反应详情

温度

80 °C

To a solution of 5-(6-azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole (264 mg, 0.87 mmol) in EtOH (8.8 mL) was added ammonium chloride (360 mg 6.73 mmol) water (0.88 mL) and iron powder (51 mg, 0.91 mmol). The reaction mixture was heated at 80° C. for 16 hr and then cooled to room temperature. The crude slurry was filtered through Celite® washing with DCM (200 mL). The solution was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in isopropanol (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (255 mg, 0.92 mmol) and DIPEA (0.59 mL, 3.50 mmol) were added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.46 mL, 0.96 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) followed by preparative HPLC gave 122 (Diastereomer 2) as a colourless solid (24 mg, 6% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.43 and 9.39 (2s, 1H), 8.09 and 8.07 (2s, 1H), 7.32 (tt, J=8.4, 6.1 Hz, 1H), 7.06-6.96 (m, 2H), 6.19 (s, 2H), 4.92 and 4.81 (d, J=11.4 Hz, 1H), 4.27 and 4.08 (2dd, J=12.5, 5.2 Hz, 1H), 3.88 (dd, J=12.5, 6.4 Hz, 1H), 3.83 and 3.81 (2s, 3H), 3.46-3.36 (m, 1H), 2.65-2.46 (m, 1H), 2.45-2.27 (m, 2H), 1.25 (s, 3H). LCMS (ES+) m/z 485 (M+1).

1. temperaturecooled to room temperature
2. filtrationThe crude slurry was filtered through Celite®
3. washwashing with DCM (200 mL)
4. customThe solution was passed through a phase separation cartridge
5. concentrationconcentrated under reduced pressure
6. dissolutionThe residue was dissolved in isopropanol (10 mL)
7. concentrationThe reaction mixture was concentrated under reduced pressure
8. customPurification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM)