Hydrochloric Acid → 1-(5-Bromo-2-fluorophenyl)-2,2-difluoroethanone

Temperature

-78 °C

To a solution of diisoprpopylamine (343 g, 3.39 mol) in THF (4 L) was added slowly n-BuLi (1.4 L, 3.5 mol, 2.5 M in hexane) at −78° C. while keeping reaction temperature under −55° C. After addition, the mixture was stirred at −78° C. for 15 min. At this point, a solution of 4-bromo-1-fluorobenzene (540 g, 3.08 mol) in THF (1 L) was cooled to −60° C. before adding to the reaction mixture gradually while keeping reaction temperature under −55° C. and the resulting yellow solution was stirred at −78° C. for 150 min. Ethyldifluoroacetate (421 g, 3.39 mol) was added to the reaction mixture over 15 min and then the mixture was stirred at −78° C. for 15 min. 1 M HCl (6.0 L) was added to the reaction mixture with stirring. Aqueous layer was extracted with TBME (3×4 L). The combined organic phases were washed with water, dried (MgSO4) and evaporated in vacuo. The resulting residue was distilled under vacuum (90˜95° C./0.19 mbar) and fraction at 54˜62° C. was collected to obtain the title compound as a colorless liquid. ESIMS: 253 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, 1H), 7.75 (ddd, 1H), 7.13 (dd, 1H), 6.41 (dt, 1H).

1. customreaction temperature under −55° C
2. additionAfter addition
3. additionbefore adding to the reaction mixture gradually
4. customreaction temperature under −55° C.
5. stirringthe resulting yellow solution was stirred at −78° C. for 150 min
6. stirringthe mixture was stirred at −78° C. for 15 min
7. stirringwith stirring
8. extractionAqueous layer was extracted with TBME (3×4 L)
9. washThe combined organic phases were washed with water
10. dry with materialdried (MgSO4)
11. customevaporated in vacuo
12. distillationThe resulting residue was distilled under vacuum (90˜95° C./0.19 mbar) and fraction at 54˜62° C.
13. customwas collected

ORD record

ord-fde730307b974ef59b4b0d78d190741f

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08338413B1