8272 J . Org. Chem., Vol. 62, No. 23, 1997
Notes
Ta ble 1. Ep im er iza tion -Resolu tion of Dia ster eom er 5 in
chromatography equipped with a Daicel Chiralcel OD column,
250 × 4.6 mm, eluted (0.75 mL/min) with hexane-2-propanol
(with 2% diethylamine) ) 80:20 and detected by a UV lamp at
λ ) 254 nm: (S)-1, tr ) 15.6 min; (R)-1, tr ) 11.8 min. Optical
rotation was recorded at 25 °C. Concentration refers to removal
of solvent under reduced pressure using a rotary evaporator.
3-[(1-(1S)-P h en ylet h yl)a m in o]-1,3,4,5-t et r a h yd r o-2H -1-
(3RS)-b en za zep in -2-on e (5). A mixture of 3-bromo-2,3,4,5-
tetrahydro-2-oxo-1H-benzazepine (4) (144 g, 0.60 mol), (S)-1-
phenylethylamine (76.8 g, 0.62 mol), sodium carbonate (31.8 g,
0.30 mol), and propylene glycol (144 mL) were heated to 130 °C
for 3.5 h. The reaction mixture was cooled to 80 °C, and ethanol
(60 mL) was added. The mixture was cooled to 40 °C, and water
(180 mL) was added. The suspension was allowed to cooled to
ambient temperature and stirred for 30 min. The solid was
collected by filtration, rinsed with water (120 mL), and dried in
a vacuum oven at 60 °C to a constant weight to obtain 156 g
(93%) of diastereomer 5 (20% de) as a solid: 1H NMR (270 MHz,
CDCl3) δ 8.50 (s, 1H), 6.72-7.18 (m, 9H), 3.47-3.62 (m, 1H),
3.15 (dd, J ) 11.3, 7.8 Hz, 0.5H), 2.08-2.86 (m, 4.5H), 1.68-
1.86 (m, 1H), 1.03-1.15 (dd, J ) 6.5, 6.5 Hz, 3H, ratio of 60:40).
Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99. Found:
C, 77.08; H, 7.10; N, 9.97.
Non p ola r Solven ts
temperature/
time
(S,S)-5/(R.S)-5
%
yield
entry
solventa
ratiob
1
2
3
4
5
6
A
B
B
B
B
C
140 °C/16 h
140 °C/5 h
140 °C/10 h
140 °C/16 h
160 °C/16 h
140 °C/16 h
99:1
96.5:3.5
99:1
>99:1
94:6
93
74
81
88
81
80
99:1
a
A ) mineral oil; B ) odorless mineral spirit, bp 179-210 °C;
b
C ) decane, bp 174 °C. The diastereomeric ratios were deter-
mined by HPLC: DuPont, Zorbax C-8, methanol/0.01 M KH2PO4
(pH 7) ) 65/35, UV detector, 254 nm; (S,S)-5, tr ) 11.0 min; (R,S)-
5, tr ) 13.1 min.
Sch em e 4
3-[(1-(1S)-P h en ylet h yl)a m in o]-1,3,4,5-t et r a h yd r o-2H -1-
(3S)-ben za zep in -2-on e [(S,S)-5]. A mixture of 3-[(1-(1S)-
phenylethyl)amino]-1,3,4,5-tetrahydro-2H-1-(3S,R)-benzazepin-
2-one (5) (75 g) and odorless mineral spirits (75 mL) were heated
at 140 °C for 16 h. The reaction mixture was cooled to 80 °C,
and cyclohexane (150 mL) was added over a period of 30 min
under stirring. The mixture was further cooled to ambient
temperature. The product was isolated by filtration and rinsed
with cyclohexane (75 mL) to offer 66 g (88%) of (S,S)-5 (>98%
epimerization of a single diasteromer (S,S)-5 (99:1 ratio)
in xylene solution at reflux (138 °C, 16 h) resulted in the
formation of diastereomer 5 at an equilibrium ratio of
60:40. Having established a suitable laboratory proce-
dure, we next examined its capability in our plant. The
efficiency of this total resolution process was demon-
strated on a 63 mole scale, employing a recycling loop
for the mother liquors, to afford (S,S)-5 (total of 52 kg)
in 75% overall yield (99:1 diastereomeric ratio) from 4.
The synthesis of 1 (Scheme 4) was completed by
treating (S,S)-5 first with aqueous sodium hydroxide in
toluene in the presence of a catalytic amount of tetrabu-
tylammonium hydrogen sulfate followed by tert-butyl
chloroacetate to afford crude 7. Subsequent hydro-
genolysis of 7 with 5% palladium on charcoal at 60 °C
generated compound 1 in 90% overall yield from (S,S)-5.
The high chemical purity and (S)-configuration of 1 were
confirmed by comparison of its optical rotation, NMR, and
elemental analysis with an authentic sample. The enan-
tiomeric purity of 1 was established to be 99% ee by chiral
HPLC (Daicel Chiralcel OD).
de) as an off-white solid: mp 185-188 °C; [R]25 -364.1 (c )
D
1.0, methanol). 1H NMR (270 MHz, CDCl3) δ 7.79 (s, 1H), 6.92-
7.30 (m, 9H), 3.75 (q, J ) 6.5 Hz, 1H), 3.06 (dd, J ) 11.3, 8.0
Hz, 1H), 2.76-2.93 (m, 1H), 2.55 (dd, J ) 13.8, 6.4 Hz, 1H),
2.26-2.44 (m, 1H), 2.20 (bs, 1H), 1.87-2.03 (m, 1H), 1.35 (d, J
) 6.5 Hz, 3H). Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19;
N, 9.99. Found: C, 77.22; H, 7.31; N, 10.05.
ter t-Bu tyl 3-Am in o-2,3,4,5-tetr a h yd r o-2-oxo-1H-1-(3S)-
ben za zep in e-1-a ceta te (1). A mixture of 3-[(1-(1S)-phenyl-
ethyl)amino]-1,3,4,5-tetrahydro-2H-1-(3S)-benzazepin-2-one [(S,S)-
5] (60 g, 0.21 mol), tetrabutylammonium hydrogen sulfate (0.60
g, 1.8 mmol), toluene (520 mL), and 50% sodium hydroxide (43
g, 0.54 mol) were heated at 35 °C and stirred for 1 h. The
mixture was cooled to 20 °C and stirred for 16 h. A solution of
tert-butyl chloroacetate (35.5 g, 0.23 mol) in toluene (100 mL)
was added over a period of 30 min, and the mixture was stirred
for additional 1 h. Water (130 mL) was added. The organic
layer was separated, washed with water (130 mL), and concen-
trated. To the syrup were added ethanol (100 mL) and 5% Pd/C
(4.2 g, 50% w/w) and hydrogenated in a Parr apparatus at 60
°C (55 psi) for 16 h. The mixture was filtered and concentrated
to dryness. The residue was dissolved into ethyl acetate (210
mL) and washed sequentially with 1 M aqueous solution of
sodium carbonate (30 mL) and water (30 mL). The organic layer
was concentrated to dryness. A mixture of toluene (43 mL) and
heptane (345 mL) was added, and the resulting slurry was
heated to 75 °C for 30 min. The solution was cooled to -5 °C
and stirred for additional 2 h. The product was isolated by
filtration to obtain 54.5 g (90%) of 1 (99% ee) as a white solid:
mp 110-111 °C; [R]25 -274.8 (c ) 1.0, ethanol) (lit:3 [R]25
In summary, a novel thermal epimerization-resolution
methodology for the asymmetric synthesis of N-substi-
tuted R-amizobenzlactam has been presented. In prin-
ciple, 3 can be prepared from 4 via reaction with (R)-1-
phenylethylamine, followed by the thermal epimerization-
resolution process and hydrogenolysis.
D
D
-274, c ) 2.0, ethanol). 1H NMR (270 MHz, CDCl3) δ 7.10-
7.27 (m, 4H), 4.55 (AB, J ) 17.0 Hz, 1H), 4.35 (AB, J ) 17.0 Hz,
1H), 3.42 (dd, J ) 11.4, 7.8 Hz, 1H), 3.25 (td, J ) 13.2, 7.7 Hz,
1H), 2.58 (dd, J ) 13.4, 6.9 Hz, 1H), 2.40 (m, 1H), 1.91 (m, 1H),
1.40 (s, 9H). Anal. Calcd for C16H22N2O3: C, 66.18; H, 7.64; N,
9.65. Found: C, 66.26; H, 7.56; N, 9.65.
Exp er im en ta l Section
Proton magnetic resonance spectra were recorded on an FT-
NMR spectrometer (1H at 270 MHz). 1H NMR chemical shifts
were reported in ppm referenced to the residual CHCl3 (7.24
ppm), and J values were reported in hertz. Microanalysis was
performed by Robertson Laboratory Inc. of Madison, NJ . The
diastereomeric ratio of (S,S)-5 was determined by high-
performance liquid chromatography equipped with a DuPont
Zorbax C-8 column, eluted (1 mL/min) with methanol-0.01 M
KH2PO4 (pH ) 7) 65:35 and detected by a UV lamp at λ ) 254
nm: (S,S)-5, tr ) 11.0 min; (R,S)-5, tr ) 13.1 min. The enantio-
meric excess of 1 was determined by high-performance liquid
Ack n ow led gm en t. We are grateful to Drs. K.
Gelotte and J . Brokatzky for helpful discussions and
suggestions. We thank Mr. R. Winchurch for chiral
HPLC assistance, and Mr. T. Tedesco and Mr. P.
Prickett for a pilot plant demonstration.
J O971056N