Initial Route Scouting and Final Process Development for the Multi-Kg Production of 3-Fluoro-6-methoxyquinoline from p-Anisidine and 2-Fluoromalonic Acid

Abstract

A scalable route to 3-fluoro-6-methoxyquinoline needed to be developed as multi-kg amounts of this heterocycle were required. Initial route development focused on the formation of the key C–F bond via a Balz–Schiemann reaction or electrophilic fluorination using Selectfluor. Both routes were developed on laboratory scale and provided gram amounts of 3-fluoro-6-methoxyquinoline. However, due to process safety concerns and high step counts, both routes were not suitable for further scale up. Therefore, a third approach was developed, in which the desired heterocycle was formed via condensation of p-anisidine with 2-fluoromalonic acid, two inexpensive and commercially available starting materials. After intensive optimization and safety studies, this POCl3-mediated process was successfully scaled up to a 32 kg scale. After final hydrodechlorination, 12 kg of 3-fluoro-6-methoxyquinoline with excellent purity was produced.