Selector Screening for Enantioseparation of dl-[alpha]-Methyl Phenylglycine Amide by Liquid-Liquid Extraction

Enantioseparation through liquid extraction technology is an emerging field, e.g.,enantioseparations of amino acids (and derivatives thereof), amino alcohols, amines, and carboxylic acids have been reported. Often, when a new selector is developed, the versatility of substrate scope is investigated. From an industrial point of view, the problem is typically approached the other way around, and for a target racemate, a selector needs to be found in order to accomplish the desired enantioseparation. This study presents such a screening approach for the separation of the enantiomers of dl-[alpha]-methyl phenylglycine amide (dl-[alpha]-MPGA), a model amide racemate with high industrial relevance. Chiral selectors that were reported for other classes of racemates were investigated, i.e.,several macrocyclic selectors and Pd-BINAP complexes. It appeared very challenging to obtain both high extraction yields and good enantioselectivity for most selectors, but Pd-BINAP-based selectors performed well, with enantioselectivities up to 7.4 with an extraction yield of the desired enantiomer of 95.8%. These high enantioselectivities were obtained using dichloromethane as solvent. Using less volatile chlorobenzene or 1-chloropentane, reasonable selectivities of up to 1.7 were measured, making these the best alternative solvents for dichloromethane. Chirality 27:123-130, 2015. © 2014 Wiley Periodicals, Inc.