Synthesis of pyrazolo[1,5-a]-, 1,2,4-triazolo[1,5-a]- and imidazo[1,2-a]pyrimidines related to zaleplon, a new drug for the treatment of insomnia

Article abstract of DOI:10.1002/jhet.5570380516

This paper describes the preparation of some pyrazolo[1,5-a]-, 1,2,4-triazolo[1,5-a]- and imidazo[1,2-a]-pyrimidines substituted on the pyrimidine moiety by a 4-[(N-acetyl-N-ethyl)amino]phenyl group. A new synthesis of related benzo[h]pyrazolo[1,5-a]-, benzo[h]pyrazolo[5,1-b]- and benzo[h]1,2,4-triazolo[1,5-a]-quinazolines is also reported.

Full text of DOI:10.1002/jhet.5570380516

Sep-Oct 2001
Synthesis of Pyrazolo[1,5-a]-, 1,2,4-Triazolo[1,5-a]- and
Imidazo[1,2-a]pyrimidines Related to Zaleplon,
1119
a New Drug for the Treatment of Insomnia
Carlo Mustazza*, Maria Rosaria Del Giudice, Anna Borioni and Franco Gatta
Laboratorio di Chimica del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Roma, Italy
Received March 5, 2001
This paper describes the preparation of some pyrazolo[1,5-a]-, 1,2,4-triazolo[1,5-a]- and imidazo[1,2-a]-
pyrimidines substituted on the pyrimidine moiety by a 4-[(N-acetyl-N-ethyl)amino]phenyl group. A new
synthesis of related benzo[h]pyrazolo[1,5-a]-, benzo[h]pyrazolo[5,1-b]- and benzo[h]1,2,4-triazolo[1,5-a]-
quinazolines is also reported.
J. Heterocyclic Chem., 38, 1119 (2001).
The unsatisfactory use of benzodiazepines for the treat-
pyrimidine moiety a phenyl ring substituted by the (N-
acetyl-N-ethyl)amino group as the lead compound, though
in position 4 instead of 3 (Figure 1), which were prepared
in order to study their pharmacological activity.
The synthetical pathways to compounds 1 and 2 are
summarized in Scheme 1.
ment of insomnia, often associated with several adverse
effects, particularly with high doses and long-term use [1],
has promoted new researches in benzodiazepine receptor
pharmacology. The discovery of two central benzodi-
azepine receptor subtypes, BZ or ω , located in areas of
1
1
the brain that are involved in sedation, and BZ or ω espe-
The starting materials 3-dimethylamino-1-[4-(N-acetyl-
N-ethyl)aminophenyl]-2-propen-1-one (6a) and ethyl
3-dimethylamino-2-[4-(N-acetyl-N-ethyl)aminobenzoyl]-
propenoate (6b) were prepared respectively by reaction of
1-[4-(N-acetyl-N-ethyl)aminophenyl]ethanone (5a) and
ethyl 3-[4-(N-acetyl-N-ethyl)aminophenyl]-3-oxo-
propanoate (5b) with N,N-dimethylformamide dimethyl
acetal.
According to a conventional method, enaminone 6a
either by reaction with 3-aminopyrazoles or 3-amino-1,2,4-
triazole gave the 7-aryl-pyrazolo[1,5-a]pyrimidines 7d-f
[7,8] and the corresponding 1,2,4-triazolo[1,5-a]pyrimidine
8a, in high yield and in a regiospecific manner.
2
2
cially concentrated in areas responsible for cognition,
memory and psychomotor functioning [2] has opened new
perspectives for the pharmacological management strategy
of insomnia, often associated with anxiety disorders [3].
Most benzodiazepines bind nonselectively at these sites,
which may account for their unwanted central nervous sys-
tem adverse effects. Over the last few years, the search has
been undertaken for compounds chemically unrelated to
benzodiazepines which display hypnotic properties with a
better safety/efficacy profile. Typical of such compounds,
which bind selectively to BZ receptor subtypes, are the
1
imidazopyridine zolpidem [4] and, more recently, the
pyrazolopyrimidine zaleplon [5] approved in August 1999
by the Food and Drug Administration, and whose prepara-
tion has been reported only in an American Cyanamid
patent [6].
The 7-aryl substitution in compound 8a was demon-
strated on the basis of the coupling constant of pyrimidine
protons whose value of 4.4 Hz was consistent with the pro-
posed structure [9].
This paper describes the synthesis and the physical prop-
erties of some pyrazolo[1,5-a]pyrimidines (1), 1,2,4-tria-
zolo[1,5-a]pyrimidines (2), imidazo[1,2-a]pyrimidines (3)
and some related tetracyclic derivatives (4) bearing on the
Under the same conditions enaminone 6b by condensa-
tion with 4-substituted-3-aminopyrazoles and 3-amino-
1,2,4-triazole afforded only the 7-aryl-6-ethoxycar-
bonylpyrazolo[1,5-a]pyrimidines 7h,i and the 7-aryl-6-
Figure 1

1120
C. Mustazza, M. R. Del Giudice, A. Borioni and F. Gatta
Vol. 38
Scheme 1
6a,b
D
F
7f
10
7f
a: R1 = H
g: R1 = –COOC2H5, R2 = H
h: R1 = –COOC2H5, R2 = –CN
i: R1 = –COOC2H5, R2 = –CONH2
j: R2 = H, R3 = –CONH2
b: R1 = –COOC2H5
c: R1 = –CONH2
d: R1 = R2 = H
e: R1 = H, R2 = –CN
f: R1 = H, R2 = –CONH2
k: R2 = –CN, R3 = –CONH2
l: R2 = R3 = –CONH2
Reagents: A: (CH ) NCH(OCH ) ; B:
, CH COOH, reflux; C:
, CH COOH, reflux; D: MeOH / NH rt; E:
3 3
3 2
3 2
3
NH NH .H O, CH COOH, 90°; F: NH OH.HCl, K CO , EtOH reflux; G: (CH CO) O/CH COOH.
2
2
2
3
2
2
3
3
2
3
ethoxycarbonyl-1,2,4-triazolo[1,5-a]pyrimidine 8b, while
by reaction with 3-aminopyrazole provided an isomeric
1:1 mixture of 7- and 5-aryl-6-ethoxycarbonyl derivatives
7g and 9b, easily separated by column chromatography.
The structure of isomers 7g and 9b could be determined
by H- and C-nmr experiments on the basis of chemical
shift evaluation. As reported in the literature [10] for ana-
logue pyrazolo[1,5-a]pyrimidines, the H-5 and H-7 signals
are characterized by a different chemical shift value, the
first proton being shielded of about 0.5 ppm. In the protonic
spectrum of compound 7g the pyrimidine proton signal lies
at 8.96 ppm (δ), while in the spectrum of compound 9b the
same signal appears at 9.31 ppm. This observation allowed
to assign to 7g the 7-arylsubstituted structure. The structure
has been confirmed by the chemical shift values of the car-
bon atom bearing pyrimidine proton, whose signal is
located downfield (150.1 ppm) for 7g and upfield (139.4
ppm) for 9b. This deshielded position of C-5 due to near-
1
13
2
ness of the sp N-4 atom, in comparison with carbon C-7
3
adjacent to the sp N-8 atom, has been already described
for analogues heteroaromatic compounds [11]. Moreover, a
13
complete assignment of C signals of both compounds has

Sep-Oct 2001
Synthesis of Pyrazolo[1,5-a]-, 1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines
1121
Scheme 2
been performed by direct and long-range proton-carbon
correlated spectroscopy HETCOR.
1
The structure of compound 8b was determined by H-
13
and C-nmr experiments. The Nuclear Overhauser Effect
produced on the ethoxycarbonyl protons by irradiation of
the aromatic signal at 9.28 ppm (δ) allowed to assign the
1
position of the pyrimidine proton. Two-dimensional H-
13
C correlation spectroscopy and evaluation of the pyrimi-
dine CH chemical shift (δ = 155.9 ppm) led to assignment
of the 7-arylsubstitution for compound 8b.
Amides 7j-l, 8c and 9c were easily prepared from the
corresponding ethoxycarbonyl derivatives 7g-i, 8b and 9b
allowed to react at room temperature in methanol saturated
with ammonia for 72 hours.
Reagents: A: (NH ) C=NH.HCl, EtONa, EtOH, reflux;
2
2
B: BrCH CH(OCH ) , CH COOH, CH COONa.
2
3 2
3
3
compounds was confirmed by chemical shifts and proton-
proton coupling constant values which are consistent with
those reported in the literature for analogues 7-arylsubsti-
Compound 7f by reaction with N,N-dimethylformamide
dimethyl acetal in refluxing ethylene glycol monomethyl
ether gave the intermediate dimethylaminomethylenecar-
boxamide 10 which then reacted with hydrazine hydrate in
acetic acid at 90° to give the 1,2,4-triazole derivative 11.
Treatment of nitrile 7e with hydroxylamine in aqueous
ethanol provided the amidoxime 12 which when heated
with acetic anhydride in acetic acid afforded the 1,2,4-oxa-
diazole derivative 13.
1
tuted imidazo[1,2-a]pyrimidines [9,12]. In fact, the H-nmr
spectrum of 3a, showed for pyrimidine ring protons two
doublets at 8.50 and 7.36 ppm (δ), whose coupling constant
J = 7.0 Hz has been described as characteristic for the H-5 -
H-6 sequence. In order to elucidate the structure of 3b, the
same considerations were made as reported above for 9b: in
13
the C-nmr spectrum the pyrimidine CH signal at 137.8
The preparation of imidazo[1,2-a]pyrimidines 3 is out-
lined in Scheme 2.
ppm (δ) and the position of the carbon bearing the aryl sub-
stituent at 157.5 ppm (δ), are consistent with the 6,7-disub-
stituted imidazo[1,2-a]pyrimidine structure [11].
The synthesis of 6-[4-(N-acetyl-N-ethyl)aminophenyl]-
3-cyanopyrazolo[1,5-a]pyrimidine (20) is illustrated in
Scheme 3.
The 2-amino-4-[4-(N-acetyl-N-ethyl)aminophenyl]-
pyrimidines 14, obtained by condensing enaminones 6 with
guanidine in refluxing ethanol, by cyclization with bro-
moacetaldehyde dimethyl acetal, gave the imidazo[1,2-a]-
pyrimidines 3 in 32-38% yields. The structure of these
Scheme 3
Reagents: A: POCl , DMF; B:
, CH COOH reflux; C: C H I/NaH/DMF; D: HCl, MeOH reflux; E: (CH CO) O/CH COOH.
3 2 5 3 2 3
3

1122
C. Mustazza, M. R. Del Giudice, A. Borioni and F. Gatta
Vol. 38
The 4-acetylaminophenylacetic acid (15), subjected to
desired compounds 4a-d, according to the same procedure
above reported for compounds 7 and 8.
Likewise compounds 7g and 9b, the condensation of 22
with 3-aminopyrazole led to a 1:1 isomeric mixture of
benzo[h]pyrazolo[1,5-a]- and benzo[h]pyrazolo[5,1-
b]quinazolines 4a and 23. Their structures were supported
Vilsmeier-Haack condensation [13], was hydrolyzed in the
acidic medium of the reaction mixture and the resulting
ammonium ion was N-formylated to afford the 3-dimethy-
lamino-2-[4-(N-formyl)aminophenyl]-2-propenal (16).
This compound deteriorates considerably on standing with
formation of tar products, so it was quickly used without
purification in the following step. Treatment of crude 16
with 3-amino-4-cyanopyrazole in refluxing acetic acid led
to 3-cyano-6-[4-(N-formyl)aminophenyl]pyrazolo[1,5-
a]pyrimidine (17) which successively was first N-ethyl-
ated by ethyl iodide/sodium hydride in dimethylfor-
mamide to give compound 18, then N-deformylated to
obtain the 6-[4-(N-ethyl)aminophenyl]pyrazolo[1,5-
a]pyrimidine (19). Finally, N-acetylation of 19 easily pro-
vided the expected compound 20.
The 6-[(N-acetyl-N-ethyl)amino]-1-tetralone (21) was
the key intermediate for the synthesis of benzo[h]pyra-
zolo[1,5-a]- and benzo[h]1,2,4-triazolo[1,5-a]quinazo-
lines 4 outlined in Scheme 4. These tetracyclic com-
pounds, which might be considered conformationally
restricted analogues of compounds 7 and 8, appear hitherto
not to have been extensively studied, as only three refer-
ences related to their preparation by different synthetical
pathways are reported in the chemical literature [14-16].
Compound 21 in refluxing N,N-dimethylformamide
dimethyl acetal provided a very unstable enaminone 22
which, without purification, was directly allowed to react
with aminopyrazoles or 3-amino-1,2,4-triazole to give the
1
13
13
by H- and C-nmr. The complete assignment of C sig-
nals was obtained by performing direct and long-range
1
13
heterocorrelated H- C spectra. In the carbon spectrum of
both compounds pyrimidine CH signals were observed to
have the same chemical shift value (δ = 149.3 ppm for 4a
and 149.2 ppm for 23) but this observation could not be
used to support related structures. Final structural charac-
1
terisation was achieved by H-NOE experiments. The
structure of compound 4a was determined by the irradia-
tion of doublet at 9.50 ppm (δ), assigned to H-11, which
produced a NOE only on pyrazole H-2 proton 2.8 Å far
from the irradiated proton, while no NOE was observed on
H-3 and H-5 protons, respectively at 5.2 and 5.7 Å from H-
11. On the contrary the irradiation of the analogue aro-
matic proton H-1 of compound 23 produced a NOE only
on pyrazole H-11 proton at 4.5 Å from H-1, while no effect
was observed on the farther protons H-7 and H-10.
Preliminary binding studies on membrane preparations
3
from rat brain cortex, using [ H]-Ro 15-1788 (flumazenil)
as radioligand, indicate that only tetracyclic compound 4b
showed significant Ki value (145 nM) as compared to
zaleplon (59 nM). All other tested compounds showed Ki
values > 1µM.
Scheme 4

Sep-Oct 2001
Synthesis of Pyrazolo[1,5-a]-, 1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines
1123
EXPERIMENTAL
3-Dimethylamino-1-[4-(N-acetyl-N-ethyl)aminophenyl]-2-
propen-1-one (6a).
Melting points and boiling points (mmHg as pressure unit) are
uncorrected. The H-nmr spectra were obtained on a Varian
In a flask fitted with a Dean-Stark trap to remove methanol a
mixture of 1-[4-(N-acetyl-N-ethyl)aminophenyl]ethanone (5a)
(8.2 g, 0.04 mole) and N,N-dimethylformamide dimethyl acetal
(15 ml) was heated at reflux for 4 hours. The reaction mixture
was evaporated to dryness in vacuo and the resulting 6a cristal-
1
Gemini 200 MHz instrument; all values were reported in ppm (δ)
and standard abbreviations were used (at = apparent triplet; b =
broad; d = doublet; dd = doublet of doublets; m = multiplet; q =
quadruplet; t = triplet; s = singlet, um = unresolved multiplet);
1
lyzed from ethyl acetate 7.4 g (71%), mp 92-94°; H-nmr (deu-
13
1
peak assignments were also based on C-APT, H-NOE and
teriochloroform): δ 7.86 (d, 2H, H-2' and H-6', J
= 8.4 Hz),
ortho
13
1
C- H HETCOR nmr experiments; electron ionization mass
7.77 (d, 1H, H-3, J = 12 Hz), 7.13 (d, 2H, H-3' and H-5', J
2,3
ortho
spectra were recorded on a HP 59580 B spectrometer operating at
70 eV. Column chromatographic separations were accomplished
on Merck silica gel (70-230 mesh) or Merck aluminum oxide 90.
The purity of each compound was checked on silica gel C. Erba
= 8.4 Hz), 5.63 (d, 1H, H-2, J = 12 Hz), 3.68 (q, 2H, N-CH ),
2,3
2
3.10 (bs, 3H, N-CH ), 2.88 (bs, 3H, N-CH ), 1.77 (bs, 3H, acetyl
3
3
+
CH ), 1.03 (t, 3H, N-ethyl CH ); ms: (m/z) 260 (M ), 243, 201,
3
3
174.
60 F
or Merck aluminum oxide 60 F
(type E) plates and
Anal. Calcd. for C
H
N O : C, 69.20; H, 7.74; N, 10.76.
254
254
15 20
2 2
spots were located by uv light. Sodium sulfate was used to dry
organic solutions.
Found: C, 68.98; H, 7.79; N, 10.56.
Ethyl 3-Dimethylamino-2-[4-(N-acetyl-N-ethyl)aminobenzoyl]-
propenoate (6b).
1-[4-(N-Acetyl-N-ethyl)aminophenyl]ethanone (5a).
To a stirred and cooled suspension of sodium hydride (2.8 g of
50% oil dispersion, 0.06 mole) in anhydrous dimethylformamide
(80 ml), 1-(4-acetylaminophenyl)ethanone [17] (7.1 g, 0.04
mole) was added in several portions. After stirring 1 hour at room
temperature, a solution of ethyl iodide (6.4 ml, 0.08 mole) in
dimethylformamide (10 ml) was dropwise added, the mixture
stirred for 3 hours at room temperature, then carefully poured
into water and extracted with dichloromethane. The solvent was
removed and the residue chromatographed over alumina eluting
by 1:1 ethyl acetate/n-hexane mixture to give 6.3 g (77%) of a
viscous oil. Analytical sample was obtained by distillation: bp
Compound 6b was obtained in 79% yield by reaction of ethyl
3-[4-(N-acetyl-N-ethyl)aminophenyl]-3-oxopropanoate (5b) with
N,N-dimethylformamide dimethyl acetal following the same pro-
cedure previously reported for 6a, mp 132-134° (ethyl acetate);
1
H-nmr (deuteriochloroform): δ 7.77 (um, 3H, H-2', H-6' and H-
3), 7.13 (d, 2H, H-3' and H-5', J = 8.4 Hz), 3.91 (q, 2H, O-CH ),
2
3.70 (q, 2H, N-CH ), 2.92 (bs, 6H, N(CH ) ), 1.81 (bs, 3H,
2
3 2
acetyl CH ), 1.05 (t, 3H, O-ethyl CH ), 0.85 (t, 3H, N-ethyl
3
3
+
CH ); ms: (m/z) 332 (M ), 287, 243, 215, 190, 148, 132.
3
Anal. Calcd. for C
H N O : C, 65.04; H, 7.28; N, 8.43.
18 24 2 4
Found: C, 64.87; H, 7.12; N, 8.29.
1
135-140°/0.05 mm; H-nmr (deuteriochloroform): δ 7.98 (d, 2H,
General Procedure for the Preparation of Pyrazolo[1,5-a]pyrim-
idines 7d-i, 9b and 1,2,4-Triazolo[1,5-a]pyrimidines 8a,b.
H-2' and H-6', J
= 8.4 Hz), 7.23 (d, 2H, H-3' and H-5', J
=
ortho
ortho
8.4 Hz), 3.73 (q, 2H, N-CH ), 2.59 (s, 3H, aryl-COCH ), 1.83 (s,
2
3
3H, N- COCH ), 1.07 (t, 3H, N-ethyl CH ).
A mixture of each compound 6 (0.05 mole) and 3-aminopyra-
zole [18] (to obtain 7d,g and 9b), 3-amino-4-cyanopyrazole [19]
(to obtain 7e,h), 3-amino-4-carboxamidopyrazole [19] (to obtain
7f,i) or 3-amino-1,2,4-triazole (to obtain 8a,b) (0.05 mole) in
glacial acetic acid (80 ml) was refluxed for 8 hours. After cooling,
the reaction mixture was poured into water and extracted with
dichloromethane. The organic phase was washed with 8% sodium
hydroxide solution, then with brine. Evaporation of the solvent to
dryness gave a crude product which was crystallized. The reaction
of 6b with 3-aminopyrazole provided an isomeric mixture of 7g
and 9b separated by chromatography on silica gel by eluting with
ethyl acetate. Compound 9b was eluted first, followed by 7g.
3
3
Anal. Calcd. for C
H NO : C, 70.22; H, 7.37; N, 6.82.
12 15 2
Found: C, 70.38; H, 7.49; N, 6.66.
Ethyl 3-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-oxopropanoate
(5b).
Sodium hydride (3.9 g of 50% oil dispersion, 0.08 mole) was
added with stirring to a solution of diethyl carbonate (30 ml) in
cyclohexane (80 ml). A mixture of the previously described 5a (8.2
g, 0.04 mole) and diethyl carbonate (5 ml) was added dropwise and
the whole was refluxed for 2 hours, then cooled. A small amount of
isopropanol was added to the reaction mixture to destroy excess
sodium hydride. The resulting mixture was poured into water and
ice and the layers were separated. The organic phase was washed
with water and the combined aqueous alkaline solutions were acid-
ified with 10% hydrochloric acid, then extracted with diethyl ether.
After evaporation of the solvent, the residue was purified by silica
gel chromatography using ethyl acetate as eluent, to give the desired
7-[4-(N-Acetyl-N-ethyl)aminophenyl]pyrazolo[1,5-a]pyrimidine
(7d).
This compound was obtained from 6a in 64% yield, mp 171-
1
173° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.51 (d, 1H,
H-5, J = 4.4 Hz), 8.15 (d, 1H, H-2, J = 2.6 Hz), 8.11 (d, 2H,
5,6
2,3
1
compound as a viscous oil, g 7.1 (64%); H-nmr (deuteriochloro-
H-2' and H-6', J
8.4 Hz), 6.89 (d, 1H, H-6, J = 4.4 Hz), 6.77 (d, 1H, H-3, J
= 8.4 Hz), 7.34 (d, 2H, H-3' and H-5', J
=
=
ortho
ortho
form): δ 7.99 (d, 2H, ketonic form H-2' and H-6'), 7.80 (d, 2H, eno-
lic form H-2' and H-6', keto/enolic ratio = 3:1), 7.27 (d, 2H, ketonic
form H-3' and H-5'), 7.20 (d, 2H, enolic form H-3' and H-5'), 5.63
(s, 1H, enolic H-2), 4.21 (two overlapped q, 2H, both forms O-
5,6
2,3
2.6 Hz), 3.77 (q, 2H, N-CH ), 1.89 (bs, 3H, acetyl CH ), 1.12 (t,
2
3
13
3H, N-ethyl CH ); C-nmr (deuteriochloroform): δ 169.7
3
(C=O), 150.0 (C-3a), 149.1 (C-5), 145.7 (C-7), 145.4 (C-1'),
144.9 (C-2), 130.8 (C-2' and C-6'), 130.5 (C-4'), 128.6 (C-3' and
C-5'), 107.6 (C-6), 97.5 (C-3), 44.3 (N-CH ), 23.2 (acetyl CH ),
CH ), 3.97 (s, 2H, ketonic form H-2), 3.76 (two overlapped q, 2H,
2
both forms N-CH ), 1.85 (s, 3H, acetyl CH ), 1.23 (two overlapped
2
3
2
3
+
t, 3H, O-ethyl CH ), 1.09 (two overlapped t, 3H, N-ethyl CH ).
13.5 (N-ethyl CH ); ms: (m/z) 280 (M ), 238, 223, 194, 140, 130.
3
3
3
Anal. Calcd. for C
H
NO : C, 64.96; H, 6.91; N, 5.05.
Anal. Calcd. for C
H N O: C, 68.55; H, 5.75; N, 19.99.
15 19
4
16 16 4
Found: C, 64.98; H, 7.00; N, 5.26.
Found: C, 68.66; H, 5.60; N, 20.18.

1124
C. Mustazza, M. R. Del Giudice, A. Borioni and F. Gatta
Vol. 38
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-cyanopyrazolo[1,5-a]-
pyrimidine (7e).
112.1 (C-6), 85.1 (C-3), 62.6 (O-CH ), 44.7 (N-CH ), 23.2
2 2
(acetyl CH ), 14.1 (O-ethyl CH ), 13.7 (N-ethyl CH ); ms: (m/z)
3
3
3
+
377 (M ), 335, 320, 292, 274, 246.
Anal. Calcd. for C N O : C, 63.65; H, 5.08; N, 18.56.
This compound was obtained from 6a in 91% yield, mp 169-
H
20 19 5 3
1
171° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.80 (d, 1H,
Found: C, 63.39; H, 5.30; N, 18.28.
H-5, J = 4.4 Hz), 8.45 (s, 1H, H-2), 8.14 (d, 2H, H-2' and H-6',
5,6
J
= 8.4 Hz), 7.43 (d, 2H, H-3' and H-5', J
= 8.4 Hz), 7.24
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-carboxamido-6-ethoxy-
carbonylpyrazolo[1,5-a]pyrimidine (7i).
ortho
ortho
(d, 1H, H-6, J = 4.4 Hz), 3.82 (q, 2H, N-CH ), 1.96 (bs, 3H,
acetyl CH ), 1.17 (t, 3H, N-ethyl CH ); C-nmr (deuteriochloro-
form): δ 169.7 (C=O), 152.9 (C-5), 151.6 (C-3a), 147.4 (C-7),
147.3 (C-2), 146.4 (C-4'), 131.2 (C-2' and C-6'), 128.9 (C-1'),
128.8 (C-3' and C-5'), 112.8 (CN), 110.2 (C-6), 83.8 (C-3), 44.6
(N-CH ), 23.3 (acetyl CH ), 13.6 (N-ethyl CH ); ms: (m/z) 305
(M ), 263, 248, 219, 165, 155, 130.
Anal. Calcd. for C N O: C, 66.87; H, 4.95; N, 22.94.
5,6
2
13
3
3
This compound was obtained from 6b in 51% yield, mp 235-
1
236° (methanol); H-nmr (deuteriochloroform): δ 9.14 (s, 1H, H-
5), 8.70 (s, 1H, H-2), 7.82 (bs, 1H. CONH ), 7.59 (d, 2H, H-2'
2
and H-6'), 7.36 (d, 2H, H-3' and H-5'), 5.95 (bs, 1H, CONH ),
2
2
3
3
4.18 (q, 2H, O-CH ), 3.81 (q, 2H, N-CH ), 1.95 (bs, 3H, acetyl
2
2
+
13
CH ), 1.17 (t, 3H, O-ethyl CH ), 1.10 (t, 3H, N-ethyl CH ); C-
3
3
3
H
17 15
5
nmr (deuteriochloroform): δ 169.8 (acetyl C=O), 163.8
Found: C, 66.59; H, 4.72; N, 22.81.
(CONH ), 163.6 (ethoxycarbonyl C=O), 152.6 (C-5), 150.0 (C-
2
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-carboxamidopyra-
zolo[1,5-a]pyrimidine (7f).
3a), 149.1 (C-2), 147.3 (C-7), 145.5 (C-4'), 130.9 (C-2' and C-6'),
128.7 (C-1'), 128.3 (C-3' and C-5'), 113.5 (C-6), 106.5 (C-3), 62.4
(O-CH ), 44.6 (N-CH ), 23.2 (acetyl CH ), 14.1 (O-ethyl CH ),
2
2
3
3
This compound was obtained from 6a in 76% yield, mp 268-
271° (methanol); H-nmr (deuteriochloroform): δ 8.72 (s, 1H, H-
+
13.7 (N-ethyl CH ); ms: (m/z) 395 (M ), 353, 338, 335, 321, 293,
1
3
275, 247.
2), 8.67 (d, 1H, H-5, J = 4.4 Hz), 8.13 (d, 2H, H-2' and H-6',
5,6
Anal. Calcd. for C
H N O : C, 60.75; H, 5.35; N, 17.71.
20 21 5 4
J
= 8.4 Hz), 7.95 (bs, 1H, CONH ), 7.38 (d, 1H, H-3' and H-
ortho
2
Found: C, 60.66; H, 5.33; N, 17.59.
5', J
= 8.4 Hz), 7.09 (d, 1H, H-6, J = 4.4 Hz), 5.97 (bs, 1H,
5,6
ortho
CONH ), 3.78 (q, 2H, N-CH ), 1.93 (bs, 3H, acetyl CH ), 1.14 (t,
5-[4-(N-Acetyl-N-ethylamino)phenyl]-6-ethoxycarbonylpyra-
zolo[1,5-a]pyrimidine (9b).
2
2
3
13
3H, N-ethyl CH ); C-nmr (deuteriochloroform): δ 169.8 (acetyl
3
C=O), 164.2 (CONH ), 151.1 (C-5), 147.8 (C-3a), 147.3 (C-7),
147.1 (C-2), 146.2 (C-4'), 131.1 (C-2' and C-6'), 129.4 (C-1'),
2
This compound was obtained from 6b in 32% yield, mp 134-
136° (ethyl acetate); H-nmr (deuteriochloroform): δ 9.32 (d, 1H,
1
128.8 (C-3' and C-5'), 108.8 (C-6), 105.6 (C-3), 44.6 (N-CH ),
2
H-7, J = 1.0 Hz), 8.26 (d, 1H, H-3, J = 2.2 Hz), 7.61 (d, 2H,
2,7
2,3
+
23.3 (acetyl CH ), 13.6 (N-ethyl CH ); ms: (m/z) 323 (M ), 295,
3
3
H-2' and H-6'), 7.23 (d, 2H, H-3' and H-5'), 6.76 (dd, 1H, H-2,
= 2.2 Hz, J = 1.0 Hz), 4.23 (q, 2H, O-CH ), 3.77 (q, 2H, N-
281, 266, 249, 237.
J
2,3
2,7
2
Anal. Calcd. for C
H N O : C, 63.14; H, 5.30; N, 21.66.
17 17 5 2
CH ), 1.87 (s, 3H, acetyl CH ), 1.17 (t, 3H, O-ethyl CH ), 1.12 (t,
2
3
3
Found: C, 63.08; H, 5.55; N, 21.42.
13
3H, N-ethyl CH ); C-nmr (deuteriochloroform): δ 169.9 (acetyl
3
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-ethoxycarbonylpyra-
zolo[1,5-a]pyrimidine (7g).
C=O), 164.6 (ethoxycarbonyl C=O), 157.2 (C-5), 148.6 (C-2),
148.0 (C-3a), 144.1 (C-4'), 139.4 (C-7), 138.1 (C-1'), 130.1 (C-2'
and C-6'), 128.1 (C-3' and C-5'), 112.7 (C-6), 98.4 (C-3), 62.2 (O-
This compound was obtained from 6b in 37% yield, mp 142-
CH ), 44.3 (N-CH ), 23.2 (acetyl CH ), 14.1 (O-ethyl CH ), 13.4
1
2
2
3
3
144° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.96 (s, 1H,
+
(N-ethyl CH ); ms: (m/z) 352 (M ), 324, 310, 295, 267, 249, 221.
3
H-5), 8.15 (d, 1H, H-2, J = 2.2 Hz), 7.55 (d, 2H, H-2' and H-6',
2,3
Anal. Calcd. for C
H N O : C, 64.76; H, 5.72; N, 15.90.
19 20 4 3
J
= 8.4 Hz), 6.78 (d, 1H, H-3, J = 2.2 Hz), 4.11 (q, 2H, O-
ortho
2,3
Found: C, 64.58; H, 5.55; N, 15.88.
CH ), 3.76 (q, 2H, NCH ), 1.90 (bs, 3H, acetyl CH ), 1.13 (t, 3H,
2
2
3
13
O-ethyl CH ), 1.04 (t, 3H, N-ethyl CH ); C-nmr (deuteriochlo-
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-1,2,4-triazolo[1,5-a]-
pyrimidine (8a).
3
3
roform): δ 169.5 (acetyl C=O), 164.2 (ethoxycarbonyl C=O),
150.1 (C-5), 149.4 (C-3a), 148.4 (C-7), 147.2 (C-2), 144.6 (C-4'),
130.5 (C-2' and C-6'), 129.6 (C-1'), 127.9 (C-3' and C-5'), 111.6
Compound 8a was obtained from 6a in 76% yield, mp 183-
1
185° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.87 (d, 1H,
(C-6), 98.3 (C-3), 61.6 (O-CH ), 44.2 (N-CH ), 22.9 (acetyl
2
2
H-5, J = 4.4 Hz), 8.54 (s, 1H, H-2), 8.19 (d, 2H, H-2' and H-6'),
5,6
CH ), 13.8 (O-ethyl CH ), 13.3 (N-ethyl CH ); ms: (m/z) 352
3
3
3
7.39 (d, 2H, H-3' and H-5'), 7.25 (d, 1H, H-6, J = 4.4 Hz), 3.79
5,6
+
(M ), 310, 309, 295, 267, 249, 221.
Anal. Calcd. for C N O : C, 64.76; H, 5.72; N, 15.90.
(q, 2H, N-CH ), 1.92 (bs, 3H, acetyl CH ), 1.33 (t, 3H, N-ethyl
2
3
H
19 20
4 3
13
CH ); C-nmr (deuteriochloroform): δ 169.7 (C=O), 156.5 (C-
3
Found: C, 64.61; H, 5.49; N, 15.66.
3a), 156.1 (C-5), 154.7 (C-2), 147.3 (C-7), 146.3 (C-4'), 131.0
(C-2' and C-6'), 129.1 (C-1'), 128.8 (C-3' and C-5'), 109.4 (C-6),
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-cyano-6-ethoxycar-
bonyl-pyrazolo[1,5-a]pyrimidine (7h).
44.6 (N-CH ), 23.2 (acetyl CH ), 13.6 (N-ethyl CH ); ms: (m/z)
2
3
3
+
281 (M ), 239, 224, 211.
Anal. Calcd. for C
This compound was obtained from 6b in 58% yield, mp 229-
H
N O: C, 64.04; H, 5.37; N, 24.90.
5
1
15 15
232° (methanol); H-nmr (deuteriochloroform): δ 9.20 (s, 1H, H-
Found: C, 64.12; H, 5.20; N, 24.68.
5), 8.40 (s, 1H, H-2), 7.58 (d, 2H, H-2' and H-6', J
= 8.8 Hz),
ortho
7.37 (d, 2H, H-3' and H-5', J
= 8.8 Hz), 4.20 (q, 2H, O-CH ),
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-ethoxycarbonyl-1,2,4-
triazolo[1,5-a]pyrimidine (8b).
ortho
2
3.80 (q, 2H, N-CH ), 1.94 (bs, 3H, acetyl CH ), 1.16 (t, 3H, O-
2
3
13
ethyl CH ), 1.11 (t, 3H, N-ethyl CH ); C-nmr (deuteriochloro-
3
3
Compound 8b was obtained from 6b in 68% yield, mp 150-
form): δ 169.8 (acetyl C=O), 163.4 (ethoxycarbonyl C=O), 154.0
(C-5), 151.3 (C-3a), 149.8 (C-7), 148.9 (C-2), 145.7 (C-4'), 131.0
(C-2' and C-6'), 128.3 (C-3' and C-5'), 128.2 (C-1'), 114.9 (CN),
1
152° (ethyl acetate/n-hexane); H-nmr (deuteriochloroform): δ
9.28 (d, 1H, H-5, J = 2.6 Hz), 8.47 (d, 1H, H-2, J = 2.6 Hz),
2,5
2,5

Sep-Oct 2001
Synthesis of Pyrazolo[1,5-a]-, 1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines
1125
7.61 (d, 2H, H-2' and H-6'), 7.33 (d, 2H, H-3' and H-5'), 4.17 (q,
2H, O-CH ), 3.76 (q, 2H, N-CH ), 1.89 (s, 3H, acetyl CH ), 1.12
d ): δ 174.6 (6-CONH ), 168.4 (acetyl C=O), 162.9 (3-CONH ),
6 2 2
158.0 (C-3a), 156.5 (C-5), 148.4 (C-7), 145.5 (C-4'), 144.7 (C-2),
130.6 (C-1'), 130.5 (C-2' and C-6'), 128.2 (C-3' and C-5'), 106.6
2
2
3
13
(t, 3H, O-ethyl CH ), 1.07 (t, 3H, N-ethyl CH ); C-nmr (deu-
3
3
teriochloroform): δ 169.3 (acetyl C=O), 163.3 (ethoxycarbonyl
C=O), 157.4 (C-2), 155.9 (C-5), 155.8 (C-3a), 149.4 (C-7), 145.3
(C-1' and C-4'), 130.7 (C-2' and C-6'), 128.0 (C-3' and C-5'),
(C-6), 98.9 (C-3), 43.4 (N-CH ), 22.7 (acetyl CH ), 13.1 (N-ethyl
2 3
+
CH ); ms: (m/z) 366 (M ), 350, 338, 324, 292, 280, 265.
3
Anal. Calcd. for C
H N O : C, 59.01; H, 4.95; N, 22.94.
18 18 6 3
114.2 (C-6), 62.2 (O-CH ), 44.2 (N-CH ), 22.9 (acetyl CH ),
Found: C, 59.31; H, 4.68; N, 23.15.
2
2
3
+
13.7 (O-ethyl CH ), 13.3 (N-ethyl CH ); ms: (m/z) 353 (M ),
3
3
5-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-carboxamidopyra-
zolo[1,5-a]pyrimidine (9c).
312, 296, 268, 250, 222.
Anal. Calcd. for C
H N O : C, 61.18; H, 5.42; N, 19.82.
18 19 5 3
This compound was obtained from 9b in 61% yield, mp 210-
Found: C, 61.41; H, 5.33; N, 19.59.
1
213° (ethyl acetate); H-nmr (DMSO-d ): δ 9.28 (s, 1H, H-7),
6
General Procedure for the Preparation of 6-Carboxamido-
pyrazolo[1,5-a]pyrimidines 7j-l , 9c and 6-Carboxamido-1,2,4-
triazolo[1,5-a]pyrimidine 8c.
8.32 (d, 1H, H-2, J = 2.2 Hz), 8.20 (bs, 1H, CONH ), 7.76 (d,
2,3
2
2H, H-2' and H-6'), 7.75 (bs, 1H, CONH ), 7.39 (d, 2H, H-3' and
2
H-5'), 6.79 (d, 1H, H-3, J = 2.2 Hz), 3.67 (q, 2H, N-CH ), 1.79
2,3
2
13
A solution of each compound 7g-i, 9b or 8b (0.01 mole) in
methanol saturated with ammonia (100 ml) was stirred at room
temperature until tlc on silica gel (ethyl acetate) indicated that the
starting material had disappeared (about 3 days). The solvent was
evaporated to dryness and the residue crystallized.
(bs, 3H, acetyl CH ), 1.02 (t, 3H, N-ethyl CH ); C-nmr (deu-
3
3
teriochloroform): δ 170.2 (acetyl C=O), 166.6 (CONH ), 159.2
2
(C-5), 155.2 (C-3a), 147.7 (C-2), 144.7 (C-4'), 137.0 (C-7), 130.5
(C-2' and C-6'), 130.0 (C-1'), 128.6 (C-3' and C-5'), 116.6 (C-6),
98.4 (C-3), 44.6 (N-CH ), 23.1 (acetyl CH ), 13.5 (N-ethyl CH );
2
3
3
+
ms: (m/z) 323 (M ), 305, 281, 266, 248, 221.
Anal. Calcd. for C N O : C, 63.14; H, 5.30; N, 21.66.
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-carboxamidopyra-
zolo[1,5-a]pyrimidine (7j).
H
17 17
5 2
Found: C, 63.34; H, 5.44; N, 21.60.
This compound was obtained from 7g in 69% yield, mp 244-
246° (ethyl acetate); H-nmr (deuteriochloroform) δ 8.85 (s, 1H, H-
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-carboxamido-1,2,4-tria-
zolo[1,5-a]pyrimidine (8c).
1
5), 8.20 (d, 1H, H-2, J = 2.2 Hz), 7.80 (d, 2H, H-2' and H-6', J
2,3
ortho
= 8.0 Hz), 7.41 (d, 2H, H-3' and H-5', J
= 8.0 Hz), 6.84 (d, 1H,
Compound 8c was obtained from 8b in 68% yield, mp 252-
ortho
1
H-3, J = 2.2 Hz), 6.12 (bs, 1H, CONH ), 5.87 (bs, 1H, CONH ),
255° (methanol); H-nmr (DMSO-d ): δ 11.26 (bs, 1H, CONH ),
2,3
2
2
6
2
3.81 (q, 2H, N-CH ), 1.97 (bs, 3H, acetyl CH ), 1.19 (t, 3H, N-ethyl
10.93 (bs, 1H, CONH ), 8.28 (s, 1H, H-5), 8.07 (s, 1H, H-2), 7.73
2
3
2
13
CH ); C-nmr (deuteriochloroform) δ 169.9 (acetyl C=O), 166.4
(d, 2H, H-2' and H-6'), 7.57 (d, 2H, H-3' and H-5'), 3.68 (q, 2H,
3
13
(CONH ), 149.2 (C-5), 149.1 (C-3a), 147.0 (C-2), 145.6 (C-7),
N-CH ), 1.87 (s, 3H, acetyl CH ), 1.04 (t, 3H, N-ethyl CH ); C-
2
2
3
3
145.3 (C-4'), 131.4 (C-2' and C-6'), 128.8 (C-3' and C-5'), 128.4 (C-
nmr (DMSO-d ): δ 175.0 (CONH ),168.5 (acetyl C=O), 159.8
6 2
1'), 115.9 (C-6), 98.4 (C-3), 44.8 (N-CH ), 23.2 (acetyl CH ), 13.7
(C-5), 158.3 (C-3a), 153.9 (C-2), 145.7 (C-7 and C-4'), 130.6 (C-
2' and C-6'), 130.5 (C-1'), 128.3 (C-3' and C-5'), 99.7 (C-6), 43.4
2
3
+
(N-ethyl CH ); ms: (m/z) 323 (M ), 280, 266, 249, 221.
3
Anal. Calcd. for C
Found: C, 62.96; H, 5.29; N, 21.76.
H
N O : C, 63.14; H, 5.30; N, 21.66.
(N-CH ), 22.7 (acetyl CH ), 13.2 (N-ethyl CH ); ms: (m/z) 324
17 17
5
2
2 3 3
+
(M ), 281, 267, 254, 239, 146, 131.
Anal. Calcd. for C N O : C, 59.25; H, 4.97; N, 25.91.
H
16 16
6 2
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-carboxamido-3-
cyanopyrazolo[1,5-a]pyrimidine (7k).
Found: C, 59.37; H, 5.12; N, 25.69.
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-[(dimethylaminometh-
ylene)carboxamido]-pyrazolo[1,5-a]pyrimidine (10).
This compound was obtained from 7h in 81% yield, mp 287-
290° (methanol); H-nmr (deuteriochloroform) δ 11.70 (bs, 1H,
1
CONH ), 10.68 (bs, 1H, CONH ), 8.25 (s, 1H, H-5), 7.87 (s, 1H,
A solution of 7f (3.2 g, 0.01 mole) in a 1:1 mixture of N,N-
dimethylformamide dimethyl acetal and ethylene glycol
monomethyl ether (40 ml) was stirred at 120° for 2 hours. After
cooling, the precipitate which had formed was isolated by filtra-
2
2
H-2), 7.77 (d, 2H, H-2' and H-6'), 7.54 (d, 2H, H-3' and H-5'),
3.88 (q, 2H, N-CH ), 2.07 (bs, 3H, acetyl CH ), 1.24 (t, 3H, N-
2
3
13
ethyl CH ); C-nmr (deuteriochloroform) δ 174.9 (CONH ),
3
2
168.4 (acetyl C=O), 158.1 (C-5), 157.5 (C-3a), 153.8 (C-7),
145.7 (C-4' and C-2), 130.6 (C-2' and C-6'), 130.4 (C-1'), 128.2
(C-3' and C-5'), 113.5 (CN), 99.7 (C-6), 82.4 (C-3), 43.4 (N-
tion and crystallized from methanol; yield 3.0 g (79%), mp 267-
1
270°; H-nmr (deuteriochloroform): δ 8.79 (d, 1H, H-5, J = 4.4
5,6
Hz), 8.78 (s, 1H, H-2), 8.70 (s, 1H, amidinic CH), 8.11 (d, 2H, H-
CH ); 22.7 (acetyl CH ), 13.1 (N-ethyl CH ); ms: (m/z) 348
2' and H-6'), 7.37 (d, 2H, H-3' and H-5'), 7.03 (d, 1H, H-6 J
=
2
3
3
5,6
+
(M ), 306, 291, 263, 170, 161, 131.
Anal. Calcd. for C N O : C, 62.06; H, 4.63; N, 24.13.
4.4 Hz), 3.78 (q, 2H, N-CH ), 3.22 (s, 3H, N-CH ), 3.17 (s, 3H,
2 3
H
N-CH ), 1.92 (bs, 3H, acetyl CH ), 1.14 (t, 3H, N-ethyl CH );
3 3 3
18 16
6
2
+
Found: C, 62.12; H, 4.38; N, 23.98.
ms: (m/z) 378 (M ), 349, 335, 307, 280, 238, 211.
Anal. Calcd. for C N O : C, 63.47; H, 5.86; N, 22.21.
H
20 22
6 2
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3,6-dicarboxamidopyra-
zolo[1,5-a]pyrimidine (7l).
Found: C, 63.40; H, 5.57; N, 22.39.
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-(1H-1,2,4-triazol-3-yl)-
pyrazolo[1,5-a]pyrimidine (11).
This compound was obtained from 7i in 59% yield, mp >300°
1
(methanol); H-nmr (DMSO-d ): δ 11.23 (bs, 1H, CONH ),
6
2
10.82 (bs, 1H, CONH ), 8.21 (s, 1H, H-5), 7.95 (s, 1H, H-2), 7.74
(d, 2H, H-2' and H-6'), 7.56 (d, 2H, H-3' and H-5'), 7.52 (bs, 1H,
To a solution of hydrazine hydrate (0.75 g, 0.015 mole) in acetic
acid (25 ml) was added compound 10 (3.8 g, 0.01 mole). The reac-
tion mixture was stirred at 90° for 2 hours, then evaporated under
reduced pressure. The resulting solid was suspended in a sodium
2
CONH ), 7.32 (bs, 1H, CONH ), 3.75 (q, 2H, N-CH ), 1.86 (s,
2
2
2
13
3H, acetyl CH ), 1.04 (t, 3H, N-ethyl CH ); C-nmr (DMSO-
3
3

1126
C. Mustazza, M. R. Del Giudice, A. Borioni and F. Gatta
Vol. 38
carbonate solution, collected by filtration, washed with water and
finally crystallized from methanol; yield 2.3 g (66%), mp 292-295°;
H-nmr (deuteriochloroform): δ 8.80 (s, 1H, H-2), 8.71 (d, 1H, H-5,
ride (3.8 g, 0.04 mole) was added followed by a solution of each
compound 6 (0.04 mole) in anhydrous ethanol (100 ml). The
reaction mixture was refluxed for 4 hours, evaporated under
reduced pressure and the residue treated with water (200 ml). The
crystalline precipitate was isolated by filtration and crystallized.
Compound 14a was obtained from 6a in 60% yield, mp 165-
1
J
= 4.4 Hz), 8.17 (d, 2H, H-2' and H-6'), 8.06 (s, 1H, triazole CH),
5,6
7.40 (d, 2H, H-3' and H-5'), 7.11 (d, 1H, H-6, J = 4.4 Hz), 3.81 (q,
5,6
2H, N-CH ), 1.94 (bs, 3H, acetyl CH ), 1.16 (t, 3H, N-ethyl CH );
2
3
3
13
1
C-nmr (deuteriochloroform): δ 169.8 (C=O), 151.1 (C-5), 150.6
167° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.33 (d, 1H,
(triazole C-5), 149.1 (C-3a), 147.3 (triazole C-3), 147.0 (C-7), 146.2
(C-4'), 143.6 (C-2), 131.1 (C-2' and C-6'), 129.4 (C-1'), 128.8 (C-3'
H-6, J = 5.2 Hz), 8.00 (d, 2H, H-2' and H-6'), 7.22 (d, 2H, H-3'
5,6
and H-5'), 6.98 (d, 1H, H-5, J = 5.2 Hz), 5.39 (s, 2H, NH ),
5,6
2
and C-5'), 108.8 (C-6), 99.8 (C-3), 44.6 (N-CH ), 23.3 (acetyl
3.73 (q, 2H, N-CH ), 1.82 (s, 3H, acetyl CH ), 1.07 (t, 3H, N-
2
2
3
+
+
CH ), 13.6 (N-ethyl CH ); ms: (m/z) 347 (M ), 305, 290, 248, 208.
ethyl CH ); ms: (m/z) 256 (M ), 214, 199, 186, 170.
3
3
3
Anal. Calcd. for C
H
N O: C, 62.23; H, 4.93; N, 28.23.
Anal. Calcd. for C H N O: C, 65.60; H, 6.29; N, 21.86.
18 17
7
14 16 4
Found: C, 65.61; H, 6.18; N, 21.57.
Found: C, 62.38; H, 4.69; N, 28.18.
Compound 14b was obtained from 6b in 75% yield, mp 202-
204° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.86 (s, 1H,
H-6), 7.56 (d, 2H, H-2' and H-6'), 7.20 (d, 2H, H-3' and H-5'),
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-[(N-hydroxy)carboxy-
imidamido]-pyrazolo[1,5-a]pyrimidine (12).
1
To a stirred suspension of potassium carbonate (5.6 g, 0.04
mole) and 7e (6 g, 0.02 mole) in 10% aqueous ethanol (80 ml)
hydroxylamine hydrochloride (2 g, 0.03 mole) was added. The
reaction mixture was heated at reflux for 2 hours, then stirred
overnight at room temperature. The precipitate which had formed
was isolated by filtration, washed with water, then crystallized
5.66 (s, 2H, NH ), 4.14 (q, 2H, O-CH ), 3.75 (q, 2H, N-CH ),
2
2
2
1.86 (s, 3H, acetyl CH ), 1.10 (t, 6H, O-ethyl CH and N-ethyl
3
3
+
CH ); ms: (m/z) 328 (M ), 286, 271.
3
Anal. Calcd. for C
H N O : C, 62.18; H, 6.14; N, 17.06.
17 20 4 3
Found: C, 62.02; H, 6.30; N, 17.04.
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-imidazo[1,2-a]pyrimidine
(3a).
1
from ethanol; yield 3.5 g (52%), mp 266-269°; H-nmr (DMSO-
d ): δ 9.38 (s, 1H, NOH), 8.68 (d, 1H, H-5, J = 4.4 Hz), 8.42 (s,
6
5,6
1H, H-2), 8.20 (d, 2H, H-2' and H-6'), 7.54 (d, 2H, H-3' and H-5'),
7.35 (d, 1H, H-6, J = 4.4 Hz), 6.02 (bs, 2H, NH ), 3.72 (q, 2H,
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-6-ethoxycarbonylimi-
dazo[1,2-a]pyrimidine (3b).
5,6
2
N-CH ), 1.86 (bs, 3H, acetyl CH ), 1.04 (t, 3H, N-ethyl CH );
2
3
3
+
A mixture of bromoacetaldehyde dimethyl acetal (3.4 g, 0.02
mole), anhydrous sodium acetate (1.65 g, 0.02 mole) and the
appropriate 14 (0.01 mole) in glacial acetic acid (15 ml) was
stirred and refluxed for 20 hours, then poured into a saturated
aqueous sodium carbonate solution (200 ml) and extracted with
ethyl acetate. The solvent was evaporated under reduced pressure
and the residue was subjected to column chromatography over
alumina using 5% methanol in ethyl acetate as eluent.
ms: (m/z) 338 (M ), 305, 248.
Anal. Calcd. for C N O : C, 60.34; H, 5.36; N, 24.84.
H
17 18
6 2
Found: C, 60.60; H, 5.18; N, 24.58.
7-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-(5-methyl-1,2,4-oxadia-
zol-3-yl)-pyrazolo[1,5-a]pyrimidine (13).
To a stirred mixture of 12 (3.4 g, 0.01 mole) in glacial acetic
acid (30 ml) a solution of acetic anhydride (1.5 g, 0.015 mole) in
glacial acetic acid (10 ml) was dropwise added. The mixture was
refluxed for 1 hour, cooled, poured into ice water and extracted
with ethyl acetate. The organic phase was washed with 20%
sodium carbonate solution and then water. The residue obtained
after solvent evaporation was crystallized from ethyl acetate;
Compound 3a was obtained from 14a in 38% yield, mp 200-
1
202° (ethyl acetate); H-nmr (deuteriochloroform): δ 8.50 (d, 1H,
H-5, J = 7.0 Hz), 8.22 (d, 2H, H-2' and H-6'), 7.82 (d, 1H, H-2,
5,6
J
= 1.6 Hz), 7.55 (d, 1H, H-3, J = 1.6 Hz), 7.36 (d, 1H, H-6, J
2,3
2,3 5,6
= 7.0 Hz), 7.29 (d, 2H, H-3' and H-5'), 3.77 (q, 2H, N-CH ), 1.87 (s,
2
13
1
3H, acetyl CH ), 1.12 (t, 3H, N-ethyl CH ); C-nmr (deuteriochlo-
yield g 1.7 (47%), mp 214-216°; H-nmr (deuteriochloroform): δ
3
3
roform): δ 169.9 (C=O), 155.9 (C-8a), 148.8 (C-7), 145.1 (C-4'),
136.5 (C-1'), 136.1 (C-2), 133.9 (C-5), 128.8 (C-2', C-3', C-5' and
C-6'), 111.0 (C-3), 106.3 (C-6), 44.2 (N-CH ), 23.2 (acetyl CH ),
8.81 (d, 1H, H-5, J = 4.4 Hz), 8.71 (s, 1H, H-2), 8.14 (d, 2H, H-
5,6
2' and H-6'), 7.38 (d, 2H, H-3' and H-5'), 7.08 (d, 1H, H-6, J
=
5,6
4.4 Hz), 3.79 (q, 2H, N-CH ), 2.68 (s, 3H, oxadiazole CH ), 1.93
2
3
2
3
+
13
13.5 (N-ethyl CH ); ms: (m/z) 280 (M ), 238, 223, 211, 194.
(bs, 3H, acetyl CH ), 1.15 (t, 3H, N-ethyl CH ); C-nmr (deu-
3
3
3
Anal. Calcd. for C
H N O: C, 68.55; H, 5.75; N, 19.99.
teriochloroform): δ 176.6 (oxadiazole C-5), 169.8 (C=O), 162.8
(oxadiazole C-3), 151.7 (C-5), 147.5 (C-3a), 146.8 (C-7), 145.9
(C-4'), 145.0 (C-2), 131.1 (C-2' and C-6'), 129.9 (C-1'), 128.7 (C-
16 16 4
Found: C, 68.82; H, 6.01; N, 19.67.
Compound 3b was obtained from 14b in 32% yield, mp 150-
1
152° (ethyl acetate/n-hexane); H-nmr (deuteriochloroform): δ
3' and C-5'), 109.0 (C-6), 99.4 (C-3), 44.6 (N-CH ), 23.2 (acetyl
2
9.17 (s, 1H, H-5), 7.92 (d, 1H, H-2, J = 1.8 Hz), 7.73 (d, 1H, H-
CH ), 13.6 (N-ethyl CH ), 12.8 (oxadiazole CH ); ms: (m/z) 362
2,3
3
3
3
+
3, J = 1.8 Hz), 7.68 (d, 2H, H-2' and H-6'), 7.25 (d, 2H, H-3'
(M ), 320, 305, 263, 248, 209, 182.
2,3
and H-5'), 4.25 (q, 2H, O-CH ), 3.78 (q, 2H, N-CH ), 1.89 (s, 3H,
Anal. Calcd. for C N O : C, 62.97; H, 5.01; N, 23.19.
H
2
2
19 18
6 2
acetyl CH ), 1.16 (t, 3H, O-ethyl CH ), 1.12 (t, 3H, N-ethyl
Found: C, 63.10; H, 5.22; N, 22.98.
3
3
13
CH ); C-nmr (deuteriochloroform): δ 169.9 (acetyl C=O),
3
4-[4-(N-Acetyl-N-ethyl)aminophenyl]-2-aminopyrimidine
(14a).
165.0 (ethoxycarbonyl C=O), 157.5 (C-8a), 148.0 (C-7), 144.1
(C-4'), 138.3 (C-1'), 138.1 (C-2), 137.8 (C-5), 130.3 (C-2' and C-
6'), 127.9 (C-3' and C-5'), 114.2 (C-6), 111.7 (C-3), 62.3 (O-
4-[4-(N-Acetyl-N-ethyl)aminophenyl]-2-amino-5-ethoxycar-
bonylpyrimidine (14b).
CH ), 44.3 (N-CH ), 23.2 (acetyl CH ), 14.1 (O-ethyl CH ), 13.4
2
2
3
3
+
(N-ethyl CH ); ms: (m/z) 352 (M ), 310, 295, 281, 267, 237, 221.
3
To a solution of sodium ethoxide in anhydrous ethanol (60 ml),
prepared from sodium (1.0 g, 0.04 mole), guanidine hydrochlo-
Anal. Calcd. for C H N O : C, 64.76; H, 5.72; N, 15.90.
Found: C, 64.74; H, 5.91; N, 15.69.
19 20 4 3

Sep-Oct 2001
Synthesis of Pyrazolo[1,5-a]-, 1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines
1127
3-Cyano-6-[4-(N-formyl)aminophenyl]pyrazolo[1,5-a]pyrimi-
dine (17).
a saturated sodium carbonate solution (120 ml), filtered, washed
with water then crystallized from ethyl acetate/n-hexane; yield 2.2 g
1
(84%), mp 218-221°; H-nmr (deuteriochloroform): δ 8.93 (d, 1H,
Anhydrous dimethylformamide (7.3 g, 0.1 mole) was dropwise
added with vigorous stirring to phosphorus oxychloride (8 ml,
0.087 mole) maintaining the temperature at about 30° by intermit-
tent cooling. After the addition was complete, the mixture was
stirred for 5 minutes, then a solution of 4-acetamidophenylacetic
acid (15) (7.7 g, 0.04 mole) in dimethylformamide (20 ml) was
added over a period of 5 minutes. The mixture was stirred and
heated at 70° overnight, then poured into crushed ice (100 g) and
first neutralized by addition of potassium carbonate then made
strongly alkaline by 40% aqueous sodium hydroxide, maintaining
the temperature at about 50°. After evolution of dimethylamine
ceased, the mixture was cooled and extracted with ethyl acetate.
Evaporation of the solvent gave crude compound 16 as a viscous
dark red oil (4.7 g, 54%) which could not be purified by chro-
matography because of its instability. Moreover its spectral data
H-7, J = 2.2 Hz), 8.77 (d, 1H, H-5, J = 2.2 Hz), 8.34 (s, 1H,
5,7
5,7
H-2), 7.38 (d, 2H, H-2' and H-6'), 6.70 (d, 2H, H-3' and H-5'), 3.96
13
(bs, 1H, NH), 3.21 (q, 2H, N-CH ), 1.28 (t, 3H, N-ethyl CH ); C-
2
3
nmr (deuteriochloroform): δ 153.6 (C-5), 149.9 (C-3a), 148.1 (C-2),
139.0 (C-4'), 131.8 (C-7), 128.6 (C-2' and C-6'), 126.5 (C-1'), 121.0
(C-6), 114.0 (C-3' and C-5'), 113.4 (CN), 83.5 (C-3), 38.9 (N-CH ),
2
+
15.4 (N-ethyl CH ); ms: (m/z) 263 (M ), 248, 235, 165, 125.
3
Anal. Calcd. for C
H N : C, 68.42; H, 4.98; N, 26.60.
15 13 5
Found: C, 68.71; H, 4.73; N, 26.32.
6-[4-(N-Acetyl-N-ethyl)aminophenyl]-3-cyanopyrazolo[1,5-a]-
pyrimidine (20).
A solution of 19 (2.6 g, 0.01 mole) in a mixture of acetic anhy-
dride (100 ml) and glacial acetic acid (50 ml) was heated at 80°
for 2 hours. After cooling, the mixture was poured into ice water
and the precipitate filtered, washed with water, dried and crystal-
1
were consistent with the proposed structure: H-nmr (deuterio-
chloroform): δ 9.32 (s, 1H, aldehydic CHO), 8.96 (s, 1H, ethyl-
enic CH), 8.17 (s, 1H, N-CHO), 7.39 (d, 2H, aryl protons), 6.99
1
lized from ethyl acetate; yield 2.6 g (85%), mp 186-188°; H-nmr
(deuteriochloroform): δ 8.98 (d, 1H, H-7, J = 2.2 Hz), 8.92 (d,
5,7
(d, 2H, aryl protons), 6.84 (bs, 1H, NH), 2.53 and 1.96 (two s in a
1H, H-5, J = 2.2 Hz), 8.42 (s, 1H, H-2), 7.65 (d, 2H, H-3' and
+
5,7
2:1 ratio, 6H, N(CH ) ); ms: (m/z) 218 (M ).
3 2
H-5'), 7.36 (d, 2H, H-2' and H-6'), 3.78 (q, 2H, N-CH ), 1.89 (bs,
2
A mixture of crude 16 (4.4 g, 0.02 mole) and 3-amino-4-
cyanopyrazole (2.2 g, 0.02 mole) in acetic acid was refluxed for 2
hours. After cooling the precipitate which had formed was col-
lected by filtration, washed with methanol and dried to provide
13
3H, acetyl CH ), 1.14 (t, 3H, N-ethyl CH ); C-nmr (deuteri-
3
3
ochloroform): δ 170.3 (C=O), 153.2 (C-5), 149.6 (C-3a), 148.7
(C-2), 144.7 (C-4'), 133.7 (C-7), 132.7 (C-1'), 130.2 (C-2' and C-
6'), 129.1 (C-3' and C-5'), 125.0 (C-6), 113.0 (CN), 84.1 (C-3),
1
2.1 g (40%) of 17; mp 303-307°; H-nmr (DMSO-d ): δ 10.38
6
44.8 (N-CH ), 23.6 (acetyl CH ), 13.9 (N-ethyl CH ); ms: (m/z)
(bs, 1H, NH), 9.63 (s, 1H, H-7), 9.21 (s, 1H, H-5), 8.80 (s, 1H, N-
CHO), 8.32 (s, 1H, H-2), 7.84 (d, 1H, H-3' and H-5'), 7.73 (H-2'
2
3
3
+
305 (M ), 263, 248, 235, 220, 165.
13
Anal. Calcd. for C N O: C, 66.87; H, 4.95; N, 22.94.
H
and H-6'); C-nmr (DMSO-d ): δ 160.5 (N-CHO), 153.7 (C-5),
17 15
5
6
Found: C, 66.70; H, 5.23; N, 22.68.
149.1 (C-3a), 148.8 (C-2), 139.5 (C-4'), 134.4 (C-7), 128.4 (C-2'
and C-6'), 128.0 (C-1'), 124.5 (C-6), 120.3 (C-3' and C-5'), 114.0
6-[(N-Acetyl-N-ethyl)amino]-1-tetralone (21).
Part a) 6-[(N-acetyl-N-ethyl)amino]-1,2,3,4-tetrahydronaphtalene.
+
(CN), 81.5 (C-3); ms: (m/z) 263 (M ), 235, 207, 180, 148, 117.
Anal. Calcd. for C H N O: C, 63.87; H, 3.45; N, 26.61.
14
9 5
Found: C, 63.62; H, 3.38; N, 26.31.
This compound was obtained in 70% yield by N-ethylation of
the corresponding 6-acetamido derivative [20], according to the
same procedure previously described for the preparation of
1-[(N-acetyl-N-ethyl)aminophenyl]ethanone (5a): mp: 45-46°
3-Cyano-6-[4-(N-ethyl-N-formyl)aminophenyl]pyrazolo[1,5-a]-
pyrimidine (18).
Compound 17 (5.3 g, 0.02 mole) dissolved in anhydrous
dimethylformamide (50 ml) was added over 10 minutes to a
cooled and stirred suspension of sodium hydride (1 g, 50% oil
dispersion, 0.022 mole) in dimethylformamide (50 ml). The mix-
ture was allowed to warm to room temperature and stirred for 1
hour. It was then cooled in an ice water bath and ethyl iodide (1.6
ml, 0.02 mole) was dropwise added. The mixture was stirred at
room temperature for 3 hours, then carefully diluted with ice
water. The precipitate was collected by filtration, washed with
1
(cyclohexane); H-nmr (deuteriochloroform): δ: 7.04 (d, 1H, H-
7), 6.80 (d and s, 2H, H-8 and H-5), 3.67 (q, 2H, N-CH ), 2.73
2
(um, 4H, H-1 and H-4), 1.78 (s and um, 7H, acetyl CH , H-2 and
3
+
H-3), 1.06 (t, 3H, N-ethyl CH ); ms: (m/z) 217 (M ), 175, 160,
3
147, 132.
Anal. Calcd. for C
H NO: C, 77.38; H, 8.81; N, 6.45. Found:
14 19
C, 77.40; H, 8.99; N, 6.18.
Part b)
water, dried and crystallized from ethyl acetate; yield 4.0 g
To a solution of the above reported tetraline (6.5 g, 0.03 mole)
in acetic acid (15 ml) and acetic anhydride (5 ml) was dropwise
added a solution of chromium trioxide (4.5 g, 0.045 mole) in
water (5 ml) and acetic acid (15 ml), maintaining the temperature
below 10° by external cooling. After stirring overnight, the solu-
tion was poured into ice water and extracted with
dichloromethane. The solvent was removed and the residue chro-
matographed on a silica gel column by eluting with ethyl acetate;
1
(69%), mp 248-251°; H-nmr (DMSO-d ): δ 9.73 (d, 1H, H-7,
6
J
= 2.2 Hz), 9.25 (d, 1H, H-5, J = 2.2 Hz), 8.84 (s, 1H,
5,7
5,7
CHO), 8.51 (s, 1H, H-2), 7.95 (d, 2H, H-3' and H-5'), 7.52 (d, 2H,
H-2' and H-6'), 3.85 (q, 2H, N-CH ), 1.07 (t, 3H, N-ethyl CH );
2
3
+
ms: (m/z) 291 (M ), 263, 248, 236, 220, 165, 124.
Anal. Calcd. for C N O: C, 65.97; H, 4.50; N, 24.04.
H
16 13
5
Found: C, 66.00; H, 4.33; N, 23.80.
3-Cyano-6-[4-(N-ethyl)aminophenyl]-pyrazolo[1,5-a]pyrimidine
(19).
1
yield 3.6 g (52%), viscous oil; H-nmr (deuteriochloroform): δ
8.05 (d, 1H, H-8), 7.06 (d, 1H, H-7), 7.04 (s, 1H, H-5), 3.73 (q,
2H, N-CH ), 2.96 (t, 2H, H-2), 2.65 (t, 2H, H-4), 2.14 (quintet,
A solution of 18 (2.9 g, 0.01 mole) in methanol (50 ml) containing
concentrated hydrochloric acid (12 ml) was refluxed for 5 hours.
After cooling the solvent was removed and the residue suspended in
2
2H, H-3), 1.86 (s, 3H, acetyl CH ), 1.09 (t, 3H, N-ethyl CH );
3
3
+
ms: (m/z) 231 (M ), 189, 174, 161, 145, 133, 115.

1128
C. Mustazza, M. R. Del Giudice, A. Borioni and F. Gatta
Vol. 38
Anal. Calcd. for C
H
NO : C, 72.70; H, 7.41; N, 6.06.
1H, CONH ), 7.31 (dd, 1H, H-10, J
= 8.4 Hz, J = 2.2 Hz),
8,10
14 17
2
2
10,11
7.21 (d, 1H, H-8, J
= 2.2 Hz), 6.10 (bs, 1H, CONH ), 3.83 (q,
Found: C, 72.52; H, 7.68; N, 6.00.
8,10
2
2H, N-CH ), 3.08 (s, 4H, H-6 and H-7), 1.97 (s, 3H, acetyl CH ),
2
3
General Procedure for the Preparation of the Tetracyclic
Compounds 4a-d and 23.
13
1.18 (t, 3H, N-ethyl CH ); C-nmr (deuteriochloroform): δ
3
170.2 (acetyl C=O), 164.8 (CONH ), 151.6 (C-5), 148.2 (C-3a),
2
146.8 (C-2), 146.4 (C-11b), 142.7 (C-9), 141.0 (C-7a), 131.8
(C-11), 128.2 (C-8), 127.3 (C-10), 125.7 (C-11a), 119.1 (C-5a),
A solution of 21 (11.6 g, 0.05 mole) in N,N-dimethylfor-
mamide dimethyl acetal (60 ml) was refluxed for 8 hours. The
reaction was monitored by tlc (silica gel, ethyl acetate). The sol-
vent was removed under reduced pressure and the crude enam-
inone derivative 22 was immediately condensed with 3-aminopy-
razole (to obtain 4a and 23), 3-amino-4-cyanopyrazole (to obtain
4b), 3-amino-4-carboxamidopyrazole (to obtain 4c) or 3-amino-
1,2,4-triazole (to obtain 4d) (0.05 mole) in refluxing glacial
acetic acid (80 ml) for 3 hours. After cooling the solvent was
evaporated and the residue purified by chromatography on silica
gel with ethyl acetate. Isomers 4a and 23 were separated by col-
umn chromatography using ethyl acetate as eluent. Compound 4a
was eluted first followed by the isomer 23. The yields of all com-
pounds have been calculated from starting tetralone 21.
105.3 (C-3), 44.8 (N-CH ), 29.0 (C-7), 24.6 (C-6), 23.7 (acetyl
2
+
CH ), 14.1 (N-ethyl CH ); ms: (m/z) 349 (M ), 333, 307, 292,
3
3
275, 263, 247, 219.
Anal. Calcd. for C
H N O : C, 65.31; H, 5.48; N, 20.05.
19 19 5 2
Found: C, 65.05; H, 5.77; N, 20.05.
9-[(N-Acetyl-N-ethyl)amino]-6,7-dihydrobenzo[h]1,2,4-tria-
zolo[1,5-a]quinazoline (4d).
This compound was obtained by condensation of 21 with
3-amino-1,2,4-triazole in 54% yield; mp 146-148° (methanol);
1
H-nmr (deuteriochloroform): δ 9.34 (d, 1H, H-11, J
= 8.6
10,11
Hz), 8.76 (s, 1H, H-5), 8.56 (s, 1H, H-2), 7.29 (dd, 1H, H-10,
= 8.6 Hz, J = 2.4 Hz), 7.21 (d, 1H, H-8, J = 2.4 Hz),
J
10,11
8,10
8,10
9-[(N-Acetyl-N-ethyl)amino]-6,7-dihydro-benzo[h]pyrazolo[1,5-a]-
quinazoline (4a).
3.79 (q, 2H, N-CH ), 3.09 (s, 4H, H-6 and H-7), 1.94 (s, 3H,
2
13
acetyl CH ), 1.15 (t, 3H, N-ethyl CH ); C-nmr (deuteriochloro-
3
3
form): δ 169.7 (C=O), 156.1 (C-3a), 155.5 (C-2), 154.7 (C-5),
146.1 (C-11b), 141.9 (C-9), 140.8 (C-7a), 131.1 (C-11), 127.9
This compound was obtained by condensation of 21 with
3-aminopyrazole in 34% yield; mp 174-175° (ethyl acetate/n-
1
(C-8), 127.0 (C-10), 125.2 (C-11a), 119.3 (C-5a), 44.4 (N-CH ),
hexane); H-nmr (deuteriochloroform): δ 9.50 (d, 1H, H-11, J
2
10,11
28.5 (C-7), 23.9 (C-6), 23.2 (acetyl CH ), 13.7 (N-ethyl CH );
ms: (m/z) 307 (M ), 265, 250, 221, 174, 140.
= 8.4 Hz), 8.45 (s, 1H, H-5), 8.19 (d, 1H, H-2, J = 2.4 Hz), 7.27
3
3
2,3
+
(dd, 1H, H-10, J
= 8.4 Hz, J
= 2.2 Hz), 7.17 (d, 1H, H-8,
10,11
8,10
Anal. Calcd. for C N O: C, 66.43; H, 5.58; N, 22.79.
H
J
= 2.2 Hz), 6.78 (d, 1H, H-3, J = 2.4 Hz), 3.81 (q, 2H,
17 17
5
8,10
2,3
N-CH ), 3.02 (s, 4H, H-6 and H-7), 1.94 (s, 3H, acetyl CH ), 1.16
Found: C, 66.35; H, 5.81; N, 22.58.
2
3
13
(t, 3H, N-ethyl CH ); C-nmr (deuteriochloroform): δ 169.8
3
3-[(N-Acetyl-N-ethyl)amino]-5,6-dihydrobenzo[h]pyrazolo[5,1-b]-
quinazoline (23).
(C=O), 150.1 (C-3a), 149.3 (C-5), 145.0 (C-11b), 144.2 (C-2),
141.8 (C-9), 138.9 (C-7a), 130.7 (C-11), 127.6 (C-8), 126.7
This compound was obtained by condensation of 21 with
3-aminopyrazole in 30% yield; mp 125-127° (ethyl acetate); H-
(C-10), 126.3 (C-11a), 117.1 (C-5a), 97.2 (C-3), 44.3 (N-CH ),
2
1
28.8 (C-7), 24.1 (C-6), 23.2 (acetyl CH ), 13.6 (N-ethyl CH ); ms:
3
3
+
nmr (deuteriochloroform): δ 9.40 (d, 1H, H-4, J = 2.2 Hz), 8.45
(m/z) 306 (M ), 278, 264, 249, 236, 231, 189, 174, 161, 115.
2,4
(s, 1H, H-7), 8.19 (d, 1H, H-10, J
= 2.6 Hz), 7.41 (d, 1H, H-1,
Anal. Calcd. for C N O: C, 70.56; H, 5.92; N, 18.29.
Found: C, 70.30; H, 5.98; N, 18.02.
H
10,11
18 18
4
J
= 7.8 Hz), 7.26 (dd, 1H, H-2, J = 7.8 Hz, J = 2.2 Hz),
1,2
1,2 2,4
6.78 (d, 1H, H-11, J
= 2.6 Hz), 3.84 (q, 2H, N-CH ), 3.03 (s,
2
10,11
9-[(N-Acetyl-N-ethyl)amino]-3-cyano-6,7-dihydro-benzo[h]-
pyrazolo[1,5-a]quinazoline (4b).
4H, H-5 and H-6), 1.96 (s, 3H, acetyl CH ), 1.18 (t, 3H, N-ethyl
3
13
CH ); C-nmr (deuteriochloroform): δ 170.3 (C=O), 149.9
3
(C-12a), 149.2 (C-7), 144.3 (C-10), 141.7 (C-3), 139.4 (C-11a),
138.9 (C-4a), 130.5 (C-2), 129.6 (C-4), 129.2 (C-1), 128.1
This compound was obtained by condensation of 21 with
3-amino-4-cyanopyrazole in 62% yield; mp 224-227°
1
(C-12b), 117.2 (C-6a), 97.2 (C-11), 44.2 (N-CH ), 28.4 (C-5),
(methanol); H-nmr (DMSO-d ): δ 9.18 (d, 1H, H-11, J
= 8.4
2
6
10,11
24.2 (C-6), 23.4 (acetyl CH ), 13.4 (N-ethyl CH ); ms: (m/z) 306
Hz), 8.88 (s, 1H, H-5), 8.84 (s, 1H, H-2), 7.46 (s, 1H, H-8), 7.43
(d, 1H, H-10, J = 8.4 Hz), 3.71 (q, 2H, N-CH ), 3.02 (s, 4H,
3
3
+
(M ), 278, 264, 249, 220, 194, 166.
10,11
2
Anal. Calcd. for C N O: C, 70.56; H, 5.92; N, 18.29.
H
H-6 and H-7), 1.87 (s, 3H, acetyl CH ), 1.04 (t, 3H, N-ethyl
18 18
4
3
13
Found: C, 70.77; H, 5.71; N, 18.40.
CH ); C-nmr (DMSO-d ): δ 168.4 (C=O), 153.5 (C-5), 150.6
3
6
(C-3a), 146.8 (C-2), 145.4 (C-11b), 142.4 (C-9), 139.9 (C-7a),
130.1 (C-11), 127.5 (C-8), 125.9 (C-10), 123.8 (C-11a), 120.5
Acknowledgements.
(C-5a), 113.5 (CN), 80.9 (C-3), 43.3 (N-CH ), 27.1 (C-7), 22.9
We wish to thank Prof. Ennio Ongini for pharmacological
assays, Dr. L. Turchetto for mass spectral data and Mr. R. Lecce
for microanalyses.
2
(C-6), 22.7 (acetyl CH ), 13.2 (N-ethyl CH ); ms: (m/z) 331
3
3
+
(M ), 289, 274, 245, 218, 191, 140, 127.
Anal. Calcd. for C N O: C, 68.86; H, 5.17; N, 21.14.
H
19 17
5
Found: C, 68.68; H, 5.38; N, 21.08.
REFERENCES AND NOTES
9-[(N-Acetyl-N-ethyl)amino]-3-carboxamido-6,7-dihydrobenzo-
[h]pyrazolo[1,5-a]quinazoline (4c).
[1] A. N. Vgontzas, A. Kales and E. O. Bixler, Pharmacology, 51,
205 (1995).
[2] D. B. Pritchett, H. Lüddens and P. H. Seeburg, Science, 245,
1389 (1989).
This compound was obtained by condensation of 21 with
3-amino-4-carboxamidopyrazole in 70% yield; mp >300°
1
(methanol); H-nmr (deuteriochloroform): δ 9.45 (d, 1H, H-11,
[3] H. L. Freeman, J. Drug Dev. Clin. Pract., 7, 289 (1996).
[4] J. D. Hoehns and P. J. Perry, Clin. Pharm., 12, 814 (1993).
J
= 8.4 Hz), 8.75 (s, 1H, H-5), 8.60 (s, 1H, H-2), 8.08 (bs,
10,11

Sep-Oct 2001
Synthesis of Pyrazolo[1,5-a]-, 1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines
1129
[5] K. E. Vanover, R. M. Mangano and J. E. Barrett, Drug
Develop. Res., 33, 39 (1994).
[12] P. Guerret, R. Jacquier and G. Maury, Bull. Soc. Chim. Fr.,
3503 (1972).
[6] T. Padmanathan, U.S. Patent 5,714,607; Chem. Abstr. 128,
154095h (1998).
[13] G. M. Coppola, G. E. Hardtmann and B. S. Huegi, J.
Heterocyclic Chem., 11, 51 (1974).
[7] J. P. Dusza, J. D. Albright, U.S. Patent 4,179,449; Chem.
Abstr. 92, 111055r (1980).
[14] H. Junek and W. Remp, Monatsh. Chem., 104, 433 (1973).
[15] A. Thomas, M. Chakraborty, H. Ila and H. Junjappa,
Tetrahedron, 46, 577 (1990).
[16] S. M. Desenko, V. D. Orlov, K. Estrada and S. M. Ivkov,
Khim. Geterotsikl. Soedin., 694 (1991); Chem. Abstr. 115, 256115p
(1991).
[17] W. J. Bruining, Rec. Trav. Chim. Pays-Bas, 41, 655 (1922).
[18] H. Dorn and A. Zubek, Org. Synth., 48, 8 (1968).
[19] R. K. Robins, J. Am. Chem. Soc., 78, 784 (1956).
[20] K. Schofield, T. Swain and R. S. Theobald, J. Chem. Soc.,
2399 (1949).
[8] J. I. Levin, J. W. Epstein, B. Beer, W. D. Dean, J. P. Dusza, S.
S. Tseng, H. J. Schweitzer, G. D. Francisco, W. T. Cain, R. T. Bartus and
R. L. Dean, Bioorg. Med. Chem. Lett., 1, 435 (1991).
[9] S. A. Petrich, Z. Qian, L. M. Santiago, J. Gupton and J. A.
Sikorski, Tetrahedron, 50, 12113 (1994).
[10] A. Maquestiau, H. Taghret and J.-J. Vanden Eynde, Bull. Soc.
Chim. Belg., 101, 131 (1992).
[11] R. J. Pugmire, J. C. Smith and D. M. Grant, J. Heterocyclic
Chem., 24, 805 (1987).