4-Bromo-2-fluoroaniline → Methyl 2-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Temperature

-78 °C

To a solution of 4-bromo-2-fluorobenzenamine (0.058 g, 0.31 mmol) in THF (2 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (0.56 mL, 0.56 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. Methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.060 g, 0.28 mmol) was then added dropwise as a solution in THF (1 mL) and the reaction mixture was stirred for 25 minutes at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted with 0.1M HCl and then diluted with EtOAc and saturated NaCl and the layers separated. The aqueous layer was back extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 20:1) gave 0.086 g (84%) pure desired product as a white crystalline solid. MS ESI (+) m/z 371, 373 (M+, Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 6.58 (t, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.14 (s, 3H).

1. stirringthe reaction mixture was stirred for 25 minutes at −78° C
2. customThe reaction mixture was quenched by the addition of H2O
3. additiondiluted with EtOAc and saturated NaCl
4. customthe layers separated
5. extractionThe aqueous layer was back extracted with EtOAc (1×)
6. dry with materialThe combined EtOAc layers were dried (Na2SO4)
7. concentrationconcentrated under reduced pressure
8. customPurification by flash column chromatography (methylene chloride/EtOAc, 20:1)

ORD record

ord-60a7245983a347a58bf38ccdfbcd8461

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08101611B2