Green chiral separation of racemic mixture via crystallization induced deracemization process synergistically intensified by ultrasound and temperature cycling

Deracemization is a promising chiral resolution technique that combines racemization reaction with stereoselective crystallization for complete chiral symmetry breaking and has attracted much attention. However, the integration process of reaction-crystallization is rather complex and often requires long operation time with high initial solid enantiomer excess which greatly limits its wide application. Herein, we proposed a novel strategy that combines the use of both ultrasound and temperature cycles to accelerate the process of deracemization and thereby chiral separation. A chiral compound, N-acetyl-DL-leucine, was selected as a model drug for experimental validation. We found that either ultrasound or temperature cycle process was capable of accelerating the deracemization efficiency, nonetheless, the combination of the two methods leads to the antagonistic action, decreasing process efficiency and product chiral purity. Through the time-elapsed characterizations on enantiomeric purity of N-acetyl-L-leucine over the course of deracemization, we revealed that the ultrasound negatively impacted the process efficiency of chiral separation via promotion of primary heterogeneous nucleation during the cooling stage. Finally, we strategically designed a synergistic process intensification of crystallizationinduced deracemization between temperature cycling and the periodic ultrasound that switches on only during the heating stage to achieve highly efficient separation of pure N-acetyl-L-leucine with theoretical 100% yield at extremely low initial solid ee%.