反应详情

Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (99 mg, 0.22 mmol), 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (120 mg, 0.248 mmol), 2 mL dioxane, and a solution of cesium carbonate in water (370 mg/420 μL) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged the mixture with nitrogen for 15 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (12 mg, 0.015 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature, partitioned the reaction mixture between 5 mL of 5% NaHCO3 and 10 mL of EtOAc, and separated phases. Washed the organic phase with 5 mL of water and 5 mL of brine, dried over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 2-(2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-cyclopropyl-2H-isoquinolin-1-one as a brittle amber foam. (70 mg, 0.097 mmol). MS (ESI) 718 (M+H)+.

1. customvial fitted with a stir bar
2. customSparged the mixture with nitrogen for 15 min
3. customThe reaction was sparged with nitrogen for 5 min
4. customSealed the vial and
5. custompartitioned the reaction mixture between 5 mL of 5% NaHCO3 and 10 mL of EtOAc
6. customseparated phases
7. washWashed the organic phase with 5 mL of water and 5 mL of brine
8. dry with materialdried over Na2SO4
9. concentrationconcentrated in vacuo
10. customPurified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA)
11. additionAdded 1 mL of saturated NaHCO3 to the pooled product fractions
12. concentrationconcentrated in vacuo
13. extractionExtracted the remaining aqueous mixture with 2×10 mL CH2Cl2
14. dry with materialdried over Na2SO4
15. concentrationconcentrated in vacuo