606 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Claudi et al.
8-Ben zyloxy-5-br om o-1-(2-br om o-5-m eth oxyben zyl)-2-
eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e oxa la te (24b): ob-
tained from 23 and ethyl iodide (1.9 mL, 24 mmol); yield 53%
3.00-2.62 (m, 2H, CH2), 2.44 (m, 2H, CH2), 1.15 (t, 3H, CH3).
Anal. (C19H20BrNO2‚H2C2O4) C, H, N.
4-Br om o-1-p r op yl-10-m et h oxy-2,3,12,12a -t et r a h yd r o-
1H-[1]ben zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (26c).
Obtained from 25c with the same procedure as 26a . The base
was converted to the oxalate salt and crystallized from i-PrOH/
1
(317 mg); mp 139-141 °C; H NMR (DMSO-d6) δ 7.52-7.22
(m, 7H, ArH), 6.88-6.66 (m, 3H, ArH), 4.90 (s, 2H, OCH2Ph),
4.55 (m, 1H, H-1), 3.55 (s, 3H, OCH3), 3.22-2.50 (m, 8H,
4CH2), 0.92 (t, 3H, C-CH3). Anal. (C26H27Br2NO2‚H2C2O4) C,
H, N.
1
Et2O to give 120 mg (41%) of pure 26c: mp 214-216 °C; H
NMR (DMSO-d6) δ 7.50 (m, 1H, ArH), 7.08 (m, 2H, ArH), 6.70
(m, 2H, ArH), 4.76 (dd, 1H, J ) 10.80, 2.90 Hz, H-12a), 3.64
(s, 3H, OCH3), 3.36-3.10 (m, 4H, 2CH2), 2.88-2.58 (m, 4H,
2CH2), 1.58 (m, 2H, C-CH2-C), 0.88 (t, 3H, CH3). Anal.
(C20H22BrNO2‚H2C2O4) C, H, N.
8-Ben zyloxy-5-br om o-1-(2-br om o-5-m eth oxyben zyl)-2-
p r op yl-1,2,3,4-tetr a h yd r oisoqu in olin e oxa la te (24c): ob-
tained from 23 and propyl iodide (2.4 mL, 24 mmol); yield 43%
(262 mg); mp 138 dec °C; 1H NMR (DMSO-d6) δ 7.52-7.25
(m, 7H, ArH), 6.90-6.65 (m, 3H, ArH), 5.10 (s, 2H, OCH2Ph),
4.30 (m, 1H, H-1), 3.62 (s, 3H, OCH3), 3.25-2.20 (m, 8H,
4CH2), 1.20 (m, 2H, C-CH2-C), 0.58 (t, 3H, CH3). Anal.
(C27H29Br2NO2‚H2C2O4) C, H, N.
5-Br om o-8-h yd r oxy-1-(2-b r om o-5-m et h oxyb en zyl)-2-
m eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e Oxa la te (25a ). A
solution of 24a (220 mg, 0.36 mmol) in 37% HCl-EtOH 1:1
(10 mL) was refluxed for 1 h under N2. After removal of the
solvent, H2O and Et2O were added; the aqueous phase was
made basic with saturated NaHCO3, extracted with CHCl3,
and dried. The residue was converted to the oxalate salt and
crystallized from i-PrOH/Et2O to give 122 mg (64%) of pure
25a : mp 239-241 °C; 1H NMR (DMSO-d6) δ 7.38 (dd, 2H,
ArH), 6.94 (m, 1H, ArH), 6.75 (m, 2H, ArH), 4.35 (m, 1H, H-1),
3.72 (s, 3H, OCH3), 3.58-2.43 (m, 6H, 3CH2), 2.35 (s, 3H,
NCH3). Anal. (C18H19Br2NO2‚H2C2O4) C, H, N.
5-Br om o-2-eth yl-8-h yd r oxy-1-(2-br om o-5-m eth oxyben -
zyl)-1,2,3,4-tetr a h yd r oisoqu in olin e Oxa la te (25b). Ob-
tained from 24b with the same procedure as 25a . The residue
was converted to the oxalate salt and crystallized from i-PrOH/
Et2O to give 88 mg (45%) of pure 25b: mp 188-190 °C; 1H
NMR (DMSO-d6) δ 7.42 (m, 1H, ArH), 7.30 (m, 1H, ArH), 6.90
(m, 1H, ArH), 6.74 (m, 1H, ArH), 6.60 (m, 1H, ArH), 4.52 (m,
1H, H-1), 3.68 (s, 3H, OCH3), 3.54-2.52 (m, 8H, 4CH2), 0.98
(t, 3H, C-CH3). Anal. (C19H21Br2NO2‚H2C2O4) C, H, N.
5-Br om o-8-h yd r oxy-1-(2-b r om o-5-m et h oxyb en zyl)-2-
p r op yl-1,2,3,4-tetr a h yd r oisoqu in olin e Oxa la te (25c). Ob-
tained from 24c with the same procedure as 25a . The residue
was converted to the oxalate salt and crystallized from i-PrOH/
Et2O to give 90 mg (45%) of pure 25c: mp 145-147 °C; 1H
NMR (DMSO-d6) δ 7.42-7.30 (m, 2H, ArH), 7.00-6.58 (m, 3H,
ArH), 4.28 (m, 1H, H-1), 3.70 (s, 3H, OCH3), 3.50-2.52 (m,
8H, 4CH2), 1.28 (m, 2H, C-CH2-C), 0.60 (t, 3H, CH3). Anal.
(C20H23Br2NO2‚H2C2O4) C, H, N.
10-Meth oxy-1-m eth yl-2,3,12,12a -tetr a h yd r o-1H-[1]ben -
zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (27a ). A mixture of
26a (free base, 170 mg, 0.47 mmol) and EtOH (180 mL) was
hydrogenated at room temperature over 10% Pd/C (50 mg) at
1 bar. After absorption of the calculated hydrogen amount, the
catalyst was filtered, and the solvent was evaporated. The
residue was basified with aqueosus NH4OH and extracted with
CHCl3. The extract was washed with H2O, dried, and evapo-
rated. The base was converted to the oxalate salt and crystal-
lized from i-PrOH/Et2O to give 160 mg (91%) of pure 27a : mp
1
184-187 °C; H NMR (DMSO-d6) δ 7.30-7.05 (m, 4H, ArH),
6.75 (m, 2H, ArH), 4.86 (dd, 1H, J ) 12.45, 4.02 Hz, H-12a),
3.71 (s, 3H, OCH3), 3.55-2.95 (m, 6H, 3CH2), 2.77 (s, 3H,
NCH3). Anal. (C18H19NO2‚H2C2O4) C, H, N.
1-E t h yl-10-m et h oxy-2,3,12,12a -t et r a h yd r o-1H -[1]b en -
zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (27b). Obtained
from 26b with the same procedure as 27a . The base was
converted to the oxalate salt and crystallized from i-PrOH/
1
Et2O to give 110 mg (58%) of pure 27b: mp 181-183 °C; H
NMR (DMSO-d6) δ 7.24 (m, 1H, ArH), 7.10 (m, 3H, ArH), 6.76
(m, 1H, ArH), 6.70 (m, 1H, ArH), 4.98 (dd, 1H, J ) 11.02, 3.85
Hz, H-12a), 3.68 (s, 3H, OCH3), 3.48-2.82 (m, 8H, 4CH2), 1.22
(t, 3H, CH3). Anal. (C19H21NO2‚H2C2O4) C, H, N.
10-Meth oxy-1-p r op yl-2,3,12,12a -tetr a h yd r o-1H-[1]ben -
zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (27c). Obtained
from 26c with the same procedure as 27a . The base was
converted to the oxalate salt and crystallized from i-PrOH/
Et2O to give 90 mg (49%) of pure 27a : mp 146-148 °C; 1H
NMR (DMSO-d6) δ 7.24 (m, 1H, ArH), 7.10 (m, 2H, ArH), 6.76
(m, 2H, ArH), 4.92 (dd, 1H, J ) 10.90, 2.98 Hz, H-12a), 3,68
(s, 3H, OCH3), 3.50-3.20 (m, 4H, 2CH2), 3.14-2.80 (m, 4H,
2CH2), 1.68 (m, 2H, C-CH2-C), 0.96 (t, 3H, CH3). Anal.
(C20H23NO2‚H2C2O4) C, H, N.
10-Hyd r oxy-1-m eth yl-2,3,12,12a -tetr a h yd r o-1H-[1]ben -
zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (6a ). Compound
27a (600 mg, 1.6 mmol) was dissolved in 48% hydrobromic
acid-acetic acid 1:1 (20 mL) and heated at 130 °C under N2
for 2 h. The reaction mixture was diluted with H2O, neutral-
ized with NaHCO3, and extracted with CHCl3. The extracts
were dried and evaporated to give a residue which was
converted to the oxalate salt and crystallized from i-PrOH/
Et2O to give 520 mg (90%) of pure 6a : mp 212-213 °C; 1H
NMR (DMSO-d6) δ 9.18 (s, 1H, OH), 7.13 (m, 1H, ArH), 6.95
(m, 3H, ArH), 6.53 (m, 2H, ArH), 4.25 (dd, 1H, J ) 11.72, 3.67
Hz, H-12a), 3.28-2.60 (m, 6H, 3CH2), 2.48 (s, 3H, NCH3). Anal.
(C17H17NO2‚H2C2O4) C, H, N.
4-Br om o-10-m eth oxy-1-m eth yl-2,3,12,12a -tetr a h yd r o-
1H-[1]ben zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (26a ). A
mixture of 25a (270 mg, 0.61 mmol), anhydrous pyridine (10
mL), and anhydrous potassium carbonate (670 mg, 4.8 mmol)
was heated at 135 °C under N2, and copper(II) oxide (220 mg,
2.2 mmol) was added. The resulting mixture was heated at
160 °C for 5 h. After cooling, the solution was filtered through
silica gel, which was washed thoroughly with CH2Cl2. The
solvent was removed under vacuum and the residue was taken
into CH2Cl2 and washed with H2O, with 10% cupric sulfate,
and another time with H2O. The extracts were dried and
evaporated. The residue was purified by silica gel column
chromatography (ethyl acetate/cyclohexane 9/1). The base was
converted to the oxalate salt and crystallized from i-PrOH/
1-E t h yl-10-h yd r oxy-2,3,12,12a -t et r a h yd r o-1H -[1]b en -
zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (6b). Obtained from
27b with the same procedure as 6a . The base was converted
to the oxalate salt and crystallized from i-PrOH/Et2O to
give 460 mg (59%) of pure 6b: mp 202-204 °C; 1H NMR
(DMSO-d6) δ 7.22 (m, 1H, ArH), 7.02 (m, 3H, ArH), 6.52 (m,
2H, ArH), 4.98 (dd, 1H, J ) 11.20, 3.20 Hz, H-12a), 3.50-2.80
(m, 8H, 4CH2), 1.28 (t, 3H, CH3). Anal. (C18H19NO2‚H2C2O4)
C, H, N.
1
Et2O to give 170 mg (62%) of pure 26a : mp 219-221 °C; H
NMR (DMSO-d6) δ 7.58 (d, 1H, ArH), 7.16 (m, 2H, ArH), 6.85-
6.70 (m, 2H, ArH), 4.64 (dd, 1H, J ) 12.25, 3.70 Hz, H-12a),
3.69 (s, 3H, OCH3), 3.40-2.82 (m, 6H, 3CH2), 2.70 (s, 3H,
NCH3). Anal. (C18H18BrNO2‚H2C2O4) C, H, N.
4-Br om o-1-eth yl-10-m eth oxy-2,3,12,12a -tetr a h yd r o-1H-
[1]ben zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (26b). Ob-
tained from 25b with the same procedure as 26a . The base
was converted to the oxalate salt and crystallized from i-PrOH/
10-Hyd r oxy-1-p r op yl-2,3,12,12a -tetr a h yd r o-1H-[1]ben -
zoxep in o[2,3,4-ij]isoqu in olin e Oxa la te (6c). Obtained from
27c with the same procedure as 6a . The base was converted
to the oxalate salt and crystallized from i-PrOH/Et2O to give
1
Et2O to give 195 mg (69%) of pure 26b: mp 202-203 °C; H
1
NMR (DMSO-d6) δ 7.50 (m, 1H, ArH), 7.10 (m, 2H, ArH), 6.75
(m, 1H, ArH), 6.70 (m, 1H, ArH), 4.85 (dd, 1H, J ) 10.99, 3.05
Hz, H-12a), 3.68 (s, 3H, OCH3), 3.40-3.16 (m, 4H, 2CH2),
520 mg (64%) of pure 6c: mp 122-124 °C; H NMR (DMSO-
d6) δ 7.20 (m, 1H, ArH), 7.00 (m, 2H, ArH), 6.2 (m, 2H, ArH),
4.88 (dd, 1H, J ) 10.80, 2.85 Hz, H-12a), 3.44-2.72 (m, 8H,