反应详情

A mixture of phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanone (Intermediate AL) (0.241 g, 0.00078 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.30 g, 0.00068 mol), tetrakis(triphenyl-phosphine)palladium (0.047 g, 0.000041 mol) and sodium carbonate (0.18 g, 0.0017 mol) was heated in a mixture of ethylene glycol dimethyl ether (10 mL) and water (5 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate, the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (95:4:1) as a mobile phase to give cis-{4-[4-amino-1-(4-(4-methylpiperazino)cyclohexy)]-1H-pyrazolo[3,4-d]pyrimidin-3-yl-]-phenyl}(phenyl)methanone as a white solid (0.195 g, 0.0004 mol). It was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.137 g, 0.0018 mol) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaletate as a white solid (0.221 g, 0.0003 mol): 1H NMR (DMSO-d6, 400 MHz) 8.28 (s, 1H), 7.90 (d, 2H), 7.83 (m, 4H), 7.73 (t, 1H), 7.61 (m, 2H), 6.15 (s, 4H), 4.88 (m, 1H), 3.1 (br, 9H), 2.71 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.63 min. MS: MH+ 496.

1. customsolvents were removed under the reduced pressure
2. customThe residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate
3. customthe organic layer separated
4. extractionthe aqueous layer further extracted with ethyl acetate twice
5. dry with materialThe combined organic extracts were dried over magnesium sulfate
6. customThe solvents were evaporated under the reduced pressure
7. customto leave a tan solid which
8. customwas purified by flash column chromatography on silica
9. customto give cis-{4-[4-amino-1-(4-(4-methylpiperazino)cyclohexy)]-1H-pyrazolo[3,4-d]pyrimidin-3-yl-]-phenyl}(phenyl)methanone as a white solid (0.195 g, 0.0004 mol)
10. dissolutionIt was dissolved
11. temperatureThe mixture was refluxed for 10 min
12. temperaturecooled to ambient temperature
13. filtrationthe precipitate collected by filtration
14. washwashed with ethyl acetate
15. customdried