Gas Antisolvent Fractionation: a New Method to Obtain Enantiopure Compounds, a Case Study on Mandelic Acid

Abstract

Micronization processes involving supercritical carbon dioxide are rapid methods to produce fine particles. They also might offer the possibility of using less organic solvent than conventional crystallization methods leading to an environmentally friendlier processing. The separation capabilities of such processes are now demonstrated on the diastereomeric resolution of mandelic acid using (R)-1-phenylethanamine as a resolving agent, utilizing the batch type gas antisolvent fractionation as the separation method. A detailed study was conducted on the effects of the operational parameters pressure (12-20 MPa), temperature (35-55 °C) and co-solvent concentration (33-99 mg/ml). At 12 MPa, 35 °C and 99 mg/ml methanol concentration, a selectivity of 0.52 and a diastereomeric excess of 62% was reached. The same operational parameters were applied during the investigation of the recrystallization-based further purification of the diastereomeric salts, applying the resolving agent in molar equivalent quantity to a non-racemic mixture of mandelic acid. It has been found that the more stable (R)-1-phenylethylammonium-(R)-mandelate salt can be purified to de>98% through four additional recrystallization steps following the initial, half-molar equivalent resolution step.

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

“…3 Results and discussion Antisolvent processes are usually very parameter-sensitive [6,16,26]. Our aim in this study was not only to apply the process as a separation method in chiral resolution but also to present a detailed investigation process from preliminary measurements to a high purity compound.…”

“…A simple laboratory autoclave having an approximate volume of 37 ml was used in the gas antisolvent fractionation (GASF) experiments. A schematic depiction of it can be found in a previous communication [6].…”

“…pressure, temperature and the amount of the organic solvent (mixture), by setting appropriate conditions they can be used as separation processes based on fractionated crystallization. In our study the batch-type gas antisolvent fractionation (GASF) is presented as the separation method [6].…”

“…Carbon dioxide-involving experiments have even been conducted using the supercritical fluid as an antisolvent and as a reaction medium in diastereomeric salt formation as well [14][15][16][17][18][19]. Antisolvent methods have been studied in the production of enantiomerically pure compounds too [6,14,[20][21][22]. Also, supercritical carbon dioxide was used as the reaction medium of enzymatic kinetic resolutions [23].…”

Gas antisolvent fractionation based optical resolution of ibuprofen with enantiopure phenylglycinol

“…Due to this critical mixing phenomenon [35], the results could not be evaluated statistically as an experimental design.…”