Pyridazine derivative and related compound, part 18: Pyridazino [3′,4′:3,4]pyrazolo[5,1-c]-1,2,4-triazine-3-carboxylic acid: Synthesis, reactions, and antimicrobial activity

Article abstract of DOI:10.1080/10426500600754786

A series of 3-substituted pyridazino[3′,4′:3,4]pyrazolo[5,1-c]- 1,2,4-triazens have been synthesized starting from the 3-carboxylic acid derivative 2. The reaction of the acid chloride 3 with amines gave the corresponding anilides 4. The reaction of 2 wit

Full text of DOI:10.1080/10426500600754786

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Pyridazine Derivative and
Related Compound, Part 18:1
Pyridazino [3′,4′:3,4]pyrazolo
[5,1-c]-1,2,4-triazine-3-
carboxylic Acid: Synthesis,
Reactions, and Antimicrobial
Activity
Fatma El-Mariah a , Mona Hosny a & Ali Deeb b
a Department of Chemistry, Faculty of Girls, Ain
Shams University, Cairo, Egypt
b Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt
Published online: 01 Feb 2007.
To cite this article: Fatma El-Mariah , Mona Hosny & Ali Deeb (2006) Pyridazine
Derivative and Related Compound, Part 18:1 Pyridazino [3′,4′:3,4]pyrazolo [5,1-
c]-1,2,4-triazine-3-carboxylic Acid: Synthesis, Reactions, and Antimicrobial Activity,
Phosphorus, Sulfur, and Silicon and the Related Elements, 181:11, 2505-2517, DOI:
10.1080/10426500600754786
To link to this article: http://dx.doi.org/10.1080/10426500600754786
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Phosphorus, Sulfur, and Silicon, 181:2505–2517, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600754786
Pyridazine Derivative and Related Compound, Part 18:1
Pyridazino[3‘,4‘:3,4]pyrazolo[5,1-c]-1,2,4-triazine-3-
carboxylic Acid: Synthesis, Reactions, and Antimicrobial
Activity
Fatma El-Mariah
Mona Hosny
Department of Chemistry, Faculty of Girls, Ain Shams University,
Cairo, Egypt
Ali Deeb
Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
A series of 3-substituted pyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazens have
been synthesized starting from the 3-carboxylic acid derivative 2. The reaction
of the acid chloride 3 with amines gave the corresponding anilides 4. The reaction
of 2 with ethyl chloroformate and sodium azide in the presence of triethyl amine gave
the carbonyl azide 5, which underwent a Curtius rearrangement in boiling ethanol
to afford the carbamate 6, which converted to the 3-amino derivative 7 upon alkaline
hydrolysis, and the reaction with acid chloride resulted in N-substituted products
9. On other hand, the reaction of the carboxylic acid 2 with POCl and thiosemi-
3
carbazide afforded 2-amino-1,3,4-thiadiazole derivative 13. The condensation of 13
with aldehydes furnished 14 in a good yield. The products were screened for their
antimicrobial activity against six microorganisms.
Keywords Antimicrobial; 3-subsitituted pyridazinopyrazolotriazines
INTRODUCTION
Derivatives of pyridazines and heterocyclic annelated pyridazines are
known to possess potent biological and pharmacological properties.2−5
As a part of continuing study on the synthesis and antimicro-
bial activity of fused pyridazines.6 During the biological screen-
ing of substituted pyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazines,1
Received January 9, 2006; accepted April 6, 2006.
The authors acknowledge the help of Dr. Gamal El-Sherbeny, Department of Microbi-
ology, Faculty of Science, El-Azhar University, Cairo, for carrying out the antimicrobial
activity.
Address correspondence to Ali Deeb, Zagazig University, Department of Chemistry,
Faculty of Science, Zagazig, Egypt. E-mail: dralideeb@hotmail.com
2505

2506
F. El-Mariah et al.
some showed significant activity. The most active of these was
4-amino-5-(4-methyl-9, 10-diphenyl-pyridazino[3ꢀ,4ꢀ:3, 4]pyrazolo [5,1-
c]-1,2,4-triazin-3-yl)- 2,3-dihydro-1,2,4-triazole-3-thione which had anti
S. aureus and Ps. aeruginosa activity. The work has now been extended
further, and a number of related pyridazino[3ꢀ,4ꢀ:3, 4] pyrazolo[5,1-c]-
1,2,4-triazines have been synthesized to exploit the lead.
CHEMISTRY
The required 4-methyl-9,10-diphenypyridiazino[3ꢀ,4ꢀ:3,4]pyrazolo [5,1-
c]-1,2,4-triazine-3-carboxylic acid 2 was prepared by the saponification
of 3-carboxylate ester 17 with potassium hydroxide followed by acidi-
fication (Scheme 1). The structure of compound 2 was assigned on the
basis of analytical spectral data. The infrared spectrum revealed the
presence of a broad band at 3200-2900 cm−1 (OH), and an absorption at
1725 cm−1 referred to the carbonyl of the carboxylic acid group. Treat-
ment of 2 with thionyl chloride gave the acid chloride 3, which was too
unstable to be isolated.
SCHEME 1
The reaction of 3 with aliphatic, aryl, and heteroarylamines such
as n-propylamine, isobutylamine, aniline, p-anisidine, p-toluidine,

Pyridazine Derivative and Related Compound, Part 18
2507
p-chloroaniline, p-nitroaniline, and 3-aminopyridine was carried out by
heating under reflux in excess of amine and in benzene. The products
that were identified as anilides 4a–h (Scheme 1). The structural formu-
las were assigned considering the analytical and spectroscopic data.
In addition, the reaction of compound 2 with ethyl chloroformate
and triethylamine in acetone gave a mixed acid anhydride, which was
converted to the acid azide 5 using sodium azide in a one-pot synthesis.
An IR analysis of this compound showed a strong azide absorption at
2146 cm−1. The carbonyl azide 5 was also obtained by converting the
ester 1 into the corresponding acid hydrazide 106 followed by treatment
with nitrous acid. The compound was sufficiently pure for further use
in rearrangement reactions. It underwent a Curtius rearrangement in
boiling ethanol to afford the carbamate 6, which provided the expected
3-amino derivative 7 by alkaline hydrolysis (Scheme 2). Compound 7
was also obtained following another procedure by converting the ester
1 into the corresponding amide 8 followed by treatment with bromine
and dilute aqueous potassium hydroxide at 0◦C. The resulting Hofmann
reaction product 7 was obtained in an 80% yield.
SCHEME 2
The structure of compound 7 was confirmed on the basis of analyti-
cal data and spectral evidence. The mass spectra showed the expected

2508
F. El-Mariah et al.
molecular ion peak at m/z = 353, and the IR spectra exhibited char-
acteristic bands of the amino group. Compound 7 with a free amino
group at the 3-position reacted with acetyl chloride, benzoyl chloride,
p-nitrobenzoyl chloride, or p-toluenesulfonyl chloride, by refluxing in
acetonitrile and in dry pyridine to give N-substituted products 9a–d.
The structure of compound 9a–d was established by spectral data and
elemental analysis (cf. Experimental section).
On the other hand, the reaction of the carboxylic acid 2 with phos-
phourus oxychloride and thiosemicarbazide afforded 2-amino-1,3,4-
thiadiazole derivative 13. The structure of 13 was evident from its
spectral data. The absence of a ν C O band and the appearance of
new bands in the region of 3475 and 3340 cm−1(NH2) in the IR spectra
and the mass spectral recorded molecular ion peak at m/z 437 corre-
sponding to the molecular ion were particularly diagnostic. Additional
evidence for the structure of 13 was provided by its reaction with acetyl
chloride, which yielded 2-acetylamino 12 in an 88% yield. Compound 12
was also obtained following another procedure by converting the acid
hydrazide 10 into 3-carbothiosemi-carbazide 11 followed by the cyclode-
hydration in the presence of acetyl chloride, which led to 121. The con-
densation of 13 with appropriate aldehyde in an ethanolic medium fur-
nished 14a–e in a good yields (Scheme 3). The structure of compounds
14a–e were elucidated on the basis of their analytical and IR data. The
IR absorption spectra showed the disappearance of the bands referred
to the NH2 group. The mass spectral of compounds 14a, 14c, and 14e
recorded molecular ion peaks at m/z 514, 529, and 545 corresponding
to the molecular ions that were particularly diagnostic.
ANTIMICROBIAL ACTIVITY
Applying the agar plate diffusion technique,7 some of the newly syn-
thesized compounds were screened in vitro for antimicrobial activ-
ity against representative of gram positive bacteria (Bacillus sub-
tilis, Staphylococcus aureus), gram negative bacteria (Escherichia
coli, Pseudomonas aeruginosa), yeast (Candida albicans), and fungi
(Asperggillus niger). In this method, a standard 5-mm diameter steril-
ized filter paper disc impregnated with the compound (0.3 mg/0.1 mL of
dimethylformamide) was placed on an agar plate seeded with the test
organism. The plates were incubated for 24 h at 37◦C. The zone of inhi-
bition of bacterial growth around the disc was observed. The screening
results given in Table I indicated that all the compounds exhibited an-
timicrobial activity against one or the other type of bacteria and fungi.
Series 4 showed the highest inhibitory effect against all the test organ-
isms. The N-substituted derivative 9 had activity against gram positive

Pyridazine Derivative and Related Compound, Part 18
2509
SCHEME 3
B. Subtilis and S. aureus. Almost all the thiadiazole derivatives 14
showed low inhibition.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are uncor-
rected. IR spectra of the compounds were recorded on a Perkin-Elmer
spectrophotometer model 1430 as potassium bromide pellets and fre-
quencies are reported in cm−1. The 1H NMR spectra were recorded
on a Perkin-Elmer R12 B spectrometer, and chemical shifts (δ) are in
ppm relative to internal TMS. Mass spectra were recorded on a Mass
Spectrometer HP model MS 5988 E1 70 ev. Reactions were routinely
followed by TLC on silica gel F254 aluminium sheets (Merck). The spots
were detected by UV irradiation at 254–365 nm.
Compounds 1, 2, and 11 were synthesized as reported previously.1,6

2510
F. El-Mariah et al.
TABLE I Antibacterial and Antifungal Activity
No.
B. subtitils S. aureus E. coli
P. aeurgin. C. albicans A. niger
4a
4b
4c
4d
4e
4f
4g
4h
6
++
+ + +
++
+ + +
++
++
++
+ + +
++
+
+ + +
+ + +
+ + +
+ + +
++
++
++
+ + +
++
+
++
+ + +
++
+ + +
++
++
++
+ + +
++
+
++
+ + +
++
+ + +
++
++
++
+ + +
++
+
++
+ + +
++
+ + +
++
++
++
++
+
−
−
++
+ + +
++
+
−
++
−
7
−
−
9a
9b
9c
+
++
+
−
−
−
−
+
−
−
−
−
+ + +
++
+
+ + +
+ + +
+
−
−
−
−
9d
11
13
14a
14b
14c
14d
14e
−
−
−
−
−
−
−
−
+
+
−
−
−
−
++
+
+
++
−
++
−
++
−
++
−
+
+
+
−
−
−
−
+
+
−
−
−
−
+
+
−
−
−
−
Zone of inhibition: + = 10–15 mm; ++ = 15–20 mm; +++ = 20–25 mm; − =
no inhibition.
3-Chlorocarbonyl-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (3)
A mixture of 2 (0.5 g, 1.31 mmoles) and thionyl chloride (5 mL) was
gently refluxed on a steam bath for 30 min. The excess of thionyl chloride
was removed under reduced pressure to give 0.4 g, 76.3% of 3 which was
used without purification.
3-Substituted carbamoyl-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (4a–i)
General Procedures: For 4a,b
The acid chloride 3 (0.4 g, 0.99 mmoles) and a moderate excess of the
corresponding n-propylamine and/or isobutylamine (molar ratio 1:3)
were refluxed together for 1 h. After cooling to r.t. the precipitate that
formed was filtered off and recrystallized from ethanol.

Pyridazine Derivative and Related Compound, Part 18
2511
For 4c–i
Acid chloride 3 (0.4 g, 0.99 mmoles) and appropriate amine were
refluxed in benzene (10 mL) for 1 h. The solvent was evaporated, and
the residue was treated with diethylether to give crude products, which
were recrystallized from ethanol.
4-Methyl-9,10-diphenyl-3-N-propylcarbamoylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (4a)
The yield was 88%, m.p. 220–221◦C; IR: 3423 (NH), 1660 cm−1 (C O).
Anal. calcd. for C24H21N4O: C, 68.07; H, 4.99; N, 23.15. Found: C, 67.80;
H, 4.70; N, 23.00.
3-N-Isobutylcarbamoyl-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (4b)
The yield was 90%, m.p. 160–161◦C; IR: 3406 (NH), 1655 cm−1 (C O).
Anal. calcd. for C25H23N7O: C, 68.63; H, 5.29; N, 22.41. Found: C, 68.40;
H, 5.10; N, 22.20.
4-Methyl-9,10-diphenyl-3-N-phenylcarbamoylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (4c)
The yield was 88%, m.p. 161–162◦C; IR: 3388 (NH), 1650 cm−1 (C O);
ms (m/z, %), 443 (M+-2, 2), 429 (3), 425 (5), 383 (13), 313 (10), 286 (100).
Anal. calcd. for C27H19N7O: C, 70.88; H, 4.18; N, 21.43. Found: C, 70.60;
H, 4.00; N, 21,20.
4-Methyl-9,10-diphenyl-3-N-p-
methoxyphenylcarbamoylpyridazino-[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-
c]-1,2,4-triazine (4d)
The yield was 88%, m.p. 200–201◦C; IR: 3405 (NH), 1650 cm−1
(C O); ms (m/z, %), 486 (M+-1, 3), 356 (38), 270 (26). Anal. calcd.
for C28H21N7O2: C, 68.98; H, 4.34; N, 20.11. Found: C, 68.80; H, 4.20;
N, 19.90.
4-Methyl-9,10-diphenyl-3-N-p-tolylcarbamoylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (4e)
The yield was 80%, m.p. 240–241◦C; IR: 3529 (NH), 1680 cm−1 (C O);
ms (m/z, %), 473 (M+-2, 2), 305 (10), 287 (46), 286 (84). Anal. calcd. for

2512
F. El-Mariah et al.
C28H21N7O: C, 71.32; H, 4.48; N, 20.79. Found: C, 71.10; H, 4.30; N,
20.60.
3-N-p-Chlorophenylcarbamoyl-4-methyl-9,10-
diphenylpyridazino-[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (4f)
The yield was 75%, m.p. 230–231◦C; IR: 3443 (NH), 1684 cm−1 (C O).
Anal. calcd. for C27H18ClN7O: C, 65.92; H, 3.69; N, 19.93. Found: C,
65.80; H, 3.40; N, 19.70.
4-Methyl-3-N-p-nitrophenylcarbamoyl-9,10-
diphenylpyridazino-[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (4g)
The yield was 50%, m.p. 288–290◦C; IR: 3448 (NH), 1702 (C=O), 1570–
1
1500 cm−1 (NO2), HNMR (DMSO-d6): δ 11.3 (s, 1H, NH), 8.1 (m, 4H,
Ph-3), 7.2 (m, 10H, 2Ph), 2.2 (s, 3H, CH3). Anal. calcd. for C27H18N8O3:
C, 64.53; H, 3.61; N, 22.30. Found: C, 64.40; H, 3.40; N, 22.10.
4-Methyl-9,10-diphenyl-3-N-3-pyridylcarbamoylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (4h)
The yield was 75%, m.p. 188–190◦C; IR: 3750 (NH), 1728 cm−1 (C O);
1HNMR (CDCl3): δ 7.8–7.0 (m, 14H, aromatic protons), 2.05 (s, 3H,
CH3). Anal. calcd. for C26H18N8O: C, 68.11; H, 3.95; N, 24.44. Found: C,
67.90; H, 3.70; N, 24.20.
3-Azidocarbonyl-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo-[5,1-c]-1,2,4-triazine (5)
Method A
Compound 2 (3.82 g, 10 mmoles) was suspended in 35 mL of acetone
and cooled to 0◦C, and triethylamine (5 mL) was added under stirring.
Then the solution of ethyl chloroformate (1.08 g, 10 mmoles) in 5 mL of
acetone was added dropwise keeping the temperature below 0◦C. The
mixture was stirred for 30 min, then sodium azide (0.65 g, 10 mmoles)
in 12 mL of water was added. The mixture was stirred for an additional
hour and then poured into ice water (140 mL). The yellow precipitate
was filtered off, washed with water, and air dried. Yield 9.86 g, 93%,
m.p. 160◦C (dec) (dichloromethane/hexane); IR: 2146 (N3), 1682 cm−1
(C O). Anal. calcd. for C21H13N9O: C, 61.91; H, 3.21; N, 30.95. Found:
C, 61.70; H, 3.00; N, 30.80.

Pyridazine Derivative and Related Compound, Part 18
2513
Method B
To a cold suspension of compound 10 (0.39 g, 10 mmoles) in 3 M
hydrochloric acid (3 mL), a solution of sodium nitrite (0.14 g, 20 mmoles)
in water (1 mL) was added dropwise with stirring. After 30 min, a small
amount of urea was added; then the yellow solid 5 was filtered and
washed with water, 0.36 g (90%). The products obtained by the two
synthetic routes are identical in all aspects.
3-Ethoxycarbonylamino-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (6)
A solution of the azide 5 (1.19 g, 2.94 mmoles) in absolute ethanol
(10 mL) was refluxed for 24 h. The title compound precipitated by cool-
ing as a white solid, which was recrystallized from ethanol to give 0.83
g, 67%, m.p. 135◦C (dec.); IR: 3374 (NH), 1754 cm−1 (C O). Anal. calcd.
for C23H19N7O2: C, 64.92; H, 4.50; N, 23.04. Found: C, 64.70; H, 4.20;
N, 22.80.
3-Carboxamido-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo-[5,1-c]-1,2,4-triazine (8)
Ammonia gas was bubbled for 2 h in a solution of compound 1 (0.8 g,
1.94 mmoles) in dry methanol (20 mL) at r.t. When the solution was con-
centrated to a small volume, the crystalline solid precipitated and was
collected by filtration, yield 0.63 g, 85%. An analytical sample was re-
crystallized from methanol, m.p. 240–241◦C; IR: 3381, 3197 (NH2), 1683
cm−1 (C O). Anal. calcd. for C21H15N7O: C, 66.13; H, 3.96; N, 25.71.
Found : C, 65.90; H, 3.80; N, 25.50.
3-Amino-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (7)
Method A: From 3-Ethoxycarbonylamino Derivative 6
A solution of 3-ethoxycarbonylamino derivative 6 (0.4 g, 0.94 mmoles)
in ethanol (6 mL) and 2 M sodium hydroxide (10 mL) was gently refluxed
for 5 h. After cooling, the solution was extracted with dichloromethane,
and the organic layer was evaporated to give the title compound, 0.1 g,
30%, m.p. 214–215◦C (ethanol); IR; 3420 cm−1 (NH2); ms (m/z, %): (M+-
1, 7), 351 (18), 349 (13), 270 (13). Anal. calcd. for C20H15N7: C, 67.97;
H, 4.28; N, 27.75. Found: C, 67.80; H, 4.00; N, 27.50.
Method B: From 3-Carboxamide Derivative (8)
A mixture of 3-carboxamide derivative 8 (0.78 g, 2.04 mmoles) and 1
N KOH (20 mL) was stirred at 0◦C. To the fine suspension was quickly
added with rapid stirring a mixture of bromine (0.5 mL) and 1 N KOH

2514
F. El-Mariah et al.
(5 mL). After brief stirring at 0◦C, the mixture was heated up imme-
diately in a boiling water bath for 1 h. The reaction mixture was then
cooled to 0◦Cand was acidified with a dropwise addition of 2N HCl
(10 mL). After 1 h stirring, the solid product was collected by filtra-
tion and washed with cold water. It was purified by recrystallization
from ethanol to give 0.57 g, 80%; it was identical in all aspects with the
product prepared by Method A.
3-Acetamido-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (9a)
A mixture of 3-amino derivative 7 (0.76 g, 2.15 mmoles) and acetyl
chloride (5 mL) was warmed on a water-bath for 20 minutes and then
decomposed in ice-water (20 mL). The insoluble material was collected,
washed several times with water, and recrystallized from ethanol 0.7
g, 90%, m.p. 200-201◦C; IR: 3230 (NH), 1670 cm−1 (C O); ms (m/z %):
395 (M+, 0.7), 352 (2.3), 351 (4.5). Anal. calcd. for C22H17N7O: C, 66.82;
H, 4.33; N, 24.80. Found: C, 66.60; H, 4.10; N, 24.60.
3-Benzamido-4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (9b)
To a boiling solution of 3-amino derivative 7 (0.76 g, 2.15 mmoles) in
acetonitrile (10 mL), benzoyl chloride (5 mL) was slowly dropped. Then,
the mixture was boiled for 3 h and cooled. The precipitate was collected
and recrystallized from ethanol to give 0.74 g, 90%, m.p. 290–291◦C;
IR: 3320 (NH), 1690 cm−1 (C=O). Anal. calcd. for C27H19N7O: C, 70.88;
H, 4.19; N, 21.43. Found: C, 70.60; H, 4.00; N, 21.20.
4-Methyl-3-p-nitrobenzoylamino-9,10-
diphenylpyridazino[3ꢀ,4ꢀ:3,4]-pyrazolo[5,1-c]-1,2,4-triazine (9c)
Preparation of 9c from 7 (0.76 g, 2.15 mmoles) and p-nitrobenzoyl chlo-
ride (5 mL) was carried out in a similar manner to that described for
9b, yield 0.7 g, 80%, m.p. 210–211◦C (ethanol); IR: 3144 (NH), 1696
(C=O), 1543 and 1349 cm−1 (NO2). Anal. calcd. for C27H18N8O3: C,
64.54; H, 3.61; N, 22.30. Found: C, 64.30; H, 3.40; N, 22.20.
4-Methyl-3-tosylamino-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine (9d)
A solution of 7 (0.76 g, 2.15 mmoles) and p-toluenesulfonyl chloride
(0.4 g, 2.15 mmoles) in dry pyridine (10 mL) was refluxed for 3 h and

2515

2516
F. El-Mariah et al.
then poured into water (50 mL). The resulting suspension was filtered
with suction; the remaining solid was washed several times with water
and recrystallized from ethanol to give 0.7 g, 70%, m.p. 207–208◦C; IR:
3423 (NH), 1382 and 1187 cm−1 (SO2). Anal. calcd. for C27H21N7O2S:
C, 63.89; H, 4.17; N, 19.32. Found: C, 63.70; H, 4.00; N, 19.10.
5-Amino-2-(4-methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]
pyrazolo[5,1-c]-1,2,4-triazine-3-yl)-1,3,4-thiadiazole (13)
A mixture of compound 26 (0.76 g, 1.98 mmoles), thiosemicarbazide
(0.18 g, 2.0 mmoles), and phosphorus oxychloride (1.0 mL) was refluxed
gently for half an hour. After cooling, water (2.6 mL) was added. The
mixture was refluxed for 4 h and filtered. The solution was neutralized
with potassium hydroxide. The precipitate was filtered and recrystal-
lized from ethanol to give 0.69 g, 80% of 13, m.p. 237–239◦C; IR: 3475,
3340 (NH2), 1610 cm−1 (C N); ms (m/z%): 437 (M+, 0.07), 435 (0.06),
423 (0.1), 286 (100). Anal. calcd. for C22H15N9S: C, 60.40; H, 3.46; N,
28.82. Found: C, 60.20; H, 3.20; N, 28.70.
5-Acetylamino-2-(4-methyl-9,10-diphenylpyridazino
[3ꢀ,4ꢀ:3,4]pyr-azolo[5,1-c]-1,2,4-triazin-3-yl)-1,3,4-thiadiazole
(12)
A mixture of 5-amino derivative 13 (0.87 g, 1.98 mmoles) and acetyl
chloride (20 mL) was warmed on a water-bath for 30 min and then de-
composed in ice-water (100 mL). The insoluble material was collected,
washed several times with water, and recrystallized from ethanol af-
forded 0.85 g, 85% of acetylamino derivative 12, m.p. 270–272◦C (ref.,1
268–270◦C).
Reaction of 13 with Heteroaromatic Aldehydes: The
Formation of 14a–e
General Procedure
A mixture of 5-amino derivative 13 (0.87 g, 1.98 mmoles) and het-
eroaromatic aldehydes (2.0 mmoles) in ethanol (20 mL) was refluxed
for 3 h and then allowed to cool. The solid product was collected and
recrystallized from ethanol. The results are summarized in Table II.
REFERENCES
[1] Part 17: F. El-Mariah, M. Hosny, and A. Deeb, Phosphorus, Sulphur, and Silicon,
181(4), 809–818 (2006).

Pyridazine Derivative and Related Compound, Part 18
2517
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