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

Abstract

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 (1·2 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).