Reaction Mechanism Understanding Through Process Development

A chemical transformation to aromatize a key intermediate in the synthesis of a complex API was developed rapidly to meet product deliverable timelines and quality attributes.  Initial scale-up of the process beyond kilogram scale resulted in reaction stalling and revealed that further mechanistic understanding was needed.  Small scale studies to define operating ranges provided insight into the reaction mechanism and kinetics and led to several changes to the reaction conditions to improve robustness.  These studies included sensitivity to water, solubility of reactants in reaction mixture, reagent decomposition kinetics, use of additives, and ultimately the importance of oxygen which led to the identification of a novel aromatization protocol.  Key to engineering the successful scale-up of the chemical transformation was developing mechanistic understanding of the chemistry, quickly defining the important parameters through small-scale experimentation, and leveraging this insight to design new reaction conditions. This talk will describe the development of the process and implementation of the step at 300 kg scale.