反应详情

A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (302.9 mg, 0.661 mmol), 2-fluoro-3-pyridineboronic acid (102 mg, 0.727 mmol), potassium carbonate (457 mg, 3.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (38.2 mg, 0.033 mmol). The vial was flushed with Ar (g), then dioxane (3306 μL) and water (1.7 mL) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for 2 hours. The mixture was diluted with EtOAc (15 mL) and brine (15 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 40-g Redi-Sep column, eluting with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid. Step 2: A vial was charged with (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (110 mg, 0.257 mmol), DavePhos (12.16 mg, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium(0) (11.79 mg, 0.013 mmol). The vessel was flushed with Ar(g), then lithium bis(trimethylsilyl)amide (772 μL, 0.772 mmol) (1.0 M solution in THF) and 2,2-dimethylmorpholine (61.8 μL, 0.515 mmol) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for two hours. The mixture was diluted with saturated aq. ammonium chloride solution (20 mL) and water (10 mL). The mixture was extracted with DCM (3×20 mL), leaving behing a dark oily solid. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on an 24-g Redi-Sep Gold column with 0-70% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-(2,2-dimethylmorpholino)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.

1. customThe vial was flushed with Ar (g)
2. additiondioxane (3306 μL) and water (1.7 mL) were added in sequence
3. customThe vial was sealed
4. customplaced in a 75° C.
5. customfor 2 hours
6. additionThe mixture was diluted with EtOAc (15 mL) and brine (15 mL)
7. customThe layers were separated
8. extractionthe aq. layer was extracted with EtOAc (2×15 mL)
9. dry with materialThe combined organic extracts were dried over sodium sulfate
10. filtrationfiltered
11. customevaporated
12. customThe residue was purified by chromatography on a 40-g Redi-Sep column
13. washeluting with 0-60% of a 90:10:1
14. additionmix of DCM/MeOH/NH4OH in DCM