D.A. Patrick et al. / European Journal of Medicinal Chemistry 67 (2013) 310e324
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J ¼ 2.1 Hz,1H), 7.80 (d, J ¼ 8.8 Hz,1H), 7.74 (d, J ¼ 8.4 Hz, 2H), 7.69 (d,
J ¼ 8.4 Hz, 2H), 7.44 (d, J ¼ 8.8 Hz, 1H), 5.84 (br s, 2H); MS m/z 377.2
([M þ 1]þ of free base), 378.9 ([M þ 3]þ); HPLC (Method A) tR
3.23 min (100 area % at 254 nm). Anal. (C15H15BrN4O3$2HCl) C, H, N,
Cl, Br.
5.2.3.8. 3-N0-Hydroxyamidinobenzyl 2,6-dichloro-4-N0-hydroxyamidin-
ophenyl etherdihydrochloride(44). Yield (free base, recrystallized from
ethanol/water), 2.65 g (90%): mp 198e199 ꢁC; 1H NMR
d 9.88 (s, 1H),
9.66 (s, 1H), 7.86 (m, 1H), 7.79 (s, 2H), 7.68 (dm, J ¼ 7.7 Hz, 1H), 7.54
(dm, J ¼ 7.1 Hz, 1H), 7.43 (t, J ¼ 7.6 Hz, 1H), 5.98 (br s, 2H), 5.83 (br s,
2H), 5.05 (s, 2H). Anal. (C15H14Cl2N4O3) C, H, N.
5.2.3.3. 4-N0-Hydroxyamidinobenzyl 4-N0-hydroxyamidino-2-
An aliquot of the free base (0.502 g, 1.37 mmol) was recrystal-
lized from ethanolic HCl/ether to give the hydrochloride salt as a
iodophenyl ether dihydrochloride (23). Yield (free base), 4.42 g
(104%, crude): mp 205e206 ꢁC; 1H NMR
d
9.66 (s, 1H), 9.58 (s, 1H),
white solid (0.538 g, 89%): mp 184e185 ꢁC; 1H NMR
d 11.32 (br s,
8.08 (d, J ¼ 2.1 Hz, 1H), 7.70 (d, J ¼ 8.3 Hz, 2H), 7.65 (dd, J ¼ 8.6 and
2.1 Hz, 1H), 7.49 (d, J ¼ 8.3 Hz, 2H), 7.08 (d, J ¼ 8.7 Hz, 1H), 5.84 (br s,
2H), 5.82 (br s, 2H), 5.25 (s, 2H). Anal. (C15H16N4O3) C, H, N.
An aliquot of the free base (0.508 g, 1.19 mmol) was recrystal-
lized from ethanolic HCl/ether to give the hydrochloride salt as a
2H), 9.15 (br s, 2H), 8.54 (br s, 2H), 7.98 (s, 2H), 7.90 (m, 2H),
7.77 (dm, J ¼ 7.8 Hz, 1H), 7.68 (t, J ¼ 7.1 Hz, 1H), 5.18 (s, 2H); MS m/z
369.0 ([M þ 1]þ of free base); HPLC (Method A) tR 6.82 min (100
area % at 230 nm). Anal. (C15H14Cl2N4O3$2HCl) C, H, N, Cl.
white solid (0.587 g, 90%): mp 230e235 ꢁC dec; 1H NMR
d
11.28 (br
5.2.3.9. 3-N0-Hydroxyamidinobenzyl 2,6-dibromo-4-N0-hydroxyami-
s,1H),11.22 (br s,1H), 9.04 (br s, 4H), 8.20 (d, J ¼ 2.3 Hz,1H), 7.80 (m,
3H), 7.70 (d, J ¼ 8.5 Hz, 2H), 7.25 (d, J ¼ 8.4 Hz, 1H), 5.44 (s, 2H); MS
m/z 427.0 ([M þ 1]þ of free base); HPLC (Method A) tR 5.03 min (100
area % at 230 nm). Anal. (C15H15IN4O3$2HCl) C, H, N, Cl.
dinophenyl ether dihydrochloride (47). Yield (HCl salt, recrystallized
from 1 M HCl/ethanol), 2.04 g (87%): mp 188 ꢁC dec; 1H NMR
d 11.35
(br s, 2H), 9.20 (br s, 2H), 8.85 (br s, 2H), 8.15 (s, 2H), 7.93 (m, 2H),
7.78 (dm, J ¼ 7.7 Hz),7.69 (t, J ¼ 8.0 Hz, 1H), 5.14 (s, 3H); MS m/z
456.9 ([M þ 1]þ of free base), 458.9 ([M þ 3]þ), 460.8 ([M þ 5]þ);
HPLC (Method A) tR 7.23 min (100 area % at 254 nm). Anal.
(C15H14Br2N4O3$2HCl) C, H, N, Br, Cl.
5.2.3.4. 4-N0-Hydroxyamidinobenzyl 2,6-dimethoxy-4-N0-hydroxyami-
dinophenyl ether dihydrochloride (29). Yield (free base), 4.00 g (93%).
An aliquot (1.00 g, 3.24 mmol) was recrystallized from 1 M HCl/
ethanol to give the hydrochloride salt as a white solid (1.09 g, 90%):
5.2.3.10. 3-N0-Hydroxyamidinobenzyl 4-N0-hydroxyamidino-2,6-diio-
dophenyl ether dihydrochloride (50). Yield (free base, recrystallized
from toluene/ethanol), 3.08 g (90%).
mp 230e231 ꢁC dec; 1H NMR
d 11.30 (br 2, 2H), 9.06 (br s, 4H), 7.76
(d, J ¼ 8.2 Hz, 2H), 7.66 (d, J ¼ 8.2 Hz, 2H), 7.21 (s, 2H), 5.11 (s, 2H),
3.88 (s, 6H); MS m/z 361.0 ([M þ 1]þ of free base); HPLC (Method A)
tR 4.21 min (100 area % at 254 nm). Anal. (C17H20N4O5$2HCl$0.9H2O)
C, H, N, Cl.
The hydrochloride salt was precipitated from a solution of an
aliquot of the base (1.02 g, 1.85 mmol) in dioxane (30 mL) by the
addition of 4 M HCl/dioxane (3 mL) to give a white solid (1.04 g,
90%): mp > 180 ꢁC dec; 1H NMR
d 11.30 (br s, 2H), 9.06 (br s, 4H), 8.24
5.2.3.5. 3-N0-Hydroxyamidinobenzyl 2-chloro-4-N0-hydroxyamidino-
phenyl ether dihydrochloride (34). Yield (free base), 3.58 g (94%).
An aliquot (1.20 g, 3.58 mmol) was purified by C18 reverse phase
(s, 2H), 7.96 (d, J ¼ 7.8 Hz, 1H), 7.95 (d, J ¼ 2.1 Hz, 1H), 7.76 (dd, J ¼ 7.8
and 2.1 Hz, 2H), 7.72 (dd, J ¼ 7.8 and 7.8 Hz, 1H), 5.09 (br s, 2H); MS
m/z 553.0 ([M þ 1]þ of free base); HPLC (Method B) tR 2.31 min (100
area % at 254 nm). Anal. (C15H14I2N4O3$2HCl$0.6H2O) C, H, N, Cl.
flash to give a solid (1.08, 82%): mp 130 ꢁC dec; 1H NMR
d 11.41
(br s, 1H), 11.34 (br s, 1H), 9.13 (br s, 4H), 7.96 (d, J ¼ 1.6 Hz, 1H),
7.87 (s, 1H), 7.78 (m, 3H), 7.66 (t, J ¼ 7.4 Hz), 7.49 (d, J ¼ 8.8 Hz,
1H); MS m/z 335.0 ([M þ 1]þ of free base), 337.0 ([M þ 3]þ); HPLC
5.2.3.11. 3-N0-Hydroxyamidinobenzyl
dino-6-methoxy phenyl ether dihydrochloride (53). Yield (free base,
recrystallized from toluene/ethanol), 2.95 g (72%).
2-bromo-4-N0-hydroxyami-
(Method A) tR 4.69 min (100 area
(C15H15ClN4O3$2HCl$2.2H2O) C, H, N, Cl.
% at 230 nm). Anal.
The hydrochloride salt was precipitated from a solution of an
aliquot of the base (1.00 g, 2.44 mmol) in dioxane (80 mL) by the
addition of 4 M HCl/dioxane (3 mL) to give a grey solid (1.11 g, 94%):
5.2.3.6. 3-N0-Hydroxyamidinobenzyl 2-bromo-4-N0-hydroxyamidino-
phenyl ether dihydrochloride (37). The amidoxime base was recrys-
tallized from 1 M HCl/acetonitrile to give the hydrochloride salt
mp 235e236 ꢁC dec; 1H NMR
d 11.32 (br s, 2H), 9.09 (br s, 2H), 8.98
(br s, 2H), 7.86 (m, 2H), 7.73 (d, J ¼ 7.7 Hz, 1H); 7.67 (d, J ¼ 1.6 Hz, 2),
7.65 (t, J ¼ 7.7 Hz, 1H), 7.59 (d, J ¼ 1.6 Hz, 1H), 5.17 (s, 2H), 3.98 (s,
3H); MS m/z 409.4 ([M þ 1]þ of free base), 410.9 ([M þ 3]þ); HPLC
(3.07 g, 68%): mp > 170 ꢁC dec; 1H NMR
d 11.36 (br s,1H),11.29 (br s 2,
1H), 9.08 (br 2, 4H), 8.07 (d, J ¼ 2.2 Hz,1H), 7.87 (s, 1H), 7.80 (M, 2H),
7.73 (d, J ¼ 7.7 Hz, 1H), 7.66 (t, J ¼ 7.7 Hz, 1H), 7.44 (d, J ¼ 8.8 Hz, 1H),
5.42 (s, 2H); MS m/z 379.0 ([M þ 1]þ of free base), 380.9 ([M þ 3]þ);
HPLC (Method A) tR 5.24 min (100 area % at 254 nm). Anal.
(C15H15BrN4O3$2HCl$0.5H2O) C, H, N, Br, Cl.
(Method A) tR 5.83 min (100 area
(C16H17BrN4O4$2HCl) C, H, N, Br, Cl.
% at 254 nm). Anal.
5.2.3.12. 3-N0-Hydroxyamidinobenzyl 4-N0-hydroxyamidino-2-iodo-
6-methoxyphenyl ether dihydrochloride (56). Yield (free base,
recrystallized from toluene/ethanol), 4.00 g (88%).
5.2.3.7. 3-N0-Hydroxyamidinobenzyl 4-N0-hydroxyamidino-2-
iodophenyl ether dihydrochloride (40). Yield (free base, recrystallized
The hydrochloride salt was precipitated from a solution of an
aliquot of the base (1.00 g, 2.18 mmol) in dioxane (80 mL) by the
addition of 4 M HCl/dioxane (3 mL) to give a grey solid (1.00 g, 84%):
from ethanol/water), 3.04 g (89%): mp > 125 ꢁC dec; 1H NMR
d 9.64
(s, 1H), 9.55 (s, 1H), 8.08 (d, J ¼ 2.1 Hz), 7.79 (s, 1H), 7.67 (m, 2H), 7.51
(d, J ¼ 7.71 Hz,1H), 7.42 (t, J ¼ 7.6 Hz,1H), 7.08 (d, J ¼ 8.7 Hz,1H), 5.80
(br s, 2H), 5.78 (br s, 2H), 5.23 (s, 2H). Anal. (C15H15IN4O3$H2O)
C, H, N.
mp 235e236 ꢁC dec; 1H NMR
d 11.32 (br s, 2H), 9.08 (br s, 2H), 9.00 (br
s, 2H), 7.90 (s,1H), 7.89(d, J ¼ 8.7 Hz,1H), 7.79 (d, J ¼ 1.6 Hz,1H), 7.74 (d,
J¼ 8.2Hz,1H), 7.65(t, J¼ 7.7Hz,1H), 7.57 (d, J¼ 1.6Hz,1H), 5.13(2,2H),
3.96 (s, 3H); MS m/z 457.1 ([M þ 1]þ of free base); HPLC (Method A) tR
6.20 min (100 area % at 254 nm). Anal. (C16H17IN4O4$2HCl) C, H, N, Cl, I.
An aliquot of the free base (0.510 g, 1.20 mmol) was recrystal-
lized from aqueous HCl to give the hydrochloride salt as a white
solid (0.320 g, 54%): mp 170e173 ꢁC dec; 1H NMR
d 11.30 (br s, 1H),
11.20 (br s, 1H), 8.97 (br s, 4H), 8.20 (d, J ¼ 2.3 Hz, 1H), 7.89 (s, 1H),
5.2.3.13. 3-N0-Hydroxyamidinobenzyl 2,6-dimethoxy-4-N0-hydroxya-
midinophenyl ether dihydrochloride (59). Yield (free base), 4.17 g
(97%).
An aliquot (1.17 g, 3.24 mmol) was recrystallized from 1 M HCl/
ethanol to give the hydrochloride salt as a white solid (1.24 g, 88%):
7.77 (m, 2H), 7.70 (m, 2H), 7.30 (d, J ¼ 8.8 Hz, 1H), 5.40 (s, 2H); MS
m/z 427.0 ([M
þ
1]þ of free base); HPLC (Method A) tR
5.62 min (100 area % at 230 nm). Anal. (C15H14IN4O3$2HCl$1.8H2O)
C, H, N, Cl.