Bifunctional Chiral Agent Enables One-pot Spontaneous Deracemization of Racemic Compounds

A novel one-pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral alpha, (alpha-diphenyl-2-pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)-enantiomer and (2S,3S)-enantiomer in solution, achieving a one-pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)-carprofen, (R,S)-indoprofen, and (R,S)-indobufen. The one-pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization-induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy. A crystallization-induced deracemization method using a bifunctional chiral agent (BCA) was developed. The BCA helps achieve the dual functions of catalytic racemization and cocrystallization with the resulting enantiomers (see picture). This method was successfully implemented for the deracemization of chiral drugs containing one or multiple stereocenters, thus extending current strategies to the enantioseparation of racemic compounds.+ image