Recycling of resolving agent and solvent by water-based reactions and phase diagrams: Chiral resolution study of racemic ibuprofen

Both chiral resolving agent and solvent from chiral resolution of the racemate were successfully recovered and recycled by slurry reactive crystallization of its diastereomeric salts. A solvent capable of solubilizing the resolving agent, but not the racemate and its diastereomeric salt products, was selected for chemical processing. The reaction was proceeded through the solid-solid conversion of the racemate into its diastereomeric salt pair, hence the term slurry reactive crystallization. An excessive amount of resolving agent was introduced to ensure reaction completeness, and the unreacted resolving agent was recovered in the filtrate along with the spent mother liquor which was made up by the selected solvent. The filtered solids of diastereomeric salt pair were resolved by recrystallization separately. The same mother liquor was reused as a suspending solvent medium for desalification of the diastereomeric salts by a strong achiral acid/base, in which the cracked resolving agent would be returned to the mother liquor as a solute. By this way, a closed-loop recycle of the resolving agent and suspending solvent medium could be achieved. This concept has been successfully proven by applying it to recover (S)-(-)-1-phenylethylamine as a resolving agent in the chiral resolution of (R,S)-(±)-ibuprofen, with the recovery of 68–70 wt% for up to three cycles. (R,S)-(±)-ibuprofen was resolved to 61–70 wt%R of enriched (R)-(-)-ibuprofen crystals, and up to 77–85 wt%S of enriched (S)-(+)-ibuprofen crystals for up to three cycles. By using this approach, chiral resolution of (R,S)-(±)-ibuprofen could be made to be sustainable with an E-factor of 39.8.