Synthesis of 6-bromomethyl-substituted derivatives of pyridin-2(1H)-ones and their reaction with nucleophiles

Article abstract of DOI:10.1023/B:COHC.0000044568.69817.bc

6-Bromomethyl-substituted derivatives of pyridin-2(1H)-ones were obtained by the bromination of 6-methyl-3,4-dihydropyridin-2(1H)-ones, and are the basis for the synthesis of thieno- and furo[3,4-b]pyridin-2(1H)-ones and also for obtaining new amino deriv

Full text of DOI:10.1023/B:COHC.0000044568.69817.bc

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
SYNTHESIS OF 6-BROMOMETHYL-SUBSTITUTED
DERIVATIVES OF PYRIDIN-2(1H)-ONES AND
THEIR REACTION WITH NUCLEOPHILES
Z. A. Kalme, R. A. Zhalubovskis, A. Shmidlers, J. Celmins, and G. Duburs
6-Bromomethyl-substituted derivatives of pyridin-2(1H)-ones were obtained by the bromination of
6-methyl-3,4-dihydropyridin-2(1H)-ones, and are the basis for the synthesis of thieno- and furo[3,4-b]-
pyridin-2(1H)-ones and also for obtaining new amino derivatives in the pyridin-2(1H)-one series.
Keywords: amino derivatives of pyridin-2(1H)-ones, pyridin-2(1H)-ones, thieno- and furo[3,4-b]-
pyridin-2(1H)ones, bromination.
Derivatives of pyridin-2(1H)-ones are of interest as compounds, depending on the structure, of
significant biological activity. In this series cardiovascular preparations (amrinone, milrinone) [1,2], and
compounds inhibiting HIV [3,4] were found and developed.
3,4-Dihydropyridin-2(1H)-ones 3a-c are synthesized by the condensation of β-aminocrotonic acid
methyl ester 1 with benzylidenecyanoacetamides 2 in a mixture of ethanol–acetic acid, 1:2. Judging by data of
1H NMR spectra pyridones 3 are a mixture of cis and trans isomers. According to the data of [5], the signals with
the greatest coupling constants (J34 = 7 Hz) correspond to the cis-isomer and with the least (J34 = 3 Hz) to the
trans-isomer. The ratio of cis and trans isomers was 1:9.
Bromination of the synthesized pyridin-2(1H)-ones 3 has been carried out with the aim of obtaining
furo- and thieno[3,4-b]pyridin-2(1H)-ones.
The use of N-bromosuccinimide as brominating agent (a specific reagent for brominating CH3 groups in
the allyl position) did not give the expected result. Bromo derivatives 5 were obtained by the interaction of
pyridones 3 with bromine in acetic acid. According to the data of [6], the formation of the oxidized form 5
occurs as a result of fission of a molecule of HBr from the proposed intermediate dibromo compound 4.
In a less polar solvent (CHCl3) and on irradiation with a lamp (500 watt), it is evident that the radical
mechanism dominates and bromination proceeds only at the methyl group. Unlike 6-bromomethylpyridin-2(1H)-
ones 5, the 6-bromomethyl-3,4-dihydropyridin-2(1H)-one 7 was difficult to obtain in the pure state, since on
crystallizing lactonization occurs with the formation of 2,5-dioxo-4-phenyl-1,2,3,4,5,7-hexahydrofuro[3,4-b]-
pyridine-3-carbonitrile (8). In the case of pyridin-2(1H)-ones 5 even after extended boiling in ethanol no
lactonization with the formation of furo[3,4-b]pyridin-2(1H)-ones 6 was observed (Scheme 1).
A band is observed in the IR spectra of dihydropyridones 3 for the stretching vibrations of the nitrile
group at 2260-2275 cm-1, but in the case of pyridones 5 it is displaced in the direction of lower frequencies by
25-35 cm-1, which indicates the presence of a more conjugated system.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV 1006; e-mail: kalme@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 1006-1013, July, 2004. Original article submitted March 1, 2004.
862
0009-3122/04/4007-0862©2004 Springer Science+Business Media, Inc.

Scheme 1
Ar
Ar
MeOOC
Me
CH
CN
CN
O
MeOOC
Me
+
H2N
C
O
N
H
3
NH2
2
1
Br2
Br2
CHCl3, h
MeCOOH
3a
ν
Ar
Ph
Br
CN
MeOOC
BrCH2
MeOOC
BrCH2
CN
O
N
H
O
N
H
4
7
_
HBr
EtOH
Ph
Ar
O
MeOOC
BrCH2
CN
O
CN
O
O
N
H
N
H
Ph
O
5
8
CN
O
O
N
H
6
2, 3, 5 a Ar = Ph, b Ar = m-NO2C6H4, c Ar = p-NO2C6H4
1
Doublet signals are displayed in the H NMR spectra of the dihydro derivatives 3 for the H-3 and H-4
protons, which disappear from the spectra of pyridones 5. On interacting pyridone 5a with thiourea initially
thiouronium salt 9 is formed, which in strongly alkaline medium is cyclized into 2,5-dioxo-4-phenyl-1,2,5,7-
tetrahydrothieno[3,4-b]pyridine-3-carbonitrile (10).
The signals of the 5-methoxycarbonyl and amino groups present in the spectrum of bromide 9 disappear
in the H NMR spectra of thiolactone 10. Since the electronegativity of the sulfur atom is less than that of
1
oxygen then in the IR spectra of the thiolactones the carbonyl group vibrations are displaced from 1731 (for
lactone 8) to 1670 cm-1.
On using hydrazine hydrate as the nucleophilic reagent not only is the bromine atom replaced by
hydrazine but the hydrazine hydrate also reacts with the 5-methoxycarbonyl group with the formation of
1
5-carbazoyl-3-cyano-6-hydrazinomethyl-4-phenylpyridin-2(1H)-one (11). Signals are observed in the H NMR
spectra for the methylene protons at 4.10 ppm, signals for the OMe group protons are absent and there is a
broadened singlet at 6.10 ppm which corresponds to 6 protons (2H2N-NH).
The results of the interaction of the bromomethyl derivatives 5 depend on the character of the amine
used.
863

Ph
Ph
MeOOC
CN
MeNHOC
MeNHCH2
CN
O
CH
N
H
O
N
N
H
+
2
Br
N
12
MeNH2
13
Ph
Ph
NH2
NH2
MeOOC
H2NNHOC
H2NNHCH2
CN
S=C
CN
H2NNH2
H2N
+
5a
SCH2
O
N
H
N
H
O
H2N
Br
9
HNR1R2
11
Ph
H2NR3
NaOH
MeOOC
CN
Ph
O
N
H
O
R1R2NCH2
CN
Ph
Ph
CN
O
COOMe
MeOOC
NC
14
S
N
H
C
C
H2
O
N
N
H
O
H
H2
N
10
R3
15
14 a R1 + R2 = −(CH2)5−; b R1 = H, R2 = CH2CH2Ph; c R1 = H, R2 = Ph;
d R1 = H, R2 = CH2COOEt; 15 a R3 = (CH2)3COOEt; b R3 = (CH2)3Me
The amino derivatives 14 are obtained by the reaction of pyridin-2(1H)-one 5a with piperidine,
2-phenylethylamine, aniline, and glycine ethyl ester hydrochloride. In the 1H NMR spectra of amines 14a-d the
signals for the 6-CH2 group protons are retained at 3.55-4.37 ppm.
TABLE 1. Characteristics of Compounds 3, 5, and 8-15
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C Yield, %
C
3
H
4
N
5
Br
6
S
7
1
2
8
9
3a
3b
3c
5a
5b
5c
8
C15H14N2O3
C15H13N3O5
66.72
66.65
57.35
57.14
57.37
57.14
51.40
51.89
45.69
45.94
46.01
45.94
65.60
66.14
45.05
45.40
5.03
5.22
3.95
4.16
4.01
4.16
2.90
3.19
2.32
2.57
2.22
2.57
4.05
3.96
3.53
3.57
10.29
10.36
13.28
13.33
13.39
13.33
7.80
8.07
10.47
10.71
10.55
10.71
10.73
11.02
13.16
13.24
174-176
187-189
190-193
182-184
168-170
170-172
222-224
172-174
57
60
52
42
43
45
52
85
C15H13N3O5
C15H11BrN2O3
C15H10BrN3O5
C15H10BrN3O5
C14H10N2O3
23.20
23.02
20.92
20.37
19.74
20.37
9
C16H15BrN4O3S
7.54
7.57
864

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
C14H8N2O2S×
×1/2H2O
60.74
60.64
2.96
3.27
10.33
10.10
11.79
11.56
152-154
40
11
12
C14H14N6O2
56.37
56.17
64.67
64.85
56.45
56.35
64.85
65.05
4.73
4.72
5.33
5.24
3.85
3.78
6.29
6.27
28.11
28.12
18.88
18.91
9.68
9.86
11.28
11.37
180-182
275-277
182-184
88-90
71
78
65
57
C16H16N4O2
13
C20H16BrN3O3
14a
C20H21N3O3×
×H2O
14b
14c
14d
15a
15b
C23H21N3O3
C21H17N3O3
C19H19N3O5
C36H33N5O8
C34H31N5O6
70.92
71.30
70.13
70.18
61.10
61.78
64.15
65.15
5.09
5.46
4.76
4.77
4.93
5.18
4.95
5.01
10.55
10.84
11.67
11.69
10.97
11.38
10.49
10.55
193-195
188-190
238-240
214-216
205-208
34
81
17
12
42
67.47
67.42
5.00
5.16
11.47
11.56
TABLE 2. Spectral Characteristics of Compounds 3, 5, and 8-15
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz)*
C=O
C≡N
NH
4
1
2
3
5
3а
1640,
1710
2260
2270
3170,
3280
2.40 (0.3H, s, 6-CH3, cis); 2.45 (2.7H, s, 6-CH3,
trans); 3.35 (3H, s, ОCH3); 4.45 (0.1H, d, J = 7,
3-H, cis); 4.22 (0.9H, d, J = 3.2, 3-H, trans);
4.95 (0.1H, d, J = 7.4, 4-H, cis); 4.58 (0.9H, d,
J = 3.2, 4-H, trans); 7.26 (5Н, m, C6H5);
10.48 (0.1H, s, NH, cis); 10.80 (0.9H, s, NH, trans)
1645,
1715
3180,
3280
2.35 (0.3H, s, 6-CH3, cis); 2.37 (2.7H, s, 6-CH3,
trans); 3.53 (0.3H, s, ОCH3, cis); 3.55 (2.7H, s,
ОCH3, trans); 4.28 (0.9H, d, J = 4, 3-H, trans);
4.60 (0.1H, d, J = 7.4, 3-H, cis); 4.72 (0.9H, d,
J = 4.0, 4-H, trans); 4.95 (0.1H, d, J = 7.4, 4-H,
cis); 7.40 (2Н, d, C6H4); 8.10 (2Н, d, C6H4);
10.50 (0.1H, s, NH, cis); 10.82 (0.9H, s, NH, trans)
3b
3c
1645,
1715
2275
3185,
3270
2.32 (0.3H, s, 6-CH3, cis); 2.34 (2.7H, s, 6-CH3,
trans); 3.44 (3H, s, ОCH3); 4.24 (0.9H, d, J = 3.0, 3-H,
trans); 4.48 (0.1H, d, J = 7.0, 3-H, cis); 4.55 (0.9H,
d, J = 3.0, 4-H, trans); 4.85 (0.1H, d, J = 7.0, 4-H,
cis); 7.33 (2Н, m , C6H4); 8.33 (2Н, m , C6H4);
10.44 (0.9H, s, NH, cis); 10.77 (0.1H, s, NH, trans)
1650,
1750
2240
2240
2240
3160,
3220
3.38 (3H, s, OCH3); 4.6 (2H, s, CH2);
7.38 (5H, m, C6H5); 13.10 (1H, br. s, NH)
5a
5b
5c
1650,
1735
3160,
3310
3.44 (3H, s, OCH3); 4.25 (2H, s, CH2);
7.97 (4H, m, C6H4); 13.42 (1H, br. s, NH)
1658,
1735
3160,
3310
3.45 (3H, s, OCH3); 4.60 (2H, s, CH2);
7.68 (2H, d, J = 8, C6H2); 8.32 (2H, d, J = 8, C6H2);
13.49 (1H, br. s, NH)
1678,
1731
2245
2222
3180,
3220,
3280
4.3 (1H, d, J = 8, CH); 5.1 (1H, d, J = 8, CH);
4.95 (2H, s, CH2); 7.35 (5H, s, C6H5);
11.37 (1H, s, NH)
8
9
1652,
1713
3240,
3330
3.35 (3H, s, OCH3); 4.44 (2H, s, CH2);
7.19-7.63 (5H, m, C6H5);
9.29 (4H, br. s, H2N−C=N+H2)
865

TABLE 2 (continued)
1
2
3
4
5
10
1655,
1670
2230
3140
4.5 (2H, s, CH2); 7.23-7.60 (5H, m, C6H5);
11.7 (1H, br. s, NH)
1647,
1693
2210
2218
3215,
3310
4.10 (2H, s, CH2); 5.60-6.70 (6H, br. s, 2NH−NH2);
11
12
7.35 (5H, s, C6H5)
1660,
1672
3160
2.35 (3H, s, CH2NHCH3); 2.82 (3H, s, CONHCH3);
4.02 (2H, s, CH2); 7.35 (5H, s, C6H5)
1670,
1728
2210
2218
2230
2220
2230
2230
3360
3.45 (3H, s, CH3); 6.12 (2H, s, CH2);
7.3-7.7 (5H, m, C6H5);
8.17-9.25 (5H, m, pyridinium)
13
14a
1645,
1693
3260,
3370
1.40 (6H, br. s, (−CH2−)3);
2.38 (4H, m, −CH2−N−CH2−); 3.37 (3H, s, OCH3);
3.55 (2H, s, CH2); 7.20-7.58 (5H, m, C6H5)
14b
14c
14d
15a
1640,
1730
3100,
3330
2.73−3.40 (4H, m, −CH2−CH2−);
3.44 (4H, s, CH3+NH); 4.10 (2H, s, CH2);
7.15-7.73 (10H, m, 2C6H5)
1650,
1730
3170,
3320,
3380
3.37 (4H, s, CH3+NH amine); 4.37 (2H, s, CH2);
6.47-7.60 (10H, m, 2C6H5)
1650,
1720,
1745
3150,
3210
1.26 (3H, m, CH2−CH3); 3.40 (4H, s, CH3+NH
amine); 3.60 (2H, s, CH2−СО); 4.22 (2H, q,
CH2−СН3); 4.3 (2H, s, CH2); 7.40 (5H, s, C6H5)
1.26 (3H, m, CH2−CH3); 2.00 (2H, m, 3-CH2);
2.28 (4H, m, 2CH2); 2.84 (2H, m, CH2);
3.45 (6H, s, 2OCH3); 3.96 (4H, s, CH2);
4.06 (2H, q, CH2−СН3); 7.36 (10H, m, 2C6H5)
1645,
1735
3140,
3210
15b
1685,
1730,
1745
2230
3150,
3260
0.78 (3H, t, CH2−CH3); 1.32 (4Н, m, CH2−CH2−CH3);
2.4 (2Н, t, CH2−CH2−CH2−CH3); 3.45 (6H, s, 2OCH3);
3.75 (4H, s, N(CH2)2); 7.25-7.62 (10H, m, 2C6H5);
12.85 (2H, br. s, 2NH)
_______
* The 1H NMR spectra of compounds 14a and 15a were taken in CDCl3.
On using aqueous methylamine solution under mild conditions (room temperature), besides replacement
of bromine by a methylamino group, amidation of the ester group at position 5 also occurs with the formation of
5-cyano-2-methylaminomethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-(N-methyl)carboxamide (12).
In their turn the application of γ-aminobutyric acid ethyl ester and n-butylamine as nucleophiles leads to
the formation of dimers 15, in which one molecule of amine is linked to two molecules of pyridone. The
1
integrated intensities of the proton signals of the pyridone ring substituents in the dimers 15 in the H NMR
spectra were doubled in comparison with the proton signals of the amine residue (R3).
It is known that quaternized derivatives of pyridine are potential agents for gene transfection [7].
We have shown the possibility of synthesizing quaternized derivatives in the pyridone series, using
pyridine as an example. Pyridinium bromide 13 was obtained by the interaction of pyridone 3a with pyridine. It
1
is seen from the H NMR spectra that compared with bromine the pyridinium cation displaces the signal of the
methylene protons towards low field from 4.50 to 6.10 ppm.
EXPERIMENTAL
1
The IR spectra were recorded on a Perkin-Elmer 580B instrument in Nujol, the H NMR spectra on a
WH 90/DC (90 MHz) instrument, internal standard was TMS. A check on the progress of reactions and the
homogeneity of substances was carried out by TLC on Silufol plates in acetone–hexane, 1:1.
866

The characteristics of the synthesized compounds are given in Tables 1 and 2.
5-Cyano-2-methyl-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylic Acid Methyl Ester (3a).
β-Aminocrotonic acid methyl ester 1 (1.15 g, 10 mmol) and benzylidenecyanoacetamide 2 (1.72 g, 10 mmol)
were dissolved in a mixture (20 ml) of acetic acid–ethanol, 1:2. The solution obtained was boiled for 3 h and
then maintained at 5-8°C for 24 h. The solid formed was filtered off, washed with ethanol, and crystallized from
ethanol. Compound 3a (1.6 g) was obtained.
Compounds 3b,c were obtained analogously.
2-Bromomethyl-5-cyano-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester (5a).
Dihydropyridone 3a (5 g, 18.5 mmol) was suspended in acetic acid (20 ml). Bromine (2 ml, 37 mmol) in acetic
acid (10 ml) was added dropwise with vigorous stirring during 50 min to the obtained suspension. The clear
solution obtained was left for 24 h at 20°C, and was then poured into water (800 ml) with vigorous stirring. The
resulting solid was filtered off, washed with a large amount of water, and recrystallized from ethanol. Compound
5a (2.7 g) was obtained
Compounds 5b,c were obtained analogously.
2-Bromomethyl-5-cyano-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylic Acid Methyl
Ester (7) and 2,5-Dioxo-4-phenyl-1,2,3,4,5,7-hexahydro-furo[3,4-b]pyridine-3-carbonitrile (8). Compound
3a (1.35 g, 5 mmol) was suspended in dry chloroform (12 ml) and a solution of bromine (0.88 g, 5.5 mmol) in
dry chloroform (3 ml) was added dropwise while boiling and irradiating with a lamp (500 watt). After the
addition of all the bromine, stirring and irradiation was continued for a further 10 min. The reaction mixture was
then poured into water (100 ml) and unpurified compound 7 (0.73 g) was filtered off. Furopyridone 8 (0.66 g)
was obtained after crystallization of compound 7 from ethanol.
S-[(5-Cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridyl)methyl]thiouronium
Bromide (9). Compound 5a (0.5 g, 1.44 mmol) was suspended in acetonitrile (7 ml), and thiourea (0.11 g,
1.44 mmol) was added. The mixture obtained was stirred at room temperature for 3 h. The solid formed was
filtered off, and washed with acetonitrile (2 x 5 ml). Compound 9 (0.52 g) was obtained.
2,5-Dioxo-4-phenyl-1,2,5,7-tetrahydrothieno[3,4-b]pyridine-3-carbonitrile (10). Compound 9 (0.4 g,
0.93 mmol) was added to a solution of NaOH (0.15 g, 3.7 mmol) in water (20 ml). The mixture was stirred for
24 h, acidified to pH ~4-5 with hydrochloric acid, and stirring continued for a further 30 min. The resulting solid
was filtered off, washed with water to a neutral reaction, and recrystallized from ethanol. Compound 10 (0.1 g)
was obtained.
3-Carbazoyl-5-cyano-2-hydrazinomethyl-6-oxo-4-phenyl-1,6-dihydropyridine (11).
Hydrazine
hydrate (55%) (2 ml) was added to a suspension of pyridone 5a (0.5 g, 1.44 mmol) in ethanol (7 ml), and the
mixture boiled for 40 min. The resulting solid was filtered off, and recrystallized from ethanol. Compound 11
(0.3 g) was obtained.
5-Cyano-2-methylaminomethyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-(N-methyl)carboxamide (12).
Aqueous 30% methylamine solution (1 ml, 8.6 mmol) was added to a suspension of pyridone 5a (0.3 g,
0.86 mmol) in ethanol (10 ml). The clear solution obtained was stirred at room temperature, and after 10 min a
precipitate formed, which was filtered off next day, and washed with ethanol (10 ml). Compound 12 (0.2 g) was
obtained.
1-[(5-Cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridyl)-methyl]pyridinium Bromide
(13). Pyridone 5a (0.94 g, 2.71 mmol) was dissolved with heating in acetone (75 ml) and pyridine (0.24 g,
2.71 mmol) was added. The solution obtained was stirred for 2 h at ~20°C, and the solvent evaporated in
vacuum. The residue was dissolved in methanol and left for 24 h at ~20°C. The solid was filtered off and
recrystallized from 2-propanol. Pyridinium bromide 13 (0.75 g) was obtained.
5-Cyano-6-oxo-4-phenyl-2-piperidinomethyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester
(14a). Piperidine (1.5 ml, 15.3 mmol) was added to a solution of pyridone 5a (0.5 g, 1.44 mmol) in DMF (8 ml).
The reaction mixture was stirred at 80°C for 1 h, cooled, and poured into water (15 ml). After a day the solid was
filtered off, and crystallized from ethanol–ether, 1:3. Compound 14a (0.3 g) was obtained.
867

5-Cyano-6-oxo-4-phenyl-2-[(2-phenylethyl)aminomethyl]-1,6-dihydropyridine-3-carboxylic Acid
Methyl Ester (14b). 2-Phenylethylamine (0.35 g, 2.88 mmol) was added to a solution of pyridone 5a (0.5 g,
1.44 mmol) in methanol (20 ml) . The solution obtained was boiled for 10 min, cooled, and poured into water
(50 ml). The solid was filtered off, and crystallized from ethanol–ether, 1:1. Compound 14b (0.19 g) was
obtained.
2-Anilinomethyl-5-cyano-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic Acid Methyl Ester
(14c). A solution of pyridone 5a (0.5 g, 1.44 mmol) and aniline (0.27 g, 2.88 mmol) in DMF (5 ml) was stirred
for 2 h at ~20°C, then poured into water (50 ml) acidified with hydrochloric acid (pH 4-5). The solid was filtered
off, and crystallized from ethanol. Compound 14c (0.42 g) was obtained.
5-Cyano-2-[(ethoxycarbonylmethyl)aminomethyl]-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylic
Acid Methyl Ester (14d). A solution of pyridone 5a (0.5 g, 1.44 mmol) and glycine ethyl ester hydrochloride
(0.41 g, 2.94 mmol) in DMF (5 ml) was stirred for 1 h 30 min at ~20°C, then poured into water (50 ml). The
solid was filtered off and crystallized from ethanol–ether, 1:1. Compound 14d (0.09 g) was obtained.
4-[Bis(5-cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridylmethyl)]aminobutyric Acid
Ethyl Ester (15a). A solution of pyridone 5a (0.5 g, 1.44 mmol), γ-aminobutyric acid ethyl ester hydrochloride
(0.48 g, 2.86 mmol), and triethylamine (0.4 ml, 2.86 mmol) in methanol (5 ml) was stirred at ~20°C for 6 h, and
left for a day. The reaction mixture was poured into acidified (pH ~2) water (50 ml). The solid was filtered off,
and crystallized from ethanol–chloroform, 10:1. Compound 15a (0.09 g) was obtained.
Bis(5-cyano-3-methoxycarbonyl-6-oxo-4-phenyl-1,6-dihydro-2-pyridyl-methyl)butylamine (15b). A
mixture of pyridone 5a (0.55 g, 1.58 mmol) and n-butylamine (0.31 ml, 3.14 mmol) in ethanol (35 ml) was
boiled for 2 h, cooled, and poured into acidified (pH ~4-5) water (150 ml). The solid was filtered off, and
crystallized from ethanol. Compound 15b (0.4 g) was obtained.
REFERENCES
1.
2.
3.
4.
5.
B. Wetzel and N. Havel, Trends Pharmacol. Sci., 91, 166 (1988).
C. Q. Earl, J. Linden, and J. Weglicki, J. Cardiovasc. Pharmacol., 8, 864 (1986).
R. Garg and S. P. Gupta, J. Enzyme Inhib., 12, 1 (1997).
V. Dolle, E. Fan, C. H. Nguyr, and A. M. Aubertin, J. Med. Chem., 28, 4679 (1995).
A. A. Krauze, E. E. Liepin'sh, Z. A. Kalme, Yu. E. Pelcher, and G. Ya. Dubur, Khim. Geterotsikl.
Soedin., 1504 (1984).
6.
7.
Z. A. Bomika, Yu. E. Pelcher, A. A. Krauze, Yu. Sh. Gol'dberg, and G. Ya. Dubur, Khim. Geterotsikl.
Soedin., 783 (1981).
Z. Hyvonen, A. Plotniece, I. Reine, B. Chekavichus, G. Duburs and A. Urtti, Biochim. Biophys. Acta,
1509, 451 (2000).
868