Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals

Abstract

Radiolabelling is fundamental in drug discovery and development as it is mandatory for preclinical ADME studies and late‐stage human clinical trials. Herein, a general, effective, and easy to implement method for the multiple site incorporation of deuterium and tritium atoms using the commercially available and air‐stable iridium precatalyst [Ir(COD)(OMe)]2 is described. A large scope of pharmaceutically relevant substructures can be labelled using this method including pyridine, pyrazine, indole, carbazole, aniline, oxa‐/thia‐zoles, thiophene, but also electron‐rich phenyl groups. The high functional group tolerance of the reaction is highlighted by the labelling of a wide range of complex pharmaceuticals, containing notably halogen or sulfur atoms and nitrile groups. The multiple site hydrogen isotope incorporation has been explained by the in situ formation of complementary catalytically active species: monometallic iridium complexes and iridium nanoparticles.

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

“…It should be noted that the described method gave a total deuterium incorporation which equals that obtained with previously reported Ir catalytic species (2.3 D incorporated), but at a lower temperature. 44 For easily reducible compounds such as 2-(4-methoxyphenyl)pyridine 3 or 2-benzylpyridine 4 , the labeling comes along with reductive deuteration. Based on our previous work on Ru catalysts, 45 5 mol % 1,3-dicyclohexylimidazolium (ICy) chloride was added to modify the reactivity of the catalytic surface, leading to a decreased amount of the reduced side-product for 2-benzylpyridine 4 .…”

Nanocatalyzed Hydrogen Isotope Exchange

“…We discovered that the commercially available and air-stable [Ir(COD)(OMe)] 2 used as precursor for the synthesis of the IrNP particles was a powerful catalyst precursor itself for the labelling of a wide range of compounds. 46 Selected as model substrate, 2-phenylpyridine was labelled not only at the ortho position of the phenyl ring as usually obtained using an homogeneous catalyst, or at the pyridinic core usually obtained using nanoparticles, but on both sites as a combination of the two types of catalysis (THF at 55°C and under 1 bar of D 2 gas) under mild conditions leading to a substantial deuteration of almost all positions.…”

Base‐Mediated Remote Deuteration of N‐Heteroarenes – Broad Scope and Mechanism

“…To allow for a broad range of labeling possibilities, it is desirable to have a toolkit that can access various selectivity patterns in the deuteration of pyridines. To this end, interesting approaches have been the combination of homogeneous and heterogeneous catalysts to combine their respective selectivities, [20] the use of catalysts that exhibit a purely sterically driven selectivity [21] as well as the implementation of a two‐step protocol that enables selective deuteration in position 4 of pyridines (Scheme 1). [22] On the other hand, a preference for the distal positions of pyridine derivatives was observed in kinetic experiments with osmium complexes [23] as well as with NaOD [24] .…”