Application of neutral iridium(I) N-heterocyclic carbene complexes in ortho-directed hydrogen isotope exchange.

Bench-stable complexes of the type [Ir(COD)(NHC)Cl] (NHC = N-heterocyclic carbene) have been investigated within the field of hydrogen isotope exchange. By employing a sterically encumbered NHC within such complexes and catalyst loadings of only 5 mol%, moderate to high deuterium incorporations were achieved across a range of aromatic ketones and nitrogen-based heterocycles. The simple and synthetically accessible catalysts reported herein present alternatives to phosphine-based species and increase the available labelling systems with respect to established iridium-based isotope exchange methodologies.

Use of radiolabeled compounds in drug metabolism and pharmacokinetic studies.

As part of the drug discovery and development process, it is important to understand the fate of the drug candidate in humans and the relevance of the animal species used for preclinical toxicity and pharmacodynamic studies. Therefore, various in vitro and in vivo studies are conducted during the different stages of the drug development process to elucidate the absorption, distribution, metabolism, and excretion properties of the drug candidate. Although state-of-the-art LC/MS techniques are commonly employed for these studies, radiolabeled molecules are still frequently required for the quantification of metabolites and to assess the retention and excretion of all drug related material without relying on structural information and MS ionization properties. In this perspective, we describe the activities of Isotope Chemistry at AstraZeneca and give a brief overview of different commonly used approaches for the preparation of (14)C- and (3)H-labeled drug candidates. Also various drug metabolism and pharmacokinetic studies utilizing radiolabeled drug candidates are presented with in-house examples where relevant. Finally, we outline strategic changes to our use of radiolabeled compounds in drug metabolism and pharmacokinetic studies, with an emphasis on delaying of in vivo studies employing radiolabeled drug molecules.

Highly active iridium(I) complexes for the selective hydrogenation of carbon-carbon multiple bonds.

New iridium(I) complexes, bearing a bulky NHC/phosphine ligand combination, have been established as extremely efficient hydrogenation catalysts that can be used at low catalyst loadings, and are compatible with functional groups which are often sensitive to more routinely employed hydrogenation methods.

Highly active iridium(I) complexes for catalytic hydrogen isotope exchange.

Practically convenient methods have been developed for the preparation of new iridium complexes, possessing bulky N-heterocyclic carbene and phosphine ligands; these routinely handled complexes are highly active catalysts within directed hydrogen isotope exchange processes.