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
2045