Enantioseparation of tropic acid by biphasic enantioselective liquid-liquid extraction: Experimental and simulation

Background

Nowadays, accessing optically-pure compounds from chiral drugs on a large scale in an eco-friendly and cost-effective manner remains one of the greatest challenges. Racemic separation is still the most effective approaches. And meanwhile, as one of the methods, biphasic recognition chiral extraction (BRCE) strategy, is widely recognized as a highly promising technique for industrial implementation due to its advantages of high efficiency, broad versatility, and facile scalability. The configuration of BRCE facilitates capacity expansion to multi-kilogram production scales, unconstrained by the bed-height limitations inherent to fixed-bed chromatographic systems. (88)

Results

Herein we first present, employing hydrophilic β-cyclodextrin and hydrophobic tartaric acids as the collaborative chiral additives for BRCE process to improve the efficiency of enantio-separation tropic acid mixture. The screening of chiral additives and organic solvents for BRCE framework were systematically investigated, along with the developed system was used to optimize experimental conditions in depth, including concentration of tropic acid and chiral additives, aqueous pH, and operational temperature, using response surface methodology (RSM) method. The maximum enantioselectivity (α) and enantiomeric excess (e.e.%) up to 2.28 and 12.3% were achieved by the BRCE system which is more-efficient than previous extraction systems. The principle of BRCE strategy mainly refers to the host-guest stereoselective affinity and phase transfer, forming labile diastereoisomeric complexes with the assistance of the density functional theory (DFT) method. (127)

Significance

The enhanced performance is attributed to the simultaneous biphasic recognition of both R- and S-tropic acid. This study provides critical insights for developing enhanced BRCE systems tailored to specific enantio-separation applications. Furthermore, the differing stereochemical preferences under thermodynamic and kinetic conditions could be strategically leveraged to further enhance enantio-separation efficiency through sequential BRCE framework. (55)