Resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid with enantiopure ( S)-phenylalanine N-benzylamide via diastereomeric salt formation

Abstract

The resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 1, a potent chiral synthon with high pharmacological activity, was investigated with a variety of basic chiral resolving agents via diastereomeric salt formation. The findings in the optimization of resolution conditions aiming at an industrial-scale production revealed that ( S)-phenylalanine benzylamide ( S)- 10 and 2-propanol containing ca. 4 mol % of water to ( RS)- 1 were the best conditions for obtaining enantiopure less-soluble diastereomeric salt, ( S)- 1/( S)- 10/0.5H 2O (81%, 98% de, E 79%). X-ray crystallographic analysis of the salt clearly revealed that water molecules play a key role in crystallizing the enantiopure salt crystals, while stabilizing the crystal structure via three types of hydrogen-bond network associated with water molecules in addition to usual acid–base hydrogen bond.