4
0
Vol. 57, No. 1
chloro-7-methoxyisoquinoline and 1-ethylpiperazine. H-NMR (CDCl ) d:
1
1
hydroxyisoquinoline (9o): H-NMR (CDCl ) d: 8.03 (1H, d, Jꢀ5.5 Hz), 7.70
3
3
(
1H, d, Jꢀ8.8 Hz), 7.43 (1H, d, Jꢀ2.6 Hz), 7.30—7.23 (2H, m), 3.72—3.64 8.07 (1H, d, Jꢀ5.8 Hz), 7.68 (1H, d, Jꢀ8.7 Hz), 7.40 (1H, d, Jꢀ2.5 Hz),
ꢃ
(
4H, m), 3.34—3.26 (4H, m), 1.51 (9H, s). MS m/z: 329 (M ), 173.
7.31—7.25 (1H, m), 7.21 (1H, d, Jꢀ5.8 Hz), 3.48—3.39 (4H, m), 2.79—
2.69 (4H, m), 2.55 (2H, q, Jꢀ7.2 Hz), 1.17 (3H, t, Jꢀ7.2 Hz). MS m/z: 271
Step 2 A mixture of 1-(4-tert-butoxycarbonylpiperazin-1-yl)-7-hydroxy-
ꢃ
isoquinoline (9o, 70 mg, 0.21 mmol) and 4 N hydrochloric acid-ethyl acetate
(M ), 187.
solution (3 ml) was stirred for 1 h at room temperature. Precipitates were
1-[4-(4-Fluorobenzyl)piperazin-1-yl]-7-methoxyisoquinoline (10e)
collected by filtration and washed with ethyl acetate to provide 43 mg (78%) To a solution of 9d (50 mg, 0.21 mmol) in acetone (10 ml), 4-fluorobenzyl
1
of title compound. H-NMR (CD OD) d: 8.02 (1H, d, Jꢀ8.5 Hz), 7.78 (1H,
bromide (0.10 g, 0.53 mmol) and triethylamine (0.10 g, 0.99 mmol) were
d, Jꢀ6.6 Hz), 7.72 (1H, d, Jꢀ6.6 Hz), 7.64—7.56 (2H, m), 4.06—3.98 (4H, added and heated under reflux for 5 h. Distilling the solvent off under re-
3
ꢃ
m), 3.68—3.59 (4H, m). MS m/z: 229 (M ), 173.
duced pressure, the residue was purified on silica gel column chromatogra-
7
-Dimethylamino-1-piperazin-1-ylisoquinoline (9u). General Proce- phy (methanol : chloroformꢀ1 : 19) to provide 52 mg (79%) of title com-
1
dure of 7-Methylamino and 7-Dimethyaminoisoquinoline Derivatives. pound. H-NMR (CDCl ) d: 8.07 (1H, d, Jꢀ5.5 Hz), 7.68 (1H, d, Jꢀ9.2 Hz),
3
Step 1 A mixture of 1,7-dichloroisoquinoline (3.96 g, 20.0 mmol) and ben-
7.41—7.32 (3H, m), 7.30—7.26 (1H, m), 7.21 (1H, d, Jꢀ5.5 Hz), 7.06—
zylpiperazine (10.5 g, 59.6 mmol) was stirred at 150 °C for 3 h. Water was
6.99 (2H, m), 3.93 (3H, s), 3.61 (2H, s), 3.45—3.35 (4H, m), 2.77—2.67
added to the residue, followed by extraction with chloroform, washing with (4H, m). MS m/z: 351 (M ), 187.
ꢃ
saturated aqueous sodium hydrogencarbonate solution and drying over anhy-
drous magnesium sulfate. Distilling the solvent off under reduced pressure,
1-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-yl)-7-methoxyisoquino-
line (10f) This compound was synthesized using the same procedure as for
the residue was purified on silica gel column chromatography (ethyl acetate) 15a starting with 1-chloro-7-methoxyisoquinoline and 1-benzo[1,3]dioxol-
1
to provide 4.78 g (71%) of 1-(4-benzylpiperazin-1-yl)-7-chloroisoquinoline 5-ylmethyl-piperazine. H-NMR (CDCl ) d: 8.07 (1H, d, Jꢀ5.8 Hz), 7.97
3
1
(
9q): H-NMR (CDCl ) d: 8.14 (1H, d, Jꢀ5.4 Hz), 8.04 (1H, d, Jꢀ1.9 Hz),
(1H, d, Jꢀ9.3 Hz), 7.13 (1H, d, Jꢀ5.8 Hz), 7.09 (1H, dd, Jꢀ2.7, 9.3 Hz),
7.00 (1H, d, Jꢀ2.7 Hz), 6.91 (1H, s), 6.77 (2H, t, Jꢀ7.2 Hz), 5.94 (2H, s),
3.91 (3H, s), 3.53 (2H, s), 3.39 (4H, m), 2.69 (4H, t, Jꢀ4.5 Hz). MS m/z:
3
7
7
.68 (1H, d, Jꢀ8.5 Hz), 7.53 (1H, dd, Jꢀ2.3, 8.8 Hz), 7.39—7.23 (5H, m),
.20 (1H, d, Jꢀ5.8 Hz), 3.64 (2H, s), 3.41 (4H, t, Jꢀ5.6 Hz), 2.73 (4H, t,
ꢃ
ꢃ
Jꢀ4.8 Hz). MS m/z: 337 (M ), 191, 159, 91.
377 (M ), 187, 174, 135.
Step 2 To a solution of 1-(4-benzylpiperazin-1-yl)-7-chloroisoquinoline
1-[1,4]Diazepan-1-yl-7-methoxyisoquinoline (10g) This compound
(
2
9s, 1.0 g, 3.0 mmol) in tetrahydrofuran (30 ml), palladium acetate (20 mg),
-(di-tert-butylphosphino)biphenyl (48 mg, 0.16 mmol), sodium-tert-butox-
ide (0.45 g, 4.7 mmol) and 2.0 M dimethylamine-tetrahydrofuran solution
was synthesized using the same procedure as for 15a starting with 1-chloro-
1
7-methoxyisoquinoline and homopiperazine. H-NMR (CDCl ) d: 8.02—
3
7.99 (2H, m), 7.11—7.09 (2H, m), 7.00 (1H, d, Jꢀ2.3 Hz), 3.92 (3H, s),
(
1
5 ml) were added and sealed in a tube. This mixture was stirred at 80 °C for
3.76 (2H, t, Jꢀ5.4 Hz), 3.72 (2H, t, Jꢀ5.8 Hz), 3.27 (2H, t, Jꢀ5.4 Hz), 3.16
6 h. Removing the insoluble matter by filtration, the solvent was distilled (2H, t, Jꢀ5.7 Hz), 2.75 (1H, br s), 2.00—1.95 (2H, m). MS m/z: 257 (M ),
ꢃ
off under reduced pressure and the residue was purified on silica gel column 242, 201, 187.
chromatography (methanol : chloroformꢀ1 : 19) to provide 261 mg (25%)
1-(2,5-Diazabicyclo[2.2.2]octan-1-yl)-7-methoxyisoquinoline (10h)
of 1-(4-benzylpiperazin-1-yl)-7-dimethylaminoisoquinoline (9s). H-NMR This compound was synthesized using the same procedure as for 15a start-
1
(
CDCl ) d: 7.94 (1H, d, Jꢀ5.7 Hz), 7.63 (1H, d, Jꢀ9.0 Hz), 7.45—7.20 (6H, ing with 1-chloro-7-methoxyisoquinoline and 2,5-diazabicyclo[2.2.2]octane.
3
1
m), 7.18 (1H, d, Jꢀ5.4 Hz), 7.12 (1H, d, Jꢀ2.3 Hz), 3.69 (2H, s), 3.49 (4H,
H-NMR (DMSO-d ) d: 7.97 (1H, d, Jꢀ8.9 Hz), 7.79 (1H, d, Jꢀ6.2 Hz),
6
ꢃ
t, Jꢀ4.8 Hz), 3.06 (6H, s), 2.77 (4H, t, Jꢀ5.0 Hz). MS m/z: 346 (M ), 330, 7.59 (1H, d, Jꢀ8.9 Hz), 7.48 (1H, s), 7.42 (1H, d, Jꢀ6.2 Hz), 4.63 (1H, br s),
00, 187, 91.
4.42—4.31 (1H, m), 4.10—3.98 (1H, m), 3.96 (3H, s), 3.96—3.27 (3H, m),
Step 3 To a solution of 1-(4-benzylpiperazin-1-yl)-7-dimethylaminoiso- 2.48—2.37 (1H, m), 2.28—2.13 (1H, m), 2.08—1.92 (2H, m). MS m/z: 269
2
ꢃ
quinoline (9s, 0.25 g, 0.72 mmol) in ethanol (20 ml), 10% palladium-on car-
(M ), 175.
bon (50 mg) was added. This mixture was stirred for 16 h at room tempera-
1-((8aS)-Octahydropyrrolo[1,2-a]pyrazin-2-yl)-7-methoxyisoquinoline
ture under hydrogen atmosphere. After filtration, the filtrate was distilled off (10i) This compound was synthesized using the same procedure as for 15a
under reduced pressure. The residue was purified on silica gel column chro- starting with 1-chloro-7-methoxyisoquinoline and (8aS)-octahydropyrrolo-
1
matography (methanol : chloroformꢀ1 : 9) to provide 46 mg (25%) of title [1,2-a]pyrazine. H-NMR (CDCl ) d: 8.07 (1H, d, Jꢀ5.4 Hz), 7.68 (1H, d,
3
1
compound (9u). H-NMR (CDCl ) d: 7.95 (1H, d, Jꢀ5.4 Hz), 7.64 (1H, d,
Jꢀ8.9 Hz), 7.40 (1H, d, Jꢀ2.7 Hz), 7.29 (1H, dd, Jꢀ2.3, 8.9 Hz), 7.21 (1H,
d, Jꢀ5.4 Hz), 3.94 (3H, s), 3.87—3.84 (1H, m), 3.79—3.75 (2H, m), 3.22—
3.16 (2H, m), 2.93—2.88 (1H, m), 2.64—2.58 (1H, m), 2.40—2.38 (1H, m),
3
Jꢀ8.9 Hz), 7.27 (1H, dd, Jꢀ2.3, 8.9 Hz), 7.16 (1H, d, Jꢀ5.4 Hz), 7.12 (1H,
d, Jꢀ2.3 Hz), 3.39 (4H, t, Jꢀ5.0 Hz), 3.19 (4H, t, Jꢀ5.0 Hz), 3.07 (6H, s).
ꢃ
MS m/z: 256 (M ), 200, 187.
2.29 (1H, q, Jꢀ8.5 Hz), 1.94—1.76 (3H, m), 1.65—1.52 (1H, m). MS m/z:
ꢃ
7
-Methylamino-1-piperazin-1-ylisoquinoline (9t) This compound was 283 (M ), 96.
synthesized using the same procedure as for 9u using 1-(4-benzylpiperazin-
1-((8aR)-Octahydropyrrolo[1,2-a]pyrazin-2-yl)-7-methoxyisoquinoline
1
1
-yl)-7-chloroisoquinoline and methylamine. H-NMR (CDCl ) d: 7.93 (1H, (10j) This compound was synthesized using the same procedure as for 15a
3
d, Jꢀ5.8 Hz), 7.57 (1H, d, Jꢀ8.9 Hz), 7.17 (1H, d, Jꢀ5.4 Hz), 7.01 (1H, dd, starting with 1-chloro-7-methoxyisoquinoline and (8aR)-octahydropyr-
1
Jꢀ1.3, 8.9 Hz), 6.90 (1H, d, Jꢀ1.9 Hz), 3.56 (4H, t, Jꢀ5.0 Hz), 3.33 (4H, t,
rolo[1,2-a]pyrazine. H-NMR (CDCl ) d: 8.06 (1H, d, Jꢀ5.8 Hz), 7.66 (1H,
3
ꢃ
Jꢀ5.0 Hz), 2.94 (3H, s). MS m/z: 242 (M ), 198, 186, 173.
dd, Jꢀ3.4, 8.9 Hz), 7.39 (1H, d, Jꢀ2.3 Hz), 7.27 (1H, dd, Jꢀ2.3, 8.9 Hz),
7
-Methoxy-1-(3-methylpiperazin-1-yl)isoquinoline (10a) This com- 7.19 (1H, d, Jꢀ5.4 Hz), 3.93 (3H, s), 3.85 (1H, td, Jꢀ2.3, 12.0 Hz), 3.77—
pound was synthesized using the same procedure as for 15a starting with 1-
3.74 (1H, m), 3.20—3.15 (3H, m), 2.89 (1H, t, Jꢀ10.8 Hz), 2.60 (1H, t,
Jꢀ11.2 Hz), 2.39—2.37 (1H, m), 2.32—2.25 (1H, m), 1.93—1.83 (2H, m),
1.80—1.76 (1H, m), 1.59—1.51 (1H, m). MS m/z: 283 (M ), 96.
1
chloro-7-methoxyisoquinoline and 2-methylpiperazine. H-NMR (CDCl ) d:
3
ꢃ
8
7
3
1
.07 (1H, d, Jꢀ5.8 Hz), 7.68 (1H, d, Jꢀ8.9 Hz), 7.40 (1H, d, Jꢀ2.7 Hz),
.29 (1H, dd, Jꢀ2.7, 8.9 Hz), 7.23 (1H, d, Jꢀ5.8 Hz), 3.94 (3H, s), 3.70—
7-Methoxy-1-octahydropyrido[1,2-a]pyrazin-2-ylisoquinoline (10k)
.62 (2H, m), 3.30—3.17 (3H, m), 3.08—2.99 (1H, m), 2.80—2.71 (1H, m), This compound was synthesized using the same procedure as for 15b
ꢃ
.20 (3H, d, Jꢀ6.6 Hz). MS m/z: 257 (M ), 175.
starting with 1-chloro-7-methoxyisoquinoline and octahydropyrido[1,2-a]-
1
7
-Methoxy-1-(4-methylpiperazin-1-yl)isoquinoline (10b) This com- pyrazine. H-NMR (CDCl ) d: 8.07 (1H, d, Jꢀ5.4 Hz), 7.67 (1H, d,
3
pound was synthesized using the same procedure as for 15a starting with 1-
Jꢀ8.9 Hz), 7.40 (1H, d, Jꢀ2.7 Hz), 7.28 (1H, dd, Jꢀ2.7, 8.9 Hz), 7.20 (1H,
1
chloro-7-methoxyisoquinoline and 1-methylpiperazine. H-NMR (CDCl ) d:
d, Jꢀ5.8 Hz), 3.94 (3H, s), 3.72 (1H, qd, Jꢀ2.7, 12.3 Hz), 3.57 (1H, td,
Jꢀ2.7, 12.3 Hz), 3.26—3.16 (1H, m), 2.98—2.84 (3H, m), 2.63 (1H, dt,
3
8
7
3
.07 (1H, d, Jꢀ5.8 Hz), 7.68 (1H, d, Jꢀ8.9 Hz), 7.39 (1H, d, Jꢀ2.7 Hz),
.29 (1H, dd, Jꢀ2.7, 8.9 Hz), 7.22 (1H, d, Jꢀ5.8 Hz), 3.94 (3H, s), 3.48— Jꢀ2.7, 11.6 Hz), 2.35—2.25 (1H, m), 2.25—2.15 (1H, m), 1.84—1.54 (4H,
ꢃ
ꢃ
.40 (4H, m), 2.77—2.69 (4H, m). MS m/z: 257 (M ), 187.
-(3,5-Dimethylpiperazin-1-yl)-7-methoxyisoquinoline (10c) This
compound was synthesized using the same procedure as for 15a starting
m), 1.42—1.32 (2H, m). MS m/z: 297 (M ), 110.
1
7-(4-Methylpiperazin-1-yl)furo[2,3-c]pyridine (15b) This compound
was synthesized using the same procedure as for 15a starting with 7-chloro-
1
1
with 1-chloro-7-methoxyisoquinoline and 2,6-dimethylpiperazine. H-NMR furo[2,3-c]pyridine and 1-methylpiperazine. H-NMR (CDCl ) d: 7.95 (1H,
3
(
CDCl ) d: 8.07 (1H, d, Jꢀ5.8 Hz), 7.68 (1H, d, Jꢀ8.9 Hz), 7.40 (1H, d, d, Jꢀ5.3 Hz), 7.62 (1H, d, Jꢀ1.9 Hz), 6.96 (1H, d, Jꢀ5.4 Hz), 6.72 (1H, d,
3
Jꢀ2.7 Hz), 7.29 (1H, dd, Jꢀ2.7, 8.9 Hz), 7.21 (1H, d, Jꢀ5.8 Hz), 3.93 (3H,
Jꢀ1.9 Hz), 3.88 (4H, t, Jꢀ5.0 Hz), 2.59 (4H, t, Jꢀ5.0 Hz), 2.38 (3H, s). MS
ꢃ
s), 3.70—3.62 (2H, m), 3.33—3.23 (2H, m), 2.66—2.57 (2H, m), 1.17 (6H, m/z: 217 (M ), 147.
ꢃ
d, Jꢀ6.6 Hz). MS m/z: 271 (M ), 187.
7-Piperazin-1-ylthieno[2,3-c]pyridine (15c) This compound was syn-
1
-(4-Ethylpiperazin-1-yl)-7-methoxyisoquinoline (10d) This com- thesized using the same procedure as for 15a starting with 7-chlorothi-
1
pound was synthesized using the same procedure as for 15a starting with 1-
eno[2,3-c]pyridine and anhydrous piperazine. H-NMR (CDCl ) d: 8.14
3