Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric...

Area of Science:

• Organic Chemistry
• Process Chemistry
• Crystallization Science

Background:

• Chiral amine resolution is crucial in synthesizing enantiomerically pure compounds.
• Traditional batch diastereomeric crystallization methods can be inefficient and labor-intensive.
• In situ racemization catalysts often face challenges with conflicting conditions and catalyst separation.

Purpose of the Study:

• To develop a novel dynamic diastereomeric crystallization method for efficient chiral amine resolution.
• To implement a continuous resolution-racemization-recycle (R3) process using a heterogeneous catalyst.
• To overcome limitations associated with in situ catalyst use in crystallization.

Main Methods:

• Development of a fixed-bed catalyst by immobilizing an iridium-based SCRAM catalyst on Wang resin.
• Continuous separation of mother liquors, racemization over the fixed-bed catalyst, and recirculation to the crystallizer.
• Resolution of various cyclic and acyclic amine salts using mandelic acid and ditoluoyl tartaric acid.

Main Results:

• The R3 process demonstrated significantly higher resolution efficiency (1.6-44 times) compared to batch crystallization.
• The immobilized catalyst showed good stability and reusability over multiple cycles (e.g., 40 recycles, 190 h).
• Unusual thermodynamic switching behavior was observed with difunctional resolving agents, influenced by various crystallization conditions.

Conclusions:

• The developed R3 process offers a more effective and continuous approach for chiral amine resolution.
• Heterogeneous catalysis in a fixed-bed reactor is viable for continuous racemization in dynamic crystallization.
• Further investigation into thermodynamic switching is warranted for optimizing resolutions with specific resolving agents.