4-Bromo-2-fluoroaniline → 2-(4-Bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Temperature

-78 °C

Preparation of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid: To a solution of 4-bromo-2-fluorophenylamine (10.4 g, 54.7 mmol) in THF (25 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (83.3 mL, 83.3 mmol, 1 M solution in hexanes) dropwise over 15 minutes. The reaction mixture was stirred for one hour at −78° C. 2,6-Dichloro-nicotinic acid (5.00 g, 26.0 mmol) was then added dropwise as a solution in THF (15 mL) and the reaction mixture was allowed to warm from −78° C. to room temperature and stir for 16 hours. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to 0-2 with 6 N HCl and then diluted with EtOAc. The organic layer was separated and washed with H2O, saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated several times with ethyl acetate and the resulting solid was collected, washed with dichloromethane and dried under vacuum to yield 7.50 g (83%) pure desired product as a dark pink solid.

1. temperatureto warm from −78° C. to room temperature
2. stirringstir for 16 hours
3. customThe reaction mixture was quenched by the addition of H2O
4. additiondiluted with EtOAc
5. customThe organic layer was separated
6. washwashed with H2O, saturated NaCl
7. dry with materialdried (Na2SO4)
8. concentrationconcentrated under reduced pressure
9. customThe crude product was triturated several times with ethyl acetate
10. customthe resulting solid was collected
11. washwashed with dichloromethane
12. customdried under vacuum

ORD record

ord-3223fab08a464fdc8bcbbe9249e70c1e

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08268852B2