4-Bromo-2-fluoroaniline → 4-(4-Bromo-2-fluoro-phenylamino)-6-chloro-pyridazine-3-carboxylic acid

Temperature

-78 °C

To the stirred solution of 4-bromo-2-fluorophenylamine (3.15 g, 16.58 mmol) in THF (50 ml) under argon at −78° C. is added dropwise LiHMDS (24.9 ml, 24.9 mmol, 1.0 M in hexane). After stirring for one hour at −78° C., a solution of 4,6-dichloropyridazine-3-carboxylic acid (1.6 g, 8.29 mmol) in THF (10 ml) is added dropwise. The resulting mixture is allowed to warm to room temperature slowly and was stirred continuously for 18 hours. The reaction is quenched by addition of 5 ml of water, diluted with ethyl acetate, acidified with aqueous 1.0 M HCl to pH 1-2. The layers are separated and aqueous layer is extracted with ethyl acetate (30 ml×3). The combined organic layers are washed with brine (30 ml×3), dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by flash column chromatography to give the product.

1. temperatureto warm to room temperature slowly
2. stirringwas stirred continuously for 18 hours
3. customThe reaction is quenched by addition of 5 ml of water
4. additiondiluted with ethyl acetate
5. customThe layers are separated
6. extractionaqueous layer is extracted with ethyl acetate (30 ml×3)
7. washThe combined organic layers are washed with brine (30 ml×3)
8. dry with materialdried over Na2SO4
9. concentrationconcentrated under reduced pressure
10. customThe residue is purified by flash column chromatography
11. customto give the product

ORD record

ord-22b6b66699f3481ba2455eadc5822753

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08063049B2