Sodium hydride → 5-{[(5-chloro-3-fluoro-2-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]-amino}-7-fluoro-1H-quinolin-2-one

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Reaction Steps

To 0.54 g (3 mmol) 5-amino-7-fluoro-1H-quinolin-2-one and 0.57 g (3 mmol) 5-chloro-3-fluoro-2-methoxybenzaldehyde in 9 ml toluene and 2.6 ml 1,4-dioxane are added 0.65 ml acetic acid and 2.4 ml tetrabutyl orthotitanate. The mixture is heated over 17 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 1 hour. Phases are separated and addition of ethylacetate is repeated two times while stirring is done under reflux and phases are separated while they are still hot. The combined organic phases are concentrated and the residue is purified by flash chromatography on silica gel (ethyl acetate, then methanol in dichloromethane 10% to 20%) to yield 0.63 g of 5-{[1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]-amino}-7-fluoro-1H-quinolin-2-one. 57 mg NaH (55% in mineraloil, 1.4 mmol) were washed with dry THF and suspended together with 0.63 g (1.8 mmol) of 5-{[1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]amino}-7-fluoro-1H-quinolin-2-one in 22 ml THF. t-Butyldimethylsilyl chloride is added as solid and the mixture is stirred for 2.5 hours while it becomes a clear solution. In parallel 0.24 ml 1,1,1-trifluoro-2,3-epoxypropane in 6 ml THF and 2 ml hexane are cooled to −100° C. and 1.1 ml of a 2.5 M n-butyl lithium solution in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition the previously prepared 1-{t-butyldimethylsilyl}-5-{[1-(5-chloro-3-fluoro-2-methoxyphenyl)methylidene]amino}-7-fluoroquinolin-2-one solution in THF is added over 20 minutes while the temperature does not exceed −95° C. After 3.5 hours at −100° C. 2 ml diethyl ether are added and the reaction mixture is warmed to room temperature over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. After stirring for 30 minutes the phases are separated and the aqueous layer is extracted with dichloromethan, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 0 to 100%) yields 152 mg of 5-{[(5-chloro-3-fluoro-2-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]-amino}-7-fluoro-1H-quinolin-2-one

Provenance & Evidence