Synthesis of Daprodustat

Daprodustat is synthesised using malonic acid as a raw material by Biginelli reaction, saponification and other reactions. The specific synthesis steps are as follows:

The reaction of DCC with malonic acid (59) yielded cyclic urea 60 in 72% yield, representing a creative use of the classic coupling reagent as a urea synthon within a modified Biginelli reaction. Subjection of pyrimidine trione 60 to basic conditions in the presence of ethyl isocyanoacetate provided penultimate intermediate 61, which underwent saponification to yield daprodustat in 78% yield.

Introduction of Daprodustat

Daprodustat is a novel treatment for anemia in patients with chronic kidney disease (CKD). This small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) was approved for the treatment of renal anemia in Japan in June, 2020. Additional clinical studies for the evaluation of daprodustat for other disease states are underway worldwide.