3554 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 18
Ogawa et al.
trated. Column chromatography in 10:1 dichloromethane-
methanol over silica gel followed by recrystallization from
dioxane yielded 31f (2.0 g, 77%) as colorless prisms: mp 210-
211 °C; NMR (CDCl3) δ 1.1-3.3 (m with three s at δ 2.43, 2.56,
and 2.46, 12H), 3.65-3.82 (m, 1 × 1/3H), 3.95-4.14 (m, 1 ×
1-[4-[(2-Ch lor ob en zoyl)a m in o]b en zoyl]-5-p ip er id yl-
2,3,4,5-tetr a h yd r o-1H-ben za zep in e (31o). To a stirred
solution of 30b (0.20 g, 0.48 mmol), piperidine (0.21 g, 2.4
mmol), Et3N (0.35 mL, 2.5 mmol), and dichloromethane (10
mL) was added dropwise TiCl4 (0.5 M solution in dichlo-
romethane, 1.2 mL). The mixture was stirred at room tem-
perature overnight. After removal of the solvent, the residue
was dissolved in EtOH (10 mL). To the mixture was added
NaBH4 (22 mg, 0.58 mmol), and the mixture was stirred for 2
h at room temperature. The reaction mixture was poured into
water and extracted with dichloromethane. The organic layers
were washed with water, dried over magnesium sulfate, and
concentrated. Column chromatography in 100:1 dichlo-
romethane-methanol over silica gel followed by recrystalli-
zation from ethanol afforded 31o (0.064 g, 28%) as a white
solid: mp 236-239 °C; NMR (CDCl3) δ 1.05-3.82, 3.95-4.22,
5.0-5.3 (each m, total 17H), 6.5-8.2 (m with d at δ 6.59 (J )
7.5 Hz), 13H). Anal. (C29H30ClN3O2) C, H, N.
5-(Dim eth yla m in o)-1-[4-[(N-m eth yl-2-m eth ylben zoyl)-
a m in o]ben zoyl]-2,3,4,5-tetr a h yd r o-1H-ben za zep in e (31s).
A solution of 31b (1.0 g, 2.3 mmol) in dimethylformamide (30
mL) was treated with sodium hydride (60% dispersion in oil,
0.13 g) at room temperature and the mixture was stirred for
40 min. To this mixture was added dropwise a solution of
methyl iodide (0.14 mL, 2.3 mmol) at 0-4 °C, and the mixture
was stirred at room temperature for 2.5 h. The reaction
mixture was poured into water and extracted with ethyl
acetate. The organic layers were washed with water, dried
over magnesium sulfate, and concentrated. The residue was
crystallized with ether-hexane to afford 31s (0.91 g, 90%) as
a white powder: mp 182-182.5 °C; NMR (CDCl3) δ 1.2-2.45,
2.5-3.1, 3.1-3.65, 3.95-4.25, 4.85-5.15 (each m with three s
at δ 2.01, 2.19, 2.38, total 19H), 6.3-7.65 (m, 12H). Anal.
(C28H31N3O2‚1/4H2O) C, H, N.
5-(Acetylam in o)-1-[4-[(2-m eth ylben zoyl)am in o]ben zoyl]-
2,3,4,5-tetr a h yd r o-1H-ben za zep in e (31q). To a stirred
mixture of 31m (0.27 g, 0.7 mmol) and pyridine (5 mL) was
added acetic anhydride (5 mL), and the mixture was stirred
at room temperature for 15 h. The reaction mixture was
poured into ice-water. The resulting crystals were collected
by filtration and recrystallized from ethanol to give 31q (0.3
g, 44%) as colorless needles: mp 297-299 °C; NMR (DMSO-
d6) δ 1.4-3.1 (m with two s at δ 2.00 and 2.32, 10H), 3.7-4.0
(m, 1H), 4.3-4.7 (m, 1H), 4.9-5.4 (m, 1H), 6.53 (d, J ) 7.9
Hz, 1H), 6.7-7.7 (m, 11H), 7.8-8.2 (m, 1H), 9.90 (br s, 1H).
Anal. (C27H27N3O3‚EtOH) C, H, N.
1-[4-[(2-Met h ylb en zoyl)a m in o]b en zoyl]-5-(N′-m et h yl-
u r eid o)-2,3,4,5-tetr a h yd r o-1H-ben za zep in e (31r ). A mix-
ture of 31n (0.60 g, 1.5 mmol), methyl isocyanate (0.18 mL,
3.1 mmol), and dichloromethane (10 mL) was stirred at room
temperature overnight and concentrated. The residue was
crystallized with dimethylformamide to give 31r (0.10 g, 14%)
as colorless prisms: mp 286-287 °C; NMR (DMSO-d6) δ 1.2-
3.4 (m with s at δ 2.32 and d at δ 2.61 (J ) 4.6 Hz), 11H),
4.1-5.3 (m, 2H), 5.7-6.1 (m, 1H), 6.4-7.1 (m, 13H), 10.3 (s,
1H). Anal. (C27H28N4O3‚3/4H2O) C, H; N: calcd, 11.92; found,
12.41.
2
1
2/3H), 4.41-4.65 (m, 1 × /3H), 5.01-5.26 (m, 1 × /3H), 6.66
(d, J ) 7.5 Hz, 1H), 6.90-7.72 (m, 12H). Anal. (C26H27N3O2‚1/
4H2O) C, H, N.
Eth yl N-Meth yl-N-[1-[4-[(2-m eth ylben zoyl)a m in o]ben -
zoyl]-2,3,4,5-t et r a h yd r o-5(1H )-b en za zep in yl]a m in oa ce-
ta te (31j). A mixture of 31f (1.6 g, 3.9 mmol), ethyl bromoac-
etate (0.44 mL, 4.4 mmol), potassium carbonate (0.60 g), and
acetonitrile (20 mL) was refluxed for 3 h, and concentrated.
The residue was poured into water and extracted with dichlo-
romethane. The organic layers were dried over magnesium
sulfate and concentrated. Column chromatography in 30:1
dichloromethane-methanol over silica gel followed by recrys-
tallization from ethyl acetate-petroleum ether yielded 31j
(0.82 g, 41%) as colorless prisms: mp 167-168 °C; NMR
(CDCl3) δ 1.15-2.8 (m, with t at δ 1.30 (J ) 7.2 Hz) and two
s at δ 2.47 and 2.57, 13H), 3.2-3.7, 3.9-4.4, 4.9-5.2 (each m,
with q at δ 4.21 (J ) 7.2 Hz), 7H), 6.61 (d, J ) 7.1 Hz, 1H),
6.8-7.6 (m, 11H), 7.62 (d, J ) 7.7 Hz, 1H). Anal. (C30H33N3O4)
C, H, N.
5-[N-(Cya n om eth yl)m eth yla m in o]-1-[4-[(2-m eth ylben -
zoyl)a m in o]b e n zoyl]-2,3,4,5-t e t r a h yd r o-1H -b e n za ze -
p in e (31k ). To a solution of 31f (0.60 g, 1.5 mmol) in methanol
(10 mL) was added glycolonitrile (50 wt % solution in water,
0.7 mL), and the mixture was refluxed for 6 h. After
concentration, the residue was triturated with ethyl acetate.
The resulting crystals were collected by filtration and recrys-
tallized from acetonitrile to give 31k (0.32 g, 49%) as colorless
needles: mp 227-228 °C; NMR (CDCl3) δ 1.1-4.2, 4.8-5.2
(each m, with two s at δ 2.48 and 2.58, 15H), 6.5-7.9 (m, 13H).
Anal. (C28H28N4O2) C, H, N.
5-[(2-Am in o-2-oxoeth yl)m eth yla m in o]-1-[4-[(2-m eth yl-
ben zoyl)a m in o]ben zoyl]-2,3,4,5-tetr a h yd r o-5(1H)-ben za -
zep in e (31l). A mixture of 31j (0.60 g, 1.2 mmol) and
ammonia (2 M solution in methanol, 20 mL) was heated in an
autoclave at 100 °C for 8 h and concentrated. Column
chromatography in 30:1 dichloromethane-methanol over silica
gel afforded 31l (0.40 g, 71%) as a colorless glass: NMR
(CDCl3) δ 1.3-3.6 (m with two s at δ 2.47 and 2.55, 13H), 3.8-
4.2, 4.3-4.6 (m, 1H), 4.8-5.8 (m, 1H), 6.5-7.9 (m with d at δ
6.67 (J ) 7.4 Hz), 15H). Anal. (C28H30N4O3‚1/2H2O) C, H, N.
5-(Acet oxyim in o)-1-[4-[(2-m et h ylb en zoyl)a m in o]b en -
zoyl]-2,3,4,5-tetr a h yd r o-1H-ben za zep in e (31m ). A mix-
ture of 30a (10 g, 25 mmol), hydroxylamine hydrochloride (5.23
g, 75 mmol), and pyridine (100 mL) was refluxed for 2.5 h.
After cooling to room temperature, acetic anhydride (100 mL)
was added to the mixture and stirred for 3 h. The mixture
was concentrated and poured into water and then extracted
with dichloromethane. The organic layers were washed with
aqueous cupric sulfate, brine, dried over magnesium sulfate,
and concentrated. Column chromatography in 30:1 dichlo-
romethane-methanol over silica gel followed by recrystalli-
zation from ethanol afforded 31m (9.80 g, 86%) as colorless
needles: mp 190-191 °C; NMR (CDCl3) δ 1.5-2.2 (m, 2H),
2.28 (s, 3H), 2.47 (s, 3H), 2.76-3.10 (m, 2H), 3.15-3.8 (m, 1H),
4.46 (br s, 1H), 6.73 (dd, J ) 7.2, 1.7 Hz, 1H), 7.1-7.5 (m, 10H),
7.56 (s, 1H), 7.64 (dd, J ) 7.5, 1.6 Hz, 1H). Anal. (C27H25N3O4)
C, H, N.
5-Am in o-1-[4-[(2-m eth ylben zoyl)am in o]ben zoyl]-2,3,4,5-
tetr a h yd r o-1H-ben za zep in e (31n ). A mixture of 31m (7.7
g, 17 mmol), PtO2 (0.7 g) and acetic acid (100 mL) was stirred
at room temperature under hydrogen atmosphere (1 atm) for
5 h. The mixture was filtered through Celite and evaporated.
The residue was dissolved in dichloromethane and this solu-
tion was washed with saturated NaHCO3 and water, dried over
magnesium sulfate, and concentrated. Column chromatogra-
phy (elution: 5-10% methanol/dichloromethane) over silica
gel followed by crystallization with ether afforded 31n (6.5 g,
96%) as a white solid: mp 198.5-199.5 °C; NMR (CDCl3) δ
1.2-2.6, 2.6-3.9, 4.15-4.9, 5.0-5.3 (each m with s at δ 2.47,
total 12H), 6.66 (d, J ) 7.6 Hz, 1H), 6.85-7.75 (m, 12H). Anal.
(C25H25N3O2) C, H, N.
1-[4-[(2-Am in oben zoyl)am in o]ben zoyl]-5-(dim eth ylam i-
n o)-2,3,4,5-tetr a h yd r o-1H-1-ben za zep in e (31x). A mixture
of 31w (4.65 g, 10.2 mmol), platinum oxide (0.3 g), ethanol
(100 mL), and water (4 mL) was stirred at 40-50 °C under
hydrogen atmosphere (1 atm) for 3 h. The mixture was filtered
through Celite to remove the catalyst which was rinsed with
ethanol, and the filtrate was concentrated. Column chroma-
tography (elution: 1-2% methanol/dichloromethane) followed
by recrystallization from CHCl3-AcOEt provided 31x (3.24 g,
75%) as colorless prisms: mp 224-227 °C; NMR (CDCl3) δ
1.0-2.8, 2.9-3.15, 3.4-3.7, 3.9-4.15, 4.9-5.25 (each m with
two s at δ 2.17 and 2.42, total 13H), 5.46 (br s, 2H), 6.5-6.85
(m, 3H), 6.85-7.7 (m, 9H), 7.93 (br s, 1H). Anal. (C24H28N4O2)
C, H, N.
1-[4-[[2-(Acet yla m in o)b en zoyl]a m in o]b en zoyl]-5-(d i-
m eth ylam in o)-2,3,4,5-tetr ah ydr o-1H-1-ben zazepin e (31y).
To a stirred mixture of 31x (0.90 g, 2.1 mmol) and dichlo-
romethane (24 mL) was added acetic anhydride (0.30 mL, 3.15
mmol), and the mixture was stirred at room temperature for