Characterization and preliminary use of 1-, 2- and 3-methyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine as reaction intermediates

Article abstract of DOI:10.1016/S0014-827X(03)00095-8

This paper reports synthesis and characterization, by spectroscopic methods, of three new N-methyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine isomers 3a, 3b and 3c. For comparison purpose the 3-benzyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidi

Full text of DOI:10.1016/S0014-827X(03)00095-8

Il Farmaco 58 (2003) 551ꢀ556
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Characterization and preliminary use of 1-, 2- and 3-methyl-5-phenyl-
7-chloro-1,2,3-triazolo[4,5-d]pyrimidine as reaction intermediates
Giuliana Biagi a, Irene Giorgi a, Oreste Livi a,*, Valerio Scartoni a, Pier Luigi Barili b
a Dipartimento di Scienze Farmaceutiche, Universita` di Pisa, via Bonanno 6, 56126 Pisa, Italy
b Dipartimento di Bioorganica e Biofarmacia, Universita` di Pisa, via Bonanno 6, 56126 Pisa, Italy
Received 3 January 2003; accepted 22 April 2003
Abstract
This paper reports synthesis and characterization, by spectroscopic methods, of three new N-methyl-5-phenyl-7-chloro-1,2,3-
triazolo[4,5-d]pyrimidine isomers 3a, 3b and 3c. For comparison purpose the 3-benzyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-
d]pyrimidine (7) was also prepared. Starting from the isomer mixture 3aꢀ
reaction with ethyl carbazate and subsequent intramolecular cyclization, the new tricyclic derivatives 5aꢀ
/
c and the chloroderivative 7, by nucleophilic substitution
c and 9 were prepared and
/
tested towards the benzodiazepine and adenosine A1 and A2A receptors.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 1,2,3-Triazolo[4,5-d]pyrimidines; 1,2,3-Triazolo[4,5-e]1,2,4-triazolo; [3,4-c]Pyrimidines; Benzodiazepine receptor binding; Adenosine
receptor binding
1. Introduction
salt of 1 can be delocalized on each one of the three
nitrogen atoms of the triazole ring, a mixture of three
isomers, 1-methyl- (2a), 2-methyl- (2b) and 3-methyl-
(2c) substituted, respectively, was isolated and charac-
terized.
Because attempts of fractionating the mixture, either
by gas-chromatography or by TLC analysis failed, this
mixture was directly converted to the mixture of the
corresponding 7-chloroderivatives.
The 7-chloro-1,2,3-triazolo[4,5-d]pyrimidines are very
reactive compounds towards the nucleophilic substitu-
tion and the chlorine atom can be easily substituted with
several different nucleophilic agents, to give a variety of
suitable derivatives [1ꢀ
Moreover the 1,2,3-triazolo-pyrimidines are biologi-
cally interesting molecules [7ꢀ11] and are one of our
/6].
/
The chlorination reaction was carried out with thionyl
chloride in chloroform/DMF, and the mixture of the
three isomeric chloroderivatives 3a, 3b and 3c, with well
differentiated Rf values at the TLC analysis (0.54, 0.46
and 0.32, respectively, ethyl acetate/petroleum ether
1:4), was fractionated by flash-chromatography through
a silica-gel column.
research topics concerning the synthesis of new deriva-
tives to evaluate their affinity towards the adenosine and
benzodiazepine receptors, by binding assays [3,12ꢀ
On pursuing our studies, we needed to synthesize
1,2,3-triazolo[4,5-d]pyrimidine derivatives bearing
/
16].
a
substituent with a little steric hindrance, as a methyl
group, on the 1,2,3-triazole ring.
The compounds were eluted in the following order, in
the yields reported in brackets, and were characterized
by analytical and spectroscopic methods: 3a (24.5%), 3b
(38.5%) and 3c (23.5%).
The structure attribution to the single isomers was
reasonably achieved by interpretation of their 13C NMR
and UV spectra.
Therefore the 5-phenyl-1,6-dihydro-1,2,3-triazolo[4,5-
d]pyrimidin-7-one (1) [17] underwent a N-methylation
reaction with methyl iodide in methanol, in the presence
of equimolar amount of sodium methoxide (Scheme 1).
As expected, because the negative charge on the sodium
Our previous studies on 1,2,3-triazole derivatives
[18,19] indicated that a carbon atom at the position 2
* Corresponding author.
E-mail address: livi@farm.unipi.it (O. Livi).
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00095-8

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G. Biagi et al. / Il Farmaco 58 (2003) 551ꢀ
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556
Scheme 1.
of a 1,2,3-triazole ring resonates at fields lower than a
carbon atom bonded at the position 1 or 3, for about 5ꢀ
be achieved by the observation that in the 1-methyl
substituted compound (isomer 3a), the methyl group is
g-gauche positioned regarding to the chlorine atom and
this condition agrees with a chemical shift value
remarkably shifted to higher fields. Therefore to the
compound with the methyl chemical shift at 33.6 ppm,
which is shifted 11.4 ppm from the 2-methyl substituted
compound 3b, we can assign the 1-methyl substituted
structure, corresponding to the isomer 3a. Finally to the
compound with the methyl chemical shift at 37.8 ppm
(shifted from the 2-substituted compound 3b of 7.2
ppm) we can assign the three-substituted structure
corresponding to the isomer 3c. The g-gauche effect is
also evidenced in the 1H NMR spectra, in fact the
methyl protons of the three isomers (3a,b,c) resonate at
4.35, 4.62 and 4.52 ppm, respectively and really the
/
7 ppm. The 13C NMR spectra of the 3a, 3b and 3c
isomers show the following chemical shifts for the three
methyl carbons: 45.0, 37.8 and 33.6 ppm, respectively.
The chemical shift differences between the methyl signal
which resonates at lower fields and the other two signals
are 7.2 and 11.4 ppm, respectively. Thus, according to
the literature, we can assign the 2-methyl substituted
triazole structure, corresponding to the isomer 3b, to the
compound with the lowest methyl chemical shift (45.0
ppm). The difference between this value and the next
(37.8 ppm) is 7.2 ppm and corresponds to the difference
reported between a two substituted methyl and a 1 or 3
substituted methyl of 1,2,3-triazole derivatives [18,19].
The discrimination between these last two structures can

G. Biagi et al. / Il Farmaco 58 (2003) 551ꢀ
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556
553
Table 1
Spectral data
whilst in the 3a spectrum the absorbance terminates at
330 nm.
In any case, before the isomeric chloroderivatives
were characterized, a 3a,b,c mixture was employed as a
model for the synthesis of new derivatives, especially
tricyclic structures of our interest, to submit to binding
assays and to obtain preliminary informations about
their biological activity. Thus the mixture of chloro-
derivatives 3a,b,c (Scheme 1) reacted with ethyl carba-
zate in boiling benzene, in the presence of triethylamine
(TEA), to give the corresponding mixture of N-methyl-
7-ethoxycarbonylhydrazino derivatives 4a,b,c in 47%
yield. Heating of this mixture in Dowtherm at 130 8C
for 4 h, induced the intramolecular cyclization with
elimination of ethanol and formation of the 1,2,4-
triazole ring, to give the mixture of tricyclic N-methyl-
substituted isomers 5a,b,c, bearing a hydroxyl function
in the 7 position.
3a
3b
3c
7
13C NMR d (ppm)
1H NMR d (ppm)
UV lmax (nm)
nCH3
nCH3
33.6
4.35
45.0
4.62
37.8
4.52
K band 246.1
B band 301.9
247.5
308.2
244.3
276.4
244.3
275.8
value shifted at higher fields corresponds to that of the
1-methyl substituted isomer 3a. The important spectral
values are reported in Table 1.
The UV spectra investigation led to the same conclu-
sions, in fact, a batochromic shift of the B-benzenoid
band of the two-substituted benzotriazoles with regard
to those substituted in the 1 or 3 positions is described
[20].
The UV spectra of the three isomers (Fig. 1) and their
lmax reported in Table 1, show that compound 3b
presents a shift towards greater wavelengths (308.2
nm), which confirms the substitution in the 2 position.
A further confirmation of the structure assigned to the
isomers 3a and 3c has been obtained by the comparison
of their UV spectra with the spectrum of the 3-
benzylsubstituted compound 7 (Scheme 2), purposely
prepared by chlorination of the corresponding 3-benzyl-
5-phenyl-3,6-dihydro-1,2,3-triazolo[4,5-d]pyrimidin-7-
one (6) [21].
The spectrum of the synthesized compound 7 is very
similar to the spectrum of 3c and different from the
spectrum of 3a, so that it confirms the 3-substituted
structure assigned to the isomer 3c. However, it is worth
nothing that the B-band in consequence of the comple-
xity of the chromophores, especially for the 3a and 3b
spectra, appears rather flattened with a low accuracy in
the determination of the lmax. But it is undoubted the
greater batochromic shift observed in the 3b spectrum,
also evidenced by the clear absorbance until 350 nm,
Similarly the 3-benzyl-chloroderivative 7, by reaction
with ethyl carbazate gave the ethoxycarbonylhydrazino
derivative 8 which, by heating, cyclized to the expected
tricyclic derivative 9.
2. Biological results
The new compounds as mixtures 4a,b,c and 5a,b,c
together with compounds 8 and 9, underwent binding
assays either to benzodiazepine receptors or adenosine
A1 and A2A receptors.
Their ability to inhibit benzodiazepine receptor bin-
ding was measured by the concentration which was able
to displace [3H]-Ro 15-1788 from bovine brain mem-
branes.
The inhibition of binding towards adenosine receptors
was measured by the ability of compounds to displace
[3H]N6-cyclohexyladenosine (CHA) from A1 adenosine
receptors in bovine cortical membranes and [3H]-2-[p-
(2-carboxyethyl)-phenethylamino]-5?-(N-ethylcarba-
Fig. 1. UV spectra of isomer 3aꢀc and compound 7.
/

554
G. Biagi et al. / Il Farmaco 58 (2003) 551ꢀ556
/
Scheme 2.
1
moil)-adenosine (CGS 21680) from A2A adenosine
receptors in bovine striatal membranes.
The experimental details of the receptor binding
assays are reported in a previous paper [22].
The biological evaluation towards the adenosine A1
and A2A receptors showed the triazolo-pyrimidine
isomer mixture 4a,b,c had a moderate but interesting
Lambda 15 UVꢀVis spectrophotometer in CHCl3. H
/
NMR and 13C NMR spectra were recorded with a
Varian Gemini 200 spectrometer in DMSO-d6 or CDCl3
in d units, using TMS as internal standard; in 13C NMR
spectra, the signals of the triazolo-pyrimidine ring were
not evidenced, probably in consequence of the quadru-
polar moment of the nitrogen atoms. Mass spectra were
affinity towards the A1 receptor subtype (Kiꢁ
with a high selectivity regarding to the A2A receptor
subtype (Kiꢁ5935 nM). The corresponding benzyl-
derivative 8 showed also an analogous activity with
lower effectiveness (Kiꢁ531 nM) and selectivity. An
almost equivalent activity was also present in the
tricyclic benzylderivative 9 (Kiꢁ587 nM), whilst the
mixture of the tricyclic N-methylated isomers 5a,b,c
showed a low A1-adenosine affinity (Kiꢁ1317 nM).
/
137 nM),
performed with a Perkinꢀ
with a Hewlett Packard MS/System 5988 A. Elemental
analyses (C,H,N) were within 90.4% of theoretical
values and were performed on a Carlo Erba Elemental
Analyzer Mod. 1106 apparatus. TLC data were ob-
tained with Merck silica gel 60 F254, aluminum sheets.
Gas-chromatographic analyses were performed on a GC
Erba mod. 4200 apparatus. Petroleum ether corresponds
/
Elmer SCIEX mod. API III or
/
/
/
/
/
to fraction boiling at 40ꢀ60 8C.
/
The biological evaluation towards the benzodiazepine
receptors showed the tricyclic isomer mixture 5a,b,c,
having H-bond donor (OH) and acceptor (N) sites, as
well as derivative 9 did not inhibit the binding to these
receptors, probably by the steric hindrance of the phenyl
substituent in the 5 position.
Similarly the triazolo-pyrimidine isomer mixture
4a,b,c and benzylderivative 8 are lacking of activity
towards the benzodiazepine receptors.
3.1. Mixture of 1-methyl-5-phenyl-1,6-dihydro-, 2-
methyl-5-phenyl-2,6-dihydro- and 3-methyl-5-phenyl-3,6-
dihydro-1,2,3-triazolo[4,5-d]pyrimidin-7-one (2a,b,c)
To a solution of sodium methoxide, obtained by
reaction of 0.850 g (37.0 mmol) of sodium in 160 ml of
methanol, 8.00 g (37.5 mmol) of 5-phenyl-1,6-dihydro-
1,2,3-triazolo[4,5-d]pyrimidin-7-one (1) and 3.50 ml
(56.3 mmol) of methyl iodide were added and the
mixture was heated under reflux for 24 h. The solvent
was evaporated in vacuo, the residue was treated with
water and the insoluble material was collected by
filtration. The crystallization from ethanol gave 7.47 g
3. Experimental
Melting points were determined on a Kofler hot-stage
and are uncorrected. IR spectra in nujol mulls were
recorded on a Mattson Genesis series FTIR spectro-
(yield 88%) of the title mixture; m.p. 220ꢀ260 8C;
/
1H NMR in DMSO-d6: relevant signals three singlets
at 4.39, 4.37 and 4.16 d, corresponding to the N-methyl
meter. UV spectra were obtained on a PerkinꢀElmer
/

G. Biagi et al. / Il Farmaco 58 (2003) 551ꢀ
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556
555
groups; mass (m/z): 228 (MHꢂ). Anal. (C11H9N5O): C,
H, N.
treated with water and stirred for 30 min, then the
suspension was extracted with chloroform. The com-
bined extracts were washed with 10% hydrochloric acid
and water, dried (magnesium sulfate) and evaporated in
vacuo. The residue, by trituration with ethyl acetate,
gave the title mixture which was collected by filtration
and crystallized from ethanol: 1.30 g, yield: 47%; m.p.
3.2. 1-Methyl-5-phenyl-7-chloro-1H-1,2,3-triazolo[4,5-
d]pyrimidine (3a), 2-methyl-5-phenyl-7-chloro-2H-1,2,3-
triazolo[4,5-d]pyrimidine (3b) and 3-methyl-5-phenyl-7-
chloro-3H-1,2,3-triazolo[4,5-d]pyrimidine (3c)
220ꢀ
250 8C; IR (cmꢄ1): 3255 (NH), 1722 (CO). Mass
/
To a solution of 4.00 g (17.6 mmol) of 2a,b,c isomer
mixture in 80 ml of chloroform and 3 ml of DMF, 16 ml
of thionyl chloride were added and the mixture was
heated under reflux for 4 h. The solvent was evaporated
in vacuo, the residue was treated with crushed ice and
the insoluble material was collected by filtration: 3.78 g
(yield 87%) of a yellow solid consisting with the mixture
of the title compounds. The gas-chromatographic ana-
lysis showed, in the following order, three peaks with
area 28, 40 and 29%, respectively. This solid mixture was
(m/z): 314 (MHꢂ). Anal. (C14H15N7O2): C, H, N.
3.4. Mixture of 1-methyl-5-phenyl-1H-, 2-methyl-5-
phenyl-2H- and 3-methyl-5-phenyl-3H-7-hydroxy-1,2,3-
triazolo[4,5-e]1,2,4-triazolo[3,4-c]pyrimidine (5a,b,c)
A solution of 0.500 g (1.60 mmol) of 4a,b,c mixture in
15 ml of Dowtherm was heated and stirred at 130 8C for
4 hours. After cooling the precipitated solid was
collected and crystallized by DMF-water to give the
absorbed on :
chromatography through a silica gel column (20ꢃ
/
30 g of silica gel and submitted to flash-
6 cm)
title mixture: 0.320 g, yield: 75%; m.p. 320ꢀ354 8C.
/
Mass (m/z): 268 (MHꢂ). Anal. (C12H9N7O): C, H, N.
/
eluting with ethyl acetate/petroleum ether 1:4. The title
compounds were separated by elution in the following
order: 3a, 3b and 3c; after crystallization from acetoni-
trile they were characterized.
3.5. 3-Benzyl-5-phenyl-7-chloro-3H-1,2,3-triazolo[4,5-
d]pyrimidine (7)
3a: 1.010 g, yield: 23.5%; m.p. 217ꢀ
/
220 8C; TLC:
15.09 min. 1H NMR (DMSO-d6): d
To a solution of 3-benzyl-5-phenyl-3,6-dihydro-1,2,3-
triazolo[4,5-d]pyrimidin-7-one (6) [21] (0.650 g, 2.14
mmol) in 10 ml of chloroform and 1 ml of DMF, 2
mL of thionyl chloride were added and the mixture was
heated under reflux for 4 hours. The solvent was
evaporated in vacuo and the residue was treated with
crushed ice. The title compound was obtained as a white
solid which was collected by filtration and crystallized
Rfꢁ
/
0.54; GC: tRꢁ
/
8.49 (m, 2H), 7.61 (m, 3H), 4.35 (s, 3H). 13C NMR
(CDCl3, ppm): d 33.6 (CH3); 135.6, 132.1, 129.3, 128.9
(aromatics); 162.9, 153.7 (others). Mass (m/z): 246
(MHꢂ). UV: lmax
246.1 nm, log oꢁ
3b: 1.658 g, yield: 38.5%; m.p. 197ꢀ
ꢁ
/
301.9 nm, log oꢁ
3.637. Anal. (C11H8N5Cl): C, H, N.
200 8C; TLC:
15.57 min. 1H NMR (DMSO-d6): d
/
3.398; lmax
ꢁ
/
/
/
Rfꢁ
/
0.46; GC: tRꢁ
/
from benzene: 0.624 g, yield: 90%, m.p. 176ꢀ
NMR (DMSO-d6): d 8.48 (m, 2H), 7.64ꢀ7.33 (m, 8H),
6.01 (s, 2H). Mass (m/z): 321 (Mꢂ), 91 (base). UV:
lmax 275.8 nm, log oꢁ3.900; lmax 244.3 nm, log oꢁ
4.035. Anal. (C17H12N5Cl): C, H, N.
/
179 8C. 1H
8.43 (m, 2H), 7.58 (m, 3H), 4.62 (s, 3H). 13C NMR
(CDCl3, ppm): d 45.0 (CH3); 136.2, 131.8, 129.3, 128.9
(aromatics); 162.3, 160.2, 153.8 (others). Mass (m/z):
/
246 (MHꢂ). UV: lmax
247.0 nm, log oꢁ
3c: 1.060 g, yield: 24.5%; m.p. 205ꢀ
ꢁ
/
308.2 nm, log oꢁ
3.532. Anal. (C11H8N5Cl): C, H, N.
208 8C; TLC: Rfꢁ
18.11 min. H NMR (DMSO-d6): d 8.44
/3.205; lmax
ꢁ
/
ꢁ
/
/
ꢁ
/
/
/
/
/
1
0.32; GC: tRꢁ
/
3.6. 3-Benzyl-5-phenyl-7-ethoxycarbonylhydrazino-3H-
1,2,3-triazolo[4,5-d]pyrimidine (8)
(m, 2H), 7.59 (m, 3H), 4.52 (s, 3H). 13C NMR (CDCl3,
ppm): d 37.8 (CH3); 135.8, 131.7, 129.1, 128.9 (aro-
matics); 161.4 (others). Mass (m/z): 246 (MHꢂ). UV:
A mixture of chloroderivative 7 (0.450 g, 1.40 mmol),
ethyl carbazate (0.700 g, 6.73 mmol) and TEA (0.5 ml,
3.59 mmol) in 10 ml of anhydrous benzene was heated
under reflux for 19 hours. The solvent was evaporated in
vacuo, the residue was treated with 10% hydrochloric
acid and the aqueous phase was extracted repeatedly
with chloroform. The combined extracts were washed
with 10% hydrochloric acid and water, then were dried
and evaporated. The solid residue, consisting of the title
lmax
4.110. Anal. (C11H8N5Cl): C, H, N.
ꢁ
/
276.4 nm, log oꢁ
/
3.940; lmax
ꢁ
/
244.3 nm, log oꢁ
/
3.3. Mixture of 1-methyl-5-phenyl-1H-, 2-methyl-5-
phenyl-2H- and 3-methyl-5-phenyl-3H-7-
ethoxycarbonylhydrazino-1,2,3-triazolo[4,5-d]pyrimidine
(4a,b,c)
To a solution of 2.17 g (8.87 mmol) of the isomeric
mixture 3a,b,c in 60 ml of anhydrous benzene, 4.50 g
(43.60 mmol) of ethyl carbazate and 3 ml of TEA were
added and the mixture was heated under reflux for 12 h.
The solvent was evaporated in vacuo, the residue was
compound, was crystallized from methanolꢀ
0.450 g, yield: 83%, m.p. 169ꢀ
172 8C; IR (cmꢄ1):
3256, 3187 (NH), 1727 (CO).
1H NMR (DMSO-d6): d 10.52 (d, NH), 9.78 (d, NH),
8.44 (m, 2H), 7.56ꢀ7.26 (m, 8H), 5.86 (s, 2H), 4.13 (q,
/
water:
/
/

556
G. Biagi et al. / Il Farmaco 58 (2003) 551ꢀ556
/
2H), 1.26 (t, 3H). Mass (m/z): 389 (Mꢂ), 91 (base).
Anal. (C20H19N7O2): C, H, N.
[9] J.E.R. Borges, F. Fernandez, X. Garzia, A.R. Hergueta, C.
Lopez, G. Andrei, R. Snoeck, M. Witvrounw, J. Balzarini, E. De
Clercq, Novel carbocyclic nucleosides containing a cyclobutyl
ring. Guanosine and adenosine analogs, Nucleos. Nucleot. 17
3.7. 3-Benzyl-5-phenyl-7-hydroxy-1,2,3-triazolo[4,5-
e]1,2,4-triazolo[3,4-c]pyrimidine (9)
(1998) 1237ꢀ1253.
/
[10] (a) H.-D. Kummer, Phosphodiesterase inhibitors for treatment of
bladder disorders, German Patent 19,529,102 (1997).;
(b) H.-D. Kummer, Phosphodiesterase inhibitors for treatment of
bladder disorders, Chem. Abstr. 126 (1997) 152808.
A solution of 0.200 g (0.50 mmol) of 8 in 3 ml of
Dowtherm was heated under reflux (:230 8C) for 2.5
/
[11] (a) M. Grifantini, P. Franchetti, L. Cappellacci, P. La Colla, A.G.
Loi, G. Piras, Preparation of purine and 8-azapurine derivatives
for treatment of acquired immune deficiency syndrome, World
Patent 9,609,307 (1996).;
hours. After cooling the reaction mixture was diluted
with petroleum ether and stirred for 30 min. The
precipitated solid, consisting of the title compound,
was crystallized from water: 0.134 g, yield: 77%, m.p.
(b) M. Grifantini, P. Franchetti, L. Cappellacci, P. La Colla, A.G.
Loi, G. Piras, Preparation of purine and 8-azapurine derivatives
for treatment of acquired immune deficiency syndrome, Chem.
Abstr. 125 (1997) 87111.
185ꢀ
/
189 8C. 1H NMR (DMSO-d6): d 12.6 (broad, OH),
7.76ꢀ
/
7.20 (m, 10H), 5.83 (s, 2H). Mass (m/z): 343
(Mꢂ), 91 (base). Anal. (C18H13N7O): C, H, N.
[12] L. Betti, G. Biagi, G. Giannaccini, I. Giorgi, O. Livi, A.
Lucacchini, C. Manera, V. Scartoni, Novel 3-aralkyl-7-aminosub-
stituted 1,2,3-triazolo[4,5-d]pyrimidines with high affinity towards
A1 adenosine receptors, Eur. J. Med. Chem. 34 (1999) 867ꢀ875.
/
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