A convenient synthesis of enantiomerically pure (R)-mexiletine using hydrolytic kinetic resolution method

Article abstract of DOI:10.1016/j.tetasy.2009.11.014

Enantiopure (R)-mexiletine was prepared in a simple and practical way using hydrolytic kinetic resolution method of terminal epoxide by Jacobsen's catalyst. High enantiomeric purity (98% ee) was achieved and the method is well amenable to industrial scale-up.

Full text of DOI:10.1016/j.tetasy.2009.11.014

Tetrahedron: Asymmetry 20 (2009) 2814–2817
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A convenient synthesis of enantiomerically pure (R)-mexiletine using
hydrolytic kinetic resolution method
Murugesan Sasikumar b, Milind D. Nikalje b, Murugan Muthukrishnan a,
*
a Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
b Department of Chemistry, University of Pune, Pune 411007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure (R)-mexiletine was prepared in a simple and practical way using hydrolytic kinetic resolu-
tion method of terminal epoxide by Jacobsen catalyst. High enantiomeric purity (98% ee) was achieved
and the method is well amenable to industrial scale-up.
Received 13 October 2009
Accepted 17 November 2009
Available online 6 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
molecules and natural products. As part of our ongoing program
aimed at improving the process for the preparation of various
Mexiletine is an important b-amino aryl ether class of drug used
in the treatment of arrhythmia, allodynia and myotonic syn-
dromes, etc and available in the market with the trade name Mex-
itil.1 Although it contains one stereogenic centre, it is generally
administered as a racemate. However, the (R)-isomer of mexiletine
is more potent than the (S)-isomer in experimental arrhythmias
and in binding studies on cardiac sodium channels.2 Moreover,
the use of mexiletine as a racemate in the treatment of neuromus-
cular disorders is limited due to its possible side effects.3 As a re-
sult, numerous reports describing the preparation of mexiletine
enantiomers and their analogues have been published.4–6 Gener-
ally, the methods include resolution of racemic intermediates,4
chemoenzymatic routes,5 or using stereospecific procedures.6
However, most of these methods have several drawbacks such as
tedious and time consuming experiments, unavailability or expen-
sive chiral starting materials, low yield and lower enantiomeric
purity, etc. Synthetic efforts now need to be directed at short, prac-
tical routes that are amenable to scale-up for drug preparation.
In this context, the success of the hydrolytic kinetic resolution
(HKR) technique developed by Jacobsen et al. using a chiral (salen)
Co complex catalyst has provided a powerful tool for the genera-
tion of enantioenriched terminal epoxides and vicinal diols in
excellent yields.7 The other salient features of this method include
extraordinarily high levels of selectivity, easy availability of race-
mic terminal epoxides, and the low loadings and easy recyclability
of the commercially available catalyst, which makes it extremely
simple to work with compared to other approaches.8 The synthetic
potential inherent in the efficiency and excellent enantioselectivity
of the HKR reaction inspired us and many others9 to explore this
versatile synthetic methodology for the preparation of many drug
pharmaceutically important compounds for industrial applica-
tions,10 we herein report a concise and simple synthesis of (R)-
mexiletine employing HKR as the key step (see Fig. 1).
NH2
N
O
N
O
O
Co
OAc
(R)-mexiletine 1
(R,R)-Salen Co (III) catalyst-A
Figure 1.
2. Results and discussion
A retrosynthetic analysis of (R)-mexiletine 1 is outlined in
Scheme 1. As shown in Scheme 1, we envisaged that (S)-epoxide
4 would be an ideal key intermediate for the synthesis of (R)-mex-
iletine, which can be easily obtained from its racemic epoxide 3
with high enantiopurity using Jacobsen’s HKR method. The key
intermediate 4 can be easily converted to the target molecule 1
by simple regioselective reductive ring opening and Mitsunobu
reaction protocols.
Accordingly, the substrate for HKR, the racemic epoxide 3, was
obtained from the alkylation of commercially available 2,6-di-
methyl phenol 2 with ( )-epichlorohydrin in anhydrous acetone
* Corresponding author. Tel.: +91 20 25902571; fax: +91 20 25902629.
E-mail address: m.muthukrishnan@ncl.res.in (M. Muthukrishnan).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.014

M. Sasikumar et al. / Tetrahedron: Asymmetry 20 (2009) 2814–2817
2815
OH
NH2
OH
O
O
O
O
(S)-6
(S)-4
2
(R)-mexiletine 1
Scheme 1. Retrosynthetic analysis of (R)-mexiletine.
OH
OH
O
O
O
HO
O
O
i
ii
+
(S)-4
(R)-5
2
3
OH
NH2
O
O
O
O
O
O
O
iv
iii
v
N
(S)-6
(R)-mexiletine 1
(S)-4
(R)-7
Scheme 2. Reagents and conditions: (i) ( )-epichlorohydrin, K2CO3, acetone, reflux, 20 h, 80%; (ii) (R,R) salen Co(III)-A, 0 °C–rt, 30 h; (iii) LiAlH4, THF, 0 °C, 30 min, 91%;
(iv) Ph3P, phthalimide, DIAD, THF, rt, 4 h, 83%; (v) N2H4ꢂH2O, EtOH, reflux, 3 h; 86%.
in the presence of potassium carbonate at reflux for 20 h in 80%
yield as a colorless oil (Scheme 2). The HKR of racemic epoxide 3
was performed with Jacobsen’s catalyst (R,R) salen Co(III)OAc
(0.5 mol %) and water (0.55 equiv) at ambient temperature for
30 h. After completion of the reaction, the reaction mixture was
chromatographed over a silica gel column to give the (S)-epoxide
of the catalyst and the use of water (0.55 equiv) as the medium and
reactant in the key step. Moreover, the Jacobsen catalyst can be
regenerated by treatment with acetic acid and recycled. We envis-
age that this simple protocol may be a viable alternative for the
large scale production of (R)-mexiletine in the pharmaceutical
industry.
4
½
from the racemic mixture in 43% yield and >99% ee,
a 2D5
ꢀ
¼ þ2:5 (c 2, CHCl3) and (R)-diol 5 in 47% yield ½a D25
¼ ꢁ3
ꢀ
4. Experimental
4.1. General
(c 2, CHCl3). Subsequently, the regioselective reductive ring open-
ing of (S)-epoxide 4 was carried out with lithium aluminium hy-
dride in anhydrous THF at 0 °C to provide secondary alcohol 6 in
91% yield. The regioselective reductive ring opening on the termi-
nal side of the epoxide 4 was ascertained by the appearance of a
sharp doublet at d 1.27 ppm (J = 6.0 Hz) in its 1H NMR spectrum
and d 18.5 ppm in its 13C NMR spectrum corresponding to the ter-
minal methyl group. The secondary alcohol 6 was readily trans-
formed into a phthalimido ether 7 by stereospecific substitution
of the hydroxyl group with phthalimide employing a typical Mits-
unobu procedure.1b Finally, a facile hydrazinolysis6d of phthalimi-
do ether 7 with hydrazine hydrate in ethanol afforded the crude
target molecule, which was further purified over silica gel column
Solvents were purified and dried by standard procedures prior
to use. IR spectra were obtained from Perkin–Elmer Spectrum
one spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on a Bruker AC-200 NMR spectrometer. Spectra were
obtained in CDCl3. Monitoring of reactions was carried out using
TLC plates Merck Silica Gel 60 F254 and visualization with UV light
(254 and 365 nm), I2 and anisaldehyde in ethanol as development
reagents. Optical rotations were measured with a JASCO P 1020
digital polarimeter. Mass spectra were recorded at an ionization
energy 70 eV on API Q Star Pulsar spectrometer using electrospray
ionization. Enantiomeric excess was determined by chiral HPLC.
to afford pure (R)-mexiletine
1 in 86% yield and 98% ee;
½
a 2D5
ꢀ
¼ ꢁ2:4 (c 5, CHCl3) {Lit.1b
½
a 2D5
ꢀ
¼ ꢁ2:7 (c 4.7, CHCl3)}. The
structure of (R)-mexiletine 1 was confirmed by its IR, 1H NMR,
13C NMR and mass spectroscopy analysis. The enantiomeric purity
of (R)-mexiletine 1 and the key intermediate 4 was determined by
chiral HPLC analysis.
4.2. 2-((2,6-Dimethylphenoxy)methyl)oxirane (racemic) 3
To a stirred solution of 2,6-dimethylphenol 2 (6 g, 50 mmol)
and K2CO3 (17 g, 125 mmol) in dry acetone (50 mL) was added
( )-epichlorohydrin (7 g, 75 mmol) and the reaction mixture was
refluxed until all of the 2,6-dimethylphenol had been consumed
(20 h, TLC). The reaction mixture was filtered, and the solvent
was removed under reduced pressure, after which the residue
was purified by column chromatography (silica gel, petroleum
3. Conclusion
In conclusion, a practical and highly enantioselective synthesis
of (R)-mexiletine 1 has been achieved using Jacobsen’s HKR meth-
od as the key step and source of chirality. The main advantages of
this method were the high enantioselectivity, the ready availability
ether/acetone, 97:3) to yield 3 as a colorless oil (7.1 g, 80%); IR
l
(Neat):
c
3019, 2925, 1477, 1264, 1216, 1092, 1021, 832, 756. H

2816
M. Sasikumar et al. / Tetrahedron: Asymmetry 20 (2009) 2814–2817
NMR (200 MHz, CDCl3): d 2.30 (s, 6H, 2CH3), 2.70–2.74 (dd, J = 6.0,
2.0 Hz, 1H, OCH2), 2.88–2.92 (apparent t, J = 4.0 Hz, 1H, OCH2),
3.33–3.41 (m, 1H, OCH), 3.75 (dd, J = 10.0, 6.0 Hz, 1H, OCH2),
4.01–4.08 (dd, J = 11.0, 4.0 Hz, 1H, OCH2), 6.89–7.03 (m, 3H, Harom);
l3C NMR (CDCl3): d 155.5 (C), 130.8 (C, 2 carbons), 128.8 (CH, 2 car-
bons), 124.0 (CH), 72.9 (CH2), 50.5 (CH), 44.5 (CH2), 16.2 (CH3, 2
carbons); MS: m/z 201 [M+Na]+; HRMS calcd for C11H14O2:
178.0993. Found: 178.1002.
oil (1.13 g, 83%); ½a D25
ꢀ
¼ ꢁ59 (c 2.4, CHCl3) {Lit.1b
½
a 2D5
ꢀ
¼ ꢁ55 (c 2.2,
CHCl3)} IR (Neat):
c 3053, 2925, 2985, 2254, 1774, 1711, 1469,
l
1265, 1209, 1092, 909, 829. H NMR (200 MHz, CDCl3): d 1.56 (d,
J = 8.0 Hz, 3H, CH3), 2.20 (s, 6H, 2CH3-Ar), 3.91 (dd, J = 8.0, 6.0 Hz,
1H, OCH2), 4.38 (apparent t, J = 10.0 Hz, 1H, OCH2), 4.79–4.97 (m,
1H, CH), 6.84–6.98 (m, 3H, Harom), 7.71–7.75 (m, 2H, Harom),
7.85–7.89 (m, 2H, Harom); l3C NMR (CDCl3): d 168.5 (CO, 2 carbons),
155.1 (C), 133.9 (CH, 2 carbons), 131.9 (C, 2 carbons), 130.7 (C, 2
carbons), 128.7 (CH, 2 carbons), 123.9 (CH, 2 carbons), 123.1
(CH), 71.5 (CH2), 47.1(CH), 16.2 (CH3, 2 carbons), 15.1 (CH3).
4.3. (S)-2-(2,6-Dimethylphenoxymethyl)oxirane 4
A mixture of 2-(2,6-dimethyl-phenoxymethyl)oxirane 3 (5 g,
28 mmol) and (R,R) salen Co(III)OAc complex-A (0.046 g,
0.07 mmol) were vigorously stirred for 15 min, then cooled to
0 °C, and water added (0.3 mL, 15 mmol) over a period of 15 min,
through a micro-syringe. The reaction mixture was stirred at room
temperature for 20 h, and additional (R,R) salen Co(III)OAc com-
plex-A (0.046 g, 0.07 mmol) was added, and stirring was continued
for additional 10 h. The reaction mixture was diluted with ethyl
acetate, dried over Na2SO4, and evaporated under reduced pres-
sure. The residue was purified by column chromatography (silica
gel, petroleum ether/acetone (97:3). The less polar epoxide 4
4.6. (R)-Mexiletine 1
To a stirred solution of 7 (0.92 g, 3 mmol) in ethanol (20 mL)
was added hydrazine hydrate (80%) solution (1.4 mL, 24 mmol)
and the resulting mixture was refluxed for 3 h. The precipitated so-
lid was filtered off, and the solvent was removed under reduced
pressure. The residue was dissolved in ether and extracted with
2 N HCl, and the aqueous phase was treated with 2 M NaOH until
pH >12. The aqueous phase was extracted with ether (3 ꢃ 20
mL), and the combined organic phases were dried over Na2SO4
and evaporated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3)
eluted first as a colorless oil (2.15 g, 43%); ½a D25
¼ þ2:5 (c 2, CHCl3);
ꢀ
ee >99% [chiral HPLC analysis; DAICEL CHIRALCEL OD-H (250 ꢃ 4.6
mm) column; eluent: hexane/ethanol = 99.9/0.1; flow rate: 0.5 mL/
min; detector: 254 nm [(R)-isomer tR = 30.17 min; (S)-isomer
tR = 33.22 min], followed by diol 5 as a pale brown semi solid
to afford (R)-mexiletine
1
as
a
colorless oil (0.46 g, 86%);
½
a 2D5
(Neat):
ꢀ
¼ ꢁ2:4 (c 5, CHCl3) {Lit.1b
½ ꢀ ¼ ꢁ2:7 (c 4.7, CHCl3)}; IR
a 2D5
c 3019, 2400, 1667, 1476,, 1263, 1215, 1092, 1028, 928,
853. lH NMR (200 MHz, CDCl3): d 1.17 (d, J = 6.0 Hz, 3H, CH3),
1.82 (br s, 2H, NH2), 2.29 (s, 6H, 2CH3-Ar), 3.32–3.42 (m, 1H, CH),
3.50–3.58 (apparent t, J = 10.0 Hz, 1H, OCH2), 3.63–3.70 (dd,
J = 10.0, 4.0 Hz, 1H, OCH2), 6.89–7.03 (m, 3H, Harom); l3C NMR
(CDCl3): d 155.3 (C), 130.7 (C, 2 carbons), 128.8 (CH, 2 carbons),
123.8 (CH), 77.9 (CH2), 47.2 (CH), 19.8 (CH3), 16.2 (CH3, 2 carbons);
MS: m/z 180 [M+1]+; ee >98% [The ee of 1 was determined by chiral
HPLC analysis of the corresponding N-acetyl derivative;1b DAICEL
CHIRALCEL OD (250 ꢃ 4.6 mm) column; eluent: pet. ether/isopro-
panol = 90/10; flow rate: 0.6 mL/min; detector: 254 nm [(R)-iso-
mer tR = 16.35 min; (S)-isomer tR = 23.07 min].
(2.5 g, 47%); ½a 2D5
ꢀ
¼ ꢁ3 (c 2, CHCl3); IR (Neat):
c 3361, 2924,
1592, 1477, 1377, 1264, 1203, 1023, 931, 768; NMR (200 MHz,
CDCl3): d 1.74 (br s, 1H, OH), 2.30 (s, 6H, 2CH3), 2.92 (br s, 1H,
OH), 3.77–3.93 (m, 4H, 2OCH2), 4.07–4.14 (m, 1H, CH), 6.91–7.04
(m, 3H, Harom); l3C NMR (CDCl3): d 154.9 (C), 130.6 (C, 2 carbons),
128.9 (CH, 2 carbons), 124.1 (CH), 72.9 (CH2), 71.2 (CH), 63.8
(CH2), 16.1(CH3, 2 carbons); MS: m/z 219 [M+Na]+; HRMS calcd
for C11H16O3: 196.1099. Found: 196.1056.]
4.4. (S)-1-(2,6-Dimethylphenoxy) propan-2-ol 6
To a solution of epoxide 4 (1.0 g, 5.6 mmol) in dry THF (10 mL)
at 0 °C was added slowly a pre-cooled solution of Lithium alumi-
num hydride (0.25 g, 6.7 mmol) in THF (5 mL) with stirring under
nitrogen. After 30 min, the reaction mixture was quenched with
1 mL of water and 1 mL of 15% NaOH solution and the content stir-
red for 15 min. The inorganic precipitate was filtered, washed with
ethyl acetate and the solvent evaporated under reduced pressure.
The residue was purified by a short filtration column to yield 6
Acknowledgements
M.M.K. is thankful to DST, New Delhi for the financial support
(Grant SR/FTP/CS-25/2007). The authors thank Mrs. S. S. Kunte
for chiral HPLC analysis.
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as a colorless oil (0.91 g, 91%); ½a D25
ꢀ
¼ ꢁ1:3 (c 5, CHCl3) {Lit.1b
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