Diisopropylamine → tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Diisopropylamine (3.40 mL, 24.2 mmol) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. Butyllithium (2 M in cyclohexane, 12.2 μL, 24.4 mmol) was added dropwise to the reaction. The mixture was held at −78° C. with stirring and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (5.20 g, 20.2 mmol) in tetrahydrofuran (15 mL) was added to the mixture dropwise. The mixture was held at −78° C. with stirring and held for 45 min. In a separate flask, sodium hydride (60% in mineral oil, 970 mg, 24.3 mmol) was washed with hexanes then suspended in tetrahydrofuran (50 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (4.50 g, 20.2 mmol) in tetrahydrofuran (20 mL) was added to the mixture dropwise. The mixture was held at 0° C. with stirring and held for 1 h. The above prepared aldehyde mixture was added to the ester mixture dropwise over 1.25 h. The mixture was held at −78° C. with stirring and held for 1 h. The reaction was quenched with aqueous ammonium chloride, warmed to room temperature, and diluted with water. The mixture was extracted ethyl acetate (2×) and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. Mass spec.: 381.2 (M-C4H8O2+H)+.

Provenance & Evidence