690 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3
Wu et al.
mmol) of diethyl chlorophosphate, and 0.07 g (0.5 mmol) of
potassium carbonate in acetone was heated under reflux for
15 h. It was concentrated, and the residue was diluted with
30 mL of water and extracted with four 40 mL portions of ethyl
acetate. The combined organic extracts were washed with
brine and concentrated. The residue was purified by prepara-
tive TLC, eluting with 8% methanol in methylene chloride plus
1% NH4OH to give 0.074 g (87%) of compound 27: 1H NMR
(CDCl3) δ 1.37 (t, J ) 7.3 Hz, 3 H), 1.66 (m, 1 H), 2.10 (m, 1
H), 2.47 (s, 3 H), 2.60-2.81 (m, 5 H), 3.14-3.26 (m, 3 H), 3.75
(m, 1 H), 5.01 (d, J ) 7 Hz, 1 H), 6.95 (d, J ) 8 Hz, 1 H),
7.08-7.27 (m, 4 H); 13C NMR (CDCl3) δ 14.56, 27.71, 29.31,
29.46, 34.15, 39.72, 45.93, 58.79, 66.64, 122.75, 126.72, 127.11,
127.24, 128.13, 132.02, 134.00, 135.10, 138.55, 140.80, 149.56,
169.08.
4-Chloro-3,6,7,8,8aS,9,10,14bR-octahydro-8-methyl-2H-
naphtho[1,2-a]thiazolo[4,5-i][3]benzazepin-2-one (28). A
mixture of 0.017 g (0.04 mmol) of compound 27 and 0.02 g
(0.4 mmol) of sodium methoxide in 1 mL of DMF was stirred
at room temperature for 64 h. It was quenched with 25 mL of
water and extracted with three 25 mL portions of ethyl acetate.
The combined organic extracts were washed with brine and
concentrated. The residue was purified by preparative TLC,
eluting with 8% methanol in methylene chloride plus 1%
NH4OH to give 0.010 g (66%) of compound 28: 1H NMR
(CDCl3) δ 1.64 (m, 1 H), 2.13 (m, 1 H), 2.46 (s, 3 H), 2.53-2.80
(m, 5 H), 3.21 (m, 1H), 3.66 (m, 1 H), 4.93 (d, J ) 7 Hz, 1 H),
6.97 (d, J ) 7 Hz, 1 H), 7.15 (s, 1 H), 7.22-7.26 (m, 3 H); 13C
NMR (CDCl3) δ 29.33, 29.37, 34.26, 39.72, 45.63, 58.92, 66.62,
113.02, 122.70, 126.21, 126.97, 127.53, 128.23, 131.64, 132.05,
134.56, 137.88, 139.59, 140.74, 172.13. HRMS (FAB+) m/z:
calcd, 371.0985; found, 371.0979. Degree of purity: HPLC
method 1, retention time of 5.4 min, 95.8%; method 2, retention
of 1.95 min, 98.0%.
4-Chloro-3,6,7,8,8aS,9,10,14bR-octahydro-2H-naphtho-
[1,2-a]thiazolo[4,5-i][3]benzazepin-2-one (29). This com-
pound was prepared from 28 (0.037 g, 0.1 mmol) according to
the procedure described for compound 20 (0.017 g, 48%): 1H
NMR (CDCl3) δ 1.60 (m, 1 H), 1.96 (m, 1 H), 2.73-2.80 (m, 5
H), 3.36-3.48 (m, 2 H), 4.73 (d, J ) 7 Hz, 1 H), 6.97 (d, J ) 8
Hz, 1 H), 7.09 (s, 1 H), 7.10-7.23 (m, 3 H); 13C NMR (CDCl3)
δ 29.26, 32.11, 38.62, 49.20, 51.46, 60.58, 113.00, 122.82,
126.51, 126.88, 127.42, 128.68, 131.56, 132.06, 133.96, 138.18,
139.31, 140.01, 171.66. HRMS (FAB+) m/z: calcd, 357.0828;
found, 357.0832. Degree of purity: HPLC method 1, retention
time of 8.2 min, 97.6%; method 2, retention of 1.95 min, 96.3%.
8-Chloro-2,3,4,5-tetrahydro-7-hydroxy-3-methyl-5(R)-
phenyl-1H-3-benzazepine-6-carboxaldehyde (30). A mix-
ture of 2.88 g (10 mmol) of compound 1 and 1.4 g (10 mmol) of
hexamethylenetetramine in 60 mL of TFA was heated under
reflux for 42 h. The solvent was evaporated, and the residue
was quenched with 200 mL of saturated sodium bicarbonate.
It was extracted with three 150 mL portions of ethyl acetate.
The combined organic extracts were washed with brine (80
mL) and concentrated. The residue was chromatographed on
silica gel eluting with 0.5 to 3% methanol in methylene
chloride to give 1.02 g (32%) of compound 30: 1H NMR (CDCl3)
d 2.39 (s, 3 H), 2.37-2.56 (m, 2 H), 2.74-2.93 (m, 3 H), 3.50
(dd, J ) 13, 6.6 Hz, 1 H), 5.10 (dd, J ) 6.6, 4 Hz, 1 H), 7.07
(m, 2 H), 7.20-7.32 (m, 3 H), 7.44 (s, 1 H), 10.20 (s, 1 H).
HRMS (FAB+) m/z: calcd, 316.1104; found, 316.1105,.
1 H), 5.38 (m, 1 H), 7.05 (m, 2 H), 7.17-7.28 (m, 3 H), 7.43 (s,
1 H), 10.39 (s, 1 H). MS (m/z) 394 (M+).
4-Chloro-3,6,7,8,9,10-hexahydro-3,8-dimethyl-10(R)-
phenylazepino[4,5-e]indazole (32). A mixture of 0.8 g (2
mmol) of compound 31, 0.19 g (4 mmol) of methylhydrazine,
and 0.39 g (5 mmol) of ammonium acetate in 60 mL of
m-xylene was stirred at 135 °C for 15 min and at 150 °C for 3
days with azeotropic removal of water using a Dean-Stark
apparatus. The solvent was evaporated, and the residue was
diluted with 150 mL of saturated sodium bicarbonate. It was
extracted with three 100 mL portions of ethyl acetate. The
combined organic extracts were washed with 80 mL of brine
and concentrated. The residue was chromatographed on silica
gel, eluting with 1 to 2% methanol in methylene chloride to
give 0.53 g (80%) of compound 32: 1H NMR (CDCl3) δ 2.32-
2.40 (m, 1 H), 2.39 (s, 3 H), 2.69-3.06 (m, 4 H), 3.54 (dd, J )
13, 6 Hz, 1 H), 4.37 (s, 3 H), 4.75 (m, 1 H), 7.10-7.30 (m, 6 H),
7.69 (s, 1 H). HRMS (FAB+) m/z: calcd, 326.1420; found,
326.1426.
4-Chloro-3,6,7,8,9,10-hexahydro-8-methyl-10(R)-phenyl-
azepino[4,5-e]indazole (33) and 4-Chloro-3,6,7,8,9,10-
hexahydro-10(R)-phenylazepino[4,5-e]indazole (34). Both
compound 33 and compound 34 were obtained in one pot from
compound 32 (0.33 g, 1 mmol) by following the procedure
described for compound 20. Compound 33 (0.083 g, 27%): 1H
NMR (CDCl3) δ 2.44 (s, 3 H), 2.60 (m, 1 H), 2.80 (m, 2 H), 2.93
(dd, J ) 13, 3 Hz, 1 H), 3.07 (m, 1 H), 3.44 (dd, J ) 13, 7 Hz,
1 H), 4.83 (dd, J ) 7, 3 Hz, 1 H), 7.14-7.28 (m, 5 H), 7.64 (s,
1 H); 13C NMR (CDCl3) δ 34.84, 46.85, 47.79, 57.14, 60.33,
113.04, 125.93, 126.23, 127.68, 128.33, 128.65, 133.62, 134.02,
134.24, 136.97, 141.40. HRMS (FAB+) m/z: calcd, 312.1268;
found, 312.1278.
Compound 34 (0.067 g, 21%): 1H NMR (CDCl3) δ 2.75-2.89
(m, 2 H), 3.05 (m, 1 H), 3.22 (m, 1 H), 3.40 (dd, J ) 14, 2 Hz,
1 H), 3.86 (dd, J ) 14, 5 Hz, 1 H), 4.76 (m, 1 H), 7.10-7.30
(m, 5 H), 7.88 (s, 1 H); 13C NMR (CDCl3) δ 39.08, 47.90, 49.27,
51.52, 113.01, 126.29, 126.59, 127.60, 128.69, 129.27, 133.39,
134.31, 134.93, 136.67, 139.77. HRMS (FAB+) m/z: calcd,
298.1111; found, 298.1108.
8-Chloro-2,3,4,5-tetrahydro-3-methyl-6-nitro-5(R)-phen-
yl-1H-3-benzazepin-7-ol (35). This compound was prepared
from compound 1 (8.63 g, 30 mmol) by the procedure described
for compound 4. Compound 35 (10.2 g, 100%): 1H NMR
(CDCl3) δ 2.10 (m, 1 H), 2.30 (s, 3 H), 2.60-2.90 (m, 4 H), 3.50
(br, 1 H), 4.10 (br, 1 H), 6.95-7.22 (m, 6 H). HRMS (FAB+)
m/z: calcd, 333.1006; found, 333.1014.
2-[[8-Chloro-2,3,4,5-tetrahydro-3-methyl-6-nitro-5(R)-
phenyl-1H-3-benzazepin-7-yl]oxy]acetamide (36). This
compound was synthesized from compound 35 (5.0 g, 15 mmol)
by a similar procedure described for compound 13. Compound
36 (3.89 g, 67%): 1H NMR (CDCl3) δ 2.20 (m, 1 H), 2.37 (s, 3
H), 2.60 (m, 2 H), 2.95 (m, 2 H), 3.60 (m, 1 H), 4.18 (br, 1 H),
4.60 (s, 2 H), 5.95 (br, 1 H, NH), 6.50 (br, 1 H, NH), 7.07 (d, J
) 7.4, Hz, 2 H), 7.20-7.35 (m, 4 H). HRMS (FAB+) m/z: calcd,
390.1221; found, 390.1205.
N-[8-Chloro-2,3,4,5-tetrahydro-3-methyl-6-nitro-5(R)-
phenyl-1H-3-benzazepin-7-yl]-2-hydroxyacetamide (37).
This compound was prepared from compound 36 (1.8 g, 4.6
mmol) by a similar procedure described for compound 14.
Compound 37 (1.7 g, 94%): 1H NMR (CD3OD) δ 2.20 m, 1 H),
2.32 (s, 3 H), 2.60 (m, 1 H), 2.75 (m, 1 H), 2.88 (m, 2 H), 3.75
(m, 1 H), 4.13 (s, 2 H), 4.22 (m, 1 H), 4.90 (br, 1 H), 7.10-7.30
(m, 5 H), 7.58 (s, 1 H). HRMS (FAB+) m/z: calcd, 390.1221;
found, 390.1216.
8-Chloro-2,3,4,5-tetrahydro-3-methyl-7-[(methylsul-
fonyl)oxy]-5(R)-phenyl-1H-3-benzazepine-6-carboxalde-
hyde (31). To a stirred solution of 1.0 g (3.2 mmol) of
compound 30, 0.63 g (6.3 mmol) of triethylamine, and 0.01 g
of DMAP in 20 mL of methylene chloride was added 0.44 g
(3.8 mmol) of methanesulfonyl chloride at 0 °C. The mixture
was warmed to room temperature and stirred for 18 h. It was
diluted with 200 mL of ethyl acetate and washed with 80 mL
of saturated sodium bicarbonate and 50 mL of brine. The
organic layer was concentrated to give 1.26 g (100%) of crude
product 31: 1H NMR (CDCl3) δ 2.20 (m, 1 H), 2.36 (s, 3 H),
2.53-2.60 (m, 2 H), 2.84-2.91 (m, 2 H), 3.42 (s, 3 H), 3.60 (m,
8-Chloro-2,3,4,5-tetrahydro-3-methyl-6-nitro-5(R)-phen-
yl-1H-3-benzazepin-7-amine (38). This compound was ob-
tained from compound 37 (1.5 g, 3.85 mmol) according to the
procedure described for compound 15. Compound 38 (1.3 g,
100%): 1H NMR (CDCl3) δ 2.04 (m, 1 H), 2.41 (s, 3 H), 2.80-
3.0 (m, 2 H), 3.60-3.80 (m, 3 H), 4.40 (m, 1 H), 4.76 (br, 2 H),
7.05-7.35 (m, 6 H). HRMS (FAB+) m/z: calcd, 332.1166; found,
332.1165.
8-Chloro-2,3,4,5-tetrahydro-3-methyl-5(R)-phenyl-1H-
3-benzazepine-6,7-diamine (39). This compound was pre-