A facile synthesis and heteroannulation of pyrido[2,3-d]pyrimidine and related heterocyclic systems

Article abstract of DOI:10.3184/030823409X12523324765777

7-Amino-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-(3,4,5-trimethoxyphenyl) pyrido[2,3-d]pyrimidine (1) was prepared and reacted with methyl iodide and ethyl chloroacetate to give the S-alkylated products 2 and 3, respectively. The reaction of 1 or 3 with hydraz

Full text of DOI:10.3184/030823409X12523324765777

612 RESEARCH PAPER
OCTOBER, 612–615
JOURNAL OF CHEMICAL RESEARCH 2009
A facile synthesis and heteroannulation of pyrido[2,3-d]pyrimidine and
related heterocyclic systems
M.R. Mahmoud*, A.A. Shalaby, T.A. Gad and A.A. El-Khamry
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt
7-Amino-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine (1) was prepared and
reacted with methyl iodide and ethyl chloroacetate to give the S-alkylated products 2 and 3, respectively. The reaction
of 1 or 3 with hydrazine hydrate yielded the same 2-hydrazino derivative 4. Treatment of 4 with 2,4-pentanedione,
2-acetylcyclohexanone and ethyl acetoacetate afforded the corresponding pyrazolylpyrido[2,3-d]pyrimidine
derivatives (5–7), while phthalic anhydride gave the phthalazinyl compound 8. Ethoxymethylenemalononitrile with
the hydrazine 4 formed the fused 1,2,4-triazepine 9, while triazolopyrido[2,3-d]pyrimidines were obtained from the
reaction of 4 with benzylidene malononitrile or benzaldehyde (forming 10), acetic acid/anhydride (giving 11), and
ethyl chloroformate (giving 12).
Keywords: hydrazines, pyrazoles, fused pyridines, pyrimidines, 1,2,4-triazepines, 1,2,4-triazines
Pyrido[2,3-d]pyrimidines stand out for their antitumour,1
anticonvulsive,2 antiasthmatic, antiallergic3 and antihyper-
tensive4 effects and are useful as diuretic compounds.5-7
In earlier work, we have reported several new syntheses of
fused heterocyclic compounds utilising laboratory available
activated nitrile derivatives as starting materials.8-18 We report
here on the utility of the readily obtainable substituted a-
cyanocinnamonitriles for the synthesis of several pyrido[2,3-d]
pyrimidines in the search for new chemotherapeutic agents.
Experimental). The formation of 1 assumed to proceed via
addition of thiouracil C-5 to the activated double bond in the
cinnamonitrile derivative followed by 1,6-exo-dig cyclisation
of the Michael adduct, and aromatisation.
Methylation of 1 using methyl iodide in ethanolic sodium
hydroxide resulted in the formation of a sole product
of molecular formula C19H19N5O4S [M = 413 (100%)].
The microanalysis and mass spectrum indicates incorporation
of two methyl groups in the reaction product. Several
structures involve N- and S-alkylation could be suggested
for this product. The IR spectrum of this product lacked the
absorption band for nC=S which suggest the S-methylation;
furthermore, the lower value of nC=O (1681 cm-1) than in the
Results and discussion
The reaction of a-cyano-3,4,5-trimethoxycinnamonitrile
with 6-aminothiouracil in equimolar portions in ethanol
in the presence of catalytic amount of piperidine to yield a
1:1 adduct which on aromatisation formed the pyrido[2,3-d]
pyrimidine derivative 1.
starting material (1687 cm-1) and the three bands for nNH
2
were in accordance with the proposed structure 2. Structure 2
gets a further support from 1H NMR spectrum (see
Experimental).
The structure of 1 was established as pyridopyrimidine
Alkylation of 1 using ethyl chloroacetate in refluxing
pyridine afforded the S-alkylated product ethyl [7-amino-
1
on the basis of IR, MS, and H and 13C NMR spectra (see
O
Ar
O
NC
CN
NH
NH
EtOH
piperidine
Ar
+
CN
H2N
N
H
S
S
H2N
N
N
H
1
Ar = 3,4,5-(MeO)3C6H2-
Scheme 1
Ar
N
Ar
N
O
O
NC
NC
NH
NH
SH
Ar = 3,4,5-(MeO)3C6H2-
S
H2N
N
H
H2N
N
1
a
b
c
Ar
O
Ar
Ar
N
O
N
O
N
Me
NC
NC
NC
c
N
NH
NH
NHNH2
SMe
H2N
H2N
S
CO2Et
N
N
H2N
N
2
3
4
Scheme 2 Reagents: a, Mel in MeOH/NaOH, D; b, ethyl chloroacetate in pyridine, D; c, hydrazine hydrate in ethanol, D
* Correspondent. E-mail: mrefaee2000@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2009 613
6-cyano-3,4-dihydro-4-oxo-5-(3,4,5-trimethoxyphenyl)-
pyrido[2,3-d]pyrimidin-2-ylthio]acetate (3).
When compound 4 was refluxed with phthalic anhydride in
boiling acetic acid for 3 h the solid product obtained shows
two spots by TLC, and it was possible to detect by GC-MS
two different compounds. The major product proved to be the
phthalazinedione derivative 8 (48%). The EI fragmentation
pattern of the other product was completely in accordance
with the fused triazole derivative 9 (32%). Formation of 9 can
readily be explained by acetylation of the hydrazine by acetic
phthalic anhydride formed in the reaction medium, followed
by cyclisation with dehydration.
Treatment of pyridopyrimidine-2-thione 1 with hydrazine
hydrate in boiling ethanol afforded a sulfur free compound
which was identified as 7-amino-2-hydrazino-3,4-dihydro-4-
oxo-5-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-6-
carbonitrile (4). The same product was isolated in good yield
on hydrazinolysis of compound 3 under the same conditions.
This hydrazine derivative
4 was used as the key
intermediate in the synthesis of pyrazolyl- and triazolo-
pyridopyrimidine triheterocycles.15 The reactions provided
both appended (Scheme 3) and fused ring products
(Scheme 4). Thus, compound 4 when refluxed with 2,4-
pentanedione, 2-acetylcyclohexanone or ethyl acetoacetate,
it afforded the 7-amino-2-(3,5-dimethylpyrazol-1-yl)-4-
oxo-5-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrido[2,3-d]
pyrimidine-6-carbonitrile (5), 7-amino-3,4-dihydro-2-(3-
methyl-4,5,6,7-tetrahydroindazol-1-yl)-4-oxo-5-(3,4,5-trime
thoxyphenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (6) and
7-amino-3,4-dihydro-2-(5-hydroxy-3-methyl-pyrazol-1-yl)-
4-oxo-5-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-6-
carbonitrile (7), respectively (Scheme 3).
Compound
9,
8-amino-1,5-dihydro-3-methyl-5-oxo-6-
(3,4,5-trimethoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]
pyrimidine-7-carbonitrile, could also be prepared more
conveniently by reflux of the hydrazine 4 in acetic acid and acetic
anhydride (Scheme 4). After 3 h heating a yellow solid product
with formula C19H17N7O4 was obtained. The IR spectrum
of this product displayed well defined absorption bands at
3373, 3340, and 3194 cm-1 (nNH ), 2219 cm-1 (nC=N), the nC=O
2
frequency at 1712 cm-1 indicates that the carbonyl absorption
band of pyrimidine is not enolisable which is in good accordance
with structure 9. The mass spectrum of 9 showed the expected
molecular ion peak as the base peak at m/z 407 (100%).
Ar
O
Ar
O
NC
NC
NH
Me
NH
N
H2N
H2N
N
N
N
N
N
N
N
c
a
b
Me
O
N
Ar
N
HO
N
NC
5
7
Me
NH
NHNH2
Ar
N
O
N
H2N
Ar
d
O
NC
4
NH
O
O
NC
NH
Ar = 3,4,5-(MeO)3C6H2-
H2N
H2N
N
N
N
N
HN
+ 9 (see Scheme 4)
8
6
Me
Scheme 3 Reagents: a, (MeCO)2CH2; b, 2-acetylcyclohexanone; c, MeCOCH2CO2Et; (a-c): all in pyridine, D;
d, phthalic anhydride; in AcOH, D
Ar
Ar
Ar
Me
Ar'
NH
O
O
N
O
NC
NC
NC
N
a
d
b
c
NH
NHNH2
N
N
N
N
H2N
N
N
H2N
N
H2N
N
N
H
H
4
9
10
(c)
H2N
Ar
Ar
N
Ar
CN
OEt
N
O
O
O
O
NC
NC
NC
N
N
N
NH
N
N
N
H2N
N
N
H2N
H2N
N
N
N
N
H
H
H
12
11
13
=
=
Scheme 4 Reagents: a, Ac2O in AcOH, D; b, Ar'CH C(CN)2 or Ar'CHO; c, ClCO2Et; d, EtOCH C(CN)2 (b-d):
all in pyridine, D

614ꢀ JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009
methyl iodide (2.46 g, 0.02 mol) were dissolved in 10% ethanolic
sodium hydroxide (30 mL) and stirred at room temperature for 1 h,
then refluxed for another 1 hr. The solvent was evaporated in vacuo.
The residue was acidified with cold dil. acetic acid and the precipitate
was collected by filtration and recrystallised from methanol affording
2 as white crystals (3.51 g., 85%), m.p 315–317 °C. IR: nmax 3480,
Whenꢀtheꢀhydrazinoꢀderivativeꢀ4ꢀwasꢀsubjectedꢀtoꢀreactꢀwithꢀ
4-chloro-a-cyano-cinnamonitrile in refluxing pyridine for 6 h,ꢀ
8-amino-3-(4-chlorophenyl)-1,2,3,5-tetrahydro-5-oxo-6-
(3,4,5-trimethoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]ꢀ
pyrimidine-8-carbonitrile 10 was obtained in good yield
(87%). The mass spectrum of 10ꢀ showsꢀ theꢀ molecularꢀ ionꢀ
peak at m/z 505 (100%) as the base peak, and other peaks
characteristic for (M + 1) and (M + 2) which indicated the
presence of a chlorine atom. Confirmation of the structure of
compound 10 was gained by the identity (m.p, mixed m.p,
IR and TLC comparison) with an authentic sample formed
by the reaction of 4ꢀwithꢀp-chlorobenzaldehyde in refluxing
pyridine.
1
3325, 3269 (NH2), 2212 (CN), 1681 cm-1 (CO). HꢀNMRꢀ(DMSO-
d6): d 7.52 (s, 2H, exchangeable with D2O), 6.59 (s, 2Harom), 3.78
(s, 9H), 3.34 (s, 3H, N–Me), 2.65 (s, 3H, S-Me) MS: m/z 413ꢀ
(100), 366 (17.9), 246 (32.4), 167 (21.6), 77 (67.1). Anal. Calcd for
C19H19N5O4S (413.45): C, 55.19; H, 4.63; N, 16.93; S, 7.75. Found:
C, 55.16; H, 4.7; N, 17.06; S, 8.02%.
Ethyl [7-amino-6-cyano-3,4-dihydro-4-oxo-5-(3,4,5-trimethoxy-
phenyl)pyrido[2,3-d]pyrimidin-2-ylthio]acetate (3): Compound 1ꢀ
(3.85 g, 0.01 mol) and ethyl chloroacetate (1.3 g, 0.01 mol) wereꢀ
heated under reflux for 4 h in methanol (50 mL) containing
anhydrous sodium acetate (2.5 g, 0.03 mol). The solid product that
separated from the hot mixture was filtered off, washed with hot
water and then recrystallised from methanol to give 3ꢀasꢀcolourlessꢀ
crystals (3.63 g., 77%), m.p. 261–263 °C. IR: nmax 3441, 3345, 3142
(NH2), 2216 (CN), 1713, 1686 (CO), 1646 cm-1 (C=N). 1Hꢀ NMRꢀ
(DMSO-d6): d 10.51 (s, 1H, NHCO), 7.6 (s, 2H, NH2), 6.5 (s, 2Harom.),
4.17 (m, 4H, CH3CH2–O, S–CH2CO), 3.75–3.74 (two s, 9H, 3 OCH3),ꢀ
1.26 (t, 3H, J = 6.9 Hz, CH3CH2). MS: m/z 471ꢀ (M+, 15), 425ꢀ
([M+-EtOH], 100). Anal. Calcd for C21H21N5O6S (471.49): C, 53.49;
H, 4.49; N, 14.85; S, 6.79. Found: C, 53.73; H, 4.83; N, 14.66;ꢀ
S, 6.6%.
Another triazolopyridopyrimidine (11) was synthesised
from the reaction of 4 with ethyl chloroformate in refluxing
pyridine. Spectroscopic analysis confirmed the assignment
1
of structure 11. The H NMR spectrum of 11ꢀ (DMSO-d6)
displayed signals characteristic of an ethoxy group as a 3H
triplet at d 1.25 ppm and a 2H quartet at d 4.02 ppm. This
allows the expected triazolone structure 12ꢀtoꢀbeꢀrejectedꢀasꢀ
the reaction product. Furthermore, the mass spectrum of 11ꢀ
shows the molecular ion peak at m/z 437 (5.6%), which is in
accordꢀwithꢀstructureꢀ11 (Scheme 4).
The
pyrido[2,3-d]pyrimidino[2,1-c][1,2,4]triazepine
derivativeꢀ13 was obtained as the sole product (TLC) upon
treatment of 4 with ethoxymethylene malononitrile in boiling
pyridine.
OMe
56.3
55.1
OMe
55.1
153.3
MeO
151.7
117.8
152.0
124.2
Experimental
The IR spectra are recorded on FTIR Mattson (infinity series)
spectrometers from KBr discs. The H NMR spectra were measured
130.2
O
1
113.1
NC
155.3
161.4
NH
158.1
on Varian Gemini 200 MHz instrument with chemical shifts (d)
expressed in ppm downfield from TMS. 13C NMR spectra were
measured on a JEOL spectrometer at 75 MHz.ꢀEI-MSꢀwereꢀmeasuredꢀ
on Shimadzu GC-MS QP 1000 EX instrument operating at 70 eV.
Preparations were generally monitored by thin-layer chromatography
using aluminium sheets coated with silica gel. Elemental analyses
were carried out at the Microanalytical Unit, Faculty of Science,ꢀ
Ain Shams University with a Perkin-Elmer series 11 CHNS/O
elemental analyser.
110.3
155.4
88.3
160.7
H2N
14.6
30.3
O
170.1
O
N
N
S
59.8
13C NMR for compound 3
7-Amino-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-(3,4,5-trimethoxy-
phenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile(1):6-Aminothiouracil
(1.43g,0.01mol)anda-cyano-3,4,5-trimethoxycinnamonitrile(2.44g,ꢀ
0.01 mol) were heated under reflux for 8 h in ethanol (50 mL)
containing piperidine (0.5 mL). The solid which separated from the
hot solution was filtered off, dried, and recrystallised from MeOH/
DMF to give 1 as yellow crystals (1.54 g., 40%), m.p 330–332 °C.
IR: nmax 3439, 3338, 3233, 3180 (NH2, 2NH), 2217 (C≡N), 1687
(C=O), 1645 (C=N) and 1140 cm-1 (C=S). 1Hꢀ NMRꢀ (DMSO-d6)ꢀ
d 12.3 (s, 2H, exchangeable with D2O), 6.9 (s, 2Harom.), 6.4 (s, 2H,
exchangeable with D2O), 3.9, 3.8 (two s, 9H, 3 OCH3). MS: m/z 385
(100), 370 (37.3), 312 (12.6), 284 (15.3), 177 (18.2). Anal. Calcd for
C17H15N5O4S (385.40): C, 52.98; H, 3.92; N, 18.17; S, 8.3. Found: C,
52.9; H, 4.2; N, 18.19; S, 8.7%.
7-Amino-2-hydrazino-3,4-dihydro-4-oxo-5-(3,4,5-trimethoxy-
phenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (4): Method A:ꢀEitherꢀ
compound 1 orꢀ3 (0.01 mol) was stirred for 1 h in ethanol (30 mL) at
r.t. with hydrazine hydrate (1.6 g, 0.05 mol), and the solution was then
heated under reflux for 2 h. The solid product that separated from the
mixture after cooling was filtered off, dried and recrystallised from
methanol to give 4 as pale green crystals (1.28 g, 33%), m.p 275–ꢀ
278 °C. IR: nmax 3324, 3200, 3150 (NH2), 2210 (C≡N), 1687 cm-1ꢀ
(C=O). MS: m/z 383ꢀ(M+, 44), 353 ([M–N2–H2], 100). Anal. Calcd
for C17H17N7O4 (383.36): C, 53.26; H, 4.46; N, 25.57. Found: C,
53.17; H, 4.22; N, 25.59%. Method B: Compound 3 (1.3 g, 2.7 mmol)
and hydrazine hydrate (80%) (1.3 g, 0.04 mol) in ethanol (20 mL)
were stirred under reflux for 2 h until no more substrate remained.
The solid that deposited after cooling was filtered off, dried and
recrystallised from methanol to give 4 (0.64 g, 62%).
57.1
OMe
Pyrazole and indazole derivatives 5, 6; general procedure
56.2
56.2
150.1
OMe
MeO
The hydrazine 4 (3.83 g, 0.01 mol) was stirred and heated under
reflux in ethanol (50 mL) with the appropriate 1,3-diketone (pentane-
2,4-dione, 2-acetylcyclohexanone) (0.01 mol) until no more substrate
remained (4 h). The reaction mixture was concentrated and the
solid deposited was filtered off, washed with ethanol, dried and
recrystallised from methanol.
152.1
117.2
153.0
123.4
129.8
O
114.2
NC
156.4
163.1
NH
176.4
7-Amino-2-(3,5-dimethylpyrazol-1-yl)-4-oxo-5-(3,4,5-trimethoxy-
phenyl)-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
ꢀ(5): Yellow crystals (2.77 g, 62%), m.p. 320–322 °C. IR: nmax 3483,
3345, 3287 (NH2), 3592 (NH, OH), 2210 (CN), 1704 (C=O), 1638 cm-1ꢀ
82.4
160.1
H2N
98.8
155.1
N
N
S
H
1
(C=N). HꢀNMRꢀ(DMSO-d6): d 11.06 (s, 1H, NHCO, exchangeable
13C NMR for compound 1
withꢀD2O), 7.6 (s, 2H, NH2, exchangeable with D2O), 6.68 (s, 2Harom.),
6.31 (s, 1H, C4'-H), 3.85-3.8 (two s, 9H, 3 OCH3), 2.62 (s, 3H, 3'-CH3),
2.21 (s, 3H, 5'-CH3). MS: m/z 447ꢀ(M+, 100), 353 (20), 280 (35), 167
(60), 77 (41). Anal. Calcd for C22H21N7O4 (447.45): C, 59.05; H, 4.73;
N, 21.91. Found: C, 58.73; H, 4.72; N, 21.51%.
Alkylation of 1 with methyl iodide; 7-amino-3,4-dihydro-3-methyl-
2-methylthio-4-oxo-5-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]
pyrimidine-6-carbonitrile (2): Compound 1 (3.85 g, 0.01 mol) and

JOURNAL OF CHEMICAL RESEARCH 2009 615
56.6
OMe
dried and then recrystallised from methanol to give 10 as pale yellow
crystals (4.15 g, 82%) m.p. >360 °C. IR: nmax 3433, 3355, 3112
(NH2), 2216 (CN), 1706 (CO), 1648 cm-1 (C=N). 1H NMR (DMSO-
d6): d 7.7 (br.s, 2H, exchangeable with D2O), 7.1–6.8 (m, 6Harom), 5.4
(d, 1H), 4.3 (br.s, 2H, exchangeable with D2O), 3.9–3.78 (two s, 9H).
MS: m/z 505/507 (M+, 100/32), 506 (43.3) (M + 1)+, 394 (84) [M+
– C6H4Cl]. Anal. Calcd for C24H20ClN7O4 (505.92): C, 56.97; H,
3.98; N, 19.37; Cl, 7.0. Found: C, 57.08; H, 4.23; N, 19.48; Cl, 7.05%.
Method b: Compound 4 (0.38 g, 1 mmol) and p-chlorobenzaldehyde
(0.14 g, 1 mmol) were heated under reflux in absolute ethanol
(5 mL) for 6 h. The solid product was collected by filtration, dried and
recrystallised from methanol to give 10 (identified by m.p,
mixed m.p, TLC comparison).
55.0
55.0
154.2
OMe
MeO
150.1
150.1
122.2
115.3
129.9
O
113.7
NC
156.4
163.2
NH
90.3
160.1
H2N
108.1
156.6
161.1
N
N
N
N
13.9
Me
150.3
140.2
Me
110.4
14.2
8-Amino-3-ethoxy-1,5-dihydro-5-oxo-6-(3,4,5-trimethoxy-
phenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-7-carbonitrile
(11): The hydrazine 4 (3.83 g, 0.01 mol) and ethyl chloroformate
(5 ml) were refluxed in pyridine (20 mL) for 6 h. Acidification of
the reaction mixture by cold dilute acetic acid deposited a semi
solid product which was filtered off, dried and recrystallised from
ethanol to give 11 as yellow crystals (2.27 g, 52%), m.p. 243–
245 °C. IR: nmax 3427, 3368, 3220 (NH2), 2218 (CN), 1680 (CO),
13C NMR for compound 5
7-Amino-3,4-dihydro-2-(3-methyl-4,5,6,7-tetrahydroindazol-1-
yl)-4-oxo-5-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-6-
carbonitrile (6): Yellow crystals (3.28 g, 67%), m.p. 310–313 °C. IR:
nmax 3480, 3344, 3210 (NH2), 2209 (CN), 1686 (C=O), 1636 cm-1
1
1641 cm-1 (C=N). H NMR (DMSO-d6): d 7.7–7.65 (2 s, 3H, NH2,
1
(C=N). H NMR (CDCl3) d 10.2 (s, 1H, NHCO, exchangeable with
NH), 6.64 (s, 2Harom), 4.02 (q, 2H, J = 7.1 Hz, CH2CH3), 3.8–3.75
(two s, 9H, 3OMe), 1.25 (t, 3H, J = 6.6 Hz, CH3-CH2). MS: m/z 437
(M+, 5.6), 409 (100), 392 (13.4), 168 (17.7), 77 (55.1). Anal. Calcd
for C20H19N7O5 (437.41): C, 54.91; H, 4.37; N, 22.41. Found: C,
55.09; H, 4.56; N, 22.68%.
D2O), 6.55 (m, 2Harom.), 5.99 (br.s, 2H, NH2, exchangeable with
D2O), 3.9–3.85 (two s, 9H, 3 OCH3), 2.75 (s, 3H, 3'-CH3), 2.7–1.3
(m, 8H, cyclohexyl protons'). MS: m/z 487 (M+, 100), 320 (12.7), 280
(31.4), 168 (44.1). Anal. Calcd for C25H25N7O4 (487.52): C, 61.59;
H, 5.16; N, 20.11. Found: C, 61.61; H, 4.87; N, 20.1%.
5,10-Diamino-1,7-dihydro-7-oxo-8-(3,4,5-trimethoxyphenyl)
pyrido[2',3':4,5]pyrimidino[2,1-c][1,2,4]triazepine-4,9-dicarbo-
nitrile (13): A mixture of compound 4 (3.83 g, 0.01 mol) and
ethoxymethylenemalononirile (1.22 g, 0.02 mol) in pyridine (15 mL)
was heated under reflux for 4 h. Cold dilute acetic acid was added
and the solid deposited was filtered off, dried and then recrystallised
from methanol to give 13 as yellow crystals (1.97 g, 43%), m.p. 287–
289 °C. IR: nmax 3336, 3208, 3115 (NH2), 2216 (CN), 1703 (CO),
7-Amino-3,4-dihydro-2-(5-hydroxy-3-methylpyrazol-1-yl)-4-oxo-
5-(3,4,5-trimethoxyphenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile
(7): The hydrazine 4 (3.83 g, 0.01 mol) was heated to reflux with
ethyl acetoacetate (2.6 g, 0.02 mol) in pyridine (15 mL) for 6 h.
On cooling, acidification with cold dilute acetic acid left a solid
product which was collected by filtration, dried and recrystallised
from ethanol to provide 7 (2.7 g, 60%), m.p 210–212°C. IR: nmax
3395, 3331, 3191 (NH2), 2218 (CN), 1703 (CO), 1648 cm-1 (C=N).
MS: m/z 408 (16) [M+.– HNCO], 369 (100) [M+.– HNCO – MeCN].
Anal. Calcd for C21H19N7O5 (449.42): C, 56.12; H, 4.26; N, 21.81.
Found: C, 55.96; H, 4.0; N, 22.03%.
Reaction of compound 4 with phthalic anhydride; formation
of the phthalazinedione 8 and the pyrido-triazolo-pyrimidine 9:
The hydrazine 4 (0.77 g, 2 mmol) was refluxed with phthalic
anhydride (0.30 g, 2 mmol) in boiling acetic acid (15 mL) for 3 h.
The solid which was deposited after cooling was collected by filtration
and showed two spots on TLC. Fractional crystallisation from
methanol yielded the triazolo-fused product 9 (0.26 g, 32%, identical
by m.p. and mixed m.p with the product prepared as described
below). Evaporation of the original mother liquor left a solid product
which was recrystallised from dioxan to give 7-amino-3,4-dihydro-
4-oxo-2-(1,2,3,4-tetrahydro-1,4-dioxophthalazin-2-yl)-5-(3,4,5-
trimethoxyphenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (8) (0.49 g,
48%), m.p 282–285 °C. IR: nmax 3442, 3429 (br.) (NH2), 2217
(CN), 1736, 1702 (CO), 1650 cm-1 (C=N). MS: m/z 513 (M+, 43),
353 (19), 162 (100), 119 (30), 77 (66). Anal. Calcd for C25H19N7O6
(513.47): C, 58.48; H, 3.72; N, 19.09. Found: C, 58.09; H, 4.0;
N, 18.97%.
1
1639 cm-1 (C=N). H NMR (DMSO-d6) d 9.7 (s, 1H, exchangeable
with D2O), 7.61–7.4 (br.s, 4H, exchangeable with D2O), 7.2–6.9
(m, 3Harom. + C3'-H), 3.9 (s, 9H, 3 OCH3). MS: m/z 459 (100). Anal.
Calcd for C21H17N9O4 (459.42): C, 54.09; H, 3.72; N, 27.43. Found: C,
54.37; H, 4.0; N, 27.29%.
Received 13 March 2009; accepted 31 August 2009
Paper 09/0494 doi: 10.3184/030823409X12523324765777
Published online: 8 October 2009
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