390 JOURNAL OF CHEMICAL RESEARCH 2009
1 (90.2 g, 0.50 mol) in DMF (300 mL), The reaction mixture was
heated at 70°C for 6 h. The mixture was cooled to room temperature,
and then poured slowly into ice-water (3 L) while stirring constantly.
The solid which formed was filtered off and washed with cold water.
The off-white product was recrystallised from ethyl acetate (200 mL)
to afford 132.2 g (86% yield) of white compound 2; m.p. 96–98°C.
C16H21N3O4: C, 60.17; H, 6.63; N, 13.16. Found: C, 60.05; H, 6.62;
N, 13.20%.
4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazo-
line (6): Thionyl chloride (400 mL) and N,N-dimethylformamide
(40 mL) was added to compound 5 (70.0 g, 0.22 mol), The mixture
was refluxed for 24 h, and the excess thionyl chloride distilled.
The yellow residue was dissolved in chloroform (500 mL), then
washed with a saturated solution of sodium carbonate (3 ¥ 100 mL)
and water (2 ¥ 100 mL) and dried (Na2SO4). The chloroform was
then removed under reduced pressure to give an off-white powder,
which was recrystallised from ethyl acetate to afford the product
1
IR (cm-1): 1712 (CO). H NMR (DMSO-d6) d: 1.84–1.93 (m, 2H,
–CH2–), 2.35 (t, 4H, –CH2–CH2–), 2.41 (t, 2H, –CH2–), 3.57 (t, 4H,
–CH2–CH2–), 3.81 (s, 3H, –CH3), 3.83 (s, 3H, –CH3), 4.03 (t, 2H,
–CH2–), 7.08 (d, 1H, HAr, J = 8.52 Hz), 7.44 (d, 1H, HAr, J = 2.04 Hz),
7.59 (dd, 1H, HAr, J1 = 2.04 Hz, J2 = 1.92 Hz). 13C NMR d: 25.77,
51.81, 53.31, 54.69, 55.68, 66.15, 66.66, 111.31, 112.88, 121.71,
123.13, 147.70, 153.14, 165.91. Anal. Calcd for C16H23NO5: C,
62.12; H, 7.49; N, 4.53. Found: C, 62.21; H, 7.47; N, 4.52%.
1
(60.4 g, 81% yield); m.p. 117°C. IR (cm-1): 1115 (C–Cl). H NMR
(DMSO-d6) d: 1.93–2.03 (m, 2H, –CH2–), 2.38 (s, 4H, –CH2–CH2–),
2.44 (t, 2H, –CH2–), 3.57 (t, 4H, –CH2–CH2–), 4.01 (s, 3H, –CH3),
4.23 (t, 2H, –CH2–), 7.37 (s, 1H, H8), 7.44 (s, 1H, H5), 8.87 (s, 1H,
H2). 13C NMR d: 25.49, 53.31, 54.67, 56.52, 66.15, 67.16, 102.82,
106.91, 118.54, 148.45, 150.68, 152.11, 156.82, 157.78. Anal. Calcd
for C16H20ClN3O3: C, 56.89; H, 5.97; N, 12.44. Found: C, 56.76; H,
6.60; N, 12.42%.
Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate (3):
Nitric acid (80 ml, 65–68%) was added dropwise to a solution of
compound 2 (102.9 g, 0.33 mol) in a mixture of acetic acid (360 mL)
and acetic anhydride (100 mL) at 0–5°C. The mixture was stirred at
room temperature for 6 h, and then slowly poured into ice-water (5 L)
and extracted with ethyl acetate (4 ¥ 300 mL). The combined organic
layer was washed with saturated sodium bicarbonate (2 ¥ 200 mL)
and brine (2 ¥ 100 mL) and dried (Na2SO4). The ethyl acetate was
then removed by letting it stand under vacuum to give a yellow oil
that solidified after standing in a refrigerator for 12 h. It was then
recrystallised from ethyl acetate/petroleum ether to afford the product
as light yellow crystals (87.5 g, 75% yield); m.p. 119–120°C. IR
(cm-1): 1720 (CO), 1529 (NO2). 1H NMR (DMSO-d6) d: 2.06 (t, 2H,
–CH2), 2.48–2.56 (m, 6H, –CH2–CH2–CH2–), 3.73 (t, 4H, –CH2–
CH2-), 3.91 (s, 3H, –OCH3), 3.95 (s, 3H, –OCH3), 4.19 (t, 2H, –CH2),
7.11 (s, 1H, HAr), 7.46 (s, 1H, HAr). 13C NMR d: 25.48, 52.93,
53.23, 54.45, 56.43, 66.06, 67.53, 107.47, 111.87, 120.36, 140.63,
150.38, 151.62, 165.33. Anal. Calcd for C16H22N2O7: C, 54.23; H,
6.26; N, 7.91. Found: C, 54.12; H, 7.45; N, 7.94%.
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)
quinazolin-4-amine (Gefitinib): Compound 6 (50.0 g, 0.15 mol) was
dissolved in isopropanol (300 mL), and 3-chloro-4-fluoroaniline
(36.2 g, 0.25 mol) was added. The reaction mixture was heated
under reflux for 3 h and concentrated under reduced pressure.
The mixture was cooled to room temperature, and the precipitate was
collected by filtration and washed with cold isopropanol (2 ¥ 50 mL)
to afford a white powder, which was recrystallised from ethyl acetate
to afford the white product (59.5 g, 89% yield); m.p. 195–198°C,
(lit.12 M.p. 197°C). IR (cm-1): 1502 (NH), 1209 (C–F), 1075 (C–Cl).
1H NMR(DMSO-d6) d: 2.43 (tt, 2H, –CH2CH2CH2–), 2.64 (m, 4H,),
2.73 (t, 2H, –CH2), 3.82 (m, 4H), 4.02 (s, 3H, –OCH3), 4.26 (t, 2H,
–OCH2), 7.13 (s, 1H, HAr), 7.29 (s, 1H, HAr), 7.49 (s, 1H, HAr),
7.61 (d, 1H, HAr), 7.98 (d, 1H, HAr), 8.66 (s, 1H, HAr), 10.44–10.80
(b, 1H, –NH–); 13C NMR d: 26.23, 53.79, 55.40, 56.22, 60.39, 61.67,
66.95, 67.76, 100.79, 108.19, 109.04, 118.07, 122.71, 123.13, 135.18,
136.18, 147.67, 149.15, 153.63, 155.30, 156.47, 162.74.; MS m/z:
447.1 ([M + H] +, 100%). Anal. Calcd for C22H25Cl2FN4O3: C, 54.67;
H, 5.21; N, 11.59. Found: C, 54.69; H, 5.22; N, 11.56%.
Methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzoate
(4): Sodium dithionite (80.0 g, 0.45 mol) was added to a solution of
compound 3 in water (400 mL), and the mixture was heated to 50°C
for 2 h. When the reaction was complete after 0.5 h, concentrated
hydrochloric acid (200 g) was added at 70°C. Then the mixture was
cooled to room temperature, and aqueous NaOH solution (47%) was
added to adjust the pH of the mixture to 8.0–9.0. After the pH was
adjusted, the mixture was stirred for 30 min and the product filtered
under vacuum. The filter cake was recrystallised from ethyl acetate
to afford white crystals (67.2 g, 90% yield); m.p. 89–90°C. IR
Received 17 February 2009; accepted 14 April 2009
1
(cm-1): 3472 (NH2), 1684 (CO). H NMR (DMSO-d6) d: 1.75–1.84
(m, 2H, –CH2–), 2.34–2.41 (m, 6H, –CH2–CH2–CH2–), 3.56 (t, 4H,
–CH2–CH2–), 3.73 (d, 6H, –CH3, J = 0.99 Hz), 3.83 (t, 2H, –CH2–),
6.35 (s, 1H, HAr), 6.43 (s, 2H, –NH2), 7.14 (s, 1H, HAr). 13C NMR
d: 25.99, 50.97, 53.31, 54.84, 55.20, 66.14, 67.60, 99.10, 99.74,
114.67, 148.41, 155.34, 167.26.Anal. Calcd for C16H24N2O5: C, 59.24;
H, 7.46; N, 8.64. Found: C, 54.15; H, 7.44; N, 8.66%.
References
1
2
44, 195.
3
7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one (5):
Formamidine acetate (120.0 g, 1.15 mol) and compound 4 were
added to dry alcohol (600 mL). The mixture was refluxed for 4 h, and
then cooled to 0°C. The precipitate was collected by filtration and
washed with cold ethanol to afford white powder (70.2 g, 88% yield);
m.p. 248–250°C. IR (cm-1): 1675 (CO), 1615 (NH). 1H NMR
(DMSO-d6) d: 1.89–1.96 (m, 2H, –CH2–), 2.36–2.45 (m, 6H, –CH2–
CH2–CH2–), 3.57 (t, 4H, –CH2–CH2–), 4.10 (t, 2H, –CH2–), 7.12 (s,
1H, H8), 7.43 (s, 1H, H5), 7.97 (s, 1H, H2), 12.01 (s, 1H, –NH–).
13C NMR d: 25.66, 53.31, 54.70, 55.90, 66.15, 66.75, 105.81, 108,
06, 115.55, 143.77, 144.73, 147.82, 154.56, 160.02. Anal. Calcd for
4
5
11, 1911.
6
7
8
9
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