A general approach toward the synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines

Article abstract of DOI:10.1016/S0040-4039(02)02661-8

An expedient synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines was developed by treating 8-amino-4-[N-(4-aminophenyl)-N-(methyl)amino]pyrazolo[1,5-a]-1,3,5-triazine with various acyl chlorides following by the displacement of the so-formed N-(methyl

Full text of DOI:10.1016/S0040-4039(02)02661-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 703–705
A general approach toward the synthesis of 8-acylamido-
pyrazolo[1,5-a]-1,3,5-triazines
Pierre Raboisson,a,* Dominique Schultz,a Claire Lugnier,b Romain Mathieua and
Jean-Jacques Bourguignona
aLaboratoire de Pharmacochimie de la Communication Cellulaire (CNRS, UMR 7081), Faculte´ de Pharmacie, 74 route du Rhin,
BP24, 67401 Illkirch Cedex, France
bLaboratoire de Pharmacologie et de Physico-Chimie des Interactions Cellulaires et Mole´culaires (CNRS, UMR 7034),
Faculte´ de Pharmacie, 74 route du Rhin, BP24, 67401 Illkirch Cedex, France
Received 1 November 2002; accepted 22 November 2002
Abstract—An expedient synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines was developed by treating 8-amino-4-[N-(4-
aminophenyl)-N-(methyl)amino]pyrazolo[1,5-a]-1,3,5-triazine with various acyl chlorides following by the displacement of the
so-formed N-(methyl)-N-[4-(acylamido)phenyl]amino leaving group with various amines. Applications to high-throughput synthe-
sis are suggested. © 2003 Elsevier Science Ltd. All rights reserved.
Pyrazolo[1,5-a]-1,3,5-triazines substituted in position 8
have attracted considerable interest from the medicinal
chemist community over the past few years because of
their wide range of biological activities.1 Within our
current research program on the synthesis and pharma-
cological evaluation of a variety of structurally related
9-substituted adenines as phosphodiesterase type 4
(PDE4) inhibitors2 and P2Y1-receptor antagonists3 we
became interested in bioisosteric replacement of the
purine ring that would provide increased in vivo stabil-
ity compared to the parent adenines 13 and 3.2
ido-4-(N-butylamino)-2-methylpyrazolo[1,5-a]-1,3,5-tri-
azine (4, Fig. 1), described in the literature.5 This
compound was obtained through a route that is not
readily amenable to synthesis of N4-substituted deriva-
tives in a parallel fashion. The synthesis started from a
N4-pre-substituted pyrazolotriazine, which was nitrated
selectively at position 8, followed by the reduction of
the nitro group and a subsequent acylation.5 Following
this procedure would require additional steps to intro-
duce substituents in position 4 resulting in a long
synthetic route and losses in yields. These drawbacks
We have recently reported the synthesis of the 8-(2%-
deoxy-b-D-ribofuranosyl)-2-methyl-4-(N-methylamino)-
pyrazolo[1,5-a]-1,3,5-triazine-3%,5%-bisphosphate (2), a
potent and selective P2Y1-receptor antagonist, which
possesses prolonged in vivo anti-aggregating properties
compared to those of compound 1.4 In view of this
promising result, we decided to apply the same syn-
thetic strategy to the synthesis of C-analogs of 9-substi-
tuted N6-methyladenines 3 as PDE4 inhibitors. To the
best of our knowledge, there is only one example of
8-acylamidopyrazolo[1,5-a]-1,3,5-triazine, the 8-acetam-
Keywords: pyrazolo[1,5-a]-1,3,5-triazine; adenine; bioisoster; activat-
ing group.
* Corresponding author. Present address: Department of Chemistry,
3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Exton,
PA 19341, USA. E-mail: pierreraboisson@aol.com
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02661-8

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P. Raboisson et al. / Tetrahedron Letters 44 (2003) 703–705
Scheme 1. Reagents and conditions: (a) HNO3, 0°C, 10 min; (b) H2–Pd/C, MeOH; (c) acyl chloride, TEA, CH2Cl2, 0°C; (d)
R2R3NH, THF/EtOH, 80–110°C, 2–18 h, sealed tube; (e) NH2CH3, EtOH, 110°C, 10 h.
would limit the scope of this synthesis and point to a
need for an improved method which permits an easy
and rapid access to a large number of derivatives.
Therefore, we sought to find an attractive methodology
which employed an activating group at position 4 that
could be readily displaced by various amines at the final
step of the synthesis and that offers the necessary
stability to permit the introduction of the acylamido
moiety at position 8.
Then, the displacement of the 4-substituted NMNPA
leaving groups (intermediates 6–8) was investigated
using methylamine as a typical nucleophile amine
(Table 1).
As seen previously with compound 5,4 the conversion
of intermediates 6 and 8 to the targets compounds 9
required extended reaction times at room temperature
presenting a drawback for an expedient preparation of
4-substituted derivatives, the reaction times could how-
ever be shortened to 2–18 h by running the reaction in
a sealed tube at a temperature between 80 and 110°C.8
As expected, the rate of the displacement of the
NMNPA group appeared to be highly dependent on
the substitutions at both position 8 and at the para
position of the phenyl ring: the more electron poor the
system, the faster it reacted. Thus, the order of reactiv-
ity was found to be NO2>H>NHCOR2>>>NH2, conse-
quently the displacement of the diamino derivative 7
was the most challenging, and even in a sealed tube at
110°C, we were unable to achieve significant conversion
of 7 to the target compound 9b (Table 1). In all other
cases (compounds 5, 6 and 8), the NMNPA groups
could be readily displaced with various amines and
therefore opens up access to a wide variety of N-4
Recently, we have reported the use of the N-methyl-N-
phenylamino (NMNPA) group as an optimized activat-
ing group, which possesses a number of favorable
characteristics including stability, ease of handling and
versatile reactivity.4 Thanks to its low pKa (ca. 3.0),
simple treatment of 4-(NMNPA)pyrazolo[1,5-a]-1,3,5-
triazines (e.g. 5) with an amine, either at reflux or in a
sealed tube, results in a facile displacement of the
NMNPA group, allowing for the synthesis of a variety
of N4-substituted analogs. Thus encouraged, we envi-
sion to use this activating group for the synthesis of
8-acylamidopyrazolotriazine 9c–h.
This paper features the first general method for the
synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines
substituted at position 4 (Scheme 1), which is also
applicable on both a parallel fashion and on a multi-
gram scale reaction. This methodology is based on a
di-acylation of the diamino derivative 7 followed by the
displacement of the so-formed 4-acylated NMNPA
group leading to the target final compounds 9c–h.6–8
Table 1. Synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-
triazines6–8
Compound
R1
R2
R3
Yield (%)a
104
9a
9b
9c
9d
9e
9f
H
NO2
NH2
NHCOCH3
NHCOCH3
NHCOCH3
NHCOCH3
NHCOPh
NHCOCH2Ph
CH3
CH3
CH3
H
CH3
CH3
–(CH2)4–
CH3
CH3
H
H
H
H
H
CH3
78c
86b
0c
As outlined in Scheme 1, treatment of 5 with fuming
nitric acid, afforded the dinitro compound 6 as the
major product in 85% isolated yield after a single
recrystallization from ethanol/ether.6 Palladium-cata-
lyzed hydrogenation afforded the diamino derivative 7,7
which was used as the starting material for the synthesis
of 8-acylamidopyrazolotriazines 9c–h. Acylation of 7
using 2.2 equiv. of acylchloride at 0°C, quantitatively
afforded the target diacylamido derivatives 8a–c (the
total conversion of 7 to 8 was monitored by HPLC).8
83c
81c
86c
91c
92c
88c
9g
9h
H
H
a Yields of isolated products.
b Method A: CH3NH2, THF/EtOH, 80°C, 2 h, sealed tube.
c Method B: R2R3NH, THF/EtOH, 110°C, 5–18 h, sealed tube.

P. Raboisson et al. / Tetrahedron Letters 44 (2003) 703–705
705
substituted 8-acylamido derivatives. No column chro-
matography was required and the final compounds 9a,
9c–h and 10 were generally obtained in high purity after
razolo[1,5-a]-1,3,5-triazine (6). A solution of 2-methyl-4-
(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine 5
(2.39 g, 10 mmol) in fuming nitric acid (18 mL) was stirred
at 0°C for 10 min. Then, the reaction mixture was diluted
with cold water (150 mL). The yellow precipitate was
filtered, then successively washed with cold water (2×10
mL), methanol (2×3 mL) and finally with diethyl ether.
Recrystallization from ethanol and diethyl ether yielded
compound 6 (2.7 g, 85%) as slightly yellow, crystalline
a
single recrystallization. Therefore, the process
becomes even more attractive for parallel and large-
scale applications when we found that it could be run at
high concentration without sacrificing yield.
In summary, we have developed a rapid, practical and
1
efficient procedure for the synthesis of 8-acylamido-
solid. Mp 256°C. H NMR (300 MHz, CDCl3) l 2.74 (s,
pyrazolo[1,5-a]-1,3,5-triazine
derivatives.6–8
The
3H, CH3), 3.83 (s, 3H, CH3), 7.38 (d, J=8.7 Hz, 2H,
ArH), 8.28 (s, 1H, 7-H). 13C NMR (300 MHz, DMSO-d6)
l 26.7, 42.4, 121.8, 125.0, 127.8, 142.2, 146.4, 148.1, 149.6,
150.2, 169.5. MS: (m/z)=330 (M+H)+. Anal. calcd for
C13H11N7O4: C, 47.42; H, 3.37; N, 29.78. Found: C, 47.56;
H, 3.54; N, 29.79.
impetus for this work was the easy access to the 8-
amino-4-[N-(4-aminophenyl)-N-(methyl)amino]pyra-
zolo[1,5-a]-1,3,5-triazine 7,7 which was used as the start-
ing material in a tandem of reactions involving: (i) the
diacylation of both amino moieties with a acyl chloride
and (ii) the displacement of the so-formed N-[4-
(acylamido)phenyl]-N-(methyl)amino activating group
with various amines at the end of the reaction that
represents a concise and general route for the introduc-
tion of substitutions and functionalities at the 4-posi-
tion.8 Another main advantage for this procedure is the
opening potentiality to use this strategy in a multi-gram
scale synthesis or in a parallel fashion. This novel series
of compounds are currently under biological evaluation
for their phosphodiesterase inhibition properties.
7. 8-Amino-4-[N-(4-aminophenyl)-N-methylamino]pyrazolo-
[1,5-a]-1,3,5-triazine (7). A mixture of 6 (600 mg, 1.8
mmol) and 10% Pd/C (100 mg) in absolute methanol (200
mL) was shaken in a hydrogenation apparatus at rt for 2
h. The catalyst was removed by filtration, washed with
water and the filtrate was concentrated to dryness. Recrys-
tallization from diethyl ether yielded 7 (333 mg, 68%) as
yellow solid. Mp 166°C. 1H NMR (200 MHz, CDCl3) l
2.54 (s, 3H, CH3), 3.66 (s, 3H, CH3), 6.68 (d, J=8.6 Hz,
2H, 2 ArH), 7.08 (d, J=8.6 Hz, 2H, 2 ArH), 7.50 (s, 1H,
7-H). MS: (m/z)=270 (M+H)+. Anal. calcd for C13H15N7:
C, 57.98; H, 5.61; N, 36.41. Found: C, 57.88; H, 5.58; N,
36.63.
Acknowledgements
8. 8-Acetamido-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-
1,3,5-triazine (9d). Acetyl chloride (47 mL, 0.66 mmol) was
slowly added, at 0°C, to a stirred solution of 7 (80 mg,
0.30 mmol) in anhydrous dichloromethane (7 mL). Then,
triethylamine (96 mL, 0.69 mmol) was added and stirring
was continued for 5 min at 0°C. The reaction mixture was
allowed to warm up to rt, diluted with ethyl acetate (15
mL), then washed with water (5 mL) and saturated sodium
bicarbonate (2 mL), dried (Na2SO4) and concentrated to
dryness under reduced pressure. The residue (crude 8b)
was dissolved in ethanol (5 mL) and a methylamine (1 M
in EtOH, 2 mL) was added and the reaction mixture was
stirred at 110°C in a sealed tube for 8 h. After cooling to
rt, the mixture was taken up with ice-cooled water (10 mL)
and extracted with ethyl acetate (3×10 mL). The organic
layer was dried (Na2SO4) and concentrated to dryness
under reduced pressure. The residue was triturated in
diethyl ether and filtered. Recrystallization from ethanol/
diethyl ether afforded 9d as colorless, crystalline solids
Support from the Louis Pasteur University is gratefully
acknowledged.
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