Aniline → 6-[2-(3-Fluoro-phenyl)-ethyl]-4H-benzo[1,4]oxazin-3-one

Temperatur

23 °C

To a solution of [4-(3-fluoro-phenylethynyl)-2-nitro-phenoxy]-acetic acid ethyl ester (1.72 g, 5.01 mmol, 1 equiv) in ethyl acetate (50 mL) was added palladium on carbon (500 mg, 10 wt. %, wet, Degussa type). The reaction vessel was placed under an atmosphere of hydrogen (balloon) and stirred at 23° C. for 15 h. At this time LCMS analysis indicated the reaction contains a mixture of the desired benzoxazinone product (major) and uncyclized aniline (minor). The mixture was filtered through a pad of Celite, washing with ethyl acetate (100 mL). The solution was concentrated, then re-dissolved in ethyl acetate (100 mL) and refluxed for 2 h. LCMS analysis indicates no improvement in cyclized:uncyclized ratio. Para-toluenesulfonic acid hydrate (111 mg) was added and resulting solution was refluxed for a further 1 h. The solution was cooled to 23° C. then washed successively with water, 1.0 N aqueous hydrochloric acid, saturated aqueous brine (100 mL each), 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 methanol in dichloromethane (0-5% methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min) to give 1.15 g (4.24 mmol, 85%) of the title compound as a tan solid.

1. filtrationThe mixture was filtered through a pad of Celite
2. washwashing with ethyl acetate (100 mL)
3. concentrationThe solution was concentrated
4. dissolutionre-dissolved in ethyl acetate (100 mL)
5. temperaturerefluxed for 2 h
6. additionPara-toluenesulfonic acid hydrate (111 mg) was added
7. customresulting solution
8. temperaturewas refluxed for a further 1 h
9. temperatureThe solution was cooled to 23° C.
10. washthen washed successively with water, 1.0 N aqueous hydrochloric acid, saturated aqueous brine (100 mL each)
11. dry with materialdried (MgSO4)
12. filtrationfiltered
13. concentrationconcentrated
14. customThe product was purified
15. washthen eluted with methanol in dichloromethane (0-5% methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min)

ORD-Eintrag

ord-a1b7f77bb6c7425299cf8f265ac20781

Quelldatensatz

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09023843B2