Advancing Scalable Chemistry toward Novel CELMoDs: Process Development for the Synthesis of CC-90009

CC-90009 (1) is a cereblon E3 ligase modulating drug (CELMoD) in clinical trials for the treatment of acute myeloid leukemia (AML). An efficient synthesis of 1 was required to support drug substance supply for clinical trials. The structure features an isoindolinone core, an α,α-difluorophenylacetamide, and a chemically sensitive α-amidoglutaramide moiety prone to hydrolysis or ring opening under basic or Lewis acidic conditions. A key feature of the synthesis was the transformation of a phthalide to the corresponding o-(chloromethyl)­benzoate ester while managing the tendency of intermediates to relactonize. The realization of this transformation under mild conditions also serves as a model for a broadly applicable strategy to access these valuable motifs. Optimization of the nitrile hydrogenation and the amide bond formation to form 1 afforded the API in significantly improved yield and with high purity. This route was scaled up to supply early clinical trials and served as the basis for commercial route development.