反应详情

温度

-5 °C

To a 500 mL round-bottom flask equipped with a magnetic stir-bar was added 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 20 mmole), DCM (100 mL), TEA (3.0 g, 30 mmole), and DMAP (25 mg, 0.2 mmole). To the rapidly stirred suspension at room temperature was added acetic anhydride (2.3 g, 23 mmole). The reaction was complete after 10 minutes as determined by TLC analysis. The mixture was diluted with DCM (100 mL), and washed with saturated aqueous ammonium chloride. The aqueous layer was back-extracted with additional DCM (100 mL). The combined organic fractions were washed with brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to give an amorphous orange solid. The crude product was re-dissolved in 5% MeOH/DCM (65 mL). To the stirred solution was added diethyl ether (200 mL), which resulted in the formation of a bright yellow precipitate. The stirred suspension was cooled over a salt/ice bath to −-5° C., then filtered to recover the solids. The solids were washed sparingly with diethyl ether and collected to provide acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (6.94 g, 80.4%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37-7.34 (m, 3H), 7.25 (td, 1H, J1=2.7 Hz, J2=8.2 Hz), 6.34 (app d, 11H, J=6.3 Hz), 6.17 (ddd, 1H, J1=6.3 Hz, J2=10.2 Hz, J3=16.8 Hz), 5.41 (app d, 1H, J=17.2 Hz), 5.33 (app d, 1H, J=10.2 Hz),4.18 (s, 3H),2.32 (s, 3H), 2.12 (s, 3H); ESMS (m/z): 435 M+1)+.

1. customTo a 500 mL round-bottom flask equipped with a magnetic stir-bar
2. washwashed with saturated aqueous ammonium chloride
3. extractionThe aqueous layer was back-extracted with additional DCM (100 mL)
4. washThe combined organic fractions were washed with brine (2×100 mL)
5. dry with materialdried over sodium sulfate
6. concentrationconcentrated in vacuo
7. customto give an amorphous orange solid
8. customresulted in the formation of a bright yellow precipitate
9. filtrationfiltered
10. customto recover the solids
11. washThe solids were washed sparingly with diethyl ether
12. customcollected