Industrial-Scale Preparation of a Key Intermediate for the Manufacture of Therapeutic SGLT2 Inhibitors

Abstract

Abstract (3 R ,4 S ,5 R ,6 R )-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2 H -pyran-2-one ( 1 ) is a key intermediate for the preparation of promising SGLT2 inhibitors currently undergoing clinical tests for diabetes therapy. However, fewer reports have demonstrated the preparation of compound 1 at an industrial scale. In this article, an efficient preparation of the intermediate for the industrial production was explored from commercially available methyl-α- D -glucopyranoside in seven steps, including TBS protection, benzyl protection, TBS removal, iodination, reduction, demethylation, and oxidation. The batch of the validation process was 42.82 kg with a HPLC purity of 99.31%. The main advantages of this approach are that the total cost is lower than the reported laboratory-scale synthetic method, the quality is reproducible, and the process is safe and environmentally friendly.