Citric Acid → 1,1-Dimethylethyl (3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate

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Reaction Steps

Under nitrogen atmosphere, to an N,N′-dimethylformamide solution (210 mL) of tert-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (30.05 g, 0.104 mol) was added 26.0 mL of iodomethane (59.28 g, 0.418 mol), subsequently sodium hydride (550 oily, 11.35 g, 0.260 mol) with stirring the solution at room temperature. When inner temperature reached about 50° C., the solution was cooled to 30° C. in an ice water bath, then stirred for 23 hours in a water bath having an outside temperature of 17° C. This reaction solution was poured into a cold aqueous solution of citric acid (mixed water of 1 L of 10% citric acid and 500 g of ice water), stirred for 30 minutes, and then was extracted with ethyl acetate (800 mL and 500 mL). The organic layers were combined, washed with saturated brine, subsequently dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure. Thus obtained residue was purified with flash silica gel column chromatography (hexane/ethyl acetate in the ratio of 5:1, and then 4:1 eluted parts) to obtain 10.63 g (33.7%) of the title compound as a white solid as a high polarity isomer: and 14.91 g (47.3%) of tert-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate a low polarity isomer.

Provenance & Evidence