18-Crown-6 → 2-[(5-Bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene

Temperature

130 °C

6-chloro-2-fluoro-3-methylphenol (9.96 g, 62.0 mmol) and 18-crown-6 (4.5 g, 17.03 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (34.8 g, 62.0 mmol) in THF for 15 minutes at room temperature. 5-bromo-2-chloro-1,3-difluorobenzene (14.11 g, 62.0 mmol) was added in one portion and the reaction mixture heated at 130° C. for 3 days. The reaction mixture was filtered through Celite™, 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 EtOH (150 mL). The precipitate was cooled in an ice bath and filtered to afford 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (8.7 g, 23.64 mmol, 38.1% yield) as a white solid. The mother liquor was concentrated to dryness and crystallized from IPA (70 mL) to give a second batch of the desired product (4.55 g, 12.36 mmol, 19.93% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (dd, J=8.56, 1.97 Hz, 1H), 7.30-7.47 (m, 2H), 6.74 (s, 1H), 2.29 (d, J=1.56 Hz, 3H).

1. filtrationThe reaction mixture was filtered through Celite™
2. temperaturecooled to ambient temperature
3. additionwater was added
4. customto afford the crude product as a black precipitate which
5. filtrationwas filtered off
6. washwashed with water and air
7. customdried
8. dissolutionThe crude product was dissolved in DCM
9. dry with materialdried over MgSO4
10. filtrationfiltered through a plug of 45 g silica gel which
11. washwas eluted with 500 mL DCM
12. concentrationThe filtrate was concentrated to an amber oil
13. customcrystallized by addition of EtOH (150 mL)
14. temperatureThe precipitate was cooled in an ice bath
15. filtrationfiltered

ORD record

ord-943da897e99f4cfe82d9eebf4f8c241e

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304419B2