反应详情

温度

70 °C

A 75 mL threaded pressure vessel was flushed with argon and was charged with a stir bar, bis(4-(di-tert-butylphosphino)-N,N-dimethyl-benzenamine) palladium dichloride (0.061 g, 0.086 mmol) and (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.00 g, 1.711 mmol). (2,6-Difluorophenyl)zinc(II) bromide 0.5 M in THF (Rieke metals) (5.13 mL, 2.57 mmol) was added, the reaction was sealed, and the slurry was heated to 70° C. After ˜10 min, a clear solution resulted. After 3 h the reaction was cooled and judged complete by LCMS. The reaction was treated with sodium 2,2′-(2-((carboxylatomethyl)(2-hydroxyethyl)amino)ethylazanediyl)diacetate hydrate 10 wt % in water (10.23 mL, 2.82 mmol) (10% aqueous EDTA-H) and DCM. An additional 2-3 mL of 10% EDTA-H solution was added to break up emulsion. The layers were separated, and the aqueous layer was extracted 3×DCM. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) eluting with 0-40% EtOAc/hexane. The product-containing fractions were concentrated to afford (4R)-tert-butyl 4-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.10 g, 1.781 mmol, quant.) as a light-yellow foam: MS (ESI, pos. ion) m/z: 618 (M+1)

1. customwas flushed with argon
2. additionwas charged with a stir bar
3. customthe reaction was sealed
4. customa clear solution resulted
5. temperatureAfter 3 h the reaction was cooled
6. customThe layers were separated
7. extractionthe aqueous layer was extracted 3×DCM
8. dry with materialThe combined organics were dried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. additionThe material was treated with DCM
12. custompurified by silica gel chromatography (80 g column)
13. washeluting with 0-40% EtOAc/hexane
14. concentrationThe product-containing fractions were concentrated