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Vol. 52, No. 9
8.44 (1H, dd, Jꢆ0.8, 7.6 Hz), 9.60 (1H, br s). ESI-MS m/z: 323 (MꢂH)ꢂ.
Anal. Calcd for C18H18N4O2·HCl·1.3H2O: C, 56.56; H, 5.70; N, 14.66.
Found: C, 56.21; H, 5.31; N, 14.56.
dione Hydrochloride (13) This compound was obtained from 40a
(350 mg, 1.24 mmol) in a similar manner to the preparation of 31b (200 mg,
0.58 mmol, 47%), mp 278—280 °C (EtOH). 1H-NMR (DMSO-d6) d 2.90
(6H, br s), 3.44—3.49 (2H, m), 4.41 (2H, t, Jꢆ5.6 Hz), 7.55—7.60 (1H, m),
7.67—7.72 (2H, m), 8.10 (1H, dd, Jꢆ0.8, 7.6 Hz), 8.34—8.37 (1H, m),
8.38—8.41 (1H, m), 8.58 (1H, dd, Jꢆ0.8, 7.6 Hz), 9.62 (1H, br s). ESI-MS
m/z: 308 (MꢂH)ꢂ, Anal. Calcd for C18H17N3O2·HCl: C, 62.88; H, 5.28; N,
12.22. Found: C, 62.64; H, 5.33; N, 12.12.
N-[2-(Dimethylamino)ethyl]-6-nitro-9H-carbazole-1-carboxamide
(40b) and N-[2-(Dimethylamino)ethyl]-3-nitro-9H-carbazole-1-carbox-
amide (40c) A solution of potassium nitrate (1.01 g, 10.0 mmol) in H2SO4
(2.5 ml) was added dropwise to a stirred solution of 39a (2.0 g, 9.5 mmol) in
AcOH (250 ml) at 0 °C. After stirring overnight at r.t., H2O was slowly
added to the mixture. The precipitate was collected and washed with H2O
and dried in vacuo to yield 2.3 g of crude product which was subsequently
dissolved in DMF (100 ml). The solution was treated with CDI (2.9 g,
18 mmol), and stirred for 2 h. The reaction mixture was treated with N,N-di-
methylethylenediamine (4.0 ml, 36 mmol), stirred overnight before addition
of H2O. The mixture was extracted with EtOAc–THF solution (1 : 1 in vol-
ume). The organic layer was washed successively with H2O, NaHCO3 (aq.),
and brine and then concentrated in vacuo. The residue was purified by col-
umn chromatography on SiO2 (CH2Cl2–EtOH) to yield 40b (1.46 g,
4.47 mmol, 47%) and 40c (0.21 g, 0.64 mmol, 7%). Analytical samples were
obtained by converting each free base into hydrochloride salts 41b and 41c
in a usual manner as a yellow solid.
N-[2-(Dimethylamino)ethyl]-6-nitro-9H-carbazole-1-carboxamide Hy-
drochloride (41b) 1H-NMR (DMSO-d6) d27) 2.85 (6H, br s), 3.26—3.38
(2H, m), 3.73 (2H, q, Jꢆ5.6 Hz), 7.38 (1H, t, Jꢆ7.6 Hz), 7.86 (1H, d,
Jꢆ9.0 Hz), 8.09 (1H, d, Jꢆ7.6 Hz), 8.32 (1H, dd, Jꢆ2.2, 9.0 Hz), 8.60 (1H,
d, Jꢆ7.6 Hz), 9.04 (1H, t, Jꢆ5.6 Hz), 9.22 (1H, d, Jꢆ2.2 Hz), 9.93 (1H,
br s), 12.14 (1H, s).
N-[2-(Dimethylamino)ethyl]-3-nitro-9H-carbazole-1-carboxamide Hy-
drochloride (41c) 1H-NMR (DMSO-d6) d27) 2.84 (6H, br s), 3.20—3.40
(2H, m), 3.65—3.80 (2H, m), 7.31 (1H, t, Jꢆ7.6 Hz), 7.52 (1H, t,
Jꢆ7.6 Hz), 7.81 (1H, d, Jꢆ7.6 Hz), 8.41 (1H, d, Jꢆ7.6 Hz), 8.90 (1H, d,
Jꢆ2.0 Hz), 9.20—9.28 (1H, m) 9.35 (1H, d, Jꢆ2.0 Hz), 9.64—9.86 (1H, m),
12.14 (1H, br s).
2-[2-(Dimethylamino)ethyl]-8-nitro-1H-pyrimido[5,6,1-jk]carbazole-
1,3(2H)-dione Hydrochloride (21) Sodium hydride (1.75 g, 40 mmol,
55% dispersion in oil) was added to a stirred solution of 40b (5.82 g,
17.8 mmol) in DMF (200 ml) and the mixture was stirred for 1 h at r.t. under
nitrogen atmosphere. Then the mixture was added a solution of ethyl chloro-
formate (3.8 ml, 40 mmol) in CH2Cl2 (10 ml) at 0 °C and stirred for 30 min
at the same temperature. The reaction mixture was acidified with 1 N HCl
(aq.) and the precipitate was collected before recrystallization from EtOH to
yield the title compound as pale yellow crystals (5.54 g, 14.2 mmol, 80%),
mp 288—290 °C (dec.) (EtOH). 1H-NMR (DMSO-d6) d 2.89 (6H, br s),
3.46—3.50 (2H, m), 4.43 (2H, t, Jꢆ5.6 Hz), 7.76 (1H, t, Jꢆ7.6 Hz), 8.19
(1H, d, Jꢆ7.6 Hz), 8.53—8.60 (2H, m), 8.80 (1H, d, Jꢆ7.6 Hz), 9.38 (1H, d,
Jꢆ2.0 Hz), 10.18 (1H, br s). ESI-MS m/z: 353 (MꢂH)ꢂ, Anal. Calcd for
C18H16N4O4·HCl·2.15H2O: C, 50.57; H, 5.02; N, 13.10. Found: C, 50.49;
H, 4.69; N, 13.09.
8-Amino-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-
1,3(2H)-dione (44b) and 8-Amino-2-[2-(dimethylamino)ethyl]-1H-
pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione Hydrochloride (14) A mix-
ture of 21 (5.54 g, 14 mmol) and 50% Pd–C (550 mg) in AcOH (200 ml) and
1 N HCl (aq.) (50 ml) was stirred under 1 atm of hydrogen overnight. The
catalyst was removed by filtration and the filtrate was concentrated in vacuo.
The residue was treated with H2O and NaHCO3 (aq.), and then the mixture
was extracted with EtOAc. The organic layer was washed successively with
8-Acetylamino-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]car-
bazole-1,3(2H)-dione Hydrochloride (15) A mixture of 44b (1.61 g,
4.99 mmol) and acetic anhydride (15 ml) and pyridine (15 ml) was stirred at
r.t. for 3 h. The reaction mixture was added ethyl acetate and the precipitate
obtained was collected by filtration before being suspended in EtOH. The
suspension was treated with an excess amount of 1 N HCl (aq.), and the pre-
cipitate obtained was collected to yield the title compound as a white solid
(1.81 g, 4.51 mmol, 90%), mp 285—287 °C (dec.) (EtOH). 1H-NMR
(DMSO-d6) d 2.12 (3H, s), 2.92 (6H, br s), 3.45—3.52 (2H, m), 4.40 (2H, t,
Jꢆ5.6 Hz), 7.67 (1H, t, Jꢆ7.6 Hz), 7.74 (1H, dd, Jꢆ2.0, 8.8 Hz), 8.10 (1H,
dd, Jꢆ0.8, 7.6 Hz), 8.30 (1H, d, Jꢆ8.8 Hz), 8.53 (1H, dd, Jꢆ0.8, 7.6 Hz),
8.62 (1H, d, Jꢆ2.0 Hz), 9.29 (1H, br s), 10.32 (1H, s). ESI-MS m/z: 365
(MꢂH)ꢂ. Anal. Calcd for C20H20N4O3·HCl·H2O: C, 57.35; H, 5.53; N,
13.38. Found: C, 57.18; H, 5.42; N, 13.31.
8-Pentanoylamino-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-
jk]carbazole-1,3(2H)-dione Hydrochloride (25)
A mixture of 44b
(64 mg, 0.20 mmol) and n-pentanoyl chloride (0.028 ml, 0.24 mmol) and tri-
ethylamine (0.084 ml, 0.60 mmol) in CH2Cl2 (10 ml) was stirred at r.t. for
3 h. The reaction mixture was added H2O and then extracted with EtOAc.
The organic layer was washed successively with NaHCO3 (aq.) and brine.
The organic layer was dried over MgSO4 and then concentrated in vacuo.
The residue was dissolved in EtOH and treated with an excess amount of 1 N
HCl (aq.) before evaporation. The residual solid was suspended in
EtOH–hexane (1 : 1 in volume). The precipitate was collected to yield the
title compound as a pale yellow solid (65 mg, 0.15 mmol, 75%), mp 234—
236 °C (EtOH–hexane). 1H-NMR (DMSO-d6) d 0.93 (2H, t, Jꢆ7.6 Hz),
1.36 (2H, m), 1.63 (2H, m), 2.38 (2H, t, Jꢆ7.6 Hz), 3.46—3.49 (2H, m),
4.39 (2H, q, Jꢆ5.6 Hz), 7.66 (1H, t, Jꢆ7.6 Hz), 7.73 (1H, dd, Jꢆ2.0,
8.8 Hz), 8.09 (1H, d, Jꢆ7.6 Hz), 8.28 (1H, d, Jꢆ8.8 Hz), 8.51 (1H, d,
Jꢆ7.6 Hz), 8.63 (1H, d, Jꢆ2.0 Hz), 9.25 (1H, br s), 10.22 (1H, s). ESI-MS
m/z: 407 (MꢂH)ꢂ, Anal. Calcd for C23H26N4O3·HCl·1.5H2O: C, 58.78; H,
6.43; N, 11.92. Found: C, 58.71; H, 6.40; N, 12.22.
2-[2-(Dimethylamino)ethyl]-8-methanesulfonylamino-1H-pyrim-
ido[5,6,1-jk]carbazole-1,3(2H)-dione Hydrochloride (22) A mixture of
14 (200 mg, 0.56 mmol) and methanesulfonic anhydride (976 mg, 5.6 mmol)
and pyridine (20 ml) was stirred under reflux for 1 h. The mixture was evap-
orated and NaHCO3 (aq.) was added, which was extracted with EtOAc–THF
solution (1 : 1 in volume). The organic layer was washed successively with
H2O and brine, and dried over MgSO4, and then concentrated in vacuo. The
residue was purified by column chromatography on SiO2 (CH2Cl2–MeOH)
to furnish the title compound as a free base, which was hydrochlorinated to
yield the title compound as a brown solid (110 mg, 0.25 mmol, 45%), mp
1
285—288 °C (dec.) (EtOH). H-NMR (DMSO-d6) d27) 2.90 (6H, br s), 3.05
(3H, s), 3.42—3.52 (2H, m), 4.35—4.42 (2H, m), 7.47—7.55 (1H, m), 7.67
(1H, t, Jꢆ7.6 Hz), 8.06—8.16 (2H, m), 8.32 (1H, d, Jꢆ8.8 Hz), 8.57 (1H, d,
Jꢆ7.6 Hz), 9.35 (1H, br s), 10.01 (1H, s). ESI-MS m/z: 401 (MꢂH)ꢂ, Anal.
Calcd for C19H20N4O4S·HCl·H2O: C, 50.16; H, 5.10; N, 12.32. Found: C,
50.17; H, 5.02; N, 12.30.
2-[2-(Dimethylamino)ethyl]-5-nitro-1H-pyrimido[5,6,1-jk]carbazole-
1,3(2H)-dione Hydrochloride (43c) The title compound’s free base (42c)
was obtained from 40c (210 mg, 0.64 mmol) in a similar manner to the
preparation of 21. Yield of 42c: 165 mg, 0.47 mmol, 73%. A part of 42c
(10 mg, 0.028 mmol) obtained above was converted into its HCl salt (43c) in
a usual manner as a white solid (10 mg, 0.026 mmol, 93% based on the free
base 42c).
42c (Free Base of 43c): 1H-NMR (DMSO-d6) d 2.24 (6H, s), 2.56 (2H, t,
Jꢆ6.8 Hz), 4.16 (2H, t, Jꢆ6.8 Hz), 7.61—7.65 (1H, m), 7.75—7.79 (1H,
H2O and brine and dried over MgSO4 before being concentrated in vacuo. m), 8.42 (1H, d, Jꢆ8.4 Hz), 8.57 (1H, dd, Jꢆ0.8, 7.6 Hz), 8.75 (1H, d,
The residual solid was recrystallized from EtOH to yield 44b (3.74 g,
12 mmol, 81%) as yellow crystals. Compound 44b (430 mg, 1.3 mmol) was
suspended in EtOH (20 ml) and 1 N HCl (aq.) was added and stirred
overnight. The precipitate obtained was collected by filtration to yield the
title compound 14 (480 mg, 100%) as pale yellow crystals, mp 281—283 °C
(dec.) (EtOH).
Jꢆ2.0 Hz), 9.52 (1H, d, Jꢆ2.0 Hz).
43c: H-NMR (DMSO-d6) d 2.83 (6H, br s), 3.28—3.46 (2H, m), 4.36—
4.44 (2H, m), 7.63—7.68 (1H, m), 7.77—7.82 (1H, m), 8.41—8.44 (1H, m),
8.59—8.62 (1H, m), 8.78 (1H, d, Jꢆ2.0 Hz), 9.57 (1H, d, Jꢆ2.0 Hz), 9.60—
9.88 (1H, m). Anal. Calcd for C18H16N4O4·HCl·0.4H2O: C, 54.59; H, 4.53;
N, 14.15. Found: C, 54.65; H, 4.36; N, 14.14.
5-Amino-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-
1,3(2H)-dione Dihydrochloride (16) The title compound was obtained
from 42c (150 mg, 0.43 mmol) in a similar manner to the preparation of 7 as
a white solid (170 mg, 0.43 mmol, 99%), mp 294—297 °C (dec.) (EtOH).
1H-NMR (DMSO-d6) d 2.84—2.94 (6H, m), 3.42—3.52 (2H, m), 4.40 (2H,
t, Jꢆ5.6 Hz), 7.54—7.59 (1H, m), 7.67—7.73 (1H, m), 7.86 (1H, d,
Jꢆ1.6 Hz), 8.23 (1H, d, Jꢆ1.6 Hz), 8.32—8.38 (2H, m), 10.05 (1H, br s).
1
44b (Free Base): 1H-NMR (CDCl3) d 2.36 (6H, s), 2.69 (2H, t,
Jꢆ7.0 Hz), 4.32 (2H, t, Jꢆ7.0 Hz), 6.92 (1H, dd, Jꢆ2.4, 8.8 Hz), 7.29 (1H,
d, Jꢆ2.4 Hz), 7.50 (1H, t, Jꢆ7.6 Hz), 8.09—8.12 (2H, m), 8.23 (1H, d,
Jꢆ8.8 Hz).
1
14 (HCl Salt): H-NMR (DMSO-d6) d 2.91 (6H, br s), 3.44—3.50 (2H,
m), 4.39 (2H, t, Jꢆ5.6 Hz), 7.04—7.08 (1H, m), 7.54—7.56 (1H, m), 7.63
(1H, t, Jꢆ5.6 Hz), 8.05 (1H, dd, Jꢆ0.8, 7.6 Hz), 8.12 (1H, d, Jꢆ8.8 Hz),