128
D. Zampieri et al. / European Journal of Medicinal Chemistry 44 (2009) 124e130
temperature was allowed to reach room temperature and the
mixture was stirred for additional 1 h. The organic phase
was washed with water, dried over sodium sulphate, filtered
and evaporated under reduced pressure. The oily residue solid-
ificated upon cooling to afford a yellow-light solid: yield
1.72 g (84 %); melting point 76e78 ꢁC.
of acetone was heated under reflux for 5 h. After cooling the
inorganic salts were filtered off and the solvent was evaporated
under reduced pressure. The residue was washed with water,
then with ethyl ether to afford 1a as a chromatographically
pure solid: yield 0.16 g (77%); melting point 126e128 ꢁC.
IR cmꢂ1 (nujol): 1772 cmꢂ1. 1H NMR (CDCl3eTMS) ppm
1
IR cmꢂ1 (nujol): 1690 cmꢂ1; 1168 cmꢂ1; 1360 cmꢂ1. H
0
(d): 1.37e2.03 (m, 7H, H2eH3,3 eH5,5 eH6eH4, pip.); 2.91
0
0
0
NMR (CDCl3eTMS) ppm (d): 1.23 (m, 2H, H3eH5, pip.);
(m, 2H, H2 eH6 , pip.); 3.51 (s, 2H, NeCH2eAr); 3.72 (d,
2H, NeCH2epip.); 6.94e7.40 (m, 9H, arom.). MS: m/z 323
[MHþ]. Anal. calcd. for C20H22N2O2 (MW 322.4): C, 74.51;
H, 6.88; N, 8.69%; found: C, 74.40; H, 6.85; N, 8.60%.
In an analogous way the following compounds 1bel were
similarly obtained.
0
0
1.45 (s, 9H, CH3, Boc); 1.74 (m, 2H, H3 eH5 , pip.); 1.91 (m,
1H, H4, pip.); 2.70 (m, 2H, H2eH6, pip.): 3.01 (s, 3H,
OSO2CH3); 4.06 (d, 2H, pip.eCH2eOSO2CH3); 4.14 (m, 2H,
0
0
H2 eH6 pip.). Anal. calcd. for C12H23NO5S (MW 293.38):
C, 49.13; H, 7.90; N, 4.77%; found: C, 48.90; H, 7.77:
N, 4.65%.
4.1.5. 3-[[1-(2-Chlorobenzyl)piperidin-
4.1.2. 3-[[1-(tert-Butoxycarbonyl)piperidin-
4-yl]methyl]benzo[d]oxazol-2(3H )-one 5
4-yl]methyl]benzo[d]oxazol-2(3H )-one 1b
Yield (%): 74; melting point (ꢁC): 163e167; IR cmꢂ1 (nu-
jol): 1768 cmꢂ1. 1H NMR (CDCl3eTMS) ppm (d): 1.33e2.17
A mixture of 2 (0.8 g, 5.86 mmol), K2CO3 (0.81 g,
5.86 mmol) and 3 (1.72 g, 5.86 mmol) in 50 ml of methyl isobu-
tyl ketone (MIBK) was heated under reflux at 150 ꢁC for 16 h.
After cooling the inorganic salts were filtered off and the solvent
was evaporated under reduced pressure. The residue was ex-
tracted with ethyl acetate (3 ꢃ 50 ml) and the organic phase
was washed with distilled water. The collected organic phases
were dried over sodium sulphate, filtered and concentrated
under reduced pressure. The solid residue was crystallized
from ethanol: yield 1.95 g (70%); melting point 117e119 ꢁC.
0
0
0
0
(m, 7H, H2eH3,3 eH5,5 eH6eH4, pip.); 2.94 (m, 2H, H2 eH6 ,
pip.); 3.61 (s, 2H, NeCH2eAr); 3.73 (d, 2H, NeCH2epip.);
6.93e7.54 (m, 8H, arom.). MS: m/z 357 [MHþ], 359
[MHþ þ 2]. Anal. calcd. for C20H21ClN2O2 (MW 356.85):
C, 67.32; H, 5.93; N, 7.85%; found: C, 67.50; H, 6.15; N,
7.90%.
4.1.6. 3-[[1-(4-Chlorobenzyl)piperidin-
4-yl]methyl]benzo[d]oxazol-2(3H )-one 1c
IR cmꢂ1 (nujol): 1681 cmꢂ1; 1781 cmꢂ1 1H NMR
.
(CDCl3eTMS) ppm (d): 1.31 (m, 2H, H3eH5, pip.); 1.46 (s,
Yield (%): 65; melting point (ꢁC): 122e127; IR cmꢂ1 (nu-
jol): 1772 cmꢂ1. 1H NMR (CDCl3eTMS) ppm (d): 1.30e2.04
0
0
9H, CH3, Boc); 1.70 (m, 2H, H3 eH5 , pip.); 2.07 (m, 1H,
0
0
0
0
(m, 7H, H2eH3,3 eH5,5 eH6eH4, pip.); 2.88 (m, 2H, H2 eH6 ,
pip.); 3.46 (s, 2H, NeCH2eAr); 3.72 (d, 2H, NeCH2epip.);
6.94e7.34 (m, 8H, arom.). MS: m/z 357 [MHþ], 359
[MHþ þ 2]. Anal. calcd. for C20H21ClN2O2 (MW 356.85):
C, 67.32; H, 5.93; N, 7.85%; found: C, 67.45; H, 5.95; N,
7.60%.
H4, pip.); 2.70 (m, 2H, H2eH6, pip.); 3.72 (d, 2H, NeCH2e
0
0
pip.); 4.15 (m, 2H, H2 eH6 , pip.); 6.94e7.27 (m, 4H,
arom.). Anal. calcd. for C18H24N2O4 (MW 332.39): C,
65.04; H, 7.28; N, 8.43%; found: C, 64.90; H, 7.15; N,
8.30%.
4.1.3. 3-[(Piperidin-4-yl)methyl]benzo[d]oxazol-
2(3H )-one 6
4.1.7. 3-[[1-(2,4-Dichlorobenzyl)piperidin-
4-yl]methyl]benzo[d]oxazol-2(3H )-one 1d
Compound 5 (1.0 g, 3.00 mmol) was deprotected with 2 ml
of trifluoroacetic acid at room temperature, overnight. The so-
lution was concentrated at reduced pressure and the residue
was poured into water and basified with NaOH 10% solution
(pH 10). The white solid precipitate was filtered, washed
with water and used without further purification: 0.65 g
(93%); melting point 124e126 ꢁC.
Yield (%): 84; melting point (ꢁC): 169e174; IR cmꢂ1 (nu-
jol): 1769 cmꢂ1. 1H NMR (CDCl3eTMS) ppm (d): 1.32e2.17
0
0
0
0
(m, 7H, H2eH3,3 eH5,5 eH6eH4, pip.); 2.90 (m, 2H, H2 eH6 ,
pip.); 3.56 (s, 2H, NeCH2eAr); 3.73 (d, 2H, NeCH2epip.);
6.93e7.49 (m, 7H, arom.). MS: m/z 391 [MHþ], 393
[MHþ þ 2]. Anal. calcd. for C20H20Cl2N2O2 (MW 391.29):
C, 61.39; H, 5.15; N, 7.16%; found: C, 61.55; H, 5.00; N,
7.30%.
IR cmꢂ1 (nujol): 1765 cmꢂ1. 1H NMR (CDCl3eTMS) ppm
0
(d): 1.20e188 (m, 4H, H3,3 eH5,5 , pip.); 2.06 (m, 1H, H4,
0
0
0
pip.); 2.50e3.30 (m, 4H, H2,2 eH6,6 , pip.); 3.72 (d, 2H, Ne
CH2epip.); 3.86 (br s, 1H, NH, disappearing on deuteration);
6.96e7.30 (m, 4H, arom.). Anal. calcd. for C13H16N2O2 (MW
232.29): C, 67.22; H, 6.94; N, 12.06%; found: C, 67.00; H,
6.85; N, 12.00%.
4.1.8. 3-[[1-(2-Fluorobenzyl)piperidin-
4-yl]methyl]benzo[d]oxazol-2(3H )-one 1e
Yield (%): 64; melting point (ꢁC): 137e140; IR cmꢂ1 (nu-
jol): 1770 cmꢂ1. 1H NMR (CDCl3eTMS) ppm (d): 1.31e2.10
0
0
0
0
(m, 7H, H2eH3,3 eH5,5 eH6eH4, pip.); 2.93 (m, 2H, H2 eH6 ,
pip.); 3.58 (s, 2H, NeCH2eAr); 3.72 (d, 2H, NeCH2epip.);
6.93e7.45 (m, 8H, arom.). MS: m/z 341 [MHþ]. Anal. calcd.
for C20H21FN2O2 (MW 340.39): C, 70.57; H, 6.22; N, 8.23%;
found: C, 70.50; H, 6.15; N, 8.10%.
4.1.4. 3-[(1-Benzylpiperidin-4-yl)methyl]benzo[d]
oxazol-2(3H )-one 1a
A mixture of 7 (0.15 g, 0.64 mmol), K2CO3 (0.09 g,
0.64 mmol) and benzylchloride (0.08 g, 0.64 mmol) in 50 ml