Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin

Autor:	R. Matt Weekly, Zhihui Peng, Hahdi H. Perfect, Teresa W. Makowski, Jade D. Nelson, Eric C. Hansen, Michele T. Drexler, David Place, Pascal Dube, Mark Olivier, Paul Bowles, Jason Mustakis, Nga M. Do, Stephane Caron, John J. Salisbury, John A. Ragan, Kris N. Jones, Tomislav A. Ljubicic, Shengquan Duan, Corey L. Stanchina, Brian P. Jones, Steven J. Brenek, Brian C. Vanderplas, Mark E. Webster
Rok vydání:	2014
Předmět:	chemistry.chemical_compound Aglycone chemistry Nucleophile Aryl Amide Organic Chemistry Ertugliflozin Organic chemistry Moiety Physical and Theoretical Chemistry Chemical purity Octane
Zdroj:	Organic Process Research & Development. 18:66-81
ISSN:	1520-586X 1083-6160
DOI:	10.1021/op4002802
Popis:	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.
Databáze:	OpenAIRE
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