Development of Continuous‐Flow Reactions for the Synthesis of Anti‐Alzheimer Drug Memantine

Memantine hydrochloride, a non-competitive antagonist of NMDA-type glutamate receptors, is known to suppress the progression of symptoms in Alzheimer's disease. Possessing a characteristic adamantane skeleton as its core structure and an amino group at the bridgehead position, memantine was synthesized starting from acenaphthene. The synthesis involved nucleus hydrogenation of acenaphthene to perhydroacenaphthene, skeletal rearrangement of perhydroacenaphthene, nitration of 1,3-dimethyladamantane, and reduction of the nitro groups to an amino group. In each step, continuous flow reactions were investigated to achieve continuous manufacturing of memantine.