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 (69 mg, 0.23 mmol) in EtOH (2.3 mL) was added ammonium chloride (61 mg 1.14 mmol) and water (0.23 mL) followed by iron powder (51 mg, 0.9 μmol). The reaction mixture was heated at 80° C. for 6 hr and then recharged with the same amounts of iron and ammonium chloride. Heating was continued for 60 min and the reaction mixture was cooled to room temperature. The crude slurry was filtered through Celite® washing with DCM (20 mL). The solution was passed through a phase separation cartridge and concentrated under reduced pressure. The crude residue was dissolved in MeOH (1 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.19 mL, 0.39 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL), brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) and preparative HPLC gave 5-amino-N-(5-(6-azido-4,4-difluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as a colourless oil. The compound was dissolved in MeOH (10 mL) and passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). Purification via silica gel column chromatography (0-10% MeOH/DCM, 1% 7 M NH3 in MeOH) gave 114 (Diastereomer 1) as a colourless solid (2 mg, 2% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.07 (s, 1H), 7.45-7.18 (m, 1H), 7.05-6.98 (m, 2H), 6.16 (s, 2H), 4.97-4.88 (m, 1H), 4.32-4.23 (m, 1H), 3.83 (s, 3H), 3.54-3.42 (m, 2H), 2.74-2.44 (m, 3H), 2.36-2.20 (m, 1H), 1.31-1.14 (m, 2H). LCMS (ES+) m/z 485 (M+1).

1. temperatureHeating
2. temperaturethe reaction mixture was cooled to room temperature
3. filtrationThe crude slurry was filtered through Celite®
4. washwashing with DCM (20 mL)
5. customThe solution was passed through a phase separation cartridge
6. concentrationconcentrated under reduced pressure
7. dissolutionThe crude residue was dissolved in MeOH (1 mL)
8. concentrationThe reaction mixture was concentrated under reduced pressure
9. dissolutionthe residue dissolved in EtOAc (10 mL)
10. washThe organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL), brine (10 mL)
11. dry with materialdried over Na2SO4
12. concentrationconcentrated under reduced pressure
13. customPurification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) and preparative HPLC