Hydrogen Bromide → 1-Bromo-3-fluoro-2-methoxybenzene

Temperature

0 °C

Hydrobromic acid (48% in water, 140 mL) is added slowly to an aliquot of 11 (14.33 g, 101.5 mmol) cooled to 0° C. The resulting solid is broken up with a glass rod and stirred vigorously at 0° C. for 10 min. A solution of sodium nitrite (7.40 g, 107.2 mmol) in water (50 mL) is added slowly (˜1.5 h) to the stirred slurry containing 3-fluoro-2-methoxyphenylamine and hydrobromic acid, maintaining the temperature of the reaction mixture below 5° C. A purple solution of cuprous bromide (9.62 g, 67.1 mmol) in hydrobromic acid (48% in water, 50 mL) is added dropwise to the reaction mixture, maintaining the temperature of the reaction mixture below 5° C. The resulting reaction mixture is heated at 60° C. until the evolution of gas ceases (˜2.5 h). The reaction mixture is cooled to room temperature, and the product extracted with diethyl ether (6×150 mL). The combined organic extracts are washed with brine (3×150 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give 1-bromo-3-fluoro-2-methoxybenzene as a brown oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 3.95 (d, JH-F=1.5 Hz, 3H, OCH3), 6.88 (apparent t of d, JH-H=8.0 Hz, JH-F=5.5 Hz, 1H, H-5), 7.04 (d, JH-F=10.5 Hz, JH-H=8.0 Hz, JH-H=1.5 Hz, 1H, H-4), 7.30 (d of apparent t, JH-H=8.0 Hz, JH-H=1.5 Hz, JH-F=1.5 Hz, 1H, H-6). 19F{1H} NMR (CDCl3): δ −127.7 (s). 13C{1H} NMR (CDCl3): δ 61.4 (d, JC-F=5.0 Hz, OCH3), 116.2 (d, JC-F=19.5 Hz, C-4), 117.7 (d, JC-F=3.0 Hz, C-1), 124.5 (d, JC-F=8.0 Hz, C-5), 128.5 (d, JC-F=3.5 Hz, C-6), 145.7 (d, JC-F=12.5 Hz, C-2), 156.2 (d, JC-F=250.5 Hz, C-3).

1. temperaturemaintaining the temperature of the reaction mixture below 5° C
2. temperaturemaintaining the temperature of the reaction mixture below 5° C
3. customThe resulting reaction mixture
4. temperatureis heated at 60° C. until the evolution of gas ceases (˜2.5 h)
5. temperatureThe reaction mixture is cooled to room temperature
6. extractionthe product extracted with diethyl ether (6×150 mL)
7. washThe combined organic extracts are washed with brine (3×150 mL)
8. dry with materialdried over magnesium sulfate
9. customevaporated under reduced pressure

ORD record

ord-dd4d439d1c3f47e79c6b0876a8b9ec4d

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08114888B2