(64b) Reaction Mechanism Understanding Through Process Development | AIChE

(64b) Reaction Mechanism Understanding Through Process Development


Buono, F., Bristol-Myers Squibb Co
Soumeillant, M., Bristol-Myers Squibb
Cassidy, M., Bristol-Myers Squibb

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.