Z. Zhang et al. / European Journal of Medicinal Chemistry 46 (2011) 3986e3995
3993
Anal. Calcd for (C21H22FNO3$H2C2O4: C, 62.02; H, 5.43; N, 3.14.
Found: C, 6175; H, 5.52; N, 3.12.
followed to prepare compound 6i (0.16 g, 47%) as a white solid. Mp
(oxalate salt): 208.4e209.2 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
d
3.83 (s, 3 H), 4.00 (s, 3 H), 4.29 (dt, J ¼ 27.3, 4.5 Hz, 2 H), 4.49 (s,
4.1.7.3. 6-(2-Fluoroethoxy)-7-methoxy-1-(4-(methylthio)benzyl)iso-
quinoline oxalate (6c). Starting with 5c, procedure G was followed
to prepare compound 6c (0.23 g, 72%) as a white solid. Mp (oxalate
2 H), 4.83 (dt, J ¼ 47.4, 4.5 Hz, 2 H), 6.78 (d, J ¼ 8.1 Hz, 1 H), 7.07 (s,
1H), 7.13 (dd, J ¼ 8.1,1.8 Hz,1 H), 7.32 (s,1 H), 7.43 (d, J ¼ 5.7 Hz,1 H),
7.49 (d, J ¼ 1.8 Hz, 1 H), 8.37 (d, J ¼ 5.7 Hz, 1 H). Anal. Calcd for
C20H19BrFNO3$H2C2O4: C, 51.78; H, 4.15; N, 2.74. Found: C, 51.92; H,
4.21; N, 2.80.
salt): 138.5e140.0 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
d 2.42 (s,
3 H), 3.88 (s, 3 H), 4.38 (dt, J ¼ 27.0, 4.2 Hz, 2 H), 4.55 (s, 2 H), 4.86
(dt, J ¼ 47.4, 4.2 Hz, 2 H), 7.06 (s, 1 H), 7.14e7.21 (m, 4 H), 7.38 (s,1H),
7.41 (d, J ¼ 6.0 Hz, 1 H), 8.36 (d, J ¼ 6.0 Hz, 1 H). Anal. Calcd for
C20H20FNO2S$H2C2O4$0.5H2O: C, 57.88; H, 5.08; N, 3.07. Found: C,
57.89; H, 5.03; N, 2.93.
4.1.7.10. 1-(3-Fluorobenzyl)-7-(2-fluoroethoxy)-6-methoxyisoquinoline
oxalate (6j). Starting with 5j, procedure G was followed to prepare
compound 6j (0.12 g, 35%) as a white solid. Mp (oxalate salt):
182.4e183.4 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
d 3.92 (s, 3 H),
4.1.7.4. 1-(4-Fluoro-3-methoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline oxalate (6d). Starting with 5d, procedure G
was followed to prepare 6d (0.21 g, 66%) as a white solid. Mp
(oxalate salt): 207.7e208.7 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
4.18 (dt, J ¼ 27.3, 4.2 Hz, 2 H), 4.49 (s, 2 H), 4.73 (dt, J ¼ 47.4, 4.2 Hz,
2 H), 6.76e6.87 (m, 2 H), 6.95e7.00 (m, 2 H), 7.10e7.21 (m, 2 H), 7.37
(d, J ¼ 5.7 Hz, 1 H), 8.36 (d, J ¼ 5.7 Hz, 1 H). Anal. Calcd for
C19H17F2NO2$H2C2O4: C, 60.14; H, 4.57; N, 3.34. Found: C, 59.98; H,
4.65; N, 3.42.
d
3.83 (s, 3 H), 4.00 (s, 3 H), 4.27 (dt, J ¼ 27.3, 3.9 Hz, 2 H), 4.50 (s,
2 H), 4.81 (dt, J ¼ 47.1, 3.9 Hz, 2 H), 6.82e7.00 (m, 3 H), 7.07 (s, 1 H),
7.31 (s, 1 H), 7.44 (d, J ¼ 5.7 Hz, 1 H), 8.37 (d, J ¼ 5.7 Hz, 1 H). Anal.
Calcd for C20H19F2NO3$H2C2O4: C, 58.80; H, 4.71; N, 3.12. Found: C,
58.78; H, 4.73; N, 3.23.
4.1.7.11. 7-(2-Fluoroethoxy)-1-(3-(2-fluoroethoxy)-4-methoxybenzyl)-
6-methoxyisoquinoline oxalate (6k). Starting with 5k, procedure G
was followed to prepare compound 6k (0.14 g, 58%) as a white solid.
Mp (oxalate salt): 171.2e172.0 ꢂC; 1H NMR (300 MHz, free base,
4.1.7.5. 7-(2-Fluoroethoxy)-6-methoxy-1-(4-methoxy-3-methylbenzyl)-
isoquinoline oxalate (6e). Starting with 5e, procedure G was fol-
lowed to prepare compound 6e (0.13 g, 61%) as a white solid. Mp
(oxalate salt): 179.4e180.2 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
CDCl3) d 3.74 (s, 3 H), 3.99 (s, 3 H), 4.16e4.35 (m, 4 H), 4.49 (s, 2 H),
4.70e4.80 (m, 4 H), 6.55e7.13 (m, 4 H), 7.40e7.43 (m, 2 H), 8.36 (d,
J ¼ 5.7 Hz, 1 H). Anal. Calcd for C22H23F2NO4$H2C2O4: C, 58.42; H,
5.11; N, 2.84. Found: C, 58.58; H, 5.22; N, 2.94.
d
2.14 (s, 3 H), 3.76 (s, 3 H), 3.99 (s, 3 H), 4.26 (dt, J ¼ 27.3, 4.5 Hz,
2 H), 4.48 (s, 2 H), 4.80 (dt, J ¼ 47.4, 4.5 Hz, 2 H), 6.70 (d, J ¼ 7.8 Hz,
1 H), 7.00e7.10 (m, 3 H), 7.39 (s, 1 H), 7.41 (d, J ¼ 5.7 Hz, 1 H), 8.37 (d,
J ¼ 5.7 Hz, 1 H). Anal. Calcd for C21H22FNO3$H2C2O4: C, 62.02; H,
5.43; N, 3.14. Found: C, 62.09; H, 5.51; N, 3.26.
4.1.7.12. 1-(3,5-Dimethoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline oxalate (6l). Starting with 5l, procedure G was
followed to prepare compound 6l (75 mg, 22%) as a white solid. Mp
(oxalate salt): 176.2e176.7 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
d
3.70 (s, 6 H), 3.97 (s, 3 H), 4.26 (dt, J ¼ 27.3, 4.5 Hz, 2 H), 4.50 (s,
4.1.7.6. 7-(2-Fluoroethoxy)-6-methoxy-1-(4-(methylthio)benzyl)iso-
quinoline oxalate (6f). Starting with 5f, procedure G was followed
to prepare compound 6f (0.15 g, 70%) as a white solid. Mp (oxalate
2 H), 4.78(dt, J ¼ 47.4, 4.5 Hz, 2 H), 6.28 (t, J ¼ 2.4 Hz, 1 H), 6.41 (m,
2 H), 7.04 (s, 1 H), 7.36 (s, 1 H), 7.41 (d, J ¼ 5.7 Hz, 1 H), 8.36 (d,
J ¼ 5.7 Hz, 1 H). Anal. Calcd for C21H22FNO4$H2C2O4: C, 59.87; H,
5.24; N, 3.04. Found: C, 59.91; H, 5.22; N, 3.07.
salt): 199.5e200.5 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
d 2.43 (s,
3 H), 3.99 (s, 3 H), 4.26 (dt, J ¼ 27.0, 4.2 Hz, 2 H), 4.53 (s, 2 H), 4.80
(dt, J ¼ 47.4, 4.2 Hz, 2 H), 7.07 (s, 1 H), 7.16 (m, 4 H), 7.32 (s, 1 H), 7.43
(d, J ¼ 5.7 Hz, 1 H), 8.37 (d, J ¼ 5.7 Hz, 1 H). Anal. Calcd for
C20H20FNO2S$H2C2O4: C, 59.05; H, 4.96; N, 3.13. Found: C, 59.06; H,
4.93; N, 3.10.
4.1.7.13. 1-(4-Fluoro-3-methoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline oxalate (6m). Starting with 5m, procedure G
was followed to prepare compound 6m (65 mg, 36%) as a white
solid. Mp (oxalate salt): 154.8e155.6 ꢂC; 1H NMR (300 MHz, free
base, CDCl3)
d
3.76 (s, 3 H), 3.99 (s, 3 H), 4.26 (dt, J ¼ 27.3, 4.5 Hz,
4.1.7.7. 1-(2-Fluoro-4-methoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline oxalate (6g). Starting with 5g, procedure G
was followed to prepare compound 6g (0.13 g, 67%) as a pale solid.
Mp (oxalate salt): 203.5e204.2 ꢂC; 1H NMR (300 MHz, free base,
2 H), 4.48 (s, 2 H), 4.80 (dt, J ¼ 47.4, 4.5 Hz, 2 H), 6.70 (d, J ¼ 7.8 Hz,
1 H), 7.00e7.10 (m, 3 H), 7.39 (s,1 H), 7.41 (d, J ¼ 5.7 H z,1 H), 8.37 (d,
J ¼ 5.7 Hz, 1 H). Anal. Calcd for C20H19F2NO3$H2C2O4: C, 58.80; H,
4.71; N, 3.12. Found: C, 58.82; H, 4.81; N, 3.21.
CDCl3)
d
3.74 (s, 3 H), 3.99 (s, 3 H), 4.35 (dt, J ¼ 27.3, 4.2 Hz, 2 H), 4.49
(s, 2 H), 4.85 (dt, J ¼ 47.4, 4.2 Hz, 2 H), 6.55 (dd, J ¼ 8.7, 1.8 Hz, 1 H),
6.64 (dd, J ¼ 12.0, 2.7 Hz, 1 H), 7.00e7.13 (m, 2 H), 7.40e7.43 (m,
2 H), 8.36 (d, J ¼ 5.7 Hz, 1 H). Anal. Calcd for C20H19F2NO3$H2C2O4:
C, 58.80; H, 4.71; N, 3.12. Found: C, 58.90; H, 4.75; N, 3.11.
4.1.7.14. 1-(3-(2-Fluoroethoxy)-4-methoxybenzyl)-6,7-
dimethoxyisoquinoline (6n). Starting with 5n, procedure G was
followed to prepare compound 6n (125 mg, 50%) as a pale solid. Mp
(oxalate salt): 149.7e150.6 ꢂC; 1H NMR (300 MHz, free base, CDCl3)
d
3.81 (s, 3 H), 3.90 (s, 3 H), 4.01 (s, 3 H), 4.16 (dt, J ¼ 27.9, 4.5 Hz,
4.1.7.8. 1-(5-Bromo-2-methoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline oxalate (6h). Starting with 5h, procedure G
was followed to prepare compound 6h (0.14 g, 49%) as a white solid.
Mp (oxalate salt): 195.7e197.3 ꢂC; 1H NMR (300 MHz, free base,
2 H), 4.52 (s, 2 H), 4.70 (dt, J ¼ 47.1, 4.5 Hz, 2 H), 6.78e6.89 (m, 3 H),
7.05 (s,1 H), 7.32 (s,1 H), 7.43 (d, J ¼ 5.7,1 H), 8.36 (d, J ¼ 5.7 Hz,1 H).
13C NMR (75 MHz, CDCl3)
d 37.2, 56.3, 56.6, 56.9, 69.3 (d,
J ¼ 21.6 Hz), 80.9 (d, J ¼ 169.6 Hz), 105.0, 106.0, 112.6, 115.5, 121.6,
122.1, 122.9, 128.5, 131.5, 136.9, 152.7, 154.7, 157.0, 160.7, 163.3. Anal.
Calcd for C21H22FNO4$H2C2O4: C, 59.87; H, 5.24; N, 3.04. Found: C,
59.78; H, 5.26; N, 3.04.
CDCl3)
d
3.90 (s, 3 H), 4.00 (s, 3 H), 4.27 (dt, J ¼ 27.1, 4.5 Hz, 2 H), 4.52
(s, 2 H), 4.81 (dt, J ¼ 47.4, 4.5 Hz, 2 H), 6.78 (d, J ¼ 9.0 Hz,1 H), 7.07 (s,
1 H), 7.16e7.43 (m, 4 H), 8.37 (d, J ¼ 5.7 Hz, 1 H). Anal. Calcd for
C20H19BrFNO3$H2C2O4: C, 51.78; H, 4.15; N, 2.74. Found: C, 51.90; H,
4.21; N, 2.80.
4.1.7.15. 1-(4-(Benzyloxy)-3-methoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline (6o). Starting with 5o, procedure G was fol-
lowed to prepare compound 6o (0.16 g, 40%) as a white solid. 1H
4.1.7.9. 1-(3-Bromo-4-methoxybenzyl)-7-(2-fluoroethoxy)-6-
methoxyisoquinoline oxalate (6i). Starting with 5i, procedure G was
NMR (300 MHz, free base, CDCl3) d 3.77 (s, 3 H), 3.99 (s, 3 H), 4.25