Hydrogen Bromide → 5-Bromo-2-fluoro-2'-(methylthio)biphenyl

Temperature

4 °C

To a solution of 2-fluoro-2′-(methylthio)biphenyl-5-ylamine (397 mg, 1.70 mmol) in 1,4-dioxane (2.1 ml) was added 48% aqueous hydrobromic acid (8 ml) and the mixture was cooled to 3° C. before the dropwise addition of sodium nitrite (137 mg, 1.98 mmol) in water (0.5 ml) over 5 min, while the temperature was kept below 5° C. The resulting mixture was stirred at 4±1° C. for 2 h 40 min then more sodium nitrite (26 mg, 0.37 mmol) in water (0.1 ml) was added dropwise and the mixture was stirred at 3° C. for 50 min. A cooled (3° C.) solution of copper(I) bromide (744 mg, 5.19 mmol) in 48% hydrobromic acid (2.4 ml) was added and the mixture was stirred at 3° C. for 15 min then heated to 50° C. for 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (4×35 ml). The combined organics were washed with 1M aqueous sodium sulphite solution (30 ml), then saturated aqueous ammonium chloride solution (30 ml), dried over anhydrous magnesium sulphate and evaporated to give a brown oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%) gave 5-bromo-2-fluoro-2′-(methylthio)biphenyl as a white solid (287 mg, 57%): δH (360 MHz, CDCl3) 2.40 (3H, s), 7.04 (1H, t, J 9), 7.16-7.24 (2H, m), 7.32 (1H, d, J 8), 7.36-7.51 (4H, m).

1. customwas kept below 5° C
2. stirringthe mixture was stirred at 3° C. for 50 min
3. additionwas added
4. stirringthe mixture was stirred at 3° C. for 15 min
5. temperaturethen heated to 50° C. for 1 h
6. temperatureThe mixture was cooled to ambient temperature
7. extractionextracted with ethyl acetate (4×35 ml)
8. washThe combined organics were washed with 1M aqueous sodium sulphite solution (30 ml)
9. dry with materialsaturated aqueous ammonium chloride solution (30 ml), dried over anhydrous magnesium sulphate
10. customevaporated
11. customto give a brown oil
12. customPurification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%)

ORD record

ord-89b53715e2b84a2cba7ff4aeed042005

Source dataset

uspto-grants-2005_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06900215B2