Exotic amino acids. 6. Synthesis of substituted 4-oxo-4H-pyrido[1,2-a]pyrimidines

Article abstract of DOI:10.1023/A:1020689805869

2-Pyridylaminomethyleneisopropylidenemalonates, prepared from ethoxymethyleneisopropylidenemalonate and 2-aminopyridines, form 4-oxo-4H-pyrido[1,2-a] pyrimidines at their melting points and are separated from the reaction mixture by sublimation.

Full text of DOI:10.1023/A:1020689805869

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
EXOTIC AMINO ACIDS.
6
4
*. SYNTHESIS OF SUBSTITUTED
-OXO-4H-PYRIDO[1,2-a]PYRIMIDINES
1
1
1
1
2
I. Ravina , D. Zicane , M. Petrova , E. Gudriniece , and U. Kalejs
2
-Pyridylaminomethyleneisopropylidenemalonates, prepared from ethoxymethyleneisopropylidenemalonate
and 2-aminopyridines, form 4-oxo-4H-pyrido[1,2-a]pyrimidines at their melting points and are
separated from the reaction mixture by sublimation.
Keywords:
2-aminopyridines,
4-oxo-4H-pyrido[1,2-a]pyrimidines,
2-pyridylaminomethylene-
isopropylidenemalonates, ethoxymethyleneisopropylidenemalonate.
Among pyridopyrimidines there are compounds which possess antitumour [2], antibacterial [3], diuretic
[
4], and antiviral [5] properties.
We previously reported [6] on the synthesis of 4-oxo-7R-4H-pyrido[1,2-a]pyrimidines from
-pyridylamino- and 5-methyl-2-pyridylaminomethyleneisopropylidenemalonates by melting them. This method
2
of obtaining derivatives of pyridopyrimidines had not been described in the literature at that time. However the
authors of paper [7] obtained pyrazolo[1,5-a]pyrimidines by refluxing 5-pyrazolylaminomethylene-
isopropylidenemalonates in nitrobenzene. We note that our attempts to use similar conditions for the synthesis
of pyrido[1,2-a]pyrimidines 4a-j were not crowned with success. Complex mixtures of substances which were
difficult to separate were obtained.
In this work we have studied in more detail the behavior of compounds 3a-j on heating with the
objective of using our method [6] for the synthesis of various pyridopyrimidines.
We obtained compounds 3a-j by the method described elsewhere [8] from
ethoxymethyleneisopropylidenemalonate 1 and 2-aminopyridines 2a-j in ethanol solution at room temperature
for 2-24 h.
When the pyridylaminomethylenemalonates 3a-j were heated to their melting points the dioxane ring
opened, acetone was evolved, followed by decarboxylation and cyclization to give the substituted 4-oxo-4H-
pyrido[1,2-a]pyrimidines 4a-j. Compounds 4a-g sublimed (yields 47-74%) and required no further purification.
Compound 4h sublimed along with the starting material 3h and was separated by extraction with hexane
(
29% yield). Compounds 4i,j were obtained in poor yields (4i – 24, 4j – 21%) and their preparation by this
method is of no interest.
_
*
_
______
For part 5 see [1].
_________________________________________________________________________________________
1
2
Riga Technical University, Riga LV-1048; e-mail: gudr@ktf.rtu.lv. BAPEKS Ltd., Riga LV-1048,
Latvia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 945-946, July, 2002. Original article
submitted April 20, 2000.
8
36
0009-3122/02/3807-0836$27.00©2002 Plenum Publishing Corporation

2
R
1
R
R 3
1
O
R
1
2
4
O
O
4
H N
N
R
O
O
R
R
2
2
H
C
R
N
O
O
O
– CO , – Me CO
2 2
2
H
C
3
N
R
∆
3
R
N
OEt
O
H
N
R4
R
1
3
4
1
2
4
3
1
2
4
3
1
2
4
2
–4 a R = R = R = H, R = Cl; b R = R = R = H, R = Br; c R = R = R = H,
3
2
4
1
3
2
4
1
3
2
3
4
R = NO
2
; d R = R = H, R = R = Cl; e R = R = H, R = R = Br; f R = R = R = H,
R = Me; g R = R = R = H, R = Me; h R = R = R = H, R = Me; i R = R = R = H,
1
1
3
4
2
1
2
3
4
1
3
4
2
2
3
1
4
R = Et; j R = R = H, R = Et, R = Me
TABLE 1. Characteristics of 2-Pyridylaminomethyleneisopropylidene-
malonates 3a-j
Com-
pound
1Н NMR spectrum, ppm. (J, Hz)
Yield,
%
mp, °С
3
a
193-194
1.67 (6H, s, 2CH
3
); 7.03 (1H, d, J = 9, C
.72 (1Н, dd, J = 9, J = 2, C N);
.32 (1Н, d, J = 2, C N); 9.30 (1Н, d, J = 14, =СН);
1.27 (1Н, br. d, J = 14, NH)
); 7.01 (1H, d, J = 9, С
N);
N); 9.28 (1Н, d, J = 13, =СН);
1.3 (1Н, br. d, J = 13, NH)
); 7.82 (1H, d, J = 9, C
.67 (1Н, dd, J = 9, J = 2, C N); 9.25 (1Н, d, J = 14, =СН);
.27 (1Н, d, J = 2, C N); 11.61 (1Н, br. d, J = 14, NH)
); 7.83 (1H, d, J = 2, С N);
.27 (1Н, d, J = 2, С N); 9.2 (1Н, d, J = 14, =СH–);
1.66 (1Н, br. d, J = 14, NH)
); 7.96 (1H, d, J = 2, C
.32 (1Н, d, J = 2, C N); 9.22 (1Н, d, J = 13, =СН)
1.7 (1Н, br. d, J = 13, NH)
); 2.36 (3Н, s, СН
5
H
3
N);
95
7
8
1
5
H
3
5
H
3
3
b
192-193
1.69 (6H, s, 2CH
3
5
H
3
N);
96
1
92-192.4 [9] 7.82 (1Н, dd, J = 9, J = 2, С
5
H
3
76 [9]
8
1
.41 (1Н, d, J = 2, С
5
H
3
3
3
3
3
c
d
e
f
237-238
216-220
207-208
185-186
1.72 (6H, s, 2CH
3
5
H
4
N);
47
94
80
8
5
H
4
9
5
H
4
1.65 (6H, s, 2CH
3
5
H
2
8
5
H
2
1
1.69 (6H, s, 2CH
3
5
2
H N);
8
5
H
2
1
1.69 (6H, s, 2CH
3
3
);
75
1
86-187 [9] 7.07 (1Н, dd, J = 8, J = 6, С
5
H
3
N);
56 [9]
7
8
9
.56 (1Н, dd, J = 8, J = 1.5, С
.27 (1Н, dd, J = 6, J = 1.5, С
5
H
3
N);
N);
5
H
3
.49 (1Н, d, J = 13, =СН–) 11.63 (1H, br. d, J = 13, NH)
3
3
3
3
g
h
i
197-198
153-156
1.78 (6H, s, 2CH
3
); 2.38 (3H, s, СН
.86 (1Н, d, J = 1.5, C N); 7.1 (1Н, d, J = 5, C
.25 (1Н, d, J = 5, C N); 9.33 (1Н, d, J = 14, =CH);
3
);
48
6
8
5
H
3
H
3
5
H N);
3
5
1
1.18 (1H, br. d, J = 14, NH)
); 2.49 (3H, s, СН
N); 7.03 (1Н, d, J = 8, C
N); 9.41 (1Н, d, J = 14, =CH);
1.31 (1H, br. d, J = 14, NH)
); 1.67 (6H, s, 2СН
); 6.82 (1Н, d, J = 1.5, C
N); 8.18 (1Н, d, J = 5, C
.35 (1Н, d, J = 14, =CH); 11.13 (1H, br. d, J = 14, NH)
); 1.72 (6H, s, 2СН ); 2.45 (3Н, s, СН
); 6.96 (1Н, d, J = 8, C N);
N); 9.52 (1Н, d, J = 13, =CH–);
1.7 (1H, br. d, J = 13, =СH–)
1.72 (6H, s, 2CH
3
3
);
75
1
1
55-160 [9] 6.85 (1Н, d, J = 8, С
.63 (1Н, t, J = 8, C
5
5 3
H
H
3
5
H
3
N);
45 [9]
7
1
123-125
1.18 (3H, t, J = 7, CH
3
3
);
53
2
6
9
.61 (2Н, q, J = 7, СН
2
H
5
H
3
N);
.93 (1Н, d, J = 5, C
5
3
5
3
H N);
j
162-166
1.27 (3H, t, J = 7, CH
3
3
3
);
75
62-165 [9] 2.62 (2Н, q, J = 7, СН
2
H
5
H
4
58 [9]
7
1
.49 (1Н, d, J = 8, C
5
4
8
37

TABLE 2. Characteristics of the Substituted 4-Oxo-4H-pyrido[1,2-a]pyrimidines Synthesized, 4a-j
Found, %
Com-
Empirical
formula
——————
1Н NMR spectrum, δ, ppm (J, Hz)
Yield, %
Calculated, %
mp, °С
pound
C
H
N
Hal
4
4
а
C8H5ClN2O
C8H5BrN2O
53.41
2.52
2.79
15.34
15.51
19.15
19.63
121-123
127-130
6.35 (1H, d, J = 7, 3-H); 7.55 (2Н, m, 9-Н, 8-Н); 8.15 (1Н, d, J = 7, 2-H);
9.0 (1Н, d, J = 2, 6-H)
50
62
5
3.21
b
42.40
2.41
12.71
35.65
6.33 (1H, d, J = 7, 3-H); 7.46 (1Н, d, J = 9, 9-Н);
4
2.70
2.22
12.45
35.51
7
9
.66 (1Н, dd, J = 9, J = 2, 8-H); 8.24 (1Н, d, J = 7, 2-H);
.04 (1Н, d, J = 2, 6-H)
4
4
4
4
c
d
e
f
C8H5N3O3
C8H4Cl2N2O
C8H4Br2N2O
C9H8N2O
50.12
0.27
2.73
2.64
21.99
21.98
152-154
128-129
185-188
110-113
6.42 (1H, d, J = 7, 3-H); 7.61 (1Н, d, J = 9, 6-Н); 8.23 (1Н, d, J = 7, 2-H);
.34 (1Н, dd, J = 9, J = 2, 7-H); 9.90 (1Н, d, J = 2, 9-H)
6.49 (1H, d, J = 7, 3-H); 7.79 (1Н, d, J = 2, 8-Н); 8.29 (1Н, d, J = 7, 2-H);
.91 (1Н, d, J = 2, 6-H)
6.38 (1H, d, J = 7, 3-H); 8.18 (1Н, d, J = 2, 8-Н); 8.29 (1Н, d, J = 7, 2-H);
.06 (1Н, d, J = 2, 6-H)
47
74
52
59
5
8
44.43
2.24
13.20
33.10
32.97
4
4.68
1.87
13.03
8
31.56
1.31
1.33
9.29
9.22
53.02
3
1.61
52.58
9
67.13
5.38
17.35
2.56 (3Н, s, СН3); 6.34 (1H, d, J = 7, 3-H); 6.89 (1Н, t, J = 7.5, 7-Н);
6
7.49
5.03
17.49
7
8
.52 (1Н, dd, J = 7.5, J = 1.5, 8-H); 8.23 (1Н, d, J = 7, 2-H);
.89 (1Н, dd, J = 7.5, J = 1.5, 6-Н)
4
4
4
g
h
i
C9H8N2O
C9H8N2O
C10H10N2O
67.70
7.49
4.92
5.03
17.52
17.49
136-141
111-114
73-74
2.42 (3Н, s, СН3); 6.27 (1H, d, J = 7, 3-H); 6.82 (1Н, dd, J = 8, J = 2, 7-Н);
.35 (1Н, d, J = 2, 9-H); 8.18 (1Н, d, J = 7, 2-H); 8.89 (1Н, d, J = 8, 6-Н)
3.01 (3Н, s, СН3); 6.16 (1H, d, J = 7, 3-H); 6.6 (1Н, m, 8-Н);
.33 (2Н, m, 9-H, 7-Н); 7.99 (1Н, d, J = 7, 2-H)
50
29
24
6
7
67.33
4.91
17.62
6
7.49
5.03
17.49
7
69.08
5.66
5.79
15.90
16.08
1.23 (3Н, t, J = 7, СН3); 2.71 (2Н, q, J = 7, СН2); 6.29 (1H, d, J = 7, 3-H);
6
8.95
6
8
.95 (1Н, dd, J = 8, J = 2, 7-Н); 7.41 (1Н, d, J = 2, 9-H);
.18 (1Н, d, J = 7, 2-H); 8.91 (1Н, d, J = 8, 6-Н)
4
j
C11H12N2O
70.02
0.19
6.39
6.43
16.72
14.88
57-61
1.22 (3Н, t, J = 7, СН3); 2.77 (2Н, q, J = 7, СН2); 2.91 (3Н, s, СН3);
21
7
6
8
.2 (1H, d, J = 7, 3-H); 6.6 (1Н, d, J = 7.5, 7-Н); 7.17 (1Н, d, J = 7.5, 8-H);
.03 (1Н, d, J = 7, 2 -H)

The composition of the compounds synthesized was confirmed by the results of elemental analysis, and
1
their structures by the H NMR spectra, in which the proton signal of all the fragments of the molecules
resonated in their characteristic regions.
EXPERIMENTAL
1
H NMR spectra of CDCl
3
or DMSO-d solutions with HMDS as internal standard were recorded with a
6
Bruker WH90/DS instrument (90 MHz).
The purity of the synthesized compounds were monitored by TLC on Silufol strips with the following
solvent systems: chloroform–methanol–glacial acetic acid, 9:1:1 (3b-e,j), ethyl acetate (3f-i, 4b-j), and
chloroform (3a, 4a,b).
Characteristics of the compounds synthesized are given in Tables 1 and 2.
2
-Pyridylaminomethyleneisopropylidenemalonates (3a-j). A solution of ethoxyisopropylidenemalonate
1
(0.005 mol) [7] in ethanol (10 ml) at ~20°C was added with stirring to an equimolar quantity of the
corresponding 2-aminopyridine 2a-j dissolved in ethanol. In the case of 3i the reaction mixture was heated for
h at 50°C. The precipitate was filtered off after 2-3 h (3a-e) or 24 h (3f-j). In the case of 3i, water (100 ml)
1
was added to the reaction mixture. Compound 3h was recrystallized from ethanol, 3i from 1:2 acetonitrile–
water. Compounds 3a-g,j were chromatographically homogeneous and did not require recrystallization.
Substituted 4-Oxo-4H-pyrido[1,2-a]pyrimidines (4a-j). Compounds 3a-g (0.002 mol) were melted in
a porcelain cup, closed with a glass funnel. The sublimates were chromatographically homogeneous for
compounds 4a-g. Compounds 4h-j were isolated from the fused mixture with hexane.
REFERENCES
1
.
D. R. Zicane, Z. F. Tetere, I. A. Rijkure, M. V. Petrova, E. Yu. Gudriniece, and U. O. Kalejs, Khim.
Geterotsikl. Soedin., 903 (2000).
2.
3.
4.
5.
6.
H. Akimoto, T. Miwa, and K. Otsu, Jap. Pat. 04,235,986; Chem. Abstr., 118, 213101 (1993).
B. Hurlbert and B. Valenti, J. Med. Chem., 11, 708 (1968).
H. Parish, P. Gilliom, W. Purcell, R. Browne, R. Spirk, and H. White, J. Med. Chem., 25, 98 (1982).
D. Bouzard, Anitbiotics and Antiviral Compounds, VCH (Weinheim), 186 (1993).
D. R. Zicane, I. T. Ravina, Z. F. Tetere, I. A. Rijkure, E. J. Gudrinece, and U. O. Kalejs, Khim.
Geterotsikl. Soedin., 857 (2000).
7
.
J. Quiroga, A. Hormoza, B. Insuasty, C. Saitz, C. Jullian, and A. Canete, J. Heterocycl. Chem., 35, 61
(
1998).
8
9
.
.
G. Bihlmayer, G. Derflinger, J. Derkosch, and O. Polansky, Monatsh. Chem., 98, 564 (1967).
Sterling Drug, Brit. Pat. 1147759; Chem. Abstr., 71, 70125 (1969).
8
39