Direct High-Performance Liquid Chromatographic Enantiomer Separation of Anti-Inflammatory Planar Chiral [2.2]Paracyclophane-4-acetic Acid

Abstract

The development and optimization of an enantioselective HPLC method that allows the baseline separation of the enantiomers of planar chiral [2.2]paracylophane-4-acetic acid (α=1.12; RS=2.6) is reported. The separation is carried out on a chiral anion-exchange type stationary phase based on a tert-butylcarbamoyl quinine selector employing either the reversed-phase or the polar organic mode. A variety of experimental variables have been investigated including organic modifier type and percentage, counter-ion concentration, temperature, and flow rate of the mobile phase. These optimization studies gave insight into mechanistic aspects of the present enantioselective anion-exchangers, which were thoroughly discussed. The optimized method, which was envisaged as a cross-validation study of a previously employed 1H NMR method that made use of a chiral solvating agent, was applied for the enantiomeric excess determination of enantiomeric samples. Thereby, it turned out that the presently employed chromatographic method is better suited for enantiomeric excess determinations, because of its lower limits of quantitation. Samples that were previously assessed to be enantiomerically pure by the 1H NMR technique revealed significant amounts of the enantiomeric impurities by the direct HPLC method (ca. 6–8%).