1388 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 7
Smaill et al.
equiv, 1.42 mmol, 273 mg). Standard workup, followed by
chromatography on grade III alumina, eluting with EtOAc/
hexane (1:1) to MeOH/EtOAc (2:98), gave 7 (145 mg, 58%):
mp (CH2Cl2/Et2O/hexane) 105-107 °C; 1H NMR [(CD3)2SO] δ
9.78 (s, 1 H, CONH), 9.61 (s, 1 H, NH), 8.89 (s, 1 H, H-5), 8.56
(s, 1 H, H-2), 8.17 (t, J ) 1.9 Hz, 1 H, H-2′), 7.87 (br d, J ) 8.3
Hz, 1 H, H-6′), 7.34 (t, J ) 8.3 Hz, 1 H, H-5′), 7.28 (s, 1 H,
H-8), 7.27 (obscured ddd, J ∼ 8, ∼ 1, ∼ 1 Hz, 1 H, H-4′), 6.72
(dd, J ) 17.0, 10.3 Hz, 1 H, CHdCH2), 6.32 (dd, J ) 17.0, 1.9
Hz, 1 H, CHdCH2), 5.83 (dd, J ) 10.3, 1.9 Hz, 1 H, CHdCH2),
4.26 (t, J ) 6.3 Hz, 2 H, CH2CH2CH2O), 2.47 (t, J ) 7.1 Hz, 2
H, NCH2CH2CH2), 2.42-2.27 (br s, 8 H, piperazinyl methyl-
ene), 2.15 (s, 3 H, CH3N), 1.98 (quintet, J ) 6.7 Hz, 2 H,
CH2CH2CH2). Anal. (C25H29BrN6O2‚0.5H2O) C, H, N.
N-[4-[N-(3-Br om op h en yl)a m in o]-7-[3-(4-m or p h olin yl)-
p r op oxy]qu in a zolin -6-yl]a cr yla m id e (8). Sodium metal
(0.63 g, 27.6 mmol) was added to a solution of 3-(4-morpholi-
nyl)-1-propanol (3.20 g, 22.0 mmol) in THF (60 mL) under N2.
The resulting suspension was stirred at 20 °C for 2 h and then
cannulated into a solution of 3929 (2.0 g, 5.51 mmol) in THF
(50 mL) under N2. Identical reaction procedure and workup
as above gave, after chromatography on silica gel eluting with
CH2Cl2/EtOAc (1:1) to MeOH/CH2Cl2/EtOAc (2:3:5), 4-[N-(3-
bromophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitro-
quinazoline (43b) (1.75 g, 65%): mp (MeOH) 216-220 °C; 1H
NMR [(CD3)2SO] δ 10.12 (s, 1 H, NH), 9.24 (s, 1 H, H-5), 8.69
(s, 1 H, H-2), 8.19 (t, J ) 1.8 Hz, 1 H, H-2′), 7.88 (ddd, J ) 8.0,
1.4, 1.4 Hz, 1 H, H-6′), 7.49 (s, 1 H, H-8), 7.38 (t, J ) 8.0 Hz,
1 H, H-5′), 7.34 (ddd, J ) 8.0, 1.4, 1.4 Hz, 1 H, H-4′), 4.35 (t,
J ) 6.2 Hz, 2 H, CH2CH2CH2O), 3.58 (t, J ) 4.6 Hz, 4 H,
morpholino methylene), 2.45 (t, J ) 7.0 Hz, 2 H, NCH2CH2-
CH2), 2.37 (m, 4 H, morpholino methylene), 1.94 (quintet, J )
6.6 Hz, 2 H, CH2CH2CH2); 13C NMR δ 157.76, 157.26, 153.76,
153.21, 140.32, 138.86, 130.37, 126.38, 124.26, 121.70, 121.13,
120.72, 110.11, 107.88, 67.87, 66.13 (×2), 54.42, 53.28 (×2),
25.30. Anal. (C21H22BrN5O4‚0.75H2O) C, H, N.
Reduction of 43b (1.50 g, 3.07 mmol) with Fe powder in
EtOH/H2O (2:1, 80 mL) containing glacial AcOH (2.0 mL) as
above, followed by chromatography of the product on grade
III alumina eluting with CH2Cl2/EtOAc (1:1) to MeOH/EtOAc
(2:98), gave 6-amino-4-[N-(3-bromophenyl)amino]-7-[3-(4-mor-
pholinyl)propoxy]quinazoline (47b) (1.08 g, 77%): mp (EtOAc/
hexane) 158-160 °C; 1H NMR [(CD3)2SO] δ 9.37 (s, 1 H, NH),
8.40 (s, 1 H, H-2), 8.24 (t, J ) 1.9 Hz, 1 H, H-2′), 7.86 (ddd, J
) 8.2, 1.9, 0.9 Hz, 1 H, H-6′), 7.42 (s, 1 H, H-8), 7.30 (t, J )
8.2 Hz, 1 H, H-5′), 7.21 (ddd, J ) 8.2, 1.9, 0.9 Hz, 1 H, H-4′),
7.09 (s, 1 H, H-5), 5.36 (s, 2 H, NH2), 4.20 (t, J ) 6.2 Hz, 2 H,
CH2CH2CH2O), 3.59 (t, J ) 4.6 Hz, 4 H, morpholino methyl-
ene), 2.50 (t, J ) 7.3 Hz, 2 H, NCH2CH2CH2), 2.39 (m, 4 H,
morpholino methylene), 1.99 (quintet, J ) 6.7 Hz, 2 H,
CH2CH2CH2); 13C NMR δ 154.88, 151.94, 150.19, 144.84,
141.94, 138.50, 130.16, 124.66, 123.02, 121.09, 119.65, 110.42,
106.37, 100.81, 66.45, 66.14 (×2), 54.77, 53.29 (×2), 25.50.
Anal. (C21H24BrN5O2‚0.25H2O) C, H, N.
A stirred solution of 47b (0.50 g, 1.09 mmol), acrylic acid (6
mol equiv, 6.54 mmol, 449 µL), and Et3N (excess, 2.0 mL) in
DMF (20 mL) under N2 was treated with EDCI‚HCl (3 mol
equiv, 3.27 mmol, 627 mg). The standard procedure above was
followed to give, after chromatography on grade III alumina
eluting with EtOAc/hexane (9:1) to MeOH/EtOAc (2:98), 8 (329
mg, 59%): mp (EtOAc/Et2O/hexane) 170-172 °C; 1H NMR
[(CD3)2SO] δ 9.78 (s, 1 H, CONH), 9.62 (s, 1 H, NH), 8.89 (s,
1 H, H-5), 8.56 (s, 1 H, H-2), 8.18 (t, J ) 1.9 Hz, 1 H, H-2′),
7.88 (br d, J ) 8.2 Hz, 1 H, H-6′), 7.34 (t, J ) 8.1 Hz, 1 H,
H-5′), 7.30 (s, 1 H, H-8), 7.27 (ddd, J ) 7.9, 1.4, 0.8 Hz, 1 H,
H-4′), 6.72 (dd, J ) 17.0, 10.2 Hz, 1 H, CHdCH2), 6.33 (dd, J
) 17.0, 1.9 Hz, 1 H, CHdCH2), 5.83 (dd, J ) 10.2, 1.9 Hz, 1
H, CHdCH2), 4.27 (t, J ) 6.3 Hz, 2 H, CH2CH2CH2O), 3.58 (t,
J ) 4.6 Hz, 4 H, morpholino methylene), 2.48 (t, J ) 7.1 Hz,
2 H, NCH2CH2CH2), 2.38 (m, 4 H, morpholino methylene), 1.99
(quintet, J ) 6.7 Hz, 2 H, CH2CH2CH2); 13C NMR δ 163.49,
156.68, 154.96, 153.92, 149.19, 141.20, 131.58, 130.19, 127.16,
126.95, 125.52, 123.97, 121.03, 120.52, 116.78, 108.80, 107.28,
66.96, 66.14 (×2), 54.54, 53.28 (×2), 25.31. Anal. (C24H26
BrN5O3‚0.5H2O) C, H, N.
-
N-[4-[N-(3-Br om oph en yl)am in o]-7-[4-(N,N-dim eth ylam i-
n o)bu toxy]qu in a zolin -6-yl]a cr yla m id e (9). To a suspension
of hexane-washed sodium hydride (11.0 mmol, 440 mg of a
60% dispersion in mineral oil) in THF (20 mL) was cannulated
a solution of 4-(N,N-dimethylamino)-1-butanol (8.80 mmol,
1.03 g) in THF (30 mL). The resulting suspension was stirred
at 20 °C under N2 for 2 h and then cannulated into a solution
of 39 (0.80 g, 2.20 mmol) in THF (30 mL) under N2. The dark
red solution was heated at reflux overnight, then worked up
as above. Chromatography of the crude product on grade III
alumina eluting with EtOAc to MeOH/EtOAc (5:95), gave
6-amino-4-[N-(3-bromophenyl)amino]-7-[4-(N,N-dimethylami-
no)butoxy]quinazoline (47c) (310 mg, 33%): mp (CH2Cl2/
hexane) 155-156 °C; 1H NMR [(CD3)2SO] δ 9.36 (s, 1 H, NH),
8.39 (s, 1 H, H-2), 8.23 (t, J ) 1.9 Hz, 1 H, H-2′), 7.86 (br d, J
) 8.0 Hz, 1 H, H-6′), 7.41 (s, 1 H, H-8), 7.30 (t, J ) 8.1 Hz, 1
H, H-5′), 7.20 (ddd, J ) 8.2, 1.9, 0.8 Hz, 1 H, H-4′), 7.09 (s, 1
H, H-5), 5.32 (s, 2 H, NH2), 4.17 (t, J ) 6.2 Hz, 2 H, CH2CH2-
CH2CH2O), 2.47 (t, J ) 7.3 Hz, 2 H, NCH2CH2CH2CH2), 2.15
(s, 6 H, N(CH3)2), 1.84 (quintet, J ) 6.4 Hz, 2 H, CH2CH2CH2-
CH2), 1.62 (quintet, J ) 6.9 Hz, 2 H, CH2CH2CH2CH2). Anal.
(C20H24BrN5O‚0.5H2O) C, H, N.
A solution of 47c (276 mg, 0.64 mmol), acrylic acid (6 mol
equiv, 3.85 mmol, 264 µL), and Et3N (excess, 1.0 mL) in DMA
(10 mL) under N2 was treated with EDCI‚HCl (3 mol equiv,
1.92 mmol, 369 mg). The standard procedure above, followed
by chromatography of the product on grade III alumina eluting
with EtOAc/hexane (1:1) to MeOH/EtOAc (3:97), gave 9 (98
1
mg, 32%): mp (CH2Cl2/Et2O) 112-115 °C; H NMR [(CD3)2-
SO] δ 9.77 (s, 1 H, CONH), 9.62 (s, 1 H, NH), 8.88 (s, 1 H,
H-5), 8.56 (s, 1 H, H-2), 8.17 (t, J ) 1.9 Hz, 1 H, H-2′), 7.87
(ddd, J ) 8.2, 1.9, 1.0 Hz, 1 H, H-6′), 7.34 (t, J ) 8.2 Hz, 1 H,
H-5′), 7.29 (s, 1 H, H-8), 7.27 (ddd, J ) 8.2, 1.9, 1.0 Hz, 1 H,
H-4′), 6.71 (dd, J ) 17.1, 10.2 Hz, 1 H, CHdCH2), 6.32 (dd, J
) 17.1, 1.9 Hz, 1 H, CHdCH2), 5.82 (dd, J ) 10.2, 1.9 Hz, 1
H, CHdCH2), 4.24 (t, J ) 6.6 Hz, 2 H, CH2CH2CH2CH2O), 2.27
(t, J ) 7.2 Hz, 2 H, NCH2CH2CH2CH2), 2.12 (s, 6 H, N(CH3)2),
1.85 (quintet, J ) 6.9 Hz, 2 H, CH2CH2CH2CH2), 1.60 (quintet,
J
) 7.4 Hz, 2 H, CH2CH2CH2CH2). Anal. (C23H26BrN5O2‚
1.25H2O) C, H, N.
N-[4-[N-(3-Br om op h en yl)a m in o]-7-[3-(1H -im id a zol-1-
yl)p r op oxy]qu in a zolin -6-yl]a cr yla m id e (10). To a suspen-
sion of hexane-washed sodium hydride (5.50 mmol, 220 mg of
a 60% dispersion in mineral oil) in THF (20 mL) was cannu-
lated a solution of 3-(1H-imidazol-1-yl)-1-propanol (4.84 mmol,
0.61 g) in THF (30 mL). The resulting suspension was stirred
at 20 °C under N2 for 2 h during which time the required
sodium alkoxide partially precipitated from solution. Solid 39
(0.80 g, 2.20 mmol) was then added, and the resulting dark
red solution was heated at reflux for 24 h, then worked up as
above. Chromatography of the product on silica gel, eluting
with CH2Cl2/EtOAc (1:1) to MeOH/CH2Cl2/EtOAc (3:7:10), gave
4-[N-(3-bromophenyl)amino]-7-[3-(1H-imidazol-1-yl)propoxy]-
6-nitroquinazoline (43d ) (524 mg, 51%): mp (CH2Cl2/hexane)
212-215 °C; 1H NMR [(CD3)2SO] δ 10.16 (s, 1 H, NH), 9.30 (s,
1 H, H-5), 8.70 (s, 1 H, H-2), 8.19 (t, J ) 1.6 Hz, 1 H, H-2′),
7.88 (ddd, J ) 7.8, 1.5, 1.6 Hz, 1 H, H-6′), 7.63 (s, 1 H,
imidazolyl methine), 7.48 (s, 1 H, H-8), 7.39 (t, J ) 7.9 Hz, 1
H, H-5′), 7.35 (ddd, J ) 8.0, 1.6, 1.6 Hz, 1 H, H-4′), 7.21 (s, 1
H, imidazolyl methine), 6.90 (s, 1 H, imidazolyl methine), 4.22
(t, J ) 6.0 Hz, 2 H, CH2CH2CH2), 4.18 (t, J ) 6.8 Hz, 2 H,
CH2CH2CH2), 2.26 (quintet, J ) 6.4 Hz, 2 H, CH2CH2CH2).
Anal. (C20H17BrN6O3) C, H, N.
Reduction of 43d (0.51 g, 1.08 mmol) with Fe (0.24 g, 4 mol
equiv) in refluxing EtOH/H2O (2:1, 60 mL) containing glacial
AcOH (0.7 mL) as above, followed by chromatography on grade
III alumina eluting with MeOH/EtOAc (5:95), gave 6-amino-
4-[N-(3-bromophenyl)amino]-7-[3-(1H-imidazol-1-yl)propoxy]-
quinazoline (47d ) (389 mg, 82%): mp (CH2Cl2/Et2O) 178-180
°C; 1H NMR [(CD3)2SO] δ 9.37 (s, 1 H, NH), 8.38 (s, 1 H, H-2),
8.22 (t, J ) 1.8 Hz, 1 H, H-2′), 7.86 (br d, J ) 8.1 Hz, 1 H,
H-6′), 7.66 (s, 1 H, imidazolyl methine), 7.40 (s, 1 H, H-8), 7.30