Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin

被引：57

作者：

Bowles, Paul ^{[1
]}

Brenek, Steven J. ^{[1
]}

Caron, Stephane ^{[1
]}

Do, Nga M. ^{[1
]}

Drexler, Michele T. ^{[1
]}

Duan, Shengquan ^{[1
]}

Dube, Pascal ^{[1
]}

Hansen, Eric C. ^{[1
]}

Jones, Brian P. ^{[1
]}

Jones, Kris N. ^{[1
]}

Ljubicic, Tomislav A. ^{[1
]}

Makowski, Teresa W. ^{[1
]}

Mustakis, Jason ^{[1
]}

Nelson, Jade D. ^{[1
]}

Olivier, Mark ^{[2
]}

Peng, Zhihui ^{[1
]}

Perfect, Handi H. ^{[1
]}

Place, David W. ^{[1
]}

Ragan, John A. ^{[1
]}

Salisbury, John J. ^{[2
]}

Stanchina, Corey L. ^{[1
]}

Vanderplas, Brian C. ^{[1
]}

Webster, Mark E. ^{[1
]}

Weekly, R. Matt ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Chem Res & Dev, Groton, CT 06340 USA

[2] Pfizer Worldwide Res & Dev, Analyt Res & Dev, Groton, CT 06340 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2014年 / 18卷 / 01期

关键词：

GLUCOSE COTRANSPORTER 2; ANTIDIABETIC AGENT ERTUGLIFLOZIN; TYPE-2; DIABETES-MELLITUS; ORGANIC-SYNTHESIS; STEREOSELECTIVE-SYNTHESIS; CLINICAL CANDIDATE; DISCOVERY; CONFIRMATION; PF-04971729; SILYLATION;

D O I：

10.1021/op4002802

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

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 dioxabicyclo[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.

引用

页码：66 / 81

页数：16

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