1133931-74-4

144-62-7

1171080-45-7

In a 2000-mL four-neck flask, 500 g of ethyl acetate and 135.0 g (0.4 mol) of benzyl (S,E)-5-((benzyloxy)imino)piperidine-2-carboxylate (III3) were added, a thermometer was mounted and the reaction temperature was maintained at between -20°C and -15°C. 201.0 g of concentrated sulfuric acid (2.0 moles) was slowly added dropwise, and stirring was continued for 1 hour after the drop was completed. At -20°C, 190.0 g (0.9 mol) of sodium triacetoxyborohydride was added in batches and the reaction was stirred for 5 hours keeping the reaction temperature between -20°C and -15°C. Upon completion of the reaction, keeping the temperature below 0 °C, 200 g of water was slowly added to quench the reaction, followed by neutralization with ammonia to a system pH of 7-8. The organic and aqueous layers were separated and the organic layer was washed twice with deionized water. The organic phase was concentrated under reduced pressure to recover the solvent. To the residue was added 320 g of ethyl acetate and 160 g of methanol, followed by 52.0 g (0.42 mol) of oxalic acid dihydrate, heated to 45 °C and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered, and the filter cake was washed with 100 g of a solvent mixture of ethyl acetate/methanol (2:1, v/v), and then with 50 g of ethyl acetate. All filtrates were combined and reserved for subsequent steps. The filter cake was dried under vacuum to afford 118.8 g of (2S,5R)-benzyl 5-((benzyloxy)amino)piperidine-2-carboxylic acid ethyl ester oxalate, with 99.7% purity and 69.0% yield by chiral HPLC.