Tetrahydrofuran → 3-Bromo-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile

Temperature

125 °C

6-chloro-2-fluoro-3-methylphenol (8.03 g, 50.0 mmol) and 18-crown-6 (7.7 g, 29.1 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (28.1 g, 50.0 mmol) for 15 minutes at room temperature. 3-bromo-5-fluorobenzonitrile (10 g, 50.0 mmol) was added in one portion and the reaction mixture heated at 125° C. for 20 h at which time LC-MS indicated >90% conversion. The reaction mixture was cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of IPA (100 mL). The precipitate was cooled in an ice bath and filtered to afford 3-bromo-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (10.7 g, 31.4 mmol, 62.8% yield) as a tan solid in >90% purity as determined by LCMS. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.28-7.45 (m, 2H), 2.28 (s, 3H).

1. temperatureThe reaction mixture was cooled to ambient temperature
2. customto afford the crude product as a black precipitate which
3. filtrationwas filtered off
4. washwashed with water and air
5. customdried
6. dissolutionThe crude product was dissolved in DCM
7. dry with materialdried over MgSO4
8. filtrationfiltered through a plug of 45 g silica gel which
9. washwas eluted with 500 mL DCM
10. concentrationThe filtrate was concentrated to an amber oil
11. customcrystallized by addition of IPA (100 mL)
12. temperatureThe precipitate was cooled in an ice bath
13. filtrationfiltered

ORD record

ord-e211646e48b744bc8706a88c12718428

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304419B2