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-
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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,
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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.
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[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,