High performance liquid chromatography enantioseparation of the novel designed mexiletine derivatives and its analogs

Article abstract of DOI:10.1002/chir.20880

A series of novel designed mexiletine derivatives and its analogs were prepared, the structures were confirmed by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared Spectroscopy (FTIR), and Electrospray Ionization-Mass Spectrometry (ESI-MS), and

Full text of DOI:10.1002/chir.20880

CHIRALITY 23:99–104 (2011)
High Performance Liquid Chromatography Enantioseparation of
the Novel Designed Mexiletine Derivatives and Its Analogs
1
CHENGZHEN ZHENG,1 DATONG ZHANG,2 QI WU,1 AND XIANFU LIN
*
1Department of Chemistry, Zhejiang University, Hangzhou, People’s Republic of China
2College of Biologic & Environmental Engineering, Zhejiang University of Technology, Hangzhou, People’s Republic of China
ABSTRACT
A series of novel designed mexiletine derivatives and its analogs were pre-
pared, the structures were confirmed by Nuclear Magnetic Resonance (NMR), Fourier Trans-
form Infrared Spectroscopy (FTIR), and Electrospray Ionization-Mass Spectrometry (ESI-MS),
and the enantioseparations were performed on polysaccharide-based chiral stationary phase
(CSP), Chiralcel OD-H, and Chiralcel OJ-H, under normal-phase mode. The effects of the con-
centration of isopropanol in the mobile phase were studied, seven of the eight enantiomers got
baseline separation on Chiralcel OD-H, and five of the eight enantiomers got successfully sepa-
ration on Chiralcel OJ-H. The effects of structural features were also discussed. Chirality
C
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23:99–104, 2011.
2010 Wiley-Liss, Inc.
KEY WORDS: synthesis; enantioseparation; HPLC; mexiletine; derivatives
INTRODUCTION
(Changzhou, China), (R,S)-1-methyl-3-phenylpropylamine,
and (R,S)-1-phenylethylamine were purchased from Sigma
(USA). Divinyl adipate, divinyl azelate, and divinyl seba-
cate were produced and purified as described in the litera-
ture.12 Vinyl acetate and all solvents were of analytical
grade or chromatographic grade.
As the enantiomers of a chiral drug candidate often have
differences in their pharmacokinetic, physiological, toxico-
logical, and metabolic activities, the enantiomeric purity of
a chiral drug became an important issue for both pharma-
ceutical industry and regulatory agencies.1 Therefore, chi-
ral separations are becoming increasingly important.
Apparatus
Mexiletine,
[1-(2,6-dimethylphenoxy)-2-amino-propane],
1
The H and 13C NMR spectra were recorded with tetra-
which is classified as a Class Ib antiarrhythmic drug widely
used in the treatment of ventricular tachyarrhythmias, is clini-
cally used in its racemic form.2 At the same time, a narrow ther-
apeutic ratio3 and many adverse effects of mexiletine may occur
at cardiac and central nervous system levels upon chronic treat-
ments.4,5 However, mexiletine derivatives or analogs can solve
some of these problems, such as present a wider therapeutic ra-
tio, being more selectively active on hyperexcited tissues,6 etc.
In recent years, some mexiletine derivatives or analogs have
been reported. Desaphy et al. reported that two myotonia caus-
ing mutants of the human skeletal muscle Na1 channel
showed different sensitivity to mexiletine and its derivatives.7 Li
et al. reported that a pyrroline derivative of mexiletine offered
marked protection against ischemia-/reperfusion-induced myo-
cardial contractile dysfunction.8 Clark reported that mexiletine
derivatives could be used a medicaments for pain.9
The derivatives of drugs can give therapeutic advan-
tages in improving drug delivery, solubility, and bioavaila-
bility.10,11 In this article, a series of (R,S)-N-mexiletine
derivatives with different length of the alkyl chain (Figs.
1a–1h) were synthesized. The enantioseparations were
investigated on Chiralcel OD-H and Chiralcel OJ-H col-
umn. The influences of isopropanol concentration and
structure on the chromatographic resolution were studied.
methylsilane as internal standard using a Bruker AMX 400
MHz spectrometer at 400 and 100 MHz, respectively.
Infrared spectra were measured with a Nicolet Nexus
FTIR 670 spectrophotometer. Mass spectrometric data
were obtained on Bruker ESI-MS measurements.
Sample Preparation
Preparation of Sample a, b, c, g, and h. The reac-
tion mixture, including (R,S)-mexiletine hydrochloride
(1 mmol), divinyl dicarboxylates (4 mmol), toluene (5 ml)
and sodium methoxide (0.1 mmol), was stirred at refluxed
temperature for 12 h. Formation of (R,S)-N-mexiletine vinyl
ester derivatives was monitored by Thin-Layer Chromatogra-
phy (TLC). The products were purified by silica gel chroma-
tography with an eluent consisting of petroleum ether/ethyl
acetate 7:3 (v/v) and characterized by Nuclear Magnetic Res-
onance (NMR), Fourier Transform Infrared Spectroscopy
(FTIR), and Electrospray Ionization-Mass Spectrometry (ESI-
MS). The reaction and separation method of Sample g and h
was the same with the preparation of Sample a, b and c.
Additional Supporting Information may be found in the online version of
this article.
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant numbers: 20704037 and 20872130
*Correspondence to: Xianfu Lin, Department of Chemistry, Zhejiang Uni-
versity, Hangzhou, People’s Republic of China. E-mail: llc123@zju.edu.cn
Received for publication 14 December 2009; Accepted 22 April 2010
DOI: 10.1002/chir.20880
EXPERIMENTAL
Chemicals and Reagents
(R,S)-Mexiletine hydrochloride was purchased from
Published online 11 June 2010 in Wiley Online Library
Jiangsu Jintan Yabang Pharmaceutical Co. Ltd (wileyonlinelibrary.com).
C
VV
2010 Wiley-Liss, Inc.

100
ZHENG ET AL.
The reaction time of Sample a was 12 h and the yield (t, 2H, ꢀꢀCH2ꢀꢀ), 1.69 (s, 4H, ꢀꢀCH2ꢀꢀ), 1.48 (d, 3H,
was 67%. IR (KBr): 3297 (ꢀꢀNHꢀꢀ), 1756 (OꢀꢀC¼¼O), and ꢀꢀCH3). 13C NMR (100 MHz, CDCl3): ppm 171.4
1
1646 (HNꢀꢀC¼¼O and C¼¼C) cm21. H NMR (400 MHz, (HNꢀꢀC¼¼O), 170.5 (OꢀꢀC¼¼O), 143.3 (Ar-C), 141.1
CDCl3): d 7.24 (m, 1H, ¼¼CHꢀꢀ), 7.00–6.89 (m, 3H, Ar-H), (OꢀꢀC¼¼), 128.6, 127.3, 126.1 (Ar-C), 97.7 (¼¼CH2), 48.7
5.95 (d, 1H, NH), 4.85 (m, 1H, ¼¼CH2), 4.55 (m, 1H, (HNꢀꢀCHꢀꢀ), 36.2, 33.5, 24.9, 24.0 (ꢀꢀCH2ꢀꢀ), 21.7
¼¼CH2), 4.33 (m, 1H, ꢀꢀCHꢀꢀ), 3.80–3.68 (dd, 2H, (ꢀꢀCH3). ESI-MS m/z: 298.1 [M 1 Na]1.
OꢀꢀCH2ꢀꢀ), 2.40 (t, 2H, ꢀꢀCH2ꢀꢀ), 2.22 (d, 8H, ArꢀꢀCH3
Preparation of Sample d. The method of preparation
and ꢀꢀCH2ꢀꢀ), 1.69 (m, 4H, ꢀꢀCH2ꢀꢀ), 1.38 (d, 3H,
ꢀꢀCH3). 13C NMR (100 MHz, CDCl3): ppm
171.7(HNꢀꢀC¼¼O), 170.4 (OꢀꢀC¼¼O), 154.8 (ArꢀꢀO),
141.0 (OꢀꢀC¼¼), 130.6, 128.9, 124.0 (ArꢀꢀC), 97.6 (¼¼CH2),
73.8 (OꢀꢀCH2ꢀꢀ), 45.3 (HNꢀꢀCHꢀꢀ), 36.3, 33.5, 24.9, 24.1
(ꢀꢀCH2ꢀꢀ), 17.7 (ꢀꢀCH3), 16.1 (ArꢀꢀCH3). ESI-MS m/z:
356.0 [M 1 Na]1.
of Sample d was according to the literature.13 The reaction
was controlled with TLC using petroleum ether/ethyl ace-
tate 7:3 (v/v). The structure of product was confirmed by
NMR, FTIR and ESI-MS.
The reaction time of Sample d was 5 h and the yield
was ꢁ80%. IR (KBr): 3276 (ꢀꢀNHꢀꢀ) and 1649
1
(HNꢀꢀC¼¼O) cm21. H NMR (400 MHz, CDCl3): d 7.00–
The reaction time of Sample b was 12 h and the yield
was 65%. IR (KBr): 3295 (ꢀꢀNHꢀꢀ), 1756 (OꢀꢀC¼¼O), and
6.90 (m, 3H, Ar-H), 5.97 (d, 1H, ꢀꢀNHꢀꢀ), 4.33 (m, 1H,
ꢀꢀCHꢀꢀ), 3.81–3.68 (dd, 2H, OꢀꢀCH2ꢀꢀ), 2.25 (s, 6H,
ArꢀꢀCH3), 2.02 (s, 3H, ꢀꢀCOCH3), 1.38 (d, 3H, ꢀꢀCH3).
13C NMR (100 MHz, CDCl3): ppm 169.5 (HNꢀꢀC¼¼O),
154.7 (Ar-O), 130.6, 128.9, 124.0 (Ar-C), 73.7 (OꢀꢀCH2ꢀꢀ),
45.3 (HNꢀꢀCHꢀꢀ), 23.4, 17.7 (ꢀꢀCH3), 16.0 (Ar-CH3). ESI-
MS m/z: 243.9 [M 1 Na]1.
1
1646 (HNꢀꢀC¼¼O and C¼¼C) cm21. H NMR (400 MHz,
CDCl3): d 7.25 (m, 1H, ¼¼CHꢀꢀ), 7.01–6.91 (m, 3H,
ArꢀꢀH), 5.89 (d, 1H, ꢀꢀNHꢀꢀ), 4.85 (m, 1H, ¼¼CH2), 4.55
(m, 1H, ¼¼CH2), 4.34 (m, 1H, ꢀꢀCHꢀꢀ), 3.81–3.70 (dd, 2H,
OꢀꢀCH2ꢀꢀ), 2.36 (t, 2H, ꢀꢀCH2ꢀꢀ), 2.26 (s, 6H, ArꢀꢀCH3),
2.19 (t, 2H, ꢀꢀCH2ꢀꢀ), 1.64 (t, 4H, ꢀꢀCH2ꢀꢀ), 1.39 (t, 3H,
ꢀꢀCH3), 1.35 (s, 6H, ꢀꢀCH2ꢀꢀ). 13C NMR (100 MHz,
CDCl3): ppm 172.3 (HNꢀꢀC¼¼O), 170.7 (ꢀꢀC¼¼O), 154.8
(ArꢀꢀO), 141.1 (OꢀꢀC¼¼), 130.6, 128.9, 124.0 (ArꢀꢀC), 97.4
(¼¼CH2), 73.9 (OꢀꢀCH2ꢀꢀ), 45.1 (HNꢀꢀCHꢀꢀ), 36.8, 33.8,
29.0, 28.9, 28.7, 25.5, 24.4 (ꢀꢀCH2ꢀꢀ), 17.8 (ꢀꢀCH3), 16.1
(ArꢀꢀCH3). ESI-MS m/z: 398.1 [M 1 Na]1.
Preparation of Sample e and f. The method of prep-
aration of Samples e and f was according to the litera-
ture.14 The reaction was controlled with TLC using petro-
leum ether/ethyl acetate 3:1 (v/v). Products were charac-
terized by NMR, FTIR, and ESI-MS.
The reaction time of Sample e was 12 h and the yield
was 83%. IR (KBr): 3304 (ꢀꢀNHꢀꢀ) and 1644 (HNꢀꢀC¼¼O)
cm21. 1H NMR (400 MHz, CDCl3): d 7.00–6.90 (m, 3H, Ar-
H), 5.93 (d, 1H, ꢀꢀNHꢀꢀ), 4.35 (m, 1H, ꢀꢀCHꢀꢀ), 3.80–
3.68 (dd, 2H, OꢀꢀCH2ꢀꢀ), 2.25 (s, 6H, Ar-CH3), 2.21–2.18
(t, 2H, ꢀꢀCOCH2), 1.66–1.61 (q, 2H, ꢀꢀCH2ꢀꢀ), 1.29–1.10
(dd, 8H, ꢀꢀCH2ꢀꢀ), 1.38 (d, 3H, ꢀꢀCH3), 0.88–0.85 (t, 3H,
ꢀꢀCH3). 13C NMR (100 MHz, CDCl3): ppm 172.4
(HNꢀꢀC¼¼O), 154.7 (Ar-O), 130.7, 128.9, 124.0 (Ar-C), 73.9
(OꢀꢀCH2ꢀꢀ), 45.1 (HNꢀꢀCHꢀꢀ), 36.9, 31.6, 29.2, 29.0,
25.7, 22.5(ꢀꢀCH2ꢀꢀ), 17.8, 16.0 (ꢀꢀCH3), 14.0 (Ar-CH3).
ESI-MS m/z: 328.1 [M 1 Na]1.
The reaction time of Sample f was 12 h and the yield
was 81%. IR (KBr): 3305 (ꢀꢀNHꢀꢀ) and 1644 (HNꢀꢀC¼¼O)
cm21. 1H NMR (400 MHz, CDCl3): d 7.00–6.90 (m, 3H, Ar-
H), 5.91 (d, 1H, ꢀꢀNHꢀꢀ), 4.35 (m, 1H, ꢀꢀCHꢀꢀ), 3.80–
3.68 (dd, 2H, ꢀꢀOꢀꢀCH2ꢀꢀ), 2.25 (s, 6H, ArꢀꢀCH3), 2.21–
2.18 (t, 3H, ꢀꢀCOCH2ꢀꢀ), 1.24 (t, 22H, ꢀꢀCH2ꢀꢀ), 1.38 (s,
3H, ꢀꢀCH3), 0.88–0.85 (t, 3H, ꢀꢀCH3). 13C NMR (100
MHz, CDCl3): ppm 172.4 (HNꢀꢀC¼¼O), 154.7 (Ar-O),
130.7, 128.9, 124.0 (Ar-C), 73.9 (OꢀꢀCH2ꢀꢀ), 45.1
(HNꢀꢀCHꢀꢀ), 36.9, 31.8, 29.6, 29.6, 29.5, 29.4, 29.3, 29.3,
29.2, 25.7, 22.6 (ꢀꢀCH2ꢀꢀ), 17.8, 16.1 (ꢀꢀCH3), 14.1 (Ar-
CH3). ESI-MS m/z: 412.1 [M 1 Na]1.
The reaction time of Sample c was 12 h and the yield
was 62%. IR (KBr): 3294 (ꢀꢀNHꢀꢀ), 1756 (OꢀꢀC¼¼O), and
1
1646 (HNꢀꢀC¼¼O and C¼¼C) cm21. H NMR (400 MHz,
CDCl3): d 7.25 (m, 1H, ¼¼CHꢀꢀ), 7.00–6.90 (m, 3H,
ArꢀꢀH), 5.90 (d, 1H, ꢀꢀNHꢀꢀ), 4.85 (m, 1H, ¼¼CH2), 4.54
(m, 1H, ¼¼CH2), 4.36 (s, 1H, ꢀꢀCHꢀꢀ), 3.80–3.69 (dd, 2H,
OꢀꢀCH2ꢀꢀ), 2.35 (t, 2H, ꢀꢀCH2ꢀꢀ), 2.25 (s, 6H, ArꢀꢀCH3),
2.18 (t, 2H, ꢀꢀCH2ꢀꢀ), 1.63 (t, 4H, ꢀꢀCH2ꢀꢀ), 1.39 (t, 3H,
ꢀꢀCH3), 1.32 (s, 8H, ꢀꢀCH2ꢀꢀ). 13C NMR (100 MHz,
CDCl3): ppm 172.3 (HNꢀꢀC¼¼O), 170.8 (OꢀꢀC¼¼O), 154.8
(ArꢀꢀO), 141.0 (OꢀꢀC¼¼), 130.6, 128.9, 124.0 (ArꢀꢀC), 97.4
(¼¼CH2), 73.9 (OꢀꢀCH2ꢀꢀ), 45.1 (HNꢀꢀCHꢀꢀ), 36.8, 33.8,
29.1, 29.0, 28.9, 28.9, 25.6, 24.5 (ꢀꢀCH2ꢀꢀ), 17.8 (ꢀꢀCH3),
16.1 (ArꢀꢀCH3). ESI-MS m/z: 412.1 [M 1 Na]1.
The reaction time of Sample g was 12 h and the yield was
44%. IR (liquid film, cm21): 3290 (ꢀꢀNHꢀꢀ), 1755
(OꢀꢀC¼¼O), and 1645 (HNꢀꢀC¼¼O and C¼¼C) cm21
.
1H
NMR (400 MHz, CDCl3): d 7.29–7.16 (m, 6H, ¼¼CHꢀꢀ and
Ar-H), 5.40 (d, 1H, ꢀꢀNHꢀꢀ), 4.86 (d, 1H, ¼¼CH2), 4.56 (d,
1H, ¼¼CH2), 4.02 (m, 1H, ꢀꢀCHꢀꢀ), 2.62 (t, 2H, ArꢀꢀCH2ꢀꢀ),
2.40 (t, 2H, ꢀꢀCH2ꢀꢀ), 2.13 (t, 2H, ꢀꢀCH2ꢀꢀ), 1.79ꢀꢀ1.63 (m,
6H, ꢀꢀCH2ꢀꢀ), 1.16 (d, 3H, ꢀꢀCH3). 13C NMR (100 MHz,
CDCl3): ppm 171.6 (HNꢀꢀC¼¼O), 170.5 (OꢀꢀC¼¼O), 141.7
(OꢀꢀC¼¼), 141.0, 128.4, 128.3, 125.8 (Ar-C), 97.7 (¼¼CH2),
45.1 (HNꢀꢀCHꢀꢀ), 38.5, 36.3, 33.5, 32.5, 25.0, 24.0
(ꢀꢀCH2ꢀꢀ), 15.2 (ꢀꢀCH3). ESI-MS m/z: 326.1 [M 1 Na]1.
Chromatography
The chromatographic experiments were performed
The reaction time of Sample h was 12 h and the yield using an Agilent 1100 HPLC system (Agilent, USA)
was 38%. IR (KBr): 3290 (ꢀꢀNHꢀꢀ), 1755 (OꢀꢀC¼¼O), and
equipped with a quaternary pump and a diode-array detec-
tor at room temperature. The columns used were: Chiral-
1
1645 (HNꢀꢀC¼¼O and C¼¼C) cm21. H NMR (400 MHz,
CDCl3): d 7.36–7.25 (m, 6H, ¼¼CHꢀꢀ and Ar-H), 5.88 (s, cel OD-H (cellulose tris-3,5-dimethylphenylcarbamate) and
1H, ꢀꢀNHꢀꢀ), 5.12 (m, 1H, Ar-CHꢀꢀ), 4.87 (m, 1H,
Chiralcel OJ-H (cellulose tris-4-methyl-benzoate) from Dai-
cel Chemical Industries (Tokyo, Japan). The mobile phase
¼¼CH2), 4.57 (m, 1H, ¼¼CH2), 2.39 (t, 2H, ꢀꢀCH2ꢀꢀ), 2.17
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF MEXILETINE DERIVATIVES
101
compositions were 10%, 20% and 30% of isopropanol in n- concentration of isopropanol overstepped a certain range,
hexane. The samples were dissolved in isopropanol. All the polarity alteration of mobile phase affected the nature
solvents and mobile phase were filtered by 0.45 lm filter of chiral stationary phase (CSP) discrimination. It was also
membrane. The flow rate was 1.0 ml/min. UV detection possible that enantiomeric separation was a result of more
was performed at 220 nm. The results were summarized than one type of interaction. For example, the enantiose-
in Table 1.
lectivity of the first group of samples on Chiralcel OJ-H
was from baseline to partial resolved when the content of
isopropanol increased from 10% to 20% (Table 1).
RESULTS AND DISCUSSION
The Influence of Isopropanol Concentration on
Enantioseparation
The Influence of the Structure on Enantioseparation
As seen from Figure 1, the structures of the compounds
examined were similar, all had a chiral center connected
directly to a methyl (ꢀꢀCH3) group, aminocarbonyl group,
and 2,6-dimethylphenoxy or phenyl group. The samples
were divided into three groups according to their struc-
tures. The first group included the Samples a–c, which
contains a vinyl group at the terminal and different chain
length. Group 2 comprised the Samples d–f without the
terminal vinyl group compared with the first group of sam-
ples. The Samples a, g and h, containing the terminal vinyl
group, the same chain length and different matrix, formed
Group 3.
From Table 1, it was evident that the retention factors
(k0) and the resolutions (Rs) of all samples were increased
with the decreasing isopropanol concentration in the mo-
bile phase on both columns, whereas the separation fac-
tors (a) decreased on Chiralcel OD-H and increased on
Chiralcel OJ-H. When the content of isopropanol was
reduced, the polarity of the mobile phase decreased, the
strength and number of hydrogen bonds between solutes
and stationary phase increased, the eluting ability of mo-
bile phase decreased, then the retention factors (k0) and
the resolutions (Rs) increased.
Notably, the enantioselectivity on Chiralcel OD-H col-
umn was essentially unchanged when the isopropanol con-
centration ranged from 10% to 30% (Table 1). It indicated
that, within a certain range of isopropanol concentration
and at a constant temperature, the conformation of Chiral-
cel OD-H and the selective adsorption sites were not
affected by the isopropanol concentration. But when the
It was well known that the CSP of Chiralcel OD-H con-
tains cellulose tris-3,5-dimethylphenylcarbamate as chiral
selector offers additional hydrogen-bonding sites for selec-
tor-sample interactions compared with the 4-methylben-
zoate substituents on Chiralcel OJ-H. Therefore, Chiralcel
OD-H, in general, exhibited higher chiral resolving ability
compared with Chiralcel OJ-H for numerous samples.15,16
This trend was also confirmed in the present study (Table
1, Figs. 2, 3 and the Supporting Information). The enan-
tiomers of seven samples were baseline resolved on Chir-
alcel OD-H and three got baseline separation on Chiralcel
OJ-H. The enatiomeric recognition ability of Chiralcel OD-
H toward the eight samples in descending order was b >
c > a > e > f > d > g > h and on Chiralcel OJ-H was a >
c > b > d > h > g > e > f. The retention behavior of the
CSP toward the samples was not related with enantiomeric
recognition ability. Among the samples, Sample h showed
the strongest retention on Chiralcel OD-H and only gave
little separation. In ascending order, the retention factor
was f < e < d < c < b < a < g < h on Chiralcel OD-H
and f < e < d < c < b < a < h < g on Chiralcel OJ-H.
For the first and second group of samples, the retention
factors decreased with the increasing alkyl chain length
on both Chiralcel OD-H and OJ-H column. It was probably
due to the fact that chiral recognition involved a different
stability in transient diastereomeric complexes between
the enantiomers and the CSP, and a fit of the asymmetric
sample into a chiral groove of the CSP.17–22 Other potential
interactions, including p–p interactions, dipole–dipole in-
teractions and Van der Waals interactions, had significant
impact on retention and enantioselectivity.
TABLE 1. Effects of the concentration of n-hexane and
isopropanol on enantioseparation
Chiralcel OD-H
k10
Chiralcel OJ-H
k10
Rs
Mobile phase
Sample Hex/IPA (v/v)
a
Rs
a
a
b
c
d
e
f
70:30
80:20
90:10
70:30
80:20
90:10
70:30
80:20
90:10
70:30
80:20
90:10
70:30
80:20
90:10
70:30
80:20
90:10
70:30
80:20
90:10
70:30
80:20
90:10
0.67 2.75 6.13 0.40 1.28 0.69
1.14 2.63 6.40 0.76 1.34 1.29
3.12 2.26 6.83 2.09 1.45 2.44
0.58 3.60 7.31 0.30 1.31 0.47
1.04 3.24 8.22 0.58 1.38 1.10
2.72 2.78 8.28 1.60 1.48 2.15
0.53 3.61 6.97 0.26 1.34 0.35
0.97 3.23 7.83 0.50 1.43 1.10
2.51 2.73 7.64 1.38 1.55 2.17
0.45 2.47 3.64 0.20 1.00
–
0.82 2.23 4.20 0.37 1.34 0.51
1.97 2.03 4.87 1.00 1.41 1.34
0.27 4.29 4.54 0.06 1.00
0.49 3.59 5.77 0.14 1.00
–
–
1.05 3.07 6.72 0.37 1.25 0.10
0.21 4.72 4.09 0.03 1.00
0.39 3.78 4.97 0.05 1.00
0.90 3.23 6.36 0.17 1.00
0.70 1.61 2.65 0.79 1.00
1.34 1.57 3.35 1.66 1.00
–
–
–
–
–
g
h
At the same time, Chiralcel OD-H had carbamate group
whereas Chiralcel OJ-H had ester group. The carbonyl
and amino groups of the carbamate function were consid-
ered to be a sort of Lewis acid and base, respectively.
Introduction of an electron-withdrawing atom or group on
the phenyl group can enhance the acidity of the hydrogen
on the amino group, which can lead to a stronger hydro-
Chirality DOI 10.1002/chir
4.01 1.49 3.71 5.27 1.08 0.63
0.81 1.00
1.59 1.00
–
–
0.69 1.10 0.21
1.41 1.12 0.75
4.63 1.04 0.22 4.48 1.14 1.22
k0 is the retention factor; a is separation factor; Rs is resolution. Flow rate:
1.0 ml/min; absorbance wavelength: 220 nm.

102
ZHENG ET AL.
Fig. 1. Structures of the racemic samples. N-mexiletine vinyladipoyl ester (a), N-mexiletine vinylazeloyl ester (b), N-mexiletine vinylsebacoyl ester
(c), N-mexiletine acetyl ester (d), N-mexiletine octanoyl ester (e), N-mexiletine myristoyl ester (f), N-1-methyl-3-phenylpropylamine vinyladipoyl ester
(g) and N-1-phenylethylamine vinyladipoyl ester (h).
gen bonding interaction with Lewis basic parts of samples. lecular, the polarity decreased and the steric effects
The samples a, b, c, g and h had ester group, whereas increased, leading to decreased interactions and retention
the Samples d, e and f only had alkyl line connect with factor. It was also suggested that flexibility and steric
amide group. With the increase of CH2 group in the mo- adaptability may play an important role in the enantiosepa-
Fig. 2. Chromatograms of the chiral separation of Samples a–h on Chiralcel OD-H column using the mobile phase of n-hexane/isopropanol 90:10
(v/v); flow rate: 1.0 ml/min; absorbance wavelength: 220 nm.
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF MEXILETINE DERIVATIVES
103
Fig. 3. Curves of the chiral separation of Samples a–h on Chiralcel OJ-H column using the mobile phase of n-hexane/isopropanol 90:10 (v/v); flow
rate: 1.0 ml/min; absorbance wavelength: 220 nm.
ration. Thus, higher interaction did not mean better reso- some of the samples which were effectively resolved on
lution. The retention between Samples g and h and CSPs Chiralcel OJ-H were not resolved on Chiralcel OD-H. For
were stronger than other samples. However, the resolu- example, Sample h eluted from Chiralcel OD-H as a partial
tions were lower than others. Compared with Sample d, resolved wide peak, whereas it was baseline resolved on
Sample c contained two ester groups, which provided an Chiralcel OJ-H using the same mobile phase (Figs. 2h and
additional hydrogen bonding site, leading to stronger 3h). This may indicate that the configuration of this com-
interaction between Sample c and CSPs. Thus, the reten- pound was instable. Besides a methyl and a secondary
tion factor was higher.
amine group connecting with the chiral carbon of the Sam-
The retention times of the third group of samples in the ple h, there was a phenyl group, instead of a CH2 group
descending order on Chiralcel OD-H was a > g > h, and existed in other samples, which suggest that the phenyl
on Chiralcel OJ-H was a > h > g. None but Sample a was groups of the sample might play an important role in the
resolved on both columns. Samples g and h were only enantioseparation of Sample h on CSP of cellulose tris-3,5-
resolved on Chiralcel OD-H and OJ-H, respectively. It sug- dimethylphenylcarbamate.
gested that the selectivity can be changed by varying cel-
lulose derivatives CSP, as hydrogen bond was possible
CONCLUSIONS
both for the samples and for protic (proton-donating)
modifiers,23 which was not only in competition between
A series of novel derivatives of mexiletine and its ana-
samples and solvent for the CSP but also altered the steric
environment of the chiral grooves on the CSP by binding
to or close to the achiral sites at the groove.24 Although
Chiralcel OD-H allowed the resolution of more samples,
logs on enantioseparation by HPLC using Chiralcel OD-
H and OJ-H column were studied. Based on the set of
chromatographic data collected, the mechanism regard-
ing of enantioseparation and the structure of the sam-
Chirality DOI 10.1002/chir

104
ZHENG ET AL.
12. Wang N, Liu BK, Wu Q, Wang JL, Lin XF. Regioselective enzymatic
synthesis of non-steroidal anti-inflammatory drugs containing glucose
in organic media. Biotechnol Lett 2005;27:789–792.
ples were discussed. The methods have potential appli-
cations in the determination of mexiletine and its ana-
logs’ derivatives. Furthermore, it is important to study
the relation between the samples’ structure and CSP for
enantioseparation.
13. Tekewe A, Singh S, Singh M, Mohan U, Banerjee UC. Development
and validation of HPLC method for the resolution of drug intermedi-
ates: DL-3-phenyllactic acid, DL-O-acetyl-3-phenyllactic acid and (1/-)-
mexiletine acetamide enantiomers. Talanta 2008;75:239–245.
14. Zheng XM, Hu WX, Wang GH. Synthesis of cyanoacetamide via DCC
coupling. Chin J Appl Chem 2007;24:850–852.
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