Multikilogram-Scale Process Development for a Key Intermediate of a Clinical-Stage MTA-Cooperative PRMT5 Inhibitor

Abstract A multikilogram-scale, scalable, and cGMP-compliant synthesis of 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (TM), a key intermediate for the MTA-cooperative PRMT5 inhibitor GTA182, has been developed to address the limitations of the original medicinal chemistry route. The initial synthesis suffered from poor reproducibility, cumbersome workups, and a high-pressure carbonylation step that introduced equipment constraints and elevated metal residues, creating a supply bottleneck for early clinical development. The redesigned route starts from commercially available 3-fluoro-4-nitrobenzoic acid (SM6), a low-cost commodity chemical, and proceeds through seven steps, including a continuous-flow amination and chromatography-free purifications. This approach improves the overall yield from 7% to 24%, eliminates the need for specialized high-pressure equipment, and ensures metal residues are compliant with ICH guidelines. The process has been successfully demonstrated on a multikilogram scale under cGMP conditions, enabling reliable supply of TM to support ongoing early-stage clinical studies of GTA182.