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A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor
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 t...
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Published in: | Organic process research & development 2012-04, Vol.16 (4), p.577-585 |
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creator | 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 |
description | 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. |
doi_str_mv | 10.1021/op200306q |
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Process Res. Dev</addtitle><date>2012-04-20</date><risdate>2012</risdate><volume>16</volume><issue>4</issue><spage>577</spage><epage>585</epage><pages>577-585</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>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.</abstract><pub>American Chemical Society</pub><doi>10.1021/op200306q</doi><tpages>9</tpages></addata></record> |
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title | A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor |
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