Abstract

Flow Chemistry from Milligrams to Metric Tons

Scott May, Senior Research Advisor, Eli Lilly & Co

In this presentation, a continuous, high pressure, Iridium-catalyzed reductive amination will be described from early proof-of-concept (milligrams) to a large scale manufacturing (2MT) demonstration under cGMP conditions.  In this chemistry, a well established batch process utilizing the bulky reducing agent sodium triacetoxyborohydride (STAB) was successfully replaced with a safer, greener and more economic Ir-catalyzed continuous process.  Key drivers for moving from a previously established high yielding batch process to a continuous process will be discussed.  The choice of catalyst, solvent, reagent choices, additives and reaction conditions were important parameters that influenced catalyst stability and the impurity profile.  The challenges of translating batch conditions into a continuous pipes-in-series reactor at several reaction scales will also be highlighted.  The implementation of on-line HPLC will be presented to demonstrate the impact of this and other PAT on the development and manufacturing phases.  Finally the technical transfer to manufacturing, plant operation considerations and campaign highlights will be presented.