Journal of Medicinal Chemistry
ARTICLE
with 13c, triethylamine, and 4-fluorobenzyl bromide to afford 14e
(m, 5H), 7.95ꢀ7.99 (m, 2H). The free base was converted to the oxalate
salt. Mp: 152 °C (dec). Anal. (C24H27FN2O3 H2C2O4 H2O) C, H, N.
1
(24.5 mg, 63%). H NMR (CDCl3): δ 1.56ꢀ2.28 (m, 8H), 2.18ꢀ
3
3
(4-(4-Fluorobenzoyl)-30-hydroxy-[1,40-bipiperidin]-10-yl)-
(pyridin-3-yl)methanone (15d). Procedure D was followed with
13a, BOP-Cl, triethylamine, and pyridine-3-carboxylic acid to afford 15d
(33 mg, 83%). The mobile phase used for column chromatographic
separation was triethylamine/ethyl acetate/methanol (1/9/1, v/v/v).
1H NMR (CDCl3): δ 1.44ꢀ2.11 (m, 6H), 2.20ꢀ2.40 (m, 1H), 2.40ꢀ
2.60 (m, 1H), 2.60ꢀ3.10 (m, 5H), 3.10ꢀ3.30 (m, 1H), 3.38ꢀ3.85 (m,
2H), 3.90ꢀ4.30 (m, 1H), 4.80ꢀ5.10 (m, 1H), 7.12ꢀ7.18 (m, 2H),
7.34ꢀ7.38 (m, 1H), 7.73ꢀ7.75 (m, 1H), 7.95ꢀ7.99 (m, 2H), 8.66ꢀ
8.68 (m, 2H). The free base was converted to the oxalate salt. Mp:
2.30 (m, 2H), 2.70ꢀ2.74 (m, 2H), 2.92ꢀ2.99 (m, 2H), 3.19ꢀ3.23 (m,
2H), 3.48ꢀ3.62 (m, 4H), 3.87 (s, 3H), 6.83ꢀ6.95 (m, 4H), 7.18ꢀ7.21
(m, 2H), 7.90ꢀ7.94 (m, 2H). Mp (oxalate salt): 231 °C (dec). Anal.
(C25H31FN2O3 H2C2O4 0.5H2O) C, H, N.
3
3
(30-Hydroxy-10-(4-methoxybenzyl)-[1,40-bipiperidin]-4-yl)-
(4-methoxyphenyl)methanone (14f). Procedure C was followed
with 13c, triethylamine, and 4-methoxybenzyl bromide to afford 14f
(30 mg, 73%). 1H NMR (CDCl3): δ 1.51ꢀ2.00 (m, 8H), 2.20ꢀ2.32 (m,
2H), 2.71ꢀ2.76 (m, 2H), 2.91ꢀ3.01 (m, 2H), 3.17ꢀ3.22 (m, 2H),
3.51ꢀ3.63 (m, 4H), 3.79 (s, 3H), 3.86 (s, 3H), 6.96ꢀ7.02 (m, 2H),
7.10ꢀ7.17 (m, 2H), 7.23ꢀ7.27 (m, 2H), 7.93ꢀ7.98 (m, 2H). Mp
(oxalate salt): 225 °C (dec). Anal. (C25H31FN2O3 H2C2O4 0.5H2O)
215 °C (dec). Anal. (C23H26FN3O3 H2C2O4 0.25H2O) C, H, N.
3
3 0
(10-(4-Fluorobenzoyl)-30-hydroxy-[1,4 -bipiperidin]-4-yl)-
(4-methoxyphenyl)methanone (15e). Procedure D was followed
with 13c, BOP-Cl, triethylamine, and 4-fluorobenzoic acid to prepare
15e (84 mg, 67%). 1H NMR (CDCl3): 1.30ꢀ1.98 (m, 5H), 2.16ꢀ2.33
(m, 1H), 2.34ꢀ2.41 (m, 1H), 2.45ꢀ3.65 (m, 8H), 3.77 (s, 3H), 4.03 (br
s, 1H), 4.72 (br s, 1H), 6.83ꢀ6.87 (m, 2H), 6.97ꢀ7.03 (m, 2H),
7.29ꢀ7.35 (m, 2H), 7.81ꢀ7.85 (m, 2H). The free base was converted to
3
3
C, H, N.
(10-Benzyl-30-hydroxy-[1,40-bipiperidin]-4-yl)(4-methoxy-
phenyl)methanone (14g). Procedure C was followed with 13c,
triethylamine, and benzyl bromide to afford 14g (32 mg, 34%). 1H NMR
(CDCl3): δ 1.54ꢀ2.04 (m, 8H), 2.22ꢀ2.27 (m, 2H), 2.70ꢀ2.75 (m,
2H), 2.93ꢀ3.00 (m, 2H), 3.20ꢀ3.25 (m, 2H), 3.54ꢀ3.62 (m, 4H), 3.86
(s, 3H), 6.94 (d, J = 9 Hz, 2H), 7.26ꢀ7.31 (m, 5H), 7.93 (d, J = 9 Hz,
the oxalate salt. Mp: 216 °C (dec). Anal. (C25H29FN2O4 H2C2O4)
3
C, H, N.
2H). Mp (oxalate salt): 234 °C (dec). Anal. (C25H32N2O3 2H2C2O4).
3
(10-Benzoyl-30-hydroxy-[1,40-bipiperidin]-4-yl)(4-methox-
yphenyl)methanone (15f). Procedure D was followed with 13c,
BOP-Cl, triethylamine, and benzoic acid to afford 15f (0.14 g. 80%). 1H
NMR (CDCl3): δ 1.60ꢀ1.90 (m, 5H), 2.10ꢀ2.50 (m, 2H), 2.60ꢀ3.00
(m, 5H), 3.20ꢀ3.50 (m, 2H), 3.65 (s, 1H), 3.87 (s, 3H), 4.10 (s br, 1H),
5.30 (br s 1H), 6.94 (d, J = 8.7 Hz, 2H), 7.38ꢀ7.40 (m, 5H), 7.92 (d, J =
9 Hz, 2H). The free base was converted to the oxalate salt. Mp: 188 °C
(dec). Anal. (C25H30N2O8 H2C2O4 1.5H2O) C, H, N.
(30-Hydroxy-10-(pyridin-3-ylmethyl)-[1,40-bipiperidin]-4-yl)-
(4-methoxyphenyl)methanone (14h). Procedure C was followed
with 13c, triethylamine, and pyridin-4-methyl bromide to prepare 14h
(20 mg, 52%). The mobile phase used for column chromatographic
separation was triethylamine/ethyl acetate/methanol (1/9/1, v/v/v).
1H NMR (CDCl3): δ 1.72ꢀ2.03 (m, 8H), 2.25ꢀ2.29 (m, 2H), 2.74ꢀ
2.76 (m, 2H), 2.91ꢀ3.00 (m, 2H), 3.19ꢀ3.21 (m, 2H), 3.55ꢀ3.61 (m,
4H), 3.87 (s, 3H), 6.95 (d, J = 9 Hz, 2H), 7.23ꢀ7.27 (m, 1H), 7.62ꢀ7.65
(m, 1H), 7.93 (d, J = 9 Hz, 2H), 8.50ꢀ8.52 (m, 2H). The free base was
3
3
(30-Hydroxy-10-isonicotinoyl-[1,40-bipiperidin]-4-yl)(4-
methoxyphenyl)methanone (15g). Procedure D was followed
with 13c, BOP-Cl, triethylamine, and pyridine-3-carboxylic acid to
afford 15g (36 mg, 90%). The mobile phase used for column chromato-
graphic separation was triethylamine/ethyl acetate/methanol (1/9/1,
v/v/v). 1H NMR (CDCl3): δ 1.61ꢀ1.96 (m, 6H), 2.04ꢀ2.08 (m, 1H),
2.27ꢀ2.56 (m, 2H), 2.80ꢀ2.09 (m, 4H), 2.09ꢀ3.27 (m, 2H), 3.44ꢀ
3.69 (m, 2H), 3.87 (s, 3H), 4.85ꢀ5.15 (m, 1H), 6.93ꢀ6.97 (m, 2H),
7.28ꢀ7.38 (m, 1H), 7.73ꢀ7.80 (m, 1H), 7.85ꢀ7.94 (m, 2H), 8.67ꢀ
8.68 (m, 2H). The free base was converted to the oxalate salt. Mp:
converted to the oxalate salt. Mp: 188 °C (dec). Anal. (C24H31N3O3
3
2H2C2O4 0.5H2O) C, H, N.
3
Procedure D. General Method for Preparation of Benza-
mides (15aꢀg). (30-Hydroxy-[1,40-bipiperidine]-10,4-diyl)bis-
(4-fluorophenyl)methanone (15a). Into a solution of 13a (50 mg,
0.163 mmol), BOP-Cl (100 mg, 0.40 mmol), and triethylamine (1 mL)
in methylene chloride (30 mL) was added 4-fluorobenzoic acid (40 mg,
0.28 mmol). The reaction mixture was stirred overnight at room
temperature. The reaction mixture was washed with saturated sodium
carbonate (20 mL ꢁ 5) and brine solution (20 mL). The organic layer
was dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography using
triethylamine/ethyl acetate (1/50, v/v) as mobile phase to afford 15a
(62 mg, 89%). 1H NMR (CDCl3): δ 1.54ꢀ1.93 (m, 7H), 2.27ꢀ2.34 (m,
1H), 2.44ꢀ2.52 (m, 1H), 2.80ꢀ2.98 (m, 5H), 3.23ꢀ3.26 (m, 1H),
3.30ꢀ3.60 (m, 1H), 4.80 (br s, 1H), 7.07ꢀ7.18 (m, 4H), 7.40ꢀ7.44 (m,
2H), 7.94ꢀ7.99 (m, 2H). The free base was converted to the oxalate salt.
220 °C (dec). EIMS: calcd, 429.1843; found, 429.1843. Anal. (C24H29N3O4
H2C2O4) C, H, N.
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(10-(4-Fluorobenzyl)-40-hydroxy-[1,30-bipiperidin]-4-yl)(4-
fluorophenyl)methanone (16a). Procedure C was followed with
13b, triethylamine and 4-fluorobenzyl bromide to yield 16a as a pale
yellow oil (28.7 mg, 43%). 1H NMR (CDCl3): δ 1.55ꢀ2.05 (m, 9H),
2.24ꢀ2.31 (m, 1H), 2.49ꢀ2.57 (m, 1H), 2.71ꢀ2.83 (m, 3H), 2.94ꢀ
3.04 (m, 2H), 3.17ꢀ3.20 (m, 1H), 3.40ꢀ3.49 (m, 3H), 6.98ꢀ7.05 (m,
2H), 7.10ꢀ7.17 (m, 2H), 7.25ꢀ7.30 (m, 2H), 7.92ꢀ7.97 (m, 2H). The
free base was converted to the oxalate salt. Mp: 209 °C (dec). Anal.
Mp: 213 °C (dec). Anal. (C24H26F2N2O5 H2C2O4) C, H, N.
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(4-(4-Fluorobenzoyl)-30-hydroxy-[1,40-bipiperidin]-10-yl)-
(4-methoxyphenyl)methanone (15b). Procedure D was followed
with 13a, BOP-Cl, triethylamine, and 4-methoxybenzoic acid to afford
15b (48 mg, 22%). 1H NMR (CDCl3): δ 1.54ꢀ1.93 (m, 7H), 2.31ꢀ
2.34 (m, 1H), 2.44 ꢀ2.51 (m, 1H), 2.79 ꢀ2.98 (m, 5H), 3.23ꢀ3.26 (m,
1H), 3.47 (m, 2H), 3.82 (s, 3H), 6.91 (d, J = 9 Hz, 2H), 7.14 (t, J = 6 Hz,
2H), 7.38 (d, J = 9 Hz, 2H), 7.94ꢀ7.99 (m, 2H). The free base was
(C24H28F2N2O2 H2C2O4) C, H, N.
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(4-Fluorophenyl)(40-hydroxy-10-(4-methoxybenzyl)-[1,30-
bipiperidin]-4-yl)methanone (16b). Procedure C was followed
with 13b, triethylamine, and 4-methoxybenzyl bromide to afford 16b
(28 mg, 45%). 1H NMR (CDCl3): δ 1.56ꢀ2.06 (m, 8H), 2.26ꢀ2.30 (m,
1H), 2.53ꢀ 2.56 (m, 1H), 2.72ꢀ2.86 (m, 3H), 3.00ꢀ3.03 (m, 2H),
3.17ꢀ3.20 (m, 1H), 3.40ꢀ3.50 (m, 4H), 3.81 (s, 3H), 6.86ꢀ6.89 (m,
2H), 7.10ꢀ7.27 (m, 4H), 7.92ꢀ7.97 (m, 2H). The free base was
converted to the oxalate salt. Mp: 206 °C (dec). Anal. (C24H27FN2O3
3
H2C2O4 0.5H2O) C, H, N.
3
(10-Benzoyl-30-hydroxy-[1,40-bipiperidin]-4-yl)(4-fluoro-
phenyl)methanone (15c). Procedure D was followed with 13a,
BOP-Cl, triethylamine, and benzoic acid to afford 15c (0.34 g, 78%). 1H
NMR (CDCl3): δ 1.75ꢀ1.80 (m, 2H), 1.80ꢀ1.95 (m, 4H), 2.20ꢀ2.40
(m, 1H), 2.40ꢀ2.60 (m, 1H), 2.60ꢀ3.00 (m, 5H), 3.10ꢀ3.30 (m, 1H),
4.10 (s br s, 1H), 4.86 (br s, 1H), 7.12ꢀ7.18 (m, 2H), 7.28ꢀ7.42
converted to the oxalate salt. Mp: 204 °C (dec). Anal. (C25H31FN2O3
H2C2O4) C, H, N.
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(10-Benzyl-40-hydroxy-[1,30-bipiperidin]-4-yl)(4-fluoro-
phenyl)methanone (16c). Procedure C was followed with 13b,
triethylamine, and benzyl bromide to afford 16c (40 mg, 62%). 1H NMR
(CDCl3): δ 1.56ꢀ2.06 (m, 8H), 2.24ꢀ2.3 (m, 1H), 2.51ꢀ2.59
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dx.doi.org/10.1021/jm200203f |J. Med. Chem. 2011, 54, 5362–5372