Synthesis of Deuterated Heterocycles with MeNCD(OMe) and Evaluation of the Products for Metabolism by Aldehyde Oxidase.

The metabolic oxidation of drug-like small molecules by aldehyde oxidase (AO) has commonly been mitigated through the incorporation of deuterium at the oxidation site. We report that dimethylformamide dimethyl acetal and related compounds undergo rapid CH to CD isotopic exchange upon exposure to methanol- and similar deuterated alcohols. This isotopic exchange process can be used to synthesize MeNCD(OMe) and has significant implications for the use of MeNCD(OMe) in the synthesis of specifically deuterium-labeled compounds. The application of MeNCD(OMe) to the synthesis of various heterocycles that have been associated with AO metabolism is described, and we report the impact of deuteration on the rate of AO-mediated metabolism.