tert-Butanol → (1S,2S)-Ethyl 2-((S)-1-phenylethyl amino)cyclohexanecarboxylate

Participants

Reaction Conditions

Reaction Steps

Tetrahydrofuran (1.25 L) was charged to a reactor followed by t-butanol (150 mL), and sodium t-butoxide (313 g) under nitrogen at ambient temperature. Additional tetrahydrofuran (1.0 L) was added and then the contents were cooled to <10° C. A solution of (1R,2S)-ethyl 2-((S)-1-phenylethylamino)cyclohexane carboxylate (9, 243.9 g) in tetrahydrofuran (300 mL) was added in NLT 30 minutes, while maintaining the temperature between 6-12° C. After the addition was complete, the mixture was warmed to 22° C. in NLT 30 minutes and further mixed for NLT 4 hours under nitrogen. The contents were cooled to <10° C. and the reaction was quenched with a solution of ammonium chloride (269.3 g) and water in NLT 30 minutes, while maintaining the temperature between 6-12° C. The lower aqueous layer was separated and extracted with 750 mL of heptanes. The upper organic layer was concentrated to about 0.8 L volume and extracted with the heptanes solution. The aqueous layer was separated and extracted with fresh heptanes (2×0.75 L) and the combined organic layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L), and dried with anhydrous magnesium sulfate. Concentration of the organic layer under vacuum gave 237.9 g of (1S,2S)-ethyl 2-((S)-1-phenylethyl amino)cyclohexane carboxylate (10) as a major isomer.

Provenance & Evidence