反应详情

温度

140 °C

To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (100 mg, 0.28 mmol) in 2-propanol (3 mL) were added cyclopropylamine (0.1 mL) and 3 Å (8-12 mesh) molecular sieves, and the mixture was heated at 140° C. in a Biotage microwave reactor. Additional cyclopropylamine (0.15 mL) was added and the mixture in a sealed vial was heated conventionally at 90° C. for 4 d. Then a suspension of sodium borohydride (140 mg) in 2-propanol was added dropwise and the mixture was stirred at rt for 1 h. Then MeOH (0.1 mL), sodium borohydride (100 mg), and more MeOH (2 mL) were added, and the mixture was filtered and the filtrate was concentrated. To the residue were added THF (5 mL), MeOH (2 mL) and sodium borohydride (100 mg) and the mixture was stirred for 1 h at rt. AcOH (0.4 mL) was then added and the mixture was concentrated. DMSO (3 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) followed by further purification by preparative HPLC (Phenomonex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) to afford 2-((cyclopropylamino)(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (5.5 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ 0.34 (m, 4H) 1.24 (m, 1H) 2.03 (m, 1H) 2.26 (s, 3H) 4.91 (s, 1H) 6.41 (m, 1H) 7.11 (t, 2H) 7.4-7.6 (m, 3H) 7.76 (m, 2H) 8.56 (d, 1H) 10.38 (bs, 1H) 12.15 (bs, 1H); LC-MS (ESI) m/z 389 (M+H)+.

1. temperaturethe mixture in a sealed vial was heated conventionally at 90° C. for 4 d
2. additionwas added dropwise
3. filtrationthe mixture was filtered
4. concentrationthe filtrate was concentrated
5. additionTo the residue were added THF (5 mL), MeOH (2 mL) and sodium borohydride (100 mg)
6. stirringthe mixture was stirred for 1 h at rt
7. additionAcOH (0.4 mL) was then added
8. concentrationthe mixture was concentrated
9. additionDMSO (3 mL) was added
10. customthe mixture was purified by preparative HPLC (Varian diphenyl reverse phase column
11. washeluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O)
12. customfollowed by further purification by preparative HPLC (Phenomonex C-18 reverse phase column
13. washeluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O)