Resolution of -cyclohexyl-mandelic acid enantiomers
by two-phase (O/W) recognition chiral extraction
TANG KeWen1,2, ZHANG GuoLi2, HUANG KeLong2†, LI Yuanjian2 & YI JianMin1
1
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414000, China;
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China;
3
College of Pharmaceutical Science, Central South University, Changsha 410078, China
2
This paper presents a new chiral separation technology: two-phase (O/W) recognition chiral extraction.
Distribution behavior of -cyclohexyl-mandelic acid enantiomers was studied in the extraction system
with D(L)-isobutyl tartrate in 1,2- dichloroethane organic phase and  -CD derivatives in aqueous phase,
and the influence of the kind and concentration of extractant and pH on extraction performance was
investigated. The experimental results indicate that two-phase (O/W) recognition chiral extraction is of
strong chiral separation ability. HP- -CD, HE- -CD and Me--CD have higher recognition ability for
S-CHMA than that for R-CHMA, among which HP--CD has the strongest ability; whereas, D-isobutyl
tartrate has reversed recognition ability for them. In the extraction system containing HP- -CD and
D-isobutyl tartrate, e.e. % of S-CHMA in aqueous phase reached 27.6% by one stage extraction, and the
distribution ratio for R-CHMA(kR) and for S-CHMA(kS) and separation factor() are 2.44, 0.89 and 2.49,
respectively. Meanwhile, pH and concentration of extractant have great effects on chiral separation
ability. Two-phase (O/W) recognition chiral extraction has great significance for preparative separation
of racemic compounds.
two-phase(W/O) recognition, chiral extraction, -cyclohexyl-mandelic acid enantiomers
At present, study on chiral compounds has become one
of the hottest subjects, especially on single enantiomer
drugs[1,2]. With further study about the relation of drug
chirality and pharmaceutical effects, people have come
to know the significance of chirality in clinical application. Drug enantiomers have different effects on pharmacological activity, metabolism process and toxicity in
human body[3,4]. Today, there are more than 50% clinical
drugs with chiral factors, above 85% of which exist in
racemic mixture. Asymmetric synthesis is an important
method to obtain single enantiomer drug. However, it
involves relatively high cost and is time-consuming to
develop a suitable separation method for each chiral
compound, so preparative separation for chiral drug appears necessary[5].
Many studies have been made for the preparative
separation of drug enantiomers. Such chiral separation
technologies as crystallization, enzyme, chromatography,
kinetic resolution, etc. accelerate researches about chiral
compounds, but defects still exist for most racemic
compounds and are hard for pratical application. Jung et
al. prepared a homochiral metal-organic porous material
for enantioselective separation racemic [Ru(2,2-bipyridine)3]Cl2, which achieved good separation[2]. However,
it is difficult to prepare it. Chiral liquid-liquid extraction
follows certain rules for the choice of separation system
and has a large application range. Chiral extraction
technology has large potentiality and has attracted atten―
tion of many researchers in recently years[6 10].  is the
most important parameter for chiral extraction, which
Received
doi: 10.1007/s11426-007-0053-5
†
Corresponding author (email: klhuang@mail.csu.edu.cn)
Supported by the National Natural Science Foundation of China (Grant No.
20376085)
1
Michael. Single enantiomer drugs: new strategies and directions.
9
Chemistry & Industry, 1996, 5(20): 374―378
2
Jung S S, Dongmok W, Hyoyoung L, Sung I J, Jinho O, Young J J,
Kimoon K. A homochiral metal-organic porous material for enantiose-
10
lective separation and catalysis. Nature, 2000, 404: 982―986
3
Rosa H H, Pilar C F. Chromatographic separation of chlothalidone
enantiomers using β-cyclodextrins as chiral additives. J Chromatogr B,
11
2000, 740: 169―177
4
Abolfazl S M, Robert T F. Pharmacokinetics of metoprolol enantiomers
following single and multiple administration of racemate in rat. Internal
12
J pharm, 2002, 2: 97―102
5
James E R. Chiral separations. AIChE J., 2001, 47: 2―5
6
Cen Zhongzhe, Cai Shuihong. Solvent extraction of ephedrine
13
epimerides with chiral agents. J Chemical Industry and Engineering
(in Chinese), 2000, 51(3): 418―420
7
Vladimir P, Mi¿e K, Martin E. Lipophilic tartaric acid esters as enanti-
14
oselective ionophores. Angew Chem, 1989, 28(9): 1147―1152
8
Jérôme L, Catherine G G, Sonya T H, Jonathan J J. Efficient enantioselective extraction tris (diimine) ruthenium (Ⅱ) compexes by chiral,
lipophilic TRISPHAT anions. Angew Chem, 2000, 39(20): 3695―3697
2
15
TANG KeWen, CHEN GuoBin, Yi JianMin. Enantioselective separation of ofloxacin enantiomers by chiral ligand exchange. J Acta Chimica
Sinica (in Chinese), 2004, 62(17): 1621―1625
TANG KeWen, ZHOU ChunShan, JANG XinYu. Racemic of loxacin
separation by supported-liquid membrane extraction with two organic
phases. Sci China Ser B-Chem (in Chinese), 2002, 32(6): 491―496
Feitsm K G, Drenth B F H, de Zeeuw R A. Comparison of two - cyclodextrin bonded stationary phases for high-performance liquid
chromatography. Journal of Chromatography, 1987, 387: 447―452
Heldin E, Lindner K J, Pettersson C, Lindner W, Rao R. Tartaric acid
derivatives as chiral selectors in liquid chromatography. Chromatographia, 1991, 32(9-10): 407―416
HU Shanshan, WU Yizu, SHI Meiren. Resolution of -cyclohexylmandelic acid into enantiomers by HPLC with -cyclodextrin as additive in mobile phase. Fine Chemicals (in Chinese), 2004, 21(10):
730―732
Keurentjes J T F, Nabuurs L J W M, Vegter E A. Liquid membrane
technology for the separation of racemic mixtures. J Membrane Sci,
1996, 113: 354―360
Ding H B, Carr P W, Cussler E L. Racemic leucine separation by
hollow-fiber extraction. AIChE J, 1992, 38(10): 1493―149