Chemistry of Heterocyclic Compounds 2017, 53(10), 1094–1097
Table 1. The analgesic activity of compounds 6а,b
through a paper filter, and acidified with dilute
in the acetic acid-induced writhing test
hydrochloric acid until the appearance of a flaky
precipitate. The obtained precipitate was filtered off,
washed with water, and dried. The product was
recrystallized from a mixture of hexane–chloroform, 2:1.
Yield 5.7 g (70%), red-orange needle-shaped crystals,
mp 105–106°С (hexane–chloroform, 2:1). IR spectrum,
Reduction in the number
of writhings
in % relative to control
Compound
dose)
Number of writhings
in 15 min
(
6
6
a (100 mg/kg)
b (100 mg/kg)
38.2 ± 5.2
44.8 ± 6.9
45.0 ± 6.8
31.5
19.7
19.4
–1
ν, cm : 3098 (OH), 2996 (C–H), 1731, 1622 (C=O), 1250
Metamizole sodium
100 mg/kg)
1
(
(
С–O). H NMR spectrum (400 MHz, CDCl
J, Hz): 1.42 (6H, t, J = 7.1, 2ОСН CH ); 2.80 (6H, s,
); 4.41 (4H, q, J = 7.1, 2ОСH ); 6.82 (2H, s,
=CН); 8.11 (1H, s, H-4). C NMR spectrum (100 MHz,
), δ, ppm: 14.1 (2СН CH ); 24.5 (2,6-CH ); 62.9
3
), δ, ppm
(
2
3
Control (untreated
animals)
55.8 ± 5.8
–
2
2
,6-CH
3
2
13
CDCl
3
2
3
3
obtain diethyl (2Z,2'Z)-4,4'-(2,6-dimethylpyridine-3,5-diyl)-
bis(2-hydroxy-4-oxobut-2-enoate), which further reacted
with о-phenylenediamine and о-aminophenol, forming
derivatives of bis-3,4-dihydroquinoxalin-2(1H)-one and bis-
(2ОСН ); 101.4 (2 =CH); 128.9 (C-3,5 Py); 136.8 (C-4 Py);
160.3 (2 COO); 161.7 (C-2,6 Py); 169.7 (2 =C–OH); 192.3
(2C=O).
2
(3Z,3'Z)-3,3'-[(2,6-Dimethylpyridine-3,5-diyl)bis(2-oxo-
ethan-2-yl-1-ylidene)]bis(3,4-dihydroquinoxalin-2(1H)-one)
(6a). A mixture of pyruvate 4 (391 mg, 1 mmol) and
о-phenylenediamine (216 mg, 2 mmol) in 2-propanol (10 ml)
was stirred and refluxed for 3 h. The solution containing a
bright-yellow precipitate was cooled, filtered, the
precipitate was washed with 2-propanol and recrystallized
from a mixture of 2-propanol–chloroform. Yield 393 mg
(82%), bright-yellow crystals, mp >330°С. IR spectrum,
3
,4-dihydro-2H-1,4-benzoxazin-2-one. Biological testing
revealed that the synthesized compounds in some cases had
stronger analgesic activity than the reference drug,
metamizole sodium.
Experimental
IR spectra were recorded on an FT-801 FTIR
1
13
spectrometer in KBr pellets. H and С NMR spectra were
–1
acquired on a Jeol JNM-ECA 400 instrument (400 and
ν, cm : 3175 (N–H), 2922 (С–Н), 1688, 1609 (С=О).
1
1
00 MHz, respectively) in CDCl
3
or DMSO-d
6
, using TMS
H NMR spectrum (400 MHz, DMSO-d
2.66 (6H, s, 2,6-CH ); 6.46 (2H, s, 2 =CH); 7.13–7.18 (6H,
m, H-5,5',6, 6',7,7' Ar); 7.54 (2H, d, J = 4.6, H-8,8' Ar);
6
), δ, ppm (J, Hz):
or residual signals of the deuterated solvent as internal
standard. The signals of carbon nuclei were assigned by
using APT method, taking into account the reference
values for 13C NMR signals of various functional groups.
Elemental analysis was performed on a Carlo Erba 1106
CHN instrument. Melting points were determined on a
Kofler bench.
3
13
8.05 (1H, s, H-4); 12.06 (2H, br. s, 2NН). C NMR
spectrum (100 MHz, DMSO-d ), δ, ppm: 23.6 (CH -2,6);
15
6
3
92.5 (2 =CH); 115.4; 116.7; 123.7; 123.9 (C-4a,4a'); 124.2;
126.8 (C-8a,8a'); 132.4 (C-3,5 Py); 135.1 (C-4 Py); 145.4
(C-3,3'); 155.5; 156.6; 190.8 (2C=O). Found, %: C 68.01;
1
,1'-(1,4-Dihydro-2,6-dimethylpyridine-3,5-diyl)dietha-
H 4.73; N 14.26. C27
H
21
N
5
O . Calculated, %: C 67.63;
4
none (2) was synthesized according to a published
H 4.41; N 14.61.
16
procedure.
(3Z,3'Z)-3,3'-[(2,6-Dimethylpyridine-3,5-diyl)bis(2-oxo-
ethan-2-yl-1-ylidene)]bis(3,4-dihydro-2H-1,4-benzoxazin-
2-one) (6b) was obtained from pyruvate 4 (391 mg, 1 mmol)
and о-aminophenol (218 mg, 2 mmol) analogously to the
procedure for preparation of compound 6a. Yield 449 mg
(93%), orange crystals, mp 266–268°С (2-propanol–
1
,1'-(2,6-Dimethylpyridine-3,5-diyl)diethanone (3). A
suspension of 1,4-dihydropyridine 2 (10.0 g, 50 mmol) in
glacial acetic acid (25 ml) was vigorously stirred and
treated by the addition of chromium trioxide (7.5 g,
7
5 mmol) as a solution in water (10 ml) at such a rate that
–1
the temperature of the reaction medium did not exceed 30°С.
Following the addition of chromium trioxide, the reaction
mixture was stirred for 1 h at room temperature, then
poured into a beaker with ice and neutralized with aqueous
ammonia solution. After cooling, the precipitate was
filtered off, washed with ice water, air-dried, and
recrystallized from hexane. Yield 8.0 g (81%), white
dioxane). IR spectrum, ν, cm : 2979 (С–Н), 1760, 1622
1
(С=О), 1270 (С–О). H NMR spectrum (400 MHz,
CDCl
3
), δ, ppm (J, Hz): 2.78 (6H, s, 2,6-CH ); 6.74 (2H, s,
3
2 =CH); 7.20–7.25 (8H, m, H-5,5',6,6',7,7',8,8' Ar); 8.11 (1H,
13
s, H-4 Py); 13.02 (2H, br. s, 2NН). C NMR spectrum
(100 MHz, CDCl ), δ, ppm: 24.0 (2,6-CH ); 97.4 (2 =CH);
3
3
116.2; 117.2; 123.3; 124.5; 126.0 (C-8a,8a'); 132.2 (C-3,5
Py); 135.8 (C-4 Py); 139.3 (C-4a,4a'); 141.4 (C-3,3');
155.7; 158.3; 193.5 (2C=O). Found, %: C 67.90; H 4.35;
1
7
crystals, mp 69–70°С (mp 68–70°С ).
Diethyl (2Z,2'Z)-4,4'-(2,6-dimethylpyridine-3,5-diyl)bis-
(
2-hydroxy-4-oxobut-2-enoate) (4). A solution of 3,5-di-
N 8.48. C27
H
19
N
3
O . Calculated, %: C 67.36; H 3.98; N 8.73.
6
acetyl-2,6-dimethylpyridine 3 (4.0 g, 20 mmol) in benzene
60 ml) was treated with diethyl oxalate (11.7 g, 80 mmol),
X-ray structural study of compound 4 was performed
at room temperature on a Bruker Kappa Apex II
diffractometer (MoKα radiation, graphite monochromator).
Absorption was accounted for by using the SADABS
program.18 The structures were solved by direct method
and refined anisotropically with full-matrix method of least
squares by all reflections using the SHELXTL software
(
then metallic sodium (1.2 g, 50 mmol) was added with
stirring. Following the dissolution of sodium, the mixture
was stirred for additional 2 h. The precipitate of sodium
salts was then filtered off, washed with benzene, and dried.
The precipitate was dissolved in warm water, filtered
1
096