Integrating continuous flow reaction and work-up: chiral amine resolution, separation and purification using a novel coalescing filter system

To maximize the benefits of a continuous flow reaction, a continuous work-up is also needed. Herein, we present a process design and novel equipment for a continuous amine resolution reaction, integrated with liquid-liquid (L-L) extraction, back-extraction into a different solvent, and crystallisation purification for product isolation. The reaction, in iso-propyl acetate, flows through a heated fixed-bed reactor with solid supported <i>Candida antarctica</i> lipase which catalyses the resolution of (<i>rac</i>)-1-phenylethylamine to give the (<i>R</i>)-amide in 50% conversion and 96% enantiomeric excess (ee). This is separated from the unreacted (<i>S</i>)-amine co-product by mixing with an acidic aqueous stream and separating the phases using our recently reported coalescence filter separator. The aqueous stream is neutralised by mixing with base and back-extracted into methyl-THF solvent before separating the phases using a membrane separator. Finally, a solid amine salt is isolated by filtration, achieved by mixing the free base with an organic acid to cause crystallisation to give the (<i>S</i>)-1-phenylethylamine in 43% yield and >99% ee from racemate. The work illustrates how typical reactions, work-up and purification steps that involve multiple phases can be telescoped together using both new and commercially available laboratory equipment. This continuous system uses mild reaction conditions, green solvents and minimises their use for reduced waste.