(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl) pentanoic acid → (2R)-4-[5-Fluoro-2-(methyloxy)phenyl]-4-methyl-2-(trifluoromethyl)-1,2-pentanediol

Participants

Reaction Conditions

Reaction Steps

A solution of lithium aluminium hydride (1M in tetrahydrofuran, 12.6 mL, 12.6 mmol) was introduced into a flask under a nitrogen atmosphere. The solution was heated to 50° C. under nitrogen. (2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid (2 g, 6.17 mmol) in tetrahydrofuran (4 mL) was then added dropwise using a syringe pump (50 mL/h addition rate). The solution was then stirred for 13 h at 50° C. The reaction mixture was then cooled to 0° C. and quenched with a slow addition (10 mL/h addition rate) of water (0.5 mL) keeping the temperature below 5 C. Once gas evolution stopped, the cloudy solution was allowed to warm to 20° C. and 15% aqueous sodium hydroxide solution (0.5 mL) followed by water (1.5 mL) were added dropwise (40 mL/h addition rate). The slurry was stirred for 15 min at room temperature, filtered and the inorganic salts were washed twice with ethyl acetate (2×10 mL). The organic liquors were then washed successively with 7.5% aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL). The organic liquor was split into two equal amounts, the first half was concentrated to dryness to afford the title compound (851 mg) and the second half was re-crystallised from methyl-cyclohexane to afford the title compound (595 mg).

Provenance & Evidence