Scalable Synthesis of Naldemedine Tosylate via O-to-C Ethoxycarbonyl Group Transfer of Carbonate

A practical process for the preparation of naldemedine tosylate hydrate was developed from naltrexone hydrochloride. The key β-keto ester intermediate was prepared through an O-to-C carbonate transfer using diethyl pyrocarbonate. The subsequent aminolysis with the oxadiazole-containing amine was accomplished by simple heating of a neat mixture under reduced pressure. Final debenzylation, tosylate salt formation, and hydrate formation furnished naldemedine tosylate hydrate on a 300 g scale in four steps and 52% overall yield with >99.5% purity.