反应详情

温度

90 °C

2-Bromoethanol (47 μl, 0.66 mmol) was added to a stirred suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (250 mg, 0.53 mmol) (Example 16) and anhydrous potassium carbonate (150 mg, 1.08 mmol) in tetrahydrothiophene 1,1-dioxide (Sulfolane) (5 ml). The mixture was heated at 90° C. for 3 hours and partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was washed with brine and evaporated. The residues were purified by column chromatography on silica, eluting with 7M ammonia in methanol/methylene chloride (16/84). Fractions containing the desired product were combined and evaporated to a foam. This was triturated with diethyl ether to give the title product as a white solid (43 mg, 16%); 1H NMR Spectrum: (DMSO-d6+CD3COOD) 2.13-2.21 (m, 2H), 2.25 (s, 3H), 2.26-2.33 (m, 2H), 3.13-3.17 (t, 2H), 3.17-3.25 (m, 2H), 3.42-3.49 (m, 2H), 3.71-3.77 (m, 4H), 3.94 (s, 3H), 7.18-7.22 (m, 1H), 7.23 (s, 1H), 7.33-7.38 (m, 1H), 7.58-7.63 (m, 1H), 8.28 (s, 1H), 8.39 (s, 1H); Mass Spectrum: (M+H)+ 517.

1. custompartitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate
2. washThe organic phase was washed with brine
3. customevaporated
4. customThe residues were purified by column chromatography on silica
5. washeluting with 7M ammonia in methanol/methylene chloride (16/84)
6. additionFractions containing the desired product
7. customevaporated to a foam
8. customThis was triturated with diethyl ether