Spontaneous Deracemization of the DMY Racemic Compound with Two Stereocenters through a Stepwise Process of Cocrystallization-Induced Resolution and Solution Racemization

Processes that allow access to enantiomerically pure drugs are of the utmost importance to maximize pharmacological activity while minimizing the side effects. This work develops a novel diastereomeric cocrystallization-induced spontaneous deracemization process for a racemic compound, dihydromyricetin (DMY), which contains two stereocenters. A pair of diastereomeric cocrystals, (2R,3R-DMY)₂:R-N-benzyl-1-phenylethylamine and (2R,3R-DMY)₂:S-N-benzyl-1-phenylethylamine, the latter of which is equivalent to (2S,3S-DMY)₂:R-N-benzyl-1-phenylethylamine, was discovered via a complete screening of 12 chiral coformers using both slurry and liquid-assisted grinding methods. Crystal structure of these cocrystals was determined using single-crystal X-ray diffraction and reported for the first time. Enantioseparation of rac-DMY by virtue of diastereomeric cocrystals was designed and optimized through slurry and cooling crystallization methods, resulting in a product of 81% enantiomeric purity with a yield of only 31%. Further, the racemization process of DMY enantiomers with various influence factors was examined, and the optimal racemization condition that achieves simultaneous racemization of the two stereocenters was determined. Finally, a stepwise cocrystallization-induced deracemization process of rac-DMY that combines chiral resolution by cocrystallization and racemization of recycling mother liquor was developed, producing an enantiomeric purity of 97.5% and a maximal yield of 68%.