A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor

• Published in: Organic process research & development 2012-04, Vol.16 (4), p.577-585
• Main Authors: Deshpande, Prashant P, Singh, Janak, Pullockaran, Annie, Kissick, Thomas, Ellsworth, Bruce A, Gougoutas, Jack Z, Dimarco, John, Fakes, Michael, Reyes, Mayra, Lai, Chiajen, Lobinger, Hidegard, Denzel, Theo, Ermann, Peter, Crispino, Gerard, Randazzo, Michael, Gao, Zenrong, Randazzo, Renee, Lindrud, Mark, Rosso, Victor, Buono, Frederic, Doubleday, Wendel W, Leung, Simon, Richberg, Pricilla, Hughes, David, Washburn, William N, Meng, Wei, Volk, Kevin J, Mueller, Richard H
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op200306q

A practical synthesis of the SGLT-2 inhibitor β-C-aryl-d-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-d-glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with l-phenylalanine and l-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The l-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale.