Gas Antisolvent Fractionation: A New Approach for the Optical Resolution of 4-chloromandelic Acid

Abstract

A new, rapid optical resolution method of 4-chloromandelic acid is presented using (R)-1-phenylethanamine as the resolving agent. Gas antisolvent fractionation was investigated as the separation method, studying the effect of pressure, temperature and carbon dioxide to organic solvent mass ratio in details. Generally, the method offers green operation using supercritical carbon dioxide as the precipitative agent, and can be less time- and organic solvent-intensive than conventional processes. By upscaling, the possibility of controlling the crystal-morphology might also be improved. At 16 MPa, 40 °C and 7.5 carbon dioxide to methanol ratio 72 % enantiomeric excess was reached in the crystalline product, along a 73 % yield. The resolution efficiency was not affected by any of the operational parameters. Enantiomeric enrichment beyond 90 % can be carried out by repeated resolution of a scalemic mixture of the acid. Solid products were investigated using differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy confirming the formation of a crystalline (R)-1-phenylethanammonium-4-chloromandelate salt.

Preface

“…[4,5] The expanded liquids play key role in all gas antisolvent processes, which can be used for diastereomeric salt based chiral resolution as well. [6] A special case of diastereomeric salt formation based chiral resolution is described by Lőrincz et al, where novel resolving agents are formed with CO2. [7] Reactivity of carbon dioxide, especially its effect on shifting chemical equilibrium is also critical when its geological sequestration is considered in deep saline aquifers.…”