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

Makoto Iwata; Yuichi Furiya; Haruro Ishitani; Shū Kobayashi

doi:10.1002/chem.202403562

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

Chemistry. 2024 Nov 29:e202403562. doi: 10.1002/chem.202403562. Online ahead of print.

Authors

Makoto Iwata¹, Yuichi Furiya¹, Haruro Ishitani², Shū Kobayashi^{1

2}

Affiliations

¹ Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
² GSC Social Cooperation Laboratory, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

PMID: 39611355
DOI: 10.1002/chem.202403562

Abstract

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.

Keywords: Continuous-flow; Drug synthesis; Heterogeneous catalyst; Memantine; Sequential-flow.