Water → HCID 86594620, compound

Potassium carbonate (62 mg, 0.45 mmol), 3-(4-bromofuran-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one (61 mg, 0.14 mmol), and 2-(3-ethylsulfanyl-5-trifluoromethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (59 mg, 0.18 mmol) were combined in a mixture of THF (3 mL), and H2O (1 mL). The resulting biphasic mixture was sparged with nitrogen for 10 minutes. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12 mg, 15 μmol) was then added to afford a dark red-brown solution. After stirring at ambient temperature for 16 hours, HPLC analysis of the reaction showed a later eluting peak present as well as a quantity of the starting 3-(4-bromo-furan-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one remaining. An additional portion of the Pd catalyst was added and the reaction was then heated in an oil bath held at 60° C. After stirring for 150 minutes at 60° C., HPLC analysis showed the starting 3-(4-bromo-furan-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one to be consumed. The reaction was allowed to cool to ambient temperature, then diluted with Et2O (50 mL), and H2O (20 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×5 mL). The combined ether layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under educed pressure to afford a brown film. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 0% to 12% EtOAc/Hexane. The broad peak that was observed to elute from the column was concentrated under reduced pressure to afford 8-chloro-2-(2,4-difluorobenzyl)-3-[4-(3-ethylsulfanyl-5-trifluoromethylphenyl)furan-2-yl]-2H-isoquinolin-1-one (34 mg, 43% yield) as a clear film. 1H-NMR (400 MHz, CDCl3): δ 7.79 (1H, d, J=0.8 Hz), 7.56-7.53 (2H, m), 7.49-7.41 (4H, m), 7.12-7.04 (1H, m), 6.81-6.71 (4H, m), 5.39 (2H, s), 3.02 (2H, q, J=7.3 Hz), 1.37 (3H, t, J=7.3 Hz).

1. customThe resulting biphasic mixture was sparged with nitrogen for 10 minutes
2. customto afford a dark red-brown solution
3. washa later eluting peak present as well as a quantity of the starting 3-(4-bromo-furan-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one remaining
4. additionAn additional portion of the Pd catalyst was added
5. temperaturethe reaction was then heated in an oil bath
6. customheld at 60° C
7. stirringAfter stirring for 150 minutes at 60° C.
8. customto be consumed
9. temperatureto cool to ambient temperature
10. additiondiluted with Et2O (50 mL), and H2O (20 mL)
11. customThe layers were separated
12. extractionthe aqueous layer was extracted with Et2O (3×5 mL)
13. washThe combined ether layers were washed with brine (10 mL)
14. dry with materialdried over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated under educed pressure
17. customto afford a brown film
18. customThe crude product was purified by silica gel column chromatography
19. washeluting with a gradient from 0% to 12% EtOAc/Hexane
20. washto elute from the column
21. concentrationwas concentrated under reduced pressure

ORD record

ord-1c4e1de1466d4fd3917c61e61eb4dc91

Source dataset

uspto-grants-2007_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07265131B2