Novel and Cost-EffectiveManufacturing Process Development of Daprodustat

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor indicated for treating anemia in patients with chronic kidney disease (CKD). This study describes a novel, efficient, and robust kilogram-scale manufacturing process for daprodustat starting from commercially available malonic acid by implementing quality by design (QbD) principles. A novel synthetic approach was adopted for the synthesis of methyl (1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)­glycinate by avoiding the use of ethyl isocyanatoacetate and replacing it with methyl glycinate and CDI. To our delight, we achieved a throughput of 76% with over 99% purity for daprodustat, compared to the previously reported throughput of 52%. This approach has enabled us to develop a more environmentally friendly process for synthesizing daprodustat than the prior method.