Synthesis of novel pyrazolopyrrolopyrazines, potential analogs of sildenafil

Article abstract of DOI:10.1002/jhet.5570380506

Synthesis of novel pyrazolopyrrolopyrazines is herein described with the aim to reach new specific PDE-5 inhibitors of potential clinical interest in male erectile dysfunction.

Full text of DOI:10.1002/jhet.5570380506

Sep-Oct 2001
Synthesis of Novel Pyrazolopyrrolopyrazines,
Potential Analogs of Sildenafil
1045
Marina Kopp, Jean-Charles Lancelot, Patrick Dallemagne*, and Sylvain Rault
Centre d'Etudes et de Recherche sur le Médicament de Normandie
5, rue Vaubénard, 14032 Caen, France
Received May 2, 2001
Synthesis of novel pyrazolopyrrolopyrazines is herein described with the aim to reach new specific PDE-
5 inhibitors of potential clinical interest in male erectile dysfunction.
J. Heterocyclic Chem., 38, 1045 (2001).
Scheme 2
Sildenafil [1] (1, VIAGRA®, Scheme 1) is a potent
inhibitor of phosphodiesterase type 5 (PDE 5) [2] whose
effectiveness in treating male erectile dysfunction was
recently discovered. PDE5 is the primary cGMP hydrol-
yzing enzyme present in the corpus cavernosal smooth
muscle of the penis. Upon sexual stimulation, nitric oxyde
(NO) is released and activates guanylyl cyclase which pro-
duces cGMP [3]. The latter initiates a protein phosphoryla-
tion cascade that causes a decrease in intracellular calcium,
resulting in vasorelaxation. Inhibition of PDE5 by silde-
nafil elevates levels of cGMP and hence leads to an
improved erection. Despite the efficacy of 1, clinically
notable adverse effects such as headache, nausea, cuta-
neous flushing and visual disturbance [4,5] have been
noted with its use and attributed to its limited selectivity
against other PDE enzymes. Thus, with the aim to reach
more selective PDE5 inhibitors, devoid of such side
effects, this paper describes the access to new Sildenafil
analogs 2, belonging to the pyrrolopyrazine series, which
were prepared in order to study the replacement of the
pyrimidone moiety with a pyridopyrazine system.
Weinstock-Curtius rearrangement [12] in a refluxing aque-
ous hydrochloric acid solution. The sequence afforded
finally the hydrochloric acid salts of the attempted
1-methyl-, 1-ethyl- and 1-(4-methoxyphenyl)-4-amino-5-
pyrrolylpyrazoles 3a-c, with overall yields of 17%, 67%
and 31% respectively from 4a-c.
Access to the more closely related analog of Sildenafil
2d required the preparation of 1-methyl-3-propyl-4-
amino-5-(pyrrol-1-yl)pyrazole 3d (Scheme 3). The latter
was synthesized according to another pathway [13] start-
ing from diethyloxalate and pentan-2-one that were
reacted together in the presence of sodium to give the dike-
toester 8, under its enolic form. Treatment of 8 with
methylhydrazine produced a mixture of the suitably substi-
tuted pyrazole derivative 9 and of its isomer 9a (60/40).
The saponification in an alkaline medium led to a mixture
of the carboxylic acids 10 and 10a, from which 10 was iso-
lated by fractional crystallization. The subsequent nitration
of the pyrazole ring of 10 yielded the nitro derivative 11
that was, as above, involved in a Curtius rearrangement to
give the intermediate 13. A Clauson-Kaas reaction, fol-
lowed by a catalytic hydrogenation using hydrogen and
Compounds 2 were prepared according to a Pictet-
Spengler-type reaction [6] starting from various 4-amino-
5-pyrrolylpyrazoles 3 substituted or not in the 3-position.
The unsubstituted ones were synthesized according to
the following sequence (Scheme 2). Treatment of ethyl
(ethoxymethylene)cyanoacetate with an appropriate
N-substituted hydrazine yielded the expected ethyl
5-aminopyrazole-4-carboxylates [7,8] 4a-c. Compounds
4a-c, involved in a Clauson-Kaas reaction [9,10,11], fol-
lowed by an alkaline hydrolysis, led to the 5-pyrrolylpyra-
zole-4-carboxylic acids 6a-c [11]. The latter were con-
verted into the acyl azides 7a-c before being submitted to a

1046
M. Kopp, J.-C. Lancelot, P. Dallemagne, and S. Rault
Vol. 38
Biological evaluation of 2a-d demonstrated that they are
10 fold less potent than Sildenafil to inhibit PDE5.
EXPERIMENTAL
Commercial reagents were used as received without additional
purification. Melting points were determined on a Kofler melting
point apparatus and are uncorrected. IR spectra were taken with a
1
Genesis Series FTIR spectrometer. H NMR (400 MHz) were
recorded on a JEOL Lambda 400 Spectrometer. Chemical shifts
are expressed in parts per million downfield from tetramethylsi-
lane as an internal standard. Elemental analyses for new com-
pounds were performed at the "Institut de Recherche en Chimie
Organique Fine" (Rouen).
General Procedure for the Preparation of Ethyl 5-Amino-1H-
pyrazole-4-carboxylates (4a-c).
To a solution of ethyl (ethoxymethylene)cyanoacetate (20 g,
142 mmoles) in ethanol (100 ml), was added the N-substituted
hydrazine (142 mmoles). The resulting mixture was refluxed for
12 hours then the solvent was evaporated under reduced pressure
to give 4a, 4b and 4c in 86%, 99% and 86% yield respectively.
palladium on charcoal, finally converted 13 into 3d,
obtained in a global yield of 23% starting from 8.
The Pictet-Spengler preparation of 2a-d was achieved
starting from 3a-d by reaction with 2-ethoxy-5-[(4-
methylpiperazin-1-yl)sulfonyl]benzaldehyde [14,15]
(Scheme 4). The reaction was carried on in refluxing
ethanol starting either from the ammonium salts 3a,b,
from the free base 3d or previously displaced from 3c
with sodium hydrogen carbonate, in the presence of
hydrochloric (for 3c) or hydrobromic (for 3d) acid. Titled
compounds 2a-d were obtained with yields ranging from
15% to 71%).
Ethyl 5-Amino-1-methyl-1H-pyrazole-4-carboxylate (4a) [8].
This compound was obtained as a yellow powder (20.66 g, 122
mmoles, diethyl ether/hexane 60/40) starting from methylhy-
drazine (6.34 g), mp 98 °C, ir: 1682 (C=O), 1307 (C-O), 3400
-1
1
(NH) cm ; H nmr (DMSO-d ): δ 1.24 (t, J = 7.12 Hz, 3H,
6
CH ), 3.52 (s, 3H, CH ), 4.17 (q, J = 7.12 Hz, 2H, CH ), 5.16 (s,
3
3
2
2H, NH ), 7.50 (s, 1H, H3) ppm.
2
Ethyl 5-Amino-1-phenyl-1H-pyrazole-4-carboxylate (4b) [8].
This compound was obtained as a yellow powder (32.81 g, 142
mmoles, diethyl ether) starting from phenylhydrazine (15.35 g),
-1
1
mp 100 °C, ir: 1690 (C=O), 1285 (C-O), 3400 (NH) cm ; H
nmr (DMSO-d ): δ 1.26 (t, J = 7.16 Hz, 3H, CH ), 4.21 (q, J =
6
3

Sep-Oct 2001
Synthesis of novel Pyrazolopyrrolopyrazines, Potential Analogs of Sildenafil
1047
7.16 Hz, 2H, CH ), 6.33 (s, 2H, NH ), 7.54 (s, 5H, phenyl), 7.71
(s, 1H, H3) ppm.
which precipitated progressively with addition of an 37% aque-
ous hydrochloric acid solution was collected by filtration to give
6a, 6b and 6c in 97%, 94% and 82% yield respectively.
2
2
Ethyl 5-Amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carbox-
ylate (4c) [8].
1-Methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic Acid (6a) [11].
This compound was obtained as a yellow powder (31.9 g, 122
mmoles, diethyl ether) starting from 4-(methoxy-
phenyl)hydrazine (19.62 g), mp 110 °C, ir: 1685 (C=O), 1255
This compound was obtained as a beige powder (16.92 g, 88
mmoles, acetonitrile) starting from 5a (19.70 g), mp 198 °C, ir:
-1
1
2955 (OH), 1720 (C=O) cm ; H nmr (DMSO-d ): δ 2.5 (b s,
6
-1
1
1H, OH), 3.56 (s, 3H, CH ), 6.27 (s, 2H, Hβ pyrrole), 7.00 (s,
(C-O), 3425 (NH) cm ; H nmr (DMSO-d ): δ 1.25 (t, J = 7.16
3
6
2H, Hα pyrrole), 7.89 (s, 1H, H3) ppm.
Hz, 3H, CH ), 3.80 (s, 3H, OCH ), 4.21 (q, J = 7.16 Hz, 2H,
3
3
CH ), 6.18 (s, 2H, NH ), 7.05 (d, J = 7.9 Hz, 2H, H3' and H5'),
7.41 (d, J = 7.9 Hz, 2H, H2' and H6'), 7.71 (s, 1H, H3) ppm.
2
2
1-Phenyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic Acid (6b) [11].
This compound was obtained as a beige powder (21.50 g, 85
General Procedure for the Preparation of Ethyl 5-Pyrrol-1-yl-1H-
pyrazole-4-carboxylates (5a-c).
mmoles, acetonitrile) starting from 5b (25.30 g), mp 185 °C, ir:
-1
1
3480 (OH), 1695 (C=O) cm ; H nmr (DMSO-d ): δ 2.5 (b s,
6
1H, OH), 6.16 (s, 2H, Hβ pyrrole), 6.96 (s, 2H, Hα pyrrole),
7.11 (m, 2H, phenyl), 7.36 (m, 3H, phenyl), 8.16 (s, 1H, H3)
ppm.
To a solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (4a-
c) (58 mmoles) in acetic acid (70 ml), was added dropwise 2,5-
dimethoxytetrahydrofurane (58 mmoles). The resulting mixture
was refluxed for 3 hours and acetic acid was evaporated under
reduced pressure. The oily residue was neutralised with sodium
hydrogen carbonate then was extracted with diethyl ether (2 x
500 ml). The organic layers were collected, dried over magne-
sium sulfate and the solvent was evaporated under reduced pres-
sure to give 5a, 5b and 5c in 85%, 90% and 94% yield respec-
tively.
1-(4-Methoxyphenyl)-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic
Acid (6c) [11].
This compound was obtained as a beige powder (20.90 g, 74
mmoles, acetonitrile) starting from 5c (28.00 g), mp 174 °C, ir:
-1
1
3402 (OH), 1686 (C=O) cm ; H nmr (DMSO-d ): δ 2.5 (b s,
6
1H, OH), 3.77 (s, 3H, OCH ), 6.20 (s, 2H, Hβ pyrrole), 6.87 (s,
3
2H, Hα pyrrole), 6.90 (d, J = 7.8 Hz, 2H, H3' and H5'), 7.05 (d,
J = 7.8 Hz, 2H, H2' and H6'), 8.17 (s, 1H, H3) ppm.
Ethyl 1-Methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylate (5a)
[11].
General Procedure for the Preparation of 5-Pyrrol-1-yl-1H-pyra-
zole-4-carboxylic Azides (7a-c).
This compound was obtained as a beige powder (11.01 g, 50
mmoles, cyclohexane) starting from 4a (9.81 g), mp 87 °C, ir:
-1 1
To a solution of carboxylic acid 6 (52 mmoles) in acetone (300
mL), cooled at 0 °C (ice-salt bath) was added triethylamine (7.3
ml, 52 mmoles). While maintaining the temperature at 0 °C, ethyl
chloroformate (4.97 ml, 52 mmoles) was then added slowly. The
mixture was stirred for 30 minutes at 0 °C and then a solution of
sodium azide (3.38 g, 52 mmoles) in water (10 ml) was added
dropwise. The mixture was stirred at 0°C for 1 hour, the precipitate
was filtered and the solvent was removed under reduced pressure
at room temperature. The solid residue was dissolved in diethyl
ether, filtered and evaporation of the solvent at room temperature
afforded the azides 7a, 7b and 7c in 72%, 91% and 78% yield
respectively. The latter were used without further purification.
1693 (C=O), 1514 (C=C), 1235 (C-O) cm ; H nmr (DMSO-d ):
6
δ 1.20 (t, J = 7.08 Hz, 3H, CH ), 3.67 (s, 3H, CH ), 4.17 (q, J =
3
3
7.08 Hz, 2H, CH ), 6.38 (s, 2H, Hβ pyrrole), 6.79 (s, 2H, Hα
2
pyrrole), 7.95 (s, 1H, H3) ppm.
Ethyl 1-Phenyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylate (5b)
[11].
This compound was obtained as a beige powder (14.60 g, 52
mmoles, diethyl ether) starting from 4b (13.40g), mp 113 °C, ir:
-1 1
1720 (C=O), 1605 (C=C), 1235 (C-O) cm ; H nmr (DMSO-d ):
6
δ 1.14 (t, J = 7.08 Hz, 3H, CH ), 4.13 (q, J = 7.08 Hz, 2H, CH ),
3
2
6.18 (s, 2H, Hβ pyrrole), 6.85 (s, 2H, Hα pyrrole), 7.13 (m, 2H,
phenyl), 7.37 (m, 3H, phenyl), 8.21 (s, 1H, H3) ppm.
1-Methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic azide (7a).
Ethyl 1-(4-Methoxyphenyl)-5-pyrrol-1-yl-1H-pyrazole-4-car-
boxylate (5c) [11].
This compound was obtained as a white powder (8.15 g, 38
mmoles) starting from 6a (9.90 g), mp 62 °C, ir: 2140 (N ), 1688
3
-1
1
(C=O) cm ; H nmr (DMSO-d ): δ 3.34 (s, 3H, CH ), 6.32 (s,
This compound was obtained as a beige powder (16.90 g, 54
6
3
2H, Hβ pyrrole), 7.07 (s, 2H, Hα pyrrole), 8.00 (s, 1H, H3) ppm.
1-Phenyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic azide (7b).
This compound was obtained as a white powder (14.70 g, 47
mmoles, acetonitrile), starting from 4c (15.15 g), mp 140 °C, ir:
-1 1
1720 (C=O), 1605 (C=C), 1235 (C-O) cm ; H nmr (DMSO-d ):
6
δ 1.17 (t, J = 6.96Hz, 3H, CH ), 3.77 (s, 3H, OCH ), 4.16 (q, J =
3
3
6.96Hz, 2H, CH ), 6.20 (s, 2H, Hβ pyrrole), 6.87 (s, 2H, Hα pyr-
2
mmoles) starting from 6b (13.17 g), mp 112 °C, ir: 2139 (N ),
role), 6.91 (d, J = 7.9 Hz, 2H, H3' and H5'), 7.08 (d, J = 7.9 Hz,
2H, H2' and H6'), 8.20 (s, 1H, H3) ppm.
3
-1
1
1694 (C=O) cm ; H nmr (DMSO-d ): δ 6.20 (s, 2H, Hβ pyr-
6
role), 6.86 (s, 2H, Hα pyrrole), 7.14 (m, 2H, phenyl), 7.38 (m,
3H, phenyl), 8.25 (s, 1H, H3) ppm.
General Procedure for the Preparation of 5-Pyrrol-1-yl-1H-pyra-
zole-4-carboxylic acids (6a-c).
1-(4-Methoxyphenyl)-5- pyrrol-1-yl 1H-pyrazole-4-carboxylic
azide (7c).
To a solution of ethyl 5-pyrrol-1-yl-1H-pyrazole-4-carboxylate
5a-c (90 mmoles) in ethanol (100 ml), was added an 10% aque-
ous potassium hydroxide solution (160 ml). The reaction mixture
was refluxed for 1.5 hours then was cooled at room temperature
over night. Ice and water (300 ml) were added. The beige solid
This compound was obtained as a white powder (13.80 g, 40
mmoles) starting from 6c (14.75 g), mp 99 °C, ir: 2140 (N ),
3
-1
1
1669 (C=O) cm ; H nmr (DMSO-d ): δ 3.79 (s, 3H, OCH ),
6
3

1048
M. Kopp, J.-C. Lancelot, P. Dallemagne, and S. Rault
Vol. 38
6.30 (s, 2H, Hβ pyrrole), 6.68 (s, 2H, Hα pyrrole), 6.85 (d, J =
9 Hz, 2H, H3' and H5'), 7.03 (d, J = 9 Hz, 2H, H2' and H6'), 8.11
(s, 1H, H3) ppm.
1H, OH), 2.48 (t, J = 7.44 Hz, 2H, CH ), 4.33 (t, J = 6.96 Hz,
2
2H, CH ), 6.37 (s, 1H, CH) ppm.
2
1-Methyl-3-propyl-1H-pyrazole-5-carboxylic Acid (10) and 1-
Methyl-5-propyl-1H-pyrazole-3-carboxylic Acid (10a).
General Procedure for the Preparation of 4-Amino-5-pyrrol-1-yl-
1H-pyrazole, Hydrochloride (3a-c).
To a solution of 8 (90.93 g, 490 mmoles) in dichloromethane
(750 ml), was added methylhydrazine (24.5 ml, 490 mmoles) at 0
°C for one hour. The reaction mixture was left at room tempera-
ture overnight and then refluxed for the same time. The solvent
was evaporated, water was added and the organic layer was
extracted with ethyl acetate (2 x 500 ml) to yield, after evapora-
tion, a mixture of 9 and 9a as a white powder that was refluxed
for 4 hours with an aqueous sodium hydroxide solution (5%, 500
ml). After cooling, the solution was acidified with an 10 N aque-
ous hydrochloric acid solution. The yellow precipitate was fil-
tered, then stirred at room temperature in diethyl ether (100 ml)
and finally filtered once again to give 10 as a white powder in
54% yield (44.36 g, 264 mmoles), mp 112 °C, ir: 3470-2430
To a 10 N boiling aqueous hydrochloric acid solution (10 ml),
was added 5-pyrrol-1-yl-1H-pyrazole-4-carboxylic azide 7a-c.
The mixture was refluxed for 10 minutes. After cooling at room
temperature, the hydrochloride salts 3a, 3b, 3c precipitated from
the reaction mixture in 32%, 88% and 60% yield respectively.
4-Amino-1-methyl-5-pyrrol-1-yl-1H-pyrazole, Hydrochloride
(3a).
This compound was obtained as a white powder (0.6 g, 3
mmoles, ethanol) starting from 7a (2 g, 9.4 mmoles), mp 138 °C,
-1
1
ir: 3392-3327 (NH), 1521 (C=C) cm ; H nmr (DMSO-d ): δ
6
+
3.40 (s, 3H, NH ), 3.60 (s, 3H, CH ), 6.36 (s, 2H, Hβ pyrrole),
3
3
-1
1
7.17 (s, 2H, Hα pyrrole), 7.66 (s, 1H, H3) ppm.
(OH), 1681 (C=O), 1496 (C=C) cm ; H nmr (CDCl ): δ 1.02 (t,
3
Anal. Calcd for C H N Cl: C, 48.36; H, 5.58; N, 28.20.
J = 7.44 Hz, 3H, CH ), 1.72 (st, J = 7.44 Hz, 2H, CH ), 2.59 (t,
8
11 4
3
2
Found: C, 48.32; H, 5.44; N, 28.02.
J = 7.44 Hz, 2H, CH ), 3.65 (s, 3H, CH ), 5.2 (b s, 1H, OH), 6.64
2 3
(s, 1H, H4) ppm.
Anal. Calcd for C H N O : C, 57.12; H, 7.19; N, 16.66.
Found: C, 57.33; H, 7.39; N, 16.55.
4-Amino-1-phenyl-5-pyrrol-1-yl-1H-pyrazole, Hydrochloride
(3b).
8
12 2 2
This compound was obtained as a white powder (1.66 g, 6
The ethereal filtrate was evaporated to dryness and the solid
residue was recrystallized from diethyl ether /petroleum ether to
give 10a as a white powder in 40% yield (32.9 g, 196 mmoles),
mmoles, isopropanol) starting from 7b (2 g, 7.2 mmoles), mp 203
-1
1
°C, ir: 3413-3335 (NH), 1492 (C=C) cm ; H nmr (DMSO-d ):
6
+
-1
1
δ 3.44 (s, 3H, NH ), 6.28 (s, 2H, Hβ pyrrole), 6.93 (s, 2H, Hα
mp 138 °C, ir : 2970-2320 (OH), 1707 (C=O) cm ; H nmr
(CDCl ): δ 1.00 (t, J = 7.44 Hz, 3H, CH ), 1.67 (st, J = 7.44 Hz,
3
pyrrole), 7.05 (m, 2H, phenyl), 7.35 (m, 3H, phenyl), 7.92 (s, 1H,
H3) ppm.
3
3
2H, CH ), 2.62 (t, J = 7.44 Hz, 2H, CH ), 4.16 (s, 3H, CH ), 6.5
2
2
3
Anal. Calcd for C
H N Cl: C, 59.88; H, 5.02; N, 21.49.
(b s, 1H, OH), 6.75 (s, 1H, H4) ppm.
13 13 4
Found: C, 59.67; H, 6.88; N, 21.53.
Anal. Calcd for C H N O : C, 57.12; H, 7.19; N,16.66.
8
12 2 2
Found: C, 57.23; H, 7.52; N, 16.35.
4-Amino-1-(4-methoxyphenyl)-5-pyrrol-1-yl-1H-pyrazole,
Hydrochloride (3c).
1-Methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid (11).
This compound was obtained as a white powder (1.13 g, 4
To a solution of 10 (25 g, 148 mmoles) in sulfuric acid (150
ml), was added at –5 °C nitric acid (13 ml, 309 mmoles). The
reaction mixture was stirred for 15 minutes at 0 °C and for 30
minutes at room temperature. The solution was then stirred at 80
°C for 4 hours. After temperature decreased to room temperature,
iced water was poured into the reaction mixture until a precipitate
appeared. The later was collected by filtration, dried and recrys-
tallized from cyclohexane to give 11 as a white powder in a quan-
titative yield (31.52 g, 148 mmoles), mp < 50 °C, ir: 2955 (OH),
mmoles, acetonitrile) starting from 7c (2 g, 6.4 mmoles), mp
-1
1
120°C, ir: 3407-3332 (NH), 1505 (C=C) cm ; H nmr (DMSO-
+
d ): δ 3.40 (s, 3H, NH ), 3.82 (s, 3H, OCH ), 6.32 (s, 2H, Hβ
6
3
3
pyrrole), 6.93 (s, 2H, Hα pyrrole), 6.94 (d, J = 8.8 Hz, 2H, H3'
and H5'), 7.03 (d, J 8.8 = Hz, 2H, H2' and H6'), 8.13 (s, 1H, H3)
ppm.
Anal. Calcd for C
H N OCl: C, 57.83; H, 5.20; N,19.27.
14 15 4
Found: C, 57.56; H, 5.39; N, 19.03.
-1
1
1720 (C=O), 1358 (NO ) cm ; H nmr (CDCl ): δ 1.04 (t, J=
2
3
Ethyl 2,4-Dioxoheptanoate (8) [13].
7.34 Hz, 3 H, CH ), 1.71 (st, J = 7.34 Hz, 2H, CH ), 2.59 (t, J =
3
2
To a sodium ethoxide solution prepared from sodium (3.11 g,
135 mmoles) dissolved in ethanol (500 ml), was added at 0 °C a
mixture of diethyl oxalate (37 ml, 270 mmoles) and propan-2-one
(29 ml, 270 mmoles). The reaction mixture was stirred at 0 °C for
3-4 hours then was left at room temperature overnight. The solu-
tion was cooled again in an ice-bath and sulfuric acid (20%) was
added until pH=2. The sodium sulfate precipitate was filtered and
washed with ethanol. The filtrate was poured into water and was
extracted with benzene (2 x 200 ml). The organic layers were col-
lected, washed with an aqueous sodium bicarbonate solution till
neutrality and then with water, dried over magnesium sulfate and
evaporated to yield 35.19 g (70%, 189 mmoles) of a red oil (8)
that was not purified; ir: 2966 (CH), 1732 (C=O), 1633 (C=C)
7.34 Hz, 2H, CH ), 3.94 (s, 3H, CH ), 5.6 (b s, 1H, OH) ppm.
2
3
Anal. Calcd for C H N O : C, 45.06; H, 5.20; N, 19.71.
8
11 3 4
Found: C, 45.23; H, 5.35; N, 19.43.
1-Methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic Azide (12).
Compound 12 was prepared in a similar way as described for
7a-c starting from 11 (21.6 g, 101 mmoles) to give 12 in 75%
yield (18 g, 75 mmoles) as a yellow powder that was used with-
out further purification, mp 130 °C, ir: 2146 (N ), 1698 (C=O),
3
-1
1
1359 (NO ) cm ; H nmr (CDCl ): δ 1.03 (t, J = 7.44 Hz, 3H,
2
3
CH ), 1.70 (st, J = 7.44 Hz, 2H, CH ), 2.94 (t, J = 7.44 Hz, 2H,
3
2
CH ), 3.91 (s, 3H, CH ) ppm.
2
3
5-Amino-1-methyl-4-nitro-3-propyl-1H-pyrazole (13).
-1
1
cm ; H nmr (CDCl ): δ 0.97 (t, J = 7.44 Hz, 3H, CH ), 1.37 (t,
3
3
J = 6.96 Hz, 3H, CH ), 1.69 (st, J = 7.44 Hz, 2H, CH ), 2.33 (s,
To a solution of 12 (9 g, 37.8 mmoles) in benzene (250 ml),
3
2

Sep-Oct 2001
Synthesis of novel Pyrazolopyrrolopyrazines, Potential Analogs of Sildenafil
1049
was added a 10 N aqueous hydrochloric acid solution (10 ml).
The reaction mixture was refluxed for 3 hours. After this time,
benzene was evaporated and the solid that precipitated from
water was treated with sodium hydrogen carbonate until alkalin-
ity. The solid was collected by filtration, dried and then recrystal-
to give grey crystals in 71% yield (2.8 g, 5.3 mmoles), mp 258
-1
°C (acetonitrile), ir: 3124 (CH), 1596 (C=C), 1347 (C-N) cm ;
1
H nmr (DMSO-d ): δ 1.13 (t, J = 7.8 Hz, 3H, CH ), 2.71 (s, 3H,
6
3
CH ), 2.80 (s, 2H, CH ), 3.13 (s, 2H, CH ), 3.42 (s, 2H, CH ),
3
2
2
2
3.76 (s, 2H, CH ), 4.22 (q, J = 7.8 Hz, 2H, CH ), 6.83 (m, 1H,
2
2
H7), 6.87 (m, 1H, H6), 7.00 (m, 1H, H8), 7.50 (m, 1H, H3"), 7.70
(s, 5H, phenyl), 7.78 (s, 1H, H3), 7.92 (m, 1H, H4"), 8.42 (m, 1H,
H6") ppm.
lized from acetonitrile to give 13 in 86% yield (6 g, 32.6 mmoles)
-
as a yellow powder, mp 165 °C, ir: 1626 (C=C), 1341 (NO ) cm
2
1
1
; H nmr (CDCl ): δ 1.03 (t, J = 7.44 Hz, 3H, CH ), 1.70 (st, J
3
3
Anal. Calcd for C
H N O S: C, 62.77; H, 5.46; N, 16.27.
= 7.44 Hz, 2H, CH ), 1.96 (t, J = 7.44 Hz, 2H, CH ), 3.65 (s, 3H,
27 28 6 3
2
2
Found: C, 62.56; H, 5.34; N, 16.14.
CH ), 5.19 (s, 2H, NH ) ppm.
3
2
Anal. Calcd for C H N O : C, 45.64; H, 6.57; N, 30.42.
Found: C, 45.47; H, 6.39; N, 30.24.
7
12 4 2
5-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-1-(4-
methoxyphenyl)pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (2c).
1-Methyl-4-nitro-3-propyl-5-pyrrol-1-yl-1H-pyrazole (14).
Compound 3c (1.5 g, 5.15 mmoles) was washed with an aque-
ous sodium hydrogen carbonate solution to liberate the corre-
sponding free base. The latter was reacted with 2-ethoxy-5-(4-
methylpiperazine-1-sulfonyl)benzaldehyde (0.85 g, 1.79
mmoles) in refluxing ethanol for 48 hours. A 10 N aqueous
hydrochloric acid solution (0.5 ml) was added every 2 hours for
the first ten hours. The reaction mixture was then treated as for 2a
and 2b to give 2c as yellow crystals in 52% yield (1.6 g, 2.7
moles), mp 250 °C (acetonitrile), ir: 3115 (CH), 1600 (C=C),
Compound 14 was prepared in a similar way as described for
5a-c starting from 13 (5 g, 27 mmoles) and 2,5-dimethoxyte-
trahydofurane (3.8 ml, 27 mmoles) to give an yellow oil in 85%
-1
1
yield (5.4 g, 23 mmoles), ir: 1555 (C=C), 1344 (NO ) cm ; H
2
nmr (DMSO-d ): δ 0.97 (t, J = 7.56 Hz, 3H, CH ), 1.64 (st, J =
6
3
7.56 Hz, 2H, CH ), 1.99 (t, J = 7.56 Hz, 2H, CH ), 3.84 (s, 3H,
2
2
CH ), 6.22 (s, 2H, Hα pyrrole), 6.68 (s, 2H, Hβ pyrrole) ppm.
3
Anal. Calcd for C H N O : C, 56.40; H, 6.02; N, 23.92.
11 14
4 2
-1
1
1332 (C-N) cm ; H nmr (DMSO-d ): δ 1.14 (t, J = 7.8 Hz, 3H,
Found: C, 56.29; H, 6.18; N, 23.56.
6
CH ), 2.71 (s, 3H, CH ), 2.95 (s, 2H, CH ), 3.14 (s, 2H, CH ),
3
3
2
2
4-Amino-1-methyl-3-propyl-5pyrrol-1-yl-1H-pyrazole (3d).
3.42 (s, 2H, CH ), 3.77 (s, 2H, CH ), 3.88 (s, 3H, CH ), 4.21 (q,
2
2
3
J = 7.8 Hz, 2H, CH ), 6.79 (m, 1H, H7), 6.85 (m, 1H, H6), 7.00
A solution of 14 (5.4 g, 23 mmoles) in ethanol (100 ml) was
autoclaved for 2 hours in presence of palladium on charcoal at 60
°C, under a 30 Kg hydrogen pressure. Ethanol was evaporated,
water was added and the product was extracted with ethyl acetate
to give 3d as an yellow oil in 90% yield (4.2 g, 21 mmoles), ir:
2
(m, 1H, H8), 7.66 (d, J = 6.8 Hz, 2H, H2' and H6'), 7.21 (d, J =
6.8 Hz, 2H, H3' and H5'), 7.51 (m, 1H, H3"), 7.77 (s, 1H, H3),
7.93 (m, 1H, H4"), 8.37 (m, 1H, H6") ppm.
Anal. Calcd for C
H N O S: C, 61.52; H, 5.53; N,15.38.
28 30 6 4
-1
1
Found: C, 61.56; H, 5.58; N, 15.42.
3390-3326, 1525 cm ; H nmr (DMSO-d ): δ 0.94 (t, J = 7.48
6
Hz, 3H, CH ), 1.52 (st, J = 7.48 Hz, 2H, CH ), 2.5 (b s, 2H,
3
2
5-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-1-
methyl-3-propylpyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (2d).
NH ), 2.58 (t, J = 7.48 Hz, 2H, CH ), 3.63 (s, 3H, CH ), 6.16 (s,
2
2
3
2H, Hα pyrrole), 7.21 (s, 2H, Hβ pyrrole) ppm.
Anal. Calcd for C H N : C, 64.67; H, 7.90; N,27.43. Found:
To a solution of 3d (0.26 g, 1.274 mmoles) in ethanol (40 ml),
was added 2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)benzalde-
hyde (0.4 g, 1.274 mmoles). The reaction mixture was refluxed
for 24 hours in the presence of hydrobromic acid (25 ml), then
the solution was treated as for 2a-c to give 2d as green crystals in
15% yield (0.18 g, 0.19 mmoles), mp 188 °C, ir: 2960 (CH),
11 16
4
C, 64.58; H, 7.76; N, 27.75.
5-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-1-
methylpyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (2a).
To a solution of 3a (0.35 g, 1.18 mmoles) in ethanol (50 ml),
was added 2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)benzalde-
hyde (0.55 g, 1.16 mmoles) and the reaction mixture was
refluxed for 48 hours. The solvent was then evaporated to dry-
ness and the solid residue was washed with an aqueous sodium
hydrogen carbonate solution. After collection by filtration, the
solid was washed with ether, filtered and recrystallized from ace-
tonitrile to give 2a as yellow crystals in 19% yield (0.1 g, 0.33
mmoles), mp 192 °C, ir: 3156 (CH), 1595 (C=C), 1349 (C-N)
-1
1
1598 (C=C), 1352 (C-N) cm ; H nmr (DMSO-d ): δ 0.91 (t, J
6
= 8.44 Hz, 3H, CH ), 1.09 (t, J = 5.08 Hz, 3H, CH ), 1.69 (st, J
3
3
= 8.44 Hz, 2H, CH ), 2.49 (s, 3H, CH ), 2.97 (t, J = 8.44 Hz, 2H,
2
3
CH ), 3.13 (m, 4H, piperazine), 3.44 (m, 4H, piperazine), 3.95 (s,
2
3H, CH ), 4.14 (q, J = 5.08 Hz, 2H, CH ), 6.58 (m, 1H, H7),
3
2
6.79 (m, 1H, H6), 7.46 (m, 1H, H8), 7.88 (m, 2H, H3", H4"), 7.92
(m, 1H, H6") ppm.
Anal. Calcd for C
H N O S: C, 64.63; H, 6.94; N, 18.09.
25 32 6 3
-1
1
Found: C, 64.56; H, 6.88; N, 18.02.
cm ; H nmr (DMSO-d ): δ 1.20 (t, J = 7.8 Hz, 3H, CH ), 2.26
6
3
(s, 3H, CH ), 2.48 (s, 4H, CH ), 3.08 (s, 4H, CH ), 4.12 (q, J =
3
2
2
7.8 Hz, 2H, CH ), 4.42 (s, 3H, CH ), 6.57 (m, 1H, H7), 6.88 (m,
REFERENCES AND NOTES
2
3
[1] N. K. Terrett, A. Bell, D. Brown and P. Ellis, Bioorg. Med.
Chem. Lett., 15, 1819 (1996)
[2] N. Kim and K. M. Azadzoi, J. Clinic. Invest., 88, 112 (1991)
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399 (1994).
1H, H6), 7.11 (m, 1H, H8), 7.87 (m, 3H, H3, H3'', H4''), 8.01 (m,
1H, H6") ppm.
Anal. Calcd for C
H N O S: C, 60.81; H, 5.76; N, 18.50.
22 26 6 3
Found: C, 61.00; H, 5.80; N, 18.70.
[4] G. Yu, H. Mason and X. Wu, J. Med. Chem., 44, 1025 (2001).
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5-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-1-
phenylpyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (2b).
Compound 2b was prepared in a similar way as described for
2a starting from 3b (2g, 7.67 mmoles) and 2-ethoxy-5-(4-
methylpiperazine-1-sulfonyl)benzaldehyde (6.4 g, 7.57 mmoles)
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