Design and synthesis of novel pyrazole-based Lp-PLA2 inhibitors

Article abstract of DOI:10.1002/cjoc.201180354

A series of novel pyrazole-based lipoprotein-associated phospholipase A₂ (Lp-PLA₂) inhibitors have been designed and synthetized by a variety of acetophenones via a 10-step convergent approach. The synthetic approach is carefully opt

Full text of DOI:10.1002/cjoc.201180354

FULL PAPER
Design and Synthesis of Novel Pyrazole-based Lp-PLA2
Inhibitors
Wang, Yia(王毅)
Xu, Weirenb(徐为人)
Shao, Huab(邵华)
Xie, Yafeia(谢亚非)
Wang, Jianwu*,a(王建武)
a School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China
bTianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research,
Tianjin 300193, China
A series of novel pyrazole-based lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors have been de-
signed and synthetized by a variety of acetophenones via a 10-step convergent approach. The synthetic approach is
carefully optimized, and an unsuccessful alternative route is also discussed. The in vitro biological activity reveals
that all the synthesized compounds are potent Lp-PLA2 inhibitors with compound 13b being the most potent one
(Lp-PLA2, IC50＝1.5 nmol/L).
Keywords lipoprotein-associated phospholipase A2 (Lp-PLA2), inhibitors, pyrazole, pyrimidone, design, synthe-
sis
Introduction
steric volume of the designed pyrazole ring being
slightly smaller than that of the initial benzene ring, we
lengthen the tether below the pyrimidine nucleus by one
atom while removing the carbonyl group in darapladib.
Recent years, cardiovascular and cerebrovascular
diseases have become a great threat to human health.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is
an enzyme produced by inflamatory cell in the circula-
tion and vascular intima, most of which (80%) binds to
LDL (low density lipoprotein).1 Kolodgie et al.2 found
Lp-PLA2 strongly expressed in the necrotic core of
coronary lesions, and thereafter scientists found more
evidences that Lp-PLA2 was closely related with
atherogenesis diseases. Lp-PLA2 hydrolyzes oxidized
phospholipids in LDL, yielding lysophosphatidylcholine
(lysoPC), and oxidized nonesterified fatty acids (NEFA),
which are proposed to play an important role in initiat-
ing atherogenesis diseases.3 Consequently, development
of Lp-PLA2 inhibitors is a promising way to prevent
these diseases.
Lp-PLA2 may be a complementary therapeutic target
to the cardiovascular and cerebrovascular diseases,4,5
and darapladib is a highlight among the inhibitors of
Lp-PLA2, which can make sustained inhibition of
plasma Lp-PLA2 activity in patients receiving intensive
atorvastatin therapy. Changes in IL-6 and hs-CRP after
12 weeks of darapladib suggest a possible reduction in
inflammatory burden.6 Based on the structure of dara-
pladib, we design and synthetize a series of novel pyra-
zole-based compounds 13a— 13e as Lp-PLA2 inhibitors
(Figure 1). As depicted in Figure 1, in the designed
Lp-PLA2 inhibitors we replace the central benzene ring
in darapladib with a pyrazole ring, and in view of the
Experimental
Melting points were determined with an XT-4 mi-
1
croscopic melting point apparatus and uncorrected. H
and 13C NMR spectra were recorded on a Bruker 400
AV or a Bruker 300 AV with DMSO-d6 or CDCl3 as
solvent and TMS as internal standard. The HR-MS data
were collected on an Agilent Q-TOF 6510 mass spec-
trometer using electrospray ionization (ESI) technique.
Synthesis of ethyl 3-(4-substitutedphenyl)-1H-pyra-
zole-5-carboxylate (2a— 2e) was carried out according
to the procedures reported earlier.7,8 Synthesis of 12, 14
and darapladib was according to a procedure reported
earlier.9
General procedure for the synthesis of ethyl
3-(4-substituted phenyl)-1H-pyrazole-5-carboxylate
(2a— 2e)
A 250-mL three-necked round-bottomed flask was
charged with 120 mL of absolute ethanol and 3.6 g (0.16
mol) of sodium, and the mixture was mechanically
stirred under nitrogen until all the sodium disappeared.
The reaction mixture was cooled to room temperature,
then was added 23 g (0.16 mol, 21 mL) of diethyl ox-
alate. The mixture thus obtained was stirred for another
10 min, followed by dropwise addition of 0.13 mol of
*
E-mail: jwwang@sdu.edu.cn
Received December 21, 2010; revised March 30, 2011; accepted June 1, 2011.
Project supported by the National Innovative Drug of China (No. 2009ZX09301-008-P-05).
Chin. J. Chem. 2011, 29, 2039— 2048
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Wang et al.
FULL PAPER
O
N
O
N
N
N
F
N
F
F
S
S
O
F
F
N
O
R
N
N
N
_
13a 13e
darapladib
R = H, Me, Br, Cl, OMe
Figure 1 Structure of darapladib and designed Lp-PLA2 inhibitors.
1a—1e through a pressure-equallizing funnel within 1.5
h. The resulting mixture was stirred for another 4 h be-
fore 9.3 g (0.16 mol) of acetic acid was added, followed
by dropwise addition of 5.0 g (0.13 mol, 80%, 9.8 mL)
of aqueous hydrazine hydrate, and the stirring was con-
tinued at room temperature overnight.
The reaction mixture was concentrated on a rotary
evaporator to afford a reside, which was dissolved in
200 mL of dichloromethane. The organic solution thus
obtained was washed successively with saturated brine
and water, dried over sodium sulfate and evaporated on
a rotary evaporator to yield the crude product as a white
solid, which was recrystallized from ethyl acetate to
afford the pure product as a white solid.
ture was stirred for 10 min at room temperature, and
then heated to reflux for 3 h. The reaction mixture was
cooled to room temperature and filtered off, and filtrate
was evaporated on a rotary evaporator to afford the
crude product as an oil, which was purified by column
chromatography to furnish the pure products 3a—3e as
whilte solids.
Ethyl 1-(2-bromoethyl)-3-phenyl-1H-pyrazole-5-
carboxylate (3a) White solid, yield 88%, m.p. 89—90
℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.86—7.88 (m,
2H), 7.32—7.44 (m, 4H), 4.95 (t, J＝6.4 Hz, 2H), 4.33
(q, J＝7.2 Hz, 2H), 3.89 (t, J＝6.4 Hz, 2H), 1.33 (t, J＝
7.2 Hz, 2H); HR-MS (ESI-Q-TOF) calcd for C14H15Br-
N2O2 ([M＋H]＋) 323.0395, found 323.0388.
Ethyl 1-(2-bromoethyl)-3-p-tolyl-1H-pyrazole-5-
carboxylate (3b) White solid, yield 89%, m.p. 87—
Ethyl 3-phenyl-1H-pyrazole-5-carboxylate (2a)
1
White solid, yield 85%, m.p. 139—141 ℃; H NMR
1
89 ℃; H NMR (CDCl3, 300 MHz) δ: 7.69 (d, J＝8.1
(DMSO-d6, 400 MHz) δ: 13.91 (br, 1H), 7.82—7.86 (m,
2H), 7.37—7.46 (m, 4H), 4.30 (q, J＝7.2 Hz, 2H), 1.31
(t, J＝7.2 Hz, 3H).
Hz, 2H), 7.22 (d, J＝8.1 Hz, 2H), 4.97 (t, J＝7.1 Hz,
2H), 4.37 (q, J＝7.2 Hz, 2H), 3.75 (t, J＝7.1 Hz, 2H),
2.37 (s, 3H), 1.41 (t, J＝7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ: 160.18, 151.26, 138.60. 134.20, 129.98,
129.92, 126.03, 108.62, 61.80, 52.84, 30.01, 21.79,
14.75; HR-MS (ESI-Q-TOF) calcd for C15H17BrN2O2
([M＋H]＋) 337.0551, found 337.0549.
Ethyl 3-p-tolyl-1H-pyrazole-5-carboxylate (2b)
White solid, yield 84%, m.p. 141—143 ℃.
Ethyl 3-(4-bromophenyl)-1H-pyrazole-5-carbo-
xylate (2c) Yellow solid, yield 80%, m.p. 145—147
℃.
Ethyl 1-(2-bromoethyl)-3-(4-bromophenyl)-1H-
pyrazole-5-carboxylate (3c) White solid, yield 87%,
m.p. 91—92 ℃; 1H NMR (CDCl3, 300 MHz) δ: 7.68 (d,
J＝8.7 Hz 2H), 7.53 (d, J＝8.7 Hz, 2H), 7.13 (s, 1H),
4.98 (t, J＝7.1 Hz, 2H), 4.38 (q, J＝7.2 Hz, 2H), 3.76 (t,
J＝7.1 Hz, 2H), 1.42 (t, J＝7.2 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ: 159.50, 149.61, 134.07, 131.87,
131.31, 127.20, 122.24, 108.27, 61.42, 52.26, 29.37,
14.24; HR-MS (ESI-Q-TOF) calcd for C14H14Br2N2O2
([M＋H]＋) 402.9480, found 402.9478.
Ethyl 3-(4-chlorophenyl)-1H-pyrazole-5-carbo-
xylate (2d) White solid, yield 84%, m.p. 136—138
℃; 1H NMR (CDCl3, 300 MHz) δ: 11.82 (br, 1H), 7.72
(d, J＝8.4 Hz, 2H), 7.39 (d, J＝8.4 Hz, 2H), 7.07 (s,
1H), 4.38 (q, J＝7.2 Hz, 2H), 1.39 (t, J＝7.2 Hz, 3H).
Ethyl 3-(4-methoxyphenyl)-1H-pyrazole-5-carbo-
xylate (2e) White solid, yield 82%, m.p. 134—136 ℃;
1H NMR (CDCl3, 300 MHz) δ: 12.53 (br, s, 1H), 7.64 (d,
J＝8.7 Hz, 2H), 6.94 (s, 1H), 6.91 (d, J＝8.7 Hz, 2H),
4.28 (q, J＝7.2 Hz, 2H), 3.82 (s, 3H), 1.28 (t, J＝7.2 Hz,
3H).
Ethyl 1-(2-bromoethyl)-3-(4-chlorophenyl)-1H-
pyrazole-5-carboxylate (3d) White solid, yield 87%,
1
General procedure for the synthesis of ethyl
1-(2-bromoethyl)-3-p-substituted phenyl-1H-pyrazo-
le-5-carboxylate (3a— 3e)
m.p. 90—91 ℃; H NMR (DMSO-d6, 400 MHz) δ:
7.89 (d, J＝8.4 Hz, 2H), 7.48 (d, J＝8.4 Hz, 2H), 7.42
(s, 1H), 4.94 (t, J＝6.4 Hz, 2H), 4.33 (q, J＝7.2 Hz, 2H),
3.88 (t, J＝6.4 Hz, 2H), 1.33 (t, J＝7.2 Hz, 3H);
HR-MS (ESI-Q-TOF) calcd for C14H14BrClN2O2 ([M＋
H]＋) 357.0005, found 357.0008.
A 250-mL round-bottomed flask was charged with
the carboxylates 2a—2e (0.10 mol), 1,2-dibromoethane
(0.20 mol), potassium carbonate (0.40 mol), potassium
iodide (5.0 mmol) and 120 mL of acetonitrile. The mix-
Ethyl 1-(2-bromoethyl)-3-(4-methoxyphenyl)-1H-
2040
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Chin. J. Chem. 2011, 29, 2039— 2048

Design and Synthesis of Novel Pyrazole-based Lp-PLA2 Inhibitors
pyrazole-5-carboxylate (3e) White solid, yield 88%,
m.p. 88—90 ℃; 1H NMR (CDCl3, 300 MHz) δ: 7.73 (d,
J＝9.0 Hz, 2H), 6.94 (d, J＝9.0 Hz, 2H), 7.07 (s, 1H),
4.96 (t, J＝7.1 Hz, 2H), 4.37 (q, J＝7.2 Hz, 2H), 3.84 (s,
3H), 3.75 (t, J＝7.1 Hz, 2H), 1.40 (t, J＝7.2 Hz, 3H);
HR-MS (ESI-Q-TOF) calcd for C15H17BrN2O3 ([M＋
H]＋) 353.0501, found 352.0507.
127.25, 108.17, 61.49, 53.51, 50.31, 47.85, 14.75, 12.61;
HR-MS (ESI-Q-TOF) calcd for C18H24ClN3O2 ([M＋
H]＋) 350.1635, found 350.1636.
Ethyl
1-(2-(diethylamino)ethyl)-3-(4-methoxy-
phenyl)-1H-pyrazole-5-carboxylate (4e)
Colorless
1
oil, yield 80%; H NMR (CDCl3, 300 MHz) δ: 7.73 (d,
J＝9.0 Hz, 2H), 7.02 (s, 1H), 6.94 (d, J＝9.0 Hz, 2H),
4.67 (t, J＝7.1 Hz, 2H), 4.36 (q, J＝7.2 Hz, 2H), 3.83 (s,
3H), 2.90 (t, J＝7.2 Hz, 2H), 2.59 (q, J＝7.1 Hz, 4H),
1.40 (t, J＝7.2 Hz, 3H), 1.01 (t, J＝7.2 Hz, 6H);
HR-MS (ESI-Q-TOF) calcd for C19H27N3O3 ([M＋H]＋)
346.2131, found 346.2131.
General procedure for the synthesis of ethyl
1-(2-(diethylamino)ethyl)-3-p-tolyl-1H-pyrazole-5-ca-
rboxylate (4a— 4e)
A 250-mL round-bottomed flask was charged with
the carboxylates 3a—3e (0.080 mol), diethylamine
(0.16 mol), potassium carbonate (0.40 mol), potassium
iodide (5.0 mmol) and 120 mL of acetonitrile. The mix-
ture was stirred for 10 min at room temperature, and
then heated to reflux for 5 h. The reaction mixture was
cooled to room temperature and filtered off, and the
filtrate was concentrated on a rotary evaporator to afford
the crude product as an oil, which was purified by col-
umn chromatography to produce 4a—4e as colorless
oils.
General procedure for the synthesis of (1-(2-(di-
ethylamino)ethyl)-3-p-substituted phenyl-1H-pyraz-
ol-5-yl)methanol (5a— 5e)
A 250-mL round-bottomed flask was charged with
the carboxylates 5a—5e (0.060 mol) and 80 mL of dried
THF, and the solution was stirred on an ice-water bath.
Lithium aluminium hydride (0.040 mol) was added in
portions. This reaction mixture was stirred for 1.0 h at
room temperature and then 50 mL of water was added
dropwise. The mixture thus obtained was extracted with
200 mL of dichloromethane in three portions, and the
combined exacts were washed with saturated brine,
dried over anhydrous sodium sulfate and concentrated
on a rotary evaporator to yield 5a—5e as colorless liq-
uids.
Ethyl 1-(2-(diethylamino)ethyl)-3-phenyl-1H-py-
razole-5-carboxylate (4a) Colorless oil, yield 81%,
1H NMR (DMSO-d6, 400 MHz) δ: 7.82—7.86 (m, 2H),
7.28—7.46 (m, 4H), 4.57 (t, J＝6.8 Hz, 2H), 4.33 (q,
J＝7.2 Hz, 2H), 2.76 (t, J＝6.8 Hz, 2H), 2.44 (q, J＝7.2
Hz, 4H), 1.33 (t, J＝7.2 Hz, 3H), 0.86 (t, J＝7.2 Hz,
6H); HR-MS (ESI-Q-TOF) calcd for C18H25N3O2 ([M＋
H]＋) 316.2025, found 316.2027.
(1-(2-(Diethylamino)ethyl)-3-phenyl-1H-pyrazol-
5-yl)methanol (5a) Colorless oil, yield 98%; 1H NMR
(CDCl3, 400 MHz) δ: 7.77—7.79 (m, 2H), 7.37—7.41
(m, 2H), 7.29—7.31 (m, 1H), 6.50 (s, 1H), 4.57 (s, 2H),
4.23—4.26 (m, 2H), 2.85—2.87 (m, 2H), 2.46 (q, J＝
7.2 Hz, 4H), 0.92 (t, J＝7.2 Hz, 6H＋); HR-MS (ESI-Q-
TOF) calcd for C16H23N3O ([M＋H] ) 274.1919, found
274.1923.
Ethyl 1-(2-(diethylamino)ethyl)-3-p-tolyl-1H-py-
razole-5-carboxylate (4b) Colorless oil, yield 79%;
1H NMR (CDCl3, 300 MHz) δ: 7.69 (d, J＝8.1 Hz, 2H),
7.20 (d, J＝8.1 Hz, 2H), 7.06 (s, 1H), 4.68 (t, J＝7.1 Hz,
2H), 4.35 (q, J＝7.2 Hz, 2H), 2.90 (t, J＝7.1 Hz, 2H),
2.59 (q, J＝7.2 Hz, 4H), 2.36 (s, 3H), 1.39 (t, J＝7.2 Hz,
3H), 1.00 (t, J＝7.2 Hz, 6H); 13C NMR (CDCl3, 75
MHz) δ: 160.32, 150.54, 138.18, 134.18, 130.44, 129.83,
125.96, 108.11, 61.44, 53.50, 50.12, 47.87, 21.76, 14.79,
12.59; HR-MS (ESI-Q-TOF) calcd for C19H27N3O2 ([M
＋H]＋) 330.2182, found 330.2186.
(1-(2-(Diethylamino)ethyl)-3-p-tolyl-1H-pyrazol-
5-yl)methanol (5b) Colorless oil, yield 98%; 1H
NMR (CDCl3, 300 MHz) δ: 7.67 (d, J＝8.1 Hz, 2H),
7.19 (d, J＝8.1 Hz, 2H), 6.46 (s, 1H), 4.55 (s, 2H), 4.22
—4.24 (m, 2H), 2.83—2.86 (m, 2H), 2.45 (q, J＝7.2 Hz,
4H), 2.36 (s, 3H), 0.91 (t, J＝7.2 Hz, 6＋H); HR-MS
(ESI-Q-TOF) calcd for C17H25N3O ([M＋H] ) 288.2076,
found 288.2076.
Ethyl 3-(4-bromophenyl)-1-(2-(diethylamino)eth-
yl)-1H-pyrazole-5-carboxylate (4c)
Colorless oil,
1
yield 79%; H NMR (DMSO-d6, 400 MHz) δ: 7.80 (d,
J＝8.4 Hz, 2H), 7.59 (d, J＝8.4 Hz, 2H), 7.33 (s, 1H),
4.57 (t, J＝6.8 Hz, 2H), 4.32 (q, J＝7.2 Hz, 2H), 2.76 (t,
J＝6.8 Hz, 2H), 2.43 (q, J＝7.2 Hz, 4H), 1.32 (t, J＝7.2
Hz, 3H), 0.84 (t, J＝7.2 Hz, 6H); H＋R-MS (ESI-Q-TOF)
calcd for C18H24BrN3O2 ([M＋H] ) 394.1130, found
394.1130.
(3-(4-Bromophenyl)-1-(2-(diethylamino)ethyl)-1H-
pyrazol-5-yl)methanol (5c) White solid, yield 98%,
1
m.p. 56—57 ℃; H NMR (DMSO-d6, 400 MHz) δ:
7.71 (d, J＝8.4 Hz, 2H), 7.55 (d, J＝8.4 Hz, 2H), 6.66
(s, 1H), 4.51 (s, 2H), 4.13—4.17 (m, 2H), 2.75—2.78
(m, 2H), 2.45 (q, J＝7.2 Hz, 4H), 0.88 (t, J＝7.2 Hz,
6H); HR-MS (ESI-Q-TOF) calcd for C16H22BrN3O ([M
＋H]＋) 352.1024, found 352.1027.
Ethyl 3-(4-chlorophenyl)-1-(2-(diethylamino)eth-
yl)-1H-pyrazole-5-carboxylate (4d) Colorless oil,
1
yield 80%; H NMR (CDCl3, 300 MHz) δ: 7.73 (d, J＝
(3-(4-Chlorophenyl)-1-(2-(diethylamino)ethyl)-1H-
pyrazol-5-yl)methanol (5d) Colorless oil, yield 97%,
1H NMR (CDCl3, 300 MHz) δ: 7.70 (d, J＝8.1 Hz, 2H),
7.36 (d, J＝8.1 Hz, 2H), 6.47 (s, 1H), 4.56 (s, 2H), 4.22
—4.25 (m, 2H), 2.84—2.87 (m, 2H), 2.47 (q, J＝7.2 Hz,
4H), 0.92 (t, J＝7.2 Hz, 6H); 13C NMR (CDCl3, 75
8.4 Hz, 2H), 7.39 (d, J＝8.4 Hz, 2H), 7.06 (s, 1H), 4.67
(t, J＝7.1 Hz, 2H), 4.37 (q, J＝7.2 Hz, 2H), 2.91 (t, J＝
7.1 Hz, 2H), 2.58 (q, J＝7.2 Hz, 4H), 1.42 (t, J＝7.2 Hz,
3H), 0.98 (t, J＝7.2 Hz, 6H); 13C NMR (CDCl3, 75
MHz) δ: 160.08, 149.24, 134.43, 134.07, 131.76, 129.25,
Chin. J. Chem. 2011, 29, 2039— 2048
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wang et al.
FULL PAPER
MHz) δ: 150.28, 145.45, 133.75, 132.56, 129.20, 127.29,
J ＝ 7.2 Hz, 6H); HR-MS (ESI-Q-TOF) calcd for
C21H31N3O4 ([M＋H]＋) 390.2393, found 390.2386.
103.32, 54.48, 54.32, 50.36, 49.39, 11.30; HR-MS
(ESI-Q-TOF) calcd for C16H22ClN3O ([M ＋ H] ＋
)
General procedure for the synthesis of tert-butyl
2-((1-(2-(diethylamino)ethyl)-3-phenyl-1H-pyrazol-5-
yl)methoxy)acetate (7a— 7e)
308.1530, found 308.1536.
(1-(2-(Diethylamino)ethyl)-3-(4-methoxyphenyl)-
1H-pyrazol-5-yl)methanol (5e) White solid, yield
1
A 250-mL round-bottomed flask was charged with
150 mL of dried t-butanol and 4.80 g of potassium (0.12
mol), the mixture was stirred under nitrogen until all the
potassium disappeared completely. The alcohols 5a—5e
(0.060 mol) were dissolved into 50 mL dried t-butanol
and added dropwise to the solution of potassoium
t-butoxide prepared above. The mixture thus obtained
was stirred for 10 min and ethyl chloroacetate (0.18 mol)
was added. The stirring was continued at reflux for an
additional 3.0 h. The mixture was cooled to room tem-
perature and concentrated on a rotary evaporator, fol-
lowed by addition of 100 mL of water. The solution
thus obtained was extracted with 250 mL of dichloro-
methane in three portions. The combined exacts were
washed with saturated brine, dried over anhydrous so-
dium sulfate and concentrated on a rotary evaporator to
give the crude products as red oils, which were purified
by column chromatography to give the pure products 7a
—7e as colorless oils.
96%, m.p. 52—54 ℃; H NMR (DMSO-d6, 400 MHz)
δ: 7.68 (d, J＝8.8 Hz, 2H), 6.94 (d, J＝8.8 Hz, 2H),
6.488 (s, 1H), 5.568 (Br, s, 1H), 4.509 (s, 2H), 4.14 (t,
J＝6.4 Hz, 2H), 3.766 (s, 3H), 2.78 (t, J＝6.4 Hz, 2H),
2.47 (q, J＝7.2 Hz, 4H), 0.89 (t, J＝7.2 Hz, 6H);
HR-MS (ESI-Q-TOF) calcd for C17H25N3O2 ([M＋H]＋)
304.2025, found 304.2028.
General procedure for the synthesis of ethyl 2-((1-
(2-(diethylamino)ethyl)-3-p-substituted phenyl-1H-
pyrazol-5-yl)methoxy)acetate (6a, 6b, 6e)
A 250-mL round-bottomed flask was charged with
the alcohols 5a, 5b or 5e (0.060 mol) and 50 mL dried
THF, and then 1.80 g (0.075 mol) sodium hydride was
added slowly. The mixture thus obtained was stirred for
10 min under nitrogen prior to ethyl chloroacetate (0.18
mol) was added dropwise and then heated to reflux for 3
h. The mixture was cooled to room temperature prior to
the dropwise addition of 50 mL water, and the resulting
mixture was extracted with 250 mL of dichloromethane
in three portions. The combined exacts were washed
with saturated brine, dried over anhydrous sodium sul-
fate and concentrated on a rotary evaporator to give the
crude products as yellow oils, which were purified by
column chromatography to give the pure products 6a,
6b, 6e as colorless oils.
tert-Butyl 2-((1-(2-(diethylamino)ethyl)-3-phenyl-
1H-pyrazol-5-yl)methoxy)acetate (7a) Colorless oil,
1
yield 54%; H NMR (CDCl3, 400 MHz) δ: 7.76—7.79
(m, 2H), 7.28—7.40 (m, 3H), 6.50 (s, 1H), 4.72 (s, 2H),
4.29 (t, J＝6.8 Hz, 2H), 3.98 (s, 2H), 2.92 (t, J＝6.8 Hz,
2H), 2.56 (q, J＝7.2 Hz, 4H), 1.48 (s, 9H), 0.99 (t, J＝
7.2 Hz, 6H); HR-MS (ESI-Q-TOF) calcd for
C22H33N3O3 ([M＋H]＋) 388.2600, found 388.2609.
tert-Butyl 2-((1-(2-(diethylamino)ethyl)-3-p-tolyl-
1H-pyrazol-5-yl)methoxy)acetate (7b) Colorless oil,
Ethyl 2-((1-(2-(diethylamino)ethyl)-3-phenyl-1H-
pyrazol-5-yl)methoxy)acetate (6a)
Colorless oil,
1
yield 11%; H NMR (CDCl3, 300 MHz) δ: 7.76—7.79
(m, 2H), 7.28—7.40 (m, 3H), 6.51 (s, 1H), 4.73 (s, 2H),
4.33 (t, J＝6.8 Hz, 2H), 4.23 (q, J＝7.2 Hz 2H), 4.10 (s,
2H), 2.97 (t, J＝6.8 Hz, 2H), 2.60 (q, J＝7.2 Hz, 4H),
1.29 (t, J＝7.2 Hz, 3H), 1.02 (t, J＝7.2 Hz, 6H);
HR-MS (ESI-Q-TOF) calcd for C20H29N3O3 ([M＋H]＋)
360.2287, found 360.2285.
1
yield 52%; H NMR (CDCl3, 400 MHz) δ: 7.67 (d, J＝
8.1 Hz, 2H), 7.19 (d, J＝8.1 Hz, 2H), 6.46 (s, 1H), 4.72
(s, 2H), 4.28 (t, J＝6.8 Hz, 2H), 3.98 (s, 2H), 2.92 (t,
J＝6.8 Hz, 2H), 2.56 (q, J＝7.2 Hz, 4H), 2.37 (s, 3H),
1.48 (s, 9H), 0.99 (t, J＝7.2 Hz, 6H); HR-MS (ESI-Q-
TOF) calcd for C23H36N3O3 ([M＋H]＋) 402.2757, found
402.2764.
Ethyl 2-((1-(2-(diethylamino)ethyl)-3-p-tolyl-1H-
pyrazol-5-yl)methoxy)acetate (6b)
Colorless oil,
tert-Butyl 2-((3-(4-bromophenyl)-1-(2-(diethyla-
1
yield 10%; H NMR (CDCl3, 300 MHz) δ: 7.66 (d, J＝
8.1 Hz, 2H), 7.19 (d, J＝8.1 Hz, 2H), 6.48 (s, 1H), 4.72
(s, 2H), 4.26 (t, J＝6.8 Hz, 2H), 4.19 (q, J＝7.2 Hz, 2H),
4.06 (s, 2H), 2.94 (t, J＝6.8 Hz, 2H), 2.57 (q, J＝7.2 Hz,
4H), 2.36 (s, 3H), 1.29 (t, J＝7.2 Hz, 3H), 0.99 (t, J＝
7.2 Hz, 6H); HR-MS (ESI-Q-TOF) calcd for C21H31-
N3O3 ([M＋H]＋) 374.2444, found 374.2445.
mino)ethyl)-1H-pyrazol-5-yl)methoxy)acetate
(7c)
Colorless oil, yield 54%; 1H NMR (CDCl3, 400 MHz) δ:
7.65 (d, J＝6.8 Hz, 2H), 7.49 (d, J＝6.8 Hz, 2H), 6.47
(s, 1H), 4.70 (s, 2H), 4.28 (t, J＝6.8 Hz, 2H), 3.98 (s,
2H), 2.91 (t, J＝6.8 Hz, 2H), 2.55 (q, J＝7.2 Hz, 4H),
1.48 (s, 9H), 0.98 (t, J＝7.2 Hz, 6H); HR＋-MS (ESI-Q-
TOF) calcd for C22H32BrN3O3 ([M＋H] ) 466.1705,
found 466.1709.
Ethyl
2-((1-(2-(diethylamino)ethyl)-3-(4-meth-
oxyphenyl)-1H-pyrazol-5-yl)methoxy)acetate
(6e)
tert-Butyl
2-((3-(4-chlorophenyl)-1-(2-(diethyl-
Colorless oil, yield 10%; 1H NMR (CDCl3, 300 MHz) δ:
7.69 (d, J＝9.0 Hz, 2H), 6.91 (d, J＝9.0 Hz, 2H), 6.43
(s, 1H), 4.69 (s, 2H), 4.29 (t, J＝6.6 Hz, 2H), 4.23 (q,
J＝7.2 Hz, 2H), 4.10 (s, 2H), 3.83 (s, 3H), 2.96 (t, J＝
6.6 Hz, 2H), 2.59 (q, J＝7.2 Hz, 4H), 1.29 (t, J＝7.2 Hz,
3H), 1.02 (t, J＝7.2 Hz, 6H); HR-MS (ESI-Q-TOF)
amino)ethyl)-1H-pyrazol-5-yl)methoxy)acetate (7d)
Colorless oil, yield 55%; 1H NMR (CDCl3, 400 MHz) δ:
7.70 (d, J＝8.4 Hz, 2H), 7.29 (d, J＝8.4 Hz, 2H), 6.48
(s, 1H), 4.70 (s, 2H), 4.29 (t, J＝6.8 Hz, 2H), 3.98 (s,
2H), 2.92 (t, J＝6.8 Hz, 2H), 2.56 (q, J＝7.2 Hz, 4H),
1.48 (s, 9H), 0.99 (t, J＝7.2 Hz, 6H); HR-MS (ESI-Q-
2042
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Chin. J. Chem. 2011, 29, 2039— 2048

Design and Synthesis of Novel Pyrazole-based Lp-PLA2 Inhibitors
TOF) calcd for C22H32ClN3O3 ([M＋H]＋) 422.2210,
3.65—3.68 (m, 2H), 2.95 (t, J＝6.8 Hz, 2H), 2.55 (q,
J＝7.2 Hz, 4H), 1.02 (t, J＝7.2 Hz, 6H); HR-MS (ESI-
Q-TOF) calcd for C18H26ClN3O2 ([M＋H]＋) 352.1792,
found 352.1795.
found 422.2218.
tert-Butyl 2-((1-(2-(diethylamino)ethyl)-3-(4-me-
thoxyphenyl)-1H-pyrazol-5-yl)methoxy)acetate (7e)
Colorless oil, yield 55%; 1H NMR (CDCl3, 400 MHz) δ:
7.70 (d, J＝7.2 Hz, 2H), 6.92 (d, J＝7.2 Hz, 2H), 6.42
(s, 1H), 4.70 (s, 2H), 4.27 (t, J＝6.8 Hz, 2H), 3.97 (s,
2H), 3.83 (s, 3H), 2.91 (t, J＝6.8 Hz, 2H), 2.55 (q, J＝
7.2 Hz, 4H), 1.48 (s, 9H), 0.99 (t, J＝7.2 Hz, 6H);
HR-MS (ESI-Q-TOF) calcd for C23H35N3O4 ([M＋H]＋)
418.2706, found 418.2710.
2-((1-(2-(Diethylamino)ethyl)-3-(4-methoxyphen-
yl)-1H-pyrazol-5-yl)methoxy)ethanol (8e) Colorless
1
oil, yield 98%; H NMR (DMSO-d6, 400 MHz) δ: 6.93
—6.95, 7.67—7.69 (d, J＝8.8 Hz, 2H), 6.57 (s, 1H),
4.57 (s, 2H), 4.13 (t, J＝6.8 Hz, 2H), 3.77 (s, 3H) 3.52
—3.54 (m, 2H), 3.46—3.48 (m, 2H), 2.76—2.80 (t, J＝
6.8 Hz, 2H), 2.49 (q, J＝7.2 Hz, 4H), 0.92 (t, J＝7.2 Hz,
6H); HR-MS (ESI-Q-TOF) calcd for C19H29N3O3 ([M＋
H]＋) 348.2287, found 348.2290.
General procedure for the synthesis of 2-((1-(2-(di-
ethylamino)ethyl)-3-(4-substituted phenyl)-1H-pyra-
zol-5-yl)methoxy)ethyl methanesulfonate (9a— 9e)
General procedure for the synthesis of 2-((1-(2-(di-
ethylamino)ethyl)-3-(4-substituted phenyl)-1H-
pyrazol-5-yl)methoxy)ethanol (8a— 8e)
A 250-mL round-bottomed flask was charged with
the acetates 7a—7e (0.030 mol) and 100 mL of dried
THF, the solution thus obtained was stirred for 10 min
on an ice-water bath. Lithium aluminium hydride (0.020
mol) was added in portions. The mixture was stirred for
1.0 h at room temperature and 50 mL of water was
added dropwise under stirring. The mixture was ex-
tracted with 200 mL of dichloromethane in three por-
tions, and the combined exacts were dried over anhy-
drous sodium sulfate and concentrated on a rotary
evaporator to yield 8a—8e as colourless liquids.
A 250-mL round-bottomed flask was charged with
the compounds 8a — 8e (0.030 mol), triethylamine
(0.060 mol) and 100 mL of dried dichloromethane.
Methanesulfonyl chloride (0.030 mol) or 4-toluenesul-
fonyl chloride (0.030 mol) were added dropwise upon
cooling. The mixture was stirred at room temperature
for 1.0 h and concentrated on a rotary evaporator to give
the crude products 9a—9e, which were purified by col-
umn chromatography to give the pure products 9a—9e
as colorless oils.
2-((1-(2-(Diethylamino)ethyl)-3-phenyl-1H-pyraz-
ol-5-yl)methoxy)ethanol (8a) Colorless oil, yield
98%; 1H NMR (DMSO-d6, 400 MHz) δ: 7.75—7.77 (m,
2H), 7.27—7.39 (m, 3H), 6.68 (s, 1H), 4.63 (s, 2H),
4.17 (t, J＝6.4 Hz, 2H), 3.75—3.77 (m, 2H), 3.70—
3.73 (m, 2H), 2.81 (t, J＝6.4 Hz, 2H), 2.48 (q, J＝7.2
Hz, 4H), 0.91 (t, J＝7.2 Hz, 6H); HR-MS (ESI-Q-TOF)
calcd for C18H27N3O2 ([M＋H]＋ ) 318.2182, found
318.2188.
2-((1-(2-(Diethylamino)ethyl)-3-phenyl-1H-pyra-
zol-5-yl)methoxy)ethyl methanesulfonate (9a) Col-
1
orless oil, yield 98%; H NMR (CDCl3, 400 MHz) δ:
7.76—7.78 (m, 2H), 7.29—7.40 (m, 3H), 6.50 (s, 1H),
4.68 (s, 2H), 4.36—4.38 (m, 2H), 4.21—4.25 (m, J＝
6.8 Hz, 2H), 3.74—3.77 (m, 2H), 3.02 (s, 3H), 2.91 (t,
J＝6.8 Hz, 2H), 2.55 (q, J＝7.2 Hz, 4H), 0.99 (t, J＝7.2
Hz, 6H); HR-MS (ESI-Q-TOF) calcd for C19H29N3O4S
([M＋H]＋) 396.1957, found 396.1959.
2-((1-(2-(Diethylamino)ethyl)-3-p-tolyl-1H-pyraz-
ol-5-yl)methoxy)ethanol (8b) Colorless oil, yield
97%; 1H NMR (CDCl3, 400 MHz) δ: 7.64 (d, J＝8.1 Hz,
2H), 7.17 (d, J＝8.1 Hz, 2H), 6.43 (s, 1H), 4.61 (s, 2H),
4.28 (t, J＝6.8 Hz, 2H), 3.70—3.73 (m, 2H), 3.66—
3.68 (m, 2H), 2.89 (t, J＝6.8 Hz, 2H), 2.46 (q, J＝7.2
2-((1-(2-(Diethylamino)ethyl)-3-p-tolyl-1H-pyrazol-
5-yl)methoxy)ethyl 4-methylbenzenesulfonate (9b)
Colorless oil, yield 98%; 1H NMR (CDCl3, 300 MHz) δ:
7.76 (d, J＝8.1 Hz, 2H), 7.66 (d, J＝8.1 Hz, 2H), 7.28
(d, J＝7.8Hz, 2H), 7.19 (d, J＝7.8 Hz, 2H), 6.39 (s, 1H),
4.56 (s, 2H), 4.15—4.18 (m, 2H), 4.14 (t, J＝6.9 Hz,
2H), 3.62—3.65 (m, 2H), 2.85 (t, J＝6.9 Hz, 2H), 2.51
(q, J＝7.2 Hz, 4H), 2.39 (s, 3H), 2.35 (s, 3H), 0.96 (t,
J＝7.2 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ: 150.73,
145.37, 139.79, 137.69, 133.40, 131.24, 130.32, 129.74,
128.41, 125.88, 104.30, 69.48, 67.77, 63.97, 53.84,
49.09, 48.16, 22.09, 21.72, 12.52; HR-MS (ESI-Q-TOF)
calcd for C26H35N3O4S ([M＋H]＋ ) 486.2427, found
486.2426.
Hz, 4H), 2.37 (s, 3H), 1.00 (t, J＝7.2 Hz, 6H); HR-MS
＋
(ESI-Q-TOF) calcd for C19H29N3O2 ([M ＋ H]
)
332.2338, found 332.2338.
2-((3-(4-Bromophenyl)-1-(2-(diethylamino)ethyl)-
1H-pyrazol-5-yl)methoxy)ethanol (8c) Colorless oil,
1
yield 98%; H NMR (CDCl3, 400 MHz) δ: 7.69 (d, J＝
8.8 Hz, 2H), 7.34 (d, J＝8.8 Hz, 2H), 6.44 (s, 1H), 4.61
(s, 2H), 4.29 (t, J＝6.8 Hz, 2H), 3.71—3.74 (m, 2H),
3.65—3.68 (m, 2H), 2.92 (t, J＝6.8 Hz, 2H), 2.53 (q,
J＝7.2 Hz, 4H), 1.01 (t, J＝7.2 Hz, 6H); HR-MS (ESI-
Q-TOF) calcd for C18H26BrN3O2 ([M＋H]＋) 396.1287,
found 396.1290.
2-((3-(4-Bromophenyl)-1-(2-(diethylamino)ethyl)-
1H-pyrazol-5-yl)methoxy)ethyl methanesulfonate (9c)
Colorless oil, yield 97%; 1H NMR (CDCl3, 400 MHz) δ:
7.64 (d, J＝8.8 Hz, 2H), 7.39 (d, J＝8.8 Hz, 2H), 6.47
(s, 1H), 4.66 (s, 2H), 4.36—4.38 (m, 2H), 4.20—4.25 (t,
2H, J＝6.8 Hz), 3.74—3.77 (m, 2H), 3.02 (s, 3H), 2.92
(t, J＝6.8 Hz, 2H), 2.56 (q, J＝7.2 Hz, 4H), 0.98 (t, J＝
7.2 Hz, 6H); HR-MS (ESI-Q-TOF) calcd for
2-((3-(4-Chlorophenyl)-1-(2-(diethylamino)ethyl)-
1H-pyrazol-5-yl)methoxy)ethanol (8d) Colorless oil,
1
yield 98%; H NMR (CDCl3, 400 MHz) δ: 7.64 (d, J＝
8.4 Hz, 2H), 7.50 (d, J＝8.4 Hz, 2H), 6.45 (s, 1H), 4.61
(s, 2H), 4.31 (t, J＝6.8 Hz, 2H), 3.72—3.76 (m, 2H),
Chin. J. Chem. 2011, 29, 2039— 2048
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2043

Wang et al.
FULL PAPER
C19H28BrN3O4S ([M＋H]＋) 474.1062, found 474.1067.
2-((3-(4-Chlorophenyl)-1-(2-(diethylamino)ethyl)-
1H-pyrazol-5-yl)methoxy)ethyl methanesulfonate (9d)
Colorless oil, yield 97%; 1H NMR (CDCl3, 400 MHz) δ:
7.70 (d, J＝8.8 Hz, 2H), 7.35 (d, J＝8.8 Hz, 2H), 6.47
(s, 1H), 4.67 (s, 2H), 4.36—4.38 (m, 2H), 4.20—4.24
(m, 2H, J＝6.8 Hz), 3.75—3.77 (m, 2H), 3.02 (s, 3H),
2.92 (t, J＝6.8 Hz, 2H), 2.56 (q, J＝7.2 Hz, 4H), 0.99 (t,
J ＝ 7.2 Hz, 6H); HR-＋MS (ESI-Q-TOF) calcd for
C19H28ClN3O4S ([M＋H] ) 430.1567, found 430.1564.
2-((1-(2-(Diethylamino)ethyl)-3-(4-methoxyphen-
yl)-1H-pyrazol-5-yl)methoxy)ethyl methanesulfonate
20.51.
General procedure for the synthesis of 2-(4-fluoro-
benzylthio)-1-(2-((1-(2-(diethylamino)ethyl)-3-p-tolyl-
1H-pyrazol-5-yl)methoxy)ethyl)-6,7-dihydro-1H-
cyclopenta[d]pyrimidin-4(5H)-one (13a— 13e)
A 250-mL round-bottomed flask was charged with
the compound 12 (0.030 mol), compounds 9a—9e
(0.030 mol), potassium carbonate (0.10 mol), and 100
mL of DMF. The mixed solution was heated to 80 ℃
for 3.0 h and then cooled to room temperature. The re-
action mixture was filtered off and the filtrate was di-
luted with 300 mL of dichloromethane and washed with
50 mL of water. The organic layer was dried over anhy-
drous sodium sulfate and concentrated on a rotary
evaporator to afford the crude products 13a—13e as
colorless oils, which were purified by column chroma-
tography to afford the pure products 13a—13e as color-
less oils. Compounds 13a — 13e (0.025 mol) and
L-tartaric acid (0.025 mol) were dissovled in methanol,
and the solution thus obtained was stirred for 0.5 h and
then evaporated on a rotary evaporator to give the salts
of 13a—13e after washing with diethyl ether and drying
in vacuo at room temperature to give the pure salts of
13a—13e as white solid.
1
(9e) Colorless oil, yield 98%; H NMR (CDCl3, 400
MHz) δ: 7.69 (d, J＝8.8 Hz, 2H), 6.92 (d, J＝8.8 Hz,
2H), 6.42 (s, 1H), 4.66 (s, 2H), 4.36—4.38 (m, 2H),
4.21—4.24 (m, J＝6.8 Hz, 2H), 3.83 (s, 3H), 3.74—
3.76 (m, 2H), 3.02 (s, 3H), 2.92 (t, J＝6.8 Hz, 2H), 2.57
(q, J＝7.2 Hz, 4H), 1.00 (t, J＝7.2 Hz, 6H); HR-MS
(ESI-Q-TOF) calcd for C20H31N3O5S ([M ＋ H] ＋ )
426.2063, found 426.2070.
General procedure for the synthesis of synthesis of
2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[d]-
pyrimidin-4(5H)-one (12)
A 250-mL round-bottomed flask was charged with
120 mL of absolute ethanol and 3.50 g sodium (0.15
mol), and the mixture was stirred under nitrogen until
the sodium disappeared. Subsequently, 9.0 g of thiourea
(0.12 mol) was added, and the solution was stirred for
30 min. After 16.0 g of ethyl 2-oxocyclopentane car-
boxylate (0.096 mol) was added, the mixture thus ob-
tained was heated to reflux for 2.0 h under nitrogen. On
cooling, the reaction mixture was concentrated on a ro-
tary evaporator, then 30 mL of water was added. The
pH of the solution was adjusted to 5 using concentrated
hydrochloric acid followed by precipitation of crude 11,
which were collected by suction filtration.
2-(4-Fluorobenzylthio)-1-(2-((1-(2-(diethylamino)-
ethyl)-3-phenyl-1H-pyrazol-5-yl)methoxy)ethyl)-6,7-
dihydro-1H-cyclopenta[d]pyrimidin-4(5H)-one (13a)
Colorless oil, yield 92%; 1H NMR (CDCl3, 400 MHz) δ:
7.75—7.77 (m, 2H), 7.35—7.40 (m, 4H), 7.28—7.30
(m, 1H), 6.94—6.98 (m, 2H), 6.47 (s, 1H), 4.65 (s, 2H),
4.50 (t, J＝4.8 Hz, 2H), 4.34 (s, 2H), 4.22 (t, J＝7.2 Hz,
2H), 3.77 (t, J＝4.8 Hz, 2H), 2.85—2.91 (m, 4H), 2.78
(t, J＝7.2 Hz, 2H), 2.53 (q, J＝7.6 Hz, 4H), 2.05—2.11
(m, 2H), 0.99 (t, J＝7.6 Hz, 6H); 13C NMR (CDCl3, 100
MHz) δ: 175.69, 168.54, 165.03, 163.06, 160.62, 150.17,
139.72, (133.71, 133.50), (130.36, 130.28), 128.53,
127.46, 125.46, 115.57, (115.30, 115.09), 103.95, 67.88,
65.26, 63.43, 53.30, 48.55, 47.61, 34.53, 34.06, 26.29,
21.82, 11.98; HR-M＋S (ESI-Q-TOF) calcd for
C32H38FN5O2S ([M＋H] ) 576.2808, found 576.2811.
2-(4-Fluorobenzylthio)-1-(2-((1-(2-(diethylamino)-
ethyl)-3-p-tolyl-1H-pyrazol-5-yl)methoxy)ethyl)-6,7-
dihydro-1H-cyclopenta[d]pyrimidin-4(5H)-one (13b)
Colorless oil, yield 91%; 1H NMR (CDCl3, 300 MHz) δ:
7.65 (d, J＝7.8 Hz, 2H), 7.34—7.38 (m, 2H), 7.18 (d,
J＝7.8 Hz, 2H), 6.92—6.98 (m, 2H), 6.43 (s, 1H), 4.64
(s, 2H), 4.50 (t, J＝4.8 Hz, 2H), 4.33 (s, 2H), 4.23 (t,
J＝7.2 Hz, 2H), 3.76 (t, J＝4.8 Hz, 2H), 2.84—2.92 (m,
4H), 2.77 (t, J＝7.2 Hz, 2H), 2.53 (q, J＝7.2 Hz, 4H),
2.355 (s, 3H), 2.02—2.12 (m, 2H), 0.99 (t, J＝7.6 Hz,
6H); 13C NMR (CDCl3, 75 MHz) δ: 176.20, 169.10,
165.57, 164.01, 160.76, 150.78, 140.15, 137.66, (134.28,
134.23), (130.89, 130.78), 129.72, 125.90, (116.09,
115.84), 115.56, 104.26, 68.41, 65.78, 63.98, 53.83,
49.03, 48.15, 35.06, 34.58, 26.81, 22.34, 21.71, 12.49;
HR-MS (ESI-Q-TOF) calcd for C33H40FN5O2S ([M＋
H]＋) 590.2965, found 590.2964.
A 250-mL round-bottomed flask was charged with
the crude compoud 11 (0.050 mol) and 100 mL of ace-
tone. Potassium carbonate (0.10 mol), potassium iodide
(5.0 mmol) and 4-flurobenzyl chloride (0.060 mol) were
added, and the mixture was strirred for 10 min at room
temperature and then heated to reflux for 1.0 h. On
cooling, the solution was evaporated on a rotary evapo-
rator and 50 mL water was added. The pH of the solu-
tion was adjusted to 7 using concentrated hydrochloric
acid followed by precipitation of crude 12, which was
collected by suction filtration and recrystallized from
ethyl acetate to afford the pure products as a white solid.
2-(4-Fluorobenzylthio)-6,7-dihydro-1H-cyclopen-
ta[d]pyrimidin-4(5H)-one (12) White solid, yield
1
38%, m.p. 209—210 ℃; H NMR (DMSO-d6, 300
MHz) δ: 12.49 (br, s, 1H), 7.46 (dd, J＝8.4, 1.5 Hz, 2H),
7.14 (t, J＝8.4, 8.4 Hz, 2H), 4.38 (s, 2H), 2.69 (t, J＝7.5
Hz, 2H), 2.59 (t, J＝7.2 Hz, 2H), 1.91—2.01 (m, J＝7.2,
13
7.5 Hz, 2H); C NMR (DMSO-d6, 75 MHz) δ: 168.67,
162.94, 160.68, 159.71, (133.58, 133.54), (131.05,
130.95), 119.37, (115.29, 115.00), 34.20, 32.69, 26.66,
2044
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2039— 2048

Design and Synthesis of Novel Pyrazole-based Lp-PLA2 Inhibitors
2-(4-Fluorobenzylthio)-1-(2-((3-(4-bromophenyl)-
1-(2-(diethylamino)ethyl)-1H-pyrazol-5-yl)methoxy)-
ethyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-4(5H)-
calcd for C16H17FN2O2S ([M＋H]＋) 321.1073, found
321.1075.
2-(4-Fluorobenzylthio)-1-(2-chloroethyl)-6,7-dihy-
1
one (13c) Colorless oil, yield 90%; H NMR (CDCl3,
dro-1H-cyclopenta[d]pyrimidin-4(5H)-one
(17)
400 MHz) δ: 7.63 (d, J＝6.8 Hz, 2H), 7.49 (d, J＝6.8
Hz, 2H), 7.34—7.39 (m, 2H), 6.93—6.98 (m, 2H), 6.44
(s, 1H), 4.64 (s, 2H), 4.49 (t, J＝4.8 Hz, 2H), 4.34 (s,
2H), 4.21 (t, J＝7.2 Hz, 2H), 3.76 (t, J＝4.8 Hz, 2H),
2.85—2.90 (m, 4H), 2.78 (t, J＝7.2 Hz, 2H), 2.52 (q,
J＝7.2 Hz, 4H), 2.04—2.09 (m, 2H), 0.96 (t, J＝7.2 Hz,
6H); 13C NMR (CDCl3, 100 MHz) δ: 175.67, 168.57,
165.02, 163.06, 160.62, 149.08, 140.08, (133.70,
133.49), (130.34, 130.26), 128.49, 127.45, 125.45,
115.52, (115.26, 115.05), 103.93, 68.04, 65.23, 63.41,
53.13, 48.48, 47.57, 34.52, 34.04, 26.27, 21.79, 11.80;
HR-MS (ESI-Q-TOF) calcd for C32H37BrFN5O2S ([M＋
H]＋) 654.1914, found 654.1918.
Colorless oil, yield 20%; 1H NMR (CDCl3, 300 MHz) δ:
7.36—7.41 (m, 2H), 6.94—7.02 (m, 2H), 4.57 (t, J＝6.0
Hz, 2H), 4.35 (s, 2H), 3.75 (t, J＝6.0 Hz, 2H), 2.91 (t,
J＝7.8 Hz, 2H), 2.79 (t, J＝7.5 Hz, 2H), 2.04—2.14 (m,
2H); HR-MS (ESI-Q-TOF) calcd for C16H16ClFN2O1S
([M＋H]＋) 339.0734, found 339.0742.
4-(4-Fluorobenzyl)-6-oxo-1,2,3,4,6,7,8,9-octahy-
drocyclopenta[e][1,3]thiazino[3,2-a]pyrimidin-4-
1
ium-chloride (18) Colorless oil, yield 80%; H NMR
(CDCl3, 300 MHz) δ: 7.35—7.42 (m, 2H), 6.98—7.04
(m, 2H), 4.40 (s, 2H), 4.34 (t, J＝7.2 Hz, 2H), 3.73 (t,
J＝7.2 Hz, 2H) 2.75—2.86 (m, 4H), 2.04—2.12 (m,
2H); HR-MS (ESI-Q-TOF) calcd for C16H16ClFN2OS
([M＋H]＋) 339.0734, found 339.0743.
2-(4-Fluorobenzylthio)-1-(2-((3-(4-chlorophenyl)-
1-(2-(diethylamino)ethyl)-1H-pyrazol-5-yl)methoxy)-
ethyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-4(5H)-
2-(5-((4-Fluorobenzyloxy)methyl)-3-(4-chlorophe-
nyl)-1H-pyrazol-1-yl)-N,N-diethylethanamine
(19)
1
one (13d) Colorless oil, yield 90%; H NMR (CDCl3,
Colorless oil, yield 95%; 1H NMR (CDCl3, 300 MHz) δ:
7.68—7.72 (m, 2H), 7.32—7.36 (m, 2H), 7.24—7.28
(m, 2H), 6.97—7.24 (m, 2H), 6.34 (s, 1H), 4.16 (t, J＝
6.6 Hz, 2H), 3.69 (s, 2H), 3.66 (s, 2H), 2.87 (t, J＝6.6
Hz, 2H), 2.51 (q, J＝7.2 Hz, 4H), 0.96 (t, J＝7.2 Hz,
6H); HR-MS (ESI-Q-TOF) calcd for C13H27ClFN3O
([M＋H]＋) 416.1905, found 416.1917.
400 MHz) δ: 7.69 (d, J＝6.8 Hz, 2H), 7.34—7.39 (m,
2H), 7.33 (d, J＝6.8 Hz, 2H), 6.93—6.98 (m, 2H), 6.44
(s, 1H), 4.64 (s, 2H), 4.49 (t, J＝4.8 Hz, 2H), 4.34 (s,
2H), 4.21 (t, J＝7.2 Hz, 2H), 3.76 (t, J＝4.8 Hz, 2H),
2.85—2.90 (m, 4H), 2.78 (t, J＝7.2 Hz, 2H), 2.52 (q,
J＝7.2 Hz, 4H), 2.05—2.09 (m, 2H), 0.96 (t, J＝7.2 Hz,
6H); 13C NMR (CDCl3, 100 MHz) δ: 175.59, 168.51,
164.94, 162.99, 160.55, 148.93, 139.96, (133.68,
133.65), 132.03, (130.27, 130.20), 128.56, 126.62,
115.45, (115.19, 115.98), 103.73, 67.93, 65.14, 63.33,
53.21, 48.60, 47.55, 34.44, 33.98, 26.20, 21.72, 11.92;
HR-MS (ESI-Q-TOF) calcd for C32H37ClFN5O2S ([M＋
H]＋) 610.2419, found 610.2425.
Results and discussion
The synthetic route to target compounds 13a—13e is
outlined in Scheme 1. Commercially available aceto-
phenones 1a—1e reacted with diethyl oxalate in the
presence of EtONa in EtOH to give the intermediates
ethyl
2,4-dioxo-4-(p-substitutedphenyl)butanoates,
2-(4-Fluorobenzylthio)-1-(2-((1-(2-(diethylamino)-
ethyl)-3-(4-methoxyphenyl)-1H-pyrazol-5-yl)metho-
xy)ethyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-
which was then reacted with N2H4•H2O to aford the
pyrazolecarboxylates 2a—2e. Treatment of 2a— 2e with
BrCH2CH2Br in the presence of K2CO3 as base and KI
as catalyst in refluxing MeCN produced 3a—3e, which
were sequentially treated with Et2NH in the presence of
K2CO3 and KI in refluxing MeCN to yield 4a— 4e. 4a—
4e were reduced with LiAlH4 in dried THF at 0—5 ℃
to furnish alcohols 5a—5e.
1
4(5H)-one (13e) Colorless oil, yield 92%; H NMR
(CDCl3, 400 MHz) δ: 7.69 (d, J＝6.8 Hz, 2H), 7.34—
7.39 (m, 2H), 6.93—6.98 (m, 2H), 6.92 (d, J＝6.8 Hz,
2H), 6.39 (s, 1H), 4.64 (s, 2H), 4.48—4.51 (t, J＝4.8 Hz,
2H), 4.34 (s, 2H), 4.20 (t, J＝7.2 Hz, 2H), 3.83 (s, 3H),
3.76 (t, J＝4.8 Hz, 2H), 2.85—2.90 (m, 4H), 2.78 (t,
J＝7.2 Hz, 2H), 2.53 (q, J＝7.2 Hz, 4H), 2.05—2.09 (m,
2H), 0.96 (t, J＝7.2 Hz, 6H); 13C NMR (CDCl3, 100
MHz) δ: 175.22, 168.18, 164.66, 162.65, 160.21, 158.79,
149.54, 139.34, (133.48, 133.45), (130.01, 129.93),
126.28, 115.14, (114.86, 114.64), 113.53, 102.99, 67.55,
64.91, 63.04, 54.77, 52.90, 48.05, 47.23, 34.10, 33.66,
25.89, 21.38, 11.63; H＋R-MS (ESI-Q-TOF) calcd for
C33H40FN5O3S ([M＋H] ) 606.2914, found 606.2915.
2-(4-Fluorobenzylthio)-1-(2-hydroxyethyl)-6,7-di-
The conversion of 5a—5e to 6 and 7 was intensively
investigated, and the products and corresponding yields
were summarized in Table 1. Noteworthy was that 7a—
7e were isolated as t-butyl esters arising from trans-
esterification. As can be seen from Table 1, the condi-
tions 3 and 4 were most preferred albeit with only mod-
est conversions (54%—55%), whereas conditions 1, 2
and 5 gave unsatisfactory results with no or only mar-
ginal conversions (0—11%).
Synthesis of the sulfonates 9a—9e was prepared by
two steps as shown in Scheme 1. The esters 6 and 7
were reduced by the LiAlH4 in THF, and the alcohols
8a—8e thus obtained were converted to the corre-
sponding sulfonates 9a—9e with MsCl or TsCl in the
presence of Et3N in CH2Cl2 at room temperature.
hydro-1H-cyclopenta[d]pyrimidin-4(5H)-one
(15)
1
White solid, yield 86%, m.p. 97—99 ℃; H NMR
(CDCl3, 300 MHz) δ: 7.36—7.41 (m, 2H), 6.94—7.00
(m, 2H), 4.48 (t, J＝4.8 Hz, 2H), 4.35 (s, 2H), 3.93 (t,
J＝4.8 Hz, 2H), 2.90 (t, J＝7.8 Hz, 2H), 2.80 (t, J＝7.5
Hz, 2H), 2.05—2.15 (m, 2H); HR-MS (ESI-Q-TOF)
Chin. J. Chem. 2011, 29, 2039— 2048
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2045

Wang et al.
FULL PAPER
Scheme 1 Synthetic route to the title compounds 13a— 13e
Br
OEt
NH
N
N
O
N
(i)
(ii)
O
(iii)
NEt2
O
OEt
O
R
R
R
_
_
_
1a 1e
2a 2e
3a 3e
NEt2
NEt2
N
N
_
N
_
N
N
N
(vi)
(iv)
(v)
CH2OH
COOEt
NEt2
R
R
R
R
R
OR1
4a 4e
5a 5e
O
6a, 6b, 6e,
NEt2
_
7a 7e
N
N
N
N
F
(vii)
O
O
OR1
Et2N
OH
O
_
_
8a 8e
S
9a 9e
N
N
(x)
N
N
O
O
O
O
NH
N
O
R
(viii)
_
N
(ix)
13a 13e
S
OEt
HS
N
H
10
11
12
F
1a, R = H, 1b, R = CH3, 1c, R = Br, 1d, R = Cl, 1e, R = CH3O
2a, R = H, 2b, R = CH3, 2c, R = Br, 2d, R = Cl, 2e, R = CH3O
3a, R = H, 3b, R = CH3, 3c, R = Br, 3d, R = Cl, 3e, R = CH3O
4a, R = H, 4b, R = CH3, 4c, R = Br, 4d, R = Cl, 4e, R = CH3O
5a, R = H, 5b, R = CH3, 5c, R = Br, 5d, R = Cl, 5e, R = CH3O
6a, R = H, R1 = Et, 6b, R = CH3, R1 = Et, 6e, R = CH3O, R1 = Et
7a, R = H, R1 = C(CH3)3, 7b, R = CH3, R1 = C(CH3)3, 7c, R = Br, R1 = C(CH3)3, 7d, R = Cl, R1 = C(CH3)3,
7e, R = CH3O, R1 = C(CH3)3,
8a, R = H, 8b, R = CH3, 8c, R = Br, 8d, R = Cl, 8e, R = CH3O,
9a, R = H, R1 =Ms, 9b, R= CH3, R1 = Ts, 9c, R = Br, R1 = Ms, 9d, R = Cl, R1 = Ms, 9e, R = CH3O R1 = Ms,
13a, R = H, 13b, R = CH3, 13c, R = Br, 13d, R = Cl, 13e, R = CH3O
Reagents and conditions: (i) (COOEt)2/EtONa, EtOH, r.t.; then AcOH, N2H4; (ii) BrCH2CH2Br/K2CO3/KI, CH3CN, reflux; (iii) HN(Et)2/
K2CO3/KI, CH3CN, reflux; (iv) LiAlH4, THF, ice bath to r.t.; (v) NaH/ClCH2COOEt, THF, reflux or t-BuOK/ClCH2COOEt, t-BuOH, reflux;
(vi) LiAlH4, THF, ice bath to r.t.; (vii) (MsCl or TsCl)/NEt3, CH2Cl2, r.t.; (viii) EtONa/CS(NH2)2, EtOH, reflux; (ix) K2CO3/KI/ 4-fluorobenzyl
chloride, acetone, reflux; (x) K2CO3, DMF, 80 °C
Reaction of commercially available ethyl 2-oxocy-
clopentanecarboxylate 10 and thiourea in the presence
of EtONa in EtOH gave rise to the thiouracil derivative
11, which was in turn alkylated with 4-fluorobenzyl
chloride to yield thioether 12 in refluxing acetone in
presence of K2CO3 and KI.
Finally, coupling of compounds 9a—9e and com-
pound 12 was effective to give the targets 13a—13e on
treatment of a mixture of 9 and 12 with K2CO3 in DMF
at 80 ℃. The target compounds 13a—13e were con-
verted to L-tartaric acid salts thereof.
As shown in Scheme 3, an unsuccessful alternative
synthetic route to the title compound has ever been at-
tempted, in which compound 16 was initially expected
to react with 5a—5e to give the title compounds 13a—
13e. Compound 12 was successfully converted to com-
pound 15 in two steps. Unfortunately, treatment of
compound 15 with MsCl in the presence of Et3N in
CH2Cl2 produced cyclic sulfonium 18 as a single prod-
uct, instead of the expected mesylate 16. This outcome
may be attributable to the powferful nucleophilicity of
the sulfur atom, which displaced the mesyloxy group in
2046
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2039— 2048

Design and Synthesis of Novel Pyrazole-based Lp-PLA2 Inhibitors
Scheme 2 Synthetic route to the carboxylates 6a— 6b, 6e, 7a— 7e
NEt2
O
N
N
O
(i)
EtO
R
6a, 6b, 6e
NEt2
NEt2
N
OH
N
_
N
_
O
O
N
(ii)
OC(CH3)3
R
R
7a 7e
5a 5e
(iii)
No Reaction
Reagents and conditions: (i) NaH/ClCH2COOEt, THF, reflux; (ii) ClCH2COOEt/t-BuOK/t-BuOH, reflux; (iii) K2CO3/KI/ClCH2COOEt, DMF, 80 o
Scheme 3 An unsuccessful alternative route to the title compounds
C
O
O
O
N
N
N
(i)
(ii)
S
N
S
N
S
N
H
F
O
F
F
HO
12
15
14
EtO
(iv)
(iii)
O
O
O
-
N
N
N
Cl
+
S
S
N
N
S
N
F
F
F
16
17
18
MsO
Cl
F
Et2N
_
O
5a 5e
S
N
N
N
N
O
_
R
13a 13e
Reagents and conditions: (i) K2CO3/KI/ClCH2COOEt, CH3CN, reflux; (ii) LiAlH4, THF, ice bath to r.t.; (iii) MsCl/Et3N, CH2Cl2, r.t; (iv)
SOCl2, reflux
16 by SN2 pathway. Also, compound 15 reacted with
thionyl chloride at reflux to give a mixture of 17 and 18
in a steady ratio of 1∶4, and the formation of the cyclic
sulfonium 18 herein was obviously due to the identical
reason as described above.
which are summarized in Table 2.
As can be learned from Table 2, all the synthesized
compounds 13a—13e were potent Lp-PLA2 inhibitors,
－
1
with all IC50 being no more than 10 nmol•L . Sub-
stituents in para-position can enhance the potency, as
can be seen from the fact that the IC50 for 13a is larger
than those of 13b—13e, and the methyl group is most
The Lp-PLA2 inhibitory activities of 13a—13e were
determined according to a well-established method,10,11
Chin. J. Chem. 2011, 29, 2039— 2048
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2047

Wang et al.
FULL PAPER
Table 1 Formation of 6 and 7 under different conditionsa
Shandong University for her wonderful analytical work.
R＝H
R＝CH3
R＝Cl
R＝CH3O
References
5a 89%
6a 11%
5a 89%
6a 11%
5a 46%
7a 54%
5a 46%
7a 54%
5b 90%
6b 10%
5b 90%
6b 10%
5b 48%
7b 52%
5b 48%
7b 52%
5e 90%
6e 10%
5e 90%
6e 10%
5e 45%
7e 55%
5e 45%
7e 55%
5e 100%
Condition 1
Condition 2
Condition 3
Condition 4
—
1
Zalewski, A.; Macphee, C. Arterioscl. Throm. Vas. 2005, 25,
923.
—
2
(a) Epps K. C.; Wilensky, R. L. J. Intern. Med. 2010, 268,
348.
5d 45%
7d 55%
5d 45%
7d 55%
(b) Kolodgie, F. D.; Burke, A. P.; Skorija, K. S. Arterioscler.
Thromb. Vasc. Biol. 2006, 26, 2523.
3
4
5
Karabina, S. A.; Gora, S.; Atout, R.; Ninio, E. Biochimie
2010, 92, 594.
Boyd, H. F.; Hammond, B.; Smith, S. A. Bioorg. Med.
Chem. Lett. 2001, 11, 701.
Blackie, J. A.; Bloomer, J. C.; Brown, M. J. B.; Cheng, H.
Y.; Elliott, R. L.; Hammond, B.; Hickey, D. M. B.; Ife, R. J.;
Leach, C. A.; Lewis, V. A.; Macphee, C. H.; Milliner, K. J.;
Moores, K. E.; Pinto, I. L.; Smith, S. A.; Stansfield, I. G.;
Stanway, S. J.; Taylor, M. A.; Theobald, C. J.; Whittaker, C.
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Coll. Cardiol. 2008, 51, 1632.
Condition 5 5a 100% 5b 100% 5d 100%
a Condition 1: NaH (1.5 equiv.)/ClCH2CO2Et (2.0 equiv.), THF,
reflux; Condition 2: NaH (2.0 equiv)/ClCH2CO2Et (3.0 equiv.),
THF, reflux; Condition 3: t-BuOK (1.5 equiv.)/ClCH2CO2Et (2.0
equiv.)/t-BuOH, reflux; Condition 4: t-BuOK (2.0 equiv.)/
ClCH2CO2Et (3.0 equiv.)/t-BuOH, reflux; Condition 5: K2CO3
(3.0 equiv.)/KI (0.05 equiv.)/ClCH2CO2Et (2.0 equiv.)/DMF, 80
℃.
Table 2 The inhibitory activities (IC50) of 13a—13e
6
Compound
13a
13b 13c 13d 13e
－
1
IC50/(nmol•L )
10.0
1.5
3.6 5.7
7.7
7
8
9
Zheng, L. W.; Zhu, J.; Zhao, B. X. Eur. J. Med. Chem. 2010,
12, 5792.
preferred one with 13b being the most potent one (1.5
nmol•L ).
－
1
Dong, W. L.; Xu, J. Y.; Xiong, L. X.; Liu, X. H.; Li, Z. M.
Chin. J. Chem. 2009, 27, 579.
In clonclusion, 5 Lp-PLA2 inhibitors were designed
and synthesized by a convergent 10-step procedure, and
in vitro evaluation demonstrated that all the prepared
compounds 13a—13e showed potent Lp-PLA2 inhibi-
tory activities with compound 13b being the most potent
Boyd, H. F.; Fell, S. C. M.; Hickey, D. M. B.; Ife, R. J.;
Leach, C. A.; Macphee, C. H.; Milliner, K. J.; Pinto, I. L.;
Rawlings, D. A.; Smith, S. A.; Stansfield, I. G.; Stanway, S.
J.; Theobald, C. J.; Whittaker, C. M. Bioorg. Med. Chem.
Lett. 2002, 12, 51.
－
1
one (IC50＝1.5 nmol•L ). An unsuccessful alternative
synthetic route was also discussed, providing useful
insight into the synthesis and structural nature of this
class of compounds.
10 Washburn, W. N.; Dennis, E. A. J. Am. Chem. Soc. 1990,
112, 2040.
11 Boyd, H. F.; Fell, S. M.; Flynn, S. T.; Hickey, D. M. B.; Ife,
R. J.; Leach, C. A.; Macphee, C. H.; Milliner, K. J.; Moores,
K. E.; Pinto, I. L.; Porter, R. A.; Rawlings, D. A.; Smith, S.
A.; Stans, I. G.; Tew, D. G.; Theobald, C. J.; Whittak, C. M.
Bioorg. Med. Chem. Lett. 2000, 10, 2557.
Acknowledgement
The authors are very grateful to Professor Jiong Jia
of School of Chemistry and Chemical Engineering of
(E1012211 Zhao, X.)
2048
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2039— 2048