Institution: | aSpecialty Chemicals Research Laboratory, Toray Fine Chemicals Co., Ltd, Minato-ku, Nagoya, Aichi 455-8502, Japan bGraduate School of Science and Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan |
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)-10/0.5H2O (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. |