Resolution of (±)-Imeglimin-2,4-dichlorophenylacetate Methanol Solvate by Preferential Crystallization

The resolution of this derivative was optimized at 2-L scale in methanol by using two preferential crystallization modes (auto-seeded polythermic programmed preferential crystallization, hereafter AS3PC, and seeded isothermal preferential crystallization, hereafter SIPC) and by tuning the starting temperature. The results evidenced that the AS3PC mode is more efficient than the SIPC mode, and the higher the starting temperature, the higher the productivity. Despite a careful tuning of the operating conditions and a stable conglomerate offering a full chiral discrimination in the solid state, the enantiomeric excess of the crude solid obtained by preferential crystallization remained lower than 90%. However, this can be improved up to 99% by a single recrystallization of the methanol solvate of the imeglimin-2,4-dichlorophenylacetate since it crystallizes as a stable conglomerate without any detectable partial solid solution.