(138c) Control of Ritter Side Products Via Reaction Engineering and Kinetic Modeling to Enable Robust Scale-up

The final transformation step for an API requires the installation of a glutarimide ring using a t-butyl deprotection/cyclization sequence. The release of isobutylene from the t-butyl group during the reaction leads to the formation of impurities via the Ritter reaction. Reaction engineering efforts were undertaken to minimize these impurities through mechanistic understanding and process optimization. Kinetic profiling experiments provided insight into the fate of the t-butyl cation through formation of the impurities, consumption by the solvent acetonitrile, and evolution of isobutylene in the gas phase. A kinetic model was developed, enabling prediction of the impurities and side product with acetonitrile. The reaction was optimized leveraging temperature and dilution as scale-independent parameters in combination with nitrogen sparging. The use of fundamental data and modeling enabled the development of the control strategy for this final transformation of the API.