Synthesis of new imidazo-[4,5-b]pyridine derivatives

Article abstract of DOI:10.1023/A:1020637821799

New imidazo[4,5-b]pyridine derivatives with various substituents in the 2-position (α, β-unsaturated ketones, imines, Δ²-pyrazolines, pyrimidines, 1,2,3,4-tetrahydropyrimidines) and derivatives of the new pyrido[3′,2′:4,5]imidazo[1,2-d][1,2,4]triazine ring system were synthesized. Biological data for selected compounds are presented.

Full text of DOI:10.1023/A:1020637821799

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
SYNTHESIS OF NEW IMIDAZO-
b
[4,5- ]PYRIDINE DERIVATIVES
L. Bukowski
New imidazo[4,5-b]pyridine derivatives with various substituents in the 2-position (α,β-unsaturated
ketones, imines, ∆2-pyrazolines, pyrimidines, 1,2,3,4-tetrahydropyrimidines) and derivatives of the new
pyrido[3',2':4,5]imidazo[1,2-d][1,2,4]triazine ring system were synthesized. Biological data for
selected compounds are presented.
Keywords: imidazo[4,5-b]pyridine, pyrido[3',2':4,5]imidazo[1,2-d][1,2,4]triazine, antituberculotic activity.
Imidazo[4,5-b]pyridine can be considered as 1-deazapurine or 4(7)-azabenzimidazole. Such an analogy
induces interest in the biological activity of this system's derivatives. To date some of them have been applied in
pharmacotherapy [1]. As a continuation of our interest in the chemistry and biological properties of
imidazo[4,5-b]pyridines [2, 3], we synthesized some new derivatives of this heterocycle.
As the starting compound for the syntheses, 2-acetylimidazo[4,5-b]pyridine (1), reported previously [2],
was used. In reactions of this compound with several aromatic aldehydes or aromatic amines, corresponding
α,β-unsaturated ketones 2-8 and imines 9-14 were obtained. The reaction of 1 with acetic hydrazide or ethyl
carbazate led to the acetylhydrazone 15 and ethoxycarbonylhydrazone 16, respectively (Scheme 1).
Scheme 1
O
N
Me
ArCHO
CH Ar
N
H
N
O
N
1
ArNH2
CH
N
N
Me
N
H
NH2NHCOR
2–8
Ar
N
N
N
H
Me
N
9–14
NNH
N
COR
N
H
15, 16
2 Ar = Ph; 3 Ar = C6H4Cl-p; 4 Ar = C6H4OH-p; 5 Ar = C6H4CN-p; 6 Ar = C6H4CF3-p;
7 Ar = C6H3(Cl)2-2,4; 8 Ar = C6H3Me2-2,4; 9 Ar = C6H4Cl-p; 10 Ar = C6H4F-p; 11 Ar = C6H4CN-p;
12 Ar = C6H4Me2-p; 13 Ar = CH2Ph; 14 Ar = 4-methylpiperidin-4-yl; 15 R = Me; 16 R = OEt
__________________________________________________________________________________________
Department of Organic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 937-944, July, 2002. Original article submitted
July 9, 2001.
828
0009-3122/02/3807-0828$27.00©2002 Plenum Publishing Corporation

It was found that the compounds 15 and 16 upon heating in boiling N,N-dimethylaniline undergo
intramolecular cyclization to the new heterocyclic ring system, pyridoimidazo[1,2,4]triazine (compounds 17 and
18, Scheme 2). Due to the tautomeric properties of the imidazo[4,5-b]pyridine system, compounds 17, 18 may
be of A or B structure (ring closure with participation of N-1 or N-3 atoms is possible).
Scheme 2
Me
N
N
N
N
Me
N
∆
or
H
N
N
Me
15
16
N
N
H3C
N
17
A
B
H
O
N
N
N
Me
N
N
N
∆
or
Me
N
N
O
N
H
N
18
A
B
MeI
(MeO)2SO2
Me
N
H3CO
N
O
NOE
N
N
H
N
N
Me
Me
N
N
N
N
20
19
As in NOE investigation of compound 17, a positive effect between CH3 group protons of the
[1,2,4]triazine ring and α-proton of the pyridine ring was observed; one can thus conclude that compound 17
has in fact the structure B.
In order to find the correct structure of the compound 18, synthesis of its O-methyl derivative was
attempted. However, probably due to its "amide" character, on reaction of 18 with CH3I as alkylating agent (in
alkaline medium) the N-methyl derivative 19 was obtained. Finally, the desired O-methyl derivative 20 was
synthesized by the reaction of 18 with dimethyl sulfate in nitrobenzene. Compound 20 was then examined by
the NOE method. Since in this investigation a positive effect between O-methyl group protons of 1,2,4-triazine
-proton of pyridine ring was found, one can conclude that compound
In the next set of experiments the reactions of α,β-unsaturated ketones 2, 3 with hydrazine,
ring and
18 has in fact the structure A.
methylhydrazine, guanidine, as well as thiourea were investigated. New imidazo[4,5-b]pyridine derivatives with
various substituents in the 2-position (∆2-pyrazolines 21-24, pyrimidines 25, 26, and
1,2,3,4-tetrahydropyrimidines 27, 28) were obtained from these reactions (Scheme 3).
According to the literature data [4-7], reaction of α,β-enones with hyd-razines can lead to two different
pyrazolines (1,4 or 1,2 addition). The type of product obtained from these reactions depends mainly on the
catalyst used.
829

Scheme 3
H
H
N
Ar
Ar
R
N
N
H2NNHR
NH
or
N
R
N
N
H
N
N
H
N
B
A
21–24
N
HN=C(NH2)2
Ar
Ar
2, 3
N
H
N
N
N
NH2
25, 26
N
CS(NH2)2
N
H
N
HN
NH
S
27, 28
21, 22 R = H; 23, 24 R = Me; 21, 23, 25, 27 Ar = Ph; 22, 24, 26, 28 Ar = p-ClC6H4
Thus, the compounds 21-24 prepared in our work can be of A or B structure (our reactions were carried
out without a catalyst). Because in the 1H NMR spectra of compounds 21-24 signals of the CH2−CH fragment of
the pyrazoline ring were present (CH2 protons as two doublets of doublets at δ 3.02-3.12 and 3.62-3.74 as well
as CH proton as a triplet at δ 4.75-5.16 ppm), it can be concluded that they have in fact the structure B.
Compounds 3, 6, 8, 10, 11, 21, 25, 27 chosen as examples were tested in vitro for their antituberculotic
activity against Mycobacterium tuberculosis H37Rv and two strains isolated from a tuberculosis patient: the
210 strain, resistant to isoniazide, ethambutol, and rifampicine, as well as the 192 strain, fully susceptible
towards isoniazide, ethambutol, and rifampicine. The antibacterial activity of the compounds was determined in
liquid Youmans medium containing 10% bovine serum using the method previously described [2]. The lowest
concentration of the investigated compound at which no growth of strains could be observed was taken as the
MIC. The results obtained are given in Table 1. Pyrazinamide was used as a positive control (its MIC was
30-60 µg/ml).
TABLE 1. Antituberculotic Activity, MIC Values (µg/ml)
Mycobacterium
Compound
H37Rv
192
210
25
25
25
12.5
100
12.5
50
25
50
50
50
25
50
12.5
50
50
100
50
3
8
11
21
25
27
830

TABLE 2. Physical and Analytical Data of the Compounds 2-28
Found, %
——————
Com-
pound
mp, °C,
solvent
Empirical
formula
Yield,
%
Calculated, %
C
H
N
248-250
Toluene
C15H11N3O
72.08
72.27
4.52
4.45
17.14
16.86
80
76
80
59
22
63
70
80
70
56
71
70
76
73
75
40
72
50
46
63
70
65
70
65
70
70
65
2
270-272
C15H10ClN3O
C15H11N3O2
C16H10N4O
C16H10F3N3O
C15H9Cl2N3O
C17H15N3O
C14H11ClN4
C14H11FN4
C15H11N5
63.27
3.60
14.96
3
63.50
3.55
14.81
DMF
309-311
67.82
67.91
4.26
4.18
16.12
15.84
4
DMF–H2O
292-294
69.85
3.92
20.67
5
70.06
3.68
20.43
Dioxane
251-253
EtOH
60.42
60.56
3.26
3.17
13.47
13.24
6
280-282
56.48
3.07
13.46
7
56.62
2.85
13.20
DMF
255-257
DMF
73.38
73.63
5.53
5.45
15.46
15.15
8
258-260
61.93
4.18
20.84
9
62.11
4.09
20.69
Toluene
224-226
Toluene
66.04
66.12
4.52
4.36
22.34
22.03
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
233-235
68.72
4.16
27.06
68.95
4.24
26.81
Toluene
295-298
Toluene
C16H17N5
68.64
68.79
6.18
6.13
25.32
25.07
202-204
C15H14N4
71.73
5.81
22.76
71.97
5.64
22.39
Benzene
282-dec.
Dioxane
C14H19N5
65.26
65.34
7.51
7.44
27.46
27.22
281-283
C10H11N5O
C11H13N5O2
C10H9N5
55.18
5.12
32.50
55.29
5.10
32.24
DMF–H2O
248-250
53.36
53.43
5.38
5.30
28.48
28.33
Dioxane
181-183
60.17
4.60
35.24
60.29
4.55
35.16
Cyclohexane
320-322
C9H7N5O
53.66
53.73
3.58
3.51
34.97
34.81
DMF–H2O
174-176
C10H9N5O
C10H9N5O
C15H13N5
55.60
4.28
32.72
55.81
4.22
32.54
EtOH–H2O
252-254
55.72
55.81
4.30
4.22
32.80
32.54
EtOH–H2O
205-207
68.34
5.04
26.83
68.42
4.98
26.60
DMF–H2O
231-233
C15H12ClN5
C16H15N5
60.45
60.50
4.12
4.06
23.64
23.52
DMF–H2O
280-282
69.21
5.52
25.34
69.29
5.45
25.26
DMF–H2O
308-310
C16H14ClN5
C16H12N6
61.46
61.63
4.64
4.52
22.60
22.46
DMF
307-309
66.53
4.30
29.36
66.65
4.19
29.15
DMF–H2O
312-314
C16H11ClN6
C16H13N5S
C16H12ClN5S
59.46
59.53
3.58
3.43
26.31
26.04
DMF–H2O
341-344
62.47
4.31
22.93
62.53
4.26
22.79
DMF–H2O
337-340
56.18
56.21
3.67
3.54
20.72
20.49
DMF–H2O
831

TABLE 3. IR and MS Data for Compounds 2-28
Com-
IR, cm-1
m/z (I, %)
pound
1
2
3
3600-2400 (NH), 1680 (C=O),
M+ 249 (36), 221 (18), 220 (100), 119 (22),
103 (20), 77 (18)
2
3
1610 (C=C), 980 (trans C=C)
3600-2400 (NH), 1670 (C=O),
1590 (C=C), 980 (trans C=C),
820 (1,4-disubst. arom.)
M+ 285 (11), 283 (27), 256 (36), 255 (20),
254 (100), 137 (12), 119 (34), 102 (19), 101 (23),
75 (11), 44 (10)
3600-2400 (NH, OH), 1680
M+ 265 (25), 237 (10), 236 (58), 161 (86), 146 (16),
4
5
(C=O), 1600 (C=C), 1260 (C–O), 133 (37), 120 (12), 119 (100), 118 (15), 92 (47),
980 (trans C=C),
91 (20), 73 (22), 65 (18), 64 (19), 57 (11), 45 (13),
44 (24), 43 (87), 42 (14), 41 (17), 39 (18), 38 (12)
840 (1,4-disubst. arom.)
3600-2400 (NH), 2220 (C≡N),
1670 (C=O), 1600 (C=C),
980 (trans C=C),
M+ 274 (38), 246 (16), 245 (100), 128 (18),
119 (36), 101 (10)
840 (1,4-disubst. arom.)
3600-2400 (NH), 1660 (C=O),
1610 (C=C), 980 (trans C=C),
830 (1,4-disubst.arom.)
M+ 317 (56), 289 (24), 288 (100), 171 (13),
151 (23), 119 (56), 41 (10)
6
7
3500-2400 (NH), 1670 (C=O),
1580 (C=C), 980 (trans C=C),
870, 805 (1,2,4-trisubst. arom.)
M+ 318 (7), 320 (5), 317 (32), 290 (17), 289 (10),
288 (27), 284 (12), 282 (45), 256 (30), 255 (16),
254 (100), 171 (14), 137 (15), 136 (29), 135 (28),
119 (62), 99 (24), 92 (19), 64 (20)
3500-2200 (NH), 1670 (C=O),
1600 (C=C), 980 (trans C=C),
880, 820 (1,2,4-trisubst. arom.)
M+ 277 (11), 262 (10), 250 (15), 249 (90), 248 (87),
234 (90), 130 (21), 129 (32), 128 (37), 119 (64),
116 (37), 115 (100), 91 (70), 64 (45), 51 (18)
8
3200-2400 (NH), 1650 (C=N)
M+ 270 (52), 272 (14), 269 (100), 255 (21),
229 (17), 111 (28), 92 (9), 75 (16), 57 (10)
9
3200-2400 (NH), 1640 (C=N)
M+ 254 (100), 253 (97), 239 (84), 213 (50),
212 (34), 186 (28), 145 (10), 136 (33), 127 (11),
95 (99), 92 (16), 91 (15), 75 (47)
10
3200-2400 (NH), 2230 (C≡N),
M+ 261 (44), 260 (100), 246 (22), 220 (18),
219 (16), 193 (16), 143 (12), 102 (56), 92 (13),
91 (11), 75 (12), 64 (11), 51 (11), 39 (10)
11
12
13
14
1660 (C=N)
3400-2400 (NH), 1610 (C=N)
3600-2600 (NH), 1630 (C=N)
3500-2400 (NH), 1600 (C=N)
M+ 279 (100), 278 (40), 264 (19), 145 (14),
119 (12), 92 (17), 91 (17), 77 (14), 65 (12), 64 (11),
42 (16), 39 (11)
M+ 250 (79), 234 (16), 208 (12), 173 (14), 146 (11),
131 (23), 130 (14), 120 (15), 91 (100), 90 (11),
65 (24), 39 (10)
M+ 257 (2), 161 (22), 160 (31), 159 (18), 148 (25),
147 (100), 146 (97), 144 (14), 133 (18), 120 (34),
119 (43), 96 (23), 93 (26), 92 (30), 82 (26), 66 (21),
56 (46), 42 (36), 39 (44), 38 (20)
3600-2600, 1690, 1630, 1280
M+ 217 (9), 175 (46), 174 (80), 146 (100), 145 (19),
144 (16), 93 (17), 66 (10), 43 (31), 39 (10)
15
16
3600-2400 (NH), 1720 (C=O),
1270, 1060 (C–O)
3080, 2970, 1580, 1520, 1420
M+ 247 (54), 175 (11), 174 (100), 147 (16), 146 (99),
145 (13), 144 (15), 119 (12), 93 (27), 66 (17)
M+ 199 (100), 170 (15), 159 (45), 117 (18), 65 (10)
17
18
3300-2400, 1730, 1610, 1560,
M+ 201 (100), 145 (31), 144 (63), 120 (12), 119 (66),
117 (14), 92 (20), 91 (62), 65 (20), 64 (30), 56 (24),
40 (18), 39 (15), 38 (19)
1410, 1370, 1140
2960, 1720, 1610, 1410
M+ 215 (100), 173 (17), 172 (19), 158 (12), 146 (10),
145 (25), 144 (30), 120 (12), 119 (65), 91 (50), 70
(35), 69 (13), 64 (24), 44 (17), 43 (47), 42 (23), 40
(16), 38 (15)
19
20
3050, 2960, 1650, 1610, 1550,
1480, 1430, 1320, 1130
M+ 215 (100), 201 (61), 173 (11), 160 (22), 159 (35),
158 (28), 145 (12), 144 (22), 133 (39), 119 (33),
118 (68), 105 (12), 91 (44), 79 (11), 78 (13), 64 (28),
44 (74), 43 (30), 42 (26), 40 (17), 39 (23)
832

TABLE 3 (continued)
1
2
3
3600-2400 (NH), 1630 (C=N)
M+ 263 (100), 262 (22), 234 (26), 186 (59), 145 (13),
144 (15), 115 (10), 77 (10)
21
22
3400-2400 (NH), 1630 (C=N),
860(1,4-disubst. arom.)
M+ 297 (100), 299 (29), 296 (29), 268 (19), 233 (11),
232 (11), 186 (78), 145 (21), 144 (24), 117 (15),
83 (10), 71 (12), 69 (11), 57 (21), 44 (13),
43 (16), 41 (11)
3400-2400 (NH), 1620 (C=N)
M+ 277 (84), 276 (17), 234 (15), 200 (100),
115 (10), 104 (16), 28 (20)
23
24
3200-2200 (NH), 1630 (C=N),
815 (1,4-disubst. arom.)
3500, 3300, 1640, 1590
3520, 3360, 1650, 1600, 850
3500-2400, 1620, 1520
M+ 311 (74), 313 (21), 310 (18), 233 (12), 232 (12),
200 (100), 138 (16), 93 (10)
M+ 288 (100), 287 (12), 144 (12), 57 (14), 43 (11)
M+ 322 (100), 324 (30), 321 (12), 161 (10), 144 (11)
25
26
27
M+ 307 (5), 306 (16), 305 (100), 304 (29),
247 (23), 144 (20)
3600-2600, 1600, 1520
M+ 341 (32), 340 (26), 339 (100), 338 (31),
281 (24), 145 (10), 144 (45), 119 (17),
92 (11), 65 (11), 44 (12)
28
TABLE 4. 1H NMR Data for Compounds 15-26
Compound
Solvent
Chemical shifts, δ, ppm (J, Hz)
DMSO-d6
2.18 (3H, s, CH3); 3.30 (3H, s, COCH3); 7.05-7.22 (1H, m, C(6)H);
15
7.80 (1H, d, J = 6.0, C(7)H); 8.25 (1H, d, J = 5.0, C(5)H)
CD3OD
1.37 (3H, t, J = 7.0, –CH2CH3); 2.39 (3H, s, CH3);
16
4.34 (2H, q, J = 7.0, –CH2CH3); 7.27-7.36 (1H, m, C(6)H);
8.00 (1H, d, J = 7.0, C(7)H); 8.37 (1H, d, J = 4.0, C(5)H)
DMSO-d-6
DMSO-d6
DMSO-d6
2.81 (3H, s, CH3); 3.20 (3H, s, CH3); 7.49 (1H, dd, J = 4.0, C(3)H);
17
18
19
8.50 (1H, d, J = 7.0, C(4)H); 8.74 (1H, d, J = 6.0, C(2)H)
2.56 (3H, s, CH3); 7.56 (1H, dd, J = 4.7, C(3)H);
8.63 (1H, d, J = 6.0, C(4)H); 8.76 (1H, d, J = 7.0, C(2)H)
2.56 (3H, s, CH3); 3.71 (3H, s, –NCH3); 7.57 (1H, dd, J1 = 5.0,
J2 = 4.0, C(3)H); 8.63 (1H, d, J = 6.0, C(4)H);
8.76 (1H, d, J = 3, C(2)H)
DMSO-d6
+ TFA
2.64 (3H, s, CH3); 4.41 (3H, s, OCH3); 7.74 (1H, dd, J = 6.0,
20
21
C(3)H); 8.86 (1H, d, J = 7.0, C(4)H); 9.18 (1H, d, J = 8.0, C(2)H)
DMSO-d6
3.05 (1H, dd, J = 2.0, CH2CH); 3.62 (1H, dd, J = 10, CH2CH);
5.15 (1H, t, J = 10, CH2CH); 7.20-7.31 (5H, m, Ar–H);
7.46 (1H, dd, J = 6.0, C(6)H); 8.20 (1H, d, J = 8.0, C(7)H);
8.37 (1H, d, J = 5.0, C(5)H)
+ TFA
DMSO-d6
+ TFA
3.02 (1H, dd, J = 10, CH2CH); 3.62 (1H, dd, J = 12, CH2CH);
5.16 (1H, t, J = 10, CH2CH); 7.19 (4H, s, Ar–H);
7.31 (1H, dd, J = 6, C(6)H); 8.21 (1H, d, J = 8, C(7)H);
8.40 (1H, d, J = 6, C(5)H)
2.96 (3H, s, NCH3); 3.12 (1H, dd, J = 13, CH2CH);
3.73 (1H, dd, J = 11, CH2CH); 4.75 (1H, t, J = 13, CH2CH);
7.31-7.45 (5H, m, Ar–H); 7.57 (1H, dd, J = 6, C(6)H);
8.30 (1H, d, J = 8, C(7)H); 8.50 (1H, d, J = 5, C(5)H)
22
23
24
DMSO-d6
+ TFA
DMSO-d6
+ TFA
2.95 (3H, s, NCH3); 3.10 (1H, dd, J = 15, CH2CH);
3.74 (1H, dd, J = 12, CH2CH); 4.75 (1H, t, J = 12, CH2CH);
7.42 (4H, m, Ar–H); 7.58 (1H, dd, J = 6, C(6)H);
8.33 (1H, d, J = 7, C(7)H); 8.52 (1H, d, J = 6, C(5)H)
DMSO-d6
+ TFA
7.48-7.56 (3H, m, NH2, C(5)H pyrimidine);
25
26
7.70 (1H, dd, J = 6, C(6)H); 8.02-8.08 (5H, m, Ar–H);
8.57 (1H, d, J = 8, C(7)H); 8.66 (1H, d, J = 5, C(5)H)
DMSO-d6
6.89 (2H, br. s, NH2); 7.31 (1H, dd, J = 5, C(6)H);
7.60 (2H, d, J = 9, Ar–H); 7.97 (1H, s, C(5)H pyrimidine);
8.04 (1H, d, J = 5, C(7)H); 8.20 (2H, d, J = 9, Ar–H);
8.44 (1H, d, J = 4, C(5)H)
833

EXPERIMENTAL
1
Melting points are uncorrected. IR spectra: Specord 75 spectrophotometer (pellets in KBr). H NMR:
80 MHz Tesla 478 or Varian Unity 500 Plus spectrometers with TMS as internal standard; chemical shifts in
δ ppm. MS spectra: LKS 9000 S apparatus with direct inlet, ionization energy 70 eV. The characteristics of the
synthesized compounds are given in Tables 2-4.
The biological tests were performed in the Institute of Tuberculosis and Pulmonary Diseases in
Warsaw.
b
-
To a suspension of ketone
1-(Imidazo[4,5- ]pyridin-2-yl)-3-aryl-2-propen-1-ones (2 8).
1
[2]
(0.002 mol) and an appropriate aldehyde (0.003 mol) in anhydrous ethanol (10 ml) 0.2 ml of piperidine was
added and the mixture was refluxed with stirring for 1-2 h. The solid that precipitated after cooling was filtered
off and recrystallized.
b
-
2-(1-Aryliminoethyl)imidazo[4,5- ]pyridines (9 14) 1
. Compound [2] (0.002 mol) and an appropriate
amine (0.003 mol) were heated at 155-165°C with stirring for 20 min. After cooling, the solid obtained was
washed with ether and recrystallized. Compound 13 was obtained by refluxing of 1 and benzylamine in
anhydrous xylene (5 ml) for 3 h. The precipitate obtained after cooling was filtered off and recrystallized.
b
b
N-[1-(Imidazo[4,5- ]pyridin-2-yl)ethylidene]acetohydrazide (15), Ethyl 2-[1-(Imidazo[4,5- ]-
pyridin-2-yl)ethylidene]hydrazine-1-carboxylate (16). To a suspension of ketone 1 [2] (0.003 mol) and
acetohydrazide or ethyl carbazate (0.004 mol) in anhydrous ethanol (10 ml) glacial acetic acid (5 drops) was
added and the mixture was refluxed with stirring for 5 h. The solid that precipitated after cooling (16) or after
evaporation of the solvent (15) was filtered off and recrystallized.
d
15
6,9-Dimethylpyrido[3',2':4,5]imidazo[1,2- ][1,2,4]triazine (17), 9-methylpyrido[2',3':4,5]imidazo-
d
Compound
(0.003 mol) or
[1,2- ][1,2,4]triazin-6(7H)-one (18).
16
(0.002 mol) was refluxed in
N,N-dimethylaniline (10 ml) for 20 h (15) or 10 h (16). The solid that precipitated after cooling (18) or after
evaporation of the solvent (17) was filtered off and recrystallized.
d
To a stirred suspension of
7,9-Dimethylpyrido[2',3':4,5]imidazo[1,2- ][1,2,4]triazin-6-one (19).
finely powdered KOH (0.003 mol) in dry DMF (15 ml) cooled to about 5°C compound 18 was added in
portions. The reaction mixture was stirred for 1 h, then a cooled solution of methyl iodide (0.0035 mol) in DMF
(1 ml) was added dropwise during 10 min and stirring was continued for 3 h. After that time the solvent was
evaporated in vacuo and the remaining product was triturated with a small amount of H2O, filtered off, and
recrystallized.
d
To a stirred solution of
6-Methoxy-9-methylpyrido[2',3':4,5]imidazo[1,2- ][1,2,4]triazine (20).
compound 18 (0.002 mol) in nitrobenzene (15 ml) (heated at 135-140°C) a solution of dimethyl sulfate
(0.003 mol) in nitrobenzene (1 ml) was added dropwise during 10 min. The stirring was then continued at the
same temperature for 4 h. After cooling, the solid formed was filtered off, washed with ether and then dissolved
in a small amount of H2O, and alkalized with NH3. The resultant yellow precipitate was filtered off and
recrystallized.
2
2
b
,
∆
2-(5-Aryl-∆ -pyrazolin-3-yl)imidazo[4,5- ]pyridines (21 22), 2-(1-Methyl-5-aryl- -pyrazolin-3-
b
,
yl)imidazo[4,5- ]pyridines (23 24). 2 3
To a suspension of compound or (0.002 mol) in anhydrous ethanol
(15 ml) hydrazine hydrate (100%) or methylhydrazine (0.0025 mol) was added and the mixture was refluxed
with stirring for 2-3 h. The resulting solid was filtered off and recrystallized.
b
,
2-(2-Amino-6-arylpyrimidin-4-yl)imidazo[4,5- ]pyridines (25 26).
To a refluxing mixture of
compound 2 or 3 (0.002 mol) and guanidine carbonate (0.002 mol) in ethanol (15 ml) a water solution of sodium
hydroxide (40%, 1 ml) was added portionwise during 30 min and refluxing was continued for 7-8 h. After
cooling, the separated solid was filtered off and the filtrate was concentrated to half of its volume and poured
into H2O. The precipitated solid was filtered off and recrystallized.
834

b
To
a
2-(4-Aryl-2-thioxo-1,2,3,4-tetrahydropyrimidin-6-yl)imidazo[4,5- ]pyridines (27, 28).
suspension of compound 2 or 3 (0.002 mol) and thiourea (0.002 mol) in ethanol (20 ml) a water solution of
sodium hydroxide (40%, 1 ml) was added and the resulting mixture was refluxed for 15 h. Then, the solvent was
completely removed and the remaining product was dissolved in 10 ml of water. The solution was filtered and
the filtrate was acidified with acetic acid to pH 3-4. The precipitated solid was filtered off and recrystallized.
We are grateful to Dr. P. Sowinski, head of the Inter-University NMR Laboratory in Gdansk for helpful
discussion.
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1.
M. Negwer, Organic-Chemical Drugs and Their Synonyms, 7 Ed., Akademie-Verlag, Berlin, 1994,
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