Process Development and Kilogram-Scale Manufacture of Key Intermediates toward Single-Enantiomer CELMoDs: Synthesis of Iberdomide·BSA, Part 1

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 structure features an isoindolinone core as well as a chiral α-amidoglutaramide moiety. An efficient kilogram-scale synthesis of the drug substance was required to enable clinical trials and development activities. The retrosynthetic disconnections, which proceed through acid-catalyzed glutarimide formation, lead to three starting materials, the syntheses of which are discussed. A benzylic chloride was formed through morpholine alkylation of a bisbenzylic chloride and efficient selective removal of the undesired minor bisamino impurity. Duff formylation was used to prepare the salicylaldehyde building block, and the isolation of this compound was enabled by an innovative simultaneous addition of acidic and basic solutions. A short sequence to l-isoglutamine tert-butyl ester was developed to supply the chiral amine crucial to the formation of the α-amidoglutaramide.