A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor
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- 作者：Prashant P. Deshpande ; Janak Singh ; Annie Pullockaran ; Thomas Kissick ; Bruce A. Ellsworth ; Jack Z. Gougoutas ; John Dimarco ; Michael Fakes ; Mayra Reyes ; Chiajen Lai ; Hidegard Lobinger ; Theo Denzel ; Peter Ermann ; Gerard Crispino ; Michael Randazzo ; Zenrong Gao ; Renee Randazzo ; Mark Lindrud ; Victor Rosso ; Frederic Buono ; Wendel W. Doubleday ; Simon Leung ; Pricilla Richberg ; David Hughes ; William N. Washburn ; Wei Meng ; Kevin J. Volk ; Richard H. Mueller
- 刊名：Organic Process Research & Development
- 出版年：2012
- 出版时间：April 20, 2012
- 年：2012
- 卷：16
- 期：4
- 页码：577-585
- 全文大小：317K
- 年卷期：v.16,no.4(April 20, 2012)
- ISSN：1520-586X
文摘
A practical synthesis of the SGLT-2 inhibitor 尾-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.