反应详情

A solution of (E)-ethyl 3-amino-4,4,4-trifluorobut-2-enoate (4.24 g, 23.2 mmol) was added dropwise at 5° C. under N2 to a stirred solution of sodium hydride (1.01 g of a 55% suspension in mineral oil, 23.2 mmol) in dry DMF. The light yellow suspension was stirred for 1 hour, while allowing the reaction mixture to warm to room temperature. After that period, a solution of 2,2,7-trifluoro-6-isocyanato-4-(prop-2-ynyl)-2Hbenzo[b][1,4]oxazin-3(4H)-one (6.54 g, 23.2 mmol) in toluene was added dropwise, after which the mixture was heated at 80° C. overnight under nitrogen. As LC/MS indicated that the reaction was not fully complete, heating was continued for a further 3 hours at 100° C., after which the light brown solution was concentrated in vacuo. The dark residue was partitioned between ethyl acetate and aqueous ammonium chloride solution, and the aqueous phase was extracted with additional ethyl acetate. The combined organic fractions were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave 10.68 g crude brown oil. This was purified by column chromatography (EtOAc:heptane, 20-60%) to give three fractions in which the desired product was the major component (present as a mixture of keto and enol tautomers). These three fractions were combined and further purified by column chromatography, eluting with di-isopropyl ether, to give the product (3.0 g) as an offwhite fluffy solid (94% purity according to NMR, with ca. 20% existing as the enol tautomer).

1. waitAfter that period
2. temperatureafter which the mixture was heated at 80° C. overnight under nitrogen
3. temperatureheating
4. waitwas continued for a further 3 hours at 100° C.
5. concentrationafter which the light brown solution was concentrated in vacuo
6. customThe dark residue was partitioned between ethyl acetate and aqueous ammonium chloride solution
7. extractionthe aqueous phase was extracted with additional ethyl acetate
8. washThe combined organic fractions were washed with brine
9. dry with materialdried over Na2SO4
10. filtrationFiltration and evaporation of the solvent
11. customgave 10.68 g crude brown oil
12. customThis was purified by column chromatography (EtOAc:heptane, 20-60%)