Control Strategies for Mitigating Ritter and Methyl Ester Impurities in Mezigdomide Manufacturing

During a tert-butyl ester deprotection/imide cyclization sequence designed to form the glutarimide ring of Mezigdomide (CC-92480), side reactions were observed. In particular, the N-(tert-butyl)benzamide impurity, formed by the Ritter reaction between the tert-butyl cation and the aryl nitrile, was observed at high and variable levels during early development and did not purge sufficiently to meet product specifications. Reaction engineering efforts were undertaken to optimize the process, minimize this challenging Ritter impurity, and avoid the need for extensive downstream purifications. Kinetic profiling revealed that the Ritter reaction involving the acetonitrile solvent could be leveraged to deplete the tert-butyl cation concentration. Combining nitrogen sparging (to remove isobutylene from the gas phase) and dilution provided a scalable control strategy for this impurity. A kinetic model was developed to accurately predict impurity levels, although some outliers could not be explained. Further investigations revealed an unrelated, coeluting methyl ester impurity, caused by residual methanol used as a cleaning solvent. A second control strategy was developed for the methyl ester impurity, leveraging fate and purge experiments, robust analytical methods, and most importantly, a comprehensive cleaning protocol for manufacturing. Combining these two control strategies, the optimized process provided excellent control of both impurities and was scaled up to enable the production of highly pure Mezigdomide.