Overcoming a Solid Solution System on Chiral Resolution: Combining Thermodynamics of Crystallization and Kinetics of Enantioselective Dissolution

We have successfully performed chiral resolution of a key synthetic intermediate of ozanimod, rac-4-cyano-1-aminoindane, by combining crystallization and enantioselective dissolution. 4-Cyano-1-aminoindane forms a diastereomeric salt with di-p-toluoyl-L-tartaric acid, however the single crystallization gave moderate enantiomeric excess, which indicated the formation of solid solution. The formation of solid solution is typical trouble in chiral resolution, and the limitation of enrichment by the crystallization was indicated by the construction of binary and ternary phase diagrams. Thorough phase diagram study revealed the solid-state landscape of the diastereomeric salt and determined the condition for chiral resolution. Additionally, further enrichment was achieved by following enantioselective dissolution using the difference in dissolution rates of the diastereomeric pairs. This combination of crystallization and dissolution demonstrated chiral resolution of 4-cyano-1-aminoindane up to 96%, and proposed a new solution to the solid solution formation which is typical trouble of chiral resolution for the first time.