Benzoxazoles as 5-HT3 Receptor Partial Agonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16 3019
(3H, s), 2.65-2.77 (2H, m), 2.78-2.81 (2H, m), 3.76-3.83 (4H,
m), 7.02 (1H, t, J ) 8 Hz), 7.16 (1H, t, J ) 8 Hz), 7.26 (1H, d,
J ) 8 Hz), 7.30 (1H, d, J ) 8 Hz). MS (EI) m/z: 231 (M+). IR
(KBr, cm-1): 1638, 1578, 1250. Anal. (C13H17N3O) C, H, N.
5-Ch lor o-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6g).
P r oced u r es C17 a n d D. This procedure illustrates the
general method of preparation of compounds 6b-e. 2-Amino-
4-chlorophenol (8g; 10 g, 70 mmol) was refluxed for 8 h with
potassium hydroxide (4.7 g, 84 mmol) and carbon disulfide (100
mL) in ethanol (150 mL). The reaction mixture was concen-
trated in vacuo; 1 N aqueous hydrochloric acid (100 mL) and
ethyl acetate (200 mL) were added to the residue. The organic
layer was washed with water (100 mL), dried over MgSO4, and
concentrated in vacuo. The 11.5 g of 5-chloro-2-mercaptoben-
zoxazole (9g) was obtained as a yellow powder and used in
the next reaction without further purification.
Phosphorus pentachloride (1.35 g, 6.5 mmol) was added to
the solution of 5-chloro-2-mercaptobenzoxazole (9g; 1 g, 5.4
mmol) in dry toluene (50 mL) at 20 °C. The reaction mixture
was stirred at 120 °C for 1 h and cooled in an ice bath.
1-Methylpiperazine (5.4 g, 54 mmol) was added dropwise to
the mixture, and the mixture stirred for 30 min at 0 °C. The
reaction mixture was diluted with chloroform (100 mL) and
washed with water. The organic layer was dried over MgSO4
and concentrated in vacuo. The residue was chromatographed
on silica gel with chloroform-methanol (20:1) to give 6g (1 g,
67% from 8g) as a white needle, mp 118-119 °C (acetone-
hexane). NMR (CD3OD) δ: 2.34 (3H, s, CH3-), 2.57 (4H, t, J
) 5 Hz, piperazine -CH2- × 2), 3.71 (4H, t, J ) 5 Hz,
piperazine -CH2- × 2), 7.03 (1H, d, J ) 7 Hz, benzoxazole
6-H), 7.22 (1H, s, benzoxazole 4-H), 7.26 (1H, d, J ) 7 Hz,
benzoxazole 7-H). MS (EI) m/z: 251 (M+). IR (KBr, cm-1):
1634, 1574, 1449, 1398, 1368, 1356. Anal. (C12H14N3OCl) C,
H, N.
4-Meth yl-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6b):
obtained as a colorless oil, 461 mg, 68% yield from 2-amino-
m-cresol. NMR (CDCl3) δ: 2.35 (3H, s), 2.49 (3H, s), 2.52 (4H,
t, J ) 5 Hz), 3.72 (4H, t, J ) 5 Hz), 6.92 (1H, t, J ) 7 Hz), 6.97
(1H, d, J ) 7 Hz), 7.08 (1H, d, J ) 7 Hz). MS (EI) m/z: 231
(M+). IR (neat, cm-1): 1620, 1590, 1489, 1454, 1306, 1277.
HR-MS Calcd for C13H18N3O: 232.1450. Found: 232.1443.
5-Meth yl-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6c):
obtained as a yellow plate, 1.8 g, 73% yield from 2-amino-p-
cresol, mp 63-64 °C (methanol-ether). NMR (CDCl3) δ: 2.35
(3H, s), 2.39 (3H, s), 2.52 (4H, t, J ) 5 Hz), 3.71 (4H, t, J ) 5
Hz), 6.82 (1H, d, J ) 8 Hz), 7.11 (1H, d, J ) 8 Hz), 7.15 (1H,
s). MS (EI) m/z: 231 (M+). IR (KBr, cm-1): 1638, 1586, 1451,
1356. Anal. (C13H17N3O‚1/8H2O) C, H, N.
6-Meth yl-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6d ):
obtained as a white needle, 166 mg, 50% yield from 6-amino-
m-cresol, mp 62-63 °C (methanol-ether). NMR (CDCl3) δ:
2.35 (3H, s), 2.40 (3H, s), 2.52 (4H, t, J ) 5 Hz), 3.70 (4H, t, J
) 5 Hz), 6.97 (1H, d, J ) 8 Hz), 7.07 (1H, s), 7.23 (1H, d, J )
8 Hz). MS (EI) m/z: 231 (M+). IR (KBr, cm-1): 1650, 1578,
1489, 1397. Anal. (C13H17N3O) C, H, N.
illustrates the general method of preparation of compounds
6f,h ,m -q,u . 4-Chloro-2-methyl-6-nitrophenol30 (7v; 2.0 g, 10.7
mmol) was dissolved in ethyl acetate (60 mL), and 5% platinum
on sulfide carbon (60 mg; Aldrich Chemical Co.) was added to
the solution. The reaction mixture was stirred under a
hydrogen atmosphere for 24 h, and platinum on sulfide carbon
was removed by filtration. The solution was concentrated in
vacuo. The 1.7 g of 2-amino-4-chloro-6-methylphenol (8v) was
obtained as a brown powder and used in the next reaction
without further purification.
2-Amino-4-chloro-6-methylphenol (8v; 1.68 g, 10.7 mmol)
was treated as described for the preparation of 9g to afford
893 mg of 5-chloro-2-mercapto-7-methylbenzoxazole (9v) as a
light-brown needle, mp 233-234 °C (methanol-ether). NMR
(CDCl3) δ: 2.43 (3H, s), 6.98 (1H, s), 7.03 (1H, s). MS (EI)
m/z: 199 (M+). IR (KBr, cm-1): 1609, 1514, 1443, 1339. Anal.
Calcd for C8H6NOClS: C, 48.13; H, 3.03; N, 7.02. Found: C,
48.02; H, 2.90; N, 6.90.
5-Chloro-2-mercapto-7-methylbenzoxazole 9v (200 mg, 1.00
mmol) and 1-methylhomopiperazine (0.55 mL, 5.0 mmol) were
dissolved by toluene (10 mL). The mixture was refluxed for
16 h and evaporated. The residue was chromatographed on
silica gel with dichloromethane-methanol (10:1) to give 6v
(260 mg, 33% from 7v) as a white needle, mp 116-117 °C
(water-methanol). NMR (CDCl3) δ: 2.00-2.07 (2H, m, homo-
piperazine 6-CH2), 2.37 (3H, s, homopiperazine 1-CH3), 2.40
(3H, s, benzoxazole 7-CH3), 2.63 (2H, t, J ) 5 Hz, homo-
piperazine -CH2-), 2.74 (2H, t, J ) 5 Hz, homopiperazine
-CH2-), 3.79 (2H, t, J ) 5 Hz, homopiperazine -CH2-), 3.85
(2H, t, J ) 6 Hz, homopiperazine -CH2-), 6.78 (1H, d, J ) 2
Hz, benzoxazole 6-H), 7.13 (1H, d, J ) 2 Hz, benzoxazole 4-H).
MS (TSP) m/z: 280 (M+ + 1), 282 (M+ + 3). IR (KBr, cm-1):
1642, 1622, 1572, 1458. Anal. (C14H18N3OCl) C, H, N.
5-F lu or o-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6f):
obtained as a white needle, 207 mg, 70% yield from 4-fluoro-
2-nitrophenol,31 mp 116-117 °C (ether-hexane). NMR (CDCl3)
δ: 2.35 (3H, s), 2.52 (4H, t, J ) 5 Hz), 3.72 (4H, t, J ) 5 Hz),
6.71 (1H, dt, J ) 2, 9 Hz), 7.04 (1H, dd, J ) 2, 9 Hz), 7.14 (1H,
dd, J ) 4, 9 Hz). MS (EI) m/z: 235 (M+). IR (KBr, cm-1):
1640, 1578, 1476, 1464. Anal. (C12H14N3OF) C, H, N.
5-Br om o-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6h ):
obtained as a white needle, 178 mg, 60% yield from 4-bromo-
2-nitrophenol,31 mp 100-101 °C (ether-hexane). NMR (CDCl3)
δ: 2.36 (3H, s), 2.47 (3H, s), 2.53 (4H, t, J ) 5 Hz), 3.74 (4H,
t, J ) 5 Hz), 7.26 (1H, s). MS (TSP) m/z: 296 (M+), 298 (M+
+ 2). IR (KBr, cm-1) 1636, 1568, 1460, 1366. Anal. (C12H14N3-
OBr) C, H, N.
5-Ch lor o-7-m eth yl-2-(4-m eth yl-1-p ip er a zin yl)ben zox-
a zole (6m ): obtained as a yellow plate, 270 mg, 85% yield from
4-chloro-2-methyl-6-nitrophenol,31 mp 62-64 °C (ether-hex-
ane). NMR (CDCl3) δ: 2.36 (3H, s), 2.37 (3H, s), 2.53 (4H, t,
J ) 5 Hz), 3.72 (4H, t, J ) 5 Hz), 6.81 (1H, d, J ) 2 Hz), 7.14
(1H, d, J ) 2 Hz). MS (TSP) m/z: 266 (M+ + 1), 268 (M+ + 3).
IR (KBr, cm-1): 1644, 1626, 1576, 1449, 1410, 1356. Anal.
(C13H16N3OCl) C, H, N.
7-Meth yl-2-(4-m eth yl-1-p ip er a zin yl)ben zoxa zole (6e).
2-Methyl-6-nitrophenol28 (7e; 880 mg, 5.75 mmol) was dis-
solved in ethanol (25 mL), and 10% palladium-carbon (90 mg)
was added to the solution. The reaction mixture was stirred
under a hydrogen atmosphere for 24 h, and palladium-carbon
was removed by filtration. The solution was concentrated in
vacuo. The 730 mg of 2-amino-6-methylphenol (8e) was
obtained as a brown powder and used in the next reaction
without further purification.
2-Amino-6-methylphenol (8e; 700 mg, 5.69 mmol) was
treated as described for the preparation of 6g to afford 6e as
a yellow oil, 392 mg, 70% yield from 7e. NMR (CDCl3) δ: 2.36
(3H, s), 2.42 (3H, s), 2.53 (4H, t, J ) 5 Hz), 3.73 (4H, t, J ) 5
Hz), 6.83 (1H, d, J ) 8 Hz), 7.06 (1H, t, J ) 8 Hz), 7.19 (1H,
d, J ) 8 Hz). MS (EI) m/z: 231 (M+). IR (neat, cm-1): 1650,
1580, 1450, 1270, 1150. HR-MS Calcd for C13H18N3O: 232.1450.
Found: 232.1448.
5,7-Dich lor o-2-(4-m et h yl-1-p ip er a zin yl)b en zoxa zole
(6n ): obtained as a yellow needle, 90 mg, 37% yield from 2,4-
dichloro-6-nitrophenol, mp 106-107 °C (hexane). NMR (CDCl3)
δ: 2.36 (3H, s), 2.53 (4H, t, J ) 5 Hz), 3.75 (4H, t, J ) 5 Hz),
7.00 (1H, d, J ) 2 Hz), 7.18 (1H, d, J ) 2 Hz). MS (EI) m/z:
285 (M+), 287 (M+ + 2), 289 (M+ + 4). IR (KBr, cm-1): 1638,
1572, 1447, 1300, 1273, 1143. Anal. (C12H13N3OCl2) C, H, N.
5-Ch lor o-6-m eth yl-2-(4-m eth yl-1-p ip er a zin yl)ben zox-
a zole (6o): obtained as a yellow needle, 170 mg, 65% yield
from 4-chloro-5-methyl-2-nitrophenol,32 mp 115-116 °C (ether-
hexane). NMR (CDCl3) δ: 2.35 (3H, s), 2.39 (3H, s), 2.51 (4H,
t, J ) 5 Hz), 3.70 (4H, t, J ) 5 Hz), 7.10 (1H, s), 7.31 (1H, s).
MS (TSP) m/z: 266 (M+ + 1), 268 (M+ + 3). IR (KBr, cm-1):
1630, 1568, 1451, 1267. Anal. (C13H16N3OCl) C, H, N.
4-Ch lor o-2,3-d im eth ylp h en ol.33 Ether (3.7 g, 50 mmol)
was added slowly at 20 °C to a stirred solution of 2,3-xylenol
(6.1 g, 50 mmol) and sulfuryl chloride (6.8 g, 50 mmol) in
dichloromethane (50 mL). The reaction mixture was stirred
for 30 min at room temperature and evaporated. The residue
5-Ch lor o-7-m eth yl-2-(4-m eth yl-1-h om opiper azin yl)ben -
zoxa zole (6v). P r oced u r es B, C, a n d E. This procedure