Synthesis and biologic activity of aryloxyaminopropanoles based on substituted p-tolylalkylamines

Article abstract of DOI:10.1134/S1070428016020081

Reaction of 2,2-dimethyl-2-(p-tolyl)ethyl-, 1-p-tolylcyclopenthylmethyl- and 4-(p-tolyl)tetrahydro-2H-pyran-4-ylmethylamines with phenoxymethyloxiranes substituted in the aromatic ring afforded new aryloxypropanolamines, some of which show moderate adrenoblocking activity.

Full text of DOI:10.1134/S1070428016020081

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 2, pp. 209–213. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © А.А. Аghekyan, G.G. Мkryan, A.S. Tsatinyan, О.S. Noravyan, G.V. Gasparyan, 2016, published in Zhurnal Organicheskoi Khimii,
2016, Vol. 52, No. 2, pp. 226–230.
Synthesis and Biologic Activity of Aryloxyaminopropanoles
Based on Substituted p-Tolylalkylamines
А. А. Аghekyan, G. G. Мkryan, A. S. Tsatinyan, О. S. Noravyan, and G. V. Gasparyan
R&D Center of Organic and Pharmaceutical Chemistry of the National Academy of Sciences of Armenia,
Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
е-mail: aaghekyan@mail.ru
Received September 23, 2015
Abstract—Reaction of 2,2-dimethyl-2-(p-tolyl)ethyl-, 1-p-tolylcyclopenthylmethyl- and 4-(p-tolyl)tetrahydro-
2Н-pyran-4-ylmethylamines with phenoxymethyloxiranes substituted in the aromatic ring afforded new
aryloxypropanolamines, some of which show moderate adrenoblocking activity.
DOI: 10.1134/S1070428016020081
Compounds containing aminopropanol fragment
possess high biologic activity and are widely used in
medicine for treating cardiovascular and eye diseases,
and also various drug hangover syndromes [1]. They
also participate in metabolism of unsaturated
carcinogenes [2], possess antihyperglycemic [3] and
fungicidal activity [4] and also are inhibitors of HIV-
protease [5]. Hence the interest to the synthesis of
compounds containing aminopropanol fragment
remains in the focus of scientific investigations.
investigations and aiming at the search for new
bioactive compounds we describe in the present study
the synthesis of aryloxypropanolamines with various
substituents either in benzene ring or in amine
component. The latter are various substituted aryl-
alkylamines: 2,2-dimethyl-2-p-tolylethyl-, 1-p-tolyl-
cyclopenthylmethyl-, and 4-tetrahydro-2Н-pyran-4-
ylmethylamines.
As initial reactants we used nitriles of 2,2-dimethyl-
2-(p-tolyl)acetic, 1-(p-tolyl)-cyclopentane-, and 4-(p-
tolyl)tetrahydro-2Н-pyrancarboxylic acids 1a–1c. A
method was described of preparation of nitrile 1a by
reaction of p-tolylacetonitrile with methyl iodide in
tetrahydrofuran applying sodium hydride [7]. By
Previously we described synthesis of amino-
propanols containing phenylcyclopentane fragment
that possessed pronounced sympatholytic and
antiarrhythmic activity [6]. In extension of these
R
R
R
R
CN
RHlg
LiAlH4
CN
NH2
Me
Me
Me
2a_2c
1a_1c
R
R
O
R'
1.
2.
O
HA
HN
.
O
R'
Me
OH
3a_3o
HA
1, 2, R = Me (a); R,R = (CH2)4 (b), (CH2)2O(CH2)2 (c); 3, A = HOOCCOO: R = Me, R' = H (a), Me (b), MeО (c), Cl (d),
F (e); R,R = (СН2)4, R' = H (f), Me (g), MeО (h), Cl (i), F (j); A = Cl: R,R = (CH2)2O(CH2)2, R' = H (k), Me (l), MeО (m),
Cl (n), F (o).
209

АGHEKYAN et al.
210
condensation of this acetonitrile with dibromobutane
using sodium amide nitrile 1b was obtained that was
then reduced in methanol in the presence of Raney
nickel catalyst to amine 2a [8]. We prepared nitriles
1а–1c in 65–70% yields by condensation of p-
tolylacetonitrile with methyl iodide, 4-dibromobutane
or 2,2-dichlorodiethyl ether respectively in DMF in the
presence of sodium hydroxide.
derivative 4 depending on concentration suppresses the
activity of monoaminooxidaze to 50–73%.
EXPERIMENTAL
IR spectra were recorded on a spectrometer Nicolet
1
Avatar 330 FT-IR from mulls in mineral oil. Н NMR
spectra were registered on a spectrometer Varian
Mercury-300 in DMSO-d6, working frequency 300
МHz, internal reference TMS. Melting points were
determined on Boёtius heating microblock. TLC was
performed on Silufol UV-254 plates, eluent for salts 1-
butanol–acetic acid–water, 10 : 5 : 3, development in
iodine vapor.
Reduction of nitriles 1a–1c was performed with
lithium aluminum hydride, the corresponding amines
2a–2c were obtained in high yields. The reaction of the
latter with various substituted oxiranes obtained from
the corresponding phenols and epichlorohydrin [9]
resulted in aryloxyaminopropanols isolated as salts
(hydrochlorides or oxalates) 3а–3о. As known, some
drugs containing aminopropanol fragment (atenolol,
for example), may be transformed into oxazolidine
derivatives, whose biologic activity is not described,
only physicochemical constants of obtained
compounds [10] are published. Therefore with the goal
of further investigation of biological properties by one
example we carried out the cyclization with
formaldehyde that resulted in oxazolidine 4.
Nitriles 1a–1c. General method. To solution of
19.6 g (0.1 mol) of 4-methylbenzyl cyanide in 100 mL of
anhydrous DMF under stirring was added 8 g (0.3 mol)
of NaOH powder, after 30 min 0.1 mol of dihaloalkane
(dibromobutane or dichlorodiethyl ether) was added at
a rate maintaining the reaction temperature no higher than
70–75°C (at the preparation of compound 1а 0.3 mol
of MeI was added and the temperature of the mixture
was maintained no higher than 40°C), and the mixture
was stirred at this temperature for 4 h. After cooling
the mixture was diluted with 100 mL of benzene and
200 mL of water, the organic layer was separated, the
aqueous layer was twice extracted with benzene. The
combined benzene extracts were washed with water,
dried with MgSO4, the solvent was distilled off, the
residue was distilled in a vacuum.
O
CH2O
3k
N
OPh
Me
O
4
Nitrile of 2-methyl-2-(4-methylphenyl)propionic
acid (1а). Yield 65%, bp 103–105°C (6 mmHg), {bp 88–
91°C (4 mmHg) [7]}, Rf 0.54 (benzene–ether, 10 : 1).
The structure and the purity of obtained compounds
were confirmed by physicochemical methods and by
TLC.
Nitrile of 1-(4-methylphenyl)cyclopentanecarbo-
xylic acid (1b). Yield 68%, bp 148–152°C (7 mmHg)
{bp 158–160°C (12 mmHg) [8]}, mp 89–90°C, Rf 0.52
(benzene–ether, 10 : 1).
The effect of salts of synthesized compounds on
cardio-vascular system was investigated by method
[11], for comparison bethanidine and propranolol were
used. The investigated compounds provoke the
blockade of sympathetic nerves responding to the
nerve impulse and show a long and strong sympa-
tholytic effect for 10 min (86–92%) and for 60 min
(63–85%). The compounds also show moderate adre-
nolytic activity, only compound 3j shows a significant
and long adrenolytic effect (76–80%), and in
compound 3f the adrenolytic effect changes for
adrenomimetic (78%). Compounds 3a, 3e, 3h, 3i, and
3k in doses of 0.05 mg/kg and 5 mg/kg show moderate
β1- and β2-adrenoblocking activity. Oxazolidine
Nitrile of 4-(4-methylphenyl)tetrahydro-2Н-py-
ran-4-carboxylic acid (1c). Yield 70%, bp 155–159°C
(3 mmHg), mp 63–64°C, Rf 0.51 (benzene–ether, 10 : 1).
1
IR spectrum, ν, cm–1: 2220 (CN), 1608 (Ar). Н NMR
spectrum, δ, ppm: 1.96–2.15 m (4Н, 2ССН2), 2.36 s
(3Н, СН3), 3.72–3.82 m (2Н, ОСН2), 3.97–4.04 m (2Н,
ОСН2), 7.17–7.22 m (2Нarom), 7.33–7.38 m (2Нarom).
Amines (2a–2c). General method. To suspension
of 0.1 mol of LiAlH4 in 100 mL of anhydrous ether
0.05 mol of nitrile 1а–1c in 50 mL of benzene was added
and the mixture was boiled for 12 h. Then 100 mL of
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SYNTHESIS AND BIOLOGIC ACTIVITY OF ARYLOXYAMINOPROPANOLES BASED ON
211
water was added, the organic layer was separated,
filtered, the filtrate was dried, the solvent was distilled
off, the residue was distilled in a vacuum.
1-{[2-Methyl-2-(4-methylphenyl)propyl]-amino}-
3-(4-methylphenoxy)propan-2-ol oxalate (3b). Yield
1
63%, mp 150–151°C, Rf 0.42. Н NMR spectrum, δ,
ppm: 1.42 s (6Н, 2СН3), 2.26 s (3Н, СН3), 2.31 s (3Н,
СН3), 2.86 d.d (1Н, NСН2СН, J 12.6, 9.3 Hz), 3.06
d.d (1Н, NСН2СН, J 12.6, 3.2 Hz), 3.16 d (1Н,
NСН2CMе2, J 12.5 Hz), 3.19 d (1Н, NСН2CMе2, J
12.5 Hz), 3.78 d.d (1Н, ОСН2, J 9.7, 5.9 Hz), 3.88 d.d
(1Н, ОСН2, J 9.7, 5.0 Hz), 4.16 m (1Н, ОСН), 5.89 br
(4Н, ОН, NH), 6.70–6.75 m (2Н, С6Н4О), 6.98–7.03
m (2Н, С6Н4О), 7.10–7.15 m (2Н, С6Н4), 7.23–7.28 m
(2Н, С6Н4). Found, %: C 66.31; Н 7.35; N 3.25.
С23Н31NО6. Calculated, %: C 66.17; Н 7.48; N 3.35.
2-Methyl-2-(4-methylphenyl)propan-1-amine
(2а). Yield 78%, bp 93_95°C (5 mmHg), Rf 0.49
1
(benzene–acetone, 1 : 2, NH3 vapor). Н NMR spec-
trum, δ, ppm: 0.91 br (2Н, NН2), 1.25 s (6Н, 2СН3),
2.32 s (3Н, СН3arom), 2.67 s (2Н, СН2), 7.03–7.08 m
(2Нarom), 7.14–7.19 m (2Нarom). Found, %: C 80.68; H
10.35; N 8.79. С11Н17N. Calculated, %: C 80.93; H
10.50; N 8.58.
1-[1-(4-Methylphenyl)cyclopentyl]methylamine
(2b). Yield 80%, bp 120–124°C (6 mmHg) {bp 130°C
(10 mmHg) [8]}, Rf 0.50 (benzene–acetone, 1 : 2, NH3
vapor). 1Н NMR spectrum, δ, ppm: 0.65 br (2Н, NН2),
1.63–1.95 m (8Н, С5Н8), 2.30 s (3Н, СН3), 2.59 s
(СН2), 7.01–7.11 m (4Нarom).
1-{[2-Methyl-2-(4-methylphenyl)propyl]-amino}-
3-(4-methoxyphenoxy)propan-2-ol oxalate (3c).
1
Yield 69%, mp 135–137°C, Rf 0.40. Н NMR spec-
trum, δ, ppm: 1.42 s (6Н, 2СН3), 2.31 s (3Н, СН3),
2.87 d.d (1Н, NСН2СН, J 12.1, 9.4 Hz), 3.08 d.d (1Н,
NСН2СН, J 12.1, 3.2 Hz), 3.18 d (1Н, NСН2CMе2, J
13.0 Hz), 3.20 d (1Н, NСН2CMе2, J 13.0 Hz), 3.72 s
(3Н, ОСН3), 3.76 d.d (1Н, ОСН2, J 9.6, 5.6 Hz), 3.86
d.d (1Н, ОСН2, J 9.6, 4.7 Hz), 4.15 m (1Н, ОСН),
5.58 br (4Н, ОН and NH), 6.73–6.81 m (4Н, С6Н4О),
7.07–7.12 m (2Н, С6Н4), 7.25–7.30 m (2Н, С6Н4).
Found, %: C 63.52; Н 7.34; N 3.39. С23Н31NО7.
Calculated, %: C 63.73; Н 7.21; N 3.23.
[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-yl]-me-
thylamine (2c). Yield 80%, bp 140–145°C (4 mmHg),
mp 28–29°C, Rf 0.48 (benzene–acetone, 1 : 2, NH3
vapor). 1Н NMR spectrum, δ, ppm: 0.64 br (2Н, NН2),
1.71–1.82 m (2Н) and 2.01–2.10 m [2Н, C(СН2)2],
2.33 s (3Н, СН3), 2.66 s (2Н, СН2), 3.38–3.46 m (2Н),
3.62–3.70 m [2Н, О(СН2)2], 7.08–7.17 m (4Нarom).
Found, %: C 76.21; Н 9.49; N 6.59. С13Н19NО.
Calculated, %: C 76.06; Н 9.33; N 6.82.
1-{[2-Methyl-2-(4-methylphenyl)propyl]-amino}-
Salts of aminopropanoles (3a–3o). General me-
thod. Mixture of 0.01 mol of amine 2а–2c, 0.011 mol
of substituted aryloxymethyloxirane, and 2–3 drops of
water in 30 mL of isopropyl alcohol were stirred for 20 h
at boiling. The solvent was distilled off till dryness, the
residue was dissolved in 30 mL of anhydrous ether and
by treatment with ether solution of oxalic acid or
hydrogen chloride oxalates or hydrochlorides were
obtained and recrystallized from ethanol.
3-(4-chlorophenoxy)propan-2-ol oxalate (3d). Yield
71%, mp 175–176°C Rf 0.44. Н NMR spectrum, δ,
1
ppm: 1.38 s (6Н, 2СН3), 2.31 s (3Н, СН3), 2.70–2.80
m (1Н), 2.87–2.95 m (1Н, NСН2СН), 3.08 s (2Н,
NСН2CMе2), 3.80–3.90 m (2Н, ОСН2), 4.04 m (1Н,
ОСН), 5.32 br (4Н, ОН, NH), 6.82–6.87 m (2Н,
С6Н4О), 7.16–7.21 m (2Н, С6Н4О), 7.05–7.10 m (2Н,
С6Н4) and 7.22–7.27 m (2Н, С6Н4). Found, %: C
60.53; Н 6.28; N 3.31. С22Н28ClNО6. Calculated, %: C
60.34; Н 6.44; N 3.20.
1-{[2-Methyl-2-(4-methylphenyl)propyl]-amino}-
3-phenoxypropan-2-ol oxalate (3a). Yield 61%, mp
142–143°C, Rf 0.43. 1Н NMR spectrum, δ, ppm: 1.43 s
(6Н, 2СН3), 2.31 s (3Н, СН3), 2.87 d.d (1Н, NСН2СН,
J 12.6, 9.2 Hz), 3.07 d.d (1Н, NСН2СН, J 12.6, 3.2 Hz),
3.16 d (1Н, NСН2CMе2, J 12.5 Hz), 3.20 d (1Н,
NСН2CMе2, J 12.5 Hz), 3.83 d.d (1Н, ОСН2, J 9.7,
5.8 Hz), 3.92 d.d (1Н, ОСН2, J 9.7, 5.0 Hz), 4.18 m
(1Н, ОСН), 6.83–6.91 m (3Н), 7.08–7.13 m (2Н) and
7.19–7.30 m (4Н, Ar), 7.06 br (4Н, ОН, NH). Found,
%: C 65.67; Н 7.38; N 3.29. С22Н29NО6. Calculated,
%: C 65.49; Н 7.24; N 3.47.
1-{[2-Methyl-2-(4-methylphenyl)propyl]-amino}-
3-(4-fluorophenoxy)propan-2-ol oxalate (3e). Yield
1
60%, mp 159–160°C, Rf 0.43. Н NMR spectrum, δ,
ppm: 1.41 s (6Н, 2СН3), 2.31 s (3Н, СН3), 2.84 d.d
(1Н, NСН2СН, J 12.0, 9.0 Hz), 3.03 d.d (1Н,
NСН2СН, J 12.0, 3.1 Hz), 3.13 s (2Н, NСН2CMе2),
3.77–3.91 m (2Н, ОСН2), 4.13 m (1Н, ОСН), 5.63 br
(4Н, ОН, NH), 6.82–6.88 m (2Н, С6Н4О), 6.91–6.99
m (2Н, С6Н4О), 7.07–7.12 m (2Н, С6Н4), 7.25–7.30 m
(2Н, С6Н4). Found, %: C 62.53; Н 6.82; N 3.47.
С22Н28FNО6. Calculated, %: C 62.70; Н 6.70; N 3.32.
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АGHEKYAN et al.
212
1-({[1-(4-Methylphenyl)cyclopenthyl]-methyl}-
С6Н4), 7.22–7.27 m (2Н, С6Н4). Found, %: C 62.34; Н
6.38; N 3.11. С24Н30ClNО6. Calculated, %: C 62.13; Н
6.52; N 3.02.
amino)-3-phenoxypropan-2-ol oxalate (3f). Yield
1
65%, mp 169_171°C, Rf 0.45. Н NMR spectrum, δ,
ppm: 1.58–1.84 m (4Н, Cyp), 1.93–2.09 m (4Н, Cyp),
2.31 s (3Н, Ме), 2.73 d.d (1Н, NСН2СН, J 12.5, 9.1 Hz),
2.92 d.d (1Н, NСН2СН, J 12.5, 3.3 Hz), 3.15 s (2Н,
NСН2CMе2), 3.76 d.d (1Н, ОСН2, J 9.7, 5.9 Hz), 3.87
d.d (1Н, ОСН2, J 9.7, 5.0 Hz), 4.08 m (1Н, ОСН),
6.31 br (4Н, ОН, NH), 6.80–6.90 m (3Н, Ph), 7.18–
7.22 m (2Н, Ph), 7.07–7.12 m (2Н, С6Н4), 7.22–7.27
m (2Н, С6Н4). Found, %: C 67.35; Н 7.12; N 3.17.
С24Н31NО6. Calculated, %: C 67.11; Н 7.27; N 3.26.
1-({[1-(4-Methylphenyl)cyclopenthyl]-methyl}-
amino)-3-(4-fluorophenoxy)propan-2-ol oxalate
(3j). Yield 63%, mp 170–172°C, Rf 0.40. Н NMR
1
spectrum, δ, ppm: 1.57–1.84 m (4Н, Cyp), 1.93–2.08
m (4Н, Cyp), 2.31 s (3Н, СН3), 2.73 d.d (1Н,
NСН2СН, J 12.5, 9.1 Hz), 2.92 d.d (1Н, NСН2СН, J
12.5, 3.3 Hz), 3.16 s (2Н, NСН2CMе2), 3.75 d.d (1Н,
ОСН2, J 9.7, 5.8 Hz), 3.84 d.d (1Н, ОСН2, J 9.7, 5.0 Hz),
4.07 m (1Н, ОСН), 6.79–6.86 m (2Н, ОС6Н4), 6.91–
6.99 m (2Н, ОС6Н4), 7.07–7.12 m (2Н, С6Н4), 7.22–
7.27 m (2Н, С6Н4), 7.15 br (4Н, ОН and NH). Found,
%: C 64.57; Н 6.62; N 3.21. С24Н30FNО6. Calculated,
%: C 64.42; Н 6.76; N 3.13.
1-({[1-(4-Methylphenyl)cyclopenthyl]-methyl}-
amino)-3-(4-methylphenoxy)propan-2-ol oxalate
1
(3g). Yield 67%, mp 158–160°C, Rf 0.41. Н NMR
spectrum, δ, ppm: 1.58–1.83 m (4Н, Cyp), 1.92–2.08
m (4Н, Cyp), 2.26 s (3Н, ОС6Н4СН3), 2.31 s (3Н,
С6Н4СН3), 2.71 d.d (1Н, NСН2СН, J 12.5, 9.1 Hz),
2.90 d.d (1Н, NСН2СН, J 12.5, 3.1 Hz), 3.16 s (2Н,
NСН2CMе2), 3.72 d.d (1Н, ОСН2, J 9.6, 5.9 Hz), 3.82
d.d (1Н, ОСН2, J 9.6, 5.0 Hz), 4.06 m (1Н, ОСН),
6.18 br (4Н, ОН, NH), 6.68–6.73 m (2Н, ОС6Н4),
6.98–7.03 m (2Н, ОС6Н4), 7.07–7.12 m (2Н, С6Н4),
7.22–7.27 m (2Н, С6Н4). Found, %: C 67.48; Н 7.63;
N 3.29. С25Н33NО6. Calculated, %: C 67.70; Н 7.50; N
3.16.
1-({[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-
yl]methyl}amino)-3-phenoxypropan-2-ol hydro-
chloride (3k). Yield 65%, mp 169–170°C, Rf 0.56. 1Н
NMR spectrum, δ, ppm: 1.90–2.02 m (2Н, ССН2),
2.14–2.24 m (2Н, ССН2), 2.31 s (3Н, СН3), 2.79–3.04
m (2Н, NСН2СН), 3.25–3.41 m (4Н, 2ОСН2), 3.67–
3.76 m (2Н, NСН2), 3.85 d.d (1Н, ОСН2СН, J 10.0,
5.4 Hz), 3.89 d.d (1Н, ОСН2СН, J 10.0, 5.0 Hz), 4.14–
4.23 m (1Н, ОСН), 5.79 br.s (1Н, ОН), 6.87–6.97 m
(3Н), 7.21–7.37 m (6Н, Ar), 8.16 br.s (2Н, NH, НCl).
Found, %: C 67.57; Н 7.55; Cl 9.16; N 3.45.
С22Н30ClNО3. Calculated, %: C 67.42; Н 7.72; Cl
9.05; N 3.57.
1-({[1-(4-Methylphenyl)cyclopenthyl]-methyl}-
amino)-3-(4-methoxyphenoxy)propan-2-ol oxalate
1
(3h). Yield 65%, mp 123–125°C, Rf 0.44. Н NMR
spectrum, δ, ppm: 1.58–1.83 m (4Н, Cyp), 1.93–2.08
m (4Н, Cyp), 2.31 s (3Н, С6Н4СН3), 2.72 d.d (1Н,
NСН2СН, J 12.5, 9.0 Hz), 2.91 d.d (1Н, NСН2СН, J
12.5, 3.2 Hz), 3.14 s (2Н, NСН2CMе2), 3.70 d.d (1Н,
ОСН2, J 9.7, 5.9 Hz), 3.72 s (3Н, ОСН3), 3.81 d.d (1Н,
ОСН2, J 9.7, 5.0 Hz), 4.04 m (1Н, ОСН), 6.02 br (4Н,
ОН, NH), 6.75 s (4Н, ОС6Н4), 7.07–7.12 m (2Н,
С6Н4), 7.23–7.28 m (2Н, С6Н4). Found, %: C 65.54; Н
7.12; N 3.16. С25Н33NО7. Calculated, %: C 65.34; Н
7.24; N 3.05.
1-({[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-
yl]methyl}amino)-3-(4-methylphenoxy)-propan-2-ol
hydrochloride (3l). Yield 68%, mp 183–184°C, Rf
1
0.53. Н NMR spectrum, δ, ppm: 1.98–2.10 m (2Н,
ССН2), 2.24–2.34 m (2Н, ССН2), 2.26 s (3Н, СН3),
2.35 s (3Н, СН3), 2.73–3.02 m (2Н, NСН2СН), 3.14–
3.29 m (2Н, ОСН2), 3.36–3.48 m (2Н, ОСН2), 3.70–3.78
m (2Н, NСН2), 3.74 d.d (1Н, ОСН2СН, J 9.7, 6.0 Hz),
3.87 d.d (1Н, ОСН2СН, J 9.7, 4.8 Hz), 4.19–4.28 m
(1Н, ОСН), 5.70 br.s (1Н, ОН), 6.70–6.75 m (2Н,
ОС6Н4), 6.98–7.03 m (2Н, ОС6Н4), 7.17–7.22 m (2Н,
С6Н4), 7.33–7.38 m (2Н, С6Н4), 8.52 br.s (1Н, NH),
8.81 br.s (1Н, НCl). Found, %: C 68.29; Н 7.78; Cl
9.16; N 3.52. С23Н32ClNО3. Calculated, %: C 68.05; Н
7.95; Cl 8.73; N 3.45.
1-({[1-(4-Methylphenyl)cyclopenthyl]-methyl}-
amino)-3-(4-chlorophenoxy)propan-2-ol oxalate
1
(3i). Yield 72%, mp 167–169°C, Rf 0.42. Н NMR
spectrum, δ, ppm: 1.58–1.83 m (4Н, Cyp), 1.93–2.07
m (4Н, Cyp), 2.31 s (3Н, СН3), 2.72 d.d (1Н,
NСН2СН, J 12.4, 9.0 Hz), 2.90 d.d (1Н, NСН2СН, J
12.4, 3.2 Hz), 3.14 s (2Н, NСН2CMе2), 3.77 d.d (1Н,
ОСН2, J 9.7, 5.6 Hz), 3.85 d.d (1Н, ОСН2, J 9.7, 5.0 Hz),
4.07 m (1Н, ОСН), 6.83–6.88 m (2Н), 7.14–7.19 m
(2Н, ОС6Н4), 6.95 br (4Н, ОН, NH), 7.07–7.12 m (2Н,
1-({[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-
yl]methyl}amino)-3-(4-methoxyphenoxy)-propan-2-
ol hydrochloride (3m). Yield 71%, mp 171–172°C, Rf
1
0.52. Н NMR spectrum, δ, ppm: 1.98–2.10 m (2Н,
ССН2), 2.23–2.33 m (2Н, ССН2), 2.35 s (3Н, СН3),
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SYNTHESIS AND BIOLOGIC ACTIVITY OF ARYLOXYAMINOPROPANOLES BASED ON
213
2.73–3.02 m (2Н, NСН2СН), 3.14–3.29 m (2Н,
ОСН2), 3.36–3.48 m (2Н, ОСН2), 3.68–3.78 m (3Н,
NСН2, ОСН2СН), 3.72 s (3Н, ОСН3), 3.85 d.d (1Н,
ОСН2СН, J 9.8, 4.8 Hz), 4.18–4.28 m (1Н, ОСН),
5.69 br.s (1Н, ОН), 6.72–6.80 m (4Н, ОС6Н4), 7.17–
7.22 m (2Н, С6Н4), 7.33–7.38 m (2Н, С6Н4), 8.50 br.s
(1Н, NH), 8.78 br.s (1Н, НCl). Found, %: C 65.62; Н
7.51; Cl 8.52; N 3.22. С23Н32ClNО4. Calculated, %: C
65.47; Н 7.64; Cl 8.40; N 3.32.
was boiled for 24 h. After cooling the formed crystals
were filtered off, washed with water, then with
ethanol. Yield 0.95 g (51%), mp 98–99°C (ethanol), Rf
1
0.59. Н NMR spectrum, δ, ppm: 1.79–1.90 m (2Н,
ССН2), 2.04–2.16 m (2Н, ССН2), 2.32 s (3Н, СН3),
2.53 d.d (1Н, NСН2СН, J 11.3, 6.3 Hz), 2.66 d (1Н, J
13.5 Hz), 2.70 d (1Н, СН2С, J 13.5 Hz), 2.71 d.d (1Н,
NСН2СН, J 11.3, 6.7 Hz), 3.36–3.46 m (2Н, ОСН2),
3.62–3.70 m (2Н, ОСН2), 3.79 d,d (1Н, СН2Оarom, J
9.8, 5.4 Hz), 3.81 d (1Н, NСН2О, J 4.8 Hz), 3.86 d,d
(1Н, СН2Оarom, J 9.8, 5.2 Hz), 3.91 d (1Н, NСН2О, J
4.8 Hz), 4.01 d.d.d.d (1Н, СН, J 6.7, 6.3, 5.4, 5.2 Hz),
6.77–6.89 m (3Н), 7.04–7.09 m (2Н), 7.14–7.23 m
(4Н, Ar). Found, %: C 75.52; Н 7.74; N 3.65.
С23Н29NО3. Calculated, %: C 75.17; Н 7.95; N 3.81.
Mp of hydrochloride 188–189°C (acetone).
1-({[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-
yl]methyl}amino)-3-(4-chlorophenoxy)-propan-2-ol
hydrochloride (3n). Yield 75%, mp 205–206°C, Rf
1
0.55. Н NMR spectrum, δ, ppm: 1.99–2.10 m (2Н,
ССН2), 2.23–2.33 m (2Н, ССН2), 2.34 s (3Н, СН3),
2.73–3.01 m (2Н, NСН2СН), 3.14–3.29 m (2Н,
ОСН2), 3.36–3.48 m (2Н, ОСН2), 3.69–3.77 m (2Н,
NСН2), 3.81 d.d (1Н, ОСН2СН, J 9.8, 5.8 Hz), 3.90
d.d (1Н, ОСН2СН, J 9.8, 4.8 Hz), 4.22–4.31 m (1Н,
ОСН), 5.74 br.s (1Н, ОН), 6.84–6.89 m (2Н, ОС6Н4),
7.17–7.23 m (4Н, ОС6Н4, С6Н4), 7.33–7.38 m (2H,
С6Н4), 8.53 br.s (1Н, NH), 8.83 br.s (1Н, НCl). Found,
%: C 61.75; Н 6.72; Cl 16.49; N 3.16. С22Н29Cl2NО3.
Calculated, %: C 61.97; Н 6.86; Cl 16.63; N 3.29.
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye sredtsva (Drugs),
Moscow: Novaya volna, 2012.
2. Stayer, J.M., Chadha, A., and Agarwal, S.K., J. Org.
Chem., 1991, vol. 56, p. 20.
3. Satyanarayana, M., Tiwari, P., and Triphati, B.K.,
Bioorg. Med. Chem., 2004, vol. 12, p. 883.
1-({[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-
yl]methyl}amino)-3-(4-fluorophenoxy)-propan-2-ol
hydrochloride (3o). Yield 70%, mp 185–186°C, Rf
4. Sun, Q.-Y., Zhang, W.-N., and Xu, J.-M., Eur. J. Med.
Chem., 2007, vol. 42, p. 1151.
5. Bonini, C., Chiummiento, L., Di Blasio, N., Funice-
llo, M., Lupattelli, P., Tramutola, F., Berti, F., Ostric, A.,
Miertus, S., Frecer, V., and Kong, D.-X., Bioorg. Med.
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6. Aghekyan, A.A., Mkryan, G.G., Gukasyan, T.G.,
Tsatinyan, A.S., Shirinyan, E.A., Asatryan, T.O.,
Markaryan, K.Zh., Grigoryan, A.V., and Markaryan, E.A.,
Khim. Zh. Armenii, 2010, vol. 63, p. 398.
7. Adachi, K., Aoki, Y., Hanano, T., Morimoto, H., and
Hisadome, M., US Patent no. 6455528, 2002.
8. Krohs, W., Ther, L., and Vogel, G., FRG Patent
no. 1124485, 1962.
1
0.52. Н NMR spectrum, δ, ppm: 1.99–2.10 m (2Н,
ССН2), 2.23–2.34 m (2Н, ССН2), 2.34 s (3Н, СН3),
2.74–3.02 m (2Н, NСН2СН), 3.15–3.29 m (2Н,
ОСН2), 3.37–3.48 m (2Н, ОСН2), 3.70–3.79 m (2Н,
NСН2), 3.78 d.d (1Н, ОСН2СН, J 9.8, 5.9 Hz), 3.88
d.d (1Н, ОСН2СН, J 9.8, 4.8 Hz), 4.21–4.29 m (1Н,
ОСН), 5.72 br.s (1Н, ОН), 6.82–6.89 m (2Н, ОС6Н4),
6.91–7.00 m (2Н, ОС6Н4), 7.17–7.22 m (2Н, С6Н4),
7.33–7.38 m (2Н, С6Н4), 8.52 br.s (1Н, NH), 8.82 br.s
(1Н, НCl). Found, %: C 64.62; Н 7.05; Cl 8.78; N
3.29. С22Н29ClFNО3. Calculated, %: C 64.46; Н 7.13;
Cl 8.65; N 3.42.
9. Petrov, V. and Stephenson, O., J. Pharm. Pharmacol.,
1953, vol. 5, p. 359.
3-{[4-(4-Methylphenyl)tetrahydro-2Н-pyran-4-
yl]-methyl}-5-(phenoxymethyl)oxazolidine (4). A
mixture of 1.8 g (5 mmol) of reagent 3k and 5 mL of
23% formaldehyde water solution in 20 mL of ethanol
10. Taba, H.D., Hassan, M.A., Hijawi, A.S., and Voelter, J.,
Qatar Univ. Sci., 2002, vol. 22, p. 107.
11. Avakyan, O.M., Simpato-adrenalinovaya sistema
(Sympathetic–Adrenal System), Moscow: Nauka, 1977.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016