Overcoming a solid solution system on chiral resolution: combining crystallization and enantioselective dissolution

Abstract

Chiral resolution of rac-4-cyano-1-aminoindane, a key intermediate of ozanimod, was successfully achieved through a combination of crystallization and enantioselective dissolution up to 96%ee. The disastereomeric salt with di-p-toluoyl-L-tartaric acid was...

Crystallization-Induced Diastereomeric Transformation of Chiral Ozanimod Key Intermediate Using Homogeneous Ir-Based Racemization Catalyst

“…Figure a–c shows the ternary isotherm of THF, the salts S - 1 · l - 2 , and R - 1 · l - 2 . Similar to the previously reported ternary isotherm of methanol, the salts S - 1 · l - 2 , and R - 1 · l - 2 , it clearly showed solid solution behavior, which accompanies continuous solubility change without any clear eutectic composition over the whole composition. The solubility of R - 1 · l - 2 is higher than that of S - 1 · l - 2 .…”

“…We have previously reported that 1 forms a diastereomeric solid solution with di-p-toluoyl-L-tartaric acid study (Figure 1a). 27 While the resolution by enantioselective dissolution was successfully applied to enrich the diastereomeric excess (de) of the salt, the de of 1•2 in the solid could reach up to 15% from the racemic composition by a single operation. Here, we introduced (pentamethylcyclopentadienyl) iridium(III) diiodide dimer 3 as a racemization catalyst and successfully carried out CIDT of 1 in the solid phase up to 60% in a single crystallization (Figure 1b).…”

“…We have previously reported that 1 forms a diastereomeric solid solution with di- p -toluoyl- l -tartaric acid 2 . Its resolution was achieved by combining crystallization and enantioselective dissolution on the basis of the phase diagram study (Figure a) . While the resolution by enantioselective dissolution was successfully applied to enrich the diastereomeric excess ( de ) of the salt, the de of 1 · 2 in the solid could reach up to 15% from the racemic composition by a single operation.…”

“…Such near-equilibrium conditions can be understood by constructing a phase diagram. ,− A ternary system isotherm of THF and salts S - 1 · l - 2 and R - 1 · l - 2 was created. Various compositions of salts suspended in THF were allowed to reach thermodynamic equilibrium, and the compositions of the solid and liquid phases were measured.…”

Strategies for chiral separation: from racemate to enantiomer

“…To avoid a strenuous cascade of the crystallization process, the Ss obtained from single-stage crystallization (28% ee S ) underwent an enantioselective dissolution process to remove the soluble R -4C1A: l -DMTA salt, and crystals with final ee S of 96% could be obtained. 164 Compared to selective crystallization, this enrichment pathway, according to the lever rule, seems particularly efficient in Ss systems, where the tie line traversing the racemic composition has a steep slope.…”