反应详情

温度

100 °C

To a stirred solution of 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbonitrile (which may be prepared as described in Description 138) (4.76 g, 17.61 mmol) in ethanol (25 mL) was added 8M sodium hydroxide (13.21 mL, 105.66 mmol). The resulting mixture was left to stir at 100° C. for 5 h. The reaction mixture was cooled and concentrated. The pH was adjusted to 1 with the careful addition of 5M aq. HCl. The reaction mixture was extracted with DCM and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvent under reduced pressure gave a colourless oily solid. This was dissolved in ethanol (60 mL) and sulfuric acid (5.18 mL, 96.73 mmol) was added. The resulting mixture was left to stir under reflux for 24 h. The solution was allowed to cool and concentrated. It was quenched with crushed ice and treated with 2M aq. NaOH to give pH=7. The mixture was extracted with DCM twice and the combined organic layers dried over sodium sulfate, filtered and evaporated. The crude residue was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (10-70%). Evaporation of desired fractions gave ethyl 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carboxylate (D139) (5.51 g, 17.363 mmol, 98.6% yield) as colourless solid;

1. waitThe resulting mixture was left
2. temperatureThe reaction mixture was cooled
3. concentrationconcentrated
4. additionThe pH was adjusted to 1 with the careful addition of 5M aq. HCl
5. extractionThe reaction mixture was extracted with DCM
6. customthe organic layers were collected
7. customEvaporation of solvent under reduced pressure
8. customgave a colourless oily solid
9. waitThe resulting mixture was left
10. stirringto stir
11. temperatureunder reflux for 24 h
12. temperatureto cool
13. concentrationconcentrated
14. customIt was quenched with crushed ice
15. additiontreated with 2M aq. NaOH
16. customto give pH=7
17. extractionThe mixture was extracted with DCM twice
18. dry with materialthe combined organic layers dried over sodium sulfate
19. filtrationfiltered
20. customevaporated
21. customThe crude residue was purified by silica gel chromatography (50 g SiO2)
22. washeluting with ethyl acetate in iso-hexane (10-70%)
23. customEvaporation of desired fractions