July 2014
Studies on the Reactivity of Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazole-
903
4-carboxylic Acid Hydrazide Towards Some Reagents for Biological Evaluation
5-Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic
11.20 (s, 1H, NH, D2O exchangeable). MS, m/z (%): 361 (M+, 100),
346 (4.94), 319 (94.54), 289 (10.49), 262 (95.51), 221 (14.94), 197
(18.80), 139 (13.85), 115 (21.44), 101 (20.14), 91 (4.06), 77 (21.14).
Anal. Calcd. for C18H15N7O2 (361.35): C, 59.82; H, 4.18; N, 27.13.
Found: C, 60.03; H, 4.01; N, 26.91.
acid hydrazide (3). Compound 2, 3.09 g (0.01 mol), was heated in
50 mL hydrazine hydrate (99%) for 6 h. After cooling, the
precipitated material was filtered off, washed several times with
water, dried, and recrystallized from dioxane to give compound
3 (2.74 g, 92.88%); mp 297–298 ꢀC. IR spectrum (KBr, n, cmꢁ1):
[5-Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazol-4-yl]-(3,5-
dimethylpyrazol-1-yl)-methanone (7). A solution of compound
3, 2.95 g (0.01 mol) in 20 mL acetylacetone was refluxed for 10 h.
The solvent was then removed in vacuo and the remaining oily
product was washed several times with dimethyl ether, dried,
and recrystallized from chloroform to give compound 7 (3.05 g,
84.95%); mp 261–262 ꢀC. IR spectrum (KBr, n, cmꢁ1): 3444, 3318
1
3430, 3410, 3260 (NH2, NH), and 1654 (CO); H NMR spectrum
(DMSO-d6, d ppm): 4.30 (s, 2H, NH2, D2O exchangeable),
7.50–7.70 (m, 5H, 3ArꢁH+NH2, exchangeable with D2O), 8.05
(s, 1H, pyrazole-H), 8.10–8.25 (m, 3H, 2Ar–H + pyridazine-H),
8.43 (d, J= 8.5 Hz, 1H, pyridazine-H), and 9.15 (s, 1H, NH, D2O
exchangeable); MS, m/z (%): 295 (M+, 33.06), 264 (100), 236
(1.17), 197 (3.39), 171 (1.83), 155 (4.76), 140 (2.17), 115 (15.26),
104 (4.13), 77 (12.29). Anal. Calcd. for C14H13N7O (295.29):
C, 56.94; H, 4.43; N, 33.20. Found: C, 56.97; H, 4.34; N, 33.25.
5-Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazole - 4-
carbonylazide (4). To a solution of compound 3, 2.95 g (0.01 mol)
in 10 mL glacial acetic acid at 5–10 ꢀC, 3.5 mL chilled sodium nitrite
solution 10% (0.01 mol), was added dropwise during 5 min with
stirring. The reaction mixture was allowed to stand at room
temperature for 1 h and then diluted with 25 mL water. The formed
precipitate was filtered off and recrystallized from dioxane to give
compound 4 (2.99 g, 97.71%); mp 194–196 ꢀC. IR spectrum
(KBr, n, cmꢁ1): 3444, 3313 (NH2), 2152 (N3), and 1662 (C═O);
1H NMR spectrum (DMSO-d6, d ppm): 7.50–7.65 (m, 3H, Ar–H),
7.90 (s, 1H, pyrazole-H), 8.05–8.25 (m, 4H, 2Ar–H +NH2, D2O
exchangeable), and 8.30–8.50 (m, 2H, 2pyridazine-H); MS,
m/z (%): 306 (M+, 52.33), 278 (56.92), 264 (12.14), 250 (2.84),
223 (15.43), 209 (3.31), 197 (100), 168 (10.92), 155 (12.71),
140 (33.01), 115 (58.97), 104 (24.65), 77 (24.10). Anal. Calcd.
for C14H10N8O (306.27): C, 54.89; H, 3.29; N, 36.58. Found:
C, 54.64; H, 3.39; N, 36.74.
1
(NH2), and 1657 (C═O); H NMR spectrum (DMSO-d6, d ppm):
2.25 (s, 3H, CH3), 2.50 (s, 3H, CH3), 6.20 (s, 1H, pyrazol-H),
7.50–7.65 (m, 3H, Ar–H), 8.10–8.40 (m, 5H, 2Ar–H+NH2, D2O
exchangeable + pyridazine-H), 8.50 (d, J= 9.0 Hz, 1H, pyridazine-H),
and 8.60 (s, 1H, pyrazole-H). 13C NMR spectrum (DMSO-d6,
d ppm): 10.5 (CH3), 13.2 (CH3), 100 (C4), 105 (C40), 133 (C3), 146
(C30), 147 (C50) 153 (C5), 181 (C═O), 118–157 (C-phenyl and
C-pyridazine). MS, m/z (%): 359 (M+, 61.00), 334 (2.33), 319 (3.41),
264 (100), 197 (34.9), 179 (5.96), 155 (7.15), 140 (5.5), 115 (20.13),
104 (10.29), 77 (8.81). Anal. Calcd. for C19H17N7O (359.38):
C, 63.49; H, 4.76; N, 27.28. Found: C, 63.24; H, 5.04; N, 27.22.
[5-Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazol-4-yl]-(5-
amino-4-cyano-pyrazol-1-yl)-methanone (8).
To a solution
of compound 3, 1.47 g (0.005 mol) in 20 mL dimethyl formamide,
(0.005 mol) ethyl(ethoxymethylene)cyanoacetate was added, then
the reaction mixture was refluxed for 3 h. The product that
separated on cooling was filtered off and recrystallized from
dioxane to give compound 8 (1.78 g, 95.96%,); mp 316–318 ꢀC. IR
spectrum (KBr, n, cmꢁ1): 3419–3299 (2 NH2), 2227 (CN), and
1
1660 (CO); H NMR spectrum (DMSO-d6, d ppm): 7.45–7.80 (m,
N-[4-oxo-1-(6-phenyl-pyridazin-3-yl)-1,4-dihydro-pyrazolo[3,4-
d]pyrimidin-5-yl]formamidic acid ethyl ester (5). Compound 3,
2.95 g (0.01 mol) was refluxed in 40 mL triethyl orthoformate
for 12 h. The formed precipitate on cooling was filtered off and
recrystallized from dioxane to give compound 5 (3.33 g, 92.24%);
mp 223–224 ꢀC. IR spectrum (KBr, n, cmꢁ1): 1700 (CO);
1H NMR spectrum (DMSO-d6, d ppm): 1.36 (t, J=7.2Hz, 3H,
OCH2CH3), 4.37 (q, J= 7.2 Hz, 2H, OCH2CH3), 7.56–7.58
(m, 3H, Ar–H), 8.17–8.20 (m, 2H, Ar–H), 8.31 (d, J= 9.3 Hz, 1H,
pyridazine-H), 8.46–8.51 (m, 3H, pyrazole-H + pyridazine-
H+N═CH), and 8.54 (s, 1H, pyrimidine-H). 13C NMR spectrum
(DMSO-d6, d ppm): 15 (CH3), 69.5 (OCH2), 108 (C3a), 135 (C3),
137 (C7a), 160 (C6), 168 (C═O), 119–154 (C-phenyl + C-
pyridazine + C═N). MS, m/z (%): 361 (M+, 72.71), 332 (24.90),
316 (13.04), 305 (34.44), 290 (100), 261 (30.50), 248 (17.17),
235 (12.30), 221 (10.74), 206 (12.11), 197 (14.35), 155 (12.22),
140 (12.64), 115 (20.95), 102 (15.35), 77 (17.73). Anal. Calcd.
for C18H15N7O2 (361.35): C, 59.82; H, 4.18; N, 27.13. Found:
C, 59.59; H, 4.06; N, 27.39.
5H, 3Ar–H+NH2, D2O exchangeable), 7.90–8.05 (m, 2H, Ar–H),
8.10–8.30 (m, 3H, pyrazole-H + NH2, D2O exchangeable), and
8.35–8.60 (m, 3H, 2pyridazine-H + pyrazole-H); MS, m/z (%): 371
(M+, 25.10), 305 (1.18), 264 (100), 197 (2.90), 155 (1.40), 140
(3.01), 115 (5.76), 104 (1.45), 77 (1.60). Anal. Calcd. for
C18H13N9O (371.34): C, 58.21; H, 3.52; N, 33.94. Found: C, 58.27;
H, 3.24; N, 34.11.
5-Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic
acid
amide (9).
(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-
A mixture of compound 3, 2.95g (0.01mol) and
tetrachlorophthalic anhydride (2.85 g, 0.01 mol) in glacial acetic
acid (50 mL) was refluxed for 3 h. The formed precipitate was
filtered on hot, dried, and recrystallized from dioxane to give
compound 9 (5.57 g, 98.93%); mp 340–341 ꢀC. IR spectrum
(KBr, n, cmꢁ1): 3442, 3360 (NH2, NH), 1799, 1743 (anhydride
C═O), and 1647 (amide C═O); 1H NMR spectrum (DMSO-d6,
d ppm): 7.50–7.80 (m, 5H, 3Ar–H+NH2, D2O exchangeable),
8.05 (s, 1H, pyrazole-H), 8.15–8.40 (m, 2H, Ar–H), 8.50–8.60
(m, 2H, 2pyridazine-H), and 12.60 (s, 1H, NH, D2O exchangeable).
13C NMR spectrum (DMSO-d6, d ppm): 99 (C4), 133 (C3),
151 (C5), 166 (C═O) and 167.5 (C═O), 120–132 (C-phenyl and
C-pyridazine). Anal. Calcd. for C22H11Cl4N7O3 (563.19): C, 46.91;
H, 1.97; N, 17.41. Found: C, 46.73; H, 2.20; N, 17.40.
N-[6-Methyl-4-oxo-1-(6-phenyl-pyridazin-3-yl)-1,4-dihydro-
pyrazolo[3,4-d]pyrimidin-5-yl]acetamide (6).
A mixture of
compound 3, 2.95 g (0.01 mol) in glacial acetic acid (20 mL) and
acetic anhydride (20 mL) was refluxed for 12 h. The solution was
cooled and poured into water and the formed precipitate was filtered
off, washed with water, dried, and recrystallized from ethanol to give
6 (2.97 g, 82.27%); mp 165–167 ꢀC. IR spectrum (KBr, n, cmꢁ1):
3210 (NH), 1710 (CO) and 1685 (CO); 1H NMR spectrum (DMSO-
d6, d ppm): 2.11 (s, 3H, COCH3), 2.43 (s, 3H, CH3), 7.57–7.59 (m,
3H, Ar–H), 8.19–8.22 (m, 2H, Ar–H), 8.32 (d, J= 9.0 Hz, 1H,
pyridazine-H), 8.49–8.52 (m, 2H, pyrazole-H + pyridazine-H), and
5-Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic
acid (2,3,4,5,6-pentahydroxy-hexylidine)-hydrazide (10).
A
mixture of 2.95 g (0.01 mol) of compound 3, D-glucose
(1.8 g, 0.01 mol) in dry dimethylformamide (50 mL) and a catalytic
amount of acetic acid were heated at 80 ꢀC for 1 h. The formed
precipitate was filtered on hot, washed with ethanol several times
and dried to give compound 10 (4.43 g, 96.93% yield); mp 248–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet