Artigo Revisado por pares

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

2012; American Chemical Society; Volume: 16; Issue: 4 Linguagem: Inglês

10.1021/op200306q

ISSN

1520-586X

Autores

Prashant P. Deshpande, Janak Singh, Annie Pullockaran, Thomas P. Kissick, Bruce A. Ellsworth, Jack Z. Gougoutas, John D. DiMarco, M. Fakes, Mayra Reyes, Chiajen Lai, Hidegard Lobinger, Theo Denzel, P. Ermann, Gerard A. Crispino, Michael Randazzo, Zenrong Gao, Renee Randazzo, Mark Lindrud, Victor W. Rosso, Frédéric G. Buono, Wendel W. Doubleday, Simon Leung, Pricilla Richberg, David Hughes, William N. Washburn, Wei Meng, Kevin J. Volk, Richard H. Mueller,

Tópico(s)

Fluorine in Organic Chemistry

Resumo

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.

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