B. S. Priya et al. / Bioorg. Med. Chem. 13 (2005) 2623–2628
2627
crude acid chlorides were taken directly to the next
reactions.
5.1.6. Synthesis of [4-(6-fluoro-benzo[d]isoxazol-3-yl)-pip-
eridin-1-yl]-pyridin-2-yl-methanone 4IV. It was obtained
from
(0.2g, 0.909 mmol), picolinic acid chloride (0.134 g,
6-fluoro-3-piperidin-4yl-benzo[d]isoxazole
3
5
.1.2. General procedure for the synthesis of 1,2-benzis-
oxazole substituted amides. A solution of amine 3
1 equiv) in dichloroethane was taken and cooled to
ꢁC. The crude acid chloride (1.2equiv) was added
1.0908 mmol), and triethylamine (0.551 g, 5.454 mmol).
The product obtained was oily. IR (cm Nujol):
1624.1, 1510, 1480, 1060. H NMR (CDCl , 400 MHz)
À1
(
0
1
3
dropwise and triethylamine was added at the same tem-
perature. The reaction mixture was stirred for another
1
to room temperature. After completion of the reaction,
the solvent was evaporated under vacuum and extracted
with dichloroethane thrice. The organic layer was
d: 1.8–1.95 (q, 4H), 2.5 (m, 1H), 3.46 (t, 4H), 6.97 (s,
1H, Ar–H), 7.25–7.30 (dd, 1H, Ar–H), 7.34–7.38 (d,
1H, Ar–H), 7.64–7.7 (t, 1H, Ar–H), 7.81–7.85 (t, 1H,
Ar–H), 8.6 (d, 1H, J = 10 Hz, Ar–H), 8.12(d, 1H, Ar–
H). Anal. Calcd CHN: 66.461, 4.923, 12.923. Found
66.321, 4.965, 12.894.
h at 0 ꢁC. The reaction mass was gradually allowed
washed with 5% HCl solution and 10% NaHCO solu-
3
tion in order to remove unreacted amines and acids,
respectively. Finally water wash was given to the organic
layer and dried with anhydrous sodium sulfate, evapo-
rated the solvent. Using appropriate mixture of solvent
like benzene, n-hexane, ethylacetate as eluent in silica
gel column, pure product was separated.
5.1.7. Synthesis of (2-chloro-phenyl)-[4-(6-fluoro-
benzo[d]isoxazol-3-yl)-piperidin-1-yl]-methanone 4V. It
was obtained from 6-fluoro-3-piperidin-4yl-benzo-
[d]isoxazole 3 (0.2g, 0.909 mmol), 2- chloro benzoyl
chloride (0.170 g, 1.0908 mmol) and triethylamine
(0.551 g, 5.454 mmol). The product obtained was oily.
À1
1
IR (cm Nujol): 1670, 1492, 1450, 1244. H NMR
(CDCl , 400 MHz) d: 1.65 (q, 4H), 3.12–3.2 (m, 1H),
5
[
.1.3. Synthesis of (2-ethoxy-phenyl)-[4-(6-fluoro-benzo-
d]isoxazole-3-yl)-piperidin-1-yl]-methanone 4I. It was
3
3.72(t, 4H), 7.39 (t, 1H, Ar–H), 7.74 (d, 1H,
J = 12Hz, Ar–H), 6.9 (s, 1H, Ar–H), 6.96–7.02(d, 1H,
Ar–H), 7.05–7.11 (dd, 1H, Ar–H), 7.6–7.67 (t, 1H, Ar–
H). 7.15–7.2(d, 1H, Ar–H). Anal. Calcd CHN:
63.598, 4.463, 7.810. Found 63.556, 4.461, 7.825.
obtained from 6-fluoro-3-piperidin-4yl-benzo[d]isoxaz-
ole 3 (0.2g, 0.909 mmol), 2- ethoxybenzoyl chloride
(
0.201 g, 1.09 mmol), and triethylamine (0.551 g,
5
.454 mmol). The product obtained was pure white
solid. IR (cm Nujol): 1620.1, 1454.2, 1492.8, 1348.1,
À1
1
1
3
4
7
244, 1043.4. H NMR (CDCl , 400 MHz) d: 1.42(t,
5.1.8. Synthesis of (2,3-dichloro-phenyl)-[4-(6-fluoro-
benzo[d]isoxazol-3-yl)-piperidin-1-yl]-methanone 4VI. It
was obtained from 6-fluoro-3-piperidin-4yl-benzo-
[d]isoxazole 3 (0.2g, 0.909 mmol), 2, 3-dichloro benzoyl
chloride (0.209 g, 1.0908 mmol), and triethylamine
(0.551 g, 5.454 mmol). The product obtained was yellow
3
H), 1.65 (q, 2H), 3.0–3.18 (m, 1H), 3.53 (q, 4H),
.02–4.15 (t, 2H), 6.9 (d, 1H, J = 18 Hz, Ar–H), 6.96–
.02(t, 2H , Ar–H), 7.4 (t, 1H, Ar–H), 7.8 (d, 1H, Ar–
H), 6.85 (s, 1H, Ar–H), 7.6–7.67 (dd, 1H, J = 2Hz,
J = 13 Hz, Ar–H). Anal. Calcd CHN: 68.478, 5.706,
À1
1
7
.608. Found 68.602, 5.689, 7.312.
solid. IR (cm Nujol): 1656.9, 1480, 1440, 1228.6. H
NMR (CDCl , 400 MHz) d: 1.98 (q, 4H), 3.14 (t, 4H),
3
5.1.4. Synthesis of [4-(6-fluoro-benzo[d]isoxazole-3yl)-
piperidin-1-yl]-(6-fluoro-chroman-2yl)-methanone 4II. It
4.13–4.29 (m, 1H), 6.75 (s, 1H, Ar–H), 7.32 (t, 1H,
Ar–H), 7.35 (d, 1H, Ar–H), 7.45 (dd, 1H, Ar–H), 7.52
(t, 1H, Ar–H), 7.24 (d, 1H, Ar–H). Anal. Calcd CHN:
58.015, 3.817, 7.12. Found 58.142, 3.792, 7.20.
was obtained from 6-fluoro-3-piperidin-4yl-benzo-
[
d]isoxazole 3 (0.2g, 0.909 mmol), nebulic acid chloride
0.213 g, 1.0908 mmol), and triethylamine (0.551 g,
(
5
yellow solid. IR (cm Nujol): 1640, 1434.9, 1515.9,
.454 mmol). The product obtained was brownish
5.1.9. Synthesis of 6-fluoro-chroman-2-carboxylic acid (4-
chloro-3-trifluoromethyl-phenyl)-amide 6I. It was ob-
tained from 5-amino-2-chloro-benzotrifluoride (0.2 g,
1.022 mmol), nebulic acid chloride (0.24 g, 1.227 mmol),
and triethyl amine (0.62g, 6.132mmol). The product
À1
1
1
060. H NMR (CDCl , 400 MHz) d: 1.8 (q, 4H), 3.4
3
(
t, 4H), 2.5–2.6 (t, 2H, chroman-CH ), 2.6–2.8 (m,
2
1
(
7
H), 2.2 (q, 2H), 4.4 (t, 2H), 6.78 (s, 1H, Ar–H), 6.65
d, 1H, Ar–H), 6.9 (d, 1H, Ar–H), 7.31 (d, 1H, Ar–H),
.12(d, 1H, Ar–H), 7.4 (s, 1H, Ar–H). Anal. Calcd
CHN: 66.331, 5.02, 7.035. Found 66.521, 4.98, 7.21.
À1
obtained was oily. IR (cm Nujol): 3360, 1640, 1458.
1
H NMR (CDCl , 400 MHz) d: 2.42 (t, 2H), 2.12–2.2
3
(q, 2H), 4.1 (t, 2H), 3.12 (s, 1H, –NH), 7.39 (d, 1H,
Ar–H), 7.74 (s, 1H, Ar–H), 6.9 (d, 1H, Ar–H), 6.96–
7.02(dd, 1H, J = 8 Hz, Ar–H), 7.05–7.11 (t, 1H, Ar–
H), 7.5 (dd, 1H, Ar–H). Anal. Calcd CHN: 54.618,
3.212, 3.748. Found 54.653, 3.199, 3.792.
5
.1.5. Synthesis of [4-(6-fluoro-benzo[d]isoxazole-3-yl)-
piperidin-1-yl]-pyridin-3-yl-methanone 4III. It was ob-
tained from 6-fluoro-3-piperidin-4yl-benzo[d]isoxazole
3
(0.2g, 0.909 mmol), nicotinic acid chloride (0.134 g,
.0908 mmol), and triethylamine (0.551 g, 5.454 mmol).
1
The product obtained was pale yellow solid. IR (cm
5.1.10. Synthesis of 6-fluoro-chroman-2-carboxylic acid
(4-nitro-3-trifluoromethyl-phenyl)-amide 6II. It was ob-
tained from 5-amino-2-nitro-benzotrifluoride (0.2 g,
À1
1
Nujol): 1654, 1480, 1440, 1210. H NMR (CDCl3,
4
6
6
1
00 MHz) d: 1.65 (q, 4H), 2.9 (m, 1H), 3.46 (t, 4H),
.85 (d, 1H, Ar–H), 7.24–7.28 (dd, 1H, Ar–H), 6.90–
.95 (s, 1H, Ar–H), 7.34–7.48 (t, 1H, Ar–H), 7.82(d,
H, Ar–H), 7.99 (dd, 2H, Ar–H), 8.59–8.62 (s, 1H,
0.970 mmol),
nebulic
acid
chloride
(0.228 g,
1.1643 mmol), and triethyl amine (0.589 g, 5.82mmol).
The product obtained was white crystalline solid. IR
(cm
À1
1
Nujol): 3320, 1660, 1425, 1594. H NMR
Ar–H). Anal. Calcd CHN: 66.461, 4.923, 12.923. Found
6.625, 4.879, 12.982.
(CDCl , 400 MHz) d: 2.1 (q, 2H), 2.9 (t, 2H), 3.46
(m, 1H), 4.1 (s, 1H, –NH), 6.65–6.70 (d, 1H, Ar–H),
3
6