Method of preparing 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid or a derivative thereof

A method of preparing 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid or a derivative thereof, wherein 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid (IIb) or derivative thereof refers to 5R-[(benzyloxy) amino] piperidine-2S-carboxylate (IIa) or 5R-[(benzyloxy) amino] piperidine-2S-carboxylate oxalate (IIc), the method comprising steps of:

• (1) reacting L-glutamic acid with alcohol via esterification reaction in the presence of an acidic reagent to prepare compound III, namely diester of L-glutamic acid hydrochloride;
• (2) upon completion of the reaction of step (1), distilling the reaction system to recover excess acidic reagent and alcohol, then adding the same alcohol as in step (1) to the remnant, and then successively adding a base, 2-haloacetate, and N-protecting agent, or successively adding the base, N-protecting agent, and 2-haloacetate;
• after twice substitution reactions, obtaining compound IV;
• (3) subjecting compound IV to intramolecular condensation into a ring under the action of a solvent and a strong base, to obtain compound V, namely, N-protecting group piperidine-5-one-2S-carboxylate;
• the obtained compound V being used for preparing 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid (IIb) or its derivative, wherein a specific Route and corresponding steps are selected based on a target product:
• Route 1:
• compound V is subjected to removal of protecting group, condensation with benzyloxyamine hydrochloride, imine reduction-chiral resolution, neutralization, and hydrolysis;
• Route 2:
• compound V is subjected to hydrolysis, removal of protecting group, condensation with benzyloxyamine hydrochloride, imine reduction-chiral resolution, and neutralization;
• Route 3:
• compound V is subjected to condensation with benzyloxyamine hydrochloride, imine reduction-chiral resolution, removal of protecting group, neutralization, and hydrolysis.