Iron-catalysed tritiation of pharmaceuticals

Abstract

A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process--ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials--to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain (14)C or (3)H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium ((3)H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct (3)H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.

Cobalt-Catalyzed Stereoretentive Hydrogen Isotope Exchange of C(sp3)–H Bonds

“…7 Our laboratory recently reported a bis( N -heterocyclic-carbene)pyridine pincer iron-catalyst that exhibited highly predictable, sterically driven C(sp 2 )−H site selective HIE that is orthogonal to that observed with iridium (Scheme 1A). 8 …”

Ambireactive (R3P)2BH2 Groups Facilitating Temperature‐Switchable Bond Activation by an Iron Complex

“…In recent years increasing effort has been made to develop homogeneous C−H activation catalysts based on iron . The first example of an iron‐catalyzed deuterium or tritium labeling of C−H bonds in pharmaceutically active compounds was just recently reported by the Chirik group …”

Ruthenium(II)‐Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs by C−H Deuteration and C−H Tritiation

“…Despite the increasing synthetic abilities of metal complexes towards C−H activation of organic molecules, selective HIE of pharmaceuticals continuous to be extremely rare. A recent example that addresses this synthetic challenge by the Chirik group achieved the deuteration and tritiation of pharmaceutical drugs at aromatic C−H moieties with orthogonal site selectivity relative to Crabtree's iridium catalyst (Figure a) . Furthermore MacMillan described the direct HIE of α‐amino C−H bonds mediated by photoredox catalysis (Figure b) .…”