Spontaneous Deracemization\nof the DMY Racemic Compound\nwith Two Stereocenters through a Stepwise Process of Cocrystallization-Induced\nResolution and Solution Racemization

Processes that allow access to enantiomerically pure\ndrugs are\nof the utmost importance to maximize pharmacological activity while\nminimizing the side effects. This work develops a novel diastereomeric\ncocrystallization-induced spontaneous deracemization process for a\nracemic compound, dihydromyricetin (DMY), which contains two stereocenters.\nA pair of diastereomeric cocrystals, (2<i>R</i>,3<i>R</i>-DMY)<sub>2</sub>:<i>R</i>-<i>N</i>-benzyl-1-phenylethylamine and (2<i>R</i>,3<i>R</i>-DMY)<sub>2</sub>:<i>S</i>-<i>N</i>-benzyl-1-phenylethylamine,\nthe latter of which is equivalent to (2<i>S</i>,3<i>S</i>-DMY)<sub>2</sub>:<i>R</i>-<i>N</i>-benzyl-1-phenylethylamine, was discovered via a complete screening\nof 12 chiral coformers using both slurry and liquid-assisted grinding\nmethods. Crystal structure of these cocrystals was determined using\nsingle-crystal X-ray diffraction and reported for the first time.\nEnantioseparation of <i>rac</i>-DMY by virtue of diastereomeric\ncocrystals was designed and optimized through slurry and cooling crystallization\nmethods, resulting in a product of 81% enantiomeric purity with a\nyield of only 31%. Further, the racemization process of DMY enantiomers\nwith various influence factors was examined, and the optimal racemization\ncondition that achieves simultaneous racemization of the two stereocenters\nwas determined. Finally, a stepwise cocrystallization-induced deracemization\nprocess of <i>rac</i>-DMY that combines chiral resolution\nby cocrystallization and racemization of recycling mother liquor was\ndeveloped, producing an enantiomeric purity of 97.5% and a maximal\nyield of 68%.