反应详情

温度

-20 °C

To a solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (51.03 g, 74.5% w/w %, 143.8 mmol; Example 5) in toluene (204.1 ml) was added a solution of 3-fluoro-4-nitrobenzonitrile (24.5 g, 151 mmol) in tetrahydrofuran (357 ml) and the solution was degassed three times with nitrogen and then cooled to −20° C. Lithium tert-butoxide solution in tetrahydrofuran (137. ml, 20 w/w %, 302 mmol) was added dropwise over 1 hr. After stirring for an additional 1 hr 20 min the reaction mixture was then added to a cold aqueous solution of ammonium chloride (188 ml, 4.58M, 6862.7 mmol) at 0° C. The biphasic mixture was warmed to 30° C. and Celite® (76.5 g) added, then filtered. The filter cake was washed twice with toluene (153 ml) then the combined filtrate was separated and the organic layer washed twice with water (153 ml). The organic layer was concentrated by distillation to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a toluene solution (196 ml) (titration, HClO4, assay 80.47 w/w %). The crude product mixture is directly used in the next step.

1. customthe solution was degassed three times with nitrogen
2. temperatureThe biphasic mixture was warmed to 30° C.
3. additionCelite® (76.5 g) added
4. filtrationfiltered
5. washThe filter cake was washed twice with toluene (153 ml)
6. customthe combined filtrate was separated
7. washthe organic layer washed twice with water (153 ml)
8. concentrationThe organic layer was concentrated by distillation