Molecules 2006, 11
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2H, -CH2CH2CH2-), 2.16-2.35 (m, 6H, 3 x CH2N), 3.80 (s, 3H, OCH3), 4.00-4.09 (t, 2H, CH2O), 7.41
(s, 1H, HAr), 7.45 (s, 1H, HAr), 8.76 (s, 1H, HAr); 13C-NMR (CDCl3): 26.22, 27.94, 30.27, 51.45, 52.97,
56.54, 70.03, 101.88, 108.52, 121.57, 147.07, 155.26, 160.95, 157.28, 159.32.
N-(4-Isopropoxyphenyl)-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)quinazolin-4-yl]piperazine-1-
carboxamide (1)
A suspension of N-(4-isopropoxyphenyl)piperazine-1-carboxamide (9, 6.90 g, 88%, 23 mmol) and
potassium carbonate (12.7 g, 96.2 mmol) in dry DMF (60 mL) was stirred at room temperature for 20
min, then 4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)quinazoline (10, 7.83 g, 23 mmol, 98.8%)
was added and this mixture was heated at 50 °C for 18 h. The reaction was monitored by HPLC and
found to be complete. The reaction mixture was poured on water (500 mL) and extracted with
dichloromethane (4 x 150 mL). The combined phases were washed with brine (2 x 80 mL), dried
(Na2SO4), decolorized (charcoal) and the solvent was removed under reduced pressure to dryness to
give a crude yellow, sticky material (12.4 g, yield 96%, 95% HPLC purity) which was crystallized
from ethyl acetate/petroleum ether to afford the product >99% HPLC purity. 1H-NMR (CDCl3): 1.29-
3
1.32 (d, 6H, 2 x CH3, J=6.06 Hz) 1.39-1.50 (m, 2H, CH2pip.), 1.53-1.64 (m, 4H, 2 x CH2pip.), 2.03-
3
3
2.17 (tt, 2H, -CH2CH2CH2-, Ja= 6.84 Hz, Jb= 6.65 Hz), 2.38-2.43 (m, 4H, 2 x CH2N), 2.47-2.54 (t,
3
2H, CH2N, Ja= 6.84 Hz), 3.71 (w, 8H, 4 x CH2N), 3.96 (s, 3H, OCH3), 4.19-4.25 (t, 2H, CH2O,
3Jb=6.65 Hz), 4.38-4.56 (m, 1H, (CH3)2CH), 6.50 (s, 1H, NH), 6.81-6.86 (m, 2H, HAr) 7.09 (s, 1H, HAr),
7.22-7.27 (m, 3H, HAr), 8.67 (s, 1H, HAr); 13C-NMR (CDCl3): 23.02, 25.65, 28.82, 31.11, 49.89, 52.20,
54.70, 56.76, 58.89, 72.31, 73.76, 103.11, 108.99, 114.45, 118.25, 122.43, 131.32, 148.87, 150.12,
155.67, 158.87, 160.76, 161.73, 165.75, 180.11.
N-(4-Isopropoxyphenyl)piperazine-1-carboxamide (9)
A solution of 4-isopropoxyphenylamine (1.0 g, 6.61 mmol) in dry toluene (10 mL) was added
drop- wise to a solution of trichloromethyl chloroformate (13.0 g, 9.94 mmol) in dry toluene (10 mL)
at 0-5 °C and the mixture was stirred at the same temperature for 20 min. The reaction mixture was
then stirred and heated to 100 °C over 1h and kept at this temperature for 1 h. Reaction progress was
monitored by HPLC and found to be complete by this time. The reaction mixture was cooled to room
temperature and extracted with saturated solution of sodium bicarbonate (1 x 10 mL). The toluene
solution was separated and aqueous phase extracted with toluene (5 mL). The combined toluene layers
were added dropwise to a solution of piperazine (2.80 g, 32.5 mmol) in toluene (10 mL) and this
mixture was heated at 90 °C for 3 h, cooled and washed with water (2 x 15). The toluene layer was
1
dried (Na2SO4) and evaporated to afford the product (0.91 g, 52%, 95% HPLC purity). H-NMR
(DMSO): 1.20-1.23 (d, 6H, 2 x CH3, 3J= 6.06), 2.73-2.78 (m, 4H, 2 x CH2N), 3.15 (w, 1H, NH), 3.39-
3
3
3.48 (m, 4H, 2 x CH2N), 4.41-4.53 (s, 1H, J=6.06), 6.75-6.80 (d, 2H, HAr, J=8.9), 7.31-7.36 (d, 2H,
HAr, 3J=8.9), 8.37 (s, 1H, NH); 13C-NMR (DMSO): 20.28, 49.05, 55.63, 68.82, 111.33, 120.20, 126.35,
155.05, 160.01.