Synthesis of Vadadustat

Vadadustat is used as raw material of boronic acid and is prepared by coupling, substitution and hydrolysis reactions. The specific synthesis steps are as follows:

Suzuki coupling of boronic acid 69 and picolinonitrile 70 generated biaryl 71. A crystallization of 71 was required to purge the minor, undesired regioisomeric coupling product. Aromatic substitution by methoxide and nitrile hydrolysis were independent operations that were conducted in one pot to yield 72 in 92% yield over two steps. The authors reported that anhydrous conditions for the sodium methoxide substitution reaction were necessary because the substitution reaction stalled when premature nitrile hydrolysis (facilitated by water) took place. Amidation utilizing CDI as a coupling agent provided 74 from the carboxylic acid 72 and amine 73. Interestingly, the stoichiometry of CDI needed to be carefully controlled to avoid any overaddition of 73 to 74. Aluminum-mediated demethylation of 74 removed both the ester and ether functionalities to yield vadadustat in 84% yield.

Introduction of Vadadustat

Vadadustat is a treatment for CKD-associated anemia in adults and was originally developed by Akebia Therapeutics, Inc.79,80 This oral inhibitor of prolyl hydroxylase (PDH) was first approved in Japan (PMDA) in June 2020.81,82 Inhibition of PDH leads to increased production of erythropoietin by preventing degradation of HIF-α.