Development of a Scalable Manufacturing Process for Kv1.3 Antagonist LY3972406 Hemiglutarate Hemihydrate

A scalable and sustainable process for manufacturing LY3972406 hemiglutarate hemihydrate (1) was developed. It features a robust continuous stir tank reactor (CSTR) continuous-flow process that enables excellent process control in lithiation by n-BuLi and subsequent asymmetric addition assisted by the Ellman chiral auxiliary. This CSTR process addressed multiple challenges and successfully produced >1 MT of a chiral sulfonamide intermediate in high purity (>98%) and yield. An efficient CDMT/NMM-mediated amide formation was developed to yield a more sustainable process while affording high-quality products. Drug substance salt form switching from HCl salt to hemiglutarate hemihydrate was significantly improved by employing glutaric acid sodium salt at neutral conditions to minimize drug substance decomposition. The optimized process improved the overall yield from <15% to >40% with >300 kg of drug substance manufactured, demonstrating significant robustness. An alternative route highlighting the use of Ru-catalyzed direct asymmetric reductive amination has also been developed.