Characterization of Dispersion Effects on Reaction Optimization and Scale-Up for a Packed Bed Flow Hydrogenation Reactor
John W. Eschelbach A D , David Wernick B , Marian C. Bryan C and Elizabeth M. Doherty CA Amgen, Inc. – Research Automation and Technology, Thousand Oaks, California, CA 91320, USA.
B Department of Chemical and Biomolecular Engineering, University of California at Los Angeles, Los Angeles, California, CA 90095, USA.
C Amgen, Inc. – Medicinal Chemistry Research Technologies, Therapeutic Discovery, Thousand Oaks, California, CA 91320, USA.
D Corresponding author. Email: jeschelb@amgen.com
Australian Journal of Chemistry 66(2) 165-171 https://doi.org/10.1071/CH12450
Submitted: 5 October 2012 Accepted: 31 October 2012 Published: 17 December 2012
Abstract
A well known advantage of flow chemistry reactors in chemical synthesis is the ability to screen multiple catalysts and reaction parameters with optimal conditions scaled accordingly. This approach, however, consumes significant quantities of material as the reactor must be equilibrated with the reactants in a continuous, steady-state mode before the start of the reaction. In this work we explore a screening and reaction approach using bolus injections, which is more conducive to the lower material consumption that may be required in a drug discovery setting. A commercially available ThalesNano H-Cube® was evaluated to determine the practicality of this approach for heterogeneous hydrogenations. When working with boluses in flow systems, one of the biggest limitations can be the inherent dispersion of the reactant stream caused by the reactor. The dispersion on the H-Cube® was characterized to determine the minimum volume for the reactor to reach a steady-state. The H-Cube® fluidics and heating coil were found to generate significantly more dispersion than the reaction cartridge (CatCart®) itself, increasing the minimum volume of injection required to achieve steady-state. A 2 mL injection was found as a good compromise between maximizing material conservation and sufficient volume of reaction at steady-state condition. Conditions optimized at 2 mL screening scale were successfully scaled five-fold, while lower volume bolus injections were shown to be less predictable. A stacked injection protocol using lower volume boluses was found to be a reliable alternative to scale reactions while efficiently conserving material. This application of small bolus injections to flow reaction screening and scale-up provides a desirable alternative to traditional continuous flow approaches in the material-limited discovery setting.
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