Sulfuric Acid → (3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic acid

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Reaction Steps

A mixture of 48.8 g (146 mmol) (3R,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic acid and 15.6 mL sulfuric acid in 400 mL methanol was heated to reflux for 21 h and evaporated. the residue was diluted with ice-water and extracted with ethyl acetate. the combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and heptane. The intermediate was dissolved in 500 mL methanol and 4.06 mL sodium methoxide (5.4N in methanol) was added and stirred at room temperature overnight. Another 31.3 mL sodium methoxide (5.4N in methanol) was added and stirred for 1 h at room temperature. Water was added and the mixture was stirred for 2 h at room temperature. After evaporation of methanol, water was added and the pH was adjusted to 6-7 with acetic acid. The product precipitated and the mixture was decanted. The organic layer from the extraction with THF and ethyl acetate was washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was washed with hexane and diethyl ether and filtered to yield after drying 44 g (49%) of the title compound as colorless solid. MS m/e: 334.3 [M+H]+.

Provenance & Evidence