Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis
详细信息 查看全文
- 作者：Jeevanandam Arumugasamy ; Kannan Arunachalam ; David Bauer ; Alan Becker ; Catherine A. Caillet ; Roberta Glynn ; G. Mark Latham ; Jinsoo Lim ; Jia Liu ; Benjamin A. Mayes ; Adel Moussa ; Elodie Rosinovsky ; Aurelien E. Salanson ; Adrien F. Soret ; Alistair Stewart ; Jingyang Wang ; Xinghua Wu
- 刊名：Organic Process Research & Development
- 出版年：2013
- 出版时间：May 17, 2013
- 年：2013
- 卷：17
- 期：5
- 页码：811-828
- 全文大小：527K
- 年卷期：v.17,no.5(May 17, 2013)
- ISSN：1520-586X
文摘
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.