Abstract:

A synthetic method of deuterium labeled memantine-methyl-D6 hydrochloride was investigated. The Grignard reagent methyl-D3 magnesium iodide was used as a source of the isotope deuterium. The first methyl-D3 group of the key intermediate 1，3-dimethyl-D6 adamantane was introduced by a Grignard coupling reaction between methyl-D3 magnesium iodide and 1-bromoamantadane， and the second methyl-D3 group was introduced by bromination reaction and Grignard coupling reaction. Memantine-methyl-D6 hydrochloride was synthesized by chlorination method from 1，3-dimethyl-D6 adamantane， and the by-product demethyl memantine-methyl-D3 hydrochloride was obtained simultaneously. The yields of memantine-methyl-D6 hydrochloride and demethyl memantine-methyl-D3 hydrochloride were 47% and 39% based on 1-bromoadamantane consumed. The structure， chemical purity and deuterium isotopic enrichment of the product were identified as the target compound by nuclear magnetic resonance （NMR）， hign performance liguid chromatography （HPLC） and electrospray ionization mass spectrometry （ESI-MS）. The chemical purity of memantine-methyl-D6 hydrochloride is 99.32%， and the deuterium isotopic enrichment is 99.70%. The chemical purity and deuterium isotopic nrichment were higher than 99.00%. The result showed that the memantine-methyl-D6 hydrochloride could be used as isotope internal standard in the determination of memantine hydrochloride.

Key words: Memantine hydrochloride, Demethyl memantine hydrochloride, Stable isotope labeling, Synthesis, Characterization