Synthesis of a new series of pyrazolo[1,5-a]pyrimidines structurally related to zaleplon

Article abstract of DOI:10.1002/jhet.5570440212

(Chemical Equation Presented) The reaction between 3-(dimethylamino)/3,3- bis(methylthio)-1-(substituted)prop-2-en-1-ones and 4-substituted-5-amino-1H- pyrazoles afforded new pyrazole[1,5-a]pyrimidines structurally related to Zaleplon. The chemical modifications introduced at the 3-, 5-, and 7-positions of the bicyclic structure revealed new promising candidates for the treatment of sleep disorders.

Full text of DOI:10.1002/jhet.5570440212

Mar-Apr 2007
355
Synthesis of a New Series of Pyrazolo[1,5-a]pyrimidines
Structurally Related to Zaleplon
Pier Giovanni Baraldi,*a Francesca Fruttarolo,a Mojgan Aghazadeh Tabrizi,a Romeo
Romagnoli,a Delia Preti,a Ennio Ongini,d Hussein El-Kashef,e María Dora Carrión,c
Pier Andrea Boreab.
a Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy
b Dipartimento di Medicina Clinica e Sperimentale-Sezione di Farmacologia,
Università di Ferrara, 4100 Ferrara, Italy
c Departamento de Química Farmacéutica y Orgánica, Campus Universitario de Cartuja s/n, Universidad de
Granada, 18071 Granada, Spain
d NicOx Research Institute, 20091 Bresso, Milano, Italy
e Department of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt.
Received May 30, 2006
O
R1
R2
N
R
R
N
R4
R1
N
N
N
NH2
H
R= (substituted)heterocycle; R1= CN, small
alkyl/(substituted)benzyloxy carbonyl;
R2= CH3S, CH3SO2, N-Me-piperazine, morpholine
The reaction between 3-(dimethylamino)/3,3-bis(methylthio)-1-(substituted)prop-2-en-1-ones and 4-
substituted-5-amino-1H-pyrazoles afforded new pyrazole[1,5-a]pyrimidines structurally related to
Zaleplon. The chemical modifications introduced at the 3-, 5-, and 7-positions of the bicyclic structure
revealed new promising candidates for the treatment of sleep disorders.
J. Heterocyclic Chem., 44, 355 (2007).
There are only few examples in the literature
concerning the chemical modifications introduced to
Zaleplon structure. These inventions described the
replacement of the 3-cyano group with oxadiazole nucleus
and/or the substitution of the pyrazole moiety with other
hereocycles (triazole or imidazole) [8,9].
INTRODUCTION
In the last decade, the treatment of insomnia has been
supplemented by the introduction of a number of non-
benzodiazepine hypnotics including zolpidem, zopiclone
and, most recently, zaleplon [1-4].
Zaleplon (N-[3-(cyanopyrazolo[1,5-a]pyrimidin-7-yl)-
phenyl]-N-ethylacetamide, 1a, Figure 1) is a new
pyrazolopyrimidine hypnotic that selectively binds to the
α1-GABAA receptor subunit, enhancing the function of
GABA as a result of an allosteric interaction with the
GABAA-receptor chloride anion channel complex [5,6].
Zaleplon was approved in August 1999 by the Food and
Drug Administration and its preparation has been reported
only in an American Cyanamid patent [7].
Here we report the synthesis of a new series of zaleplon
analogs in which the phenyl N-ethylacetamido moiety
was replaced by (substituted)heterocycles and the 3- and
5-positions of the pyrazolo[1,5-a]pyrimidine nucleus were
differently functionalised (Table 1).
The phenyl N-ethylacetamido molecular fragment was
replaced by different examples of substituted heterocycles
like pyridine, thiophene, pyrrole and furane whereas the
cyano group at the 3-position was replaced by substituted
carboxylates such as linear or branched alkyl ester
functions (ethyl, methyl, tert-butyl, isopropyl, n-propyl, 2-
phenyl ethyl), simple benzyl esters or benzyl esters 4-
substitued with electron withdrawing radicals (chloro,
fluoro, nitro) or electron donor groups (methoxy). The 5-
position, unmodified in the parent compound 1a, was also
analyzed by the introduction of short thioalkyl radical like
SCH3, alkyloxy group and basic centres such as 1-methyl-
piperazine and morpholine.
CN
N
N
N
Zaleplon, 1a
Ki= 57.3 nM
O
N
CH3
CH3
Figure 1. Zaleplon, a pyrazolopyrimidine hypnotic that selectively binds
to GABAA receptor.

356
P.G. Baraldi, F. Fruttarolo, M.A. Tabrizi, R. Romagnoli, D. Preti, E. Ongini,
H. El-Kashef, M.D. Carrión, P.A. Borea.
Vol 44
Table 1. Pyrazolo[1,5-a]pyrimidines synthesized
R1
N
R
R2
N
N
Compound
R
R1
R2
15
16
17
18
19
20
21
22
23
24
25
26
28
29
30
31
32
33
34
35
36
38
39
40
41
42
43
Pyridin-2-yl
N-methyl-pyrrol-2-yl
Furan-2-yl
Pyridin-3-yl
Thiophen-2-yl
Pyridin-2-yl
CN
CN
CN
CN
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Furan-2-yl
Pyridin-3-yl
Thiophen-2-yl
2,5-dimethyl-thiophen-3-yl
5-bromo-thiophen-2-yl
5-bromo-thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
Benzyloxy carbonyl
4-methoxy benzyloxy carbonyl
4-chloro benzyloxy carbonyl
4-fluoro benzyloxy carbonyl
4-nitro benzyloxy carbonyl
tert-butyloxycarbonyl
Isopropyloxy carbonyl
n-propyloxy carbonyl
2-phenylethyloxy carbonyl
CO2Et
H
H
H
H
H
CH3S
CH3SO2
Morpholine
N-CH3-piperazine
N-CH3-piperazine x 2HCl
EtO
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
O
O
RESULTS AND DISCUSSION
i
R
C
R
C
CH3
N
The synthetic pathways employed for the synthesis of
compounds 15-43 is depicted in the Schemes 1-3. The
starting materials 3-(dimethylamino)-1-(substituted)prop-
2-en-1-ones 8-14 were prepared by reacting the
corresponding commercially available acetyl heterocycles
1-7 with N,N-dimethylformamide dimethyl acetal at
100°C for 18 hours. The enaminones obtained were then
reacted with 4-cyano-5-amino-1H-pyrazole [10] or 5-
amino-1H-pyrazole-4-carboxylate [11] to furnish the
corresponding 3-cyano or 3-carboxylic acid ethyl ester
derivatives 15-19 and 20-25 respectively in a quite good
yield (Scheme 1).
1-7
8-14
ii
CN
CO2Et
NH2
N
N
N
H
N
NH2
H
CN
CO2Et
N
R
N
N
R
N
N
N
15-19
20-25
iii
The introduction of (substituted)benzyl esters or alkyl
esters at the 3-position of the pyrazolo[1,5-a]pyrimidine
nucleus is shown in the synthetic Scheme 2. The 3-
CO2Me
N
R
N
N
(dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-one
12
was reacted with 5-amino-1H-pyrazole-4-carboxylic acid
[11] in a mixture of acetic acid and water to afford the 7-
(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid 27. The carboxylic group of 27 was converted into
ester (compounds 28-36) by reaction with several
commercially available alkylating agents, using DMF as
solvent and K2CO3 as a base.
26
Scheme 1. Reagents and conditions: (i) N,N-Dimethylformamide
dimethyl acetal, 100°C, 18 h; (ii) Acetic acid/water 2:1, 110°C; (iii)
CH3ONa, 65°C, 6 h. R= Pyridin-2-yl (1, 8, 15, 20); N-methyl-pyrrol-2-
yl (2, 9, 16); furan-2-yl (3, 10, 17, 21); pyridin-3-yl (4, 11, 18, 22);
thiophen-2-yl (5, 12, 19, 23); 2,5-dimethyl-thiophen-3-yl (6, 13, 24); 5-
bromo-thiophen-2-yl (7, 14, 25, 26).

Mar-Apr 2007
New Series of Pyrazolo[1,5-a]pyrimidines Structurally Related to Zaleplon
357
CO2H
CO2R
CO2H
N
N
N
N
NH2
H
ii
N
S
N
S
N
N
N
i
S
O
12
27
28-36
Scheme 2. Reagents and conditions: (i) Acetic acid/water 2:1, 110°C; (ii) alkyl halides, K2CO3.
R= Benzyl (28); 4-methoxy benzyl (29); 4-chloro benzyl (30); 4-fluoro benzyl (31); 4-nitro benzyl (32);
tert-butyl (33); isopropyl (34); n-propyl (35); 2-phenylethyl (36).
The 5-position of the pyrazolo[1,5-a]pyrimidine core
was functionalised by the introduction of basic groups or
short alkyloxy radical like ethoxy. The synthetic pathway
used is depicted in the Scheme 3. The 2-acetyl thiophene
methylsulfonyl derivative 39 in a quantitative yield by
treatment with 70% m-chloroperbenzoic acid [13] in
dichloromethane as solvent. This intermediate was reacted
in neat with an excess of morpholine, N-methyl
piperazine or just refluxed in ethanol to afford the 5-
substituted compounds 40-43. The piperazino radical of
compound 41 was converted into the hydrochloric salt 42
by treatment with a saturated solution of hydrochloric
acid in methanol.
5
was transformed into the corresponding 3,3-
bis(methylthio)-prop-2-en-1-one 37 by reaction with
carbon disulfide and methyl iodide in the presence of 60%
NaH. This intermediate was cyclized into 38 by reaction
with 5-amino-1H-pyrazole-4-carboxylate and a catalytic
amount of piperidine [12]. In order to increase the
reactivity and the exchangeability of the thiomethyl
radical of compound 38, it was oxidized into the
To determine the relative affinities of compounds 15-43
to the α1-GABAA receptor in rat cerebral cortex,
membranes were labelled with the benzodiazepine site
CO2Et
CO2Et
N
H3CS
N
N
NH2
H
i
CH3
SCH3
SCH3
N
S
N
S
S
ii
O
O
5
38
37
O
CO2Et
iii
N
N
N
S
N
v
O
S
O
CO2Et
N
40
41
H3C
N
S
N
N
CO2Et
N
N
vi
39
N
S
N
iv
CO2Et
EtO
N
vii
N
S
N
x 2 HCl
N
N
CO2Et
43
N
N
S
N
42
Scheme 3. Reagents and conditions: (i) CS2, CH3I, NaH; (ii) acetic acid/water 3:1, piperidine; (iii) m-chloroperbenzoic acid,
CH2Cl2; (iv) abs. EtOH, reflux; (v) morpholine, 60°C, 30’; (vi) N-methyl piperazine, 70°C, 30’; (vii) HCl g/MeOH, 0°C.

358
P.G. Baraldi, F. Fruttarolo, M.A. Tabrizi, R. Romagnoli, D. Preti, E. Ongini,
H. El-Kashef, M.D. Carrión, P.A. Borea.
Vol 44
ms: m/z 165 (M+). Anal. Calcd. for C9H11NO2: C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.28; H, 6.59; N, 8.26.
antagonist [3H]Ro 15-1788 (Flumazenil). The majority of
compounds synthesized exhibited improved or
comparable affinity with respect to zaleplon (Ki= 57.3
nM) [14] and were able to compete for the binding of
[3H]Ro 15-1788. The replacement of the phenyl N-
ethylacetamido moiety of 1a with heterocycles, preferably
with thiophene, along with oxycarbonyl radicals at the 3-
position, preferably (4-methoxy)benzyloxy carbonyl
radicals, revealed new chemical candidates with an
enhanced receptor affinity with respect to that of zaleplon
(compounds 23, 28 and 29, Ki= 18 nM, 14 nM and 7.6
nM respectively).
3-(Dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (11).
Yield 55%; red scarlet crystals; mp 113°C; 1H nmr (CDCl3) δ
2.95 (s, 3H), 3.17 (s, 3H), 5.70 (d, 1H, J=12), 7.35 (m, 1H), 7.87
(d, 1H, J=11.9), 8.17 (m, 1H), 8.67 (dd, 1H), 9.08 (d, 1H, J=2);
ir (KBr) 1688 cm-1; ms: m/z 176 (M+). Anal. Calcd. for
C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C, 68.09; H,
6.78; N, 15.96.
3-(Dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-one (12).
1
Yield 73%; yellow crystals; mp 128°C; H nmr (CDCl3) δ 2.93
(bs, 3H), 3.11 (bs, 3H), 5.65 (d, 1H, J=12.1), 7.07 (m, 1H), 7.46
(d, 1H, J=6), 7.62 (d, 1H, J=4), 7.81 (d, 1H, J=13); ir (KBr)
1691 cm-1; ms: m/z 181 (M+).
Anal. Calcd. for C9H11NOS: C, 59.64; H, 6.12; N, 7.73.
Found: C, 59.39; H, 6.02; N, 7.59.
3-(Dimethylamino)-1-(2,5-dimethyl-thiophen-3-yl)prop-2-
EXPERIMENTAL
1
en-1-one (13). Yield 56%; orange crystals; mp 114°C; H nmr
Reaction courses and product mixtures were routinely
monitored by thin-layer chromatography (TLC) on silica gel
(precoated F254 Merck plates) and visualized with aqueous
potassium permanganate or ethanolic ninhydrin solutions.
Infrared spectra (ir) were measured on a Perkin-Elmer 257
instrument using KBr Wafer technique. 1H nmr were determined
in CDCl3, or DMSO-d6 solutions with a Varian VXR 200
spectrometer. Peak positions are given in parts per million (δ)
downfield from tetramethylsilane as internal standard, and J
values are given in Hz. Light petroleum refers to the fractions
boiling at 40-60°C. Melting points were determined on a Buchi-
Tottoli instrument and are uncorrected. Mass spectra (ms) were
obtained with a Shimadzu QP5050 DI 50 spectrometer.
Chromatography was performed with Merck 60-200 mesh silica
(CDCl3) δ 2.39 (s, 3H), 2.67 (s, 3H), 2.98 (bs, 6H), 5.44 (d, 1H,
J=12), 7.28 (s, 1H), 7.68 (d, 1H, J=12.1); ir (KBr) 1710 cm-1;
ms: m/z 209 (M+). Anal. Calcd. for C11H15NOS: C, 63.12; H,
7.22; N, 6.69. Found: C, 62.98; H, 7.11; N, 6.54.
3-(Dimethylamino)-1-(5-bromo-thiophen-2-yl)prop-2-en-1-
one (14). Yield 64%; yellow crystals; mp 120-3°C; 1H nmr
(CDCl3) δ 2.42 (s, 3H), 2.71 (s, 3H), 5.61 (d, 1H, J=12.6), 6.89
(d, 1H, J=4), 7.11 (d, 1H, J=3.8), 7.70 (d, 1H, J=12.1); ir (KBr)
1699 cm-1; ms: m/z 258 (M+). Anal. Calcd. for C9H10BrNOS: C,
41.55; H, 3.87; N, 5.38. Found: C, 41.29; H, 3.79; N, 5.28.
General Procedure for the preparation of 7-(substituted)-
pyrazolo[1,5-a]pyrimidine-3-carbonitriles (15-19). To
a
solution of compounds 8-14 (2.8 mmol) in a mixture of acetic
acid/water (2:1, 10 mL) was added 4-cyano-5-amino-1H-
pyrazole (1 mol eq) and the reaction was heated at reflux for 1-2
h. Then was added cold water until the complete precipitation of
compound was observed*. The solid formed was collected by
filtration and recrystallized from hot methanol to furnish 15-19
as solids.
*For compound 16: the aqueous phase was extracted with
CH2Cl2 (3X20 mL), the recombined organic layers were washed
two time with NaOH 5% (15 mL), anhydrified over Na2SO4 and
evaporated under reduced pressure. The residue obtained was
recrystallized from a mixture of CH2Cl2 /Et2O.
1
gel. All products reported showed H nmr spectra in agreement
with the assigned structures. Organic solutions were dried over
anhydrous sodium sulphate. Elemental analyses were performed
by the micro analytical laboratory of Dipartimento di Chimica,
University of Ferrara, and were within ± 0.4% of the theoretical
values for C, H and N
General Procedure for the Preparation of 3-(Dimethyl-
amino)-1-(substituted)prop-2-en-1-ones (8-14). To the acetyl
compounds 1-7 (1 mL) was added N,N-dimethylformamide
dimethyl acetal (1.03 mol eq) and the mixture was heated at
100°C for 18 h. The solvent was removed at reduced pressure
and the residue was recrystallized from EtOAc to furnish
derivatives 8-14 as solids.
7-(Pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile
1
(15). Yield 83%; yellow solid; mp 192-4°C. H nmr (CDCl3) δ
7.56 (m, 1H), 7.98 (m, 2H), 8.50 (s, 1H), 8.87 (m, 2H), 8.97 (d,
1H, J=7.9); ir (KBr) 2229 cm-1; ms: m/z 221 (M+). Anal. Calcd.
for C12H17N5: C, 65.15; H, 3.19; N, 31.66. Found: C, 65.10; H,
3.15; N, 31.58.
7-(N-Methyl-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidine-3-
carbonitrile (16). Yield 45%; pale yellow solid; mp 180-2°C.
1H nmr (CDCl3) δ 3.79 (s, 3H), 6.39 (m, 1H), 7.11 (m, 2H), 7.13
(m, 1H), 8.42 (s, 1H), 8.71 (d, 1H, J=6); ir (KBr) 2231 cm-1; ms:
m/z 223 (M+). Anal. Calcd. for C12H9N5: C, 64.56; H, 4.06; N,
31.37. Found: C, 64.49; H, 4.01; N, 31.29.
7-(Furan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (17).
Yield 89%; pale yellow crystals; mp 204-5°C. 1H nmr (CDCl3) δ
6.77 (m, 1H), 7.56 (d, 1H, J=4.1), 7.79 (s, 1H), 8.24 (d, 1H,
J=4), 8.48 (s, 1H), 8.77 (d, 1H, J=5.9); ir (KBr) 2228 cm-1; ms:
m/z 210 (M+). Anal. Calcd. for C11H6N4O: C, 62.86; H, 2.88; N,
26.66. Found: C, 62.87; H, 2.75; N, 26.58.
3-(Dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one (8).
1
Yield 70%; yellow crystals; mp 110°C; H nmr (CDCl3) δ 2.98
(s, 3H), 3.17 (s, 3H), 6.5 (d, 1H, J=14), 7.32 (m, 1H), 7.91 (m,
1H), 7.99 (d, 1H, J=13.8), 8.19 (d, 1H, J=7.9), 8.65 (dd, 1H,
J=2); ir (KBr) 1693 cm-1; ms: m/z 176 (M+). Anal. Calcd. for
C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C, 68.24; H,
6.73; N, 15.77.
3-(Dimethylamino)-1-(1-methyl-1H-pyrrol-2-yl)prop-2-en-
1-one (9). Yield 11%; yellow crystals; mp 115°C; 1H nmr
(CDCl3) δ 2.98 (s, 3H), 3.98 (bs, 6H), 5.63 (d, 1H, J=12), 6.09
(m, 1H), 6.71 (m, 1H), 6.80 (m, 1H), 7.63 (d, 1H, J=12.2); ir
(KBr) 1699 cm-1; ms: m/z 178 (M+). Anal. Calcd. for C10H14N2O:
C, 67.39; H, 7.92; N, 15.72. Found: C, 67.01; H, 7.88; N, 15.64.
3-(Dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (10).
Yield 74%; pale orange solid; mp 121°C; 1H nmr (CDCl3) δ 2.91
(s, 3H), 3.12 (s, 3H), 5.68 (d, 1H, J= 12), 6.47 (m, 1H), 7.05 (d,
1H, J=2), 7.48 (s, 1H), 7.82 (d, 1H, J=12.3); ir (KBr) 1701 cm-1;
7-(Pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile
(18). Yield 86%; pale yellow solid; mp 268-9°C. 1H nmr

Mar-Apr 2007
New Series of Pyrazolo[1,5-a]pyrimidines Structurally Related to Zaleplon
359
(DMSO-d6) δ 7.48 (d, 1H, J=4), 7.57 (m, 1H), 8.50 (m, 1H),
8.59 (s, 1H), 8.63 (m, 1H), 8.87 (d, 1H, J=4.2), 9.23 (m, 1H); ir
(KBr) 2236 cm-1; ms: m/z 221 (M+). Anal. Calcd. for C12H7N5:
C, 65.15; H, 3.19; N, 31.66. Found: C, 65.09; H, 3.17; N, 31.58.
7-(Thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile
(19). Yield 88%; yellow solid; mp 272-3°C. 1H nmr (DMSO-d6)
δ 7.35 (m, 1H), 7.80 (d, 1H, J=6), 7.99 (d, 1H, J=4.3), 8.50 (d,
1H, J=2.3), 8.68 (s, 1H), 8.76 (d, 1H, J=6); ir (KBr) 2239 cm-1;
ms: m/z 226 (M+). Anal. Calcd. for C11H6N4S: C, 58.39; H, 2.67;
N, 24.76. Found: 58.29; H, 2.59; N, 24.68.
General Procedure for the preparation of ethyl 7-
(substituted)pyrazolo[1,5-a]pyrimidine-3-carboxylates (20-
25). To a solution of compounds 8-14 (2.8 mmol) in a mixture
of acetic acid/water (2:1, 10 mL) was added ethyl 5-amino-1H-
pyrazole-4-carboxylate (1 mol eq) and the reaction was heated at
reflux for 1-2 h. After cooling, water was added (30 mL)* and
the aqueous phase was extracted with CH2Cl2 (3X25 mL). The
recombined organic layer was washed with NaOH 5% (2 X 5
mL), dried (Na2SO4) and evaporated under reduced pressure.
The residue was recrystallized from a mixture of CH2Cl2/Et2O to
afford compounds 20-25 as solids.
5°C.1H nmr (CDCl3) δ 1.43 (t, 3H, J=6.1), 4.43 (q, 2H, J=6.2),
7.20 (s, 1H), 7.41 (d, 1H, J=3.8), 8.01 (d, 1H, J=3.9), 8.63 (s,
1H), 8.80 (d, 1H, J=4); ms: m/z 352 (M+). Anal. Calcd. for
C13H10BrN3O2S: C, 44.33; H, 2.86; N, 11.93. Found: C, 44.29;
H, 2.81; N, 11.88.
Preparation of methyl 7-(5-bromo-thiophen-2-yl)pyrazolo-
[1,5-a]pyrimidine-3-carboxylate (26). To a solution of 25 (80
mg, 0.23 mmol) in CH3OH (10 mL) was added CH3ONa (12
mg, 1 mol eq) and the mixture was heated at 65°C for 6 h. After
cooling the solid formed was collected by filtration and washed
with cold CH3OH (20 mL) and then with Et2O (15 mL) to
furnish 26 as pale yellow solid. Yield 90% (70 mg, 2 mmol); mp
211-3°C.1H nmr (CDCl3) δ 4.01 (s, 3H), 7.23 (s, 1H), 7.38 (d,
1H, J=3.8), 8.11 (d, 1H, J=3.9), 8.56 (s, 1H), 8.82 (d, 1H, J=4);
ms: m/z 338 (M+). Anal. Calcd. for C12H8BrN3O2S: C, 42.62; H,
2.38; N, 12.43. Found: C, 42.59; H, 2.32; N, 12.40.
Preparation of 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimid-
ine-3-carboxylic acid (27). To a solution of compound 12 (0.2
g, 1.10 mmol) in a mixture of acetic acid/water (2:1, 12 mL)
was added 5-amino-1H-pyrazole-4-carboxylic acid (0.14 g, 1
mol eq) and the reaction was heated at reflux for 1 h. Water
was added until the complete precipitation of compound was
observed. The solid formed was collected by filtration and
recrystallized from hot CH3OH to furnish 27 as pale yellow
*For compounds 21 and 23: after addition of water the
formation of a fine precipitate was observed. The solid formed
was filtered off and recrystallized from hot CH3OH (21) or
EtOAc (23).
1
solid. Yield 88% (0.22 g, 0.90 mmol); mp 270-1°C; H nmr
Ethyl 7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbox-
1
ylate (20). Yield 48%; pale green needles; mp 145°C. H nmr
(DMSO-d6) δ 7.40 (m, 1H), 7.97 (d, 1H, J=6), 8.17 (m, 1H),
8.55 (m, 1H), 8.74 (s, 1H), 8.81 (d, 1H, J=4.1), 12.45 (bs, 1H);
ir (KBr) 1694, 3321 cm-1; ms: m/z 245 (M+). Anal. Calcd. for
C11H7N3O2S: C, 53.87; H, 2.88; N, 17.13. Found: C, 53.66; H,
2.74; N, 17.02.
General Procedure for the Preparation of (substituted)-7-
(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylates (28-
36). To a solution of 27 (0.1 g) in DMF (8 mL) was added
K2CO3 (2.5 mol eq) and the appropriate alkyl halide (1.2 mol
eq), then the reaction was heated at 80-100°C for 3-4 h. After
cooling, the solid formed* was collected by filtration under
reduced pressure, washed with cold water (15 mL), dried and
recrystallized from CH3OH to afford 28-36 as solids.
*For compounds 32 and 36: after addition of water the
reaction was extracted with EtOAc (3X15 mL) and the
recombined organic phases were anhydrified (Na2SO4) and
evaporated at reduced pressure. The residue obtained was
recrystallized from CH3OH.
Benzyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-car-
boxylate (28). Yield 68%; pale yellow solid; mp 176°C.1H nmr
(CDCl3) δ 5.46 (s, 2H), 7.35 (m, 7H), 7.78 (dd, 1H), 8.39 (d, 1H,
J=3.4), 8.70 (s, 1H), 8.79 (d, 1H, J=5.8); ms: m/z 335 (M+).
Anal. Calcd. for C18H13N3O2S: C, 64.40; H, 3.91; N, 12.53.
Found: C, 64.46; H, 3.87; N, 12.58.
(CDCl3) δ 1.45 (t, 3H, J=8), 4.51 (q, 2H, J=8), 7.52 (m, 1H),
7.88 (d, 1H, J=4), 7.96 (m, 1H), 8.67 (s, 1H), 8.86 (m, 1H), 8.93
(d, 1H, J=4), 8.97 (d, 1H, J=6); ms: m/z 267 (M+). Anal. Calcd.
for C14H12N4O2: C, 62.08; H, 4.51; N, 20.88. Found: C, 62.66; H,
4.49; N, 20.65.
Ethyl 7-(furan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbox-
1
ylate (21). Yield 70%; pale yellow solid; mp 140°C. H nmr
(CDCl3) δ 1.44 (t, 3H, J=6.2), 4.49 (q, 2H, J=6), 6.75 (m, 1H),
7.51 (d, 1H, J=4), 7.76 (m, 1H), 8.27 (d, 1H, J=4.1), 8.67 (s,
1H), 8.82 (d, 1H, J=4.1); ms: m/z 257 (M+). Anal. Calcd. for
C13H11N3O3: C, 60.70; H, 4.31; N, 16.33. Found: C, 60.66; H,
4.24; N, 16.29.
Ethyl 7-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbox-
ylate (22). Yield 78%; pale pink solid; mp 177-8°C. H nmr
1
(CDCl3) δ 1.45 (t, 3H, J=6.2), 4.49 (q, 2H, J=6.1), 7.15 (d, 1H,
J=4), 7.56 (m, 1H), 8.49 (m, 1H), 8.62 (s, 1H), 8.84 (m, 2H),
9.15 (d, 1H, J=3.8); ms: m/z 268 (M+). Anal. Calcd. for
C14H12N4O2: C, 62.68; H, 4.51; N, 20.88. Found: C, 62.72; H,
4.55; N, 20.81.
Ethyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbox-
ylate (23). Yield 60%; yellow solid; mp 145°C. 1H nmr (CDCl3)
δ 1.47 (t, 3H, J=6), 4.49 (q, 2H, J=6.1), 7.33 (m, 1H), 7.42 (d,
1H, J=3.9), 7.81 (d, 1H, J=4), 8.38 (d, 1H, J=4.1), 8.70 (s, 1H),
8.78 (d, 1H, J=4); ms: m/z 273 (M+). Anal. Calcd. for
C13H11N3O2S: C, 57.13; H, 4.06; N, 15.37. Found: C, 57.10; H,
3.99; N, 15.29.
Ethyl 7-(2,5-dimethyl-thiophen-3-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxylate (24). Yield 75%; yellow solid; mp 90-2°C.
1H nmr (CDCl3) δ 1.42 (t, 3H, J=6.2), 2.41 (s, 3H), 2.51 (s, 3H),
4.45 (q, 2H, J=6.1), 6.92 (d, 1H, J=3.8), 7.05 (s, 1H), 8.60 (s,
1H), 8.81 (d, 1H, J=4); ms: m/z 301 (M+). Anal. Calcd. for
C15H15N3O2S: C, 58.79; H, 5.02; N, 13.94. Found: C, 58.70; H,
4.99; N, 13.91.
4-Methoxybenzyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrim-
idine-3-carboxylate (29). Yield 75%; pale yellow solid; mp
175°C. 1H nmr (DMSO-d6) δ 3.75 (s, 3H), 5.29 (s, 2H), 6.92 (d,
2H, J=8), 7.42 (d, 2H, 7.8), 7.98 (d, 1H, J=4), 8.18 (d, 1H,
J=4.1), 8.57 (d, 1H, J=3.9), 8.80 (s, 1H), 8.84 (d, 2H, J=4); ms:
m/z 365 (M+). Anal. Calcd. for C19H15N3O3S: C, 62.45; H, 4.14;
N, 11.50. Found: C, 62.41; H, 4.05; N, 11.40.
4-Chlorobenzyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimi-
dine-3-carboxylate (30). Yield 34%; pale yellow solid; mp 146-
1
8°C. H nmr (CDCl3) δ 5.41 (s, 2H), 7.37 (m, 6H), 7.80 (d, 1H,
J=4), 8.38 (d, 1H, J=3.9), 8.69 (s, 1H), 8.77 (d, 1H, J=4.1); ms:
m/z 369 (M+). Anal. Calcd. for C18H12ClN3O2S: C, 58.46; H,
3.27; N, 11.36. Found: C, 58.41; H, 3.26; N, 11.32.
Ethyl 7-(5-bromo-thiophen-2-yl)pyrazolo[1,5-a]pyrimid-
ine-3-carboxylate (25). Yield 71%; yellow solid; mp 164-

360
P.G. Baraldi, F. Fruttarolo, M.A. Tabrizi, R. Romagnoli, D. Preti, E. Ongini,
H. El-Kashef, M.D. Carrión, P.A. Borea.
Vol 44
4-Fluorobenzyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimid-
ine-3-carboxylate (31). Yield 57%; pale yellow solid; mp 149-
g, 1 mol eq) and a catalytic amount of piperidine (2 drops). The
resulting solution was heated at reflux for 20 h then, after
cooling, water was added (35 mL). The solid formed was
collected by filtration and recrystallized from a mixture of
CHCl3/n-hexane to furnish 38 as yellow solid. Yield 32% (0.1 g,
0.31 mmol); mp 195-6°C. 1H nmr (CDCl3) δ 1.43 (t, 3H, J=7.3),
2.76 (s, 3H), 4.40 (q, 2H, J=8), 7.18 (s, 1H), 7.27 (m, 1H), 7.72
(d, 1H), 8.27 (d, 1H, J=3.9), 8.54 (s, 1H); ms: m/z 319 (M+).
Anal. Calcd. for C14H13N3O2S2: C, 52.64; H, 4.10; N, 13.16.
Found: C, 52.58; H, 3.98; N, 13.05.
Preparation of ethyl 5-(methylsulfonyl)-7-(thiophen-2-
yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (39). A solution
of MCPBA (70% strength, 0.26 g, 1.5 mmol, 3 mol eq) in
CH2Cl2 (10 mL) was added to a stirred solution of 38 (0.16 g,
0.5 mmol) in CH2Cl2 (10 mL). The resulting solution was
strirred at room temperature for 6 h, then the solvent was
removed under reduced pressure and abs. EtOH (15 mL) added
to the residue. The solid formed was collected by filtration,
washed with cold abs. EtOH and dried to give 39 as a yellow
solid. Quantitative yield; mp 210-1°C. 1H nmr (CDCl3) δ 1.44 (t,
3H, J=8), 3.48 (s, 3H), 4.46 (q, 2H, J=8.1), 7.36 (t, 1H, J=3.6),
7.94 (d, 1H, J=4), 8.05 (s, 1H), 8.48 (d, 1H, J=3.9), 8.82 (s, 1H);
ms: m/z 351 (M+). Anal. Calcd. for C14H13N3O4S2: C, 47.85; H,
3.73; N, 11.96. Found: C, 47.77; H, 3.69; N, 11.92.
1
151°C. [Found: C, 61.09; H, 3.37; N, 11.82. H nmr (CDCl3) δ
5.41 (s, 2H), 7.06 (t, 2H, J=8), 7.30 (t, 2H, J=7.8), 7.52 (m, 2H),
7.79 (d, 1H, J=4), 8.38 (d, 1H, J=3.8), 8.69 (s, 1H), 8.78 (d, 1H,
J=4.1); ms: m/z 353 (M+). Anal. Calcd. for C18H12FN3O2S: C,
61.18; H, 3.42; N, 11.89. Found: C, 61.09; H, 3.37; N, 11.82.
4-Nitrobenzyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-
3-carboxylate (32). Yield 75%; pale yellow solid; mp 188-9°C.
1H nmr (CDCl3) δ 5.55 (s, 2H), 7.32 (t, 1H, J=4.1), 7.68 (d, 1H,
J=4), 7.81 (d, 2H, J=8), 7.84 (d, 1H, J=5.8), 8.26 (d, 2H, J=8.1),
8.39 (m, 1H), 8.74 (s, 1H), 8.81 (d, 1H, J=4); ms: m/z 380 (M+).
Anal. Calcd. for C18H12N4O4S: C, 56.84; H, 3.18; N, 14.73.
Found: C, 58.79; H, 3.19; N, 14.69.
tert-Butyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-
1
carboxylate (33). Yield 81%; pale orange solid; mp 248°C. H
nmr (DMSO-d6) δ 2.6 (s, 9H), 7.41 (t, 1H), 7.96 (d, 1H, J=4),
8.18 (d, 1H, J=3.8), 8.58 (d, 1H, J=3.9), 8.75 (s, 1H), 8.82 (d,
1H, J=4.1); ms: m/z 301 (M+). Anal. Calcd. for C15H15N3O2S: C,
59.78; H, 5.02; N, 13.94. Found: C, 59.72; H, 4.98; N, 13.89.
Isopropyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-
1
carboxylate (34). Yield 69%; pale yellow solid; mp 124°C. H
nmr (CDCl3) δ 1.39 (s, 3H), 1.42 (s, 3H), 5.33 (m, 1H), 7.30 (t,
1H, J=4), 7.38 (d, 1H, J=6), 7.80 (d, 1H, J=4), 8.37 (m, 1H),
8.65 (s, 1H), 8.76 (d, 1H, J=4.1); ms: m/z 287 (M+). Anal. Calcd.
for C14H13N3O2S: C, 58.52; H, 4.56; N, 14.62. Found: C, 58.58;
H, 4.51; N, 14.55.
Preparation of ethyl 5-morpholino-7-(thiophen-2-yl)py-
razolo[1,5-a]pyrimidine-3-carboxylate (40). The compound 39
(60 mg, 0.17 mmol) was suspended in morpholine (2 mL, exc.)
and the mixture was heated at 60°C for 30 min. Then water was
added (20 mL) and the solid formed was collected by filtration,
dried and recrystallized from EtOAc to furnish 40 as yellow
n-Propyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-
1
carboxylate (35). Yield 35%; yellow solid; mp 128°C. H nmr
(CDCl3) δ 1.05 (t, 3H, J=6.1), 1.86 (q, 2H, J=6), 4.36 (t, 2H,
J=6.2), 7.28 (t, 1H, J=4), 7.40 (d, 1H, J=4), 7.81 (d, 1H, J=3.9),
8.38 (d, 1H, J=3.8), 8.69 (s, 1H), 8.78 (d, 1H, J=5.8); ms: m/z
287 (M+). Anal. Calcd. for C14H13N3O2S: C, 58.52; H, 4.56; N,
14.62. Found: C, 58.39; H, 4.55; N, 14.63.
1
solid. Yield 69% (40 mg, 0.11 mmol); mp 204-6°C. H nmr
(CDCl3) δ 1.40 (t, 3H, J=8), 3.84 (m, 8H), 4.39 (q, 2H, J=7.8),
6.71 (s, 1H), 7.23 (m, 1H), 7.68 (d, 1H, J=3.9), 8.23 (d, 1H,
J=4), 8.40 (s, 1H); ms: m/z 358 (M+). Anal. Calcd. for
C17H18N4O3S: C, 56.97; H, 5.06; N, 15.63. Found: C, 56.91; H,
5.01; N, 15.59.
2-Phenylethyl 7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-
3-carboxylate (36). Yield 68%; pale yellow solid; mp 99-
1
100°C. H nmr (CDCl3) δ 3.13 (t, 2H, J=8), 4.60 (t, 2H, J=7.8),
Preparation of ethyl 5-(4-methylpiperazin-1-yl)-7-(thio-
phen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (41). The
compound 39 (20 mg, 0.057 mmol) was suspended in N-methyl-
piperazine (1.5 mL, exc.) and the mixture was heated at 70°C for
30 min. Then water was added (18 mL) and the aqueous layer
was extracted with EtOAc (3X8mL). The recombined organic
phases were dried (Na2SO4) and evaporated at reduced pressure.
The residue was recrystallized from EtOAc to furnish 41 as
orange solid. Quantitative yield; mp 138-141°C. 1H nmr (CDCl3)
δ 1.41 (t, 3H, J=8), 2.37 (s, 3H), 2.58 (m, 4H), 3.87 (m, 4H),
4.38 (q, 2H, J=7.8), 6.73 (s, 1H), 7.23 (m, 1H), 7.67 (d, 1H,
J=5.8), 8.21 (d, 1H, J=4.1), 8.39 (s, 1H); ms: m/z 371 (M+).
Anal. Calcd. for C18H21N5O2S: C, 58.20; H, 5.70; N, 18.85.
Found: C, 57.99; H, 5.62; N, 18.83.
7.32 (m, 6H), 7.44 (d, 1H, J=6), 7.82 (d, 1H, J=4), 8.38 (d, 1H,
J=3.9), 8.66 (s, 1H), 8.78 (d, 1H, J=3.9); ms: m/z 349 (M+).
Anal. Calcd. for C19H15N3O2S: C, 65.33; H, 4.33; N, 12.03.
Found: C, 65.27; H, 4.28; N, 12.00.
Preparation of 3,3-bis(methylthio)-1-(thiophen-2-yl)prop-
2-en-1-one (37). An ice chilled solution of 5 (3 mL, 28 mmol) in
dry toluene (50 mL) was treated with 60% NaH (2.3 g, 2 mol eq)
and the mixture was stirred at 0°C for 10 min. Carbon disulfide
(2.52 mL, 1.5 mol eq) and methyl iodide (5.23 mL, 3 mol eq)
were added to the cold solution over a period of 20 min.
Dimethylacetamide (1.8 mL) was added dropwise while the
mixture was kept below 45°C. After the mixture was stirred for
24 h at room temperature, a small amount of crash ice was added
to consume the unreacted NaH. The toluene was removed at
reduced pressure and the residue was portioned between water
and chloroform. The organic layer was dried (Na2SO4) and
evaporated at reduced pressure. The residue was recrystallized
from abs. EtOH to furnish 37 as yellow needles. Yield 67% (4.3
g, 18.7 mmol); mp 94-5°C; 1H nmr (CDCl3) δ 2.53 (s, 3H), 2.56
(s, 3H), 6.62 (s, 1H), 7.10 (t, 1H, J=4), 7.56 (d, 1H, J=3.9), 7.66
(d, 1H, J=4.1); ms: m/z 229 (M+).
Preparation of ethyl 5-(4-methylpiperazin-1-yl)-7-(thio-
phen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate dihydro-
chloride (42). A solution of 41 (20 mg, 0.054 mmol) in a
methanolic satured solution of HCl (5 mL) was stirred at 0°C for
10 min and then at room temperature for additional 10 min. The
solvent was removed at reduced pressure and the residue was
recrystallized from MeOH to afford 42 as pale yellow solid.
1
Quantitative yield; mp >240°C. H nmr (DMSO-d6) δ 1.35 (t,
Preparation of ethyl 5-(methylthio)-7-(thiophen-2-yl)-
pyrazolo[1,5-a]pyrimidine-3-carboxylate (38). To a solution
of 37 (0.3 g, 1.3 mmol) in a mixture of acetic acid/water (3:1, 16
mL) was added ethyl 5-amino-1H-pyrazole-4-carboxylate (0.20
3H, J=8), 2.95 (s, 3H), 3.35 (m, 8H), 4.25 (q, 2H, J=7.9), 4.72
(bs, 2H), 7.29 (m, 1H); 7.43 (s, 1H), 7.95 (d, 1H, J=4), 8.15 (s,
1H), 8.49 (d, 1H, J=3.9). Anal. Calcd. for C18H23Cl2N5O2S: C,
48.65; H, 5.22; N, 15.96. Found: C, 48.32; H, 5.25; N, 15.09.

Mar-Apr 2007
New Series of Pyrazolo[1,5-a]pyrimidines Structurally Related to Zaleplon
361
[4] Beer, B.; Ieni, J.R.; Wu, W.H. J. Clin. Pharmacol. 1994, 34,
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Res. 1994, 33, 39.
[6] Noguchi, H.; Kitazumi, K.; Mori, M.; Shiba, T. Eur. J.
Preparation of ethyl 5-ethoxy-7-(thiophen-2-yl)pyrazolo-
[1,5-a]pyrimidine-3-carboxylate (43). A solution of 39 (60 mg,
0.17 mmol) in abs. EtOH (10 mL) was refluxed for 8 h. The
solvent was removed at reduced pressure and the residue was
recrystallized from cold abs. EtOH to give 43 as pale orange
335.
Pharmacol. 2002, 21, 434.
1
solid. Yield 74% (40 mg, 0.12 mmol); mp 139-141°C. H nmr
[7] Thurairajah, P. US 5714607, 1998.
(CDCl3) δ 1.44 (m, 6H), 4.41 (q, 2H, J=8), 4.65 (q, 2H, J=7.8),
6.83 (s, 1H), 7.25 (m, 1H), 7.72 (m, 1H), 8.25 (m, 1H), 8.49 (s,
1H); ms: m/z 317 (M+). Anal. Calcd. for C17H18N4O3S: C, 56.77;
H, 4.76; N, 13.24. Found: C, 56.74; H, 4.69; N, 13.18.
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[11] Lubbers, T.; Anghern, P.; Gminder, H.; Herzig, S.; Kulhanek,
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