Chiral Resolution of dl-Leucine by the Diastereomeric Salt/Cocrystal Method

The diastereomeric salt/cocrystal method is an efficient and economical resolution approach to resolving racemic compounds. Currently, limited resolution methods are available for dl-leucine (DL-LEU). In this study, resolving agents were screened by liquid-assisted grinding. It was found that (−)-dibenzoyl-L-tartaric acid (L-DBTA) formed two distinct diastereomeric solid forms: a salt and a cocrystal with DL-LEU, which had a potential resolution effect. Two multicomponent crystals, L-LEU-L-DBTA and D-LEU-L-DBTA, were prepared by using the slow evaporation method and analyzed by various characterization methods. It was confirmed that L-LEU-L-DBTA was a salt and that D-LEU-L-DBTA was a cocrystal. The intermolecular forces of the two diastereomers were compared through molecular electrostatic potential, independent gradient model based on Hirshfeld partition, and Hirshfeld surfaces. The solubility differences between L-LEU-L-DBTA and D-LEU-L-DBTA were revealed from a thermodynamic perspective. Molecular simulations revealed that the binding ability of L-DBTA and L-LEU is stronger. Finally, the optimal resolution conditions were determined. Through secondary crystallization, the enantiomeric excess values of L-LEU-L-DBTA and D-LEU-L-DBTA reached 95.48 and 84.52%, respectively.