Journal of Medicinal Chemistry
Article
(Taufkirchen, Germany). Compounds 6−31 were synthesized as
were dried over anhydrous MgSO4 and the solvent evaporated under
reduced pressure. The crude product was further purified by column
chromatography on silica gel (n-hexane−ethyl acetate) to obtain 4-
(3,4-dichlorophenyl)-1,3-thiazol-2-amine as a slightly yellow solid;
described in Scheme 1. All commercial chemicals and solvents are of
1
reagent grade and were used without further purification. H and 13C
NMR spectra were measured in DMSO-d6 or CDCl3 on a Bruker AM
250, DPX 250, AV 300, or AV 400 spectrometer. Chemical shifts are
reported in parts per million (ppm) using tetramethylsilane (TMS) as
internal standard. Mass spectra were obtained on a Fisons Instruments
VG Platform II spectrometer (ESI-MS system) or on a PerSeptive
Biosystems Mariner biospectrometry workstation (nanospray ESI-MS
system) measuring in the positive- and/or negative-ion mode. The
purities of the final compounds were determined by combustion
analysis, which has been performed by the Microanalytical Laboratory
of the Institute of Organic Chemistry and Chemical Biology, Goethe-
University Frankfurt, on a Foss Heraeus CHN-O rapid elemental
analyzer. All compounds described here have a purity of 95% or
higher. The synthesis of the presented compounds according to the
synthetic Scheme 1 is exemplified by compound 21. For more detailed
information and analytical data of the other compounds, see
Supporting Information.
1
yield 97% (0.58 g). H NMR (250.13 MHz, (CD3)2SO) δ: 7.16 (s,
2H, −NH2), 7.24 (s, 1H, thiazole-H5), 7.63 (d, 1H, Ph-H5, J = 7.50
Hz), 7.79 (dd, 1H, Ph-H6, J = 7.50 Hz), 8.02 (s, 1H, Ph-H2). 13C
NMR (75.44 MHz, (CD3)2SO) δ: 103.75 (thiazole-C5), 125.48 (Ph-
C6), 127.10 (Ph-C2), 129.20 (Ph-C5), 130.65 (Ph-C3), 131.21 (Ph-C1),
135.39 (Ph-C4), 147.15 (thiazole-C4), 168.40 (thiazole-C2). MS (ESI
+): m/e = 244.6 [M + H]+.
Step IV. Synthesis of 21d (ethyl 2-[(4-chloro-6-{[4-(3,4-dichlor-
ophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoate):
21b (0.4 g, 1.14 mmol, 1 equiv), 21c (0.35 g, 1.37 mmol, 1.2 equiv),
Xantphos (0.043 g, 0.07 mmol, 0.06 equiv), and Na2CO3 (0.17 g, 1.59
mmol, 1.4 equiv) were dissolved in toluene (8 mL) in a three neck
round-bottom flask, which was three times evacuated and backfilled
with argon before adding Pd2(dba)3 (0.024 g, 0.02 mmol, 0.02 equiv)
and water (20 mL). The mixture was heated at 90 °C for 18 h. The
reaction mixture was cooled to room temperature and diluted with
THF. The organic layer was separated from the water layer, filtered
over Celite, and evaporated under reduced pressure. The crude
product was further purified by column chromatography on silica gel
(n-hexane−ethyl acetate) to obtain ethyl 2-[(4-chloro-6-{[4-(3,4-
dichlorophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-
octanoate as a white solid; yield 70% (0.45 g). 1H NMR (250.13 MHz,
(CD3)2SO) δ: 0.86 (t, 3H, hexyl-CH3, J = 7.50 Hz), 1.20 (t, 3H, O-
ethyl-CH3, J = 7.50 Hz), 1.27−1.42 (m, 8H, hexyl-CH2), 1.84−1.98
(m, 2H, hexyl-CH2), 4.16 (q, 2H, O-ethyl-CH2, J = 6.67 Hz), 4.59 (t,
1H, S-CH, J = 7.50 Hz), 6.82 (s, 1H, Pyr-H5), 7.72 (d, 1H, Ph-H5, J =
7.50 Hz), 7.90 (d, 1H, Ph-H6, J = 7.50 Hz), 7.94 (s, 1H, thiazole-H5),
8.15 (s, 1H, Ph-H2), 12.32 (s, 1H, −NH). 13C NMR (75.44 MHz,
(CD3)2SO) δ: 13.82 (hexyl-CH3), 13.96 (O-ethyl-CH3), 21.89 (hexyl-
CH2), 26.31 (hexyl-CH2), 28.05 (hexyl-CH2), 30.85 (hexyl-CH2),
31.29 (hexyl-CH2), 47.02 (S-CH), 61.11 (O-ethyl-CH2), 102.09 (Pyr-
C5), 110.07 (thiazole-C5), 125.66 (Ph-C6), 127.32 (Ph-C2), 130.09
(Ph-C5), 131.01 (Ph-C3), 131.55 (Ph-C1), 134.65 (Ph-C4), 146.60
(thiazole-C4), 157.64 (Pyr-C6), 157.82 (Pyr-C4), 157.93 (thiazole-C2),
169.63 (−COOEt), 170.87 (Pyr-C2). MS (ESI−): m/e = 557.4 [M -
H]−.
Synthesis of Compound 21 2-[(4-Chloro-6-{[4-(3,4-dichlor-
ophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-
octanoic Acid. Step I. Synthesis of 21a (ethyl 2-[(4,6-dihydroxypyr-
imidin-2-yl)sulfanyl]octanoate): Thiobarbituric acid (3.5 g, 24 mmol,
1 equiv) and triethylamine (5.05 mL, 36 mmol, 1.5 equiv) were first
dissolved under slightly heating in 20 mL of DMF, followed by
dropwise addition of ethyl 2-bromooctanoate (7.32 g, 29 mmol, 1.2
equiv), and the mixture was refluxed for 3 h. The reaction was
quenched by addition of 150 mL of water, and the product was
extracted by ethyl acetate. The solvent of the organic phase was
evaporated under reduced pressure, and the crude product was directly
recrystallized by n-hexane/ethyl acetate to obtain ethyl 2-[(4,6-
dihydroxypyrimidin-2-yl)sulfanyl]octanoate as a white solid; yield 34%
1
(2.58 g). H NMR (250.13 MHz, (CD3)2SO) δ: 0.85 (t, 3H, hexyl-
CH3, J = 6.59 Hz), 1.18 (t, 3H, O-ethyl-CH3, J = 7.09 Hz), 1.24−1.32
(m, 8H, hexyl-CH2), 1.73−1.94 (m, 2H, hexyl-CH2), 4.13 (q, 2H, O-
ethyl-CH2, J = 7.05 Hz), 4.51 (t, 1H, S-CH, J = 7.08 Hz), 5.23 (s, 1H,
Pyr-H5), 11.75 (s, 2H, −OH). 13C NMR (50.32 MHz, (CD3)2SO) δ:
13.83 (hexyl-CH3), 13.91 (O-ethyl-CH3), 21.89 (hexyl-CH2), 26.28
(hexyl-CH2), 28.07 (hexyl-CH2), 30.92 (hexyl-CH2), 31.59 (hexyl-
CH2), 46.46 (S-CH), 61.07 (O-ethyl-CH2), 85.65 (Pyr-C5), 162.69
(Pyr-C2), 167.80 (Pyr-C4/6), 170.87 (−COOEt). MS (ESI+): m/e =
315.1 [M + H]+.
Step V. Synthesis of 21 (2-[(4-chloro-6-{[4-(3,4-dichlorophenyl)-
1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid): To a
solution of 21d (0.16 g, 0.29 mmol, 1 equiv) in THF (10 mL) was
added LiOH·H2O (0.06 g, 1.43 mmol, 5 equiv) dissolved in water (2
mL). The reaction was stirred for 24 h at 45 °C. The solvent was
evaporated under reduced pressure, and the residue was solved in
water and a small amount of methanol. The water layer was acidified
by 2 N HCl, and the resulting precipitate was extracted with ethyl
acetate. The organic layer was dried over anhydrous MgSO4, and the
solvent was evaporated under reduced pressure. The crude product
was finally recrystallized by ethyl acetate to obtain 2-[(4-chloro-6-{[4-
(3,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-
Step II. Synthesis of 21b (ethyl 2-[(4,6-dichloropyrimidin-2-
yl)sulfanyl]octanoate): Precursor 21a (2.57 g, 8.19 mmol, 1 equiv)
and N,N-diethylaniline (1.31 mL, 8.19 mmol, 1 equiv) were dissolved
in phosphoryl chloride (13.47 mL, 147 mmol, 18 equiv) and refluxed
at 90 °C for 5 h. At the end of the reaction, POCl3 was distillated in
vacuo. The residue was poured on crushed ice, and the product was
extracted two times by 200 mL of ethyl acetate. The organic layer was
washed two times with 2 N HCl, saturated NaHCO3, and saturated
NaCl. The solvent of the organic layer was evaporated, and the crude
product was further purified by column chromatography on silica gel
(n-hexane−ethyl acetate) to obtain ethyl 2-[(4,6-dichloropyrimidin-2-
1
octanoic acid as a slightly yellow solid; yield 93% (0.14 g). H NMR
1
yl)sulfanyl]octanoate as a yellow oil; yield 82% (2.35 g). H NMR
(250.13 MHz, (CD3)2SO) δ: 0.85 (t, 3H, hexyl-CH3, J = 7.50 Hz),
1.25−1.44 (m, 8H, hexyl-CH2), 1.84−2.02 (m, 2H, hexyl-CH2), 4.59
(t, 1H, S-CH, J = 7.50 Hz), 6.81 (s, 1H, Pyr-H5), 7.71 (d, 1H, Ph-H5, J
= 7.50 Hz), 7.90 (dd, 1H, Ph-H6, J = 7.50 Hz), 7.93 (s, 1H, thiazole-
H5), 8.15 (s, 1H, Ph-H2), 12.23 (s, 1H, −NH), 13.00 (s, 1H,
−COOH). 13C NMR (62.90 MHz, (CD3)2SO) δ: 13.82 (hexyl-CH3),
21.92 (hexyl-CH2), 26.35 (hexyl-CH2), 28.16 (hexyl-CH2), 30.91
(hexyl-CH2), 31.71 (hexyl-CH2), 47.27 (S-CH), 101.95 (Pyr-C5),
110.64 (thiazole-C5), 125.66 (Ph-C6), 127.33 (Ph-C2), 130.09 (Ph-C5),
130.99 (Ph-C3), 131.56 (Ph-C1), 134.68 (Ph-C4), 146.63 (thiazole-C4),
157.64 (Pyr-C4), 157.88 (Pyr-C2), 157.95 (thiazole-C2), 170.07 (Pyr-
C6), 172.18 (−COOH). MS (ESI−): m/e = 529.4 [M − H]−. Anal.
Calcd C21H21Cl3N4O2S2 C, H, N, S: C 47.42, H 3.98, N 10.53, S
12.06. Found C 47.42, H 4.14, N 10.25, S 11.99. Diff. C 0.00, H
+0.16, N −0.28, S −0.07.
(250.13 MHz, (CD3)2SO) δ: 0.85 (t, 3H, hexyl-CH3, J = 6.56 Hz),
1.19 (t, 3H, O-ethyl-CH3, J = 7.09 Hz), 1.25−1.39 (m, 8H, hexyl-
CH2), 1.76−2.00 (m, 2H, hexyl-CH2), 4.14 (q, 2H, O-ethyl-CH2, J =
7.07 Hz), 4.36 (t, 1H, S−CH, J = 7.12 Hz), 7.75 (s, 1H, Pyr-H5). 13
C
NMR (62.90 MHz, (CD3)2SO) δ: 13.80 (hexyl-CH3), 13.94 (O-ethyl-
CH3), 21.86 (hexyl-CH2), 26.30 (hexyl-CH2), 27.94 (hexyl-CH2),
30.63 (hexyl-CH2), 30.83 (hexyl-CH2), 47.80 (S-CH), 61.17 (O-ethyl-
CH2), 117.19 (Pyr-C5), 160.93 (Pyr-C4/6), 170.55 (−COOEt), 171.01
(Pyr-C2). MS (ESI+): m/e = 351.3 [M + H]+.
Step III. Synthesis of 21c (4-(3,4-dichlorophenyl)-1,3-thiazol-2-
amine): To a solution of 2-bromo-1-(3,4-dichlorophenyl)ethan-1-one
(0.66 g, 2.45 mmol, 1 equiv) in methanol thiourea (0.28 g, 3.67 mmol,
1.5 equiv) was added, and the solution was stirred 3 h at room
temperature. The solvent was evaporated under reduced pressure. The
crude product was suspended in a 5% NaHCO3 solution and extracted
with dichloromethane (3 × 25 mL). The combined organic layers
Computational. Structures of mPGES-1 and 5-LO were obtained
from the Protein Data Bank (PDB IDs 4al0 and 3o8y). Virtual
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dx.doi.org/10.1021/jm401557w | J. Med. Chem. 2013, 56, 9031−9044