Chirality Control in the Kilogram-Scale Manufacture of Single-Enantiomer CELMoDs: Synthesis of Iberdomide·BSA, Part 2

Iberdomide (1·HCl) is a cereblon E3 ligase-modulating drug (CELMoD) in clinical trials for the treatment of systemic lupus erythematosus (SLE) and relapsed and refractory multiple myeloma (MM). The enantioselective synthesis of iberdomide to supply clinical and development activities proceeds through the late-stage intermediate iberdomide BSA salt (1·BSA). The route features a reductive amination between a chiral isoglutamine and a salicylaldehyde derivative to form the isoindolinone core. The penultimate intermediate is prepared by phenol alkylation with a benzylic chloride that requires detailed understanding of reaction parameters to avoid overreaction of the product and concomitant stereochemical ablation. The chiral α-amidoglutarimide moiety is constructed from an acid-catalyzed intramolecular lactamization of an isoglutamine tert-butyl ester moiety with high retention of the enantiomeric ratio (e.r.). This process was demonstrated on a kilogram scale over multiple batches and serves as the basis for the commercial synthesis of iberdomide.