Hydrogen Bromide → 5'-Bromo-3,2'-difluorobiphenyl-2-carbonitrile

Temperature

0 °C

5′-Amino-3,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 mL), 48% aqueous hydrobromic acid (40 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 mL) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 mL) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography on silica gel eluting with isohexane (containing 0.5% methanol) on a gradient of ethyl acetate (2-6%) gave 5′-bromo-3,2′-difluoro-biphenyl-2-carbonitrile (2.48 g, 68%) as a yellow solid: δH (400 MHz, CDCl3) 7.13 (1H, dd, J 9 and 9), 7.27-7.30 (2H, m), 7.53-7.59 (2H, m), 7.64-7.69 (1H, m).

1. additionthen poured onto
2. stirringThe solution was stirred at 0° C. for 15 min
3. temperaturethen heated at 50° C. for 20 min
4. temperatureThe mixture was cooled to ambient temperature
5. extractionextracted with ethyl acetate (2×300 ml)
6. washThe combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (200 mL)
7. dry with materialdried over anhydrous magnesium sulfate
8. filtrationfiltered
9. customevaporated
10. customto give a black solid
11. customPurification by chromatography on silica gel eluting with isohexane (containing 0.5% methanol) on a gradient of ethyl acetate (2-6%)

ORD record

ord-3ab35001c93e4371862feeae6ea504dd

Source dataset

uspto-grants-2005_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06960598B2