Absolute Configuration of Key Intermediates and the Gram Scale Synthesis of Berotralstat and ent-Berotralstat

Berotralstat (BCX-7353) is a potent plasma kallikrein inhibitor developed to prevent hereditary angioedema attacks. Initial racemic synthesis yielded limited quantities of the active (R)-enantiomer. To support clinical studies, a stereoselective synthetic route was developed. Key intermediates were isolated, and their stereochemistry confirmed via X-ray diffraction. These efforts enabled the scalable preparation of 16 g of berotralstat in 61% yield and nearly 1 g of its enantiomer in 23% yield─representing the first reported gram-scale synthesis of both compounds.