Development of a Scalable Manufacturing Synthesis for Enarodustat

Enarodustat (brand name Enaroy) is an oral hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitor for the treatment of renal anemia in chronic kidney disease (CKD) patients. Establishing a commercial synthetic route for drug substances is essential for ensuring stable delivery to patients. To overcome challenges associated with the medicinal chemistry route, such as avoiding a cryogenic reaction and column purification, we devised a synthetic route incorporating the dichlorotriazolopyridine derivative 14 as a key intermediate, with the regioselective introduction of a phenethyl group onto it as a key step. This key step was resolved through a nucleophilic substitution employing a malonate derivative. We prepared the key intermediate by improving a known reaction which gave extremely low yields. After thorough investigation, we achieved a kilogram-scale synthesis, successfully overcoming these challenges. The overall yield was 23% in 8 chemical steps, with a purity suitable for human administration.