Selective Inhibitors of CYP11B2
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 21 6639
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General Procedure for the Synthesis of Compounds
(1-2, 4-9, 12-14, 16, 19-22). A mixture of substituted
2-bromo- or 2-trifluoromethanesulfonate compound (1.50 mmol),
3-pyridylboronic acid (1.95 mmol), aqueous Na2CO3
(3.15 mmol) and Pd(PPh3)4 (0.03 mmol) in 15 mL of ethylene
glycol dimethyl ether or toluene was stirred overnight at
80 °C under nitrogen. The reaction was cooled to room
temperature, and water was added. The mixture was extracted
with ethyl acetate, dried (MgSO4), filtered and evaporated in
vacuo.
3-(2-Naphthyl)pyridine (1). Purification: CC (CH2Cl2/
MeOH, 97:3). Yield 82%, mp 101 °C. 1H NMR (CDCl3): δ 7.43-
7.45 (m, 1H, Pyr. H-5), 7.51-7.56 (m, 2H, Ar H), 7.71 (dd, 1H,
3J ) 8.5 Hz, 4J ) 1.6 Hz, Ar H), 7.88-7.90 (m, 2H, Ar H), 7.96
(d, 1H, 3J ) 8.5 Hz, Ar H), 8.03-8.05 (m, 2H, Ar H, Pyr. H-4),
8.63 (dd, 1H, 3J ) 4.7 Hz, 4J ) 1.6 Hz, Pyr. H-6), 8.99
(dd, 1H, 4J ) 1.6 Hz, Pyr. H-2). IR cm-1: νmax 3392, 3051, 3029,
1599, 1484. MS m/z 206 (MH+), 178, 151, 77, 51. Anal.
(C15H11N‚0.04H2O) C, H, N.
2H, Ar H, Pyr.H-4), 8.07 (d, 1H, J ) 1.6 Hz, Ar H), 8.62 (d,
1H, 3J ) 5.0 Hz, Pyr. H-6), 8.68 (s, 1H, Pyr. H-2), 8.70 (d, 1H,
3J ) 5.0 Hz, Pyr. H-6), 8.97 (s, 1H, Pyr. H-2). IR cm-1
:
νmax 3031, 2950, 2842, 1599, 1488, 1258. MS m/z 313 (MH+).
Synthesis of 3-(3-Methoxy-2-naphthyl)pyridine (15). A
mixture of 3-bromopyridine (0.20 g, 1.25 mmol), 2-methoxy-
3-naphthylboronic acid (0.30 g, 1.50 mmol), aqueous Na2CO3
(0.27 g, 2.50 mmol) and Pd(PPh3)4 (30 mg) in 15 mL of ethylene
glycol dimethyl ether was stirred at 90 °C for 4 h and at room-
temperature overnight. Water was added, and the mixture was
extracted with dichloromethane, dried (MgSO4), filtered and
evaporated in vacuo. The product was purified by column
chromatography, eluting with CH2Cl2/MeOH (98:2). Yield 31%,
mp 189 °C. 1H NMR (CDCl3): δ 3.94 (s, 3H, OCH3), 7.25
(s, 1H, Ar H), 7.35-7.40 (m, 2H, Ar H, Pyr. H-5), 7.48 (td, 1H,
3J ) 8.2 Hz, J ) 1.3 Hz, Ar H), 7.77 (s, 1H, Ar H), 7.78 (d,
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3
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1H, J ) 8.2 Hz, Ar H), 7.81 (d, 1H, J ) 8.2 Hz, Ar H), 7.93
(dt, 1H, 3J ) 7.9 Hz, 4J ) 1.9 Hz, Pyr. H-4), 8.60 (dd, 1H,
3J ) 4.9 Hz, 4J ) 1.8 Hz, Pyr. H-6), 8.85 (s, 1H, Pyr. H-2). IR
cm-1: νmax. 3054, 2962, 2832, 1631, 1599, 1504, 1466, 1410,
1254. MS m/z 236 (MH+). Anal. (C16H13NO‚HCl‚0.26H2O)
C, H, N.
3-(6-Methoxy-2-naphthyl)pyridine (2). Purification: CC
(CH2Cl2/MeOH, 97:3). Yield 77%, mp 120 °C. 1H NMR
(CDCl3): δ 3.95 (s, 1H, OCH3), 7.17 (d, 1H, 4J ) 2.5 Hz,
Ar H), 7.22 (dd,1H, 3J ) 8.8 Hz, 4J ) 2.2 Hz, Ar H), 7.45-7.47
General Procedure for the Synthesis of Compounds
(17, 18). A stirred mixture of compound 16 (0.60 mmol) and
formamide (1.90 mmol) under nitrogen was charged with
anhydrous DMF (2 mL) and heated at 100 °C. Methanolic
sodium methoxide (0.40 mmol) was added, and stirring was
continued for 1 h. The mixture was cooled and water was
added (2 mL), then extracted with ethyl acetate, dried
(MgSO4), filtered and evaporated in vacuo. The product was
purified by column chromatography, eluting with CH2Cl2/
MeOH (95:5).
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(m, 1H, Pyr. H-5), 7.67 (dd, 1H, J ) 8.5 Hz, J ) 1.8 Hz, Ar
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H), 7.81 (d, 1H, J ) 8.5 Hz, Ar H), 7.85 (d, 1H, J ) 8.5 Hz,
Ar H), 7.98 (s, 1H, Ar H), 8.04-8.06 (m, 1H, Pyr. H-4), 8.61
(dd, 1H, 3J ) 4.7 Hz, 4J ) 1.3 Hz, Pyr. H-6), 8.97 (s, 1H, Pyr.
H-2). IR cm-1: νmax 3058, 2938, 1605, 1489. MS m/z 236 (MH+).
Anal. (C16H13NO‚0.04H2O) C, H, N.
Synthesis of 6-Pyridin-3-ylnaphthalen-2-ol (3). BBr3
(2.55 mL, 2.55 mmol) was slowly added to compound 2
(150 mg, 0.64 mmol) in 25 mL of dry CH2Cl2 at -78 °C under
nitrogen atmosphere. After 30 min stirring, the cooling was
stopped and the reaction was stirred at room temperature
overnight. The reaction was slowly quenched with methanol
and then washed with a saturated NaHCO3 solution. The
organic layer was dried (MgSO4), filtered and evaporated in
vacuo. The product was purified by column chromatography,
eluting with CH2Cl2/MeOH (99:1). Yield 65%, mp 253 °C.
6-Pyridin-3-yl-2-naphthamide (17). Yield 61%, mp
227 °C. 1H NMR (CDCl3): δ 7.42-7.45 (m, 1H, Pyr. H-5), 7.75
3
4
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(dd, 1H, J ) 8.5 Hz, J ) 1.9 Hz, Ar H), 7.90 (dd, 1H, J )
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8.5 Hz, J ) 1.9 Hz, Ar H), 7.96 (d, 1H, J ) 8.8 Hz, Ar H),
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8.01-8.04 (m, 2H, Ar H, Pyr. H-4), 8.06 (d, 1H, J ) 1.3 Hz,
Ar H), 8.38 (d, 1H, 4J ) 1.3 Hz, Ar H), 8.59 (dd, 1H, 3J )
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4.7 Hz, J ) 1.6 Hz, Pyr. H-6), 8.92 (d, 1H, J ) 1.9 Hz, Pyr.
H-2). IR cm-1: νmax.3335, 3066, 1664, 1590, 1426. MS m/z 249
(MH+). Anal. (C16H12NO) C, H, N.
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1H NMR (CDCl3): δ 7.20 (dd, 1H, J ) 8.8 Hz, J ) 1.9 Hz,
Ar H), 7.23 (d, 1H, 4J ) 1.9 Hz, Ar H), 7.60-7.62 (m, 1H, Pyr.
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H-5), 7.83 (dd, 1H, J ) 8.5 Hz, J ) 1.6 Hz, Ar H), 7.87 (d,
N-Methyl-6-pyridin-3-yl-2-naphthamide (18). N-Methyl-
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3
1H, J ) 8.8 Hz, Ar H), 7.92 (d, 1H, J ) 8.8 Hz, Ar H), 8.24
formamide was used instead of formamide. Yield 83%, mp
(s, 1H, Ar H), 8.29 (dt, 1H, 3J ) 7.9 Hz, 4J ) 1.9 Hz, Pyr. H-4),
1
158 °C. H NMR (CDCl3): δ 3.10 (s, 3H, OCH3), 6.33 (s, 1H,
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8.65 (d, 1H, J ) 4.7 Hz, Pyr. H-6), 9.08 (d, 1H, J ) 1.6 Hz,
Pyr. H-2), 9.95 (s, 1H, OH). IR cm-1: νmax 3634, 3021, 1594,
1489, 1308, 793. MS m/z 222 (MH+). Anal. (C15H11NO‚0.24H2O)
C, H, N.
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NH), 7.42-7.44 (m, 1H, Pyr. H-5), 7.77 (dd, 1H, J ) 8.5 Hz,
4J ) 1.8 Hz, Ar H), 7.87 (dd, 1H, J ) 8.5 Hz, J ) 1.8 Hz,
Ar H), 7.96-8.07 (m, 4H, Ar H, Pyr. H-4), 8.33 (s, 1H, Ar H),
8.65 (dd, 1H, 3J ) 4.6 Hz, 4J ) 1.5 Hz, Pyr. H-6), 8.98 (d, 1H,
4J ) 1.5 Hz, Pyr. H-2). IR cm-1: νmax 3316, 3059, 2929, 1644,
1549, 1313. MS m/z 263 (MH+). Anal. (C17H14N2O‚0.15H2O)
C, H, N.
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Synthesis of 3-(5-Bromo-6-methoxy-2-naphthyl)pyri-
dine (10) and 3,3′-(2-Methoxynaphthalene-1,6-diyl)di-
pyridine (11). A mixture of 1,6-dibromo-2-methoxynaph-
thalene 10i (223 mg, 0.71 mmol), 3-pyridylboronic acid
(0.26 g, 2.12 mmol), Na2CO3 (0.30 g, 2.82 mmol) and Pd(PPh3)4
(16 mg) in ethylene glycol dimethyl ether was stirred overnight
at 80 °C under nitrogen. The reaction was cooled to room
temperature, and water was added. The mixture was extracted
with ethyl acetate, dried (MgSO4), filtered and evaporated in
vacuo. The mixture of compounds 10 and 11 was purified by
column chromatography, eluting with CH2Cl2/MeOH (98:2).
General Procedure for the Synthesis of Compounds
(23, 25).25 A mixture of 2-naphthylboronic acid (1.00 mmol),
imidazole (0.50 mmol), copper(II) acetate (0.75 mmol), pyridine
(1.00 mmol) and 4 Å molecular sieve in 6 mL of anhydrous
dichloromethane was stirred at room temperature for 2 days.
The mixture was filtered and evaporated in vacuo. The product
was purified by chromatography, eluting with CH2Cl2/MeOH
(99:1).
3-(5-Bromo-6-methoxy-2-naphthyl)pyridine (10). Yield
66%, mp 162 °C. 1H NMR (CDCl3): δ 4.07 (s, 3H, OCH3), 7.36
1-(2-Naphthyl)-1H-imidazole (23). Yield 34%, mp 123 °C.
1H NMR (CDCl3): δ 7.26 (s, 1H, Im. H-4), 7.40 (s, 1H, Im. H-5),
7.51-7.58 (m, 3H, Ar H), 7.82 (d, 1H, 4J ) 1.5 Hz, Ar H), 7.88
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(d, 1H, J ) 8.8 Hz, Ar H), 7.60-7.63 (m, 1H, Pyr. H-5), 7.79
(dd, 1H, 3J ) 8.8 Hz, 4J ) 2.2 Hz, Ar H), 7.92 (d, 1H, 3J )
(t, 2H, J ) 7.6 Hz, Ar H), 7.96 (d, 1H, 3J ) 7.6 Hz, Ar H),
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8.8 Hz, Ar H), 8.02 (d, 1H, J ) 1.9 Hz, Ar H), 8.22 (dt, 1H,
8.05 (s, 1H, Im. H-2). IR cm-1: νmax. 3116, 3058, 1688, 1602,
1493. MS m/z 195 (MH+), 167, 139, 115, 77, 51. Anal.
(C13H10N2‚0.08H2O) C, H, N.
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3J ) 7.9 Hz, J ) 2.2 Hz, Pyr. H-4), 8.36 (d, 1H, J ) 8.8 Hz,
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Ar H), 8.65 (dd, 1H, J ) 5.0 Hz, J ) 1.6 Hz, Pyr. H-6), 9.01
(d, 1H, 4J ) 2.2 Hz, Pyr. H-2). IR cm-1: νmax 3045, 2955, 2832,
1601, 1488, 1272. MS m/z 317-314 (MH+), 270, 227, 191, 163.
Anal. (C16H12NO) C, H, N.
1-(6-Methoxynaphthalen-2-yl)-1H-imidazole (25). Yield
1
13%, mp 85 °C. H NMR (CDCl3): δ 3.95 (s, 3H, OCH3), 7.18
(d, 1H, 4J ) 2.5 Hz, Ar H), 7.24 (dd, 1H, 3J ) 8.5 Hz, 4J )
3,3′-(2-Methoxynaphthalene-1,6-diyl)dipyridine (11).
Yield 5%, mp 173 °C. 1H NMR (CDCl3): δ 3.89 (s, 3H, OCH3),
7.43-7.46 (m, 2H, Ar H, Pyr. H-5), 7.54-7.56 (m, 2H, Ar H,
2.5 Hz, Ar H), 7.28 (s, 1H, Im. H-4), 7.38 (s, 1H, Im. H-5), 7.48
3
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(dd, 1H, J ) 8.5 Hz, J ) 2.5 Hz, Ar H), 7.76 (s, 1H, Ar H),
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Pyr. H-5), 7.62 (dd, 1H,3J ) 8.8 Hz, J ) 1.9 Hz, Ar H), 7.86
7.77 (d, 1H, J ) 8.5 Hz, Ar H), 7.85 (d, 1H, J ) 8.5 Hz, Ar
H), 8.07 (s, 1H, Im. H-2). IR cm-1: νmax. 3113, 3003, 2962, 2842,
(dt, 1H, 3J ) 7.9 Hz, 4J ) 1.9 Hz, Pyr. H-4), 8.01-8.04 (m,