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European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2015	Atlanta	Publishing	House	LLC	‐	All	rights	reserved	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.6.2.204‐210.1252	

	
	

	

	

European	Journal	of	Chemistry	
Journal	webpage:	www.eurjchem.com	 	

	 	 	

Pyridazine	and	its	related	compounds:	Part	38.		
Pyrimido[1,2‐b]pyridazinone,	synthesis	and	some	reactions	

Ali	Abdel	Hamid	Deeb	1,*,	Fatma	Abdel	Rahman	El‐Mariah	2	and	Heba	Kamal	Abd	El‐Mawgoud	2	

1	Department	of	Chemistry,	Faculty	of	Science,	Zagazig	University,	Zagazig,	44519,	Egypt	
2	Department	of	Chemistry,	College	of		Women	for	Arts,	Science,	and	Education,	Ain	Shams	University,	Cairo,	11753,	Egypt	

*	Corresponding	author	at:	Department	of	Chemistry,	Faculty	of	Science,	Zagazig	University,	Zagazig,	44519,	Egypt.		
Tel.:	+20.55.2303252.	Fax:	+20.55.2308213.	E‐mail	address:	dralideeb@hotmail.com	(A.A.	Deeb).	

	
	

	 	

	 	 	

ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.6.2.204‐210.1252	

Received:	04	February	2015	
Received	in	revised	form:	20	April	2015	
Accepted:	25	April	2015	
Published	online:	30	June	2015	
Printed:	30	June	2015	

	 A	 new	 method	 of	 generating	 the	 fused	 heterocyclic	 system	 with	 bridge	 head	 nitrogen
pyrimido[1,2‐b]pyridazinone,	 from	 3‐amino‐4,5,6‐triphenylpyridazine	 and	 malonic	 acid	 in
presence	of	phosphoryl	 chloride	 is	described.	The	 structures	of	 the	synthesized	compounds
were	 confirmed	 by	 their	 infrared,	 mass	 spectrum,	 1H	 NMR	 and	 elemental	 analyses.	 The
antimicrobial	 activity	 of	 the	 compounds	 obtained	 was	 examined	 against	 some	 selected
microorganisms.	

KEYWORDS	
3‐Aminopyridazine	
Anti‐microbial	activity	
Electrophilic	substitutions	
Nuecleophilic	substitutions	
Pyaranopyrimidopyridazine	
Pyrimido[1,2‐b]pyridazinone	

Cite	this: Eur.	J.	Chem.	2015,	6(2),	204‐210

	
1.	Introduction	
	

The	 pyridazines	 and	 pyrimidines	 are	 important	 and	
significant	classes	of	heterocyclic	compounds	[1‐3].	A	number	
of	 their	 derivatives	 have	 found	 diverse	 uses	 in	 synthetic,	
analytical,	 medicinal,	 pharmaceutical,	 agrochemical,	 and	
photographic	chemistry.	Sometimes	the	fusion	of	heterocyclic	
nuclei	 enhances	 the	 pharmacological	 activities	 much	 more	
than	 its	 parent	 nucleus.	 Hence,	 it	 was	 thought	 that	 the	
incorporation	 of	 the	 latter	 heterocyclic	 moieties	 into	 a	
pyridazine	system	might	modify	their	biological	activities.		

The	 present	 investigation	 is	 in	 continuation	 of	 our	
previous	work	[4‐6]	on	the	synthesis	and	biological	activity	of	
other	pyridazine	derivatives.	 In	 the	accompanying	 	paper	 [5],	
we	have	described	the	preparation	of	3‐amino‐4,5,6‐triphenyl	
pyridazine	 a	 useful	 starting	 material	 for	 the	 preparation	 of	
7,8,9‐triphenyl‐2H‐pyrimido[1,2‐b]pyridazine‐2,4(3H)‐dione,	
1.	 In	 this	 paper,	 we	 wish	 to	 show	 that	 compound	 1	 is	 also	
useful	 building	 blocks	 for	 the	 synthesis	 of	 a	 wide	 variety	 of	
pyrimidopyridazine	derivatives	and	to	test	their	anti‐microbial	
activity.	
	
2.	Experimental	
	
2.1.	Instrumentation	

Melting	 points	were	 determined	 in	 open	 glass	 capillaries	
and	 are	 uncorrected.	 Elemental	 analyses	were	 carried	 out	 in	
the	Micro	Analytical	Laboratory	of	the	Faculty	of	Science,	Cairo	
University,	Egypt.	The	IR	spectra	of	compounds	were	recorded	
on	 a	 Nicolet	 6700	 FT‐IR	 (Thermo	 Scientific)	 as	 potassium	
bromide	 pellets	 and	 frequencies	 are	 reported	 in	 cm‐1.	 The	
mass	spectra	were	recorded	on	a	GC‐MS	model	Shimadzu	Qp‐
2010	plus	EI	70	eV.	The	1H	NMR	spectra	were	recorded	on	a	
Varian	 Gemini‐300	 MHz	 NMR	 spectrometer	 and	 chemical	
shifts	 δ	 are	 in	 ppm	 relative	 to	 internal	 TMS.	 Reactions	were	
routinely	 followed	 by	 thin	 layer	 chromatography	 (TLC)	 on	
silica	 gel;	 F254	 aluminum	 sheets	 (Merck).	 The	 spots	 were	
detected	by	UV	irradiation	at	254‐365	nm.	
	
2.2.	Synthesis	
	
2.2.1.	Synthesis	of	7,8,9‐triphenyl‐2H‐pyrimido[1,2‐b]	
pyridazine‐2,4(3H)‐dione	(1)	
	

A	mixture	of	3‐amino‐4,5,6‐triphenylpyridazine	[5]	(0.5	g,	
1.55	mmol),	malonic	acid	(0.16	g,	1.55	mmol)	and	phosphoryl	
chloride	(10	mL)	was	heated	under	reflux	for	1	h.	The	reaction	
mixture	was	cooled	to	room	temperature	and	poured	into	ice	
cooled	water	(200	mL).	



Deeb	et	al.	/	European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	 205	
 

	

	
	

Scheme	1
	
	
The	 solid	 product	 was	 filtered	 off,	 washed	 with	 water,	

dried	 and	 recrystallized	 from	 ethanol	 (Scheme	 1).	 Color:	
Yellow.	Yield:	72.70%.	M.p.:	 188‐190	 °C.	FT‐IR	 (KBr,	 ν,	 cm‐1):	
3057	(CH	Arom.),	2923	(CH	Aliph.),	1703	 (C=O),	1636	 (C=N).	
1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	3.99	(s,	2H,	CH2),	6.78‐
7.65	 (m,	 15H,	 3Ph).	 MS	 (EI,	m/z	 (%)):	 391	 (M+,	 72.07),	 363	
(11.24),	349	(10.60),	335	(5.41),	321	(16.82),	314	(4.59),	288	
(3.35),	 213	 (3.30),	 178	 (25.40),	 103	 (4.85),	 69	 (100).	 Anal.	
calcd.	 for	 C25H17N3O2:	 C,	 76.71;	 H,	 4.38;	 N,	 10.74.	 Found:	 C,	
76.50;	H,	4.4.20;	N,	10.60%.	
	
2.2.2.	Synthesis	of	2‐chloro‐7,8,9‐triphenyl‐4H‐pyrimido	
[1,2‐b]pyridazin‐4‐one	(2)	
	

A	 mixture	 of	 7,8,9‐triphenyl‐2H‐pyrimido[1,2‐b]	 pyridazi	
ne‐2,4(3H)‐dione	 (1)	 (0.5	 g,	 1.28	 mmol)	 and	 phosphoryl	
chloride	 (10	mL)	was	 refluxed	 for	 3	 h.	 The	 reaction	mixture	
was	cooled,	poured	into	ice	cold	water	(200	mL),	and	then	the	
solid	 product	 formed	 was	 filtered	 off,	 washed	 with	 water,	
dried,	 and	 recrystallized	 from	 ethanol	 to	 give	 compound	 2	
(Scheme	 1).	 Color:	 Brown.	 Yield:	 84.13	%.	M.p.:	 226‐228	 °C.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3057	 (C‐H,	 Arom.),	 1703	 (C=O),	 1638	
(C=N).	 1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	6.65	(s,	1H,	CH,	
pyrimidine	 ring),	 6.78‐7.65	 (m,	 15H,	 3Ph).	MS	 (EI,	m/z	 (%)):	
412	(M++2,	3.50),	410	(M+,	51.22),	408	(100),	374	(5.13),	369	
(5.29),	 349	 (5.54),	 333	 (8.63),	 307	 (7.82),	 267	 (9.93),	 178	
(11.32),	 103	 (5.46),	 76	 (9.69),	 60	 (11.07).	 Anal.	 calcd.	 for	
C25H16ClN3O:	 C,	 73.26;	 H,	 3.93;	 N,	 10.25.	 Found:	 C,	 73.59;	 H,	
3.78;	N,	10.52%.	
	
2.2.3.	Synthesis	of	2‐methoxy‐7,8,9‐triphenyl‐4H‐pyrimido	
[1,2‐b]pyridazin‐4‐one	(3a)	
	

Compound	2	(0.5	g,	1.22	mmol)	was	added	to	a	solution	of	
sodium	methoxide	 (0.1	 g	 of	 Na	 in	 10	mL	 of	 pure	methanol).	
The	 reaction	mixture	 was	 refluxed	 for	 3	 h.	 The	 solvent	 was	
concentrated,	 and	 then	 the	 solid	 product	 was	 filtered	 off,	
dried,	 and	 recrystallized	 from	 ethanol	 to	 give	 compound	 3a	
(Scheme	 1).	 Color:	 Brown	 crystals.	 Yield:	 74.75%.	M.p.:	 146‐
148	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3056	 (C‐H,	 Arom.),	 2927	 (C‒H,	
Aliph.),	1705	(C=O),	1645	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	
δ,	 ppm):	 5.66	 (s,	 3H,	 CH3),	 5.87	 (s,	 1H,	 CH,	 pyrimidine	 ring),	
6.89‐7.65	(m,	15H,	3Ph).	MS	(EI,	m/z	(%)):405	(M+,	96.55),	390	
(72.41),	376	(75.86),	349	(81.61),	334	(59.77),	200	(100),	71	

(75.86),	 57	 (31.03).	 Anal.	 calcd.	 for	 C26H19N3O2:	 C,	 77.02;	 H,	
4.72;	N,	10.36.	Found:	C,	77.39;	H,	4.53;	N,	10.62%.	
	
2.2.4.	Synthesis	of	2‐ethoxy‐7,8,9‐triphenyl‐4H‐pyrimido	
[1,2‐b]pyridazin‐4‐one	(3b)	
	

Compound	2	(0.5	g,	1.22	mmol)	was	added	to	a	solution	of	
sodium	 ethoxide	 (0.1	 g	 of	 Na	 in	 10	mL	 of	 absolute	 ethanol).	
The	 reaction	 mixture	 was	 refluxed	 for	 3	 h.	 The	 solvent	 was	
concentrated;	 and	 then	 the	 solid	 product	 was	 filtered	 off,	
dried,	 and	 recrystallized	 from	 ethanol	 to	 give	 compound	 3b	
(Scheme	 1).	 Color:	 Brown.	 Yield:	 74.26	%.	 M.p.:	 200‐205	 °C.	
FT‐IR	(KBr,	ν,	cm‐1):	3058	(CH,	Arom.),	2975,	2924	(CH,	Aliph.),	
1695	 (C=O),	 1643	 (C=N),	 1234	 (C‒O).	 1H	 NMR	 (300	 MHz,	
DMSO‐d6,	δ,	ppm):	1.14	(t,	3H,	CH2CH3),	4.05	(q,	2H,	CH2CH3),	
5.67	(s,	1H,	CH,	pyrimidine	ring),	6.94‐7.65	(m,	15H,	3Ph).	MS	
(EI,	m/z	 (%)):419	 (M+,	 14.45),	 404	 (7.00),	 390	 (23.58),	 322	
(100),	 307	 (4.01),	 178	 (18.86),	 138	 (4.78),	 77	 (43.56).	 Anal.	
calcd.	 for	 C27H21N3O2:	 C,	 77.31;	 H,	 5.05;	 N,	 10.02.	 Found:	 C,	
77.67;	H,	4.88;	N,	10.25%.	
	
2.2.5.	Synthesis	of	2‐azido‐7,8,9‐triphenyl‐4H‐pyrimido[1,2‐
b]pyridazin‐4‐one	(3c)	
	

A	solution	of	compound	2	(0.5	g,	1.22	mmol),	and	sodium	
azide	(0.24	g,	3.66	mmol)	in	dimethylformamide	(10	mL)	was	
heated	 at	 100	 °C	 for	 3	 h.	 The	 reaction	 mixture	 was	 cooled,	
poured	 into	 ice	 cold	water	 (100	mL).	 The	 solid	 product	was		
filtered	off,	washed	with	water,	dried,	and	recrystallized	from	
ethanol	to	give	compound	3c	(Scheme	1).	Color:	Brown.	Yield:	
76.77	 %.	 M.p.:	 190‐192	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3057	 (CH,	
Arom.),	 2209	 (N3),	 1652	 (C=O),	 1612	 (C=N).	 1H	 NMR	 (300	
MHz,	DMSO‐d6,	δ,	ppm):	5.88	(s,	1H,	CH,	pyrimidine	ring),	6.89‐
7.37	 (m,	 15H,	 3Ph).	 MS	 (EI,	m/z	 (%)):	 416	 (M+,	 3.20),	 388	
(33.45),	 374	 (5.81),	 322	 (100),	 237	 (7.83),	 178	 (9.25),	 77	
(17.08).	Anal.	calcd.	for	C25H16N6O:	C,	72.10;	H,	3.87;	N,	20.18.	
Found:	C,	72.48;	H,	3.99;	N,	20.01%.	
	
2.2.6.	Synthesis	of	2‐hydrazinyl‐7,8,9‐triphenyl‐4H‐
pyrimido[1,2‐b]pyridazin‐4‐one	(3d)	
	

A	 solution	 of	 compound	 2	 (0.5	 g,	 1.22	 mmol),	 and	
hydrazine	hydrate	(0.1	mL,	1.22	mmol)	in	ethanol	(10	mL)	was	
heated	under	reflux	for	3	h.	



206	 Deeb	et	al.	/	European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	
	

	

N
N

N

O

O

Ph

Ph

Ph NO2

10

r.t., 2 h

N
N

N

O

Ph

Ph

Ph

Cl

NO2

11

N
N

N

O

O

Ph

Ph

Ph NH2

9

N
N

N

O

O

Ph

Ph

Ph Cl

Cl

6

N
N

N

O

O

Ph

Ph

Ph Cl

87

N
N

Ph

Ph

Ph

N

O

Cl

N
N

N

O

O

Ph

Ph

Ph Br

Br

5

aq. Na2CO3

Reflux 6 h

Zn / AcOH,

Reflux 1.5 h

Reflux 30 min.

AcOH / NaNO2 / HNO3
70 oC, stirring

for 1 h

Zn / AcOH,

Reflux 3 h

Reflux 2 h

Sand bath,

210 oC for 30 min

Br2, CHCl3

SO2Cl2

POCl3

AcONH4

N
N

N

O

O

Ph

Ph

Ph

1

	
	

Scheme	2	
	
	
The	 solvent	 was	 evaporated,	 and	 the	 residue	 was	

triturated	 with	 cold	 water.	 The	 solid	 product	 formed	 was	
filtered	off,	washed	with	water,	dried,	and	recrystallized	from	
ethanol	to	give	compound	3d	(Scheme	1).	Color:	Brown.	Yield:	
68.69	%.	M.p.:	>	300	°C.	FT‐IR	(KBr,	ν,	cm‐1):	3313,	3204	(NH,	
NH2),	 3058	 (C‒H,	 Arom.),	 1691	 (C=O).	MS	 (EI,	m/z	 (%)):405	
(M+,	7.26),	388	(6.15),	322	(100),	306	(5.49),	251	(4.10),	178	
(10.99),	 98	 (3.26),	 77	 (17.97).	 Anal.	 calcd.	 for	 C25H19N5O:	 C,	
74.06;	H,	4.72;	N,	17.27.	Found:	C,	74.38;	H,	4.83;	N,	17.54%.	
	
2.2.7.	Synthesis	of	7,8,9‐triphenyl‐2‐thioxo‐2H‐pyrimido	
[1,2‐b]pyridazin‐4(3H)‐one	(4)	
	

A	solution	of	compound	2	(0.5	g,	1.22	mmol),	and	thiourea	
(0.5	g)	in	ethanol	(10	mL)	was	heated	under	reflux	for	2	h.	The	
solvent	 was	 evaporated,	 and	 the	 residue	 was	 dissolved	 in	
sodium	 hydroxide	 (10	%).	 The	 reaction	mixture	 was	 heated	
under	reflux	 for	30	min.,	and	 filtered	on	hot.	The	 filtrate	was	
cooled,	 neutralized	 with	 hydrochloric	 acid;	 the	 formed	
precipitate	 was	 filtered	 off,	 washed	 with	 water,	 dried,	 and	
recrystallized	 from	 ethanol	 to	 give	 compound	4	 (Scheme	 1).	
Color:	 Brown.	 Yield:	 68.4	%.	M.p.:	 212‐213	 °C.	 FT‐IR	 (KBr,	 ν,	
cm‐1):	3057	(CH,	Arom.),	2968,	2926	(CH,	Aliph.),	1705	(C=O),	
1638	 (C=N),	 1236	 (C=S).	 MS	 (EI,	m/z	 (%)):407	 (M+,	 44.59),	
377	 (36.31),	 349	 (39.49),	 336	 (51.59),	 320	 (33.12),	 307	
(38.22),	 268	 (42.04),	 229	 (35.03),	 178	 (35.03),	 139	 (44.59),	
100	(7.01),	86	(45.22),	64	(100).	Anal.	calcd.	for	C25H17N3OS:	C,	
73.69;	H,	4.21;	N,	10.31.	Found:	C,	73.98;	H,	4.06;	N,	10.53%.	
	
2.2.8.	Synthesis	of	3,3‐dibromo‐7,8,9‐triphenyl‐2H‐pyrimido	
[1,2‐b]pyridazine‐2,4(3H)‐dione	(5)	
	

To	 a	 solution	 of	 compound	 1	 (0.5	 g,	 1.28	 mmol)	 in	
chloroform	(10	mL),	bromine	(2.56	mmol)	was	added,	and	the	

reaction	mixture	was	stirred	at	room	temperature	for	2	h.	The	
solvent	was	 evaporated,	 and	 the	 residue	was	 triturated	with	
water.	The	solid	product	was	 filtered	off,	washed	with	water,	
dried,	 and	 recrystallized	 from	methanol	 to	 give	 compound	5	
(Scheme	 2).	 Color:	 Brown.	 Yield:	 68.41	%.	 M.p.:	 118‐120	 °C.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3056	 (CH,	 Arom.),	 1710	 (C=O),	 1637	
(C=N).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 6.96‐7.65	 (m,	
15H,	3Ph).	MS	(EI,	m/z	(%)):	549	(M+,	30.60),	520	(21.35),	508	
(34.52),	 469	 (23.13),	 388	 (23.13),	 377	 (19.57),	 372	 (22.06),	
357	 (20.64),	 193	 (6.76),	 172	 (24.20),	 160	 (25.27),	 80	 (100).	
Anal.	calcd.	for	C25H15Br2N3O2:	C,	54.67;	H,	2.75;	N,	7.65.	Found:	
C,	55.03;	H,	2.86;	N,	7.51%.	
	
2.2.9.	Synthesis	of	3,3‐dichloro‐7,8,9‐triphenyl‐2H‐pyrimido	
[1,2‐b]pyridazine‐2,4(3H)‐dione	(6)	
	

A	 solution	 of	 compound	1	 (0.5	 g,	 1.28	mmol)	 in	 sulfuryl	
chloride	 (10	 mL)	 was	 refluxed	 for	 30	 min.	 The	 reaction	
mixture	was	cooled,	poured	into	ice	cold	water	(100	mL),	and	
the	precipitate	was	filtered	off,	washed	with	water,	dried,	and	
recrystallized	 from	 ethanol	 to	 give	 compound	6	 (Scheme	 2).	
Color:	Yellow.	Yield:	73.13	%.	M.p.:	119‐120	°C.	FT‐IR	(KBr,	ν,	
cm‐1):	 3056	 (CH,	 Arom.),	 1713	 (C=O),	 1643	 (C=N).	 1H	 NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	7.23‐7.62	(m,	15H,	3Ph).	MS	(EI,	
m/z	 (%)):460	 (M+,	 62.86),	 417	 (77.14),	 384	 (64.76),	 377	
(57.14),	284	(72.38),	230	(64.76),	176	(100),	154	(15.24),	126	
(33.33),	83	(66.67).	Anal.	calcd.	for	C25H15Cl2N3O2:	C,	65.23;	H,	
3.28;	N,	9.13.	Found:	C,	65.51;	H,	3.18;	N,	8.99%.	
	
2.2.10.	Synthesis	of	3‐chloro‐6,7,8‐triphenylimidazo[1,2‐b]	
pyridazin‐2(3H)‐one	(7)	
	

A	mixture	of	compound	6	(0.5	g,	1.09	mmol)	in	aq.	sodium	
carbonate	 solution	 was	 refluxed	 for	 6	 h.	 After	 cooling,	 the	



Deeb	et	al.	/	European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	 207	
 

reaction	mixture	was	 filtered	 off.	 The	 residue	was	 triturated	
with	water,	 filtered	off,	dried,	and	recrystallized	from	ethanol	
to	give	compound	7	(Scheme	2).	Color:	Brown.	Yield:	53.23%.	
M.p.:	215‐217	°C.	FT‐IR	(KBr,	ν,	cm‐1):	3057	(CH,	Arom.),	1704	
(C=O),	1632	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	5.82	
(s,	1H,	CH,	imidazol	ring),	6.89‐7.28	(m,	15H,	3Ph).	MS	(EI,	m/z	
(%)):400	(M+	+	2,	0.02),	398	(M+,	0.15),	321	(2.10),	307	(2.37),	
294	(2.11),	277	(100),	206	(0.30),	192	(1.44),	178	(10.14),	117	
(27.40),	 103	 (1.37),	 91	 (1.93),	 77	 (40.94).	 Anal.	 calcd.	 for	
C24H16ClN3O:	 C,	 72.45;	 H,	 4.05;	 N,	 10.56.	 Found:	 C,	 72.78;	 H,	
4.17;	N,	10.34%.	
	
2.2.11.	Synthesis	of	3‐chloro‐7,8,9‐triphenyl‐2H‐pyrimido	
[1,2‐b]pyridazine‐2,4(3H)‐dione	(8)	
	

A	 solution	 of	 compound	 6	 (0.5	 g,	 1.09	 mmol)	 in	 glacial	
acetic	acid	 (10	mL)	 in	presence	of	 zinc	dust	was	 refluxed	 for	
1.5	h,	then	filtered	on	hot.	The	filtrate	was	cooled,	poured	into	
water	 (100	mL),	 and	 the	precipitate	was	 filtered	 off,	washed	
with	 water,	 dried,	 and	 recrystallized	 from	 acetone	 to	 give	
compound	8	(Scheme	2).	Color:	Colorless.	Yield:	69.17	%.	M.p.:	
160‐162	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3057	 (CH,	 Arom.),	 1704	
(C=O),	1632	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	5.02	
(s,	1H,	CH,	pyrimidine	ring),	7.23‐7.65	 (m,	15H,	3Ph).	MS	(EI,	
m/z	(%)):427.5	(M+	+2,	1.02),	425.5	(M+,	76.29),	409	(86.60),	
185	 (100).	 Anal.	 calcd.	 for	 C25H16ClN3O2:	 C,	 70.51;	H,	 3.79;	N,	
9.87.	Found:	C,	70.23;	H,	3.85;	N,	10.08%.	
	
2.2.12.	Synthesis	of	3‐amino‐7,8,9‐triphenyl‐2H‐pyrimido	
[1,2‐b]pyridazine‐2,4(3H)‐dione	(9)	
	

Method	A:	A	mixture	of	compound	8	(0.5	g,	1.17	mmol)	and	
excess	of	ammonium	acetate	(3.0	g)	was	heated	in	a	sand	bath	
at	 210	 °C	 for	 30	 min.	 After	 cooling,	 the	 solid	 product	 was	
washed	with	water,	 filtered	off,	dried	and	recrystallized	 from	
acetone	 to	 give	 compound	9	 (Scheme	 2).	 Color:	 Pale	 brown.	
Yield:	 58.70%.	 M.p.:	 128‐130	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3326,	
3188	(NH2),	3058,	3031	(CH,	Arom.),	1751,	1681	(C=O),	1599	
(C=N).	 MS	 (EI,	 m/z	 (%)):	 406	 (M+,	 0.01),	 389	 (0.23),	 378	
(0.07),	 335	 (0.42),	 307	 (0.67),	 281	 (1.02),	 277	 (100),	 267	
(2.15),	 228	 (1.10),	 214	 (0.32),	 206	 (1.04),	 200	 (2.39),	 192	
(1.10),	178	(1.19),	139	(2.23),	125	(3.61),	99	(0.03),	71	(0.93).	
Anal.	calcd.	for	C25H18N4O2:	C,	73.88;	H,	4.46;	N,	13.78.	Found:	
C,	74.17;	H,	4.38;	N,	13.91%.	

Method	B:	A	solution	of	compound	10	(0.5	g,	1.15	mmol)	in	
glacial	 acetic	 acid	 (10	 mL)	 in	 presence	 of	 zinc	 dust	 was	
refluxed	 for	 2	h,	 then	 filtered	on	hot.	 The	 filtrate	was	 cooled	
and	poured	into	water	(100	mL).	The	precipitate	was	filtered	
off,	 washed	 with	 water,	 dried,	 and	 recrystallized	 to	 give	
compound	9.	Yield:	0.26	g,	55.79	%.	
	
2.2.13.	Synthesis	of	3‐Nitro‐7,8,9‐triphenyl‐2H‐pyrimido	
[1,2‐b]pyridazine‐2,4‐(3H)‐dione	(10)	
	

A	 solution	 of	 compound	 1	 (0.5	 g,	 1.28	 mmol)	 in	 glacial	
acetic	 acid	 (5	 mL)	 was	 warmed	 up	 to	 70	 °C	 with	 stirring	
reacted	 with	 a	 mixture	 of	 NaNO2	 (0.18	 g,	 2.56	 mmol),	 then	
with	concentrated	nitric	acid	(1	mL).	The	reaction	mixture	was	
stirring	for	h.	The	solid	product	was	filtered	off,	washed	with	
water,	dried	and	recrystallized	from	ethanol	to	give	compound	
10	(Scheme	2).	Color:	Yellow.	Yield:	66.43%.	M.p.:	110‐111	°C.	
FT‐IR	(KBr,	ν,	cm‐1):	3431	(OH),	3057	(CH,	Arom.),	1721	(C=O),	
1645	(C=N),	1521	(NO2,	Asym.),	1345	(NO2,	Sym.).	MS	(EI,	m/z	
(%)):436	 (M+,	 14.91),	 419	 (16.26),	 393	 (14.63),	 355	 (14.09),	
333	 (14.91),	 307	 (14.63),	 230	 (14.09),	 206	 (17.62),	 155	
(19.24),	80	(100).	Anal.	calcd.	for	C25H16N4O4:	C,	68.80;	H,	3.70;	
N,	12.84.	Found:	C,	68.55;	H,	3.87;	N,	13.09%.	
	
2.2.14.	Synthesis	of	2‐chloro‐3‐nitro‐7,8,9‐triphenyl‐4H‐
pyrimido[1,2‐b]pyridazin‐4‐one	(11)	
	

A	 mixture	 of	 compound	 10	 (0.5	 g,	 1.15	 mmol)	 and	
phosphoryl	chloride	(10	mL)	was	refluxed	for	3	h.	The	reaction	
mixture	was	cooled,	and	poured	into	ice	water	(200	mL).	The	
solid	product	was	 filtered	off,	washed	with	water,	 dried,	 and	
recrystallized	from	ethanol	 to	give	compound	11	(Scheme	2).	
Color:	Brown.	Yield:	69.10%.	M.p.:	152‐154	 °C.	FT‐IR	 (KBr,	 ν,	
cm‐1):	3057	(CH,	Arom.),	1718	(C=O),	1640	(C=N),	1524	(NO2,	
Asym.),	 1345	 (NO2,	 Sym.).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	 6.94‐7.66	 (m,	 15H,	 3Ph).	 MS	 (EI,	 m/z	 (%)):455	 (M+,	
0.54),	 409	 (0.33),	 393	 (1.95),	 378	 (0.33),	 281	 (0.87),	 277	
(1.63),	 267	 (1.41),	 249	 (0.43),	 206	 (2.28),	 188	 (0.54),	 178	
(5.85),	174	(0.87),	77(72.48),	62	(6.50),	56	(100).	Anal.	calcd.	
for	C25H15ClN4O3:	C,	66.01;	H,	3.32;	N,	12.32.	Found:	C,	66.27;	H,	
3.46;	N,	12.09%.	
	
2.2.15.	Synthesis	of	3‐(1‐hydroxyethylidene)‐7,8,9‐
triphenyl‐2H‐pyrimido[1,2‐b]pyridazine‐2,4(3H)‐dione	(12)	
	

A	 solution	 of	 compound	 1	 (0.5	 g,	 1.28	 mmol)	 in	 glacial	
acetic	 acid	 (10	mL)	 in	 presence	 of	 an	 excess	 polyphosphoric	
(1.0	 g)	 acid	 was	 refluxed	 for	 2	 h.	 The	 reaction	 mixture	 was	
cooled,	poured	into	ice	cold	water	(200	mL),	and	then	the	solid	
product	formed	was	filtered	off,	washed	with	water,	dried,	and	
recrystallized	from	acetone	to	give	compound	12	(Scheme	3).	
Color:	Yellow.	Yield:	70.43%.	M.p.:	214‐215	 °C.	FT‐IR	 (KBr,	 ν,	
cm‐1):	3056	(CH,	Arom.),	2921,	2851	(CH,	Aliph.),	1713	(C=O),	
1647	 (C=N).	 MS	 (EI,	m/z	 (%)):433	 (M+,	 70.87),	 415	 (61.71),	
390	(58.25),	348	(61.17),	326	(100),	319	(76.70),	307	(73.79),	
279	(53.40),	152	(52.43),	126	(64.08),	109	(89.32),	83	(18.45),	
79	(83.50),	76	(67.96).	Anal.	calcd.	for	C27H19N3O3:	C,	74.81;	H,	
4.42;	N,	9.69.	Found:	C,	75.13;	H,	4.58;	N,	9.87%.	
	
2.2.16.	Synthesis	of	3‐(1‐hydroxy‐3‐phenylallylidene)‐7,8,9‐
triphenyl‐2H‐pyrimido[1,2‐b]pyridazine‐2,4(3H)‐dione	(13)	
	

A	 solution	 of	 compound	 12	 (0.5	 g,	 1.15	 mmol)	 and	
benzaldehyde	 (0.12	 mL,	 1.15	 mmol)	 in	 ethanol	 (10	 mL)	 in	
presence	 of	 sodium	 hydroxide	 (0.1	 g)	 was	 stirred	 at	 room	
temperature	 for	1	h.	The	solid	product	 formed	was	collected,	
washed	with	water,	 dried,	 and	 recrystallized	 from	ethanol	 to	
give	 compound	13	 (Scheme	3).	 Color:	 Yellow.	 Yield:	 68.11%.	
M.p.:	 >	 300	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3372	 (OH),	 3057,	 3028	
(CH,	 Arom.),	 1695	 (C=O),	 1645	 (C=N).	MS	 (EI,	m/z	 (%)):521	
(M+,	6.45),	504	(0.95),	444	(2.50),	427	(3.68),	416	(7.77),	349	
(13.68),	334	(33.44),	186	(12.63),	178	(20.22),	103	(100),	76	
(37.66).	Anal.	calcd.	 for	C34H23N3O3:	C,	78.30;	H,	4.44;	N,	8.06.	
Found:	C,	78.51;	H,	4.59;	N,	8.26%.	
	
2.2.17.	Synthesis	of	3‐acetyl‐2‐chloro‐7,8,9‐triphenyl‐4H‐
pyrimido[1,2‐b]pyridazin‐4‐one	(14)	
	

A	 mixture	 of	 compound	 12	 (0.5	 g,	 1.15	 mmol)	 and	
phosphoryl	chloride	(10	mL)	was	refluxed	for	3	h.	The	reaction	
mixture	was	cooled,	and	poured	into	ice	water	(200	mL).	The	
solid	product	was	 filtered	off,	washed	with	water,	 dried,	 and	
recrystallized	from	ethanol	 to	give	compound	14	(Scheme	3).	
Color:	Reddish	brown.	Yield:	65.22%.	M.p.:	175‐177	°C.	FT‐IR	
(KBr,	ν,	cm‐1):	3058	(CH,	Arom.),	2923,	2853	(CH,	Aliph.),	1717	
(C=O),	1619	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.09	
(s,	 3H,	 CH3),	 6.99‐7.63	 (m,	 15H,	 3Ph).	 MS	 (EI,	m/z	 (%)):454	
(M+	 +	 2,	 0.34),	 452	 (M+,	 0.38),	 437	 (4.81),	 409	 (33.37),	 408	
(100),	 375	 (0.63),	 349	 (23.65),	 281	 (8.56),	 274	 (2.79),	 178	
(6.63),	 171	 (2.55),	 103	 (22.60),	 77	 (23.94).	 Anal.	 calcd.	 for	
C27H18ClN3O2:	 C,	 71.76;	 H,	 4.01;	 N,	 9.30.	 Found:	 C,	 71.98;	 H,	
4.12;	N,	9.48%.	
	
2.2.18.	Synthesis	of	2,3,4‐triphenylpyrano[2',3':4,5]	
pyrimido[1,2‐b]pyridazine‐7,9,10(8H)‐trione	(15)	
	

A	mixture	of	 compound	1	 (0.5	g,	 1.28	mmol)	 and	diethyl	
malonate	(1.28	mmol)	was	refluxed	for	3	h.		



208	 Deeb	et	al.	/	European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	
	

	 	

N
N

N

O

O

Ph

Ph

Ph

OH

Ph

13
N

N

N

O

Ph

Ph

Ph

O

O

O

15

N
N

N

O

O

Ph

Ph

Ph

OH

H

16

N
N

N

O

Cl

Ph

Ph

Ph CHO

17

14

N
N

Ph

Ph

Ph

N Cl

O

COCH3

N
N

N

O

O

Ph

Ph

Ph

OH

CH3

12

PhCHO / NaOH / EtOH
Stirring at r.t. for 1 h

DEM,

Fusion 3 h

Reflux 3 h.

KOH / CHCl3

Reflux 12 h

stirring at 60 oC, for 2h

AcOH/ PPA,

Reflux 2 h

Reflux 1 hPOCl3

POCl3 / DMF

POCl3

N
N

N

O

O

Ph

Ph

Ph

1

	
	

Scheme	3
	
	
The	 reaction	 mixture	 was	 cooled,	 treated	 with	 diethyl	

ether	(50	mL),	then	the	solid	product	was	filtered	off,	washed	
with	diethyl	ether,	dried,	and	recrystallized	from	methanol	to	
afford	compound	15	(Scheme	3).	Color:	Brown.	Yield:	64.75%.	
M.p.:	174‐176	°C.	FT‐IR	(KBr,	ν,	cm‐1):	3057	(CH,	Arom.),	1707	
(C=O),	1646	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	4.11	
(s,	 2H,	 CH2),	 6.78‐7.65	 (m,	 15H,	 3Ph).	 MS	 (EI,	m/z	 (%)):459	
(M+,	1.47),	441	(0.59),	431	(1.24),	418	(0.17),	414	(0.98),	408	
(100),	 398	 (3.56),	 382	 (3.13),	 373	 (2.64),	 356	 (0.84),	 349	
(1.59),	 307	 (3.97),	 281	 (0.18),	 253	 (0.66),	 231	 (0.47),	 178	
(10.91),	 152	 (3.47),	 110	 (0.69),	 103	 (2.57),	 86	 (1.46),	 77	
(34.97),	 76	 (9.35),	 51	 (34.85).	 Anal.	 calcd.	 for	 C28H17N3O4:	 C,	
73.20;	H,	3.73;	N,	9.15.	Found:	C,	73.48;	H,	3.62;	N,	9.38%.	
	
2.2.19.	Synthesis	of	3‐(hydroxymethylene)‐7,8,9‐triphenyl‐
2H‐pyrimido[1,2‐b]pyridazine‐2,4(3H)‐dione	(16)	
	

A	solution	of	compound	1	(0.5	g,	1.28	mmol)	in	potassium	
hydroxide	 (10	 mL,	 50	 %)	 and	 chloroform	 (10	 mL)	 was	
refluxed	 for	 12	 h.	 The	 aq.	 layer	 was	 separated	 and	 acidified	
with	hydrochloric	acid.	The	solid	product	formed	was	filtered	
off,	washed	with	water,	and	recrystallized	from	chloroform	to	
give	 compound	16	 as	pale	brown	crystals	 (Scheme	3).	Color:	
Pale	brown.	Yield:	70.92%.	M.p.:	143‐145	°C.	FT‐IR	(KBr,	ν,	cm‐

1):	3423	(OH),	3057	(CH,	Arom.),	1714	(C=O),	1635	(C=N).	MS	
(EI,	 m/z	 (%)):420	 (M+,	 8.23),	 402	 (6.96),	 391	 (6.58),	 350	
(7.97),	 337	 (8.86),	 277	 (100),	 267	 (7.59),	 191	 (6.58),	 152	
(8.99),	143	(6.84),	82	(6.84),	76	(8.23),	69	(11.39).	Anal.	calcd.	
for	C26H17N3O3:	C,	74.45;	H,	4.09;	N,	10.02.	Found:	C,	74.63;	H,	
4.17;	N,	10.18%.	
	
2.2.20.	Synthesis	of	2‐chloro‐4‐oxo‐7,8,9‐triphenyl‐4H‐
pyrimido[1,2‐b]pyridazine‐3‐carbaldehyde	(17)	
	

Method	A:	A	solution	of	compound	1	(0.5	g,	1.28	mmol)	in	
dimethylformamide	 (10	mL)	and	phosphoryl	chloride	 (2	mL)	
was	 stirred	 at	 60	 °C	 for	 2	 h,	 then	 the	 reaction	mixture	 was	
cooled,	 and	 poured	 into	 ice	 cold	 water	 (200	 mL).	 The	

precipitate	 was	 filtered	 off,	 washed	 with	 water,	 dried,	 and	
recrystallized	from	acetone	to	give	compound	17	(Scheme	3).	
Color:	 Dark	 brown.	 Yield:	 69.73%.	 M.p.:	 179‐180	 °C.	 FT‐IR	
(KBr,	ν,	cm‐1):	3057	(CH,	Arom.),	2925,	2854	(CH	Aliph.),	1714	
(C=O),	 1635	 (C=N).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	
6.60‐7.66	(m,	15H,	3Ph),	10.22	(s,	1H,	CHO).	MS	(EI,	m/z	(%)):	
440	(M+	+2,	0.2),	438	(M+,	10.96),	410	(9.31),	409	(9.76),	401	
(7.81),	 397	 (8.71),	 361	 (11.41),	 348	 (9.01),	 333	 (11.11),	 277	
(40.54),	 161	 (8.11),	 104	 (10.51),	 89	 (12.31),	 77	 (25.83),	 64	
(100).	Anal.	calcd.	 for	C26H16ClN3O2:	C,	71.31;	H,	3.68;	N,	9.60.	
Found:	C,	71.69;	H,	3.76;	N,	9.74%.	

Method	B:	A	mixture	of	 compound	16	 (0.5	 g,	 1.19	mmol)	
and	 phosphoryl	 chloride	 (10	 mL)	 was	 refluxed	 for	 1	 h.	 The	
reaction	mixture	was	 cooled,	 and	 poured	 into	 ice	 cold	water	
(200	 mL).	 The	 solid	 product	 was	 filtered	 off,	 washed	 with	
water,	 dried,	 and	 recrystallized	 from	 acetone	 to	 give	
compound	17	as	dark	brown	crystals.	
	
2.2.21.	Measuring	the	antimicrobial	activity	of	compounds	
(2‐17)	
	

Applying	the	agar	plate	diffusion	technique	[7],	the	newly	
synthesised	compounds	were	screened	for	their	antimicrobial	
activity	 against	 Gram	 positive	 bacteria	 (Staphylococcus	
aureus),	 Gram	 negative	 bacteria	 (Escherichia	 coli),	 yeast	
(Candida	 albican),	 and	 fungi	 (Aspergillus	 flavus).	 Briefly,	 100	
μL	of	 the	tested	bacteria/fungi	were	grown	in	10	mL	of	fresh	
media	 until	 they	 reached	 a	 count	 of	 approximately	 108	
cells/mL	 for	bacteria	or	105	 cells/mL	 for	 fungi	 [8],	100	μL	of	
microbial	suspension	was	spread	onto	agar	plates	correspon‐
ding	 to	 the	broth	 in	which	 they	were	maintained.	 The	 plates	
inoculated	with	filamentous	fungi	were	incubated	at	25	°C	for	
48	h,	bacteria	at	35‐37	°C	 for	24‐48	h,	and	yeast	at	30	°C	 for	
24‐48	h.	The	diameters	of	the	inhibition	zones	(the	area	of	no	
growth	 of	 the	 organism	 around	 the	 disk)	 were	 measured	 in	
millimetersusing	 slipping	 calipers	 of	 National	 Committee	 for	
Clinical	Laboratory	Standards	[9].		

	



Deeb	et	al.	/	European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	 209	
 

	
Table	1.	Antimicrobial	activity	of	the	investigated	conmpounds	*. 

Inhibition	zone	diameter	(mm/mg)	sample	Compound	
Aspergillus	flavusCandida	albicans	Escherichia	coli	(G‐)Staphylococcus	aureus (G+)
‐	‐	++	++	2	
‐	‐	++	++	3b	
‐	‐++++	3c	
‐	‐++++	3d	
+	++++++	4	
‐	‐++++	5	
‐	‐++++	6	
‐	‐++++	7 
‐	++	++	+++	8 
‐	+	++	++	10	
‐	‐	++	++	13	
‐	‐++++	15 
‐	‐	++	++	16 
‐	‐++++	17 
‐	‐	‐	‐	Control:	DMSO	
‐	‐	++	+++	Ampicillin	(Antibacterial	agent)	
++	++	‐	‐	Amphotericin	B	(Antifungal	agent)	

*	Zone	of	inhibition:	+	=	<	11	mm;	++	=	11‐20	mm;	+++	=	20‐30	mm;	‐	=	no	inhibition.	

 
Standard	 discs	 of	 ampicillin	 (Antibacterial	 agent),	

amphotericin	B	(Antifungal	agent)	severed	as	positive	controls	
for	antimicrobial	activity,	but	filter	discs	impregnated	with	10	
μL	of	dimethylsulfoxide	were	used	as	a	negative	control.	Blank	
paper	discs	(Schleicher	&	Schuell,	Spain)	with	a	diameter	of	8.0	
mm	were	 impregnated	with	10	μL	of	 tested	concentration	of	
the	stock	solution.	
	
3.	Results	and	discussion	
	
3.1.	Synthesis	
	

It	 was	 reported	 that	 the	 reaction	 of	 3‐amino‐4,5,6‐
triphenylpyridazine	 with	 malonic	 acid	 in	 presence	 of	
phosphoryl	 chloride	 led	 to	 the	 pyrimido[1,2‐b]pyridazinone	
derivative,	 1	 [5].	 The	 various	 reactions	 of	 the	 pyrimido	
pyridazinone	derivative	1	are	shown	in	Scheme	1.	Chlorination	
of	 compound	 1	 with	 phosphoryl	 chloride	 led	 to	 the	
corresponding	2‐chloro	derivative,	2.	Taking	the	advantage	of	
the	 reactivity	 of	 the	 2‐chloro	 atom	 in	 compound	 2,	 it	 was	
subjected	 to	 nucleophilic	 substitution	 reactions	 in	 order	 to	
prepare	 other	 derivatives	 of	 the	 system.	 Thus,	 reaction	 of	
compound	 2	 with	 sodium	 methanolate,	 ethanolate,	 sodium	
azide,	 and	 hydrazine	 hydrate,	 gave	 compounds	 3a‐d,	
respectively	 (Scheme	 1).	 Also,	 the	 chloro	 derivative	 2	
underwent	 thionation	 with	 thiourea	 in	 refluxing	 ethanol	
leading	 to	 thiouronium	salt,	which	can	be	 isolated.	The	7,8,9‐
triphenyl‐2‐thioxo‐2H‐pyrimido[1,2‐b]pyridazin‐4(3H)‐one	
(4)	 was	 obtained	 from	 the	 thiouronium	 salt	 in	 aqueous	
solution	 by	 basic	 hydrolysis	 followed	 by	 acidification	 with	
hydrochloric	acid	(Scheme	1).	

Some	 other	 reactions	 of	 compound	 1	 are	 shown	 in	
(Scheme	2).	Bromination	with	an	excess	of	bromine,	a	dibromo	
derivative	5	was	 obtained.	 Chlorination	 of	 compound	1	with	
sulfuryl	 chloride	 led	 to	 3,3‐dichloro‐7,8,9‐triphenyl‐2H‐
pyrimido[1,2‐b]pyridazine‐2,4(3H)‐dione,6.	 The	 usefulness	 of	
the	latter	compound	is	demonstrated	in	(Scheme	2).	The	ring	
contraction	 of	 compound	 6	 was	 obtained	 on	 boiling	 with	
aqueous	 solution	 of	 sodium	 carbonate	 to	 afford	 3‐chloro	
imidazo[1,2‐b]pyridazin‐2(3H)‐one,	 7.	 However,	 reaction	 of	
the	 compound	 6	 with	 zinc	 in	 acetic	 acid	 at	 refluxing	
temperature	led	to	3‐chloro	derivative	8	in	a	good	yield,	which	
underwent	direct	amination	by	fusion	with	ammonium	acetate	
at	 210	 °C	 for	 30	 min	 to	 give	 3‐amino‐7,8,9‐triphenyl‐2H‐
pyrimido[1,2‐b]pyridazine‐2,4(3H)‐dione	 derivative	 9.	 The	
action	 of	 nitric	 acid	 in	 acetic	 acid	 could	 be	 performed	 using	
sodium	nitrite	as	catalyst	 led	to	3‐nitropyrimidopyridazinone	
derivative10.	 The	 catalytic	 effect	 of	 sodium	 nitrite	 can	 be	
explained	by	an	initial	nitrosation	of	compound	1	in	position	3	
and	subsequent	oxidation	of	 the	nitroso	group	 to	 the	desired	
nitro	 group	 [10].Treatment	 of	 the	 nitro	 derivative	 10	 with	

phosphoryl	 chloride	 gave	 the	 corresponding	2‐chloro	 deriva‐
tive	11.	Also,	reduction	of	compound	10	was	carried	out	with	
zinc	dust	in	acetic	acid	at	refluxing	temperature,	and	gave	the	
3‐amino	derivative	9	(Scheme	2).	

Introduction	of	an	acetyl	 group	 into	 the	3‐position	of	 the	
pyrimidopyridazinone	derivative	1	was	obtained	by	direct	C‐
acetylation	with	 acetic	 acid	 in	polyphosphoric	 acid	 according	
to	 known	 method	 [11],	 gave	 3‐acetyl	 pyrimidopyridazinone	
derivative	 12	 in	 good	 yield.	 The	 α,β‐unsaturated	 ketone	 13	
was	 synthesized	 employing	 Claisen‐Schmidt	 reaction	 by	
treating	 the	 3‐acetyl	 derivative	 12	 with	 benzaldehyde	 in	
presence	 of	 base.	 Refluxing	 compound	 12	 with	 phosphoryl	
chloride	 gave	 the	 corresponding	 3‐acetyl‐2‐chloropyrimido	
pyridazinone	derivative	14	(Scheme	3).	

When	 the	 1,3‐dinucleophilic	 7,8,9‐triphenyl‐2H‐pyrimido	
[1,2‐b]pyridazine‐2,4(3H)‐dione	 (1)	 was	 condensed	 with	
diethyl	 malonate	 at	 refluxing	 temperature,	 furnished	 pyrano	
pyrimidopyridazinone	derivative	15	 (Scheme	3).	Formylation	
of	compound	1	at	position	3	was	achieved	by	its	reaction	with	
chloroform/potassium	 hydroxide	 mixture,	 and	 afforded	 3‐
(hydroxymethylidene)‐7,	 8,	 9‐triphenyl‐2H‐pyrimido[1,	 2‐b]	
pyridazine‐2,4(3H)‐dione,	16.	However,	reaction	of	compound	
1	 with	 Vilsmeier	 reagent	 (dimethylformamide/phosphoryl	
chloride)	 led	 to	 2‐chloro‐4‐oxo‐7,8,9‐triphenyl‐4H‐pyrimido	
[1,2‐b]pyridazine‐3‐carbaldehyde	17,	which	was	also	obtained	
by	 the	 reaction	of	 compound	16	with	phosphoryl	 chloride	at	
refluxing	 temperature	 (Scheme	 3).	 The	 newly	 synthesized	
compounds	were	 characterized	 by	 IR,	 NMR	 and	mass	 spect‐
rum	 as	well	 as	 the	 elemental	 analysis,	 listed	 in	 experimental	
section.	 The	 spectral	 analyses	 were	 in	 accordance	 with	 the	
assigned	structures.	
	
3.2.	Screening	for	antimicrobial	activities	
	

The	given	results	in	Table	1	revealed	that	compound	8	was	
highly	active	against	Staphylococcus	aureus.	On	the	other	hand,	
compounds	 2,	 3b‐d,	 4‐7,	 10,	 13,	 15,	 16	 and	 17)	 showed	
moderate	 activity	 against	 both	 Staphylococcus	 aureus	 and	
Escherichia	coli.	Also,	 the	 results	 indicated	 that	 compounds	4	
and	 8	 showed	 moderate	 antifungal	 activity	 against	 Candida	
albicans.	 In	 general,	 the	 synthesised	 compounds	 showed	
moderate	antimicrobial	activity	against	the	examined	bacteria	
comparable	with	the	standard	antibacterial	ampicillin.	
	
4.	Conclusion	
	

A	 new	 series	 of	 pyrimidopyridazine	 bearing	 different	
substiutents	 were	 synthesized	 and	 biological	 evaluation	
compound	 8	 showed	 promising	 antibacterial	 activities,	
compared	with	the	reference	drugs.	
	



210	 Deeb	et	al.	/	European	Journal	of	Chemistry	6	(2)	(2015)	204‐210	
	
Acknowledgement	
	

The	 author	 acknowledges	 the	 help	 of	 Prof.	 Yehia	 Ahmed	
El‐Zawahry,	Department	of	Microbiology	 for	 carrying	out	 the	
antimicrobial	activity.	
	
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