Process Development of a Novel Azetidinyl Ketolide Antibiotic

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• 作者：Bryan Li ; Thomas V. Magee ; Richard A. Buzon ; Daniel W. Widlicka ; Dave R. Bill ; Thomas Brandt ; Xiaoping Cao ; Michael Coutant ; Haijian Dou ; Karl Granskog ; Mark E. Flanagan ; Cheryl M. Hayward ; Bin Li ; Fengwei Liu ; Wei Liu ; Thuy-Trinh Nguyen ; Jeffrey W. Raggon ; Peter Rose ; Joseph Rainville ; Usa Datta Reilly ; Yue Shen ; Jianmin Sun ; Glenn E. Wilcox
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：May 18, 2012
• 年：2012
• 卷：16
• 期：5
• 页码：788-797
• 全文大小：476K
• 年卷期：v.16,no.5(May 18, 2012)
• ISSN：1520-586X

文摘

Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4-carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.