Resolution of ibuprofen with primary amine carbamates in supercritical carbon dioxide

Abstract

Three new, successful resolving agents, namely (S)-2-phenylglycinol, (R)-1-phenylethanaminium (R)-(1-phenylethyl) carbamate and (S)-2-hydroxy-1-phenylethanaminium (S)-(2-hydroxy-1-phenylethyl) carbamate of ibuprofen are presented. The carbamate salts are stable white crystals, they can be easily stored and handled. All salt forming resolution were performed in supercritical carbon dioxide as the only solvent. The enantioseparations were efficient (approx. 50 % enantiomeric purities, > 90 % yields in the crystalline phase) and robust. Unlike previous experiences with primary amine resolving agents, the diastereomeric salt formations and resolutions were competed in short times, even within one hour suggesting that the carbamates are intermediates of the salt formation reaction.

Preface

“…[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. [8] Supercritical water has especially high reactivity, being a critical issue when it is applied as coolant in a nuclear power plant [9], furthermore the possibility of unintended phase transitions has to be also carefully considered.…”