Carbon Isotope Exchange in Aryl Nitriles

Carbon Isotope Exchange in Aryl Nitriles


Radiolabeled pharmaceutically active compounds are useful in drug development. They can be used to trace the drugs and their metabolites. Carbon-14 (14C) is useful for these types of applications, as it provides a robust radiolabel—in contrast to tritium (3H), which can be exchanged quite easily. However, incorporating the radiolabel into the carbon skeleton of drugs can be challenging because there is a limited range of 14C-containing starting materials. It also produces larger amounts of radioactive waste. Introducing the radiolabel late in the synthesis would be preferable.

Sean W. Reilly, Neil A. Strotman, Merck & Co., Inc., Rahway, NJ, USA, and colleagues have developed a simple, late-stage, one-pot strategy for 13CN and 14CN exchange with the CN groups of aryl, heteroaryl, and alkenyl nitriles (example product pictured). The team used radiolabeled Ni(CN)2 as a reactant, Ni(COD)DQ (COD = 1,5‐cyclooctadiene, DQ = duroquinone) as a catalyst, PMe3 or PPh2Me as a ligand, BPh3 as a Lewis acid, and N-methyl-2-pyrrolidone (NMP) as the solvent. The reactions were performed at 80 °C.

According to the team, this is the first carbon isotope exchange method for aryl, heteroaryl, and alkenyl nitriles that allows the late-stage incorporation of isotopic labels. It has a broad substrate scope and can be used for the labeling of complex drug-like molecules. As a proof of concept, the team converted the drug candidate belzutifan to the corresponding 14C-labeled tracer, with 52 % 14C incorporation and in 72 % isolated yield.



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