反应详情

温度

80 °C

To a stainless steel pressure vessel containing 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.2 g, 0.407 mmol) was added 1,4-dioxane (5 mL), water (0.037 mL, 2.035 mmol), tetrakis(triphenylphosphine)palladium(0) (0.071 g, 0.061 mmol), triethylamine (0.567 mL, 4.07 mmol), and methylamine (2M in THF) (2.035 mL, 4.07 mmol). The vessel was sealed and purged with N2 3 times. The vessel was filled with carbon monoxide to 50 psi, and purged 2 times, then finally was filled to 80 psi of carbon monoxide. The vessel was heated to 80° C. for 16 h then was cooled to rt. The mixture was transferred to a rb flask and the solvent was removed under reduced pressure. The residue was dissolved in DMF and was passed through a plug of CELITE® to remove the solids. The DMF solution was purified by prep HPLC. The fractions containing the expected product were concentrated under reduced pressure. The residue was dissolved in dichloromethane and was partitioned with aq. sat. NaHCO3. The organic layer was collected, and dried with MgSO4. The drying agent was removed by filtration and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient using a BIOTAGE® flash chromatography. The expected product, 4-methoxy-N-methyl-3-(2-oxo-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (0.065 g, 0.133 mmol, 32.7% yield), was isolated as an off-white solid. LC/MS: m/z 470.24 (M+H)+, 1.582 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.13 (br. s., 1H) 8.60-8.77 (m, 1H) 8.14-8.26 (m, 1H) 7.70-7.94 (m, 3H) 7.02-7.47 (m, 5H) 4.73-5.01 (m, 2H) 3.88-3.97 (m, 3H) 3.66-3.88 (m, 2H) 2.92-3.11 (m, 5H).

1. customThe vessel was sealed
2. custompurged with N2 3 times
3. additionThe vessel was filled with carbon monoxide to 50 psi
4. custompurged 2 times
5. additionfinally was filled to 80 psi of carbon monoxide
6. temperaturethen was cooled to rt
7. customThe mixture was transferred to a rb flask
8. customthe solvent was removed under reduced pressure
9. dissolutionThe residue was dissolved in DMF
10. customto remove the solids
11. customThe DMF solution was purified by prep HPLC
12. additionThe fractions containing the expected product
13. concentrationwere concentrated under reduced pressure
14. dissolutionThe residue was dissolved in dichloromethane
15. customwas partitioned with aq. sat. NaHCO3
16. customThe organic layer was collected
17. dry with materialdried with MgSO4
18. customThe drying agent was removed by filtration
19. concentrationthe organic solution was concentrated under reduced pressure
20. customThe residue was purified by BIOTAGE® flash chromatography