A Scalable Synthesis of Roxadustat (FG-4592)

A scalable five-step protocol for synthesis of roxadustat, an orally administered h oxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI), was developed with an emphasis placed on aspects of medicinal chemistry. The isoquinoline core of the molecule was prepared using a purposefully designed cyclocondensation in which both the cyclocondensation and demasking of the groups being condensed is promoted by a common acid agent in one step. Roxadustat was obtained pure in a very competitive overall yield across all reaction steps and in compliance with permissible residual Pd level in API.

Automated summary

A scalable five-step synthesis protocol was developed for the synthesis of roxadustat, focusing on medicinal chemistry aspects. The isoquinoline core of the molecule was prepared using a specifically designed cyclocondensation reaction, where both the condensation and demasking of groups were facilitated by a common acid agent in a single step. Roxadustat was obtained in high overall yield and met the permissible residual Pd level in API.