Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl3‑Promoted Silane Reduction of a β‑Glycopyranoside

• Published in: Organic letters Vol. 16; no. 16; pp. 4090 - 4093
• Main Authors: Wang, Xiao-jun, Zhang, Li, Byrne, Denis, Nummy, Larry, Weber, Dirk, Krishnamurthy, Dhileep, Yee, Nathan, Senanayake, Chris H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.08.2014
• Subjects: Aluminum Compounds - chemistry; Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Chlorides - chemistry; Glucosides - chemical synthesis; Glucosides - chemistry; Glucosides - pharmacology; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Molecular Structure; Oxidation-Reduction; Silanes - chemistry; Sodium-Glucose Transporter 2 - antagonists & inhibitors
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol501755h

An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside 4 which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH2Cl2/MeCN to afford 5 in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.