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

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.

Unconventional approaches for chiral resolution

“…Another interesting approach is the so-called enantioselective crystallization of chiral molecules [ 40 ]. Different methods based on the formation of diastereomeric salts or co-crystallization have been developed and scaled up to the industrial level [ 41 – 43 ]. However, additional purification steps are required due to the strong binding between the antipode of interest and the chiral resolving agent.…”

Design and process study of chiral separation of (2S,4S)-1-(tert-butoxy carbonyl)-4-(methoxymethyl) pyrrolidine-2-carboxylic acid for green manufacturing

“…This distinct XRD profile serves as a valuable means of distinguishing between the crystal forms of these compounds. 53,54 It is important to note that subjecting the monohydrate crystal form to vacuum drying within the temperature range of 40-45 °C leads to the loss of water and the transformation into an anhydrate form. However, during this drying process, careful attention should be paid to the melting phenomenon to ensure proper control of the conditions.…”

A perspective on renewable production of amino acids from biomass through the chemocatalytic method

“…The chiral resolution has been demonstrated as an effective method for separating two racemic amino acids, which includes kinetic resolution, chromatographic resolution, crystallization resolution, and membrane-based resolution. 4,79 Thus, integrating this process with the chemocatalytic method can also achieve the conversion of biomass into chiral amino acids, but they have been rarely reported so far.…”