Chiral resolution of dl-leucine via salifying tartaric acid derivatives†

Abstract

Diastereomeric salt formation is suitable for chiral resolution of racemic compounds and is the most effective way to obtain enantiomers. At present, there are few resolution methods for DL-leucine (DL-LEU), and the corresponding mechanism of resolution has not been studied. In this study, (+)-di-1,4-toluoyl-D-tartaric acid monohydrate (D-DTTA) was selected as the ligand. Diastereomeric salts D-LEU:D-DTTA (D–D) and L-LEU:D-DTTA (L–D) were synthesized by liquid-assisted grinding and then identified by powder X-ray diffraction, thermal analysis, Fourier transform infrared spectroscopy and single crystal X-ray diffraction. Their difference in crystal structures, thermodynamic properties and intermolecular interactions showed that D–D is more stable and has lower solubility, which makes chiral resolution possible. Furthermore, the mechanism of chiral recognition was investigated, which showed that D-DTTA was more easily bound to D-LEU. Finally, the optimized resolution condition was confirmed, and the ee values of D–D and L–D reached 91.20% and −73.32% respectively by the multi-stage crystallization process. This study provides an effective and industrially applicable method for the separation of the DL-LEU racemic compound, and provides a reference for the screening of salt-forming chiral resolution agents.