反应详情

温度

70 °C

LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) was added to a degassed suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (200 mg; 0.44 mmol; 1.0 eq.), 3-Amino-1-methylpiperidine dihydrochloride, 98% (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (7.0 mg; 0.01 mmol; 0.02 eq.) and dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) in DMF (500 μl). The reaction mixture was then heated at 70° C. O/N. As the reaction was not completed, further 3-Amino-1-methylpiperidine dihydrochloride (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (7.0 mg; 0.01 mmol; 0.02 eq.), dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) and LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) were added and the reaction mixture was heated again at 70° C. for 12 h. It was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a brown solid (10 mg; 5%). 1H NMR (300 MHz, DMSO-d6-d6): 12.96 (brs, 1H), 9.26 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.36-7.33 (m, 1H), 6.96-6.92 (m, 2H), 5.36 (m, 1H), 3.64-3.55 (m, 1H), 3.00 (m, 1H), 2.73 (m, 1H), 2.23 (m, 3H), 1.99-1.59 (m, 3H), 1.30 (m, 1H). HPLC (max plot) 94.3%; Rt % 1.99 min. UPLC/MS: (MS+) 487.3, (MS−) 485.3.

1. addition4.5 eq.) were added
2. temperaturethe reaction mixture was heated again at 70° C. for 12 h
3. washwashed with water
4. dry with materialThe organic phase was dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated
7. customPurification by preparative HPLC