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L. Zhang et al. / Bioorg. Med. Chem. 15 (2007) 6920–6926
J2 = 8.1 Hz, 2H), 6.80 (s, 2H), 6.74 (d, J = 8.1 Hz, 2H),
3.60 (s, 4H), 3.17 (s, 4H), 3.17 (br s, 4H), 2.82 (t,
J1 = 7.5 Hz, J2 = 7.5 Hz, 4H), 2.38 (t, J1 = 7.8 Hz,
J2 = 7.2 Hz, 4H), 2.32 (s, 12H); HRMS (ESI+) MH+:
471.2962 (Calcd mass for C26H38N4O4MH+: 471.2966).
Yield: 80 mg (60%). 1H NMR (300 MHz, CDCl3)
d = 7.36 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H),
7.22 (s, 1H), 7.11 (s, 2H), 6.86 (s, 1H), 6.78 (d,
J = 8.4 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H),
3.88 (s, 3H), 3.54 (s, 2H), 3.52 (s, 2H), 2.30 (s, 12H);
HRMS (ESI+) MH+: 519.2705 (Calcd mass for
C28H34N6O4MH+: 519.2714).
4.1.3. N-(3-((Dimethylamino)methyl)-4-hydroxyphenyl)
acetamide (7). N-(3-((Dimethylamino)methyl)-4-hydro-
xyphenyl) acetamide (500 mg, 3.3 mmol) was dissolved
in ethanol and aqueous solutions of dimethylamine
(3.0 equiv, 33%) and formaldehyde (4.0 equiv, 37%)
were added. After the reaction mixture was stirred over-
night at room temperature, the solvents were then evap-
orated under reduced pressure and the crude product
was subjected to silica gel chromatography eluting with
a mixture of CHCl3/CH3OH (5:1). After evaporation of
the solvent, the product was obtained. Yield: 240 mg
(35%). 1H NMR (300 MHz, CDCl3) d = 7.29 (d,
J = 2.1 Hz, 1H), 7.06 (dd, J1 = 2.7 Hz, J2 = 9 Hz, 1H),
6.72 (d, J = 8.4 Hz, 1H), 3.58 (s, 2H), 2.30 (s, 6H),
2.11 (s, 3H); HRMS (ESI+) MH+: 209.1284 (Calcd mass
for C11H16N2O2MH+: 209.1285).
4.1.6. 4-(4-Amino-6,7-dimethoxyquinazolin-2-ylamino)-2-
((dimethylamino)methyl)phenol (10). Compound
7
(104 mg, 0.5 mmol) was dissolved in 15 mL of 20%
HCl (W/W) and refluxed for 10 h under nitrogen. After
reaction, the solvent was evaporated under reduced
pressure. The solid was dissolved in ethanol and
2-chloro-4-amino-6,7-dimethoxyquinazoline (390 mg,
1.5 mmol) was added to the mixture. The mixture was
refluxed for 10 h and the solvent was evaporated under
reduced pressure. The crude product was neutralized
using the solution of 10% sodium hydrogen carbonate
(20 mL). The mixture was extracted three times with
CHCl3 (a total of 120 mL). The organic phase was
washed with saturated NaCl solution, dried over
Na2SO4, filtered, and the filtrate was evaporated under
reduced pressure. The product was purified by chroma-
tography on silica gel using the eluent methyl alcohol.
Yield: 258 mg (70%). 1H NMR (300 MHz, CDCl3)
d = 7.40 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 6.92 (s, 1H),
6.85 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H),
3.91 (s, 3H), 3.60 (s, 2H), 2.30 (s, 6H); HRMS (ESI+)
MH+: 370.1880 (Calcd mass for C19H23N5O3MH+:
370.1874).
4.1.4. 4-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)2-
((dimethyl amino)methyl)phenol (8). Compound
7
(300 mg, 1.44 mmol) was dissolved in 20 mL 20% HCl
(W/W) and refluxed for 10 h under a nitrogen atmo-
sphere. After reaction, the solvent was evaporated under
reduced pressure. The solid was dissolved in ethanol
and 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg,
0.77 mmol) was added to the mixture. The mixture
was stirred for 10 h at room temperature and the solvent
was evaporated under reduced pressure. The crude
product was neutralized using the solution of 10% so-
dium hydrogen carbonate (20 mL). The mixture was ex-
tracted three times with CHCl3 (a total of 150 mL). The
organic phase was washed with saturated NaCl solution,
dried over Na2SO4, filtered, and the filtrate was evapo-
rated under reduced pressure. The product was purified
by chromatography on silica gel using the eluent methyl
alcohol. Yield: 224 mg (75%). 1H NMR (300 MHz,
CDCl3) d = 7.34 (s, 2H), 7.16 (s, 1H), 6.92 (s, 1H),
6.84 (d, J = 9 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.67
(s, 2H), 2.36 (s, 6H); HRMS (ESI+) MH+: 389.1368
(Calcd mass for C19H21N4O3Cl MH+: 389.1365).
4.1.7. (5,50-(3,30-(ethane-1,2-diylbis(azanediyl))bis(3-oxo-
propane-3,1-diyl))bis(2-hydroxy-5,1-phenylene))bis(N,N,N-
trimethanaminium)iodine (1). Compound
6 (25 mg,
0.053 mmol) was dissolved in CH3CN (20 mL), and
methyl iodide (0.15 g, 1.059 mmol) was added to this
solution. The mixture was stirred at room temperature
for 12 h. After finishing the reaction, the solution was
concentrated to about 3 mL and then 30 mL of ether
was poured into the mixture. A precipitate was obtained
which was collected by filtration and dried under vac-
uum. Yield: 37 mg (92%).1H NMR (300 MHz, DMSO-
d6) d = 7.01 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 2H), 6.98 (s,
2H), 6.71 (d, J = 8.1 Hz, 2H), 4.19 (s, 4H), 2.86 (s,
18H), 2.62 (t, J1 = 6.3 Hz, J2 = 6.6 Hz, 4H), 2.52 (s,
4H), 2.74 (t, J1 = 7.2 Hz, J2 = 6.9 Hz, 4H); HRMS
4.1.5. 4,40-(6,7-Dimethoxyquinazoline-2,4-diyl)bis(azane-
diyl)bis(2-((dimethyl-amino)methyl)phenol) (9). Com-
pound 7 (300 mg, 1.44 mmol) was dissolved in 20 mL
of 20% HCl (W/W) and mixture was refluxed for 10 h
under a nitrogen atmosphere. After reaction, the solvent
was evaporated under reduced pressure. The solid was
(ESI+)
(MꢀI)+:
627.2402
(Calcd
mass
for
C28H44N4O4(MꢀI)+: 627.2402).
4.1.8. (5,50-(6,7-Dimethoxyquinazoline2,4diyl)bis(azane-
diyl)bis(2-hydroxy-5,1phenylene))bis(N,N,N-trimethyl-
methanaminium) iodide (2). Compound 9 (40 mg,
dissolved in ethanol and compound
8
(272 mg,
0.7 mmol) was added to the mixture. The mixture was
refluxed for 24 h and the solvent was evaporated under
reduced pressure. The crude product was neutralized
using the solution of 10% sodium hydrogen carbonate
(20 mL). The mixture was extracted three times with
CHCl3 (a total of 150 mL). The organic phase was
washed with saturated NaCl solution, dried over
NaSO4, filtered, and the filtrate was evaporated under
reduced pressure. The product was purified by chroma-
tography on silica gel using the eluent methyl alcohol.
0.077 mmol) was dissolved in CH3CN (20 mL), and
methyl iodide (0.15 g, 1.059 mmol) was added to this
solution. The mixture was stirred at room temperature
for 12 h. After finishing the reaction, the solution was
concentrated to about 3 mL and then 30 mL of ether
was poured into the mixture. The precipitate was ob-
tained by filtering and dried under vacuum. Yield:
59 mg (94%). H NMR (300 MHz, DMSO-d6) d = 7.94
(br, 1H), 7.63 (br, 2H), 7.40 (br, 2H), 7.16 (br, 1H),
7.04 (br, 2H), 4.47 (s, 3H), 4.42 (s, 3H), 3.92 (s, 2H),
1