Deracemization in a Complex Quaternary System with a Second‐Order Asymmetric Transformation by Using Phase Diagram Studies

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second‐order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate‐forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes. Phase diagram enabled chiral resolution. Based on a quaternary phase diagram study, a second‐order asymmetric transformation of an axially chiral naphthamide that forms multiple solid phases involving two racemic compound forming systems has been demonstrated (see figure). This methodology could prove the efficiency of the phase diagram approach to chiral resolution by the crystallization of molecules showing complicated solid‐phase behavior.