Separation of enantiomers by diastereomeric salt formation and precipitation in supercritical carbon dioxide: Application to the resolution of mandelic acid

A novel process for the resolution of enantiomers by simultaneous reaction of the enantiomers with a chiral agent, and precipitation of the formed diastereomeric salts in a supercritical carbon dioxide environment, is presented. This method allows to take advantage of the favorable kinetics of the process, in addition to the favorable phase and chemical equilibrium properties that are exploited by other processes. The method has been applied to separate the enantiomers of mandelic acid using R(+)-α-methylbenzylamine as the chiral agent. Different process configurations, including partial or total diastereomeric salt formation, performed before or simultaneously with the precipitation, have been studied. The highest resolution efficiency (e.e = 63%) was achieved when a partial diastereomeric salt formation was performed simultaneously with the precipitation, at 8 MPa and 328 K. A mathematical model of the phase equilibrium of the system based on the Peng–Robinson equation of state is also presented.