反应详情

温度

40 °C

To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.49 g, 1.6 mmol, Example #10, Step B) in MeOH (10 mL) was added hydroxylamine (50% in water, 0.199 mL, 3.25 mmol). The reaction mixture was heated to about 40° C. After about 2 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. To a solution of the crude oxime in THF (10 mL) and AcOH (0.93 mL, 16 mmol) was added zinc dust (<10 micron, 0.425 g, 6.50 mmol). After about 4 h at ambient temperature, the reaction mixture was diluted with DCM and saturated aqueous NaHCO3 and filtered through Celite®. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, treated with HCl (4 N in 1,4-dioxane, 1 mL) and concentrated under reduced pressure. To a solution of the crude amine in DCM (10 mL) was added 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (0.48 g, 1.8 mmol, Prime Organics), TEA (0.23 mL, 1.6 mmol) and HATU (0.618 g, 1.63 mmol). After about 4 h at ambient temperature, the reaction mixture was diluted with DCM and saturated aqueous NaHCO3 and filtered through Celite®. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude amide was purified by chromatography on silica gel eluting with a gradient of 20-80% EtOAc in DCM to provide tert-butyl-4-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)bicyclo[2.2.2]octan-1-ylcarbamate as a tan solid (0.205 g, 23%). LC/MS (Table 2, Method a) Rt=2.52 min; MS m/z: 554 (M+H)+.

1. temperaturethe reaction mixture was cooled to ambient temperature
2. concentrationconcentrated under reduced pressure
3. waitAfter about 4 h at ambient temperature
4. filtrationfiltered through Celite®
5. customThe layers were separated
6. dry with materialthe organic layer was dried over anhydrous Na2SO4
7. filtrationfiltered
8. additiontreated with HCl (4 N in 1,4-dioxane, 1 mL)
9. concentrationconcentrated under reduced pressure
10. waitAfter about 4 h at ambient temperature
11. filtrationfiltered through Celite®
12. customThe layers were separated
13. dry with materialthe organic layer was dried over anhydrous Na2SO4
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure
16. customThe crude amide was purified by chromatography on silica gel eluting with a gradient of 20-80% EtOAc in DCM