反应详情

温度

85 °C

A microwave vial was charged with 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (32.2 mg, 0.153 mmol), (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (64 mg, 0.128 mmol, Example 1), bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (4.53 mg, 6.39 μmol) and potassium phosphate (81 mg, 0.383 mmol). The vial was evacuated and backfilled with nitrogen (procedure was repeated twice). Dioxane (2 mL) and water (0.7 mL) were added and the reaction mixture was purged for 1 min with nitrogen. The vial was placed in a preheated oilbath and heated to 85° C. After 12 hours an additional portion of all reagents were added and the reaction mixture was heated for 4.5 hs to 100° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 14 mg of (S)—N-(2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide were obtained as a tan solid. MS m/z=503.7 [M]+. Calculated for C26H22ClN5O4: 503.94.

1. customThe vial was evacuated
2. additionDioxane (2 mL) and water (0.7 mL) were added
3. customthe reaction mixture was purged for 1 min with nitrogen
4. additionAfter 12 hours an additional portion of all reagents were added
5. temperaturethe reaction mixture was heated for 4.5 hs to 100° C
6. temperatureThe reaction mixture was cooled to room temperature
7. custompartitioned between EtOAc and water
8. customThe organic phase was separated
9. dry with materialdried over MgSO4
10. customThe solvent was removed under reduced pressure
11. customThe residue was purified by preparative reversed-phase
12. customover 20 min
13. concentrationThe combined fractions were concentrated
14. dissolutionThe residue was dissolved in MeOH
15. washThe product was eluted with a 2M solution of NH3 in MeOH