High-throughput on demand access of single enantiomers by a continuous flow crystallization process

Abstract

A novel continuous flow reactive crystallization process for the in situ on-demand access of single enantiomer crystals is reported and exemplified for a chiral pharmaceutical intermediate that crystallizes as a racemic conglomerate. During this process, a nearly racemic feed suspension with a racemization catalyst is circulated through a tubular coiled milli-reactor immersed in two thermostatic baths set at different temperatures. This flow configuration enables rapid heat transfer, which in turn results in successive spatial cycles of dissolution and re-crystallization carried out at extremely short residence times, unattainable in batchwise operations. By tuning the number of cycles, residence time per cycle and feed suspension density we show that unprecedented productivities (>20 g L⁻¹ h⁻¹) of the preferred enantiomer at purities >98% can be attained that could easily suit industrial demand in a directly scalable process.