4-[3-(Piperidin-4-yl) Propyl]Piperidine Derivatives
expressed in d, and the following abbreviations are used: s (sin-
glet), d (doublet), t (triplet), q (quartet), and m (multiplet). The purity
of the compounds was checked by thin layer chromatography (TLC).
Silica gel column chromatography was performed using Merck 7734
silica gel (60–120 mesh) and Merck made TLC plates. All the
reagents and chemicals used were from Sigma Aldrich Chemicals
Pvt Ltd.
Synthesis of (2-amino-1,2,3,4-
tetrahydronaphthalen-2-yl) {4-[3-(piperidin-4-yl)
propyl]piperidin-1-yl}methanone 3b
The product obtained was white solid from 2-amino-1,2,3,4-tetrahy-
dronaphthalene-2-carboxylic acid 2b (0.25 g, 1.30 mmol), isobutyl
chloroformate (0.23 g, 1.69 mmol), N-methyl morpholine (0.39 g,
3.9 mmol), and 4-[3-(piperidin-4-yl)propyl]piperidine
1
(0.27 g,
1
1.30 mmol). H NMR (DMSO-d6, 400 MHz) d: 7.12 (dd, 2H, Ar–H),
6.90 (d, 2H, Ar–H), 3.90 (s, 2H, –NH2), 3.43 (m, 2H, –CH2), 2.95–
2.98 (m, 8H), 2.91 (t, 2H, –CH2), 2.81 (bs, 2H), 2.18 (t, 2H, –CH2),
2.04 (s, 1H, –NH), 1.74 (m, 2H), 1.09–1.26 (m, 12H). MS (ESI) m ⁄ z:
384.3 (M+H+). IR (KBr, ⁄ cm): 3329, 3074, 1656, 1615, 1525, 1169.
Chemistry
For the synthesis of the novel compounds 3(a–i), the reaction
sequences outlined in Scheme 1 were followed. The coupling reac-
tion of 4-[3-(piperidin-4-yl)propyl]piperidine (1) with different substi-
tuted aromatic ⁄ heterocyclic acids 2(a–i) were carried out in the
presence of base N-methyl morpholine, isobutyl chloroformate, and
tetrahydrofuran (THF) as solvent with the yield ranging from 75% to
90%. Synthesized molecules 3(a–i) were structurally characterized
Synthesis of 2-amino-3-(2¢-ethyl-4¢-
methoxybiphenyl-4-yl)-1-{4-[3-(piperidin-4-yl)
propyl]piperidin-1-yl}propan-1-one 3c
1
by H NMR, mass and IR spectroscopic analyses. Compounds 3(a–i)
were confirmed by IR data, which showed disappearance of stretch-
ing frequencies of –COOH at 2995 ⁄ cm. From H NMR spectra, this
showed disappearance of –COOH at 12.03 ppm. The chemical struc-
tures and yield of the synthesized compounds are given in Table 1.
The product obtained was white amorphous solid from 2-amino-3-
(2¢-ethyl-4¢-methoxylbiphenyl-4-yl)propanoic acid 2c (0.25 g,
0.83 mmol), isobutyl chloroformate (0.147 g, 1.08 mmol), N-methyl
morpholine (0.25 g, 2.49 mmol), and 4-[3-(piperidin-4-yl)propyl]piperi-
1
1
dine 1 (0.174 g, 0.83 mmol). H NMR (DMSO-d6, 400 MHz) d: 7.47
(d, 2H, Ar–H), 7.35 (d, 1H, Ar–H), 7.21 (d, 2H, Ar–H), 6.71 (s, 1H,
Ar–H), 6.62 (d, 1H, Ar–H), 3.95 (m, 1H, –CH), 3.92 (s, 2H, –NH2),
3.87 (s, 3H, –OCH3), 3.23 (d, 2H, –CH2), 2.89–2.98 (m, 8H), 2.81 (bs,
2H), 2.62 (m, 2H, –CH2), 2.08 (s, 1H, –NH), 1.74 (m, 2H), 1.23 (t, 3H,
–CH3), 1.09–1.98 (m, 12H). MS (ESI) m ⁄ z: 492.35 (M+H+). IR (KBr,
⁄ cm): 3315, 3052, 1668, 1610, 1538, 1180.
General procedure for the synthesis of 4-(3-
(piperidin-4-yl)propyl) piperidine derivatives
3(a–i)
A solution of different substituted aromatic ⁄ heterocyclic acids 2(a–
i) (1.0 eq) in dry THF was taken and cooled to 0–5 ꢀC. Then, isobu-
tyl chloroformate (1.3 eq) and N-methyl morpholine (3.0 eq) were
added to the cold reaction mixture. The reaction mixture was stirred
for 15 min at same temperature, then added 4-[3-(piperidin-4-yl)pro-
pyl]piperidine 1 (1.0 eq) to the reaction mixture, and allowed the
reaction mixture at room temperature for 4–5 h with stirring. The
progress of the reaction was monitored by TLC. After completion of
the reaction, water was added and the reaction mixture was fil-
tered, washed with ether, and dried under vacuum.
Synthesis of [3-(cyclopentyloxy)-4-
methoxyphenyl] {4-[3-(piperidin-4-yl)propyl]
piperidin-1-yl}methanone 3d
The product obtained was pale yellow liquid from 3-(cyclopentyl-
oxy)-4-methoxybenzoic acid 2d (0.25 g, 1.05 mmol), isobutyl chloro-
formate (0.18 g, 1.37 mmol), N-methyl morpholine (0.32 g,
3.17 mmol), and 4-[3-(piperidin-4-yl)propyl]piperidine
1 (0.22 g,
1.05 mmol). 1H NMR (DMSO-d6, 400 MHz) d: 7.45 (d, 1H, Ar–H),
7.32 (s, 1H, Ar–H), 6.87 (d, 1H, Ar–H), 3.79 (s, 3H, –OCH3), 3.72 (m,
1H, –CH), 2.88–2.93 (m, 8H), 2.83 (bs, 2H), 2.12 (m, 4H, –CH2), 2.10
(s, 1H, –NH), 1.72 (m, 2H), 1.59 (m, 4H, –CH2), 1.10–1.23 (m, 12H).
MS (ESI) m ⁄ z: 429.31 (M+H+). IR (KBr, ⁄ cm): 3430, 3042, 1641,
1603, 1366, 1190, 1057.
Synthesis of (4-fluoro-3-nitrophenyl) {4-[3-
(piperidin-4-yl)propyl]piperidin-1-yl} methanone
3a
The product obtained was yellow oily from 4-fluoro-3-nitro benzoic
acid 2a (0.25 g, 1.35 mmol), isobutyl chloroformate (0.239 g,
1.79 mmol), N-methyl morpholine (0.409 g, 4.05 mmol), and 4-[3-
(piperidin-4-yl)propyl]piperidine 1 (0.28 g, 1.35 mmol). 1H NMR
(DMSO-d6, 400 MHz) d: 8.81 (s, 1H, Ar–H), 8.28 (d, 1H, Ar–H), 7.56
(d, 1H, Ar–H), 2.93–3.08 (m, 4H), 2.45–2.60 (m, 4H), 2.04 (s, 1H, –
NH), 1.92 (bs, 2H), 1.60 (m, 2H), 1.09–1.31 (m, 12H). MS (ESI) m ⁄ z:
378.21 (M+H+). IR (KBr, ⁄ cm): 3343, 3092, 1671, 1517, 1335, 1256,
1176, 612.
Synthesis of (4-aminophenyl){4-[3-(piperidin-4-
yl)propyl]piperidin-1-yl}methanone 3e
The product obtained was pale yellow liquid from 4-amino-
benzoic acid 2e (0.25 g, 1.82 mmol), isobutyl chloroformate
(0.32 g, 2.37 mmol), N-methyl morpholine (0.55 g, 5.46 mmol), and
Scheme 1: Synthesis of 4-[3-(piperidin-4-yl)propyl]piperidine derivatives. Reagents and conditions: (i) Aromatic ⁄ heterocyclic acids 2(a–i),
isobutyl chloroformate, N-methylmorpholine, tetrahydrofuran, 5–6 h.
Chem Biol Drug Des 2011; 78: 622–630
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