Cyclohexane → (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol

참여 물질

반응 단계

To a suspension of (R)-(+)-methyl p-tolylsulfoxide (28.2 g, 183 mmol) in 200 mL of anhydrous THF at −78° C. was added lithium diisopropylamide (LDA) mono(tetrahydrofuran), 1.5 M solution in cyclohexane (122 mL, 183 mmol) over 30 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (46.3 g, 166 mmol) dissolved in 125 mL of THF was then added via cannula over 30 minutes. After 1.5 hours at −78° C., the reaction mixture was quenched with 600 mL of water and extracted first with a 600 mL portion of EtOAc and then a 400 mL portion of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate (NaHCO3) solution, washed with brine, dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 10%-30% EtOAc/hexanes) afforded sequentially (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (44.2 g, 62%) and (R)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (20.6 g, 29%). The diastereomeric excess was determined to be >99% for both isomers (HPLC peak area).

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