2,6-Difluoroaniline → HCID 67056864, compound

To a solution of (2,6-difluorophenyl)amine (15.5 g) in THF (140 mL) was added dropwise an 1 M THF solution of lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (120 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To the solution was added a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (20 g) in THF (60 mL) at 0° C., and the resulting mixture was stirred at the same temperature for 2 hr. The reaction was quenched with a mixture of EtOAc (200 mL) and 0.5 M HCl (200 mL). The aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was diluted with MeOH (100 mL), and to the resulting solution was added 28% sodium methoxide in MeOH (38.6 mL). The resulted mixture was heated to reflux for 6 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (200 mL) and 1 M HCl (300 mL). The aqueous layer was separated and extracted with EtOAc (200 mL). The organic layers were combined, washed with saturated aqueous NaHCO3 (300 mL) and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was triturated with IPE, and the precipitates produced were collected by filtration to give methyl 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (5.34 g).

1. stirringthe resulting mixture was stirred at the same temperature for 2 hr
2. customThe reaction was quenched with a mixture of EtOAc (200 mL) and 0.5 M HCl (200 mL)
3. extractionThe aqueous layer was extracted with EtOAc (200 mL)
4. washwashed with brine
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. customevaporated in vacuo
8. additionThe residue was diluted with MeOH (100 mL)
9. additionto the resulting solution was added 28% sodium methoxide in MeOH (38.6 mL)
10. temperatureThe resulted mixture was heated
11. temperatureto reflux for 6 hr under a nitrogen atmosphere
12. concentrationThe reaction mixture was concentrated under reduced pressure
13. customthe residue was partitioned between EtOAc (200 mL) and 1 M HCl (300 mL)
14. customThe aqueous layer was separated
15. extractionextracted with EtOAc (200 mL)
16. washwashed with saturated aqueous NaHCO3 (300 mL) and brine successively
17. dry with materialdried over MgSO4
18. customevaporated in vacuo
19. customThe residue was triturated with IPE
20. customthe precipitates produced
21. filtrationwere collected by filtration

ORD record

ord-01a1edaf031e4e0ea94ad1e0ca07687b

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08173684B2