Dimethylformamide → {3-Chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine

Temperature

0 °C

To a solution of dimethylformamide (0.82 mL, 10.6 mmol, 2.5 equiv) in chloroform (10 mL) at 0° C. was added phosphorus(V) oxychloride (0.78 mL, 8.49 mmol, 2 equiv). After stirring 10 min at 0° C., the reaction vessel was warmed to 23° C. for 10 min then re-cooled to 0° C. A solution of 6-[2-(3-fluoro-phenyl)-ethyl]-4H-benzo[1,4]oxazin-3-one in chloroform (7 mL) was added. After stirring a further 5 min at 0° C. the reaction was warmed to reflux (oil bath) for 4 h then cooled to 23° C. and partitioned between dichloromethane and water (100 mL each). The aqueous layer was adjusted to pH 12 with 5 N aqueous sodium hydroxide, and then the organic layer was separated. The organic layer was washed with brine (100 mL) and set aside. The original aqueous layer was re-extracted with dichloromethane (100 mL). The two organic extracts were combined, dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 60 mL/min) to give 985 mg (2.86 mmol, 67%) of the title compound as an orange/brown oil.

1. temperaturethe reaction vessel was warmed to 23° C. for 10 min
2. temperaturethen re-cooled to 0° C
3. stirringAfter stirring a further 5 min at 0° C. the reaction
4. temperaturewas warmed
5. temperatureto reflux (oil bath) for 4 h
6. temperaturethen cooled to 23° C.
7. custompartitioned between dichloromethane and water (100 mL each)
8. customthe organic layer was separated
9. washThe organic layer was washed with brine (100 mL)
10. extractionThe original aqueous layer was re-extracted with dichloromethane (100 mL)
11. dry with materialdried (MgSO4)
12. filtrationfiltered
13. concentrationconcentrated
14. customThe product was purified
15. washthen eluted with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 column volumes at a flow rate of 60 mL/min)

ORD record

ord-878c5a9b8aba4e73bc227b4293a23f0e

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09023843B2