Development of a pilot scale process for the anti-Alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion

(-)-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.