Synthesis and reactions of some novel triazolo-, azolo-, tetrazolo-pyridopyrimidine and their nucleoside derivatives

Article abstract of DOI:10.1002/jccs.200800031

Pyridopyrimidine reacted with aromatic aldehydes afforded the arylhydrazone 2a,b which could be cyclized into the pyrido[2,3-d][1,2,4]triazolo[4,3-a] pyrimidine 3a,b, with formic acid, and carbon disulphide to give pyrido[2,3-d][1,2,4]traizolo[4,3-a]pyrimidine 4, 5. Reaction of 1 with nitrous acid afforded tetrazolo[1,5-a]pyrido[2,3-d]pyrimidine 6, which was reduced by zinc dust to give 2-amino-pyrido-[2,3-d]pyrimidine 7. Finally the reaction of 2-hydrazino 1 with D-xylose or D-glucose afforded the acyclic N-nucleoside 8, 11 which were converted into tetra/penta O-acetate acyclic C-nucleoside 9, 12 in acetic anhydride/pyridine. De-acetylation of compounds 9, 12 afforded C-nucleosides 10, 13.

Full text of DOI:10.1002/jccs.200800031

Journal of the Chinese Chemical Society, 2008, 55, 209-216
209
Synthesis and Reactions of Some Novel Triazolo-, Azolo-,
Tetrazolo-pyridopyrimidine and their Nucleoside Derivatives
Kh. M. Abu-Zied,* A. B. A. El-Gazzar and N. A. Hassan
National Research Centre, Photochemistry Department, (Heterocyclic Unit), El-Tahrir Street,
Dokki, Cairo 12622, Egypt
Pyridopyrimidine reacted with aromatic aldehydes afforded the arylhydrazone 2a,b which could be
cyclized into the pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine 3a,b, with formic acid, and carbon disul-
phide to give pyrido[2,3-d][1,2,4]traizolo[4,3-a]pyrimidine 4, 5. Reaction of 1 with nitrous acid afforded
tetrazolo[1,5-a]pyrido[2,3-d]pyrimidine 6, which was reduced by zinc dust to give 2-amino-pyrido-
[2,3-d]pyrimidine 7. Finally the reaction of 2-hydrazino 1 with D-xylose or D-glucose afforded the acy-
clic N-nucleoside 8, 11 which were converted into tetra/penta O-acetate acyclic C-nucleoside 9, 12 in ace-
tic anhydride/pyridine. De-acetylation of compounds 9, 12 afforded C-nucleosides 10, 13.
Keywords: Pyridopyrimidine; Azolopyridopyrimidine; C- and N-nucleosides; IR; 1H-NMR and
13C spectra.
INTRODUCTION
Pyridopyrimidine and their derivatives have exhib-
ited promising biological and pharmacological activities
such as antifolate,1 antibacterial,2 tyrosine kinas activity,3
antimicrobial,4 calcium channel antagonist,5 antiinflam-
matory and analgesic activity,6 antileishmania,7 tuberculo-
static,8 anti-convulsant,9 diuretic and potassium-sparing,10
and anti-aggressive activities.11 Also, C-nucleosides and
acyclic C-nucleosides have shown marked biological ac-
tivities towards antiviral activities.12 This encouraged us to
become involved in a program directed to the development
of syntheses of various new pyridopyrimidines and fused
pyridopyrimidines such as azolopyridopyrimidine deriva-
tives and some acyclic C- and N-nucleosides.
acid and anhydrous sodium acetate.
The IR spectrum of 2a displayed absorption bands at
3330 cm-1 (NH) and 1670 cm-1 (CO). The 1H-NMR (DMSO-
d6) spectrum of 2a as an example, showed signals at d 7.45
(s, 1H, CH, ethylinic proton), d 7.55-7.65 (m, 10H, phenyl
protons), d 7.75 (m, 4H, phenyl protons), d 8.05 (s, 1H, CH,
pyridinyl proton), d 11.01 (br. s, 1H, NH, D2O exchange-
able) and d 11.5 (br. s, 1H, NH, D2O exchangeable). More-
over, the correct values in elemental analysis, IR, 1H-NMR
RESULTS AND DISCUSSION
The reaction of 2-hydrazino-5-phenyl-7-(4-chloro
phenyl)-3H,4H-pyrido[2,3-d]pyrimidine-4-one (1)13 with
aromatic aldehyde in boiling dioxane afforded the aryl-
hydrazones 2a,b which could be cyclized into the 3-aryl-5-
phenyl-7-(4-chlorophenyl)-1H,4H-pyrido[2,3-d][1,2,4]-
triazolo[4,3-a]pyreimidin-5-ones (3a,b) when they were
treated with catalytic amounts of bromine in glacial acetic
* Corresponding author. E-mail: khashaheen@hotmail.com

210 J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Abu-Zied et al.
spectra of 3a,b are in agreement with the assigned struc-
ture. It’s reported in the literature that the N-3 nitrogen
atom and not the N-1 nitrogen atom are involved in the
cyclization.14-17 (Experimental)
band for the azido group at 2231 cm-1.
Compound 6 was reduced into 2-amino-5-phenyl-7-
(4-chlorophenyl)-3H,4H-pyrido[2,3-d]pyrimidin-4-one 7
1
by zinc dust and acetic acid. The H-NMR (DMSO-d6)
Heating under reflux, compound 1 with formic acid
resulted in the formation of 6-phenyl-8-(4-chlorophenyl)-
1H,3H-pyrido[2,3-d][1,2,4]traizolo[4,3-a]pyrimidin-
5(5H)-one (4).
spectrum of 7 showed signals at d 7.39 (m, 5H, phenyl pro-
tons), d 7.45-7.55 (m, 4H, phenyl protons), d 7.88 (s, 1H,
CH, pyridinyl proton) and d 10.90 (br. s, 1H, NH, D2O ex-
changeable). The IR spectrum of 7 displayed absorption
bands at 3420 cm-1 (NH2), 3240 cm-1 (NH), 3034 cm-1 (CH),
2908 cm-1 (CH alkyl) and 1666 cm-1 (CO).
Besides the biological activities of the pyridopyrimi-
dine derivatives as described above, acyclic C-nucleosides
also act as antivirals and antiherpetices. We report here a
simple and convenient method to synthesize new acyclic
C- and N-nucleoside derivatives derived from 2-hydrazi-
no-5-phenyl-7-(4-chlorophenyl)-3H,6H-pyrido[2,3-d]pyr-
imidin-4(4H)one (1).
Compound 1 reacted with carbon disulphide in eth-
anolic potassium hydroxide solution to afford 3-mercapto-
6-phenyl-8-(4-chlorophenyl)-1H,3H-pyrido[2,3-d][1,2,4]-
traizolo[4,3-a]pyrimidin-5(5H)-one (5), (Experimental).
Treatment of compound 1 with nitrous acid at 0 °C led to
the formation of 6-phenyl-7-(4-chlorophenyl)-1H,5H-tet-
razolo[1,5-a]pyrido[2,3-d]pyrimidin-5-one (6), which was
found in equilibrium with the 2-azido toutomer.
Heating under reflux 1 with aldopentose, namely D-
xylose in dioxane in the presence of a catalytic amount of
pipridine, yielded acyclic N-nucleoside 8.
The 1H-NMR (DMSO-d6) spectrum of 6 showed sig-
nals at d 7.38 (m, 5H, phenyl protons), d 7.45 (m, 4H, phen-
yl protons), 7.88 (s, 1H, pyridinyl proton) and d 13.65 (br s,
1H, NH, D2O exchangeable). The IR spectrum of 6 dis-
played absorption bands around 3210 (NH), 3022 (CH),
2928 (CH alkyl), 1686 (CO) and a characteristic absorption
The 1H-NMR spectrum of compound 8 showed sig-
nals at d 3.45 (m, 4H, 4OH ,OH-2¢-OH-5¢, D2O exchange-
able), d 4.25 (m, 1H, H-4¢), d 4.35 (m, 2H, CH2, H-5¢), d
4.60 (m, 1H, H-3¢), d 5.65 (m, 1H, H-2¢), d 7.25 (m, 1H,
H-1¢), d 7.45 (m, 5H, phenyl protons), d 7.65 (m, 4H, phen-
yl protons), d 7.90 (s, 1H, CH, pyridinyl proton), d 11.20
(br. s, 1H, NH, D2O exchangeable) and d 11.40 (br. s, 1H,
NH, D2O exchangeable). Its IR spectrum displayed absorp-
tion bands at 3460-3455 cm-1 (broad OH), 3250 cm-1 (NH),
3026 cm-1 (CH), 2924 cm-1 (CH alkyl) and 1667 cm-1 (CO).

Tetrazolopyridopyrimidine
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008 211
The acyclic N-nucleoside 8 was stirred at room tem-
perature in acetic anhydride/pyridine mixture (1:1) to af-
ford the corresponding protected tetra O-acetate acyclic
able), d 3.70 (m, 1H, H-5¢), d 4.35 (m, 2H, H-6¢), d 4.40 (m,
1H, H-4¢), d 4.60 (m, 1H, H-3¢), d 5.35 (m, 1H, H-2¢), d
6.15 (d, 1H, H-1¢), d 7.55-7.65 (m, 5H, phenyl protons), d
7.70-7.75 (m, 4H, aryl protons), d 8.20 (s, 1H, CH, pyr-
idinyl proton), d 11.05 (brs, 1H, NH, D2O exchangeable)
and d 11.25 (brs, 1H, NH, D2O exchangeable). Its IR spec-
trum displayed absorption bands at 3265 cm-1 (NH), 3224
cm-1 (NH), 3030 cm-1 (CH), 2920 cm-1 (CH alkyl) and
1670 cm-1 (CO).
1
C-nucleoside 9. The H-NMR spectrum of compound 9
showed signals at d 1.65 (s, 3H, OCH3), d 1.85 (s, 3H,
OCH3), d 2.00 (s, 3H, OCH3), d 2.15 (s, 3H, OCH3), d 5.25
(m, 1H, H-3¢), d 5.35 (m, 2H, CH2, H-4¢), d 5.55 (m, 1H,
H-2¢), d 5.75 (m, 1H, H-1¢), d 7.40-7.55 (m, 5H, phenyl
protons), d 7.85 (m, 4H, phenyl protons), d 7.90 (s, 1H, 1H,
CH, pyridinyl proton) and d 11.40 (br. s, 1H, NH, D2O ex-
changeable). Its IR spectrum displayed absorption bands at
3300 cm-1 (NH), 3025 cm-1 (CH), 2900 cm-1 (CH alkyl),
1740-1760 cm-1 (ester carbonyl) and 1700 cm-1 (CO).
De-acetylation of 9 could be achieved by treatment
with methanolic sodium methoxide solution to give the
de-protected acyclic C-nucleoside 10.
On the other hand, acetylation of compound 11 with
an acetic anhydride/pyridine mixture (1:1) at room temper-
ature afforded the protected penta O-acetylated acyclic C-
1
nucleoside 12. The H-NMR spectrum of compound 12
showed signals at d 1.85 (s, 3H, OCH3), d 1.95 (s, 3H,
OCH3), d 2.00 (s, 3H, OCH3), d 2.15 (s, 3H, OCH3), d 2.40
(s, 3H, OCH3), d 4.85 (m, 1H, H-4¢), d 5.45 (m, 1H, H-3¢), d
5.55 (m, 2H, CH2, H -5¢), d 5.65 (m, 1H, H-2¢), d 5.70 (m,
1H, H-1¢), d 6.85 (m, 5H, phenyl protons), d 7.65 (m, 4H,
phenyl protons), d 8.00 (s, 1H, CH, pyridinyl proton) and d
11.45 (br s, 1H, HN, D2O exchangeable). Its IR spectrum
displayed absorption band at 3230 cm-1 (NH), 3030 cm-1
(CH), 2920 cm-1 (CH alkyl), 1745-1715 cm-1 (ester car-
bonyl) and 1685 cm-1 (CO).
De-protection of the acyclic C-nucleoside could be
achieved when it was stirred in methanolic sodium meth-
oxide solution at room temperature to give the acyclic C-
nucleoside 13. The structure of 13 was confirmed by spec-
tral and elemental analysis. (Experimental)
Also, heating under reflux 1 with aldohexoses, namely
D-glucose in dioxane in the presence of a catalytic amount
of pipridine, yielded acyclic N-nucleoside 11.
EXPERIMENTAL
Solid compounds were re-crystallized to constant
melting points and dried in vacuum in a drying pistol con-
taining sodium hydroxide. All melting points are uncor-
rected and were taken in open capillaries on a Gallenkamp
apparatus. Micro analyses were carried out at the Micro
Analytical Unit of the National Research Centre and Fac-
The 1H-NMR spectrum of compound 11 showed sig-
nals at d 3.60 (m, 5H, 5OH, OH-2¢-OH-6¢, D2O exchange-

212 J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Abu-Zied et al.
ulty of Science, Cairo University. IR spectra were carried
1
out on an FT/IR 300 E Jasco using KBr discs. H-NMR
mL) to yield the title compound as shining yellow crystals
(3.07 g, 68%); m.p. 287-2 °C. [C26H18N5ClO] (541.91).
Require: C, 69.10%; H, 4.01%; N, 15.50%. Found: C,
68.60%; H, 3.78%; N, 15.10%. 13C-NMR (DMSO-d6) d
ppm: 65.92 (CH), 131.03, 132.41, 134.60, 134.06, 134.12,
137.61, 138.22, 139.43, 138.18, 138.61, 138.83, 139.13,
139.24, 140.77, 142.15, 142.40, 146.76, 147.88, 150.13,
162.05, 163.05, 165.60, and 166.00, 166.18 (Pyridopyr-
imidone carbon atoms and aromatic carbon atoms) and
167.81 (CO). MS (EI + Q1MS LMR UP LR): 451.9 (M+)
100%.
spectra were measured in DMSO or CDCl3, using a Joel
Ex. 270 NMR spectrometer. Signals were measured with
reference to TMS as an internal standard. The mass spectra
were recorded on a Finnigan SSQ 7000 spectrometer. All
reactions were followed up by TLC using CHCl3/MeOH
(9:1, v/v) and/or ethyl acetate/benzene (7:3) and detected
under a UV lamp.
2-Hydrazino-5-phenyl-7-(4-chlorophenyl)-3H,6H-pyr-
ido[2,3-d]pyrimidin-4(4H)one (1)
A mixture of 7-(4-chlorophenyl)-2-methylthio-5-
phenyl-3H,4H-pyrido[2,3-d]pyrimidin-4-one (3.80 g, 0.01
mole) and hydrazine hydrate (99-100%) (11.40 mL, 0.03
mole) in dioxane (20 mL) and ethanol (10 mL) was heated
under reflux for five hours. The solid that separated upon
cooling the reaction mixture was filteredoff and recrys-
tallized from dioxane (45 mL) to yield the title compound
as pale yellow crystals (2.3 g, 63%), mp. 313-2 °C.
[C19H14N5OCl] (363.80) Required: C, 62.73%; H, 3.88%;
N, 19.25. Found: C, 62.41%; H, 3.54%; N, 19.11%. IR
(KBr) cm-1: 3330 (NH2), 3225 (NH), 3020 (CH) and 1666
2-(4-Methoxyphenylmethylenehydrazone)-5-phenyl-7-
(4-chlorophenyl)-3H,4H-pyrido[2,3-d]pyrimidin-4-one
(2b)
From compound 1 and 4-methoxybenzaldehyde (1.36
g, 0.01 mole). The product was recrystallized from dioxane
(35 mL) to yield the title compound as orange crystals (3.40
g, 71%); m.p. > 300 °C. [C27H20N5ClO2] (481.94) Re-
quired: C, 67.29%; H 4.18%; N, 14.53%. Found: C,
67.01%; H, 3.78%; N, 14.34%. IR (KBr) cm-1: 3222 (NH),
1
3020 (CH), 2928 (CH alkyl) and 1672 (CO). H-NMR
(DMSO-d6) d ppm: 3.80 (s, 3H, OCH3), 6.95-7.25 (m, 5H,
phenyl protons), 7.40-7.55 (m, 4H, phenyl protons),7.65
(s, 1H, CH, ethylenic proton), 7.70-7.80 (m, 4H, aromatic
protons), 8.00 (s, 1H, CH, pyridinyl proton), 11.15 (br. s,
1H, NH, D2O exchangeable) and 11.55 (br. s, 1H, NH, D2O
exchangeable). 13C-NMR (DMSO-d6) d ppm: 54.61 (OCH3),
66.71 (CH), 129.71, 131.33, 131.62, 133.92, 135.51,
137.11,137.73, 138.32, 139.14, 139.84, 138.61, 138.83,
139.13, 139.24, 140.77, 142.15, 142.40, 146.76, 147.88,
151.11, 162.11, 163.04, 165.31, and 166.08, 166.27 (Pyri-
dopyrimidone carbon atoms and aromatic carbon atoms)
and 167.92 (CO). MS (EI + Q1MS LMR UP LR): 481.9
(M+) 100%.
1
(CO). H-NMR (DMSO-d6) d ppm: 7.30-7.40 (m, 5H,
phenyl protons), 7.45-7.55 (m, 4H, phenyl protons), 8.05
(s, 1H, CH) and 8.75 (br s, 1H, NH, D2O exchangeable).
MS (EI+Q1MS LMR UP LR): 363.8 (M+) 100%.
2-(Arylmethylenehydrazone)-5-phenyl-7-(4-chloro-
phenyl)-3H,4H-pyrido[2,3-d]pyrimidin-4-one (2a,b)
General procedure
A mixture of compound 1 (3.63 g, 0.01 mole), the ap-
propriate aromatic aldehyde (0.01 mole), dioxane (30 mL)
and a catalytic amount of piperidine was heated under re-
flux for six hours. The reaction mixture was allowed to cool
to room temperature and then it was poured into water (100
mL). The formed precipitate was filteredoff, washed with
water, dried and recrystallized from the proper solvent to
yield 2a,b.
3-Aryl-5-phenyl-7-(4-chlorophenyl)-1H,4H-pyrido[2,3-
d][1,2,4]triazolo[4,3-a]pyrimidin-5-one (3a,b)
General Procedure
A mixture of either of 3a (4.51 g, 0.01 mol) or 3b
(4.81 g, 0.01 mol) with 2 g anhydrous sodium acetate, bro-
mine (2.44 g, 0.01 mol) and glacial acetic acid (25 mL) was
heated on a water bath at 80 °C for about 8 hours (under
TLC control). The reaction mixture was poured onto water
2-(Phenylmethylenehydrazone)-7-(4-chlorophenyl)-
3H,4H-pyrido[2,3-d]pyrimidin-4-one (2a)
From compound 1 and benzaldehyde (1.06 g, 0.01
mole). The product was recrystallized from dioxane (35

Tetrazolopyridopyrimidine
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008 213
and the formed solid was collected by filtration and crystal-
alkyl) and 1680 (CO). 1H-NMR (DMSO-d6) d ppm: 7.15 (s,
1H, triazolo proton), 7.56 (m, 5H, phenyl protons), 7.73
(m, 4H, phenyl protons), 7.90 (s, 1H, pyridinyl proton) and
9.66 (br. s, 1H, NH, D2O exchangeable). MS (EI + Q1 MS
LMR UP LR): 373.79 (M+) 100%.
lized from the proper solvent to give 3a,b.
3,5-Diphenyl-7-(4-chlorophenyl)-1H,4H-pyrido[2,3-d]
[1,2,4]triazolo[4,3-a]pyrimidin-5-one (3a)
Compound 3a was obtained in 60% yield; m.p. 304
°C; [C26H16N5ClO] (449.90); Required: C, 69.41%; H
3.58%; N, 15.56%. Found: C, 69.10%; H 3.33%; N,
15.14%. IR (KBr) cm-1: 3225 (NH), 3030 (CH), and 1700
(CO). 1H-NMR (DMSO-d6) d ppm: 7.25-7.35 (m, 10H, ar-
omatic protons), 7.45-7.55 (m, 4H, aromatic protons), 7.80
(s, 1H, CH, pyridinyl proton) and 11.25 (br. s, 1H, NH, D2O
exchangeable). MS (EI + Q1MS LMR UP LR): 449.90
(M+) 100%.
3-Mercapto-1,6,7,8-tetrahydrocyclopentanothieno[2,3-d]
[1,2,4]traizolo[4,3-a]pyrimidin-5(5H)-one (5)
To a warmed ethanolic sodium hydroxide solution
(prepared by dissolving sodium hydroxide (0.40 g, 0.01
mole) in ethanol (50 mL), compound 1 (3.63 g, 0.01 mole)
and carbon disulphide (10 mL) were added. The mixture
was heated on a water bath at 80 °C under reflux for eight
hours, then allowed to cool to room temperature, poured
into water (100 mL), and neutralized by dilute acetic acid.
The formed precipitate was filteredoff, dried and crystal-
lized from dioxane (30 mL) to yield the title product as a
pale yellow powder (1.70 g, 64%), m.p. > 300 °C.
[C10H8N4S2O] (264.31); Required: C, 45.44%; H, 3.05%;
N, 21.19%. Found: C, 45.10%; H, 3.30%; N, 20.82%. IR
(KBr) cm-1; 3100 (broad NH), 3010 (CH), 2920 (CH alkyl)
and 1690 (CO) 1H-NMR (DMSO-d6) d ppm: 1.43 (s, 1H,
SH), 7.30 (m, 5H, phenyl protons), 7.35-7.42 (m, 2H,
phenyl protons), 7.64-7.70 (m, 2H, phenyl protons), 7.95
(s, 1H, CH, pyridinyl proton) and 12.60 (br. s, 1H, NH,
D2O exchangeable). 13C-NMR (DMSO-d6) d ppm: 128.76,
130.33, 131.00, 133.14, 134.60, 134.06, 134.12, 137.61,
139.24, 144.11, 144.26, 147.06, 151.33, 162.05, 163.05,
165.60, and 166.00, 166.18 (Pyridopyrimidone carbon at-
oms, triazol carbon atom and aromatic carbon atoms) and
166.13 (CO). MS (EI + Q1 MS LMR UP LR): 373.79 (M+)
100%.
8-(4-Chlorophenyl)-3-(4-methoxyphenyl)-1H,5H-
pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyremidin-5-one
(3b)
Compound 3b was obtained in 63% yield; m.p. 317
°C; [C27H18N5ClO2] (479.92); Required: C, 67.57%; H
3.77%; N, 14.59%. Found: C, 67.24%; H 3.61%; N,
14.13%. IR (KBr) cm-1: 3256 (NH), 3020 (CH aromatic),
2928 (CH alkyl) and 1685 (CO). 1H-NMR (DMSO-d6) d
ppm: 3.80 (s, 3H, OCH3), 7.25-7.37 (m, 5H, phenyl pro-
tons), 7.40-7.55 (m, 4H, phenyl protons), 7.60-6.70 (m,
4H, aromatic protons), 7.80 (s, 1H, CH, pyridinyl proton)
and 11.25 (br. s, 1H, NH, D2O exchangeable). MS (EI +
Q1MS LMR UP LR): 479.92 (M+) 100%.
6-Phenyl-8-(4-chlorophenyl)-1H,3H-pyrido[2,3-d][1,2,4]-
traizolo[4,3-a]pyrimidin-5(5H)-one (4)
A mixture of compound 1 (3.63 g, 0.01 mole), formic
acid (1 mL) and a catalytic amount of concentrated hydro-
chloric acid solution was heated under reflux for five
hours. The reaction mixture was allowed to cool to room
temperature, then poured into water (100 mL). The formed
solid was collected by filtration, washed with ethanol (20
mL), dried and crystallized from dioxane (35 mL) to yield
the title compound as colorless crystals (1.42 g, 61%), m.p.
281-82 °C and crystallized from acetic acid to yield the title
product as pale yellow crystals (2.50 g, 67%), mp. 239-41
°C. [C9H11N5SO] (233.27); Required: C, 46.34%; H,
5.03%; N, 13.75%. Found: C, 45.81%; H, 3.10%; N,
13.45%. IR (KBr) cm-1: 3211 (NH), 3022 (CH), 2890 (CH
7-(4-Chlorophenyl)-6-phenyl-1H,5H-tetraazolo[1,5-a]-
pyrido[2,3-d]pyrimidin-5-one (6)
To an ice-cold solution of compound 1 (3.63 g, 0.01
mole) in acetic acid (15 mL) was added dropwise, a solu-
tion of sodium nitrite (prepared by dissolving sodium ni-
trite (1.70 g, 0.015 mole) in the least amount of water) in an
icebath at -5 °C. The reagent mixture was allowed to stand
overnight at room temperature, and then it was poured into
water (100 mL). The solid so-precipitated was filteredoff
and recrystallized from acetic acid to yield the title com-
pound as yellow crystals (2.50g, 67%), m.p.301-2 °C.

214 J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Abu-Zied et al.
[C19H11N6OCl] (374.78); Required: C, 60.89%; H, 2.95%;
N, 22.42%. Found: C, 60.64%; H, 2.88%; N, 22.01%. MS
(EI + Q1 MS LMR UP LR): 374.7 (M+) 100%.
2-Glucosylhydrazino-5-phenyl-7-(4-chlorophenyl)-
3H,6H-pyrido[2,3-d]pyrimidin-4-one (11)
Amixture of compound 1 and D-glucose (1.80 g, 0.01
mole), dioxane (30 mL), ethanol (10 mL) and catalytic
amounts of piperidine was stirred under reflux for eight
hours. The reaction mixture was allowed to cool to room
temperature. The precipitate so-formed was filteredoff,
washed with ethanol and recrystallized from dioxane (35
mL) to afford the title compound as yellow crystals (3.34,
63%); m.p. 281-2 °C [C25H24N5O6 Cl] (525.95); Required:
C, 57.09%; H, 4.59%; N, 13.31%. Found: C, 56.48%; H,
4.38%; N, 12.76%.
2-Amino-5-phenyl-7-(4-chlorophenyl)-3H,4H-pyrido-
[2,3-d]pyrimidin-4-one (7)
To a well-stirred solution of compound 6 (3.74. g,
0.01 mole) in glacial acetic acid (40 mL) was added por-
tionwise activated zinc dust (5.00 g) at room temperature
over a period of 30 minutes. Stirring was continued for an
additional three hours. Thereafter, the reaction mixture was
heated on a water bath (80-90 °C) for three hours. The
progress of reduction was monitored by TLC. After allow-
ing the reaction mixture to cool to room temperature, it was
poured into cold water to (100 mL). The insoluble solid,
which separated, was filtered, washed with water and dried.
The crude solid was extracted with hot benzene and the
solid obtained after removal of benzene under reduced
pressure was crystallized from acetic acid to yield the title
product as yellow crystals (2.14 g, 61.5%), m.p. 243-45 °C.
[C19H13N4OCl] (348.78), Required: C, 65.43%; H, 3.75%;
N, 16.06%. Found: C, 65.03%; H, 3.60%; N, 15.71%. MS
(EI + Q1 MS LMR UP LR): 348.7 (M+) 100%.
3-(O-Acetylglycosyl)-6-phenyl-8-(4-chlorophenyl)-
1H,7H-pyrido[2,3-d][1,2,4]triazolo[4,3-a] pyrimidin-
5(5H)-one (9, 12)
General Procedure
A solution of compounds 8 or compounds 11 (0.01
mole) in a mixture of acetic anhydride-pyridine (20 mL: 20
mL) was stirred at room temperature overnight, then it was
poured into water. The reaction mixture was then extracted
with chloroform several times and after the removal of
chloroform under reduced pressure, the formed crystals
were recrystallized from the proper solvent to produce 9 or
12.
2-Glycosylhydrazino-5-phenyl-7-(4-chlorophenyl)-
3H,6H-pyrido[2,3-d]pyrimidin-4-one (8, 11)
General Procedure
3-(1¢,2¢,3¢,4¢-O-tetraacetylxylosyl)-6-phenyl-8-(4-chloro-
phenyl)-1H,7H-pyrido[2,3-d][1,2,4]triazolo[4,5-a]pyr-
imidine-5(5H)-one (9)
A mixture of compound 1 (3.63 g, 0.01 mole) and the
appropriate monosaccharide (0.01 mole), dioxane (30 mL),
ethanol (10 mL) and catalytic amounts of piperidine was
stirred under reflux for eight hours. The reaction mixture
was allowed to cool to room temperature. The precipitate
so-formed was filteredoff, washed with ethanol and recrys-
tallized from dioxane (30 mL) to afford the title com-
pounds.
From compound 8 (4.95 g, 0.01 mole). The product
was recrystallized from methanol (30 mL) to afford the title
compound as golden yellow crystals (3.26 g, 66%); m.p.
156-2 °C. [C32H20N5O9] (662.05). Required: C, 58.05%;
H, 4.26%; N, 10.57%. Found: C, 57.51%; H, 3.81%; N,
10.12%.
2-Xylosylhydrazino-5-phenyl-7-(4-chlorophenyl)-
3H,6H-pyrido[2,3-d]pyrimidin-4-one (8)
3-(1¢,2¢,3¢,4¢,5¢-O-pentaacetylglucosyl)-6-phenyl-8-(4-
chlorophenyl)-1H,7H-pyrido[2,3-d][1,2,4]triazolo[4,3-
a]pyrimidin-5(5H)-one (12)
From compound 1 and D-xylose (1.50 g, 0.01 mole).
The product was recrystallized from dioxane (35 mL) to
yield the title compound as yellow powder (3.20 g, 64.60%);
m.p. 283-2 °C. [C24H22N5O5] (495.91); Required: C,
58.12%; H, 4.47%; N, 14.12%. Found: C, 58.00%; H,
4.11%; N, 13.34%.
From compound 11 (5.25 g, 0.01 mole). The product
was recrystallized from methanol (35 mL) to yield the title
compound as yellow crystals (4.38 g, 65%); m.p. 161-2 °C.
[C30H34N5O11Cl] (676.08). Required: C, 53.30%; H, 5.11%;
N, 10.36%. Found: C, 53.01%; H, 4.93%; N,10%. 13C-

Tetrazolopyridopyrimidine
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008 215
NMR (CDCl3) d ppm : 20.00, 20.30, 20.50, 20.80, and
23.30 (CH3), 29.60 (CH2), 66.70, 67.00, 67.40 and 69.10
(CH), 137.30, 137.60, 138.00, 138.40, 138.30, 138.60,
139.00, 139.30, 139.80, 141.61, 142.73, 143.00, 145.11,
145.31, 147.10, 153.40, 155.00, 155.66, and 157.15 (Pyr-
idopyrimidone carbon atoms, triazol carbon atoms and aro-
matic carbon atoms) and 168.36, 168.70, 168.90, 170.00,
170.30 and 171.10 (CO).
able),4.00 (m, 1H, H-2¢), 4.30 (m, 1H, H-3¢), 4.45 (m, 2H,
H-5¢, H-5¢¢), 4.50 (m, 1H, H-4¢), 4.65 (m, 1H, H-1¢), 7.20
(brs, 1H, NH, D2O exchangeable), 7.35 (m, 5H, phenyl
protons), 7.40 (m, 2H, phenyl protons), 7.55 (m, 2H, phen-
yl protons) and 7.85 (s, 1H, CH, pyridinyl proton). 13C-
NMR (DMSO-d6) d ppm: 26.60 (CH2), 60.05, 63.71, 64.43
and 66.30 (CH), 134.60, 137.11, 137.22, 138.00, 138.18,
138.61, 138.83, 139.13, 139.24, 139.33, 139.91, 142.40,
144.31, 144.55, 144.60, 144.72, 146.00, 151.42, and
157.64 (Pyridopyriidone carbon atoms, triazol carbon at-
oms and aromatic carbon atoms) and 167.69 (CO).
3-Glycosyl-6-phenyl-8-(4-chlorophenyl)-1H,7H-pyrido-
[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(5H)-one (10, 13)
General procedure
Received March 2, 2007.
A solution of methanolic sodium methoxide (pre-
pared by dissolving sodium metal (0.23 g, 0.01 mole) in ab-
solute methanol (25 mL)) was added to either compounds 9
(0.01 mole) or compounds 12 (0.01 mole). The reaction
mixture was allowed to stire for eight hours, and then neu-
tralized with hydrochloric acid solution (neutralization
takes place under pH control). The excess methanol was
removed under reduced pressure, whereby a solid was
precipitated. The precipitate so-formed was filteredoff,
washed with cold water, dried and recrystallized from the
proper solvent to produce the title compounds in good
yield.
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