反应详情

温度

22 °C

To a stirred solution of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (221 g, 0.53 mol) and O-(2-vinyloxyethyl)-hydroxylamine (63 g, 0.61 mol) in THF (2.85 L), under nitrogen, was added 1M lithium bis(trimethylsilylamide) solution in hexanes (1431 g), over 55 minutes, keeping the temperature between −14.7 and −12.4° C. After 2 hours at −15° C., water (165 mL, 9.2 mol) was added to the mixture, followed by 2M HCl solution (1.98 L), which was added over 20 minutes. The mixture was then allowed to warm to 22° C. and the lower aqueous phase (2.25 L) was separated and discarded. The organic phase was washed with sodium chloride solution (15% w/w, 1100 mL) and the volume was reduced to approximately 1.75 L by distillation of 2.25 L of solvent at ambient pressure. Iso-hexane (3.35 L) was added to the mixture over 2.5 hours with the temperature held at approximately 58° C. After a further 1 hour at this temperature the mixture was cooled to 20° C., held for 1 hour and then cooled to 0° C. and held at this temperature overnight. A further quantity of iso-hexane (500 mL) was added and the mixture was held for 1 hour, then more iso-hexane (500 mL) was added. After 45 minutes at 0° C. the slurry was filtered and the solid was washed with chilled iso-hexane (1.1 L) then dried in vacuum oven at 30° C. to provide 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (190 g, 0.39 mol, 74% yield). 1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.52 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.55-6.46 (m, 2H, ArH/OCH═CH2), 4.18 (dd, 1H, J 14, 2 Hz, OCH═CH2), 3.99 (dd, 1H, J 7, 2 Hz, OCH═CH2), 3.90-3.88 (m, 2H, OCH2), 3.81-3.79 (m, 2H, OCH2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, ArCH3).

1. customthe temperature between −14.7 and −12.4° C
2. waitAfter 2 hours at −15° C.
3. additionwas added over 20 minutes
4. customthe lower aqueous phase (2.25 L) was separated
5. washThe organic phase was washed with sodium chloride solution (15% w/w, 1100 mL)
6. distillationthe volume was reduced to approximately 1.75 L by distillation of 2.25 L of solvent at ambient pressure
7. additionIso-hexane (3.35 L) was added to the mixture over 2.5 hours with the temperature
8. customheld at approximately 58° C
9. temperatureAfter a further 1 hour at this temperature the mixture was cooled to 20° C.
10. waitheld for 1 hour
11. temperaturecooled to 0° C.
12. customheld at this temperature overnight
13. additionA further quantity of iso-hexane (500 mL) was added
14. waitthe mixture was held for 1 hour
15. additionmore iso-hexane (500 mL) was added
16. filtrationAfter 45 minutes at 0° C. the slurry was filtered
17. washthe solid was washed with chilled iso-hexane (1.1 L)
18. customthen dried in vacuum oven at 30° C.