Enhancing temperature cycle-induced deracemization via combined cooling and antisolvent crystallization: A proof of concept study

Abstract

This study investigates the enhancement possibilities of the temperature cycle-induced deracemization (TCID) process by solubility adjustments through solvent system compositions. The research hypothesizes that combined cooling and antisolvent crystallization (CCAS) can accelerate the deracemization through two effect. Firstly, the higher solubility at the beginning of the process ensures that the concentrations are raised, which translates to higher racemization reaction productivity. Secondly, well-chosen antisolvent dosing can reduce the solubility (hence, increase the solid loading) in line with the progression of deracemization. This means that the solid phase’s enantiomeric excess (EE) remains relatively high throughout the process, a condition known to accelerate deracemization. The concept is tested in TCID experiments at different solvent system compositions, indicating that higher solubility increases the apparent deracemization rate, partly at the expense of yield. The CCAS experiment revealed that the yield and the product’s EE could be improved simultaneously. The case study analyzed the glutamic acid (Glu) deracemization in the presence of the salicylaldehyde catalyst, using water as the solvent and acetic acid (AA) as the antisolvent. Comprehensive solubility measurements that enabled the design of experiments are also a part of this study.

Keywords

• Deracemization
• Cooling and antisolvent crystallization
• Temperature cycling
• Solubility
• Enantiomers