Synthesis and biologic properties of new thiazolylbenzodioxane derivatives

Article abstract of DOI:10.1134/S1070428016020159

Reaction of 4-(1,4-benzodioxan-2-yl)thiazol-2-amine with acid chlorides afforded N-substituted amides which further were reduced into the corresponding amines. A new method was developed of preparation of 2-acetyl-1,4-benzodioxane, the initial compound in the synthesis of thiazolylbenzodioxane and numerous derivatives of this series. The adreno- and sympatholytic as well as antihypoxic effect of the obtained biheterocyclic 1,4-benzodioxane derivatives were investigated.

Full text of DOI:10.1134/S1070428016020159

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 2, pp. 244–248. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © S.O. Vartanyan, A.S. Avakyan, A.B. Sargsyan, S.A. Arutyunyan, О.S. Noravyan, A.S. Tsatinyan, 2016, published in Zhurnal
Organicheskoi Khimii, 2016, Vol. 52, No. 2, pp. 261–265.
Synthesis and Biologic Properties of New
Thiazolylbenzodioxane Derivatives
S. O. Vartanyan, A. S. Avakyan, A. B. Sargsyan, S. A. Arutyunyan,
О. S. Noravyan, and A. S. Tsatinyan
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
e-mail: avagal@mail.ru
Received June 29, 2015
Abstract—Reaction of 4-(1,4-benzodioxan-2-yl)thiazol-2-amine with acid chlorides afforded N-substituted
amides which further were reduced into the corresponding amines. A new method was developed of
preparation of 2-acetyl-1,4-benzodioxane, the initial compound in the synthesis of thiazolylbenzodioxane and
numerous derivatives of this series. The adreno- and sympatholytic as well as antihypoxic effect of the obtained
biheterocyclic 1,4-benzodioxane derivatives were investigated.
DOI: 10.1134/S1070428016020159
Biheterocyclic 1,4-benzodioxane derivatives exhibit
versatile pharmacologic properties. Among their number
adrenolytics, antioxidants, hypoglycemic, antiphlogistic,
and other pharmaceuticals were found [1, 2]. In our
laboratory 4-(1,4-benzodioxan-2-yl)thiazol-2-amine and
its N-methyl derivative were synthesized that showed a
high α2-adrenoblocking activity as well as pronounced
antihypoxic, anti-burn, and radiation protective
properties [3–5].
containing N-alkyl-, aryl-, arylalkyl-, and heteryl-
substituted fragments in the thiazole ring.
The initial compound for the synthesis of target
substances is 2-acetyl-1,4-benzodioxane
1
that
formerly has been prepared by condensation of
pyrocatechol with 3,4-dibromobutan-2-one in the
presence of dry potassium carbonate in anhydrous
acetone [6]. Since methyl vinyl ketone and dibromide
obtained from it are lachrymators and possess a sharp
smell we have developed a new procedure for the
preparation of 2-acetyl-1,4-benzodioxane by Grignard
reaction from the nitrile of 1,4-benzodioxane-2-
carboxylic acid 2 [7]. The overall yield of 2-acetyl-1,4-
Looking for new compounds of analogous effect
and exploring some structure–activity relationship we
synthesized new biheterocyclic derivatives of the
thiazolylbenzodioxane series, amides and amines
Scheme 1.
O
O
O
O
O
O
CN
CH2Br
CH3MgI
Br2
CH3
O
O
2
1
3
S
S
.
O
NH2 HBr
O
O
NH2
NH2C(S)NH2
NaOH
N
N
O
5
4
244

SYNTHESIS AND BIOLOGIC PROPERTIES OF NEW THIAZOLYLBENZODIOXANE
245
Scheme 2.
O
S
S
S
O
O
R
O
O
NH
NH
O
O
NH2
R
RCOCl
LiAlH4
N
N
N
5
6a_6g
7a_7g
S
O
O
NH
R
HCl (dry)
N
7c_7g
.
HCl
8c_8g
O
O
O
O
(b), C6H5OCH2 (c),
(d), C4H9 (e), C6H5 (f),
(a),
H3CO
(g).
R =
Cl
benzodioxane proved to be quite comparable with the
yield in the formerly used method. The bromination of
compound 1 provided bromoketone 3. The method of
its synthesis described in [8] resulted in a low yield of
the target compound. We developed a new procedure
of bromoketone 3 preparation in anhydrous ether in the
presence of calcium carbonate at 17–18°С that
provided the yield attaining 70–72%. Further by
cyclization of compound 3 with thiourea followed by
alkalinizing the formed hydrobromide 4 4-(1,4-
benzodioxan-2-yl)thiazol-2-amine 5 [3] was obtained
that was used for the synthesis of amides and amines
of thiazolylbenzodioxane series (Scheme 1).
The study of antihypoxic properties [9] of the
synthesized amides and amines of the thiazolyl-
benzodioxane series showed that only substances 6а,
6е, and 8е in a dose 50 mg/kg increased the survival of
animals under oxygen deficit in the inhaled air by 34,
53, and 54% respectively. As a result of the inves-
tigation of the compounds effect on the adrenoreactive
systems [10] it was found that compounds 6b, 6d, and
7a, 8d, 8e, 8f showed a moderate α- and β1-
adrenomimetic effect.
EXPERIMENTAL
IR spectra were recorded on a spectrometer Nicolet
1
Avatar 330 FT-IR from mulls in mineral oil. Н NMR
By the reaction of 4-(1,4-benzodioxan-2-yl)-thi-
azol-2-amine 5 with chlorides of valeric, benzoic,
phenoxyacetic acids, and also of phenylcyclopentane-,
4-chloro-, 4-methoxyphenyltetrahydropyran-, and 1,4-
benzodioxane-2-carboxylic acids we prepared the
corresponding amides 6a–6g, white crystalline
substances (Scheme 2).
spectra were registered on a spectrometer Varian
Mercury-300 in DMSO-d6, working frequency 300 MHz,
internal reference TMS. Melting points were deter-
mined on Boёtius heating microblock. The reaction
progress was monitored and the homogeneity of
compounds synthesized was checked by TLC on
Silufol UV-254 plates (eluent benzene–acetone, 3 : 1,
eluent for hydrochlorides 8 benzene–acetone, 3 : 1,
ammonia vapor, development in iodine vapor).
The reduction of amides 6а–6g with lithium
aluminum hydride furnished the corresponding
biheterocyclic amines 7а and 7b as white crystalline
substances, 7с–7g as oily substances that by treating
with an ether solution of hydrogen chloride were
converted into hydrochlorides 8c–8g, also white
crystalline substances.
2-Acetyl-1,4-benzodioxane (1). To 5.0 g (0.2 mol)
of Mg was added 200 mL of anhydrous ether and 1–2
crystals of iodine, then slowly was added dropwise
13.0 mL (0.21 mol) of methyl iodide in 100 mL of
anhydrous ether. The reaction mixture was stirred at
boiling for 1 h more till complete dissolution of mag-
nesium turnings. From the reaction mixture 150 mL of
ether was distilled off, 100 mL of anhydrous benzene
The structure and purity of all prepared compounds
1
were confirmed by IR and Н NMR spectra as well as
by thin layer chromatography.
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VARTANYAN et al.
246
was added, and the distillation was continued till the
boiling point rose to 60°С. On cooling 16.1 g (0.1 mol)
of nitrile of 1,4-benzodioxane-2-carboxylic acid 2 [7]
in 100 mL of anhydrous benzene was added, and the
mixture was boiled for 6 h. On cooling to 10°С 150 mL
of 6 N HCl solution was added till acid pH. The reaction
mixture was boiled for 4 h, cooled, the organic layer
was separated, washed with water, with 10% solution
of Na2CO3, again with water, and dried with sodium
sulfate. The solvent was distilled off, the residue was
distilled in a vacuum at 115–120°С (1 mm Hg). Yield
8.5 g (47%), {bp 130–140°С (3 mm Hg) [6]}.
30 mL of anhydrous benzene. The reaction mixture
was boiled for 8–9 h. The benzene solution was
decanted while hot, cooled, washed with 10% solution
of sodium carbonate, dried with sodium sulfate,
benzene was distilled off, the residue was crystallized
from ether and recrystallized from benzene.
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]-4-(4-
chlorophenyl)tetrahydro-2Н-pyran-4-carboxamide
(6а). Yield 70%, mp 155–157оС, Rf 0.42. IR spectrum,
ν, cm–1: 3155 (NH-amide), 1672 (С=O), 1600 (arom).
1Н NMR spectrum, δ, ppm: 1.92–2.04 m (2Н) and
2.66–2.75 m (2Н, СН2), 3.49–3.59 m (2Н) and 3.75–3.83
m (2Н, ОСН2), 4.14 d.d (1Н, OCH2, J 11.3, 7.9 Hz),
4.42 d.d (1H, OCH2, J 11.3, 2.5 Hz), 5.17 d.d.d (1Н,
OCH, J 7.9, 2.5, 0.8 Hz), 6.76–6.86 m (4Н, С6Н4),
7.03 d (1Н, =CHS, J 0.8 Hz), 7.29–7.44 m (4H,
C6H4Cl), 11.79 br.s (1H, NH). Found, %: С 60.23; Н
4.91; N 5.89. C23H21ClN2O4S. Calculated, %: С 60.46;
Н 4.63; N 6.13.
2-Bromo-1-(1,4-benzodioxan-2-yl)ethanone (3).
To a slurry of 17.8 g (0.1 mol) of 2-acetyl-1,4-benzo-
dioxane 1 and 12.0 g (0.12 mol) of powdered anhyd-
rous calcium carbonate in 300 mL of anhydrous ether
cooled to 16°С was slowly added 16.0 g (0.1 mol) of
bromine in 10 mL of hexane maintaining the mixture
temperature at ~17–18°С. The reaction mixture was
stirred at this temperature for 1 h more, then it was
filtered, the filtrate was washed with 100 mL of 1%
solution of sodium hydrogen carbonate, and dried with
sodium sulfate. Ether was distilled off in a vacuum at
15–20°С. The residue was crystallized from petroleum
ether, dried in air, and recrystallized from mixture
petroleum ether–anhydrous ether, 2 : 1. Yield 18.7 g
(72%), mp 70–72°С (mp 69–71°С [8]).
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]-4-(4-
methoxyphenyl)tetrahydro-2Н-pyran-4-carboxami-
de (6b). Yield 77%, mp 160–161°С, Rf 0.52. IR spec-
trum, ν, cm–1: 3185 (NH-amide), 1670 (С=O), 1596
1
(arom). Н NMR spectrum, δ, ppm: 1.91–2.05 m (2Н)
and 2.63–2.72 m (2Н, СН2), 3.53 and 3.77 br.t (2Н
each, ОСН2, J 11.0 Hz), 3.76 s (3H, OCH3), 4.15 d.d
(1Н, OCH2, J 11.3, 7.9 Hz), 4.42 d.d (1H, OCH2, J
11.3, 2.5 Hz), 5.16 d.d (1Н, OCH, J 7.9, 2.5 Hz), 6.76–
6.86 m (6Н) and 7.29–7.35 m (2Н, С6Н4), 7.01 br.s
(1Н, =CHS), 11.65 s (1H, NH). Found, %: С 63.41; Н
5.74; N 6.43. C24H24N2O5S. Calculated, %: С 63.70; Н
5.35; N 6.19.
4-(1,4-Benzodioxan-2-yl)thiazol-2-amine (5). A
mixture of 25.7 g (0.1 mol) of compound 3 and 7.6 g
(0.1 mol) of thiourea in 50 mL of anhydrous ethanol
was boiled for 4 h and left overnight. The precipitated
crystals were filtered off, washed with 20 mL of cold
ethanol, then with 30 mL of anhydrous ether. The
isolated 4-(1,4-benzodioxan-2-yl)thiazol-2-amine hyd-
robromide 4 (mp 214–216°С) was placed in a flask,
100 mL of water and 100 mL of ether was added, and
was introduced slowly 40–50 mL of 10% sodium
hydroxide solution. The stirring was continued for 30–
40 min more. The ether layer was separated, and the
water layer was extracted once more with 50 mL of
ether. The combined ether solutions were washed with
water and dried with sodium sulfate. The solvent was
distilled off, the residue was crystallized and
recrystallized from ethanol. Yield 14.0 g (60%), mp
123–124°С.
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]-2-phe-
noxyacetamide (6c). Yield 72%, mp 134–135°С, Rf
0.52. IR spectrum, ν, cm–1: 3200 (NH-amide), 1667
1
(С=O), 1610 (arom). Н NMR spectrum, δ, ppm: 4.20
d.d (1Н, OCH2, J 11.3, 7.6 Hz), 4.47 d.d (1H, OCH2, J
11.3, 2.5 Hz), 4.76 s (2Н, СОСН2), 5.24 d.d.d (1Н,
OCH, J 7.6, 2.5, 0.8 Hz), 6.78–6.96 m (7Н) and 7.23–
7.29 m (2Н, Н-Аr), 7.08 br.s (1Н, =CHS), 12.28 s (1H,
NH). Found %:
С 61.79; Н 4.54; N 7.89.
C19H16N2O4S. Calculated, %: С 61.94; Н 4.38; N 7.60.
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]-1-phe-
nylcyclopentanecarboxamide (6d). Yield 74%, mp
145–146°С, Rf 0.40. IR spectrum, ν, cm–1: 3173 (NH-
amide), 1659 (С=O), 1600 (arom). 1Н NMR spectrum,
δ, ppm: 1.67 m (4Н), 1.94–2.05 m (2Н) and 2.68–2.78
m (2Н, С5Н8), 4.13 d.d (1Н, OCH2, J 11.3, 7.9 Hz),
4.41 d.d (1H, OCH2, J 11.3, 2.5 Hz), 5.15 d.d.d
Compounds 6a–6g. General procedure. To a
mixture of 2.2 g (10 mmol) of aminothiazole 5 in 50 mL
of anhydrous benzene and 1 mL (10 mmol) of pyridine
was added 10 mmol of an appropriate acid chloride in
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SYNTHESIS AND BIOLOGIC PROPERTIES OF NEW THIAZOLYLBENZODIOXANE
247
(1Н, OCH, J 7.9, 2.5, 0.8 Hz), 6.75–6.85 m (4Н,
С6Н4), 6.98 br.s (1Н, =CHS), 7.15–7.21 m (1Н), 7.24–
7.31 m (2Н) and 7.37–7.42 m (2Н, С6Н5), 11.59 br.s
(1H, NH). Found, %: С 67.75; Н 5.29; N 7.02.
C23H22N2O3S. Calculated, %: С 67.96; Н 5.46; N 6.89.
hydrogen chloride hydrochlorides of the oily amines
were obtained, filtered off, washed with ether, dried in
air, and recrystallized from ethanol. Crystalline bases
7a and 7b were recrystallized from hexane.
4-(1,4-Benzodioxan-2-yl)-N-{[4-(4-chlorophe-
nyl)-tetrahydro-2Н-pyran-4-yl]methyl}thiazol-2-
amine (7а). Yield 52%, mp 186–188°С, Rf 0.52. IR spec-
trum, ν, cm–1: 3296 (NH-amine), 1588 (arom). 1Н NMR
spectrum, δ, ppm: 1.88–1.98 m (2Н), 2.02–2.12 m (2Н,
СН2), 3.39–3.45 m (2Н) and 3.70–3.78 m (2Н, ОСН2),
3.47 d (2Н, NCH2, J 6.2 Hz), 4.05 d.d (1Н, OCH2, J
11.3, 7.7 Hz), 4.37 d.d (1H, OCH2, J 11.3, 2.5 Hz),
4.95 d.d.d (1Н, OCH, J 7.7, 2.5, 0.9 Hz), 6.33 d (1Н,
=CHS, J 0.9 Hz), 6.75–6.86 m (4Н, С6Н4), 7.19 br.t
(1Н, NH, J 6.2 Hz), 7.26–7.36 m (4Н, С6Н4Cl). Found,
%: С 62.73; Н 5.49; Cl 8.32; N 6.71. C23H23ClN2O3S.
Calculated, %: С 62.36; Н 5.23; Cl 8.00; N 6.32.
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]-pentan-
amide (6е). Yield 76%, mp 145–148°С, Rf 0.46. IR
spectrum, ν, cm–1: 3168 (NH-amide), 1671(С=O),
1
1603 (arom). Н NMR spectrum, δ, ppm: 0.95 t (3Н,
CH3, J 7.3 Hz), 1.32–1.44 m (2H, СН2СН3), 1.59–1.69
m (2Н, СН2СН2СН3), 2.40 t (2Н, СОСН2, J 7.4 Hz),
4.16 d.d (1Н, OCH2, J 11.3, 7.7 Hz), 4.45 d.d (1H,
OCH2, J 11.3, 2.5 Hz), 5.20 d.d.d (1Н, OCH, J 7.7,
2.5, 0.9 Hz), 6.77–6.88 m (4Н, С6Н4), 6.98 d (1Н,
=CHS, J 0.9 Hz), 11.99 s (1H, NH). Found, %: С
60.11; Н 5.41; N 8.64. C16H18N2O3S. Calculated, %: С
60.36; Н 5.70; N 8.80.
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]benz-
amide (6f). Yield 78%, mp 138–140°С, Rf 0.48. IR
spectrum, ν, cm–1: 3189 (NH-amide), 1655 (С=O), 1600
(arom). 1Н NMR spectrum, δ, ppm: 4.23 d.d (1Н, OCH2,
J 11.3, 7.7 Hz), 4.52 d.d (1H, OCH2, J 11.3, 2.5 Hz),
5.27 d.d.d (1Н, OCH, J 7.7, 2.5, 0.8 Hz), 6.78–6.90 m
(4Н, С6Н4), 7.09 d (1Н, =CHS, J 0.8 Hz), 7.44–7.58 m
(3Н) and 8.12–8.17 m (2Н, С6Н5), 12.55 br.s (1H,
NH). Found, %: С 63.67; Н 4.51; N 8.44.
C18H14N2O3S. Calculated, %: С 63.89; Н 4.17; N 8.28.
4-(1,4-Benzodioxan-2-yl)-N-{[4-(4-methoxyphe-
nyl)tetrahydro-2Н-pyran-4-yl]methyl}thiazol-2-
amine (7b). Yield 54%, mp 170–171°С, Rf 0.57. IR
1
spectrum, ν, cm–1: 3288 (NH-amine), 1590 (arom). Н
NMR spectrum, δ, ppm: 1.85–1.96 m (2Н) and 2.01–
2.10 m (2Н, СН2), 3.40 d (2Н, NCH2, J 6.1 Hz), 3.40–
3.48 and 3.68–3.76 m (2Н each, ОСН2), 3.77 s (3Н,
ОСН3), 4.06 d.d (1Н, OCH2, J 11.3, 7.7 Hz), 4.38 d.d
(1H, OCH2, J 11.3, 2.5 Hz), 4.96 d.d.d (1Н, OCH, J
7.7, 2.5, 0.9 Hz), 6.33 d (1Н, =CHS, J 0.9 Hz), 6.74–
6.86 m (6Н) and 7.21–7.27 m (2Н, С6Н4), 7.03 br.t
(1Н, NH, J 6.1 Hz). Found, %: С 65.45; Н 5.61; N
6.88. C24H26N2O4S. Calculated, %: С 65.73; Н 5.98; N
6.39.
N-[4-(1,4-Benzodioxan-2-yl)thiazol-2-yl]-1,4-
benzodioxane-2-carboxamide (6g). Yield 73%, mp
165_167°С, Rf 0.58. IR spectrum, ν, cm–1: 3158 (NH-
amide), 1661 (С=O), 1595 (arom). 1Н NMR spectrum,
δ, ppm (DMSO–CCl4, 1 : 3), two diastereomers, 1: 1:
4.20 and 4.20 d.d (0.5Н each, OCH2, J 11.3, 7.6 Hz),
4.34–4.43 m (2Н, ОСН2), 4.46 and 4.47 d.d (0.5H
each, OCH2, J 11.3, 2.5 Hz), 5.01 d.d (1Н, OCH, J 4.9,
3.4 Hz), 5.24 d.d.d (1Н, OCH, J 7.6, 2.5, 0.8 Hz),
6.78–6.97 m (8Н, С6Н4), 7.10 d (1Н, =CHS, J 0.8 Hz),
12.42 s (1H, NH). Found, %: С 60.28; Н 4.41; N 7.34.
C20H16N2O5S. Calculated, %: С 60.60; Н 4.07; N 7.07.
4-(1,4-Benzodioxan-2-yl)-N-(2-phenoxyethyl)thi-
azol-2-amine hydrochloride (8c). Yield 51%, mp
170–171°С, Rf 0.38. 1Н NMR spectrum, δ, ppm: 3.91 br.t
(2H, NCH2, J 5.3 Hz), 4.21 t (2H, ОCH2, J 5.3 Hz),
4.31 d.d (1Н, OCH2, J 11.4, 6.6 Hz), 4.54 d.d (1H,
OCH2, J 11.4, 2.6 Hz), 5.37 d.d.d (1Н, OCH, J 6.6,
2.6, 0.9 Hz), 6.41 br (1Н, NH), 6.66 d (1H, =CHS, J
0.9 Hz), 6.80–6.81 m (3Н), 6.86–6.95 m (4Н) and
7.21–7.27 m (2Н, СНaroyl), 9.70 br (1H, HCl). Found,
%: С 58.61; Н 4.70; Cl 9.28; N 7.45. C19H19ClN2O3S.
Calculated, %: С 58.38; Н 4.90; Cl 9.07; N 7.17.
Compounds 7a, 7b and hydrochlorides 8с–8g.
General procedure. To 0.76 g (20 mmol) of lithium
aluminum hydride in 100 mL of anhydrous ether was
slowly added 10 mmol of an appropriate amide 6a–6g
in 100 mL of anhydrous benzene. The reaction mixture
was heated at 40–45°С for 16–18 h. The mixture was
treated with 50 mL of water, filtered, the filtrate was
dried with sodium sulfate, the solvent was distilled off.
To the oily residue 100 mL of anhydrous ether was
added, and under the treatment of ether solution of
4-(1,4-Benzodioxan-2-yl)-N-[(1-phenylcyclopen-
tyl)methyl]thiazol-2-amine hydrochloride (8d).
Yield 49%, mp 150–151°С, Rf 0.43. 1Н NMR
spectrum, δ, ppm: 1.71 m (2Н), 1.84 m (2Н), 1.96 m
(2Н) and 2.11 m (2Н, С5Н8), 3.67 br (2Н, NCH2), 3.87
br (1Н, NH), 4.15 d.d (1Н, OCH2, J 11.4, 6.6 Hz), 4.44
d.d (1H, OCH2, J 11.4, 2.5 Hz), 5.24 d.d.d (1Н, OCH,
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VARTANYAN et al.
248
J 6.6, 2.5, 0.9 Hz), 6.48 d (1Н, =CHS, J 0.9 Hz), 6.77–
6.90 m (4Н, С6Н4), 7.12 m (1Н, Н4Ph), 7.24 m (2Н,
Н3,5Ph), 7.37 m (2Н, Н2,6Ph), 9.14 br (1H, HCl).
Found, %: С 64.11; Н 5.47; Cl 8.57; N 6.21.
C23H25ClN2O2S. Calculated, %: С 64.40; Н 5.87; Cl
8.26; N 6.53.
each, OCH2, J 11.3, 6.8 Hz), 4.26 d.d (1H, OCH2, J
11.4, 6.9 Hz), 4.39–4.54 m (3Н, ОСН2 and ОСН), 5.27
br.d (1H, OCH, J 6.4 Hz), 6.60 and 6.60 d (0.5Н each,
=CHS, J 0.9 Hz), 6.75–6.91 m (8H, С6Н4), 5.94 and
9.16 br (2Н, NH and HCl). Found, %: С 57.69; Н 4.72;
Cl 8.81; N 6.44. C20H19ClN2O4S. Calculated, %: С
57.34; Н 4.57; Cl 8.46; N 6.69.
4-(1,4-Benzodioxan-2-yl)-N-pentylthiazol-2-
amine hydrochloride (8e). Yield 57%, mp 103–105°С,
1
REFERENCES
Rf 0.34. Н NMR spectrum, δ, ppm: 0.95 m (3Н, CH3,
C5H11), 1.35–1.45 m (4H, СН2, С5Н11), 1.68 m (2Н,
СН2, С5Н11), 3.45 t (2Н, NCH2, J 6.9 Hz), 4.31 d.d
(1Н, OCH2, J 11.4, 6.4 Hz), 4.54 d.d (1H, OCH2, J
11.4, 2.5 Hz), 5.40 d.d.d (1Н, OCH, J 6.4, 2.5, 0.9 Hz),
5.31 br (1Н, NH), 6.66 d (1H, =CH, J 0.9 Hz), 6.79–
6.85 m (3Н) and 6.90 m (1Н, С6Н4), 9.85 br (1H,
HCl). Found, %: С 56.61; Н 5.98; Cl 10.14; N 8.56.
C16H21ClN2O2S. Calculated, %: С 56.38; Н 6.21; Cl
10.40; N 8.22.
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Lorenzo, J.G.F., and de Athayde-Filho, P.F., Molecules,
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2. The Use of Stems in the Selection of International
Nonprietary Names (INN) for Pharmaceutical
Substances. 2011, WHO.
3. Vartanyan, S.O., Markaryan, E.A., Martirosyan, O.M.,
Shirinyan, E.A. Avakyan, O.M., Akopyan, N.E.,
Sarkisyan, L.M., and Medvedev, O.S., USSR Inventor’s
Certificate no. 1466220, 1988.
N-Benzyl-4-(1,4-benzodioxan-2-yl)-thiazol-2-
amine hydrochloride (8f). Yield 53%, mp 105–106°С,
Rf 0.41. 1Н NMR spectrum, δ, ppm: 4.27 d.d (1Н, OCH2,
J 11.3, 6.7 Hz), 4.52 d.d (1H, OCH2, J 11.3, 2.5 Hz),
4.64 br.s (2Н, NСH2), 5.31 d.d (1Н, OCH, J 6.7, 2.5 Hz),
6.06 br (1Н, NH), 6.62 br.s (1Н, =CHS), 6.78–6.92 m
(4H, C6H4), 7.24–7.45 m (5H, С6Н5), 9.67 br (1H,
HCl). Found, %: С 59.63; Н 5.00; Cl 9.59; N 7.93.
C18H17ClN2O2S. Calculated, %: С 59.91; Н 4.75; Cl
9.82; N 7.76.
4. Panossian, A., Grigorian, G., Markarian E., and
Vartanian, S., Biochim. Pharm., 1997, vol. 55, p. 1753.
5. Vartanyan, S.O., Margaryan, E.A., Arutyunyan, S.A.,
Martirosyan, O.M., and Shirinyan, E.A., Vestn.
MANEB, 2003, vol. 8, p. 135.
6. Misiti, D., de Marchi, F., Rosnati, V., and Bovet, D.,
J. Med. Pharm. Chem., 1962, vol. 5, p. 1285.
7. Koo, I., Avakian, S., and Martin, G., J. Am. Chem. Soc.,
1955, vol. 77, p. 5373.
8. McGregor, A.G., GB Patent no. 1038334, 1966; Chem.
Abstr., 1966, vol. 65, p. 16978h.
4-(1,4-Benzodioxan-2-yl)-N-[(1,4-benzodioxan-2-
yl)methyl]thiazol-2-amine hydrochloride (8g). Yield
9. Shirinyan, E.A., Martirosyan, O.M., Arutyunyan, S.A.,
1
53%, mp 98–100°С, Rf 0.38. Н NMR spectrum, δ,
and Atayan, T.K., Fiziol. Zh., 1990, vol. 76, p. 1197.
ppm (DMSO–CCl4, 1 : 3), two diastereomers, 1 : 1:
10. Avakyan, O.M., Simpato-adrenalovaya sistema,
(Sympathetic–Adrenal System), Leningrad: Nauka, 1977.
3.68–3.87 m (2Н, NCH2), 4.05 and 4.06 d.d (0.5Н
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 2 2016