Synthesis Of The Intermediate Of Anti-Diabetic Drug Saxagliptin

Saxagliptin is a highly potent, orally available reversible dipeptidyl peptidase â…£ inhibitor developed by Bristol-Myers Squibb for the treatment of type2diabetes. However, the reported synthetic process of saxagliptin suffer from some disadvantages such as the complex of routes, the high cost of production, which are considered detrimental to long-term medication of diabetic patients. Therefore, it is extremely practical significance to study the synthetic process of saxagliptin.(S)-3-hydroxyadamantylglycine is an important intermediate of saxagliptin, which was prepared by an enzyme-mediated, asymmetric reductive amimation of2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid. At the basis of many literatures, we focused on the synthesis of2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid. Next, we explored a chemical synthesis method of (S)-3-hydroxyadamantylglycine, and synthesized a new compound2-(3-hydrox-1-adamantyl)-2-hydroxyimino acetic acid.We did a lot of researches on the synthetic route of the intermediate2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid. Every step of the synthestic process has been optimized to explore a new synthetic route.It was synthesized from adamantane via successively reaction with formatic acid, thionyl chloride and sodium diethyl malonate to give dimethyl (1-adamantylcarbonyl) malonate, which was subjected to hydrolysis and decarboxylation by a mixture of acetic acid with water and sulfuric acid and then oxidation by potassium permanganate. The overall yield was about30%. This method is simple and mild reaction conditions, low production costs, which is suitable for industrial production.Research of the synthesis of the new compound2-(3-hydrox-1-adamantyl)-2-hydroxyimino acetic acid has important application value in experiment. It was prepared reacting2-(3-hydroxy-l-adamantyl)-2-oxoacetic acid potassium with hydroxylamine hydrochloride in a high yield of84%. The new compound2-(3-hydrox-1-adamantyl)-2-hydroxyimino acetic acid can be converted to (S)-3-hydroxyadamantylglycine by reduction and resolution, which provides a new idea to prepare(S)-3-hydroxyadamantylglycine with a chemical synthesis method.