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S. Bertini et al. / European Journal of Medicinal Chemistry 90 (2015) 526e536
NMR (400 MHz, CDCl3)
d
(ppm): 16.22, 22.35, 32.16, 33.32, 34.00,
¼ 2.5 Hz), 7.46 (d, 1H, J ¼ 2.4 Hz), 7.52 (AA0XX0, 2H, JAX ¼ 8.8 Hz,
XX0
JAA /XX ¼ 2.5 Hz), 8.03 (d, 1H, J ¼ 2.4 Hz); 13C NMR (400 MHz, CDCl3)
0
0
48.57, 61.37, 127.13, 127.43, 127.45, 128.03, 128.86, 131.97, 132.73,
137.62, 140.09, 155.82, 164.78; MS: m/z 337 (Mþ, 16), 225
(Mþ ꢁ NHC7H13, 61); 6 (yield 7%): 1H NMR (200 MHz, CDCl3)
d
(ppm): 14.12, 22.37, 22.95, 29.60, 32.19, 33.19, 33.33, 34.04, 48.59,
55.49, 62.27, 114.32, 127.50, 127.65, 128.20, 131.27, 132.81, 136.70,
137.29, 155.09, 159.31, 165.07; MS: m/z 409 (Mþ, 100), 297
(Mþ ꢁ NHC7H13, 81); 12 (yield: 23%): 1H NMR (400 MHz, CDCl3)
d
(ppm): 0.96 (d, 3H, J ¼ 6.4 Hz), 1.11e1.89 (m, 9H), 2.40 (s, 3H), 3.83
(s, 3H), 4.25e4.39 (m, 1H), 7.28e7.62 (m, 5H), 7.53 (d, 1H,
J ¼ 2.6 Hz), 8.09 (br, 1H), 8.16 (d, 1H, J ¼ 2.6 Hz); 13C NMR (400 MHz,
d
(ppm): 0.96 (d, 3H, J ¼ 6.6 Hz), 0.98 (t, 3H, J ¼ 7.3 Hz), 1.41e1.49
CDCl3)
d
(ppm): 16.31, 21.90, 29.91, 30.37, 31.18, 45.26, 61.59, 127.16,
(m, 2H), 1.57e1.88 (m, 11H), 2.69e2.73 (m, 2H), 3.81 (s, 3H), 3.85 (s,
3H), 4.27e4.35 (m, 1H), 6.96 (AA0XX0, 2H, JAX ¼ 8.8 Hz, JAA /
0
127.25, 127.48, 128.12, 128.88, 131.99, 132.89, 137.66, 140.09, 155.96,
164.66; MS: m/z 337 (Mþ, 38), 225 (Mþ ꢁ NHC7H13, 67).
¼ 2.3 Hz), 7.48 (d, 1H, J ¼ 2.5 Hz), 7.53 (AA0XX0, 2H, JAX ¼ 8.8 Hz,
XX0
JAA /XX ¼ 2.3 Hz), 7.95 (br, 1H), 8.08 (d, 1H, J ¼ 2.5 Hz); 13C NMR
0
0
5.1.6.5. N-cycloheptyl-40-fluoro-4-methoxy-5-methylbiphenyl-3-
carboxamide (7). Prepared from acid derivative 22 using cyclo-
heptylamine. Purified by flash column chromatography (n-hexane/
(400 MHz, CDCl3) d (ppm): 14.12, 21.73, 22.98, 29.49, 29.84, 30.40,
33.13, 45.41, 55.48, 62.48, 114.32, 127.50, 127.54, 128.20, 131.30,
132.82, 136.69, 137.31, 155.22, 159.32, 164.94; MS: m/z 409 (Mþ,
100), 297 (Mþ ꢁ NHC7H13, 51).
AcOEt 8:2). Yield: 42%. 1H NMR (200 MHz, CDCl3)
d (ppm):
2.10e1.56 (m, 12H); 2.37 (s, 3H), 3.78 (s, 3H), 4.17e4.35 (m, 1H),
7.04e7.16 (m, 2H), 7.45e7.57 (m, 3H), 7.79 (br, 1H), 8.06 (d, 1H,
5.1.7. Methyl 3-bromo-2-methoxybenzoate (24)
J ¼ 2.4 Hz); 13C NMR (400 MHz, CDCl3)
d
(ppm): 16.19, 24.24, 28.27,
Concentrated sulphuric acid (2.0 ml) was slowly added to a
solution of the commercially available 3-bromo-2-methoxybenzoic
acid 23 (2.0 g, 8.66 mmol) in methanol (40.0 ml), and the mixture
was refluxed overnight. Then the mixture was allowed to cool to
room temperature and neutralized with saturated aqueous sodium
bicarbonate solution. The aqueous layer was extracted several
times with ethyl acetate, and the combined organic phases were
dried over anhydrous Na2SO4, filtered and concentrated in vacuo to
35.20, 50.42, 61.41, 115.71 (d, J ¼ 84 Hz), 127.43, 127.89, 128.66 (d,
J ¼ 32 Hz), 132.08, 132.54, 136.19, 136.61, 155.82, 161.35, 164.23, MS:
m/z 355 (Mþ, 2), 243 (Mþ ꢁ NHC7H13, 20).
5.1.6.6. 40-Fluoro-N-(trans-4-methylcyclohexyl)-4-methoxy-5-
methylbiphenyl-3-carboxamide (8) and 40-fluoro-N-(cis-4-
methylcyclohexyl)-4-methoxy-5-methylbiphenyl-3-carboxamide (9).
Prepared from acid derivative 22 using 4-methylcyclohexylamine
(cis/trans mixture). Purification by flash column chromatography
(n-hexane/AcOEt 8:2) allowed the separation of trans- (8) and cis-
give pure 24 in 60% yield. 1H NMR (200 MHz, CDCl3)
d (ppm): 3.92
(s, 6H), 7.03 (t, 1H, J ¼ 7.9 Hz), 7.70 (dd, 1H, J ¼ 6.4 Hz, J ¼ 1.6 Hz),
7.74 (dd, 1H, J ¼ 6.4 Hz, J ¼ 1.6 Hz); MS: m/z 245 (Mþ, 100), 247
([M þ 2]þ, 88), 214 ([M ꢁ OCH3]þ, 72), 216 ([M þ 2 e OCH3]þ, 57).
(9) isomers. 8 (yield: 8%): 1H NMR (200 MHz, CDCl3)
d (ppm): 0.92
(d, 3H, J ¼ 6.0 Hz), 1.09e2.12 (m, 9H), 2.37 (s, 3H), 3.93 (s, 3H),
4.20e4.40 (m, 1H), 7.05e7.14 (m, 2H), 7.44e7.63 (m, 3H), 7.88 (br,
5.1.8. Methyl 3-n-butyl-2-methoxybenzoate (25)
1H), 8.04 (d, 1H, J ¼ 2.4 Hz); 13C NMR (400 MHz, CDCl3)
d
(ppm):
Bis(dibenzylideneacetone)dipalladium(0) (11.5 mg, 2% mol) and
1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphino)ferrocene
(29.1 mg, 1% mol) were added, under nitrogen flux, to a solution of
24 (500 mg, 2.04 mmol) in anhydrous toluene (5 ml), followed by
K3PO4 (874 mg, 4.12 mmol) and n-butyl-boronic acid (251.8 mg,
2.47 mmol). The system was sealed, and the reaction mixture was
stirred at 100 ꢀC for 19 h. After cooling to room temperature,
toluene was removed by evaporation in vacuo to afford the crude
product that was purified by flash column chromatography on silica
gel (n-hexane/AcOEt 9:1) to give pure 25 (400 mg, yield: 88%). 1H
16.23, 22.36, 30.34, 32.18, 34.01, 48.60, 61.40, 115.75 (d, J ¼ 84 Hz),
127.48, 127.94, 128.72 (d, J ¼ 32 Hz), 132.12, 132.59, 136.26, 136.68,
155.81, 161.40, 164.68; MS: m/z 355 (Mþ, 4), 243 (Mþ ꢁ NHC7H13
,
12); 9 (yield 30%): 1H NMR (200 MHz, CDCl3)
d (ppm): 0.96 (d, 3H,
J ¼ 7.0 Hz), 1.16e1.86 (m, 9H), 2.40 (s, 3H), 3.82 (s, 3H), 4.15e4.40
(m, 1H), 7.06e7.15 (m, 2H), 7.46e7.58 (m, 3H), 8.05 (br, 1H), 8.10 (d,
1H, J ¼ 2.2 Hz); 13C NMR (400 MHz, CDCl3)
d (ppm): 16.27, 22.33,
29.88, 30.35, 33.99, 45.26, 61.57, 115.72 (d, J ¼ 84 Hz), 127.29, 127.97,
128.69 (d, J ¼ 32 Hz), 132.09, 132.69, 136.23, 136.66, 155.92, 161.38,
163.83; MS: m/z 355 (Mþ, 2), 243 (Mþ ꢁ NHC7H13, 14).
NMR (200 MHz, CDCl3)
d
(ppm): 0.93 (t, 3H, J ¼ 7.3 Hz), 1.25e1.66
(m, 4H), 2.62e2.70 (m, 1H), 3.83 (s, 3H), 3.91 (s, 3H), 7.07 (t, 1H,
J ¼ 7.6 Hz), 7.35 (dd, 1H, J ¼ 7.5 Hz, J ¼ 1.8 Hz), 7.64 (dd, 1H,
J ¼ 7.5 Hz, J ¼ 1.8 Hz); MS: m/z 222 (Mþ, 40), 223 ([M þ 1]þ, 100),
191 ([M ꢁ OCH3]þ, 21).
5.1.6.7. 5-n-Butyl-4,40-dimethoxy-N-cycloheptylbiphenyl-3-
carboxamide (10). Prepared from acid derivative 29 using cyclo-
heptylamine. Purified by flash column chromatography (n-hexane/
AcOEt 8:2). Yield: 66%. 1H NMR (400 MHz, CDCl3)
d (ppm): 0.97 (t,
3H, J ¼ 7.3 Hz), 1.39e1.49 (m, 2H), 1.53e1.71 (m, 12H), 2.01e2.10 (m,
5.1.9. Methyl 5-bromo-3-n-butyl-2-methoxybenzoate (26) and
methyl 5-bromo-3-n-butyl-2-hydroxybenzoate (27)
2H), 2.67e2.71 (m, 2H), 3.78 (s, 3H), 3.84 (s, 3H), 4.20e4.29 (m, 1H),
6.96 (AA0XX0, 2H, JAX ¼ 8.7 Hz, JAA /XX ¼ 2.6 Hz), 7.47 (d, 1H,
J ¼ 2.5 Hz), 7.52 (AA’XX0, 2H, JAX ¼ 8.7 Hz, JAA’/XX’ ¼ 2.6 Hz), 7.66 (br,
Compound 25 (300 mg, 1.35 mmol) was dissolved in 2.3 ml of
chloroform. Then, a solution of bromine (0.07 ml, 1.37 mmol) in
chloroform (1.4 ml) was slowly added at room temperature. The
reaction mixture was stirred at room temperature overnight. After
washing once with saturated aqueous sodium thiosulfate solution,
the organic layer was dried over anhydrous sodium sulphate,
filtered and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (n-hexane/AcOEt 9:1)
to give 140 mg of pure 26 (yield: 34%) and 90 mg of pure 27. 26: 1H
0
0
1H), 8.04 (d, 1H, J ¼ 2.5 Hz); 13C NMR (400 MHz, CDCl3)
d (ppm):
14.09, 22.92, 24.28, 28.27, 29.53, 33.14, 35.23, 50.47, 55.43, 62.29,
114.27, 127.46, 127.60, 128.14, 131.20, 132.75, 136.65, 137.23, 155.09,
159.27, 164.61; MS: m/z 409 (Mþ, 31), 297 (Mþ ꢁ NHC7H13, 22).
5.1.6.8. 5-n-Butyl-4,40-dimethoxy-N-(trans-4-methylcyclohexyl)
biphenyl-3-carboxamide (11) and 5-n-butyl-4,40-dimethoxy-N-(cis-
4-methylcyclohexyl)biphenyl-3-carboxamide (12). Prepared from
acid derivative 29 using 4-methylcyclohexylamine (cis/trans
mixture). Purification by flash column chromatography (n-hexane/
AcOEt 8:2) allowed the separation of trans- (11) and cis- (12) iso-
NMR (200 MHz, CDCl3)
d
(ppm): 0.93 (t, 3H, J ¼ 7.14), 1.25e1.65 (m,
4H), 2.58e2.66 (m, 2H), 3.81 (s, 3H), 3.91 (s, 3H), 7.45 (d, 1H,
J ¼ 2.6 Hz), 7.76 (d, 1H, J ¼ 2.6 Hz); MS: m/z 301 (Mþ, 100), 303
([M þ 2]þ, 73), 270 ([M ꢁ OCH3]þ, 19); 27: 1H NMR (CDCl3)
d (ppm):
mers. 11 (yield 38%): 1H NMR (200 MHz, CDCl3)
d
(ppm): 0.82e1.00
0.93 (t, 3H, J ¼ 7.1 Hz), 1.24e1.65 (m, 4H), 2.56e2.69 (m, 2H), 3.95 (s,
3H), 7.40 (d,1H, J ¼ 2.4 Hz), 7.80 (d,1H, J ¼ 2.4 Hz),10.96 (s,1H); MS:
m/z 287 (Mþ, 74), 289 ([M þ 2]þ, 47), 256 ([M ꢁ OCH3]þ, 8).
(m, 6H), 1.09e1.79 (m, 13H), 2.64e2.72 (m, 2H), 3.77 (s, 3H), 3.84 (s,
3H), 3.90e4.05 (m, 1H), 6.95 (AA0XX0, 2H, JAX ¼ 8.8 Hz, JAA /
0