To a round bottom flask containing cis-3-(Boc-amino)-5-(trifluoromethyl)piperidine (Molbridge, 10.00 g, 37.27 mmol) and sodium bicarbonate (18.8 g, 224 mmol), THF (200 mL) was added, followed by water (200 mL). Benzyl chloroformate (20.1, g, 112 mmol) was then added dropwise over a period of 30 min. via a syringe pump. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (340 g, 15% EtOAc in hexanes) to give a white foamy solid which was subjected to chiral HPLC separation (Phenomenex Lux Cellulose C-1, 5 μm, 21.2×250 mm column, eluting with 15% EtOH in hexanes, at flow rate of 18 mL/min., with a loading of 100 mg in 1000 μL at 220 nm wavelength) to give the sub-title compound (retention time: 9.1 min.) as a white foamy solid (6.51 g, 43%). LCMS calc. for C19H25F3N2NaO4 (M+Na)+: m/z=425.2. found: 425.2. The sub-title compound is assigned as the (3S,5R) isomer. The alternative (3R,5S) isomer can be obtained from the same separation.
