Ethyl bromoacetate → Ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate

Participants

Reaction Steps

A solution of (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) (339.1 g) dissolved in acetonitrile (2.2 L) was charged to a reactor followed by ethyl bromoacetate (12) (234.2 mL) and anhydrous sodium carbonate (224.2 g) under nitrogen. The contents were heated to reflux temperature for NLT 18 hours with vigorous agitation. Acetonitrile was distilled under vacuum to about 1 L volume, cooled to <30° C. and diluted with 0.75 L of heptanes and 1.0 L of water. The aqueous layer was separated and extracted with heptanes (2×0.75 L), and the combined organic layers were washed with water (0.75 L) followed by 0.75 L 3.5 M aqueous sodium chloride solution. The heptane layer was dried with anhydrous magnesium sulfate and concentrated under vacuum to afford 557.8 g of ethyl 2-((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino) acetate (13) as the major isomer.

Provenance & Evidence