Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin
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- 作者：Paul Bowles ; Steven J. Brenek ; Stéphane Caron ; Nga M. Do ; Michele T. Drexler ; Shengquan Duan ; Pascal Dubé ; Eric C. Hansen ; Brian P. Jones ; Kris N. Jones ; Tomislav A. Ljubicic ; Teresa W. Makowski ; Jason Mustakis ; Jade D. Nelson ; Mark Olivier ; Zhihui Peng ; Hahdi H. Perfect ; David W. Place ; John A. Ragan ; John J. Salisbury ; Corey L. Stanchina ; Brian C. Vanderplas ; Mark E. Webster ; R. Matt Weekly
- 刊名：Organic Process Research & Development
- 出版年：2014
- 出版时间：January 17, 2014
- 年：2014
- 卷：18
- 期：1
- 页码：66-81
- 全文大小：725K
- ISSN：1520-586X
文摘
A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.