Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis

被引：21

作者：

Arumugasamy, Jeevanandam ^{[1
]}

Arunachalam, Kannan ^{[1
]}

Bauer, David ^{[1
]}

Becker, Alan ^{[1
]}

Caillet, Catherine A. ^{[1
]}

Glynn, Roberta ^{[1
]}

Latham, G. Mark ^{[1
]}

Lim, Jinsoo ^{[1
]}

Liu, Jia ^{[1
]}

Mayes, Benjamin A. ^{[1
]}

Moussa, Adel ^{[1
]}

Rosinovsky, Elodie ^{[1
]}

Salanson, Aurelien E. ^{[1
]}

Soret, Adrien F. ^{[1
]}

Stewart, Alistair ^{[1
]}

Wang, Jingyang ^{[1
]}

Wu, Xinghua ^{[1
]}

机构：

[1] Idenix Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2013年 / 17卷 / 05期

关键词：

RUTHENIUM BY-PRODUCTS; CONVENIENT METHOD; REMOVAL; DISCOVERY; SERIES; SCALE;

D O I：

10.1021/op300296t

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outperformed the original macrocyclizations in terms of reaction conditions, impurity profile, product isolation, and basic efficiency metrics. Simple nonchromatographic purification methods achieved sub-10-ppm ruthenium content in the isolated product. Overall yields to IDX316 from all five starting materials ranged from 11 to 40%, and the estimated process mass intensity was improved by a factor of 50 relative to the original unscalable discovery-based routes. Application of similar methodology in the case of IDX320 and first scale-up to half-kilogram batch sizes was demonstrated.

引用

页码：811 / 828

页数：18

共 34 条

[1] A convenient method for the efficient removal of ruthenium byproducts generated during olefin metathesis reactions [J].