been reported, the market price of this radioligand and the laborious synthesis of corresponding bromo‐intermediate potentially preclude its widespread use in biochemical, pharmacological, and pathological studies in research lab settings. We exploit recent reports on hydrogen‐isotope exchange (HIE) reactions in tertiary benzenesulfonamides where the sulfonamide represents an ortho‐directing group that facilitates CH activation in the presence of homogenous iridium(I) catalysts. Herein, we report a time‐ and cost‐efficient method for the tritium late‐stage labeling of compound 1—a remarkably electron‐poor substrate owing to the tertiary trifluoroethylsulfonamide moiety. Under a straightforward HIE condition using a commercially available Kerr‐type NHC Ir(I) complex, [(cod)Ir (NHC)Cl], the reaction with 1 afforded a specific activity of 10.8 Ci/mmol. Additionally, alternative HIE conditions using the heterogeneous catalyst of Ir‐black provided sufficient 0.72 D‐enrichment of 1 but unexpectedly failed while repeating with tritium gas.

Direct Multi‐Deuterium Labelling of Pirtobrutinib

“…Based on our previous experience with HIE reactions on various substrates, we decided to test five iridium‐based C–H activation catalysts ( 7 – 11, Figure 3) that we deemed potentially suitable for the HIE reactions. They comprised the versatile homogenous Crabtree's ( 7 ) and Kerr‐type NHC catalysts [(cod)Ir (NHC)PR 3 ] ( 8 , 10 ) and [(cod)Ir (NHC)Cl] ( 9 ) as well as [Ir (OMe)(cod)] 2 ( 11 ) used for in situ generation of nanoparticles [26–28].…”

“…Due to the limited heating capacity of our first‐choice solvent, DCM, which has a low boiling point (bp 40°C), we opted to test another chlorinated solvent, chlorobenzene (PhCl) (bp 132°C). Recent studies have shown that chlorobenzene provides a robust environment for facilitating HIE, even when using low‐reactivity substrates such as those with secondary and tertiary sulfonamide directing groups [26, 29, 30].…”