Development of a Pilot Scale Process for the Anti-Alzheimer Drug (−)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion

Abstract

(−)-Galanthamine has been synthesised using an efficient nine-step procedure, which in large scale affords 12.4 (6.7−19.1)% overall yield. The process improvements and optimization of each step are described. Notable steps include (i) an oxidative phenol coupling and (ii) crystallisation-induced chiral conversion of (±)-narwedine to (−)-narwedine. This is a practical and cost-effective synthesis of (−)-galanthamine which is amenable to pilot plant scale-up to afford sufficient material for use in clinical trials.