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A. Bisi et al. / Bioorg. Med. Chem. 11 (2003) 1353–1361
designed according to the following abbreviations:
s=singlet, d=doublet, dd=doublet of doublets, t=triplet,
m=multiplet, br s=broad singlet, br t=broad triplet.
d 7.9–7.1 (m, 4H ), 6.6 (s, 1H), 6.55 (s, 1H), 4.1–3.9
(m, 3H), 3.8 (s, 3H), 3.75 (s, 3H), 3.7 (t, 2H), 3.5 (m,
2H), 3.1 (m, 2H), 2.8–2.5 (m, 4H), 2.4 (s, 3H), 2.35
(s, 2H), 1.8 (m, 2H). MS: m/z (rel. abundance) 487
(M+, 4.2), 305 (62.1), 262 (72.7) 139 (100). Anal.
(C25H33N3O7.HCl): C, H, N.
Mass spectra were recorded on a V.G. 7070 E spectro-
meter. Elemental analyses were within 0.4% of theo-
retical value unless otherwise indicated. The names of
compound were obtained using AUTONOM, PC soft-
ware for nomenclature in organic chemistry from Beil-
stein-Institut and Springer. Optical rotations were
determined by a Perkin–Elmer 241 Polarimeter at 25 ꢀC.
Purification was performed by flash chromatography
using silica gel (particle size 40–63 mm, Merck). HPLC
analyses were performed on a Chiralcel-OD column
from Daicel using a Waters 510 pump and a Pye unicam
PU 4025 detector (l=254 nm).
3-3-[2-Hydroxy-3-(2-methylphenoxy)propyl](methyl)amino]
propyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzaze-
pin-2-one (5c). Using the previous procedure, com-
pound 5c (0.98 g, 63%) was obtained from 4 (1 g,
3.42 mmol) and 2-[(2-mꢀethylphenoxy)methyl]oxirane.24
1
mp (HCl salt) 137–140 C (methanol/diethylether). H
NMR (CDCl3) d 7.25–6.80 (m, 4H), 6.6 (s, 1H), 6.55 (s,
1H), 4.1–3.9 (m, 3H), 3.8 (s, 3H), 3.75 (s, 3H), 3.7 (t,
2H), 3.5 (m, 2H), 3.1 (m, 2H), 2.65–2.4 (m, 4H), 2.3 (s,
3H), 2.2 (s, 3H) 2.15 (s, 2H), 1.8 (m, 2H). MS: m/z (rel.
abundance) 456 (M+, 20), 305 (100), 262 (88.6). Anal.
(C26H36N2O5.HCl): C, H, N.
The (S)- and (R)-isopropylidene-glycerol, (S)-2 and
(R)-2, were prepared by chemical resolution of the
racemate as described in the literature.19
3-3-[3-(2-Acetylphenoxy)-2-hydroxypropyl](methyl)amino]
propyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzaze-
pin-2-one (5d). Using the previous procedure, com-
pound 5d (1.11 g, 67%) was obtained from 4 (1 g,
3.42 mmol) and 1-[2-(2-oxiranylmethoxy)phenyl]-1-
ethanone.25 mp (HCl salt) 182–185 ꢀC (methanol/die-
3-3-[Benzyl(methyl)amino]propyl-7,8-dimethoxy-2,3-di-
hydro-1H-3-benzazepin-2-one (3). N-Methylbenzylamine
(13 mL, 100.0 mmol) were dropped into a solution of
15.07 g (51.0 mmol) of 2 in 200 mL of toluene, and the
reaction mixture was heated under reflux for 8 h. The
solution was then washed with water and evaporated to
dryness. The compound was an oil (12.2 g, 65%), used
for the subsequent step without further purification. Mp
(HCl salt, methanol/diethylether) 148–151 ꢀC.
1
thylether). H NMR (CDCl3) d 7.8–6.9 (m, 4H), 6.6 (s,
1H), 6.55 (s, 1H), 4.1–3.9 (m, 3H), 3.8 (s, 3H), 3.75 (s,
3H), 3.7 (t, 2H), 3.5 (m, 2H), 3.1 (m, 2H), 2.7 (s, 3H),
2.65–2.4 (m, 4H), 2.3 (s, 3H), 2.15 (m, 2H), 1.8 (m, 2H).
MS: m/z (rel. abundance) 484 (M+, 33.3), 206 (77.7), 58
(100). Anal. (C27H36N2O6.HCl): C, H, N.
7,8-Dimethoxy-3-[3-(methylamino)propyl]-2,3,4,5-tetra-
hydro-1H-3-benzazepin-2-one (4). A solution of 12.2 g
of compound 3 (32.2 mmol) in acetic acid was hydro-
genated at 5 atm withPd/C as catalyst. After filtration,
the solvent was removed under reduced pressure and the
residue was dissolved in CH2Cl2, washed with a satu-
rated solution of K2CO3, dried (Na2SO4) and evapo-
rated to dryness to yield 6.11 g of 4 (65%), mp 72–75 ꢀC
3-3-[2-Hydroxy-3-(1-naphthyloxy)propyl](methyl)amino]-
propyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzaze-
pin-2-one (5e). Using the previous procedure,
compound 5e (1.11 g, 66%) was obtained from 4 (1 g,
3.42 mmol) and 2-[1(naphtyloxy)methyl]oxirane.26 Mp
(HCl salt) 187–189 ꢀC (methanol/diethylether). 1H
NMR (DMSO-d6) d 7.9–6.7 (m, 7H ), 6.7 (s, 1H), 6.55
(s, 1H), 4.22–4.15 (m, 3H), 4.12 (s, 3H), 4.10 (s, 3H), 3.9
(t, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 3.41 (m, 2H), 2.9–
2.75 (m, 4H), 2.48 (s, 3H), 1.95 (m, 2H). MS: m/z (rel.
abundance) 492 (M+, 16.7), 305 (100), 262 (72.9). Anal.
(C29H36N2O5.HCl): C, H, N.
1
(toluene). H NMR (CDCl3) d 6.6 (s, 1H), 6.55 (s, 1H),
3.8 (s, 3H), 3.75 (s, 3H), 3.65 (t, 2H), 3.5 (m, 2H), 3.05
(m, 2H), 2.8-2.5 (m, 4H), 2.4 (s, 3H), 1.8 (m, 2H).
3-3-[(2-Hydroxy-3-phenoxypropyl)(methyl)amino]propyl-
7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
(5a). A solution of 1 g of compound 4 (3.42 mmol) and
0.51 g (3.42 mmol) of 2-(phenoxymethyl)oxirane22 in
50 mL of ethanol was heated under reflux 12 h. The sol-
vent was evaporated to dryness and the product was pur-
ified as hydrochloride salt: mp 183–185ꢀC (methanol/
diethylether).Yield 1.06g (70%). 1H NMR (DMSO-d6) d
7.4–6.9 (m, 5H ), 6.7 (s, 1H), 6.6 (s, 1H), 4.2–4.15 (m, 3H),
4.12 (s, 3H), 4.10 (s, 3H), 3.9 (t, 2H), 3.55 (m, 2H), 3.45 (m,
2H), 3.40 (m, 2H), 2.9–2.75 (m, 4H), 2.48 (s, 3H), 1.9 (m,
2H). MS: m/z (rel. abundance) 442 (M+, 13.3), 305 (100),
262 (79.6). Anal. (C25H34N2O5.HCl): C, H, N.
1-(Benzylamino)-3-phenoxy-2-propanol (6). 2-(Phenoxy-
methyl)oxirane (9 g, 59.9 mmol) and 7.9 mL of benzyl-
amine (59.9 mmol) in 200 mL of toluene were heated
under reflux for 16 hafter cooling, the solution was
washed with water, dried and evaporated to dryness, to
yield 10.7 g (70%) of 6 as an oil, which was used for the
subsequent step without further purification. Mp (HCl
salt) 176–180 ꢀC.
3-3-[Benzyl(2-hydroxy -3-phenoxypropyl)amino]propyl-
7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one (7). A
solution of 4.7 g (15.9 mmol) of compound 2, 4.1 g
(15.9 mmol) of 6 and 2.3 mL of triethylamine in 50 mL
of toluene was refluxed 8 h. After cooling, the solution
was washed with water, dried and evaporated to dry-
ness, affording 2.6 g (32%) of 7. Mp (HCl salt)
3-3-[2-Hydroxy-3-(2-nitrophenoxy)propyl](methyl)amino]
propyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-
2-one (5b). Using the previous procedure, compound 5b
(1.07 g, 65%) was obtained from 4 (1 g, 3.42 mmol) and
2-[(2-nitrophenoxy)methyl)]oxirane.23 mp (HCl salt)
160–163 ꢀC (methanol/diethylether). H NMR (CDCl3)
182–185 ꢀC. H NMR (CDCl3) d 8.1–7.1 (m, 10H ), 6.6
1
1