Preparation of highly enantiopure stereoisomers of 1-(2,6-dimethylphenoxy)-2-aminopropane (mexiletine)

Article abstract of DOI:10.1016/S0957-4166(99)00311-0

Mexiletine [1-(2,6-dimethylphenoxy)-2-aminopropane], an orally effective antiarrhythmic agent, exhibits enantioselective pharmacokinetics and pharmacodynamics during mexiletine therapy. The purpose of this paper is to emphasize the advantage of tetrahydropyranyl-protected mandelic acid (THPMA) in the resolution of mexiletine enantiomers. Both enantiomers of mexiletine were obtained in 99% enantiomeric excess. Judging by the differential shielding effects in the ¹H and ¹³C NMR analyses, we have observed the opposite predominant conformation for the mexiletine mandelates in comparison with the O-methylmandelates.

Full text of DOI:10.1016/S0957-4166(99)00311-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3033–3038
Preparation of highly enantiopure stereoisomers of
1-(2,6-dimethylphenoxy)-2-aminopropane (mexiletine)
Riina Aav,a Omar Parve,a Tõnis Pehk,b Alf Claesson c and Ivar Martin a,∗
aInstitute of Chemistry, Tallinn Technical University, Akadeemia tee 15, Tallinn 12618, Estonia
bNational Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia
cAstra Pain Control AB, Preclinical R&D, S-14157, Huddinge, Sweden
Received 12 July 1999; accepted 27 July 1999
Abstract
Mexiletine [1-(2,6-dimethylphenoxy)-2-aminopropane], an orally effective antiarrhythmic agent, exhibits enan-
tioselective pharmacokinetics and pharmacodynamics during mexiletine therapy. The purpose of this paper is to
emphasize the advantage of tetrahydropyranyl-protected mandelic acid (THPMA) in the resolution of mexiletine
enantiomers. Both enantiomers of mexiletine were obtained in 99% enantiomeric excess. Judging by the differential
shielding effects in the 1H and 13C NMR analyses, we have observed the opposite predominant conformation for
the mexiletine mandelates in comparison with the O-methylmandelates. © 1999 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Mexiletine 1 (Fig. 1), is an orally effective antiarrhythmic agent and is available for clinical use as the
racemic mixture. It has been reported previously that mexiletine undergoes stereoselective disposition1 in
humans being associated with the selective binding of the (R)-(−)-mexiletine to a cardiac sodium channel2
and the higher antiarrhythmic activity3 of this enantiomer. Despite the extensive pharmacological4
and analytical5 studies over recent years, the mechanism of stereoselection in pharmacokinetics and
pharmacodynamics for the individual enantiomers of mexiletine remains unclear. Consequently, there is
a need for a multi-gram scale method for the preparation of both enantiomers of mexiletine in a high
enantiomeric purity.
An elegant method has been shown to convert both commercially available enantiomers of the
2-amino-1-propanol into the target mexiletines via nucleophilic substitution of the 1,3-dimethyl-2-
fluorobenzenetricarbonylchromium complex.6 Also a method based on the relatively expensive chiral
∗
Corresponding author. E-mail: ivarm@boc.ic.ee
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00311-0

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R. Aav et al. / Tetrahedron: Asymmetry 10 (1999) 3033–3038
Figure 1. Chemical structure of 1-(2,6-dimethylphenoxy)-2-aminopropane (mexiletine) 1
starting material, (S)-(+)-3-bromo-2-methyl-1-propanol, has been reported to allow the synthesis of
(R)-(−)-mexiletine.7 The resolution of mexiletine enantiomers from the racemic mixture by fractional
crystallisation of p-toluoyl tartrate salts has been reported previously.3 The process described needs large
volumes of solvent and is time consuming which is the drawback of this method.
Recently, we have reported the application of tetrahydropyranyl-protected mandelic acid (THPMA) as
a chiral derivatising agent for the absolute configurational assignment and semipreparative enantiomeric
resolution of secondary alcohols.8 Herein we wish to report the advantage of THPMA in the resolution
of mexiletine enantiomers by the separation of their mandelic acid amides, which were synthesised by
using THPMA. The unexpected results of the 1H and 13C NMR analyses of the mexiletine diastereomeric
amides are also presented and discussed.
2. Results and discussion
The racemic mixture of mexiletine 1 was synthesised by the coupling of sodium 2,6-dimethyl-
phenoxide with propylene oxide followed by azide synthesis with an overall yield of 64%. The chiral
derivatising agent, tetrahydropyranyl-protected (R)-(−)-mandelic acid (THPMA), was prepared accor-
ding to the reported procedure.8 A diastereomeric mixture of the amides 4 and 5 (Scheme 1) was
obtained by acylation of racemic mexiletine 1 with THPMA and subsequent hydrolytic cleavage of the
tetrahydropyranyl (THP) protecting group. The better chromatographic separability of the deprotected
amides 4 and 5 compared to the THP-protected ones 2 and 3 was observed by TLC. Thus, the chro-
matographic separation of 4 and 5 was accomplished by means of flash chromatography using silica
gel 60 (240–400 mesh, Merck) and benzene:ethyl acetate (85:15).9 As a result, (2R,20R)-amide 4 (less
polar) and (2R,20S)-amide 5 (more polar) were obtained with diastereomeric purities greater than 98%
for both according to HPLC analyses of the products. The amides 4 and 5 were further subjected to
hydrolysis with the mixture of 8N H2SO4:dioxane (1:1) at 80°C thus giving rise to crude amines 6 and
7, and offering a method to recover (R)-mandelic acid after workup procedures. Recrystallisation of
the hydrochloric acid salts of the enantiomerically pure (R)-mexiletine 6 and (S)-mexiletine 7 from the
5 M methanolic HCl:diethyl ether (1:7) afforded nicely crystalline products. The enantiomeric purity
for both mexiletine enantiomers was determined to be at least 99% ee by using HPLC analysis of the
1
corresponding methoxy(trifluoromethyl)phenylacetyl (MTPA) derivatives in combination with H and
13C NMR experiments.
The application of MTPA and the related O-methylmandelate technique to the configurational analysis
of chiral primary amines has been reported.10,11 For the MTPA amides, the predominant conformation
has been established to be analogous to that of esters of secondary alcohols: the methine hydrogen,
the carbonyl oxygen, and the trifluoromethyl groups are coplanar and syn.10 The differential shielding
effects (∆δ values) obtained from the NMR analyses of the MTPA amides 8 and 9 (Table 1) are in good
agreement with the previous findings. On the other hand, the conformations of O-methylmandelamides
are known not to be analogous to those of the O-methylmandelate esters. The major conformation of O-
methylmandelamides was deduced to have the methoxy group anti-periplanar to the carbonyl.11 Some-
what unexpectedly, judging from the 1H and 13C NMR analyses, we have observed the opposite dominant

R. Aav et al. / Tetrahedron: Asymmetry 10 (1999) 3033–3038
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Scheme 1. Preparation of enantiomerically pure mexiletine enantiomers 6 and 7. (a) DCC, THPMA, EtOAc; (b) HCl,
H2O/MeOH; (c) H2SO4, H2O/dioxane
conformation for the mexiletine mandelates 4 and 5 in comparison with the O-methylmandelates 10 and
11 (Table 1). Thus, mandelic acid amides of mexiletine as well as mandelic acid esters of secondary
alcohols behave according to the same conformational model in which the hydroxyl group is syn-coplanar
to the carbonyl.
3. Experimental
3.1. General
All solvents were reagent grade and were distilled before use. Ethyl acetate was dried over CaCl2
and freshly distilled before use. Proton magnetic resonance spectra (1H NMR) and carbon magnetic
resonance spectra (13C NMR) were recorded on a Bruker AMX-500 spectrometer operating at 500.13
MHz and 125.76 MHz, respectively. Chemical shifts are in parts per million (ppm) relative to the solvent
as the internal reference. Optical rotations (in degrees) were measured with a Carl Zeiss Polamat A
polarimeter at 546 nm. Melting points were determined on a Boetius melting point apparatus, and are
uncorrected. Elemental analyses were performed on a Perkin–Elmer 2400 Series II CHNS/O analyser.
3.2. (2RS)-1-(2,6-Dimethylphenoxy)-2-aminopropane (mexiletine) 1
To a solution of propylene oxide (9.41 g, 0.162 mol) in 65 mL ethanol was added dropwise a mixture
of 2,6-dimethylphenol (10.0 g, 0.081 mol) and sodium hydroxide (3.47 g, 0.085 mol) in 34 mL of water.
The reaction mixture was cooled down to room temperature after stirring for 6 h at 60°C followed by the
addition of water (150 mL). The mixture was extracted with 3×100 mL of chloroform. The combined
organic layers were washed with 100 mL of 1% NaOH, 3×75 mL of water and dried over Na2SO4.
Evaporation of solvents left 13.47 g (91% yield) of 1-(2,6-dimethylphenoxy)-2-propanol, which was
dissolved in 110 mL of pyridine. To this solution, methanesulphonyl chloride (16.6 g, 0.145 mol) was
added under an Ar atmosphere at 0°C. After stirring the mixture at room temperature for 4 h, it was
poured on ice-water and extracted with chloroform (3×100 mL). The combined organic extracts were
washed with water (3×100 mL), dried over Na2SO4 and concentrated to give 18.1 g (98% yield) of
mesylate. To a mixture of this mesylate in DMF (230 mL), sodium azide (24.6 g, 0.375 mol) was added

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R. Aav et al. / Tetrahedron: Asymmetry 10 (1999) 3033–3038
Table 1
1H and 13C NMR differential shielding effects and the dominant conformations for mexiletine
mandelates 4–5, O-methyl(trifluoromethyl)mandelates 8–9 and O-methylmandelates 10–11
under an Ar atmosphere. The mixture was stirred for 2.5 h at 100°C. Dilution of the reaction mixture in
500 mL water was followed by extraction with 3×150 mL of chloroform. The combined organic phases
were washed with water (3×300 mL), dried over MgSO4 and concentrated to give 12.02 g (84% yield) of
azide which was dissolved in 220 mL of methanol. To this solution, a suspension of Raney nickel (1.17
g) was added. Hydrogenation (1 atm H2) was carried out at room temperature for 5 h. The catalyst was
removed by filtration and the methanol was evaporated under reduced pressure. The residue was taken
up in 250 mL of chloroform and washed with 3×100 mL of aq. Na2CO3. The organic layer was dried
over Na2SO4, solvents were removed under reduced pressure and the racemic mexiletine 1 (8.68 g, 86%
yield) was obtained as an oil. The product obtained was identical in all respects to that described in the
literature.12
3.3. (2RS)-N-(1-(20,60-Dimethylphenoxy)-2-propyl)-tetrahydropyranyl-(R)-mandelamide 2 and 3
To a solution of (2R)-2-phenyl-2-(tetrahydro-2-pyranyloxy)acetic acid (THPMA) (12.33 g, 0.052 mol)
in dry ethyl acetate (180 mL) under an Ar atmosphere, a solution of dicyclohexylcarbodiimide (DCC)
(11.34 g, 0.055 mol) in 90 mL of dry ethyl acetate was added at 0°C. The mixture was allowed to stir
for 2 h at room temperature, then the solution of (ꢀ)-mexiletine 1 (9.85 g, 0.055 mol) in 90 mL of dry
ethyl acetate was added. The reaction mixture was stirred at room temperature for 18 h, filtered, washed
with 2×150 mL of water, 150 mL of brine and dried over Na2SO4. Removal of solvents under reduced

R. Aav et al. / Tetrahedron: Asymmetry 10 (1999) 3033–3038
3037
pressure afforded 20.15 g (97% yield) of a diastereomeric mixture of amides 2 and 3. The crude complex
mixture of four diastereomers was used in the next step without further purification.
3.4. (2R)-N-(1-(20,60-Dimethylphenoxy)-2-propyl)-(R)-mandelamide 4 and (2S)-N-(1-(20,60-dimethyl-
phenoxy)-2-propyl)-(R)-mandelamide 5
To a solution of the mixture of amides 2 and 3 (20.15 g, 50.6 mmol) in 400 mL of methanol:water
(4:1), conc. HCl (4.3 mL) was added at room temperature and stirred overnight. The reaction mixture
was neutralised with NaHCO3. Methanol was removed under reduced pressure, 250 mL of water was
added and the products were extracted with 3×100 mL of ethyl acetate. The combined extracts were
washed with 150 mL of water and 150 mL of brine and dried over Na2SO4. Removal of the solvents
gave 13.48 g (85% yield) of an oily mixture of two diastereomers 4 and 5. The chromatographic
separation was accomplished by means of flash chromatography using silica gel 60 (240–400 mesh,
Merck) and benzene:ethyl acetate (85:15) as an eluent.9 As a result, 2.94 g of less polar (2R)-N-
(1-(20,60-dimethylphenoxy)-2-propyl)-(R)-mandelamide 4 and 3.19 g of more polar (2S)-N-(1-(20,60-
20
1
dimethylphenoxy)-2-propyl)-(R)-mandelamide 5 were obtained. 4: [α]
−7.8 (c=1.66, MeOH); H
546
NMR (CDCl3, 500.13 MHz): δ 1.41 (d, J=6.5 Hz, 3H, CH3); 2.09 (s, 6H, aryl-CH3); 3.67 (dd, J=9.0 Hz,
10.7 Hz, 1H, O-CHa); 3.69 (dd, J=4.0 Hz, 10.7 Hz, 1H, O-CHb); 4.28–4.38 (m, 1H, N-CH); 5.09 (s, 1H,
O-CH); 6.70 (s, 1H, NH); 6.92 (t, J=7.5 Hz, 1H, p-O-aryl-H); 6.97 (d, J=7.5 Hz, 2H, m-O-aryl-H); 7.35
(m, 2H, m-C-aryl-H); 7.37 (t, J=7.2 Hz, 1H, p-C-aryl-H); 7.42 (d, J=7.8 Hz, 2H, o-C-aryl-H). 13C NMR
(CDCl3, 125.76 MHz): δ 15.9, 17.7, 45.6, 73.5, 74.1, 124.1, 126.8, 128.6, 128.8, 128.9, 130.7, 139.5,
154.6, 171.5. Elemental analysis for C19H23NO3: calcd C, 72.82; H, 7.40; N, 4.47; found C, 73.06; H,
20
1
7.40; N, 4.41. 5: [α]
−132.5 (c=1.28, MeOH); H NMR (CDCl3, 500 MHz): δ 1.38 (d, J=6.4 Hz,
546
3H, CH3); 2.22 (s, 6H, aryl-CH3); 3.69 (dd, J=8.8 Hz, 10.7 Hz, 1H, O-CHa); 3.73 (dd, J=4.2 Hz, 10.7
Hz, 1H, O-CHb); 4.26–4.36 (m, 1H, N-CH); 5.05 (s, 1H, O-CH); 6.78 (s, 1H, NH); 6.94 (t, J=7.5 Hz,
1H, p-O-aryl-H); 6.99 (d, J=7.5 Hz, 2H, m-O-aryl-H); 7.34 (m, 2H, m-C-aryl-H); 7.36 (t, J=7.2 Hz, 1H,
p-C-aryl-H); 7.42 (d, J=7.8 Hz, 2H, o-C-aryl-H). 13C NMR (CDCl3, 125 MHz): δ 16.1, 17.5, 45.6, 73.7,
74.2, 124.1, 126.7, 128.6, 128.8, 129.0, 130.7, 139.4, 154.7, 171.5. Elemental analysis for C19H23NO3:
calcd C, 72.82; H, 7.40; N, 4.47; found C, 72.91; H, 7.40; N, 4.45.
3.5. (2R)-1-(20,60-Dimethylphenoxy)-2-aminopropane hydrochloride
To a solution of 2.94 g (9.39 mmol) of (2R)-N-(1-(20,60-dimethylphenoxy)-2-propyl)-(R)-
mandelamide 4 in 94 mL dioxane, 75 mL of 4 M H2SO4 was added. The reaction mixture was
stirred for 72 h at 80°C, then it was neutralised by the aqueous NaOH and alkalised by Na2CO3. The
aqueous mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed
with aqueous Na2CO3 and dried over Na2SO4. Evaporation of solvents left 1.48 g (88% yield) of
(R)-(−)-mexiletine, which was dissolved in 35 mL of diethyl ether. To this solution, 4.8 mL of 20%
HCl in methanol was added. The precipitate of hydrochloride was formed immediately. The crystals
were taken up in methanol and recrystallised from methanol/diethyl ether to give 1.41 g (6.54 mmol,
70% yield) of the title compound as a white solid, mp 201–203°C. The enantiomeric purity of this
material was determined to be 99% ee by using HPLC analysis of the corresponding MTPA derivative.
20
1
[α]
−2.98 (c=1.51, MeOH); H NMR (CD3OD, 500.13 MHz): δ 1.52 (d, J=6.8 Hz, 3H); 2.35 (s,
546
6H); 3.76–3.84 (m, 1H); 3.91 (dd, J=6.57 Hz, 10.1 Hz, 1H); 3.96 (dd, J=3.95 Hz, 10.1 Hz, 1H); 6.98 (t,
J=7.55 Hz, 1H); 7.07 (d, J=7.55 Hz, 2H). 13C NMR (CD3OD, 125.76 MHz): δ 15.8, 16.8, 49.6, 73.1,

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R. Aav et al. / Tetrahedron: Asymmetry 10 (1999) 3033–3038
126.0, 130.4, 132.1, 156.1. Elemental analysis for C11H18NClO: calcd C, 61.25; H, 8.41; N, 6.49; found
C, 61.48; H, 8.34; N, 6.45.
3.6. (2S)-1-(20,60-Dimethylphenoxy)-2-aminopropane hydrochloride
The procedure described above, applied to 3.19 g (10.2 mmol) of (2S)-N-(1-(20,60-dimethylphenoxy)-
2-propyl)-(R)-mandelamide 5, provided 1.2 g (5.56 mmol, 54.5% yield) of the title compound as a white
solid, mp 201–203°C. The enantiomeric purity of this material was determined to be 99% ee by using
HPLC analysis of the corresponding MTPA derivative. [α]25406 +3.1 (c=1.47, MeOH). Elemental analysis
for C11H18NClO: calcd C, 61.25; H, 8.41; N, 6.49; found C, 61.73; H, 8.62; N, 6.56.
Acknowledgements
The authors wish to thank the Estonian Science Foundation for financial support (Grant Nos. 2151,
2858 and 3834).
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