Synthesis of Deuterated Endochin‐Like Quinolones

ABSTRACT Malaria continues to be a serious and debilitating disease. The emergence and spread of high‐level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ‐331 (MMV‐167), an alkoxy carbonate prodrug of 4(1H)‐quinolone ELQ‐300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ‐331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)‐quinolone ELQ‐300, its alkoxycarbonate prodrug ELQ‐331, and their respective N‐oxides using deuterated acetic acid. A prodrug of antimalarial drug candidate ELQ‐300 is currently in preclinical development, requiring the availability of isotopically labeled analogs. A suitable method for isotopic labeling of these compounds has not yet been reported. Here, we describe a method for the deuteration of ELQ‐300 and its prodrug using deuterated acetic acid.