Potassium Carbonate → 2-(8-Fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile

温度

40 °C

A 500 mL round-bottomed flask was charged with 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.5 g, 101 mmol, 1 equiv.) and potassium carbonate (27.9 g, 202 mmol, 2 equiv.) and the flask was subsequently purged with nitrogen (3 times). 1,4-dioxane (242 ml) and water (34.5 ml) were added. The E-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28.0 g, 142 mmol, 1.4 equiv.) was then added by syringe. The reaction mixture was heated to 40° C. To the mixture was added bis(dibenzylideneacetone)palladium (2.33 g, 4.04 mmol, 0.04 equiv.) and tricyclohexylphosphine (2.27 g, 8.09 mmol, 0.08 equiv.) and the resulting mixture was heated with stirring at 90° C. (inner temperature)/100° C. (bath) for 2 h until reaction was complete. The reaction mixture was cooled to ambient temperature and quenched with 20% NaHSO3 solution (150 mL) followed by stirring for 2 hr. The mixture was extracted with EtOAc (2 times), dried over MgSO4, and concentrated under reduced pressure. The resultant product was dissolved with TFA (138 ml) in a 350 mL pressured bottle and heated to 100° C. (bath temp.) for 3 hr. The reaction mixture was transferred to a round-bottomed flask with toluene, and the TFA was removed under reduced pressure, then basified with 20% K2CO3 solution. The reaction mixture was extracted with EtOAc and then with DCM. Crystallization from methyl-tert-butylether afforded 2-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (16.2 g, 69.6% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 6 H) 6.60 (dd, J=6.99, 1.70 Hz, 1 H) 7.16-7.28 (m, 1 H) 7.36 (dd, J=13.03, 1.70 Hz, 1 H) 7.61 (d, J=1.89 Hz, 1 H) 11.31 (br. s., 1 H).

1. customthe flask was subsequently purged with nitrogen (3 times)
2. addition1,4-dioxane (242 ml) and water (34.5 ml) were added
3. temperaturethe resulting mixture was heated
4. customuntil reaction
5. temperatureThe reaction mixture was cooled to ambient temperature
6. customquenched with 20% NaHSO3 solution (150 mL)
7. stirringby stirring for 2 hr
8. extractionThe mixture was extracted with EtOAc (2 times)
9. dry with materialdried over MgSO4
10. concentrationconcentrated under reduced pressure
11. dissolutionThe resultant product was dissolved with TFA (138 ml) in a 350 mL
12. temperatureheated to 100° C. (bath temp.) for 3 hr
13. customThe reaction mixture was transferred to a round-bottomed flask with toluene
14. customthe TFA was removed under reduced pressure
15. extractionThe reaction mixture was extracted with EtOAc
16. customCrystallization from methyl-tert-butylether

ORDレコード

ord-f4d30be8375046858a3b6cfd2275cb78

出典データセット

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08889682B2