(126b) Characterization of a Flow Hydrogenation System and Application to a Sensitive Reaction for Production of an Active Pharmaceutical Ingredient Intermediate

Hydrogenation is a chemical transformation frequently employed in the synthesis of active pharmaceutical ingredients (APIs). These reactions are traditionally performed in batch in stirred, pressure rated autoclaves. Such autoclaves can represent a significant initial capital investment and are expensive to clean and maintain. Operationally, they introduce safety concerns due to their inherent large hydrogen headspace. Further, these batch reactors often restrict the space of achievable operating conditions as a result of poor heat and mass transfer characteristics and limitations on maximum operating pressure.

Implementation of flow reactor technology offers solutions to many of the limitations of traditional batch hydrogenation. Flow reactors can be inexpensive to construct. They can be made from relatively low-cost stainless steel tubing and compression fittings capable of withstanding high pressures and temperatures. This allows a reactor to be dedicated to a single chemical transformation and may reduce or eliminate routine cleaning and maintenance. Flow reactors improve safety by minimizing the hydrogen headspace and increasing the surface-to-volume ratio available for heat removal. Of particular relevance to this presentation is the ability of flow reactors to maintain tight control of residence time and enable use of innovative process analytical technology (PAT).

This presentation will focus on characterization of a flow hydrogenation system and its application to a sensitive asymmetric hydrogenation for production of an API intermediate. Drivers for performing this reaction in flow will be discussed. Elements of both reaction and reactor design were investigated. The reaction was screened for a variety of temperatures, pressures, catalyst loadings, and solvents. Studies were performed to understand gas-liquid flow dynamics and residence time distribution (RTD).