Methyl 2-(4-fluorophenyl)acetate → 2-(4-Fluorophenyl)-1-[2-methyl-(4-pyridyl)]ethanone

Temperature

95 °C

To a freshly prepared solution of NaOMe (3.0 M in MeOH) was added a solution of methyl 2-methyl-isonicotinate (6.81 g, 45.1 mmol) in MeOH (10 mL). This was followed by the dropwise addition of a solution of methyl 4-fluorophenylacetate (8.34 g, 49.6 mmol) in MeOH (10 mL). The MeOH was distilled off while heating the reaction mixture at 95° C. After 17.5 h, the solid residue was cooled. Concentrated HCl (15 mL) was added, and the mixture was heated at reflux. After 4 h, the mixture was cooled then diluted with H2O. The aqueous mixture was washed with Et2O, adjusted to pH 5 with 1N NaOH, then adjusted to pH 8 with saturated NaHCO3. The alkaline aqueous was extracted with EtOAc. The EtOAc extracts were washed with saturated NaCl, then dried over Na2SO4. Evaporation of solvent in vacuo afforded a red oil which was purified by column chromatography, eluting with a gradient of 0-3% MeOH/CHCl3. The title compound was isolated as a red oil (1.5 g, 15%).

1. distillationThe MeOH was distilled off
2. temperaturethe solid residue was cooled
3. additionConcentrated HCl (15 mL) was added
4. temperaturethe mixture was heated
5. temperatureat reflux
6. waitAfter 4 h
7. temperaturethe mixture was cooled
8. additionthen diluted with H2O
9. washThe aqueous mixture was washed with Et2O
10. extractionThe alkaline aqueous was extracted with EtOAc
11. washThe EtOAc extracts were washed with saturated NaCl
12. dry with materialdried over Na2SO4
13. customEvaporation of solvent in vacuo
14. customafforded a red oil which
15. customwas purified by column chromatography
16. washeluting with a gradient of 0-3% MeOH/CHCl3

ORD record

ord-a106d6515bf24398a39f053ad54a3ace

Source dataset

uspto-grants-2003_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06645989B2