Total mechano-synthesis of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-acrylaldehyde—a pivotal intermediate of pitavastatin†

Abstract

Pitavastatin (PTV), a potent cholesterol-lowering agent, holds considerable commercial appeal, driving chemists to fervently pursue its efficient and sustainable synthesis. Despite prolonged efforts over several decades, the quest for a simplified, more efficacious, and environmentally conscious manufacturing process for PTV remains a significant challenge. Our study introduces a three-step total mechano-synthesis, commencing with readily available 4-bromoquinoline, to produce the key intermediate (2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-acrylaldehyde) of PTV. This methodology incorporates an extrusive Suzuki–Miyaura coupling, mechanochemical Minisci C–H alkylation, and extrusive oxidation Heck coupling, each thoroughly presented to display their scalability. Notably, we emphasize the extensive exploration of substrate versatility in Minisci reactions to access cyclopropane-bearing pharmaceutical compounds and natural products. This total mechano-synthesis route distinguishes itself through eco-friendly reaction conditions, exceptional stepwise efficiency, intuitive operability, and pronounced potential for large-scale implementation, paving the way for PTV's streamlined and sustainable manufacture.