反应详情

N,N-diisopropylethylamine (0.22 ml, 1.24 mmol) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (160 mg, 0.41 mmol prepared as described in Example 62) in dimethylformamide (1 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and tert-butyl 3-(aminocarbonyl)-3-(methylamino)azetidine-1-carboxylate (98 mg, 0.43 mmol) was added. After 30 minutes of stirring at 80° C., the reaction mixture was cooled down to room temperature, water was added and the aqueous layer was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residues were purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95) to give tert-butyl 3-(aminocarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-1-carboxylate as a yellow solid, (100 mg, 44%); 1H NMR Spectrum: (CDCl3) 1.46 (s, 9H), 2.39 (s, 3H), 3.82 (s, 2H), 3.99 (s, 3H), 4.17 (d, 2H), 4.25 (brd, 2H), 5.47 (brs, 1H), 6.79 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.66 (brs, 1H), 7.83 (s, 1H), 8.49 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 545.

1. stirringAfter 30 minutes of stirring at 80° C.
2. extractionthe aqueous layer was extracted with ethyl acetate (×2)
3. dry with materialThe combined organics were dried over magnesium sulfate
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe residues were purified by column chromatography on silica eluting
7. temperaturewith increasingly polar mixtures of methanol/dichloromethane (0/100-5/95)