Development of a Robust and Scalable Process for the Large-Scale Preparation of Vadadustat

A novel and scalable process is developed for the industrial synthesis of vadadustat. The four-step process is one step shorter compared to the reported routes with an increase in total yield to 49.1%. Detailed optimizations furnish vadadustat with a purity of >99.5% through cross-coupling, aromatic substitution and nitrile hydrolysis, amidation, and ester-ether deprotection. The process is also robust and was demonstrated in a kilogram laboratory. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.

Automated summary

A novel and scalable process has been developed for the industrial synthesis of vadadustat, achieving a total yield of 49.1% with a purity of >99.5%. The process, optimized through various steps, has been demonstrated at kilogram scale and the impurity profile has been extensively studied and documented.