Hydrogen Bromide → 5'-Bromo-2',4-difluoro-[1,1'-biphenyl]-2-carbonitrile

Temperature

2 °C

5′-Amino-4,2′-difluorobiphenyl-2-carbonitrile (23 g, 100 mmol) was dissolved in hot 1,4-dioxane (20 ml) then treated with a chilled (5° C.) solution of hydrobromic acid (200 ml of a 48% solution in water). The resulting suspension was cooled to 2° C. (internal temperature) before adding a solution of sodium nitrite (6.9 g, 100 mmol) in water (14 ml) at such a rate that the internal temperature did not exceed 4° C. Once addition was complete the reaction was stirred at <4° C. for 1 h before pouring the reaction into a cooled (5° C.) solution of copper(I) bromide (21.5 g, 150 mmol) in 48% aqueous hydrobromic acid (75 ml). The resulting dark mixture was left to stir at ambient temperature for 15 min then heated at 50° C. for 40 min. After cooling to ambient temperature the mixture was diluted with water (1 l) and then extracted with ethyl acetate (2×400 ml). The organics were combined then washed with 10% ammonium hydroxide (500 ml), water (500 ml), brine (400 ml) and dried (MgSO4). Filtration and evaporation to dryness gave a brown oil, which crystallised on standing. Purification of this residue by dry flash chromatography (silica gel, 2-4% EtOAc/isohexane) furnished 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile as a white solid (27.5 g, 94%): 1H NMR (360 MHz, CDCl3) δ 7.11 (1H, dd, J 9, 9 Hz), 7.37-7.58 (5H, m).

1. additionthen treated with
2. customdid not exceed 4° C
3. additionOnce addition
4. additionbefore pouring
5. customthe reaction into
6. waitThe resulting dark mixture was left
7. stirringto stir at ambient temperature for 15 min
8. temperaturethen heated at 50° C. for 40 min
9. temperatureAfter cooling to ambient temperature the mixture
10. extractionextracted with ethyl acetate (2×400 ml)
11. washThe organics were combined then washed with 10% ammonium hydroxide (500 ml), water (500 ml), brine (400 ml)
12. dry with materialdried (MgSO4)
13. filtrationFiltration and evaporation to dryness
14. customgave a brown oil, which
15. customcrystallised
16. customPurification of this residue
17. dry with materialby dry flash chromatography (silica gel, 2-4% EtOAc/isohexane)

ORD record

ord-d6e5a19c77c14a7b8dc7ad9e20fcd961

Source dataset

uspto-grants-2005_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06936608B2