Synthesis and reactivity of 3-amino-9-methoxymethyl-7-methyl-3,4- dihydropyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones

Article abstract of DOI:10.1007/s10593-007-0226-3

The reaction of acyl derivatives of ethyl 3-aminothieno[2,3-b]pyridine-2- carboxylate with hydrazine hydrate gives a series of tricyclic 3-amino-3,4-dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones containing aliphatic, aromatic, or heteroaromatic fragments at C₍₂₎. The reactions of 3-aminopyridothieno[3,2-d]pyrimidin-4-ones with aldehydes, formamide, 2,5-dimethoxytetrahydrofuran, acetic anhydride, and Raney nickel were studied.

Full text of DOI:10.1007/s10593-007-0226-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
SYNTHESIS AND REACTIVITY
OF 3-AMINO-9-METHOXYMETHYL-
7-METHYL-3,4-DIHYDROPYRIDO-
[3',2':4,5]THIENO[3,2-d]PYRIMIDIN-
4-ONES
E. S. Kostenko1, M. M. Lipunov1, E. A. Kaigorodova2, and L. D. Konyushkin3
The reaction of acyl derivatives of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate with hydrazine
hydrate gives a series of tricyclic 3-amino-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-ones
containing aliphatic, aromatic, or heteroaromatic fragments at C(2). The reactions of 3-amino-
pyridothieno[3,2-d]pyrimidin-4-ones with aldehydes, formamide, 2,5-dimethoxytetrahydrofuran, acetic
anhydride, and Raney nickel were studied.
Keywords: 3-amino-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-ones, hydrazine hydrate, ethyl
3-aminothienopyridinecarboxylate, desulfurization, Raney nickel.
Interest in 3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-ones is due to their analgesic [1, 2],
anti-inflammatory [2], and antimicrobial activity [3] and has led to a large number of publications on the
synthesis of these compounds.
The most common method for the synthesis of these compounds is the reaction of
pyridothienooxazinones with hydrazine hydrate [1, 4-7]. Other methods have also been used such as the reaction
of hydrazine hydrate with ethyl 3-methylcarboxamidothieno[2,3-b]pyridine-2-carboxylate [4] or ethyl
3-[(E)-1-ethoxymethylidenamino]thieno[2,3-d]pyridine-2-carboxylate [7]. None of these methods permits us to
vary the substituents at C(2) in the pyrimidine ring, which may be important in the synthesis of compounds with
potential biological activity.
We propose a two-step synthesis of 3-amino-3,4-dihydro[3',2':4,5]thieno[3,2-d]pyrimidin-4-ones,
permitting the introduction of various substituents at C(2) of the pyrimidine ring (Scheme 1). The first step entails
the reaction of ethyl 3-aminothienopyridinecarboxylate [8] 1 with acid chlorides to give amides 2a-j in
56-94% yield. The second step entails heating amides 2a-e,g-i with a five-fold excess of hydrazine hydrate in
ethanol, 2-propanol, or 1-butanol at reflux to give the corresponding pyrimidinones 3a-h in 42-84% yield
(Table 1).
__________________________________________________________________________________________
1Kuban State Technological University, Krasnodar 350072, Russia; e-mail: kosten_kate@mail.ru.
2Kuban State Agrarian University, Krasnodar 350044; e-mail: e_kaigorodova@mail.ru. 3N. D. Zelinsky Institute
of Organic Chemistry, Russian Academy of Sciences, Moscow 119992, Russia; e-mail:
LeonidK@chemical-block.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11,
pp. 1720-1732, November, 2007. Original article submitted October 2, 2006.
1466
0009-3122/07/4311-1466©2007 Springer Science+Business Media, Inc.

It was established that in the reaction of 2f with hydrazine hydrate, transacylation of the hydrazide at the
NH2 group of the hydrazine fragment occurs with formation of bright-yellow hydrazide 4 in 44% yield instead of
ring closure during formation of the hydrazide.
Scheme 1
O
O
O
H
Me
Me
Me
Me
N
COR
OEt
NH2
R
Cl
OEt
O
PhMe
S
S
O
N
N
2a–j
1
.
NH2NH2 H2O
AlkOH
R
O
O
O
Me
Me
N
NH2
H
N
NH2
N
N
H
O
O
S
Me
O
Me
N
S
Me
N
4
3a–h
2, 3 а R = Et, b R = n-Bu, c R = i-Bu, d R = Fur, e R = Ph,
2f R = 2-MeOС6Н4, 2g, 3f R = 4-MeOС6Н4, 2h, 3g R = 2-O2NС6Н4,
2i, 3h R = 4-O2NС6Н4, 2j R = 2-MeС6Н4; Alk = Et, i-Pr, n-Bu
Starting amide 2j was recovered in an attempt to synthesize the 3-aminopyrimidinone containing the
o-tolyl substituent at C(2) even upon prolonged heating at reflux.
Amides 2 and pyrimidinones 3 are colorless crystalline compounds.
The IR spectra of amides 2a-j show one NH group stretching band at 3320-3140 cm-1 as well as bands
for the ester carbonyl group at 1725-1685 cm-1 and amide carbonyl group at 1680-1640 cm-1 (Table 2). The
signal for the proton giving rise to the signal at 9.66-10.72 ppm in the 1H NMR spectra of 2 was assigned to the
amide group.
The IR spectra of amides 3a-h differ from the spectra of the starting amides by the presence of stretching
bands at 3325-3265 and 3230-3170 cm-1 belonging to the amino group of the N–NH2 fragment and only one
1
endocyclic carbonyl group band at 1690-1655 cm-1. The H NMR spectra of 3 unlike the spectra of the starting
amides 2 lack the upfield signals for the ethyl group but have a signal for NH2 group protons at 5.66-6.02 ppm.
1
The IR and H NMR spectra of hydrazide 4 differ fundamentally from both the spectra of starting
amide 2f and the spectra of 3-aminopyridothieno[3,2-d]pyrimidin-4-ones 3a-h. The IR spectra of 4 have three
pronounced bands at 3405-3315 cm-1 assigned to the N–H stretching vibrations of the amino and hydrazide
groups as well as a strong hydrazide carbonyl group stretching band νC=O at 1650 cm-1. The characteristic feature
1
of the H NMR spectra of 4 is presence of two broad singlets with intensity 2H for the protons of the amino
group (6.98 ppm) and hydrazide group (9.82 ppm).
A study of the reactivity of products 3 involved an investigation of the reactions of these compounds
with aldehydes, acetic anhydride, 2,5-dimethoxytetrahydrofuran, formamide, and Raney nickel.
1467

TABLE 1. Characteristics of Compounds 2-10
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
3
H
4
N
5
1
2
6
7
2a
2b
2c
2d
2e
2f
2g
2h
2i
C16H20N2O4S
C18H24N2O4S
C18H24N2O4S
C18H18N2O5S
C20H20N2O4S
C21H22N2O5S
C21H22N2O5S
C20H19N3O6S
C20H19N3O6S
C21H22N2O4S
C14H16N4O2S
C16H20N4O2S
C16H20N4O2S
C16H14N4O3S
C18H16N4O2S
C19H18N4O3S
C18H15N5O4S
C18H15N5O4S
C19H20N4O4S
C24H26N4O2S
C24H26N4O3S
C25H28N4O3S
C23H23N5O4S
C25H27N5O3S
C25H29N5O2S
C23H22Cl2N4O2S
C23H23BrN4O2S
C23H23BrN4O3S
C24H23BrN4O4S
C20H24N4O4S
C20H22N4O2S
57.18
57.13
59.30
59.32
59.26
59.32
57.78
57.74
62.44
62.48
60.92
60.85
60.93
60.85
55.99
55.94
56.00
55.94
63.37
63.30
55.21
55.25
57.77
57.81
57.78
57.81
56.10
56.13
61.39
61.35
59.72
59.67
54.47
54.40
54.35
54.40
56.70
56.99
66.27
66.33
63.95
63.98
64.70
64.63
59.39
59.34
62.79
62.87
64.73
64.77
56.40
56.44
55.38
55.31
53.68
53.60
53.00
53.04
57.74
57.68
62.90
62.81
5.95
5.99
6.70
6.64
6.71
6.64
4.80
4.85
5.30
5.24
5.31
5.35
5.29
5.35
4.40
4.46
3.99
4.46
5.49
5.56
5.37
5.30
6.12
6.06
6.02
6.06
4.17
4.12
4.51
4.58
4.69
4.74
3.77
3.80
3.84
3.80
5.12
5.03
6.09
6.03
5.97
5.82
6.05
6.07
4.90
4.98
5.77
5.70
6.27
6.31
4.61
4.53
4.61
4.64
4.47
4.50
4.33
4.27
5.83
5.81
5.72
5.80
8.29
8.33
7.74
7.69
7.65
7.69
7.53
7.48
7.26
7.29
6.79
6.76
6.80
6.76
9.85
9.78
9.83
9.78
6.98
7.03
18.37
18.41
16.80
16.85
16.89
16.85
16.32
16.36
15.98
15.90
14.60
14.65
17.56
17.62
17.59
17.62
14.05
13.99
12.92
12.89
12.38
12.43
11.98
12.06
15.00
15.04
14.70
14.66
15.18
15.11
11.50
11.45
11.28
11.22
10.93
10.87
10.35
10.31
13.38
13.45
14.68
14.65
109-110
111-112
125-126
97-98
89
94
81
87
93
94
75
81
67
56
84
83
80
42
58
49
54
56
44
80
98
84
77
92
80
90
91
89
66
80
75
110-111
136-137
144-145
199-200
187-188
144-145
275-276
166-167
196-197
272-273
249-250
229-230
256-257
>300
2j
3a
3b
3c
3d
3e
3f
3g
3h
4
215-216
183-184
221-222
170-171
217-218
297-298
225-226
229-230
179-180
216-217
227-228
164-165
243-244
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6
7a
1468

TABLE 1. (continued)
1
2
3
4
5
6
7
7b
7c
C22H18N4O2S
C23H20N4O3S
C17H19N5OS
C18H15N3O2S
C19H17N3O3S
C16H19N3O2S
C14H17N3O2
C16H21N3O2
C19H19N3O3
C18H18N4O2
65.72
65.65
63.93
63.87
59.87
59.80
64.00
64.08
62.20
62.11
60.59
60.54
64.80
64.85
66.82
66.88
4.48
4.51
4.61
4.66
5.55
5.61
4.51
4.48
4.63
4.66
5.98
6.03
6.67
6.61
7.42
7.37
14.00
13.92
13.02
12.95
20.44
20.51
12.49
12.45
11.53
11.44
13.20
13.24
16.27
16.20
14.59
14.62
261-262
262-263
264-265
>300
86
75
57
53
62
50
25
52
62
68
8
9a
9b
9c
>300
270-271
199-200
209-210
235-236
128-129
10a
10b
10c
10d
67.70
67.64
67.13
67.07
5.62
5.68
5.60
5.63
12.39
12.45
17.45
17.38
Product 3b was taken for the study of the reaction yielding 3-[(E)-1-arylmethylidenamino]-
3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-ones 5a-j since this compound was more soluble in toluene
than the other products obtained. Pyrimidinones 5 were obtained by heating the starting 3-aminopyrimidinone 3b
with aromatic aldehydes in toluene in the presence of p-toluenesulfonic acid at reflux with the azeotropic
removal of water. Pyrimidinones 5 are stable crystalline compounds and were obtained in 66-98% yield.
Scheme 2
Bu
N
Bu
N
O
O
Me
Me
Me
N
N
O
H
TsOH
PhMe
N
NH2
R1
R1
+
O
O
S
S
Me
N
N
5a–j
3b
5 a R1 = 4-MeС6Н4, b R1 = 4-MeOС6Н4, c R1 = 4-EtOС6Н4, d R1 = 4-O2NС6Н4,
e R1 = 4-AcNHС6Н4, f R1 = 4-Me2NС6Н4, g R1 = 3,4-Cl2С6Н3, h R1 = 4-BrС6Н4,
Br
O
O
i R1 = 2-HO-5-BrС6Н3, j R1 =
The characteristic of the IR spectra of pyrimidinones 5a-j is lack the exocyclic amino group νN–H
1
stretching band (Table 2). The structure of these products was also supported by their H NMR spectra, which
lack the signal for N–NH2 protons at 8.64-10.90 ppm but have a singlet for the CH=N group methine proton at
8.64-9.27 ppm. The protons of the aromatic rings and substituents in these compounds are found in their
characteristic spectral ranges.
Colorless crystalline diacyl derivative 6 is formed in 80% yield upon heating 3-amino-2-isobutyl-
pyridothienopyrimidine 3c in acetic anhydride at reflux for 6 h.
1469

The attemt to synthesize N-substituted pyrroles 7a-c was also successful. Pyrroles 7a-c were
synthesized in 75-86% yield according to our previous procedure [9] by heating 3-aminopyrimidinones 3c,e,f
with 2,5-dimethoxytetrahydrofuran in glacial acetic acid at reflux for 1-2.5 h.
Scheme 3
R
O
Me
N
NH2
N
O
S
N
Me
3c,e,f
DMTHF
Ac2O
AcOH
O
Me
R
N
R
O
Me
O
Me
Me
N
N
N
N
N
O
Me
O
O
S
S
N
Me
N
6
7a–c
3c, 6, 7a R = i-Bu, 3e, 7b R = Ph, 3f, 7c R = 4-MeОС6Н4,
DMTHF-dimethylhydrofuran
The structures of 6 and 7a-c were in accord with the IR and 1H NMR spectral data (Table 2).
The reactions of 3-aminopyridothienopyrimidinones 3 with formamide proceed through different
pathways. Thus, heating pyrimidinone 3b containing an n-butyl group at C(2) in formamide at reflux gives
pyrido[3',2':4,5]thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine 8 in 57% yield. On the other hand, the reaction of
tricyclic pyrimidinones 3e,f, which have aromatic substituents, with formamide is accompanied by cleavage of
the N–NH2 bond, leading to colorless crystalline pyrimidinones 9a,b, which are unsubstituted at C(3) and have
melting points above 300°C.
Scheme 4
R
O
Me
N
N
N
R = Alk
R = Ar
N
S
N
Me
Me
O
R
O
8
Me
Me
N
NH2
R
NH2
N
O
N
NH
O
O
S
N
3b,e,
S
N
Me
9a,b
3b, 8 R = n-Bu, 3e, 9a R = Ph, 3f, 9b R = 4-MeОС6Н4
1470

The molecular masses of 8, 9a,b determined by mass spectrometry correspond to the calculated values.
1
The H NMR spectra of tetracyclic derivative 8 and pyrimidinones 9a,b lack the signal for NH2 group protons
found for starting 3-aminopyrimidinones 3b,e,f. The singlet with intensity 1H in the 1H NMR spectrum of 8 was
assigned to the CH fragment of the triazole ring (Table 2), while the singlet at 12.97-13.04 ppm in the spectra of
9a,b was assigned to the pyrimidinone NH proton.
The desulfurization of dihydropyridothienopyrimidinones 3 using Raney nickel was studied for the
preparation of 4-(3-pyridyl)-1,6-dihydro-6-pyrimidinones 10. Pyrimidinone 9c was obtained in 50% yield by
this reaction according to Kadushkin et al. [10].
The 1H NMR spectrum of 9c has a broad singlet with intensity 1H at 12.78 ppm, which was assigned to
the pyrimidine N–H proton. The mass spectrum of this compound has a molecular ion peak with mass 317,
which is in accord with the calculated molecular mass.
Assuming that 9 is an intermediate in the formation of 10, variation of the reaction conditions and time
should provide the optimal conditions for the preparation of pyridyldihydropyrimidinones 10a-d. The reductive
desulfurization could be carried out with a ten-fold excess of Raney nickel, using a mixture of ethanol and DMF
as the solvent and maintaining the temperature of the reaction mixture at 100-110°C.
The reaction of 3-amino-2-(4-nitrophenyl)-3,4-dihydropyridothienopyrimidinone 3h with Raney nickel
gives, as expected, reduction of the nitro group to an amino group to give 2-(4-aminophenyl)-4-(3-pyridyl)-
1,6-dihydro-6-pyrimidinone 10d in addition to cleavage of the N–NH2 bond and desulfurization of the thiophene
ring. The yield of pyrimidinones 10a-d was 25-68%.
Scheme 5
Me
R
O
N
N
NH2
O
S
Me
N
3a-c,f,h
Ni / Ra
EtOH + DMF
Ni / Ra
EtOH
Me
O
Me
O
R
R
N
NH
N
NH
O
O
S
Me
N
Me
N
10a–d
9c
3а, 10a R = Et, 3b, 9c R = n-Bu, 3c, 10b R = i-Bu, 3f, 10c R = 4-MeOС6Н4,
3h R = 4-O2NС6Н4, 10d R = 4-H2NС6Н4
1
The structure of 10a-d was supported by the spectral data. The H NMR spectra of these compounds
have signals for all the protons expected for these structures. A singlet for the pyrimidine ring proton at C(6) is
observed at 6.32-6.50 ppm, while the signal at 8.50-8.60 ppm was assigned to the pyridine ring proton at
unsubstituted C(2). The broad signal at 12.35-12.71 ppm belongs to the pyrimidine NH fragment. The mass
spectra of these compounds have molecular ion peaks with masses equal to the calculated molecular masses. The
IR spectrum of 10d has two amino group stretching bands at 3325-3190 cm-1.
1471

TABLE 2. Spectral Characteristics of the Compounds 2-10
IR spectrum,
Com-
ν, cm-1
1Н NMR spectrum, δ, ppm (J,Hz)
pound
NH
2
C=O
1
3
4
2a
3280
1710,
1680
1.00 (3Н, t, J = 7.2, NHCOCH2CH3); 1.16 (3Н, t, J = 7.1,
COОCH2CH3); 1.30 (2Н, q, J = 7.2, NHCOCH2CH3); 2.62 (3H,
s, CH3-Py); 3.40 (3H, s, OCH3); 4.30 (2Н, q, J = 7.1, COОCH2CH3);
4.87 (2H, s, CH2O); 7.40 (1H, s, HPy); 9.66 (1Н, br. s, NH)
2b
2c
3280
1720,
1665
0.94 (3Н, t, J = 6.7, NHCOC3H6CH3); 1.29 (3Н, t, J = 7.1,
COОCH2CH3); 1.40 (2Н, m, NHCOC2H4СН2CH3); 1.65 (2Н, m,
NHCOCH2СН2С2Н5); 2.38 (2Н, t, J = 7.0, NHCOСН2C3H7);
2.62 (3H, s, CH3-Py); 3.40 (3H, s, OCH3); 4.29 (2Н, q, J = 7.1,
CОOCH2CH3); 4.89 (2H, s, CH2O); 7.40 (1H, s, HPy);
9.73 (1H, br. s, NH)
3285
1700,
1665
1.00 (6Н, d, J = 6.1, СOCH2СН(CH3)2); 1.30 (3Н, t, J = 7.1,
COОCH2CH3); 2.14 (1Н, m, СOCH2CH(CH3)2); 2.28 (2Н, d,
J = 6.5, СOCH2C3H7); 2.62 (3H, s, CH3-Py); 3.40 (3H, s, OCH3);
4.29 (2Н, q, J = 7.1, COОCH2CH3); 4.87 (2H, s, CH2O); 7.40 (1H,
s, HPy); 9.68 (1Н, br. s, NH)
2d
2e
3225
3210
1710,
1670
1.15 (3Н, t, J = 7.1, COОCH2CH3); 2.64 (3H, s, CH3-Py);
3.34 (3H, s, OCH3); 4.23 (2Н, q, J = 7.1, COОCH2CH3);
4.85 (2H, s, CH2O); 6.76 (1Н, m, НFur-4); 7.37 (1Н, m, НFur-3);
7.44 (1H, s, HPy); 8.00 (1Н, m, НFur-5); 9.73 (1Н, br. s, NH)
1.15 (3Н, t, J = 7.1, COОCH2CH3); 2.63 (3H, s, CH3-Py); 3.34 (3H,
s, OCH3); 4.26 (2Н, q, J = 7.1, COОCH2CH3); 4.87 (2H, s, CH2O);
7.43 (1H, s, HPy); 7.59 (1Н, m, НAr-4); 7.65 (2Н, dd, 3J = 7.4,
4J = 1.0, НAr-3,5); 8.03 (2Н, d, J = 7.4, НAr-2,6);
1720
1680
10.37 (1Н, br. s, NH)
2f
3320
3240
1680,
1640
1.19 (3Н, t, J = 7.1, COОCH2CH3); 2.54 (3H, s, CH3-Py);
3.30 (3H, s, OCH3); 4.02 (3H, s, С6Н4OCH3); 4.25 (2Н, q, J = 7.1,
COОCH2CH3); 4.90 (2H, s, CH2O); 7.13 (1Н, m, НAr-4); 7.25 (1Н,
d, J = 8.3, НAr-3); 7.42 (1H, s, HPy); 7.58 (1Н, m, НAr-5); 7.92 (1Н,
d, J = 7.8, НAr-6); 10.17 (1Н, br. s, NH)
2g
1715,
1655
1.16 (3Н, t, J = 7.1, COОCH2CH3); 2.64 (3H, s, CH3-Py);
3.32 (3H, s, OCH3); 3.88 (3H, s, С6Н4OCH3); 4.25 (2Н, q, J = 7.1,
COОCH2CH3); 4.86 (2H, s, CH2O); 7.12 (2Н, d, J = 8.5, НAr-3,5);
7.43 (1H, s, HPy); 8.02 (2Н, d, J = 8.5, НAr-2,6);
10.20 (1Н, br. s, NH)
2h
2i
3160
3160
3140
1700,
1650
1.29 (3Н, t, J = 7.1, COОCH2CH3); 2.66 (3H, s, CH3-Py);
3.42 (3H, s, OCH3); 4.84 (2Н, q, J = 7.1, COОCH2CH3);
5.07 (2H, s, CH2O); 7.48 (1H, s, HPy); 7.83(1Н, m, НAr-4);
7.98 (1Н, m, НAr-5); 8.11 (2Н, m, НAr-3,6); 10.72 (1Н, br. s, NH)
1685,
1640
1.15 (3Н, t, J = 7.1, COОCH2CH3); 2.62 (3H, s, CH3-Py);
3.30 (3H, s, OCH3); 4.23 (2Н, q, J = 7.1, COОCH2CH3);
4.82 (2H, s, CH2O); 7.42 (1H, s, HPy); 8.22 (2Н, d, J = 8.5, НAr-2,6);
8.42 (2Н, d, J = 8.5, НAr-3,5); 10.68 (1Н, br. s, NH)
2j
1725
1640
1.27 (3Н, t, J = 7.1, COОCH2CH3); 2.50 (3Н, s, С6Н4CH3);
2.64 (3H, s, CH3-Py); 3.35 (3H, s, OCH3); 4.32 (2Н, q, J = 7.1,
COОCH2CH3); 4.97 (2H, s, CH2O); 7.36-7.45 (4Н, m,
HPy, НAr-3,4,5); 7.79 (1Н, d, J = 7.4, НAr-6); 10.18 (1Н, br. s, NH)
3a
3b
3295,
3210
1660
1665
1.35 (3Н, t, J = 7.4, СH2CH3); 2.40 (3H, s, CH3-Py); 3.06 (2Н, q,
J = 7.4, CH2CH3); 3.50 (3H, s, OCH3); 5.25 (2H, s, CH2O);
5.66 (2Н, s, NH2); 7.40 (1H, s, HPy)
0.98 (3Н, t, J = 6.7, C3H6CH3); 1.48 (2Н, m, C2H4СН2CH3);
1.84 (2H, m, СH2СН2С2Н5); 2.64 (3H, s, CH3-Py); 3.03 (2Н, t,
J = 7.0, СН2C3H7); 3.49 (3H, s, OCH3); 5.21 (2H, s, CH2O);
5.93 (2Н, s, NH2); 7.46 (1H, s, HPy)
3320,
3215
3c
3315,
3225
1655
1.06 (6Н, d, J = 6.1, CH2СН(CH3)2); 2.40 (1Н, m, CH2CH(CH3)2);
2.65 (3H, s, CH3-Py); 2.92 (2Н, d, J = 6.5, CH2C3Н7); 3.49 (3H,
s, OCH3); 5.22 (2H, s, CH2O); 5.94 (2Н, s, NH2); 7.40 (1H, s, HPy)
1472

TABLE 2. (continued)
1
2
3
4
3d
3325,
3215
1660
2.67 (3H, s, CH3-Py); 3.57 (3H, s, OCH3); 5.31 (2H, s, CH2O);
6.02 (2H, s, NH2); 6.69 (1H, m, НFur-4); 7.45 (1H, s, HPy);
7.80 (1H, m, НFur-3); 7.87 (1H, m, НFur-5)
3e
3f
3g
3h
4
3325,
3230
1670
1665
1670
1690
2.67 (3H, s, CH3-Py); 3.44 (3H, s, OCH3); 5.20 (2H, s, CH2O);
5.90 (2H, s, NH2); 7.48 (1H, s, HPy); 7.55 (3Н, m, НAr-3,4,5);
7.96 (2Н, d, J = 7.4, НРh-2,6)
3265,
3185
2.66 (3H, s, CH3-Py); 3.46 (3H, s, OCH3); 3.82 (3H, s, C6H4OCH3);
5.23 (2H, s, CH2O); 5.94 (2Н, s, NH2); 7.19 (2Н, d, J = 8.5, НAr-3,5);
7.50 (1H, s, HPy); 8.02 (2Н, d, J = 8.5, НAr-2,6)
3305,
3170
2.68 (3H, s, CH3-Py); 3.40 (3H, s, OCH3); 5.09 (2H, s, CH2O);
5.85 (2Н, s, NH2); 7.52 (1H, s, HPy); 7.85–8.01 (3Н, m, НAr-3,4,5);
8.27 (1H, d, J = 8.0, НAr-6)
3285
3190
2.68 (3H, s, CH3-Py); 3.40 (3H, s, OCH3); 5.20 (2H, s, CH2O);
5.93 (2H, s, NH2); 7.54 (1H, s, HPy); 8.26 (2Н, d, J = 8.5, НAr-2,6);
8.40 (2H, d, J = 8.5, НAr-3,5)
3405,
3370,
3315
1650
1590
2.58 (3H, s, CH3-Py); 3.39 (3H, s, OCH3); 3.93 (3H, s, C6H4OCH3);
4.85 (2H, s, CH2O); 6.98 (2Н, br. s, NH2); 7.09 (1H, m, НAr-4);
7.18 (1H, d, J = 8.4, НAr-3); 7.26 (1H, s, HPy); 7.53 (1Н, m, НAr-5);
7.79 (1H, d, J = 7.8, НAr-6); 9.82 (2Н, br. s, NH–NH)
5a
5b
5c
—
—
—
1670
1670
1670
0.94 (3Н, t, J = 6.7, C3H6CH3); 1.45 (2Н, m, C2H4СН2CH3);
1.81 (2H, m, СH2СН2С2Н5); 2.43 (3H, s, С6Н4CH3); 2.68 (3Н, s,
CH3-Py); 2.90 (2Н, t, J = 7.0, СН2C3H7); 3.52 (3H, s, OCH3);
5.25 (2H, s, CH2O); 7.42 (2Н, d, J = 7.9, НAr-3,5); 7.53 (1H, s, HPy);
7.87 (2Н, d, J = 7.9, НAr-2,6); 8.92 (1Н, s, N=CH)
0.94 (3Н, t, J = 6.7, C3H6CH3); 1.45 (2Н, m, C2H4СН2CH3);
1.81 (2H, m, СH2СН2С2Н5); 2.66 (3H, s, CH3-Py); 2.89 (2Н, t,
J = 7.0, СН2C3H7); 3.51 (3H, s, OCH3); 3.88 (3Н, s, С6Н4OCH3);
5.25 (2H, s, CH2O); 7.14 (2Н, d, J = 8.5, НAr-3,5); 7.51 (1H, s, HPy);
7.92 (2Н, d, J = 8.5, НAr-2,6); 8.85 (1Н, s, N=CH)
0.93 (3Н, d, J = 6.1, C3H6CH3); 1.37 (3Н, t, J = 7.1,
С6Н4OCH2CH3); 1.45 (2Н, m, C2H4СН2CH3); 1.80 (2Н, m,
СH2СН2С2Н5); 2.65 (3H, s, CH3-Py); 2.89 (2Н, t, J = 7.0, СН2C3H7);
3.50 (3H, s, OCH3); 4.16 (2Н, q, J = 7.1, С6Н4OCH2CH3);
5.25 (2H, s, CH2O); 7.11 (2Н, d, J = 8.5, НAr-3,5); 7.49 (1H, s, HPy);
7.90 (2Н, d, J = 8.5, НAr-2,6); 8.84 (1Н, s, N=CH)
5d
5e
—
1670
0.95 (3Н, t, J = 6.7, C3H6CH3); 1.48 (2Н, m, C2H4СН2CH3);
1.81 (2H, m, СH2СН2С2Н5); 2.67 (3H, s, CH3-Py); 2.97 (2Н, t,
J = 7.0, СН2C3H7); 3.51 (3H, s, OCH3); 5.25 (2H, s, CH2O);
7.52 (1H, s, HPy); 8.23 (2H, d, J = 8.5, НAr-2,6); 8.39 (2Н, d,
J = 8.5, НAr-3,5); 9.27 (1Н, s, N=CH)
3340
1670,
1610
0.93 (3Н, t, J = 6.7, C3H6CH3); 1.41 (2Н, m, C2H4СН2CH3);
1.78 (2Н, m, СH2СН2С2Н5); 2.08 (3Н, s, NHСОСН3); 2.63 (3H, s,
CH3-Py); 2.86 (2Н, t, J = 7.0, СН2C3H7); 3.48 (3H, s, OCH3);
5.21 (2H, s, CH2O); 7.48 (1H, s, HPy); 7.77 (2Н, d, J = 7.9, НAr-3,5);
7.88 (2Н, d, J = 7.9, НAr-2,6); 8.82 (1Н, s, N=CH); 10.28 (1H, s,
NHСOСН3)
5f
—
—
—
1670
1660
1680
0.95 (3Н, t, J = 6.7, C3H6CH3); 1.44 (2Н, m, C2H4СН2CH3);
1.80 (2H, m, СH2СН2С2Н5); 2.66 (3H, s, CH3-Py); 2.87 (2Н, t,
J = 7.0, СН2C3H7); 3.06 (6H, s, N(CH3)2); 3.52 (3H, s, OCH3);
5.24 (2H, s, CH2O); 6.84 (2Н, d, J = 8.5, НAr-3,5); 7.49 (1H, s, HPy);
7.75 (2Н, d, J = 8.5, НAr-2,6); 8.64 (1Н, s, N=CH)
5g
5h
0.94 (3Н, t, J = 6.7, C3H6CH3); 1.44 (2Н, m, C2H4СН2CH3);
1.80 (2H, m, СH2СН2С2Н5); 2.63 (3H, s, CH3-Py); 2.92 (2Н, t,
J = 7.0, СН2C3H7); 3.49 (3H, s, OCH3); 5.23 (2H, s, CH2O);
7.48 (1H, s, HPy); 7.80 (1H, d, J = 8.9, НAr-5); 7.91 (1Н, d,
J = 8.9, НAr-6); 8.13 (1H, s, HAr-2); 9.08 (1Н, s, N=CH)
0.92 (3Н, t, J = 6.7, C3H6CH3); 1.43 (2Н, m, C2H4СН2CH3);
1.76 (2H, m, СH2СН2С2Н5); 2.64 (3H, s, CH3-Py); 2.86 (2Н, t,
J = 7.0, СН2C3H7); 3.48 (3H, s, OCH3); 5.20 (2H, s, CH2O);
7.48 (1H, s, HPy); 7.78 (2Н, d, J = 8.5, НAr-2,6); 7.89 (2Н, d,
J = 8.5, НAr-3,5); 8.99 (1H, s, N=CH)
1473

TABLE 2. (continued)
1
2
3
4
5i
–—
1660
0.96 (3Н, t, J = 6.7, C3H6CH3); 1.45 (2Н, m, C2H4СН2CH3);
1.78 (2H, m, СH2СН2С2Н5); 2.65 (3H, s, CH3-Py); 2.86 (2Н, t,
J = 7.0, СН2C3H7); 3.50 (3H, s, OCH3); 5.19 (2H, s, CH2O);
6.99 (1Н, d, J = 8.3, НAr-3); 7.48 (1H, s, HPy); 7.61 (1Н, d, J = 8.3,
НAr-4); 8.06 (1Н, s, НAr-6); 9.11 (1Н, s, N=CH); 10.90 (1Н, s, OH)
5j
—
—
1665
0.93 (3Н, t, J = 6.7, C3H6CH3); 1.42 (2Н, m, C2H4СН2CH3);
1.78 (2H, m, СH2СН2С2Н5); 2.62 (3H, s, CH3-Py); 2.87 (2Н, t,
J = 7.0, СН2C3H7); 3.48 (3H, s, OCH3); 5.17 (2H, s, CH2O);
6.20 (2H, s, OCH2O); 7.42 (1H, s, HPy); 7.45 (1Н, s, НPh-6);
7.62 (1Н, s, НPh-3); 9.15(1H, s, N=CH)
6
1725,
1700,
1670
1.07 (6Н, d, J = 6.1, CH2СН(CH3)2); 2.41 (7Н, m, CH2СН(CH3)2,
N(COCH3)2); 2.63 (2Н, d, J = 6.5, CH2C3H7); 2.69 (3H, s, CH3-Py);
3.50 (3H, s, OCH3); 5.26 (2H, s, CH2O); 7.57 (1H, s, HPy)
7a
7b
—
—
1675
0.98 (6Н, d, J = 6.1, CH2СН(CH3)2); 2.31 (3Н, m, CH2CH(CH3)2);
2.69 (3H, s, CH3-Py); 3.50 (3H, s, OCH3); 5.25 (2H, s, CH2O);
6.28 (2H, m, Нβ pyrrole); 7.10 (1H, s, HPy); 7.55 (2Н, m, Нα pyrrole)
1690
2.71 (3H, s, CH3-Py); 3.33 (3H, s, OCH3); 5.20 (2H, s, CH2O);
6.02 (2H, m, Нβ pyrrole); 7.03 (2Н, m, Нα pyrrole);
7.36 (2Н, m, НAr-3,5); 7.44 (1Н, m, НAr-4);
7.58 (2Н, d, J = 7.4, НAr-2,6); 7.60 (1H, s, HPy)
7c
8
—
—
1690
—
2.70 (3H, s, CH3-Py); 3.46 (3H, s, OCH3); 3.78 (3H, s, C6H4OCH3);
5.24 (2H, s, CH2O); 6.10 (2Н, m, Нβ pyrrole); 6.90 (2Н, d,
J = 8.5, НAr-3,5); 7.03 (2Н, m, Нα pyrrole); 7.52 (2Н, d,
J = 8.5, НAr-2,6); 7.57 (1H, s, HPy)
0.96 (3Н, t, J = 6.7, C3H6CH3); 1.43 (2Н, m, C2H4СН2CH3);
1.79 (2H, m, СH2СН2С2H5); 2.63 (3H, s, CH3-Py); 3.00 (2Н, t,
J = 7.0, СН2C3H7); 3.48 (3H, s, OCH3); 5.19 (2H, s, CH2O);
5.94 (1Н, s, N=CH); 7.45 (1H, s, HPy)
9a
9b
9c
—
—
—
1620
1625
1690
2.67 (3H, s, CH3-Py); 3.51 (3H, s, OCH3); 5.33 (2H, s, CH2O);
7.51 (1H, s, HPy); 7.60 (3Н, m, НAr-3,4,5); 8.23 (2Н, d,
J = 8.5, НAr-2,6); 13.04 (1Н, br. s, NH)
2.68 (3H, s, CH3-Py); 3.55 (3H, s, OCH3); 3.89 (3H, s, C6H4OCH3);
5.36 (2H, s, CH2O); 7.15 (2Н, d, J = 8.5, НAr-3,5); 7.52 (1H, s, HPy);
8.24 (2Н, d, J = 8.5, НAr-2,6); 12.97 (1Н, br. s, NH)
0.95 (3Н, t, J = 6.7, C3H6CH3); 1.40 (2Н, m, C2Н4СН2CH3);
1.79 (2H, m, СH2СН2С2H7); 2.65 (3H, s, CH3-Py); 2.74 (2Н, t,
J = 7.0, СН2C3Н7); 3.50 (3H, s, OCH3); 5.22 (2H, s, CH2O);
7.49 (1H, s, HPy); 12.78 (1H, br. s, NH)
10a
10b
10c
10d
—
—
—
1665
1660
1670
1630
1.21 (3Н, t, J = 7.4, СH2CH3); 2.50 (1H, s, CH3-Py); 2.61 (2Н, q,
J = 7.4, CH2CH3); 3.32 (3H, s, OCH3); 4.63 (2H, s, CH2O);
6.40 (1Н, s, Н-6 pyrimidinone); 7.40 (1Н, s, HPy-5);
8.50 (1Н, s, HPy-2); 12.51 (1Н, br. s, NH)
0.95 (6Н, m, CH2CH(CH3)2); 2.17 (1Н, m, CH2CHC2H6);
2.48 (2Н, m, CH2C3H7); 2.51 (1H, s, CH3-Py); 3.32 (3H, s, OCH3);
4.10 (2H, s, CH2O); 6.39 (1Н, s, Н-6 pyrimidinone);
7.40 (1Н, s, HPy-5); 8.50 (1Н, s, HPy-2); 12.57 (1Н, br. s, NH)
2.55 (1H, s, CH3-Py); 3.30 (3H, s, OCH3); 3.85 (3H, s, С6Н4OCH3);
4.70 (2H, s, CH2O); 6.50 (1Н, s, H-6 pyrimidinone); 7.10 (2Н,
d, J = 8.5, НAr-3,5); 7.44 (1H, s, HPy-5); 8.19 (2Н, d,
J = 8.5, НAr-2,6); 8.60 (1Н, s, HPy-2); 12.71 (1Н, br. s, NH)
3325,
3190
2.53 (1H, s, CH3-Py); 3.31 (3H, s, OCH3); 4.69 (2H, s, CH2O);
5.95 (2H, s, NH2); 6.32 (1Н, s, Н-6 pyrimidinone); 6.62 (2Н, d,
J = 8.5, НAr-3,5); 7.41 (1H, s, HPy-5); 7.92 (2Н, d, J = 8.5, НAr-2,6);
8.58 (1H, s, HPy-2); 12.35 (1H, br. s, NH)
EXPERIMENTAL
The IR spectra were taken on a Specord IR-75 spectrometer at room temperature for vaseline mulls. The
1H NMR spectra were taken on a Bruker DRX 500 spectrometer at 500 MHz in DMSO-d6 with TMS as the
1474

internal standard. The mass spectra were taken on a Varian CH-6 mass spectrometer with direct sample inlet into
the ionization chamber at 50-180°C and 70 eV ionizing voltage. The elemental analysis of the products was
carried out on a Carlo-Erba 1106 analyzer.
Ethyl Ester of 3-Ethylcarboxamido-4-methoxymethyl-6-methylthieno[2,3-b]pyridine-2-carboxylic
Acid (2a). Toluene (50 ml) was added to ester 1 (5 g, 17.8 mmol). The mixture was heated until the ester
dissolved completely and propionyl chloride (1.7 g, 19.6 mmol) was added. The mixture was heated at reflux for
1 h. The solvent was evaporated almost to dryness. The precipitate formed was filtered off, washed with
3% aqueous Na2CO3 and water until pH 7, and dried in the air. The product was recrystallized from 2-propanol.
Esters 2b-j were obtained analogously. The end of the reaction in each specific case was monitored by
thin-layer chromatography using 1:1 acetone-hexane as the eluent until the spot for starting ester 1 disappeared.
3-Amino-2-ethyl-9-methoxymethyl-7-methyl-3,4-dihydropyrido[2',3':4,5]thieno[3,2-d]pyrimidin-
4-one (3a). Hydrazine hydrate (2.1 ml, 44.5 mmol) was added to a solution of amide 2a (3 g, 8.9 mmol) in
ethanol (30 ml) at reflux. The reaction was complete in 1 h. The reaction mixture was cooled to room
temperature. The precipitate was separated off, washed with water, and dried in the air to give 3a (1.71 g). The
filtrate after separation of the precipitate was poured into 150 ml water. The crystals formed were filtered off,
washed with water, and dried. The fractions were combined and recrystallized from 10:3 (v/v) 2-propanol-DMF.
3-Amino-3,4-dihydropyridothienopyrimidinones 3b-h were obtained analogously by the same
reaction using 2-propanol as the solvent for 3b,c and 1-butanol as the solvent for 3f. The end of the reaction was
determined by thin-layer chromatography using 10:3 toluene-ethanol as the eluent relative to the consumption of
2a.
N2-(2-Methoxybenzoyl)-3-amino-4-methoxymethyl-6-methylthieno[2,3-b]pyridine-2-carbohydra-
zide (4) was obtained analogously to pyrimidinones 3.
2-Butyl-9-methoxymethyl-7-methyl-3-[(E)-1-(4-methylphenyl)methylideneamino]-3,4-dihydropyrido-
[3',2':4,5]thieno[3,2-d]pyrimidin-4-one (5a). 4-Methylbenzaldehyde (0.35 ml, 3.0 mmol) was added to a
solution of 3-aminopyrimidinone 3b (1 g, 3.0 mmol) in toluene (25 ml). The reaction mixture was heated at
reflux for 7 h and monitored by thin-layer chromatography using 20:3 toluene–ethanol as the eluent. The
colorless crystalline precipitate formed upon cooling to room temperature was filtered off, washed with ethanol,
and dried. The product was recrystallized from 1:1 2-propanol-DMF.
Pyrimidinones 5b-j were obtained analogously. The reaction times ranged from 2 to 7.5 h.
N-Acetyl-N-(2-isobutyl-9-methoxymethyl-7-methyl-4-oxo-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]-
pyrimidin-4-yl)acetamide (6). A solution of 3c (0.7 g, 2.1 mmol) in acetic anhydride (5 ml) was heated at
reflux for 6 h. After cooling to room temperature, the reaction mixture was poured into 50 ml cold water. The
solution was extracted with three 50-ml portions of ethyl acetate. The extract was maintained over Na2SO4 and
filtered. The solvent was evaporated. The crystalline product was recrystallized from 2-propanol.
2-Isobutyl-9-methoxymethyl-7-methyl-3-(1-pyrrolyl)-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrim-
idin-4-one (7a). A mixture of 3-aminopyrimidinone 3c (1 g, 3.0 mmol) and acetic acid (5 ml) was heated with
stirring. 2,5-Dimethoxytetrahydrofuran (0.47 ml, 3.6 mmol) was added to the solution at reflux. The reaction
mixture was heated at reflux for 2.5 h, cooled, and poured into 100 ml ice water. The precipitate formed was
filtered off, washed with water until the wash water was neutral, and dried in the air. The product was
recrystallized from 3:1 (v/v) 2-propanol–DMF.
Pyrimidinones 7b,c were synthesized analogously. In the synthesis of pyrrole 7b, the volume of acetic
acid per gram starting amine 3e was 30 ml. A 10:1 mixture of acetic acid and DMF was used as the solvent in
the preparation of 7c.
5-Butyl-7-methoxymethyl-9-methylpyrido[3',2':4,5]thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (8).
A mixture of pyrimidine 3b (0.8 g, 2.4 mmol) and formamide (10 ml) was heated at reflux for 4.5 h. After
cooling, the precipitate formed was filtered off, washed with water, and dried. The product was recrystallized
from petroleum ether (70-100°C).
1475

Pyrimidin-4-ones 9a,b were obtained analogously but recrystallized from 2-propanol.
2-Butyl-9-methoxymethyl-7-methyl-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-one (9c).
A suspension of Raney nickel in ethanol was added in small portions over 2 h with vigorous stirring to a solution
of 3-aminopyrimidine 3a (0.5 g, 1.5 mmol) in ethanol (30 ml) at reflux. The mixture was heated at reflux for
11 h with monitoring by thin-layer chromatography using 20:3 toluene–ethanol. Raney nickel was separated.
The mixture was cooled to room temperature. The colorless crystalline precipitate was filtered off, washed with
water, and dried in the air. The product was recrystallized from ethanol.
4-(4-Methoxymethyl-6-methyl-3-pyridyl)-2-(4-methoxyphenyl)-1,6-dihydropyrimidin-6-one (10c).
Starting pyridothienopyrimidinone 3f (0.7 g, 1.8 mmol) was dissolved in 1:1 (v/v) ethanol–DMF (30 ml) at
reflux. Then, suspension Raney nickel (10 g) in 1:1 ethanol–DMF was added into the solution at reflux. The
reaction mixture was heated at reflux for 10.5 h and cooled. Raney nickel was separated. The mixture was
evaporated to 1/5 of the original volume. The colorless crystalline precipitate was filtered off and washed with
water. The filtrate was poured into water. The precipitate formed was separated, combined with the first fraction,
and dried in the air. The product was recrystallized from 2-propanol.
Pyrimidinones 10a,b,d were synthesized analogously.
REFERENCES
1.
2.
E. Bousquet, G. Romeo, and F. Guerrera, Farmaco, 40, 869 (1985).
C. G. Dave, P. R. Shah, A. B. Shah, K. C. Dave, and V. J. Patel, J. Ind. Chem. Soc., 66, 48
(1989).
3.
4.
A. E. Abdel-Rahman, E. A. Bakhite, and E. A. Al-Taifi, J. Chin. Chem. Soc., 49, 223 (2002).
V. I. Shvedov, T. P. Sycheva, and T. V. Sakovich, Khim. Geterotsikl. Soedin., 1336 (1979).
[Chem. Heterocycl. Comp., 15, 1074 (1979)].
5.
6.
A. M. Shestopalov and Yu. A. Sharanin, Zh. Org. Khim., 9, 1991 (1984).
M. Z. A. Badr, S. A. Mahgoub, F. F. Abdel-Latif, A. A. A. Abd El-Hafez, Phosphorus, Sulfur,
Silicon, Relat. Elem., 55, 175 (1991).
7.
S. N. Sirakanyan, E. G. Paronikyan, and A. S. Noravyan, in: V. G. Kartsev (editor), Abstracts of
Second International Conference on the Chemistry and Biological Activity of Oxygen and Sulfur
Heterocycles [in Russian], Vol. 1, IBS Press, Moscow (2003), p. 398.
E. A. Kaigorodova, D. D. Konyushkin, M. E. Niyazymbetov, S. N. Kvak, V. N. Zaplishnyi, and
V. P. Litvinov, Izv. Akad. Nauk, Ser. Khim., 2215 (1994).
8.
9.
10.
E. A. Kaigorodova, A. A. Osipova, D. D. Konyushkin, and G. D. Krapivin, Izv. Akad. Nauk, Ser.
Khim., 817 (2004).
11.
A. V. Kadushkin, N. P. Solov’eva, and V. G. Granik, Khim.-Farm. Zh., 26, 40 (1993).
1476