A hybrid process for chiral separation of compound‐forming systems

Abstract

The resolution of chiral compound-forming systems using hybrid processes was discussed recently. The concept is of large relevance as these systems form the majority of chiral substances. In this study, a novel hybrid process is presented, which combines pertraction and subsequent preferential crystallization and is applicable for the resolution of such systems. A supported liquid membrane applied in a pertraction process provides enantiomeric enrichment. This membrane contains a solution of a chiral compound acting as a selective carrier for one of the enantiomers. Screening of a large number of liquid membranes and potential carriers using the conductor-like screening model for realistic solvation method led to the identification of several promising carriers, which were tested experimentally in several pertraction runs aiming to yield enriched (+)-(S)-mandelic acid (MA) solutions from racemic feed solutions. The most promising system consisted of tetrahydronaphthalene as liquid membrane and hydroquinine-4-methyl-2-quinolylether (HMQ) as chiral carrier achieving enantiomeric excesses of 15% in average. The successful production of (+)-(S)-MA with a purity above 96% from enriched solutions by subsequent preferential crystallization proved the applicability of the hybrid process.

Continuous Separation of Isomers in Fluidized Bed Crystallizers

“…The resolution of enantiomers can be achieved by various methods, like microbiological methods, kinetic enzymatic resolution, and chromatography . Some of the recent studies show that of growing importance are methods that allow continuous production of enantiopure substances, such as the combination of continuous chromatographic processes and subsequent crystallization, , chiral-membrane-based separation techniques, , and polymers imprinted with chiral templates . Although all these techniques show high chiral discrimination, they are not yet applicable for large-scale resolution.…”

Toward Continuous Deracemization via Racemic Crystal Transformation Monitored by in Situ Raman Spectroscopy

“…Overall, the results of this work emphasize the usefulness of in situ Raman spectroscopy in the development of complex (continuous) chiral crystallization processes involving various types of crystalline racemates. Although here we focused on deracemization through a metastable racemic compound to conglomerate transformation, we believe that in situ Raman spectroscopy may prove useful in other chiral resolution methods involving various types of crystalline racemates, such as preferential crystallization of racemic compound forming systems at the eutectic point …”

Selector Screening for Enantioseparation of dl‐α‐Methyl Phenylglycine Amide by Liquid–Liquid Extraction

“…3 One of the drawbacks of the ELLE technology is that a moderate selectivity (typically >1.5) 40 is required to avoid an excessive number of stages. E.g., in cases where preferential crystallization is possible from enantioenriched solutions, hybrid processing may be a solution to improve processing efficiency, e.g., by enriching racemic solutions to moderate enantiomeric excess through a CLM process, followed by preferential crystallization, 43 or involving chiral nanoparticles in the extraction process. Approaches to overcome this limitation in versatility include the application of biphasic recognition to increase the selectivity of the system, 35,36,38 or to use thin-layer extraction 41,42 to enable large numbers of stages while keeping the equipment size small.…”

“…Several hybrid processes have been published, trying to advance benefits from multiple unit operations in a single operation or in a sequence of operations. E.g., in cases where preferential crystallization is possible from enantioenriched solutions, hybrid processing may be a solution to improve processing efficiency, e.g., by enriching racemic solutions to moderate enantiomeric excess through a CLM process, followed by preferential crystallization, 43 or involving chiral nanoparticles in the extraction process. 44 Another, rather generically applicable hybrid approach, is to apply the ELLE concept in a chromatographic mode.…”