Improved Synthesis of a Macrocyclic Peptide-Like C5aR Antagonist for Intravenous Applications,Organic Process Research & Development

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Improved Synthesis of a Macrocyclic Peptide-Like C5aR Antagonist for Intravenous Applications
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-10-19 , DOI: 10.1021/acs.oprd.3c00202
Yiqing Feng ₁ , Sidney Liang ₁ , Jonathan Langille ₁ , Betsy S. Pierce ₁ , SeungWon Chung ₁ , Jan Szeliga ₁ , Glenn Wilcox ₁ , Paul Simonds ₁ , Kathleen A. Farley ₁ , Bryan Li ₁ , Carmen Garcia-Irizarry ₁ , Peter Jones ₁ , Ricardo Lira ₁

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A multigram scale synthetic procedure for the preparation of a complex and polar macrocyclic peptidic C5aR antagonist is described. The route was developed through improvements to an initial small-scale research synthesis and hinged on optimized solid-phase peptide synthesis featuring an early side chain decoration, a highly efficient off-resin macrolactamization, and global deprotection steps. These improvements resulted in a reduction in off-resin peptide manipulations and ultimately to a 6-fold increase in overall yield from 2-chlorotrityl-bound intermediate SP-7c.

中文翻译：

用于静脉注射的大环肽样 C5aR 拮抗剂的改进合成

描述了用于制备复杂的极性大环肽 C5aR 拮抗剂的多克规模合成程序。该路线是通过对最初小规模研究合成的改进而开发的，并取决于优化的固相肽合成，其特点是早期侧链装饰、高效的树脂外大环内酰胺化和全局脱保护步骤。这些改进减少了树脂外肽操作，最终使 2-氯三苯甲基结合的中间体SP-7c 的总产率增加了 6 倍。

更新日期：2023-10-19

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