Use of Modeling and Mechanistic Thinking to Aid Development of a Pd Catalyzed Amination Reaction; Understanding the Mechanism, Oxygen Sensitivity, and Impurity Formation

A Pd catalyzed amination reaction was being developed for use in the synthesis of an API.  Reaction rate variability and over-reaction impurities had been observed during development.  A combined modeling and experimental approach was undertaken to better understand the chemistry to mitigate impurities and reaction rate variability due to oxygen sensitivity and scale-up effects.  Due to the rather complicated nature of the catalytic cycle, a modeling approach was very useful to help disentangle multiple competing effects.  In addition to reaction mechanism kinetic elucidation, unit operation modeling will also be discussed to illustrate how it impacts execution of a control strategy for commercial manufacture.