Practical and Scalable Manufacturing Process for Sparsentan. Part 2: Synthesis of the Sulfonamide API via Thioether Oxidation

A practical, scalable, and sustainable manufacturing process for sparsentan has been developed and demonstrated on a multikilogram scale. The optimized route achieves a low process mass intensity (PMI of 280–300), high overall yield (57%), and significant reduction in active pharmaceutical ingredient (API) production costs. Key elements of the process include the development of a crystalline (+)-di-1,4-toluoyl-d-tartaric acid (D-DTTA) salt of an oily intermediate for impurity control, an optimized chemoselective oxidation to the sulfone intermediate, and the application of an activated sulfonyl ester strategy that consistently delivers sulfonamide sparsentan in high yield and purity. The overall process avoids chromatographic purification, ensures reproducible quality through crystalline intermediates, and provides an efficient and economical route suitable for commercial manufacturing.