Water → tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate

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Reaction Steps

A solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (79.8 g, 232 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (51.9 g, 279 mmol), and K2CO3 (44.9 g, 325 mmol) in THF (500 mL) was stirred at 56° C. for 18 hours. After cooling to ambient temperature, water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give a thick oil. The oil was dissolved in ether (200 mL) and hexane (500 mL) was added. The solution was concentrated to about 200 mL and stirred at ambient temperature for 1 hour. Hexane (300 mL) was added, and the resulting solid was collected by filtration to give tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (68.2 g, 77.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)-diastereomer).

Provenance & Evidence