Lab-Scale Preparation of a Novel Carbocyclic Chemokine Receptor Antagonist

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• 作者：Christopher A. Teleha ; Shawn Branum ; Yongzheng Zhang ; Michael E. Reuman ; Luc Van Der Steen ; Marc Verbeek ; Nagy Fawzy ; Gregory C. Leo ; Fu-An Kang ; Chaozhong Cai ; Michael Kolpak ; Derek A. Beauchamp ; Mark J. Wall ; Ronald K. Russell ; Zhihua Sui ; Hilde Vanbaelen
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：December 19, 2014
• 年：2014
• 卷：18
• 期：12
• 页码：1622-1629
• 全文大小：322K
• ISSN：1520-586X

文摘

The preparation of a novel chemokine receptor type 2 (CCR-2) antagonist is described on a 135 g scale. The synthesis of an all-carbon bicyclic core was accomplished using a radical cyclization strategy using chiral precursors, wherein elaboration led to N-Boc carboxylic acid in good yield. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents that would not be preferred in process and chromatography was used to provide the free-base diastereomer of the final succinate salt, the overall route went through stable intermediates that could be used for future scale-up. This lab-scale synthesis struck a balance between a quick scale-up and a more thorough process review of all possible methods and routes.