Synthesis of saxagliptin intermediate N-BOC-3-hydroxyadamantylglycine / 中国药学杂志

ABSTRACT

OBJECTIVE: To explore a new synthesis method of the saxagliptin intermediate of the dipeptidyl peptidase IV (DPP-IV)inhibitor saxagliptin, N-BOC-3-hydroxy-1-adamantylglycine, to reduce the synthesis cost of saxagliptin. METHODS: The synthesis used 1-adamantane carboxylic acid (1) as the starting material. Through achlorination, substitution, and decarboxylation afford 1-adamantyl methyl ketone (2) was obtained, which was then converted into 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (3)by oxidation with potassium permanganate in aqueous NaOH. Compound 3 reacted with hydroxylamine hydrochloride to give the 2-(3-hydrox-1-adamantyl)-2-hydroxyimino acetic acid(4), and then oxime 4 was reduced, and got the amino with BOC2O to afford dipeptidyl peptidase IV (DPP-IV)inhibitor saxagliptin intermediate N-BOC-3-hydroxyadamanty- lglycine(5). RESULTS: We got a new compound 4 which had not been reported. The 36% overall yield was reached. CONCLUSION: This synthetic route is simple, its reaction conditions are mild, and the raw materials are cheap and readily available, so it is suitable for manufacturing purposes.