Diastereospecific Enolate Addition and Atom-Efficient Benzimidazole Synthesis for the Production of L/T Calcium Channel Blocker ACT-280778

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• 作者：Jacques-Alexis Funel ; Stephan Brodbeck ; Yves Guggisberg ; Remy Litjens ; Thomas Seidel ; Martin Struijk ; Stefan Abele
• 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：1674-1685
• 全文大小：541K
• ISSN：1520-586X

文摘

A scalable access to 1 (ACT-280778), a potent L/T calcium channel blocker, has been developed. The synthesis, amenable to kilogram manufacturing, comprises 10 chemical steps from enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (3) and 1,4-dimethoxybenzene with a longest linear sequence of 7 steps. Key to the success of this fit-for-purpose approach are a robust and atom-efficient access to benzimidazole 4, the substrate-controlled diastereoselective enolate addition toward carboxylic acid 2 that was isolated by simple crystallization with high dr (>99:1), the convenient selective N-deacylation of intermediate 10, and the identification of a suitable solid form of 1 as the bis-maleate salt (1路2 C₄H₄O₄). As an illustration of the robustness of this process, 14 kg of drug substance, suitable for human use, was produced with an overall yield of 38% over the longest linear sequence (7 steps).