Green and Strategic Approach for Chiral Resolution by Diastereomeric Salt Formation: The Study of Racemic Ibuprofen

Hung Lin Lee, Ying Lun Hung, Ahmed Amin, Dhanang Edy Pratama, Tu Lee

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

As diastereomeric salt formation is the most popular method for the industrial preparation of single enantiomers, this method is chosen to resolve enantiomers of ibuprofen (IBU) in the present study. This type of chiral resolution process involves three steps: formation of a diastereomeric salt pair of racemic ibuprofen (Rac-IBU) with a chiral resolving agent, (S)-(−)-α-methylbenzylamine (S-MBA) in the presence/absence of a nonchiral agent, potassium hydroxide (KOH), resolution by cooling crystallization in a common solvent, and recovery of the compound with one enriched enantiomer. The present study is to investigate each of the three steps individually toward the chiral resolution of S-IBU, including the effects of (1) equivalent ratio of Rac-IBU-to-S-MBA-to-KOH on diastereomeric excess (%de) and yield upon the formation of the diastereomeric salts, (2) solvent and (3) temperature range for cooling crystallization on %de and yield upon the resolution by cooling crystallization, (4) solvent-to-antisolvent ratio, (5) aging time, and (6) addition rate of antisolvent on enantiomeric excess (%ee) and yield upon the recovery of the S-enriched IBU. Each step is optimized, and the integrated chiral resolution process is scaled up to a 0.5 L scale. Furthermore, practical guidelines are suggested for the future development of chiral resolution processes by diastereomeric salt formation.

Original languageEnglish
Pages (from-to)1946-1957
Number of pages12
JournalIndustrial and Engineering Chemistry Research
Volume62
Issue number4
DOIs
StatePublished - 1 Feb 2023

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