Journal of Medicinal Chemistry
Article
column chromatography (hexane−ethyl acetate, 19:1 to 1:1) to give
Compounds 19a−c were prepared using a similar procedure as for
the preparation of compound 7d using compound 18 and
corresponding boronic acids.
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85.8 mg (36%) of the title compound as an oil. H NMR (CDCl3) δ:
1.46 (s, 9H), 2.58 (s, 3H), 2.81 (s, 3H), 4.20−4.23 (m, 2H), 6.13 (s,
1H), 7.07−7.10 (m, 1H), 7.24−7.42 (m, 7H), 8.39 (s, 1H).
tert-Butyl {[5-(4-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-
pyrrol-3-yl]methyl}methylcarbamate (19a). A pale-yellow oil
(94%). 1H NMR (CDCl3) δ: 1.47 (s, 9H), 2.81 (brs, 3H), 4.22
(brs, 2H), 6.12 (brs, 1H), 7.00−7.06 (m, 2H), 7.18−7.31 (m, 4H),
7.56−7.60 (m, 1H), 8.54−8.55 (m, 1H), 8.73−8.75 (m, 1H).
tert-Butyl {[5-(3-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-
pyrrol-3-yl]methyl}methylcarbamate (19b). A pale-yellow oil
(90%). 1H NMR (CDCl3) δ: 1.47 (s, 9H), 2.81 (brs, 3H), 4.22
(brs, 2H), 6.16 (brs, 1H), 6.93−7.11 (m, 3H), 7.27−7.32 (m, 3H),
7.59−7.63 (m, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.73−8.75 (m, 1H).
tert-Butyl {[5-(2-Chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-
pyrrol-3-yl]methyl}methylcarbamate (19c). A pale-blue oil
(53%). 1H NMR (CDCl3) δ: 1.47 (s, 9H), 2.84 (brs, 3H), 4.26
(brs, 2H), 6.20 (d, J = 1.8 Hz, 1H), 7.26−7.36 (m, 6H), 7.65−7.71 (m,
1H), 8.58−8.59 (m, 1H), 8.75−8.79 (m, 1H).
tert-Butyl ({[1-(6-Cyanopyridin-3-yl)sulfonyl]-5-phenyl-1H-
pyrrol-3-yl}methyl)methylcarbamate (15e). Under an argon
atmosphere, a mixture of 15c (153 mg, 0.33 mmol), zinc(II) cyanide
(77 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium (77 mg,
0.066 mmol), and N,N-dimethylformamide (6 mL) was stirred at 100
°C for 2 h. The reaction mixture was diluted with ethyl acetate, washed
successively with a saturated aqueous sodium hydrogen carbonate
solution, water, and brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane−
ethyl acetate, 4:1) to give 107 mg (72%) of the title compound as an
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oil. H NMR (CDCl3) δ: 1.47 (s, 9H), 2.83 (s, 3H), 4.22 (brs, 2H),
6.17 (s, 1H), 7.19−7.23 (m, 2H), 7.28−7.29 (m, 1H), 7.32−7.44 (m,
3H), 7.59−7.67 (m, 2H), 8.54−8.55 (m, 1H).
tert-Butyl {[5-(2-Formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-
pyrrol-3-yl]methyl}methylcarbamate (19d). Compound 18 (430
mg, 0.85 mmol) was dissolved in toluene (10 mL), and the mixture
was sufficiently degassed. Dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)-
phosphine (66 mg, 0.16 mmol) and tris(dibenzylideneacetone)-
dipalladium(0) (37 mg, 0.040 mmol) were added at room temper-
ature. The mixture was stirred for 30 min with deaeration, and a 2
mol/L aqueous sodium carbonate solution (1.2 mL) and (2-
formylphenyl)boronic acid (180 mg, 1.20 mmol) were added. After
further stirring at room temperature for 15 min, the mixture was
heated to 120 °C over 1 h and further stirred for 16 h. The reaction
mixture was cooled to room temperature. Water was added, and the
mixture was extracted with ethyl acetate. The extract was washed with
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane−ethyl acetate, 4:1 to 1:1) to give 218 mg
(48%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.47
(s, 9H), 2.86 (s, 3H), 4.27 (brs, 2H), 6.23 (brs, 1H), 7.09−7.11 (m,
1H), 7.28−7.33 (m, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.53−7.61 (m,
3H), 7.96−7.99 (m, 1H), 8.49−8.50 (m, 1H), 8.75−8.77 (m, 1H),
9.61−9.62 (m, 1H).
N-Methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-
pyrrol-3-yl}methanamine Dihydrochloride (16b). Compound
15d (113 mg) was dissolved in ethanol (2 mL). A 4 mol/L hydrogen
chloride−ethyl acetate solution (1 mL) was added, and the mixture
was stirred at room temperature for 1 h. The solvent was concentrated
under reduced pressure, and the residue was recrystallized from
ethanol to give the title compound (yield 40 mg, 38%), mp 204−206
°C. 1H NMR (DMSO-d6) δ: 2.50−2.53 (m, 6H), 3.97−3.99 (m, 2H),
6.46 (s, 1H), 7.16−7.18 (m, 2H), 7.38−7.44 (m, 4H), 7.65−7.75 (m,
2H), 8.34 (s, 1H), 8.98 (br, 2H), 1H not detected. Anal.
(C18H21Cl2N3O2S) C, H, N.
Compounds 16a and 16c were prepared from compounds 15b and
15e using a similar procedure as for the preparation of compound 16b.
N-Methyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]-
methanamine Hydrochloride (16a). Pale-purple crystals, mp 211−
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214 °C (28%). H NMR (DMSO-d6) δ: 2.52 (s, 3H), 3.98 (s, 2H),
6.45 (d, J = 1.8 Hz, 1H), 6.99 (dd, J = 5.2, 1.4 Hz, 1H), 7.16−7.19 (m,
2H), 7.34−7.45 (m, 3H), 7.69 (d, J = 1.8 Hz, 1H), 7.74 (dd, J = 5.2,
3.0 Hz, 1H), 7.98 (dd, J = 3.0, 1.4 Hz, 1H). HPLC purity 98.15% (220
nM), 97.76% (254 nM). ESI-HRMS calcd for C16H16N2O2S2 m/z
333.0726 (M + H), found 333.0707 (M + H).
tert-Butyl ({5-[2-(Hydroxymethyl)phenyl]-1-(pyridin-3-ylsul-
fonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (19e). Com-
pound 19d (218 mg, 0.48 mmol) was dissolved in tetrahydrofuran
(2 mL), and sodium borohydride (24 mg, 0.63 mmol) and methanol
(1 mL) were added at 0 °C. After the mixture was stirred at the same
temperature for 30 min, water was added, and the mixture was
extracted with ethyl acetate. The extract was washed with brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane−ethyl acetate, 1:1 to 1:3) to give 132 mg (60%) of the
5-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}-
sulfonyl)pyridine-2-carbonitrile Hydrochloride (16c). A solid,
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mp 226−227 °C (38%). H NMR (DMSO-d6) δ: 2.50 (s, 3H), 3.98
(s, 2H), 6.52 (s, 1H), 7.15−7.17 (m, 2H), 7.37−7.47 (m, 3H), 7.79 (s,
1H), 8.04−8.07 (m, 1H), 8.22−8.24 (m, 1H), 8.61−8.62 (m, 1H),
9.03 (br, 2H). Anal. (C18H17ClN4O2S) C, H, N.
t ert- B u t y l [ ( 5 - B r o m o - 1 H- pyrr ol- 3-yl)methy l]-
methylcarbamate (17). This compound was prepared from
compound 11 using a similar procedure as for the preparation of
compound 14. A pale-yellow oil (61%). 1H NMR (CDCl3) δ: 1.48 (s,
9H), 2.79 (s, 3H), 4.17 (s, 2H), 6.09 (brs, 1H), 6.64 (brs, 1H), 8.07
(br, 1H).
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title compound as a colorless oil. H NMR (CDCl3) δ: 1.46 (s, 9H),
2.10−2.15 (m, 1H), 2.85 (s, 3H), 4.25 (brs, 2H), 4.30−4.38 (m, 2H),
6.12 (d, J = 1.5 Hz, 1H), 6.69−6.72 (m, 1H), 7.13−7.18 (m, 1H),
7.30−7.35 (m, 2H), 7.44−7.49 (m, 1H), 7.59−7.62 (m, 2H), 8.50 (d, J
= 2.4 Hz, 1H), 8.76−8.78 (m, 1H).
Compounds 20a−c were prepared from 19a−c using a similar
procedure as for the preparation of compound 16a.
tert-Butyl {[5-Bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-
methyl}methylcarbamate (18). To a suspension (10 mL) of
sodium hydride (60% in oil, 204 mg, 5.10 mmol) in tetrahydrofuran
was added a solution of 17 (410 mg, 1.42 mmol) in N,N-
dimethylformamide (3 mL) at 0 °C, and 15-crown-5 (938 mg, 4.26
mmol) and pyridin-3-ylsulfonyl chloride hydrochloride (456 mg, 2.13
mmol) were added at the same temperature. After the mixture was
stirred at room temperature for 2 h, water was added to the reaction
mixture, and the mixture was extracted with ethyl acetate. The extract
was washed with saturated aqueous sodium hydrogen carbonate
solution, water, and brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane−ethyl acetate, 8:1 to 3:1)
to give 522 mg (85%) of the title compound as a pale-yellow powder.
1H NMR (CDCl3) δ: 1.47 (s, 9H), 2.80 (brs, 3H), 4.18 (brs, 2H), 6.28
1-[5-(4-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
yl]-N-methylmethanamine Dihydrochloride (20a). Colorless
crystals, mp 184−187 °C (40%). 1H NMR (DMSO-d6) δ: 2.47−
2.51 (m, 3H), 3.97 (t, J = 6.0 Hz, 2H), 6.52−6.53 (m, 1H), 7.15−7.26
(m, 4H), 7.57−7.61 (m, 1H), 7.79−7.85 (m, 2H), 8.00 (d, J = 2.4 Hz,
1H), 8.85−8.87 (m, 1H), 9.22 (br, 2H), 1H not detected. Anal.
(C17H18Cl2FN3O2S·H2O) C, H, N.
1-[5-(3-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
yl]-N-methylmethanamine Hydrochloride (20b). Colorless crys-
1
tals, mp 206−210 °C (35%). H NMR (DMSO-d6) δ: 2.49−2.51 (m,
3H), 3.97 (s, 2H), 6.57 (d, J = 1.8 Hz, 1H), 6.98−7.02 (m, 2H), 7.27−
7.33 (m, 1H), 7.40−7.47 (m, 1H), 7.58−7.62 (m, 1H), 7.80−7.87 (m,
2H), 8.54 (d, J = 2.7 Hz, 1H), 8.86−8.88 (m, 1H), 9.06 (br, 2H). Anal.
(C17H17ClFN3O2S) C, H, N.
(brs, 1H), 7.35 (brs, 1H), 7.48−7.52 (m, 1H), 8.18−8.22 (m, 1H),
8.85−8.88 (m, 1H), 9.12−9.13 (m, 1H).
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dx.doi.org/10.1021/jm300318t | J. Med. Chem. 2012, 55, 4446−4456