Synthesis of (E)-N-[methyl-d3]- 4-(3-pyridinyl)-3-buten-1-amine, a deuterated analogue of the nicotinic agonist RJR-2403

Article abstract of DOI:10.1002/(SICI)1099-1344(199812)41:12<1165::AID-JLCR162>3.0.CO;2-G

The synthesis of (E)-N-[methyl-d₃]-4-(3-pyridinyl)-3-buten-1-amine ([methyl-d₃]RJR 2403; [methyl-d₃]metanicotine) is reported. The incorporation of deuterium was performed during the first step of the synthesis via N-methylation of the pyrrolidine nitrogen of racemic nornicotine with [methyl-d₃]iodomethane, in the presence of n-BuLi at -70°C to afford racemic [methyl-d₃]nicotine in high yield (91%). The pyrrolidine ring was then cleaved with ethyl chloroformate to give (E)-N-[methyl-d₃]-N-ethyloxycarbonyl-4-(3-pyridinyl)-3-buten-1-amine; in this reaction, elimination of HCl occurred during heating of the intermediate N-[methyl-d₃]-N-ethyloxycarbonyl-4-chloro-4-(3-pyridinyl)butan-1-amine under vacuum (0.5 mmHg). The last step of the synthesis, i.e. the removal of the N-carbamoyl group, was achieved via acidic hydrolysis with concentrated aqueous hydrochloric acid, to afford [methyl-d₃]metanicotine in 82% overall yield. The isotopic purity of the sample was determined by mass spectrometry and calculated to be 97.6 atom % deuterium.