Arch. Pharm. Chem. Life Sci. 2009, 342, 476–483
Novel Methanone Derivatives
481
dimethoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperi-
din-1-yl]-ethanone 6 (0.25 g, 0.491 mmol), 2-chlorophenyl isocya-
nate 7c (0.337 g, 2.27 mmol), and triethylamine (0.667 g,
6.81 mmol). 1H-NMR (DMSO-d6, 400 MHz) d: 9.20 (s, 1H, -NH), 7.80
(d, 2H, Ar-H), 7.35 (m, 2H, Ar-H), 7.12 (m, 4H, Ar-H), 6.89 (d, 1H, Ar-
H), 6.62 (d, 2H, Ar-H), 5.27 (s, 2H, -OCH2), 3.84 (s, 3H, -OCH3), 3.72
(s, 3H, -OCH3), 2.83–3.0 (m, 8H), 2.03 (bs, 2H), 1.12–1.28 (m, 14H).
IR (KBr, cm– 1): 3361, 2920, 2862, 1728, 1674, 1278, 1256, 1123,
1045, 725. MS (ESI) m/z: 662.30 [M + H+]. Anal. calcd. for
C37H44ClN3O6 (%): C, 67.11; H, 6.70; N, 6.35. Found: C, 67.16; H,
6.77; N, 6.41.
General procedure for synthesis of 2-[4-(2,4-
dimethoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-
propyl)-piperidin-1-yl]-ethanone derivatives 9a-d and
10a–d
A solution of 2-[4-(2,4-dimethoxybenzoyl)-phenoxy]-1-[4-(3-piperi-
din-4-yl-propyl)-piperidin-1-yl]-ethanone
6
(1.0 eq) in dry
dichloromethane was taken and cooled to 0–58C in an ice bath.
Triethylamine (3.0 eq) was added to this cold reaction mixture
and stirred for 10 min, then different isocyanates (1.0 eq) or iso-
thiocyanates (1.0 eq) were added and allowed to stir at room
temperature for 5–6 h. Progress of the reaction mixture was
monitored by TLC. Upon completion, the solvent was removed
under reduced pressure and the residue was taken up in water
and extracted with ethyl acetate. The organic layer was washed
with 10% ammonium chloride solution and finally the organic
layer was washed with water and dried with anhydrous sodium
sulphate. The solvent was evaporated to get the crude product
which was purified by column chromatography over silica gel
(60–120 mesh) using hexane / ethyl acetate (8 : 2) as eluent.
Synthesis of 4-[3-[1-[2-[4-(2,4-
dimethoxybenzoyl)phenoxy]acetyl]-4-piperidyl]propyl]-N-
(2,4-dichlorophenyl)piperidine-1-carboxamide 9d
The general synthetic method described above afforded 9d and
the product obtained was a pale yellow oil made from 2-[4-(2,4-
dimethoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperi-
din-1-yl]-ethanone 6 (0.25 g, 0.491 mmol), 2,4-dichlorophenyl iso-
cyanate 7d (0.413 g, 2.27 mmol), and triethylamine (0.667 g,
6.81 mmol). 1H-NMR (DMSO-d6, 400 MHz) d: 9.22 (s, 1H, -NH), 7.76
(d, 1H, Ar-H), 7.33 (d, 1H, Ar-H), 7.25 (d, 2H, Ar-H), 7.02 (m, 2H, Ar-
H), 6.94 (d, 1H, Ar-H), 6.68 (d, 2H, Ar-H), 6.51 (bs, 1H, Ar-H), 5.31 (s,
2H, -OCH2), 3.84 (s, 3H, -OCH3), 3.73 (s, 3H, -OCH3), 2.87–3.02 (m,
8H), 2.02 (bs, 2H), 1.12–1.22 (m, 14H). IR (KBr, cm– 1): 3356, 2935,
2874, 1731, 1640, 1270, 1248, 1120, 1041, 723. MS (ESI) m/z:
697.25 [M + H+]. Anal. calcd. for C37H43Cl2N3O6 (%): C, 63.79; H,
6.22; N, 6.03. Found: C, 63.84; H, 6.18; N, 6.09.
Synthesis of 4-[3-[1-[2-[4-(2,4-
dimethoxybenzoyl)phenoxy]acetyl]-4-piperidyl]propyl]-N-
(4-methoxyphenyl)piperidine-1-carboxamide 9a
The general synthetic method described above afforded 9a and
the product obtained was a pale yellow oil made from 2-[4-(2,4-
dimethoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperi-
din-1-yl]-ethanone 6 (0.25 g, 0.491 mmol), 4-methoxyphenyl iso-
cyanate 7a (0.328 g, 2.27 mmol), and triethylamine (0.667 g,
6.81 mmol). 1H-NMR (DMSO-d6, 400 MHz) d: 9.23 (s, 1H, -NH), 7.81
(d, 2H, Ar-H), 7.33 (m, 2H, Ar-H), 6.95 (m, 4H, Ar-H), 6.84 (d, 1H, Ar-
H), 6.59 (d, 2H, Ar-H), 5.29 (s, 2H, -OCH2), 3.89 (s, 3H, -OCH3), 3.83
(s, 3H, -OCH3), 3.73 (s, 3H, -OCH3), 2.85–2.98 (m, 8H), 2.05 (bs, 2H),
1.09–1.28 (m, 14H). IR (KBr, cm– 1): 3356, 2889, 1716, 1648, 1293,
1250, 1124, 1105. MS (ESI) m/z: 658.34 [M + H+]. Anal. calcd. for
C38H47N3O7 (%): C, 69.38; H, 7.20; N, 6.39. Found: C, 69.44; H, 7.26;
N, 6.36.
Synthesis of 4-[3-[1-[2-[4-(2,4-
dimethoxybenzoyl)phenoxy]acetyl]-4-piperidyl]propyl]-N-
(4-methoxyphenyl)piperidine-1-carbothioamide 10a
The general synthetic method described above afforded 10a and
the product obtained was a pale yellow oil from 2-[4-(2,4-dime-
thoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperidin-1-
yl]-ethanone 6 (0.25 g, 0.491 mmol), 4-methoxyphenyl isothio-
cyanate 8a (0.292 g, 1.77 mmol), and triethylamine (0.667 g,
6.81 mmol). 1H-NMR (DMSO-d6, 400 MHz) d: 9.25 (s, 1H, -NH), 7.79
(d, 2H, Ar-H), 7.35 (m, 2H, Ar-H), 6.96 (m, 4H, Ar-H), 6.82 (d, 1H, Ar-
H), 6.56 (d, 2H, Ar-H), 5.25 (s, 2H, -OCH2), 3.85 (s, 3H, -OCH3), 3.80
(s, 3H, -OCH3), 3.72 (s, 3H, -OCH3), 2.02 (bs, 8H), 1.58–1.75 (bs, 4H),
1.09–1.22 (m, 12H), 1.0 (m, 4H). IR (KBr, cm– 1): 2939, 2881, 1730,
1643, 1274, 1245, 1128, 1117, 1041. MS (ESI) m/z: 674.32 [M + H+].
Anal. calcd. for C38H47N3O6S (%): C, 67.73; H, 7.03; N, 6.24. Found:
C, 67.80; H, 6.98; N, 6.28.
Synthesis of 4-[3-[1-[2-[4-(2,4-
dimethoxybenzoyl)phenoxy]acetyl]-4-piperidyl]propyl]-N-
(4-fluorophenyl)piperidine-1-carboxamide 9b
The general synthetic method described above afforded 9b and
the product obtained was a pale yellow oil made from 2-[4-(2,4-
dimethoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperi-
din-1-yl]-ethanone 6 (0.25 g, 0.491 mmol), 4-fluorophenyl isocya-
nate 7b (0.301 g, 2.27 mmol), and triethylamine (0.667 g,
1
6.81 mmol). H-NMR (DMSO-d6, 400 MHz) d: 9.19 (s, 1H, -CONH),
7.79 (d, 2H, Ar-H), 7.27–7.33 (m, 2H, Ar-H), 6.94 (m, 4H, Ar-H),
6.86 (d, 1H, Ar-H), 6.54 (d, 2H, Ar-H), 5.25 (s, 2H, -OCH2), 3.87 (s,
3H, -OCH3), 3.72 (s, 3H, -OCH3), 2.89–2.98 (m, 8H), 2.81 (bs, 2H),
1.74 (m, 2H), 1.09–1.26 (m, 12H). IR (KBr, cm– 1): 3346, 2885,
1710, 1639, 1287, 1252, 1121, 1039. MS (ESI) m/z: 646.32 [M + H+].
Anal. calcd. for C37H44FN3O6 (%): C, 68.82; H, 6.87; N, 6.71. Found:
C, 68.88; H, 6.82; N, 6.73.
Synthesis of 4-[3-[1-[2-[4-(2,4-
dimethoxybenzoyl)phenoxy]acetyl]-4-piperidyl]propyl]-N-
(2-chlorophenyl)piperidine-1-carbothioamide 10b
The general synthetic method described above afforded 10b and
the product obtained was a pale yellow oil from 2-[4-(2,4-dime-
thoxybenzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperidin-1-
yl]-ethanone 6 (0.25 g, 0.491 mmol), 2-chlorophenyl isothiocya-
nate 8b (0.30 g, 1.77 mmol), and triethylamine (0.667 g,
6.81 mmol). 1H-NMR (DMSO-d6, 400 MHz) d: 9.19 (s, 1H, -NH), 7.81
(d, 2H, Ar-H), 7.33 (m, 2H, Ar-H), 7.21 (m, 4H, Ar-H), 6.91 (d, 1H, Ar-
H), 6.60 (d, 2H, Ar-H), 5.29 (s, 2H, -OCH2), 3.83 (s, 3H, -OCH3), 3.70
(s, 3H, -OCH3), 2.85–2.98 (m, 8H), 2.05 (bs, 2H), 1.12–1.2 (m, 14H).
IR (KBr, cm– 1): 2952, 2876, 1741, 1648, 1270, 1241, 1129, 1097,
Synthesis of 4-[3-[1-[2-[4-(2,4-
dimethoxybenzoyl)phenoxy]acetyl]-4-piperidyl]propyl]-N-
(2-chlorophenyl)piperidine-1-carboxamide 9c
The general synthetic method described above afforded 9c and
the product obtained was a pale yellow oil made from 2-[4-(2,4-
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