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

The synthesis of (E)-N-[methyl-d(3)]-4-(3 -pyridinyl)-3-buten-1-amine ([met hyl-d(3)]RJR 2403; [methyl-d(3)]metanicotine) is reported. The incorporatio n of deuterium was performed during the first step of the synthesis via N-m ethylation of the pyrrolidine nitrogen of racemic nornicotine with [methyl- d(3)]iodomethane, in the presence of n-BuLi at -70 degrees C to afford race mic [methyl-d(3)]nicotine in high yield (91%). The pyrrolidine ring was the n cleaved with ethyl chloroformate to give (E)-N-[methyl-d(3)]-N-ethyloxyca rbonyl-4-(3-pyridinyl)-3-buten-1-amine; in this reaction, elimination of HC l occurred during heating of the intermediate N-[methyl-d(3)]-N-ethyloxycar bonyl-4-chloro-4-(3-pyridinyl)butan-1-amine under vacuum (0.5 mm Hg). The l ast step of the synthesis, i.e. the removal of the N-carbamoyl group, was a chieved via acidic hydrolysis with concentrated aqueous hydrochloric acid, to afford [methyl-d(3)]metanicotine in 82% overall yield. The isotopic puri ty of the sample was determined by mass spectrometry and calculated to be 9 7.6 atom % deuterium.