反应详情

In a microwave tube N-Boc-3-bromo-2-fluoro-aniline (300 mg, 1.034 mmol) was dissolved in a 9:1 DME/H2O mixture (12 mL) and argon was bubbled through the solution for 10 minutes. 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (prepared as described in WO2010/010154) (576 mg, 2.071 mmol, 2 eq) was then added, followed by cesium carbonate (1.0 g, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (84 mg, 14.6 mmol, 0.1 eq) and the reaction mixture was irradiated at 100° C. for 30 minutes. A further addition of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq) was made and a second microwave cycle was performed at 100° C. for 30 min. The mixture was then filtered over a Celite pad, which was washed with AcOEt. The filtrate was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on silica gel (Hex/AcOEt 8:2) to give 570 mg of {2-Fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-carbamic acid tert-butyl ester contaminated by N-tetrahydropyranyl-pyrazole (NMR title about 57%). HPLC (254 nm): Rt: 6.82 min; 1H NMR (DMSO-d6) Shift: 9.09 (s, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.22-7.29 (m, 1H), 7.16-7.22 (m, 1H), 6.42-6.45 (m, 1H), 5.09-5.15 (m, 1H), 3.86-3.95 (m, 1H), 3.35-3.46 (m, 1H), 1.51-1.73 (many m, 6H), 1.48 (s, 9H); HRMS (ESI) calcd for C19H25FN3O3 [M+H]+ 362.1875. found 362.1874.

1. customwas bubbled through the solution for 10 minutes
2. filtrationThe mixture was then filtered over a Celite pad, which
3. washwas washed with AcOEt
4. washThe filtrate was washed with water and brine
5. dry with materialdried over Na2SO4
6. customevaporated to dryness
7. customThe crude was purified by chromatography on silica gel (Hex/AcOEt 8:2)