Acetic Acid → Ethyl 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren-2-yloxy]butyrate

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Reaction Steps

Under an argon atmosphere, ethyl 4-(4-chloro-9-oxo-9H-fluorene-2-yloxy)butyrate (69.4 g) was dissolved in THF (700 ml), and N-(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide (6.4 g) was added. To the reaction mixture was added dropwise a solution of trimethyl(trifluoromethyl)silane (52.0 ml) in THF (140 ml) at −16° C., and the mixture was stirred at the same temperature for 15 min. To the reaction mixture were successively added acetic acid (23.0 ml) and 1M tetrabutylammonium fluoride/THF solution (222 ml), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated, and to the obtained residue were added toluene (500 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) to allow for layer separation. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (150 ml, twice), 1N aqueous sodium hydroxide (100 ml), water (100 ml), 1N hydrochloric acid (100 ml), water (100 ml) and saturated brine (100 ml). To the obtained organic layer were added anhydrous magnesium sulfate and silica gel (150 g), and the mixture was stirred for 10 min. The insoluble material was filtered off, and the insoluble material was washed successively with toluene (300 ml) and ethyl acetate (800 ml). The obtained filtrate and the toluene washing were combined and the solvent was evaporated to give the title compound (72.1 g). Also, the solvent in the ethyl acetate washing was evaporated, to the obtained residue were added silica gel (40 g) and a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane 2:1, 300 ml), and the mixture was stirred at room temperature. The insoluble material was filtered off, and the insoluble material was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane=2:1, 300 ml). The solvent in the obtained filtrate was evaporated to further give the title compound (20.3 g).

Provenance & Evidence