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温度

0 °C

2-Amino-3-chloro-benzoic acid methyl ester (0.126 g, .681 mmol) and triethylamine (0.22 mL, 1.57 mmol) were dissolved in methylene chloride (3 mL) and cooled to 0° C. Triphosgene (0.067 g, 0.227 mmol) in methylene chloride (1 mL) was added dropwise to the reaction and then stirred in the cold for 1 hour. Next 4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butylamine (0.20 g, 0.681 mmol) was added in one portion and the reaction was stirred at room temperature for 15 hours. Mix was evaporated to dryness, diluted with toluene (40 mL) and refluxed for 6 hours, cooled, diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown solid. Silica gel flash chromatography using 3.5% methanol/chloroform as eluent yielded 8-Chloro-3-{4-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-1H-quinazoline-2,4-dione (0.198 g, 61%) as a white solid. Maleate salt was formed by dissolving the solid in warm chloroform (30 ml) and maleic acid (0.058 g, 1.2 eq) in warm ethyl acetate (20 ml) was added. Cooling yielded the maleate salt (0.196 g) as a white solid which had the following properties: Mp. 235-238° C., 1H NMR DMSO-d6 δ: 11.02 (brd s, 1H), 9.85 (brd s, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.79 (d, J=6.6 Hz, 1H), 7.26-7.18 (m, 3H), 6.90 (d, J=9.1 Hz, 2H), 6.00 (s, 2H), 4.17 (brd s, 2H), 3.98-3.87 (m, 2H), 3.66 (d, J=14.1 Hz, 2H), 3.11-2.93 ( m,4H), 2.19-2.06 (m, 2H), 1.97-1.85 (m, 2H), 1.77-1.6 (m, 4H). IR (KBr): 3355, 3216, 3190, 3161, 3071, 2960, 2849, 2706, 2397, 1717, 1655, 1610, 1500, 1473, 1456, 1435, 1420, 1404, 1365, 1332, 1311, 1269, 1254, 1221, 1185, 1163, 1134, 1101, 1068, 1041, 989, 973, 954, 925, 915, 882, 851, 821, 814, 790, 761, 747, 729, 701, 671, 650, 580, 545, 515, 496, 484, 437, 411, 404, (cm−1). Analysis calculated for C24H26Cl2N4O2.C4H4O4.1½ H2O: C, 54.55; H, 5.39; N, 9.08. Found: C, 54.81; H, 5.06; N, 8.91.

1. stirringthe reaction was stirred at room temperature for 15 hours
2. additionMix
3. customwas evaporated to dryness
4. additiondiluted with toluene (40 mL)
5. temperaturerefluxed for 6 hours
6. temperaturecooled
7. additiondiluted with saturated sodium bicarbonate (200 mL)
8. extractionextracted with ethyl acetate (3×100 mL)
9. washThe combined organic layers were washed with brine (200 mL)
10. dry with materialdried with magnesium sulfate
11. concentrationconcentrated to a light brown solid