Notes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3427
precipitate of aluminum hydroxide. The reaction mixture was
diluted with 30 mL of ether while stirring continued for 15
min. The white precipitate was separated by suction filtration,
and the filtrate was evaporated to give 1.21 g (90%) of a viscous
white product. The crude product was passed through a silica
gel column and eluted with ethyl acetate/hexanes (1:3) to give
a light yellow foamy solid (1.13 g, 85%). The HBr salt was
formed by bubbling HBr gas into an ether solution of the
product. Upon evaporating the solvent, a light yellow solid
was obtained which was recrystallized from 2-PrOH/ether to
give pure 5a (1.10 g, 77%): mp 165-168 °C dec; 1H NMR
(CDCl3) δ 7.40-7.25 (m, 5H1-Ph), 7.15 (d, 2Hcinnamyl-Ph, J ) 7),
7.13 (s, 1HH9), 6.83 (d, 2Hcinnamyl-Ph, J ) 8), 6.40 (d, 1H, J ) 16
for trans vinylic hydrogen), 6.30 (s, 1HH6), 6.15-6.01 (m, 1H
vinylic), 4.30 (dd, 1H, J ) 5.3, 3.3), 3.62 (s, 3H), 3.40-3.05 (m,
(()-7-Br om o-8-h yd r oxy-3-tr a n s-[4′-(N,N-d im eth yla m i-
n o)cin n a m yl]-1-p h en yl-2,3,4,5-t et r a h yd r o-1H -3-b en za -
zep in e (6b). Compound 6b was prepared (0.4 g, 1.0 mmol,
70%) from 5b according to the procedure described for the
synthesis of 6a . The crude product was passed through a silica
gel column and eluted with ethyl acetate/hexanes (1:3) to give
a white foam. The HBr salt was formed by bubbling HBr gas
into an ether solution of the product. Upon evaporating the
solvent, a light pink solid was obtained which was recrystal-
lized from 2-PrOH/ether to give pure 6b (0.40 g, 70%): mp
160-163 °C dec; 1H NMR (CDCl3) δ 7.40-7.25 (m, 5H1-Ph),
7.21 (s, 1HH9), 7.11 (d, 2Hcinnamyl-Ph, J ) 7.3), 6.65 (d, 2Hcinnamyl-Ph
,
J ) 7.3), 6.42 (d, 1H, J ) 18 for trans vinylic hydrogen), 6.25
(s, 1HH6), 6.11-6.01 (m, 1Hvinylic), 4.25 (dd, 1H, J ) 5.0, 3.3),
3.35-3.00 (m, 4H), 2.95 (s, 6H), 2.82-2.31 (m, 6H); IR 3000,
2675 (hydrogen-bonded OH group) 1601, 1490 cm-1
. Anal.
4H), 2.95 (s, 6H), 2.85-2.4 (m, 6H); IR 2990, 1590, 1490 cm-1
Anal. (C28H33N2OClBr2‚H2O) C, H, N.
.
(C27H31N2OBr3‚H2O) C, H, N.
(()-7-Ch lor o-8-h yd r oxy-3-[2-[4′-(N,N-d im eth yla m in o)-
p h en yl]et h yl]-1-p h en yl-2,3,4,5-t et r a h yd r o-1H -3-b en za -
zep in e (6c). The O-demethylation of 5c was performed under
the same conditions as for 6a using BBr3 to give 6c (0.91 g,
75%). The crude product was purified by flash column
chromatography (CHCl3/MeOH/NH4OH, 95:4.5:0.5) to give
0.80 g (70%) of a white viscous product. The HCl salt was
formed by bubbling HCl gas into an ether solution of the
product. Upon evaporating the solvent, a white solid was
obtained which was recrystallized from 2-PrOH/ether to give
pure 6c (0.70 g, 65%): mp 98-100 °C; 1H NMR (CDCl3) δ 7.30
(()-7-Br om o-8-m eth oxy-3-tr a n s-[4′-(N,N-d im eth yla m i-
n o)cin n a m yl]-1-p h en yl-2,3,4,5-t et r a h yd r o-1H -3-b en za -
zep in e (5b). Compound 5b was prepared (1.50 g, 3.1 mmol,
85%) from 4b according to the procedure described for the
synthesis of 5a . The crude product was passed through a silica
gel column and eluted with chloroform to give a light yellow
foamy solid. The HBr salt was formed by bubbling HBr gas
into an ether solution of the product. Upon evaporating the
solvent, a light yellow solid was obtained which was recrystal-
lized from 2-PrOH/ether to give pure 5b (1.41 g, 82%): mp
1
150-153 °C; H NMR (CDCl3) δ 7.40-7.25 (m, 5H1-Ph), 7.19
(t, 2H1-Ph, J ) 7.2), 7.25 (t, 1H1-Ph, J ) 7.3), 7.21 (d, 2H1-Ph
,
(s, 1HH9), 7.15 (d, 2Hcinnamyl-Ph, J ) 7), 6.83 (d, 2Hcinnamyl-Ph, J
) 8), 6.41 (d, 1H, J ) 16 for trans vinylic hydrogen), 6.11-
6.00 (m, 1Hvinylic), 4.30 (dd, 1H, J ) 5.2, 3.3), 3.62 (s, 3H), 3.4-
3.05 (m, 4H), 2.91 (s, 6H), 2.82-2.42 (m, 6H); IR 2995, 1580,
1495 cm-1. Anal. (C28H33N2OBr3‚1.5H2O) C, H, N.
J ) 7.0), 7.15 (s, 1HH9), 7.05 (d, 2Hcinnamyl-Ph, J ) 7.0), 6.65 (d,
2Hcinnamyl-Ph, J ) 8.0), 6.20 (s, 1HH6), 4.15 (dd, 1H, J ) 5.1,
3.0), 3.10-3.00 (m, 4H), 2.9 (s, 6H), 2.80-2.41 (m, 6H); IR
3010, 2660 (hydrogen-bonded OH group) 1591, 1480 cm-1
.
Anal. (C26H31N2OCl3‚0.5H2O) C, H, N.
(()-7-Ch lor o-8-m eth oxy-3-[2-[4′-(N,N-d im eth yla m in o)-
p h en yl]et h yl]-1-p h en yl-2,3,4,5-t et r a h yd r o-1H -3-b en za -
zep in e (5c). The reduction of the amide 4c was performed
under the same conditions as for 5a using AlH3 to give 5c (2.90
g, 7.1 mmol). The crude product was purified by flash column
chromatography (CHCl3/MeOH/NH4OH, 95:4.5:0.5) to give
2.11 g (60%) of a white viscous product: 1H NMR (CDCl3) δ
(()-7-Br om o-8-h yd r oxy-3-cin n a m yl-1-p h en yl-2,3,4,5-
tetr a h yd r o-1H-3-ben za zep in e (7). Into a solution of 2b
(0.70 g, 2.1 mmol) in 20 mL of DMF, 1 mL of H2O, and K2CO3
(0.30 g, 2.2 mmol) was added dropwise a solution of cinnamyl
bromide (0.44 g, 2.2 mmol) in 5 mL of DMF.23 After the
mixture stirred for 8 h, the reaction was quenched with 40
mL of H2O and the solution was then extracted with 50 mL of
ether. The ether layer was washed with H2O (2 × 25 mL) and
brine (25 mL), dried, and evaporated. The crude product was
purified by flash column chromatography, eluting with CHCl3/
MeOH/NH4OH (98:2:0.5) to give 0.60 g (60%) of a white viscous
product as 7-chloro-8-methoxy-3-cinnamyl-1-phenyl-2,3,4,5-
tetrahydro-1H-3-benzazepine: 1H NMR (CDCl3) δ 7.40-7.20
(m, 9Haromatic), 7.15 (d, 2Hcinnamyl-Ph, J ) 7), 6.50 (d, 1H, J ) 15
for trans vinylic hydrogen), 6.25 (s, 1HH6), 6.31-6.21 (m,
1Hvinylic), 4.30 (dd, 1H, J ) 5.1, 3.0), 3.60 (s, 3H), 3.30 (dd,
7.35 (t, 2H1-Ph, J ) 7.2), 7.3 (t, 1H1-Ph, J ) 7.3), 7.2 (d, 2H1-Ph
,
J ) 7.0), 7.15 (s, 1HH9), 7.05 (d, 2Hcinnamyl-Ph, J )7.0), 6.65 (d,
2Hcinnamyl-Ph, J ) 8.0), 6.2 (s, 1HH6), 4.15 (dd, 1H, J ) 5.2, 3.3),
3.62 (s, 3H), 3.11-3.01 (m, 4H), 2.92 (s, 6H), 2.80-2.40 (m,
6H); IR 3010, 1595, 1480 cm-1
.
(()-7-Ch lor o-8-h yd r oxy-3-tr a n s-[4′-(N,N-d im eth yla m i-
n o)cin n a m yl]-1-p h en yl-2,3,4,5-t et r a h yd r o-1H -3-b en za -
zep in e (6a ). O-Demethylation was performed starting with
a 1.30 g (1.3 mmol) portion of 5a which was dissolved in dry
CHCl3 (10 mL), and then 5.0 mL of BBr3 (1 M solution in CH2-
Cl2) was added at 0 °C under an atmosphere of argon. The
reaction mixture was allowed to stir for 1 h at room temper-
ature, and then 10 mL of MeOH (anhydrous) was added
dropwise at 0 °C. After refluxing the reaction mixture in an
open-mouthed reaction flask for 20 min, the solvents were
evaporated. The product was dissolved in 20 mL of ethyl
acetate/methanol (95:5), basified with 10% aqueous NaOH
solution (pH ) 7.5-8.0), diluted with 20 mL of ether, and
separated. The aqueous phase was extracted with ethyl
acetate/ether (9:1) mixture (2 × 20 mL). The combined organic
phase was washed with brine (20 mL), dried, filtered, and
evaporated to give 1.10 g (80%) of a foam. The crude product
was chromatographed by silica gel column and eluted with
ethyl acetate/hexanes (1:2) to give a white foamy solid (1.01
g, 75%). The HBr salt was formed by bubbling HBr gas into
an ether solution of the product. Upon evaporating the
solvent, a white solid was obtained which was recrystallized
from 2-PrOH/ether to give pure 6a (1.01 g, 70%): mp 180-
183 °C dec; 1H NMR (CDCl3) δ 7.40-7.25 (m, 5H1-Ph), 7.11 (d,
2Hcinnamyl-Ph, J ) 7), 7.05 (s, 1HH9), 6.65 (d, 2H, 2Hcinnamyl-Ph, J
) 7.0), 6.35 (d, 1H, J ) 18 for trans vinylic hydrogen), 6.32 (s,
1HH6), 6.10-6.00 (m, 1Hvinylic), 4.25 (dd, 1H, J ) 5.2, 3.0), 3.35-
3.01 (m, 4H), 2.95 (s, 6H), 2.85-2.41 (m, 6H); IR 3025, 2995,
2HallylicCH2, J ) 14.1, 5.0), 3.10-2.40 (m, 6H); IR 2950 cm-1
.
O-Demethylation of the above product was performed as for
compound 6a using BBr3 to give the desired phenol 7. The
crude product was purified by flash column chromatography,
eluting with CHCl3 to give 0.50 g (85%) of a white viscous
product. The HBr salt was formed by bubbling HBr gas into
an ether solution of the product. Upon evaporating the
solvent, a white product was obtained which was recrystallized
from 2-PrOH/ether to give pure 7 (0.4 g, 70%): mp 163-165
°C; 1H NMR (CDCl3) δ 7.40-7.10 (m, 9Haromatic), 7.05 (d,
2Hcinnamyl-Ph), 6.5 (d, 1H, J ) 15 for trans vinylic hydrogen),
6.25 (s, 1HH6), 6.31-6.22 (m, 1Hvinylic), 4.2 (dd, 1H, J ) 5.1,
3.0), 3.35-2.25 (m, 8H); IR 2995, 2690 (hydrogen-bonded OH
group) 1600, 1495 cm-1. Anal. (C25H24NOBr2‚0.5H2O) C, H,
N.
Mod elin g Meth od s. Molecular modeling studies were
performed using the SYBYL24 software package (Tripos, ver-
sion 6.2, R4000) installed on a Silicon Graphics IRIS Indigo
XZ workstation running IRIX 5.2. The chemical structures
were drawn using the SKETCH option. Optimized geometries
and partial charges were obtained using the AM125 model
Hamiltonian as implemented in the MOPAC26 program (ver-
sion 6.0) using the PRECISE convergence criteria.
Biologica l Eva lu a tion . Chemicals and reagents were
obtained from the following sources: [3H]SCH 23390 (specific
activity 71.3 Ci/mmol), [3H]sulpiride (specific activity 70 Ci/
2670 (hydrogen-bonded OH group) 1601, 1490 cm-1
. Anal.
(C27H31N2OClBr2‚0.5H2O) C, H, N.