Sep-Oct 2002
New 1,2,3-Triazolo[4,5-e]1,2,4-triazolo[4,3-c]pyrimidine Derivatives II
887
Table
2
for 2.5 hours. After cooling, the title compounds precipitated and
were collected by filtration (Table 1).
1
H-NMR Data of 3a-d and 6a-d
3-(2-Fluorobenzyl)-7-substituted-1,2,3-triazolo[4,5-e]1,2,4-tria-
zolo[4,3-c]pyrimidines (6a-d).
H-5
(s, 1H)
CH
(s, 2H)
3-substituent
7-substituent
2
(m, 4H)
'
A solution of 2.50 mmoles of the suitable hydrazido derivative
(5a, 5b, 5c or 5d) in 20 mL of Dowtherm was heated under reflux
(» 230 °C) for 2 hours. After cooling, petroleum ether was added
to the solution, which caused precipitation of a solid product.
This solid, collected by filtration, was extracted with boiling
petroleum ether portions. For the purification of compounds 6a
and 6d the solid was crystallized from ethanol (Table 1) while for
that of compounds 6b and 6c the solid was flash-chro-
matographed through a silica gel column (Table 1).
3a
3b
3c
3d
6a
6b
6c
6d
9.88
9.95
9.86
9.75
9.89
9.95
9.85
9.74
6.08
6.10
6.08
6.06
6.05
6.06
6.04
6.02
7.22-7.62
7.28-7.59
7.30-7.58
7.30-7.59
7.16-7.52
7.15-7.52
7.17-7.51
7.15-7.50
7.60 and 8.31 (m, 5H)
8.20 and 8.84 (d, d, 4H)
6.79, 7.36 and 7.42 (m, 3H)
2.60 (s, 3H)
7.60 and 8.30 (m, 5H)
8.20 and 8.84 (d, d, 4H)
6.78, 7.39 and 7.70 (m, 3H)
2.59 (s, 3H)
towards the adenosine A and A receptors, resulted
lacking in activity.
1
2A
3-(2-Chlorobenzyl)-7-mercapto-1,2,3-triazolo[4,5-d] pyrimidine
(7a) and 3-(2-Fluorobenzyl)-7-mercapto-1,2,3-triazolo[4,5-d]
pyrimidine (7b).
EXPERIMENTAL
A mixture of 7.00 mmoles of the appropriate chloroderivative
(1 or 4) and 1.60 g (21 mmoles) of thiourea in 60 mL of methanol
was heated under reflux for 25 minutes. The solution was evapo-
rated in vacuo and the residue was stirred with 0.5 N sodium
hydroxide. The insoluble material was filtered off and the filtrate
was acidified (pH 4) with acetic acid to precipitate the title com-
pounds which were collected by filtration and washed with
ethanol (Table 1).
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 spectrometer. Mass spectra were performed
with a Hewlett Packard MS/System 5988 A. 1H-nmr spectra were
recorded with a Varian Gemini 200 spectrometer in DMSO-d6 in d
units, using TMS as internal standard. Elemental analyses (C,H,N)
were performed on a Carlo Erba Elemental Analyzer Mod. 1106
apparatus. Petroleum ether corresponds to fraction boiling at 40-60
°C. Hydrazine hydrate 99% is a very toxic and dangerous reagent
that requires an appropriate personal protection.
3-(2-Chlorobenzyl)-7-methylthio-1,2,3-triazolo[4,5-d] pyrimi-
dine (8a) and 3-(2-Fluorobenzyl)-7-methylthio-1,2,3-tria-
zolo[4,5-d] pyrimidine (8b).
To a solution of 7.20 mmoles of the suitable mercapto deriva-
tive (7a or 7b) in 20 mL of 1 N sodium hydroxide, 0.58 mL (9.30
mmol) of methyl iodide were added and the mixture was stirred
at room temperature for 20 minutes. The title compounds precip-
itated as solids which were collected by filtration and washed
with water (Table 1).
Hydrazides.
The employed hydrazides, all described in the literature, were
prepared in the usual manner by reaction of the suitable methyl
or ethyl ester with 99% hydrazine hydrate: benzoic [7], isonico-
tinic [8], 2-furoic [9], acetic [10] and p-nitrobenzoic [11].
3-(2-Chlorobenzyl)-7-hydrazido-1,2,3-triazolo[4,5-d]pyrim-
idines (2a-e).
3-(2-Chlorobenzyl)-7-hydrazino-1,2,3-triazolo[4,5-d]pyrimidine
(9a) and 3-(2-Fluorobenzyl)-7-hydrazino-1,2,3-triazolo[4,5-d]
pyrimidine (9b).
A mixture of 1.100 g (3.93 mmol) of the chloroderivative 1,
7.86 mmoles of the suitable hydrazide (39 mmol for 2d) and 1.10
mL (7.86 mmol) of TEA in 35 mL of absolute ethanol, was
heated under reflux for 2.5 hours (16 hours for 2d). After cooling
the title compounds precipitated and were collected by filtration
(Table 1).
A suspension of 1.70 mmoles of the suitable methylthio deriv-
ative (8a or 8b) in 15 mL of methanol was heated to boiling point
until complete solution. Hydrazine hydrate (99%, 1.20 mL, 25
mmol) was added to the hot solution and the reaction mixture was
stirred and left to cool at room temperature (» 30-40 minutes).
The title compounds precipitated as crystalline solids which were
collected and washed with methanol (Table 1).
3-(2-Chlorobenzyl)-7-substituted-1,2,3-triazolo[4,5-e]1,2,4-
triazolo[4,3-c]pyrimidines (3a-d).
Acknowledgment.
A solution of 2.00 mmoles of the suitable hydrazido derivative
(2a, 2b, 2c or 2d) in 20 mL of Dowtherm was heated under reflux
(» 230 °C) for 2 hours. After cooling, petroleum ether was added
to the solution, which caused precipitation of a solid product.
This solid, collected by filtration, was extracted with boiling
petroleum ether portions. Compound 3a was further purified by
crystallization (Table 1) while compounds 3b-d were purified by
flash-chromatography through a silica gel column (Table 1).
We thank Dr. Laura Betti and Dr. Maria Letizia Trincavelli of
the Psychiatry, Neurobiology, Pharmacology and Biotechnology
Department, Pisa University, for the biological test evaluation.
REFERENCES AND NOTES
[1] G. Biagi, I. Giorgi, O. Livi, C. Manera and V. Scartoni, J.
Heterocyclic Chem., 36, 1195 (1999).
[2] G. Biagi, I. Giorgi, O. Livi, C. Manera and V. Scartoni, J.
Heterocyclic Chem., 34, 65 (1997).
[3] G. Biagi, I. Giorgi, O. Livi, C. Manera, V. Scartoni, A.
Lucacchini and G. Senatore, Farmaco., 51, 601(1996).
3-(2-Fluorobenzyl)-7-hydrazido-1,2,3-triazolo[4,5-d]-
pyrimidines (5a-e).
A mixture of 0.880 g (3.34 mmol) of the chloroderivative 4,
6.68 mmoles of the suitable hydrazide and 0.93 mL (6.68 mmol)
of TEA in 20-25 mL of absolute ethanol, was heated under reflux
Biagi, Giuliana
