Preparative Enantioseparation of β‐Substituted‐2‐Phenylpropionic Acids by Countercurrent Chromatography With Substituted β‐Cyclodextrin as Chiral Selectors

Abstract

Preparative enantioseparation of four β-substituted-2-phenylpropionic acids was performed by countercurrent chromatography with substituted β-cyclodextrin as chiral selectors. The two-phase solvent system was composed of n-hexane-ethyl acetate-0.10 mol L-1 of phosphate buffer solution at pH 2.67 containing 0.10 mol L(-1) of hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutylether-β-cyclodextrin (SBE-β-CD). The influence factors, including the type of substituted β-cyclodextrin, composition of organic phase, concentration of chiral selector, pH value of the aqueous phase, and equilibrium temperature were optimized by enantioselective liquid-liquid extraction. Under the optimum separation conditions, 100 mg of 2-phenylbutyric acid, 100 mg of tropic acid, and 50 mg of 2,3-diphenylpropionic acid were successfully enantioseparated by high-speed countercurrent chromatography, and the recovery of the (±)-enantiomers was in the range of 90-91% for (±)-2-phenylbutyric acid, 91-92% for (±)-tropic acid, 85-87% for (±)-2,3-diphenylpropionic acid with purity of over 97%, 96%, and 98%, respectively. The formation of 1:1 stoichiometric inclusion complex of β-substituted-2-phenylpropionic acids with HP-β-CD was determined by UV spectrophotometry and the inclusion constants were calculated by a modified Benesi-Hildebrand equation. The results showed that different enantioselectivities among different racemates were mainly caused by different enantiorecognition between each enantiomer and HP-β-CD, while it might be partially caused by different inclusion capacity between racemic solutes and HP-β-CD.

Spectral study on inclusion interaction and enantiorecognition of 2‐aryl carboxylic acids with hydroxypropyl‐β‐cyclodextrin

“…Racemic 2‐phenylbutyric acid, 3‐chloromandelic acid, 2‐chloromandelic acid (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), phenylsuccinic acid (Xiangfan Nuoer Chemical Co., Ltd., Hubei, China), 2‐(4‐nitrophenyl)propanoic acid, 2‐(4‐methylphenyl)propanoic acid, ibuprofen, 2‐(4‐hydroxyphenyl)propanoic acid, 2‐(3‐chlorophenyl)propanoic acid, ketoprofen, flurbiprofen, suprofen, carprofen, naproxen, tropic acid, 2,3‐diphenylpropionic acid, 2‐phenyl‐3‐methylbutyric acid, α‐cyclohexylmandelic acid, α‐cyclopentylmandelic acid, 4‐bromomandelic acid, mandelic acid, 4‐methoxymandelic acid (J&K Chemical Scientific Co., Ltd., Shanghai, China), enantiomeric naproxen, mandelic acid (Energy Chemical Co., Ltd., Shanghai, China), enantiomeric 2,3‐diphenylpropionic acid were prepared in our lab. [ 10 ]…”

“…In the past decade, more than 20 different 2‐aryl carboxylic acids have been investigated for their enantioseparation by countercurrent chromatography using HP‐β‐CD as chiral selector in our lab. [ 7–11 ] Countercurrent chromatography is a kind of liquid–liquid partition chromatography using no solid support for the stationary phase. It is believed that a high enantioseparation factor being more than 1.4 is necessary for a successful separation of the racemate by countercurrent chromatography, which is critically depended on enantiorecognition between chiral selector and enantiomer.…”

The development of biphasic chiral recognition in chiral separation

“…It is used principally in the field of chiral separation by LLE or CCC because it requires immiscible two‐phase solvent. Given the strong points of LLE and CCC such as high sample loading capacity, easy to scale‐up, and so on, BCR method provides an effective avenue for achieving chiral separation by these techniques and has enormous potential in chiral separation. Although the severe requirements for chiral selectors limited the expansion of BCR, it has made considerable progress in the past few years.…”

Lipase‐catalyzed hydrolysis of (R,S)‐2,3‐diphenylpropionic methyl ester enhanced by hydroxypropyl‐β‐cyclodextrin

“…Separation of ( R , S )‐2,3‐diphenylpropionic acid (( R , S )‐2,3‐2‐PPA) enantiomers by chromatography has been reported previously . In this work, we attempt to use lipase‐catalyzed enantioselective hydrolysis of ( R , S )‐2,3‐diphenylpropionic methyl ester (( R , S )‐2,3‐2‐PPAME) in an aqueous system to obtain ( R )‐2,3‐2‐PPA.…”

“…34 Separation of (R,S)-2,3-diphenylpropionic acid ((R,S)-2,3-2-PPA) enantiomers by chromatography has been reported previously. 35 In this work, we attempt to use lipase-catalyzed enantioselective hydrolysis of (R,S)-2,3-diphenylpropionic methyl ester ((R,S)-2,3-2-PPAME) in an aqueous system to obtain (R)-2,3-2-PPA. However, the solubility of (R)-2,-3-2-PPAME in aqueous solution is very poor, which results in a relatively low conversion of substrate and low rate of enzymatic reaction.…”