Journal of Medicinal Chemistry
ARTICLE
4-(4-(4-Fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)-N-
((R)-3-methylbutan-2-yl)pyridin-2-amine 8k. According to gen-
eral procedure A, compound 6a (0.76 g, 2.5 mmol) and (R)-(ꢀ)-3-
methyl-2-butylamine (0.67 g, 7.5 mmol) were heated for 24 h at T =
160 °C in a high pressure reactor. After extraction with EtOAc, the crude
product was purified by flash chromatography on silica gel (EtOAc/
hexane 2:3) to yield 0.56 g (60.5%) of the pale yellow product 8k. 1H
NMR (methanol-d4, 400 MHz) δ = 0.85ꢀ0.97 (m, 6H, CH(CH3)2),
1.09 (d, J = 6.6 Hz, 3H, NHCHCH3), 1.67ꢀ1.80 (m, 1H, CH(CH3)2),
2.63 (s, 3H, S-CH3), 3.46ꢀ3.56 (m, 1H, NHCHCH3), 6.48ꢀ6.63
(m, 2H, C5-HPyridine and C3-HPyridine), 7.16 (t, J = 8.3 Hz, 2H,
C3-H4-Fluorophenyl, C5-H4-Fluorophenyl), 7.42ꢀ7.52 (m, 2H, C2-H4-Fluorophenyl,
C6-H4-Fluorophenyl), 7.80 (d, J = 4.6 Hz, 1H, C6-HPyridine). HR-MS
calculated for C20H23FN4S m/z = 370.1622, measured m/z = 370.1620.
N-(4-(4-(4-Fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)
pyridin-2-yl)acetamide 8l. Compound 7a (0.51 g, 1.70 mmol) was
dissolved in 5.0 mL of pyridine. The solution was cooled in an ice bath,
and acetylchloride (0.47 g, 6.0 mmol) was added dropwise. The resulting
mixture was stirred at T = 0ꢀ5 °C. After 1 h, the solution was allowed to
warm to room temperature and an aqueous solution of NaHCO3 was
added. The aqueous/organic mixture was extracted with EtOAc, dried
over Na2SO4, and the solvents of the combined organic phases were
removed under reduced pressure. The crude product was purified by flash
chromatography (silica gel, EtOAc/EtOH 9/1) to obtain 0.3 g (52.4%)
of the yellow solid 8l. 1H NMR (methanol-d4, 400 MHz) δ = 2.14 (s, 3H,
CO-CH3), 2.65 (s, 3H, S-CH3), 7.11ꢀ7.19 (m, 3H, C5-HPyridine and
C3-H4-Fluorophenyl, C5-H4-Fluorphenyl), 7.40ꢀ7.52 (m, 2H, C2-H4-Fluorophenyl,
C6-H4-Fluorophenyl), 8.05ꢀ8.22 (m, 2H, C6-HPyridine and C3-HPyridine).
HR-MS calculated for C17H15FN4OS m/z = 342.0945, measured m/z =
342.0978.
3.5 h at T = 0 °C as a colorless solid without further purification (0.21 g,
1
65.8%). H NMR (200 MHz, DMSO-d6): δ [ppm] = 0.96ꢀ1.24 (m,
7H, CH2, cyclohexyl and SOCH(CH3)2), 1.19ꢀ1.34 (4H, CH2, cyclo-
hexyl and SOCH(CH3)2), 1.44ꢀ1.90 (m, 5H, CH2, cyclohexyl),
3.33ꢀ3.62 (m, 2H, CH, cyclohexyl and SOCH(CH3)2), 6.29 (brs,
1H, NHCyclohexyl, exchangeable with D2O), 6.39 (d, J = 5.6 Hz, 1H, C5-
HPyridine), 6.53 (s, 1H, C3-HPyridine), 7.12ꢀ7.34 (m, 2H, C3-H4-Fluorophenyl
,
C5-H4-Fluorophenyl), 7.40ꢀ7.56 (m, 2H, C2-H4-Fluorophenyl
,
C6-
H4-Fluorophenyl), 7.83 (s, 1H, C6-HPyridine), 13.66 (s, 1H, NHImidazole
,
exchangeable with D2O). HR-MS (ESI) calculated for C23H27FN4OS
[M þ Hþ] m/z = 427.1962, measured m/z = 427.1964.
4-(4-(4-Fluorophenyl)-2-(methylsulfinyl)-1H-imidazol-5-
yl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine 9d. Accord-
ing to general procedure B, the title compound 9d was obtained by the
sulfoxidation of compound 8d (8.0 g, 20.8 mmol), dissolved in 154.0 mL
of THF and 52.0 mL of H2O, with an aqueous solution of potassium
peroxomonosulfate (Oxone) (7.0 g, 11.4 mmol in 77.0 mL of H2O) after
stirring for 2 h at T = 0 °C and recrystallization from MeOH as a
1
colorless solid (6.86 g, 85.7%). H NMR (200 MHz, DMSO-d6): δ
[ppm] = 1.24ꢀ1.53 (m, 2H, C3-HTetrahydropyranyl, C5-HTetrahydropyranyl),
1.67ꢀ1.90 (m, 2H, C3-HTetrahydropyranyl, C5-HTetrahydropyranyl), 3.06 (s,
3H, SOCH3), 3.22ꢀ3.44 (m, 2H, C2-HTetrahydropyranyl, C6-HTetrahydropyranyl),
3.64ꢀ3.94(m,3H,C2-HTetrahydropyranyl,C4-HTetrahydropyranyl,C6-HTetrahydropyranyl),
6.47 (d, J = 5.1 Hz, 1H, C5-HPyridine), 6.50ꢀ6.71 (m, 2H, C3-HPyridine
and NHTetrahydropyranyl, exchangeable with D2O), 7.27 (t, J = 8.7 Hz, 2H,
C3-H4-Fluorophenyl, C5-H4-Fluorophenyl), 7.43ꢀ7.62 (m, 2H, C2-H4-Fluorophenyl
,
,
C6-H4-Fluorophenyl), 7.89 (brs, 1H, C6-HPyridine), 13.75 (s, 1H, NHImidazole
exchangeable with D2O). HR-MS (ESI) calculated for C20H21FN4O2S
[M þ Hþ] m/z = 401.1442, measured m/z = 401.1442.
4-(4-(4-Fluorophenyl)-2-(isopropylsulfinyl)-1H-imidazol-5-yl)-
N-isopropylpyridin-2-amine 9e. According to general procedure
B, the title compound 9e was obtained by the sulfoxidation of compound
8e (0.25 g, 0.68 mmol), dissolved in 5.0 mL of THF and 1.7 mL of H2O,
with an aqueous solution of potassium peroxomonosulfate (Oxone)
(0.24 g, 0.4 mmol in 1.3 mL of H2O) after stirring for 3 h at T = 0 °C and
treatment with isopropyl ether as a beige solid (0.21 g, 83.8%). 1H NMR
(200 MHz, DMSO-d6): δ = 1.08 (d, J = 6.2 Hz, 6H, NHCH(CH3)2),
1.15 (d, J = 7.0 Hz, 3H, SOCH(CH3)2), 1.25 (d, J = 6.8 Hz, 3H,
SOCH(CH3)2), 3.37ꢀ3.55 (m, 1H, SOCH(CH3)2), 3.77ꢀ4.02 (m,
1H, NHCH(CH3)2), 6.27ꢀ6.47 (m, 2H, C5-HPyridine and NHCH-
(CH3)2, exchangeable with D2O), 6.59 (s, 1H, C3-HPyridine),
7.09ꢀ7.38 (m, 2H, C3-H4-Fluorophenyl, C5-H4-Fluorophenyl), 7.42ꢀ7.60
(m, 2H, C2-H4-Fluorophenyl, C6-H4-Fluorophenyl), 7.85 (s, 1H, C6-HPyridine),
13.69 (s, 1H, NHImidazole, exchangeable with D2O). HR-MS (ESI)
calculated for C20H23FN4OS [M þ Hþ] m/z = 387.1649, measured
m/z = 387.1649.
General Procedure B for the Synthesis of the Racemic
Sulfoxides. The respective 2-thioimidazole derivative was dissolved in
THF, and water was added. The mixture was cooled in an ice bath, and
an aqueous solution of potassium peroxomonosulfate (Oxone) was
added dropwise. The resulting mixture was stirred at T = 0 °C. The
progress was monitored until HPLC analysis indicated complete con-
version. After reaction completion, the solution was allowed to warm to
room temperature and an aqueous solution of NaHCO3 (pH 8) was
added. The aqueous/organic mixture was extracted with EtOAc, dried
over Na2SO4, and the solvents of the combined organic phases were
removed under reduced pressure. The crude product was purified by
recrystallization from an appropriate solvent or by flash chromatography.
4-(4-(4-Fluorophenyl)-2-(methylsulfinyl)-1H-imidazol-5-yl)-
N-isopropylpyridin-2-amine 9b. According to general procedure
B, the title compound 9b was obtained by the sulfoxidation of
compound 8b (9.31 g, 27.2 mmol), dissolved in 177.0 mL of THF,
with an aqueous solution of potassium peroxomonosulfate (Oxone)
(8.76 g, 14.3 mmol in 183 mL water) after stirring for 2 h at T = 0 °C and
recrystallization from EtOAc as a beige solid (7.97 g, 81.9%). 1H NMR
(200 MHz, DMSO-d6): δ [ppm] = 1.10 (d, J = 6.3 Hz, 6H, NHCH-
(CH3)2), 3.07 (s, 3H, SOCH3), 3.74ꢀ4.07 (m, 1H, CH(CH3)2), 6.34 (s,
1H, NHCH(CH3)2, exchangeable with D2O), 6.42 (d, J = 5.2 Hz, 1H,
C5-HPyridine), 6.58 (s, 1H, C3-HPyridine), 7.26 (t, J = 8.6 Hz, 2H,
2-(4-Fluorophenyl)-N-(4-(4-(4-fluorophenyl)-2-(methyl-
sulfinyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide 9f. Accord-
ing to general procedure B, the title compound 9f was obtained by the
sulfoxidation of compound 8f (0.30 g, 0.69 mmol), dissolved in 5.0 mL
of THF and 0.9 mL of H2O, with an aqueous solution of potassium
peroxomonosulfate (Oxone) (0.23 g, 0.4 mmol in 1.3 mL of water) after
stirring for 1.5 h at T = 0 °C and flash chromatography on silica gel
(THF/hexane 1:1) as a yellow solid (0.16 g, 51.5%). 1H NMR
(200 MHz, DMSO-d6): δ [ppm] = 3.06 (s, 3H, SOCH3), 3.68 (s, 2H,
CH2), 7.01 (d, 1H, J = 5.1 Hz, 1H, C5-HPyridine), 7.13 (t, J = 8.7 Hz, 2H,
C3-H4-Fluorophenylacetamide, C5-H4-Fluorophenylacetamide), 7.20ꢀ7.41 (m, 4H,
C3-H4-Fluorophenyl, C5-H4-Fluorophenyl), 7.42ꢀ7.63 (m, 2H, C2-H4-Fluorophenyl
,
C6-H4-Fluorophenyl), 7.89 (d, J = 5.1 Hz, 1H, C6-HPyridine), 13.73 (s,
1H, NHImidazole, exchangeable with D2O). HR-MS (ESI) calculated
for C18H19FN4OS [M þ Hþ] m/z = 359.1336, measured m/z =
359.1336.
, , ,
C3-H4-Fluorophenyl C5-H4-Fluorophenyl C2-H4-Fluorophenylacetamide C6-
H4-Fluorophenylacetamide), 7.43ꢀ7.60 (m, 2H, C2-H4-Fluorophenyl, C6-
H4-Fluorophenyl), 8.20 (d, 1H, J = 5.1 Hz, 1H, C6-HPyridine), 8.30 (s, 1H,
C3-HPyridine), 10.70 (s, 1H, NHCO, exchangeable with D2O), 13.89
(s, 1H, NHImidazole, exchangeable with D2O). HR-MS (ESI) calculated
for C23H18F2N4O2S [M þ Naþ] m/z = 475.1011, measured m/z =
475.1013.
N-Cyclohexyl-4-(4-(4-fluorophenyl)-2-(isopropylsulfinyl)-
1H-imidazol-5-yl)pyridin-2-amine 9c. According to general pro-
cedure B, the title compound 9c was obtained by the sulfoxidation of
compound 8c (0.31 g, 0.76 mmol), dissolved in 15.0 mL of THF and
3.0 mL of H2O, with an aqueous solution of potassium peroxomono-
sulfate (Oxone) (0.25 g, 0.4 mmol in 4.5 mL of H2O) after stirring for
3294
dx.doi.org/10.1021/jm101623p |J. Med. Chem. 2011, 54, 3283–3297