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

• Main Authors: Lei Huang (Author), Yi Zhang (Author), Xiao-Hui Shan (Author), Yu Liu (Author), Jian-Qi Li (Author)
• Format: Book
• Published: Georg Thieme Verlag KG, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2628-5088; 2628-5096; 10.1055/s-0042-1750423
• Keywords: sglt2 inhibitors; (3r,4s,5r,6r)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2h-pyran-2-one; industrial production; safe and environmentally friendly; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutical Fronts, Vol 04, Iss 04, Pp e237-e243 (2022)

Abstract (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-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.