Pa. Crooks et al., Synthesis of (E)-N-[methyl-d(3)]-4-(3-pyridinyl)-3-buten-1-amine, a deuterated analogue of the nicotinic agonist RJR-2403, J LABEL C R, 41(12), 1998, pp. 1165-1171
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.