Synthesis and properties of derivatives of pyrimidin-5-ylpropanoic acids and 8-aryl-4-methyl- and 4,6-dimethyl-2-phenyl-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-7-ones

Article abstract of DOI:10.1134/S1070428015050218

Proceeding from 3-(4-methyl-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinyl)propanoic and 2-methylpropanoic acids by successive reactions of chlorination, amination, and heterocyclization 4-amino-substituted pyrimidines were synthesized: 5,6,7,8-tetrahydropyrido

Full text of DOI:10.1134/S1070428015050218

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 5, pp. 705–710. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.A. Harutyunyan, G.A. Panosyan, S.G. Chishmarityan, R.V. Paronikyan, H.M. Stepanyan, 2015, published in Zhurnal
Organicheskoi Khimii, 2015, Vol. 51, No. 5, pp. 722–726.
Synthesis and Properties of Derivatives
of Pyrimidin-5-ylpropanoic Acids and 8-Aryl-4-methyl-
and 4,6-Dimethyl-2-phenyl-5,6,7,8-tetrahydropyrido-
[
2,3-d]pyrimidin-7-ones
a
b
b
A. A. Harutyunyan , G. A. Panosyan , S. G. Chishmarityan ,
a
a
R. V. Paronikyan , and H. M. Stepanyan
a
Scientific and Technologic Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
Mnjoyan Institute of Fine Organic Chemistry, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: harutyunyan.arthur@yahoo.com
b
Center of Study of Molecular Structure, National Academy of Sciences of Armenia, Yerevan, Armenia
Received December 5, 2014
Abstract—Proceeding from 3-(4-methyl-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinyl)propanoic and 2-methyl-
propanoic acids by successive reactions of chlorination, amination, and heterocyclization 4-amino-substituted
pyrimidines were synthesized: 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine derivatives and 4-methyl-2-phenyl-
5
,6-dihydrobenzo[4',5']imidazo[2',1':6,1]pyrido[2,3-d]pyrimidine which we had previously obtained by
alternative method. Antibacterial properties of the synthesized compounds were studied.
DOI: 10.1134/S1070428015050218
Heterocyclic compounds of the pyrido[2,3-d]pyri-
The chlorination of initial acids 1a [3] and 1b [5]
midine series attract attention already for a long time
as potential sources of new biologically active
compounds of diverse effect [1, 2]. At the same time,
with POCl with subsequent workup results in 4-chloro
3
derivatives 2a and 2b. It is necessary to mention
that unlike the quite stable substituted 4-chloro-
pyrimidin-5-ylpropanoic acid 2a the corresponding
substituted 4-chloro-2-methylpropanoic acid 2b at
the attempt of purification is easily hydrolyzed into
the initial 4-hydroxypyrimidine 1b, therefore it should
be brought into further reactions immediately after
its preparation (see Experimental). By interaction of 4-
chloroderivatives 2a and 2b with amines 4-amino-
pyrimidin-5-ylpropanoic acids 3a–3k were syn-
thesized, whose cyclodehydration in PPA afforded the
corresponding 5,6,7,8-tetrahydropyrido[2,3-d]py-
rimidines 4a–4f. The attempt to synthesize 4-(2-
aminoaniline) derivative of propanoic acid 1a by
the reaction of 4-chloropyrimidine 2a with о-phe-
nylenediamine in various solvents (ethanol, dioxane,
butyl acetate, DMF) aiming at further cyclization
into pyridopyrimidine 5, unlike the similar synthesis
with monoamines, was unsuccessful due to the
formation of intractable mixture of compounds. At the
same time boiling 4-chloropyrimidine 2a and о-
phenylenediamine in isobutyl alcohol followed by
5
,6,7,8-tetrahydro derivatives of this system are
relatively few in number, and some of them show anti-
enzymatic and antitumor activities [3, 4], therefore
new compounds of this group may be of interest as
pharmacologically active compounds.
In continuation of the studies on the synthesis and
investigation of substituted pyrimidines and fused
pyrimidines [5, 6], basing on the convenient initial
compounds (pyrimidine-5-ylpropanoic acids 1a and 1b
and their 4-chloroderivatives 2a and 2b) we carried out
the synthesis of new 5,6,7,8-tetrahydropyrido[2,3-d]-
pyrimidines and some derivatives of acid 1a and
studied their antibacterial properties.
The retrosynthetic analysis of the discussed
heterocyclic system points to 4-amino-substituted
pyrimidin-5-ylpropanoic acids 3a–3k as key
intermediate compounds, which convert into the target
lactams 4a–4f through the intermolecular nucleophilic
cyclization.
7
05

7
06
HARUTYUNYAN et al.
Scheme 1.
NHR2
O
O
N
O
Cl
O
HN
OH
N
OH
N
OH
R1
R1
R1
Ph
Me
Ph
N
Me
2a, 2b
Ph
N
Me
_
1
a, 1b
3a 3k
NH2
NH2
,
PPA
PPA
NH2
PPA
NH2
Me
Me
N
R1
N
N
N
Ph
N
N
O
Ph
N
N
Ph
N
O
H N
2
N
R2
Me
_
5
6
4a 4f
1
1
2
1
1
, 2, R = H (a), Me (b); 3, R = H, R = Ph (a), 2-MeC
6
H
4
(b), 4-MeC
(i), 4-COОEtC
b), 4-Me (c), 4-OMe (d); R = Me, R = H (e), 4-COOC (f).
6
H
4
6 4 6 4
(c), 4-MeOC H (d), 4-COОEtC H (e); R = Me,
2
1
2
1
2
R = Ph (f), 2-MeC
6
H
4
(g), 4-MeC
6
H
4
2
(h), 2-MeOC
6
H
4
6
H
4
(j), H (k); 4, R = R = H (a); R = H, R = 2-Me
1
(
2 5
H
heating the obtained adduct in PPA provided,
instead of the expected substituted 5,6,7,8-tetra-
hydropyrido[2,3-d]pyrimidine 5, 4-methyl-2-phenyl
derivative of heterocyclic system 5,6-dihydrobenzo-
of synthesis of compound 6 from acid 1a and о-
phenylenediamine [5] we isolated a purine–pyrimidine
conjugate 7. Acid 1а was transformed into meta-
nitroderivative 8 under the action of equimolar amount
of KNO in H SO and into amide 9 by melting with
[
4',5']imidazo[2',1':6,1]pyrido[2,3-d]pyrimidine 6,
3
2
4
previously synthesized by a direct condensation of
propanoic acid 1a with о-phenylenediamine in PPA [5]
thiosemicarbadize in PPA. Compounds with asym-
metrical carbon atom were obtained as racemic isomer
mixtures (Scheme 2).
(
Scheme 1).
In the course of the study some transformations of
acid 1a were also performed. For instance, as a result
of its condensation with 5,6-diamino-1,3-dimethyl-
,2,3,4-tetrahydro-2,4-pyrimidinedione in conditions
Investigation of bioactivity of compounds 2a, 3a–
3k, 4a–4f, 6 and 8 on strains of gram positive
staphylococci (St. aureus 256, 1) and gram negative
bacilli (Sh. Flexneri 6858, E.coli 0-55) showed that
1
Scheme 2.
O
Me
NH2
N
O
Me
Me
O
N
O
N
N
,
O
N
NH
2
KNO3
H SO (8)
O
R2
O
N
N
HN
2
4
Me
1a, 1b
HN
N
Me
HN NH2
, PPA (9)
H
S
Ph
Me
NH2
R1
8
, 9
7
1
2
1
2
8
2 2
, R = NO , R = OH; 9, R = H, R = NH .
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015

SYNTHESIS AND PROPERTIES OF DERIVATIVES OF PYRIMIDIN-5-YLPROPANOIC ACIDS
707
the majority of the synthesized 4-substituted py-
rimidines and the corresponding 5,6,7,8-tetra-
hydropyrido[2,3-d]pyrimidines lack antibacterial
activity. Only several compounds, in particular, 3a, 3b,
3-(4-Anilino-6-methyl-2-phenylpyrimidin-5-yl)-
propanoic acid (3a). Yield 76%, mp 280–282°С, R
f
–
1
0.22. IR spectrum, ν, cm : 3240 (NH), 1704 (СО),
1
1657 (C=N). H NMR spectrum, δ, 2.35 s (3Н, СН ),
3
3
d, 4a, 4f and 8, exhibit weak activity, supressing
2.50–2.56 m (2Н, СН СО), 2.74–2.82 m (2Н, СН ),
2
2
the growth of gram positive and gram negative
microbes. At the same time the mentioned compounds
have significantly lower activity than furazolidone
control.
7.02 br.t (1Нarom, J 7.3 Hz), 7.25–7.31 m (2Нarom),
7.47–7.61 m (5Нarom), 8.05–8.11 m (2Н arom), 9.89 s
(1Н, NH), 12.60 br.s (1Н, СООН). Found, %: N
o
12.45. C H N O . Calculated, %: N 12.60.
2
0
19
3
2
3
-[4-Methyl-6-(2-methylanilino)-2-phenylpyri-
EXPERIMENTAL
midin-5-yl]propanoic acid (3b). Yield 82%, mp 291–
93°С, R 0.52. IR spectrum, ν, cm : 3262 (NH),
650 (СО), 1610 (C=N). H NMR spectrum, δ, ppm:
.19 s (3Н, СН ), 2.38 s (3Н, СН ), 2.52–2.58 m (2Н,
–
1
2
1
2
f
1
IR spectra were recorded on Nicolet Avatar 330
instrument from mulls in mineral oil, Н NMR spectra
were registered on a spectrometer Varian Mercury-300
1
3
3
СН ), 2.77–2.84 m (2Н, СН ), 6.98–7.05 m (1Нarom),
2
2
(
300 МHz) in DMSO-d –CCl , 1 : 3, internal reference
6 4
7.07–7.16 m (2Нarom), 7.27–7.51 m (4Нarom), 8.10–8.16
m (2Нarom), 9.13 s (1Н, NH), 12.51 br.s (1Н, ОН).
Found, %: N 12.33. C H N O . Calculated, %: N
TMS. Melting points were determined on Boёtius
micro-heating apparatus and were not corrected. TLC
was carried out on Silufol UV-254 plates in a system
ethanol–dichloroethane, 1 : 10 (compounds 2a, 3a–3k,
a–4f, 6, 8 and 9) and ethanol–dichloroethane, 1 : 4
compound 7), development in iodine vapor.
21
21
3
2
1
2.10.
-[4-Methyl-6-(4-methylanilino)-2-phenylpyri-
midin-5-yl]propanoic acid (3c). Yield 86%, mp 303–
3
4
(
–
1
3
(
(
04°С, R 0.56. IR spectrum, ν, cm : 3290 (NH), 1652
СО), 1610 (C=N). H NMR spectrum, δ, ppm: 2.28 s
3Н, СН ), 2.39 s (3Н, СН ), 2.47–2.53 m (2Н, СН ),
f
1
4
-Chloropyrimidine-5-ylpropanoic acids 2a and
b. A mixture of 0.01 mol of acid 1a or 1b in 20 mL
POCl was boiled at reflux for 4 h, the excess of POCl
2
3
3
2
3
3
2.77–2.84 m (2Н, СН ), 6.97–7.03 m (2Н, С Н ),
2 6 4
was distilled off, the residue was poured on 100 g of
ice and left in the cold for 4 h. Chloro derivative 2a
was filtered off and dried. Chloro derivative 2b was
extracted with dichloroethane (2 × 70 mL), the organic
layer was washed with 50 mL of water, dried
with Na SO and on removing the solvent 2.4 g (83%)
of oily chloroderivative 2b was obtained and
without further purification brought into reaction with
amines.
7
8
.39–7.45 m (3Н, Ph), 7.44–7.48 m (2Н, С Н ), 8.13–
6 4
.18 m (2Н, Ph), 9.56 s (1Н, NH), 12.44 br.s (1Н,
ОН). Found, %: N 12.42. C H N O . Calculated, %:
2
1
21
3
2
N 2.10.
-[4-Methyl-6-(4-methoxyanilino)-2-phenylpyri-
midin-5-yl]propanoic acid (3d). Yield 84%, mp 301–
3
2
4
–
1
3
02°С, R 0.39. IR spectrum, ν, cm : 3294 (NH), 1648
f
1
(
(
СО), 1610 (C=N). H NMR spectrum, δ, ppm: 2.39 s
3Н, СН ), 2.45–2.52 m (2Н, СН ), 2.77–2.84 m (2Н,
3
2
3
-(6-Methyl-2-phenyl-4-chloropyrimidin-5-yl)-
СН ), 3.74 s (3Н, ОСН ), 6.72–6.78 m (2Н, С Н ),
2 3 6 4
propanoic acid (2a). Yield 73%, mp 168–169°C
7.40–7.52 m (3Н, Ph), 7.46–7.51 m (2Н, С Н ), 8.12–
6
4
–
1
(
ethanol), R 0.73. IR spectrum, ν, cm : 1701 (CO),
8.18 m (2Н, Ph), 9.52 s (1Н, NH), 12.41 br.s (1Н,
ОН). Found, %: N 11.35. C H N O . Calculated, %:
f
1
1
660 s (C=N). H NMR spectrum, δ, ppm: 2.48–2.54
2
1
21
3
3
m, 3.01–3.07 m (2H each, СН СН ), 7.41–7.46 m
N 11.56.
-[6-Methyl-2-phenyl-4-(4-ethoxycarbonylani-
lino)pyrimidine-5-yl]propanoic acid (3e). Yield
2
2
(
3Нarom), 8.36–8.41 m (2Нarom), 11.99 b (1Н, СООН).
3
Found, %: N 9.86. C H ClN O . Calculated, %: N
1
4
13
2
2
1
0.12.
–
1
6
5%, mp 288–289°С, R 0.21. IR spectrum, ν, cm :
f
1
4-Aminoderivatives (3a–3j). A mixture of 0.01 mol
3262 (NH), 1707 (СО), 1644 (C=N). H NMR
spectrum, δ, ppm: 1.37 t (3Н, OCH СН , J 7.1 Hz),
of 4-chloropyrimidines 2a and 2b and 0.02 mol of the
corresponding amine in 7 mL of dioxane was boiled at
reflux during 7 h, left overnight, 20 mL of water was
added, the precipitate was filtered off, dried, and
recrystallized from DMF.
2
3
2.40 s (3Н, СН ), 2.55–2.60 m (2Н, СН ), 2.80–2.85 m
3
2
(2Н, СН ), 4.29 q (2Н, ОСН , J 7.1 Hz), 7.39–7.49 m
2
2
(3Н, Ph), 7.68–7.73 m and 7.84–7.88 m (2H each,
С Н ), 8.13–8.18 m (2Н, Ph), 10.01 s (1Н, NH), 12.44
6
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015

7
08
HARUTYUNYAN et al.
br.s (1Н, ОН). Found, %: N 10.20. C H N O .
(RS)-3-[4-Methyl-2-phenyl-6-(4-ethoxycarbonyl-
2
3
23
3
4
Calculated, %: N 10.36.
anilino)pyrimidin-5-yl]-2-methylpropanoic acid
(
3j). Yield 69%, mp 256–258°С, R 0.67. IR spectrum,
f
(
RS)-3-(4-Anilino-6-methyl-2-phenylpyrimidin-
–1
1
ν, cm : 3262 (NH), 1707 (СО), 1648 (C=N). H NMR
spectrum, δ, ppm: 1.22 d (3Н, CHСН , J 6.8 Hz), 1.37
t (3Н, CH СН , J 7.1 Hz), 2.35 s (3Н, 6-СН ), 2.62 d.d
5
2
1
1
-yl)-2-methylpropanoic acid (3f). Yield 75%, mp
89–290°С, R 0.62. IR spectrum, ν, cm : 3281 (NH),
644 (СО), 1600 (C=N). H NMR spectrum, δ, ppm:
.21 d (3Н, СН СН, J 6.6 Hz), 2.36 s (3Н, СН ), 2.60
d.d (1Н, HCH-CH, J 12.7, J 5.7 Hz), 2.76–2.87 m
2Н, HСН-СН), 6.93 m (1Н), 7.18 m (2Н) and 7.57 m
2Н, NHPh), 7.39–7.49 m (3H) and 8.14 m (2Н, Ph),
.58 s (1Н, NH), 12.42 b (1Н, ОН). Found, %: N
2.28. C H N O . Calculated, %: N 12.10.
–
1
3
f
1
2
3
3
2
3
(
1Н, НСН-CH, J 13.0, J 6.1 Hz), 2.82 d.d (1Н,
3
2
3
3
3
НСН-CH, J 13.0, J 7.6 Hz), 2.85–2.96 m (1Н,
CHСН ), 4.28 q (2Н, ОCH СН , J 7.1 Hz), 7.38–7.48
m (2Н, Ph), 7.67–7.72 m and 7.81–7.87 m (2H each,
С Н ), 8.12–8.17 m (2Н, Ph), 9.93 br.s (1Н, NH),
2
3
3
2
3
(
(
9
1
6
4
1
2.44 b (1Н, ОН). Found, %: N 9.76. C H N O .
24 25 3 4
2
1
21
3
2
Calculated, %: N 10.02.
(
RS)-3-[4-Methyl-6-(2-methylanilino)-2-phenyl-
(RS)-3-(4-Amino-6-methyl-2-phenylpyrimidin-5-
yl)-2-methylpropanoic acid (3k). A solution of 2.90 g
(0.01 mol) of 4-chloropyrimidine 2b in 30 mL of sa-
turated alcohol solution of ammonia was stirred for 4 h
at 100°С, distilled till dryness, the residue was treated
with water, filtered off, dried, and recrystallized
pyrimidin-5-yl]-2-methylpropanoic acid (3g). Yield
8%, mp 296–298°С, R 0.46. IR spectrum, ν, cm :
269 (NH), 1652 (СО), 1610 (C=N). H NMR spec-
trum, δ, ppm: 1.21 d (3Н, СНСН , J 6.8 Hz), 2.10 s (3Н,
–
1
5
3
f
1
3
2
СН ), 2.35 s (3Н, СН ), 2.60 d.d (1Н, НСН-CH, J
3
3
3
2
3
1
7
(
7
(
3.0, J 6.3 Hz), 2.78 d.d (1Н, НСН-CH, J 13.0, J
.7 Hz), 2.88–3.00 m (1Н, СНСН ), 6.97–7.03 m
from DMF. Yield 70%, mp 273–274°С, R 0.54. IR
f
–
1
3
spectrum, ν, cm : 3378, 3178 (NH ), 1646 (СО), 1607
(C=N). H NMR spectrum, δ, ppm: 1.09 d
(3Н, СН СН, J 6.7 Hz), 2.35 s (3Н, СН ), 2.45–2.73
2
1
1Н), 7.05–7.12 m (2Нarom), 7.30–7.35 m (1Нarom),
.42–7.53 m (3Нarom), 8.11–8.15 m (2Нarom), 9.03 br.s
1Н, NH), 12.50 b (1Н, ОН). Found, %: N 11.44.
C H N O . Calculated, %: N 11.63.
3
3
3
m (3Н, СНСН ), 6.30 b (1Н). 6.93 b (1Н, NН ),
2
2
2
2
23
3
2
7.40–7.47 m (3Нarom), 8.15 m (2Нarom), 12.40 b (1Н,
ОН).
(
RS)-3-[4-Methyl-6-(4-methylanilino)-2-phenyl-
Pyrido[2,3-d]pyrimidines (4a–4f). A mixture of
pyrimidin-5-yl]-2-methylpropanoic acid (3h). Yield
9%, mp 286–288°С, R 0.47. IR spectrum, ν, cm :
257 (NH), 1647 (СО), 1600 (C=N). H NMR spec-
trum, δ, ppm: 1.19 d (3Н, СНСН , J 6.7 Hz), 2.27 s
3Н, СН ), 2.34 m (3Н, СН ), 2.60 d.d (1Н, НСН-CH,
J 12.2, J 5.2 Hz), 2.75–2.88 m (2Н, НСН-СН), 6.98
m (2Н), 7.43 m (2Н, С Н ), 7.39–7.47 m (3Н), 8.14 m
–
1
0
.01 mol of 4-amino derivatives 3 and 5 g of PPA was
7
3
f
1
heated for 3 h on Wood’s metal bath at 170–180°С,
cooled to room temperature, and neutralized with
aqueous ammonia. After 3 h of standing in the cold the
precipitate was filtered off and recrystallized from
alcohol.
3
3
(
3 3
3
2
6
4
(
2Н, Ph), 9.47 s (1Н, NH), 12.42 br.s (1Н, ОН).
4
-Methyl-2,8-diphenyl-5,6,7,8-tetrahydropyrido-
Found, %: N 11.56. C H N O . Calculated, %: N
1
22
23
3
2
[2,3-d]pyrimidin-7(8H)-one (4a). Yield 67%, mp
52–254°С, R 0.45. IR spectrum, ν, cm : 1703 (СО),
657 (C=N). H NMR spectrum, δ, ppm: 2.57 s (3Н,
–
1
1.63.
2
1
f
1
(
RS)-3-[4-Methyl-6-(2-methoxyanilino)-2-phe-
СН ), 2.85–2.90 m (2Н, СН ), 3.07–3.13 m (2Н, СН ),
3
2
2
nylpyrimidin-5-yl]-2-methylpropanoic acid (3i).
Yield 65%, mp 242–243°С, R 0.57. IR spectrum, ν,
cm : 3323 (NH), 1650 (CO), 1600 (C=N). H NMR
spectrum, δ, ppm: 1.22 d (3Н, СНСН , J 6.8 Hz), 2.32
7
.18–7.34 m (5Н), 7.40–7.53 m (3Нarom), 7.97–8.02 m
(2Нarom). Found, %: N 13.17. C H N O. Calculated,
%: N 13.32.
f
–
1
1
20
17
3
3
3
2
3
s (3Н, СН ), 2.61 d.d (1Н, HСН-CH, J 13.1, J
4-Methyl-8-(2-methylphenyl)-2-phenyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-7(8H)-one (4b).
3
2
3
6
2
6
.5 Hz), 2.79 d.d (1Н, HСН-CH, J 13.1, J 7.4 Hz),
.93 m (1Н, СНСН ), 3.76 s (3Н, ОСН ), 6.85 m (2Н),
3
3
Yield 71%, mp 248–250°С, R 0.63. IR spectrum, ν,
f
–
1
1
.94 m (1Н) and 8.10 m (1Н, С Н ), 7.40–7.49 m (3Н)
cm : 1695 (СО), 1650 (C=N). H NMR spectrum, δ,
ppm: 2.07 s (3Н, СН C H ), 2.57 s (3Н, СН ), 2.85–
6
4
and 8.16 m (2Н, Ph), 8.30 s (1Н, NH), 12.48 b (1Н,
ОН). Found, %: N 11.72. C H N O . Calculated, %:
3
6
4
3
2
2
23
3
3
2.90 m (2Н, СН ), 3.08–3.14 m (2Н, СН ), 7.07–7.11
2
2
N 11.13.
m (1Н), 7.23–7.37 m (6Н), 7.94–7.98 m (2Нarom).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015

SYNTHESIS AND PROPERTIES OF DERIVATIVES OF PYRIMIDIN-5-YLPROPANOIC ACIDS
709
Found, %: N 12.48. C H N O. Calculated, %: N 40 min. The reaction mixture was left overnight, a
21
19
3
1
2.76.
solution of 0.8 g (0.01 mol) of NaHCO in 20 mL of
3
water was added, stirred for 15 min, distilled till
dryness, the residue was washed with water, filtered
off, dried, and heated on Wood’s metal bath with 5 g
of PPA for 2 h at 210–220°С. The cooled melt was
4
-Methyl-8-(4-methylphenyl)-2-phenyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-7(8H)-one (4c).
Yield 70%, mp 216–218°С, R 0.83. IR spectrum, ν,
f
–
1
1
cm : 1691 (СО), 1650 (C=N). H NMR spectrum, δ,
ppm: 2.49 s (3Н, СН C H ), 2.56 s (3Н, СН ), 2.82–
neutralized with solution of NH OH, the reaction
4
3
6
4
3
product was filtered off and recrystallized from
alcohol. Yield 55%, mp 176–178°С, no melting point
depression was observed with the sample of compound
2
.88 m (2Н, СН ), 3.05–3.10 m (2Н, СН ), 7.05–7.09
m (2Н), 7.25–7.35 m (5Н), 7.99–8.04 m (2Нarom).
Found, %: N 12.48. C H N O. Calculated, %: N
2
2
21
19
3
obtained by the method [5], R 0.60. IR spectrum, ν,
f
1
2.76.
-Methyl-8-(4-methoxyphenyl)-2-phenyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-7(8H)-one (4d).
Yield 80%, mp 170–172°С, R 0.80. IR spectrum, ν,
–
1
1
cm : 1644 (C=N). H NMR spectrum, δ, ppm: 2.64 s
4
(
3Н, СН ), 3.16 m (2Н), 3.32 m (2Н, СН СН ), 7.29 m
3
2
2
(
1Н), 7.37 m (1Н), 7.63 m (1Н) and 8.61 m (1Н,
f
С Н ), 7.46–7.55 m (3Н) and 8.49 m (2Н, Ph). Found,
6 4
–
1
1
cm : 1691 (СО), 1652 (C=N). H NMR spectrum, δ,
ppm: 2.56 s (3Н, СН ), 2.82–2.87 m (2Н, СН ), 3.04–
%
: N 17.80. C H N . Calculated, %: N 17.94.
20 16 4
3
2
1
,3-Dimethyl-8-[2-(4-methyl-6-oxo-2-phenyl-1,6-
dihydropyrimidin-5-yl)ethyl]-1Н-purine-2,6-
3H,9H)-dione (7). A mixture of 2.58 g (0.01 mol) of
3
.10 m (2Н, СН ), 3.89 s (3Н, ОСН ), 6.97–7.02 m
and 7.08–7.13 m (2H each, C H ), 7.26–7.36 m (3Н)
and 8.01–8.06 m (2Н, Ph). Found, %: N 12.41.
2
3
6
4
(
acid 1a and 1.70 g (0.01 mol) of 5,6-diamino-1,3-di-
methylpyrimidine-2,4(1H,3H)-dione in 15 g of PPA
was heated for 3 h on Wood’s metal bath at 210–220°С,
cooled to room temperature, the melt was neutralized
with aqueous ammonia, the precipitate was filtered off,
washed with water, dried, and recrystallized from
C H N O . Calculated, %: N 12.17.
2
1
19
3
2
(
RS)-4,6-Dimethyl-2,8-diphenyl-5,6,7,8-tetra-
hydropyrido[2,3-d]pyrimidin-7-one (4e). Yield 65%,
–
1
mp 214–215°С, R 0.65. IR spectrum, ν, cm : 1704
f
1
(
(
(
CO) 1650 (C=N). H NMR spectrum, δ, ppm: 1.36 d
3
3Н, СНСН , J 6.6 Hz), 2.56 s (3Н, СН ), 2.79 d.d
3
3
DMF. Yield 60%, mp >300°С, R 0.61. IR spectrum, ν,
f
2
3
–
1
1
1Н, HСН-СН, J 15.2, J 11.8 Hz), 2.91 m (1Н,
cm : 3150 (NH), 1704, 1700 (CO), 1648 (C=N). H
2
3
СНСН ), 3.19 d.d (1Н, HСН-СН, J 15.2, J 5.6 Hz),
3
NMR spectrum, δ, ppm: 2.28 s (3Н, СН ), 2.91 br.s
3
7
7
.19 m (2Н), 7.24–7.32 m (3Н), 7.40–7.53 m (3Н) and
.99 m (2Н, 2C H ). Found, %: N 12.58. C H N O.
(
4Н, СН СН ), 3.28 s (3Н, NСН ), 3.50 s (3Н, NСН ),
2 2 3 3
6
5
21 19
3
7
.39–7.50 m (3Н, Ph), 8.12–8.20 m (2Н, Ph), 12.50 b
Calculated, %: N 12.76.
(
1Н, NH), 13.07 br.s (1N, NH). Found, %: N 21.15.
C H N O . Calculated, %: N 21.42.
Ethyl (RS)-4-(4,6-dimethyl-7-oxo-2-phenyl-
,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-8-yl)
20 20
6
3
5
3
-[4-Methyl-2-(3-nitrophenyl)-6-oxo-1,6-dihyd-
benzoate (4f). Yield 69%, mp 210–211°С, R 0.60.
f
ro-pyrimidin-5-yl]propanoic acid (8). To a mixture
of 2.58 g (0.01 mol) of acid 1a in 10 g of conc. H SO
–
1
1
IR spectrum, ν, cm : 1715 (СО), 1692 (C=N). H
2
4
NMR spectrum, δ, ppm: 1.29 d (3Н, СНСН , J 6.7 Hz),
3
cooled with flowing water was added in small portions
.11 g (0.011 mol) of KNО , the reaction mixture
1
2
.37 t (3Н, СН СН О, J 7.1 Hz), 2.55 s (3Н, 4-СН ),
3 2 3
1
3
.82 d.d (1Н, HСН-CH, J 15.5, 12.3 Hz), 3.01 m (1Н,
was heated for 1 h at 130–135°С and poured on 100 g
of ice. The precipitated product was filtered off,
dried, and recrystallized from ethanol. Yield 76%, mp
CHCH ), 3.21 d.d (1Н, HСН-CH, J 15.5, 6.0 Hz), 4.37
3
3
,3',4
q (2Н, ОCH , J 7.1 Hz), 7.33–7.40 m (3Н, Н , Ph),
2
3
',5'
2',6'
7
(
.44 m (2Н, Н , C H ), 7.95 m (2Н, Н , Ph), 8.10 m
–1
6
4
2
1
68–270°С, R 0.49. IR spectrum, ν, cm : 1700 (CO),
652 (C=N). H NMR spectrum, δ, ppm: 2.43 s
2
',6'
f
2Н, Н , C H ). Found, %: N 10.60. C H N O .
1
6
4
24 23
3
3
Calculated, %: N 10.47.
(
3Н, СН ), 2.41–2.46 m (2Н, СН ), 2.72–2.79 m
3
2
5
1
2
4
-Methyl-2-phenyl-5,6-dihydrobenzo[4',5']-
(2Н, СН ), 7.70 d.d (1Н, Н , Ar, J 8.1, J 7.9 Hz),
8.31 d.d.d (1Н, Н , Ar, J 8.1, J 2.0, J 0.9 Hz),
8.59 d.d.d (1Н, Н , Ar, J 7.9, J 2.0, J 0.9 Hz), 9.06
t (1Н, Н , Ar, J 2.0 Hz), 12.24 b (2Н, NH, СООН).
2
6
1
2
3
imidazo[2',1':6,1]pyrido[2,3-d]pyrimidine (6). A so-
lution of 2.76 g (0.01 mol) of chloropyrimidine 2a and
.08 g (0.01 mol) of о-phenylenediamine in 20 mL of
4
1
2
3
2
1
anhydrous isobutyl alcohol was boiled at reflux for 3 h,
light-yellow precipitate started to appear already after
Found, %: N 13.69. C14
13.86.
H N O . Calculated, %: N
13 3 5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015

7
10
HARUTYUNYAN et al.
3
-(4-Methyl-6-oxo-2-phenyl-1,6-dihydropyrimi-
din-5-yl)propanamide (9). A mixture of 2.58 g
0.01 mol) of acid 1a and 1.37 g (0.015 mol) of thio-
REFERENCES
1
2
3
4
. Abdolmohammadi, S. and Balalaie, S., Int. J. Org.
Chem., 2012, vol. 2, p. 7.
(
semicarbazide in 5 g of PPA was heated for 1 h on
Wood’s metal bath at 165°С, cooled, neutralized with
aqueous ammonia, the precipitate was filtered off, dried,
and recrystallized from ethanol. Yield 73%, mp 263–
64°С, R 0.63. IR spectrum, ν, cm : 3269, 3070 (NH ),
640 (CO), 1610 (C=N). H NMR spectrum, δ, ppm:
.24 s (3Н, СН ), 2.80 br.t (2Н, СН , J 7.4 Hz), 3.00 br.t
. Nia, R.H., Mamaghani, M., Tabatabaeian, K., Shirini, F.,
and Rassa, M., Acta Chim. Slov., 2013, vol. 60, p. 889.
. Hullar, T.L. and French, W.C., J. Med. Chem., 1969,
vol. 12, p. 424.
. Taylor, E.K., Beardsley, G.P., Shih, C., and Hamby, J.M.,
EP Patent Appl. no. 255.228; Chem. Abstr., 1988,
vol. 109, no. 73909g.
–
1
2
1
2
f
2
1
3
2
(
2Н, СН , J 7.4 Hz), 6.97 b (1Н) and 6.97 br.s (1Н,
2
5. Harutyunyan A.A., Khim. Zh. Armenii, 2012, vol. 65,
NH ), 7.47–7.59 m (3Н) and 8.07–8.12 m (2Н, Ph),
p. 257.
2
1
2.62 b (1Н, NH). Found, %: N16.17. C H N O .
6. Harutyunyan A.A., Khim. Zh. Armenii, 2012, vol. 65, p.
1
4
15
3
2
Calculated, %: N 16.33.
317.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 5 2015