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Synthesis of (E)‐N‐[methyl‐d 3 ]‐4‐(3‐pyridinyl)‐3‐buten‐1‐amine, a deuterated analogue of the nicotinic agonist RJR‐2403
Author(s) -
Crooks Peter A.,
Ravard Alain,
Byrd Gary D.
Publication year - 1998
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(199812)41:12<1165::aid-jlcr162>3.0.co;2-g
Subject(s) - chemistry , nornicotine , pyrrolidine , amine gas treating , solvolysis , yield (engineering) , moiety , medicinal chemistry , ethyl chloroformate , radiosynthesis , hydrolysis , organic chemistry , alkaloid , materials science , microbiology and biotechnology , biology , in vivo , metallurgy
The synthesis of (E)‐N‐[methyl‐d 3 ]‐4‐(3‐pyridinyl)‐3‐buten‐1‐amine ([methyl‐d 3 ]RJR 2403; [methyl‐d 3 ]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‐d 3 ]iodomethane, in the presence of n‐BuLi at −70°C to afford racemic [methyl‐d 3 ]nicotine in high yield (91%). The pyrrolidine ring was then cleaved with ethyl chloroformate to give (E)‐N‐[methyl‐d 3 ]‐N‐ethyloxycarbonyl‐4‐(3‐pyridinyl)‐3‐buten‐1‐amine; in this reaction, elimination of HCl occurred during heating of the intermediate N‐[methyl‐d 3 ]‐N‐ethyloxycarbonyl‐4‐chloro‐4‐(3‐pyridinyl)butan‐1‐amine under vacuum (0.5 mm Hg). 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‐d 3 ]metanicotine in 82% overall yield. The isotopic purity of the sample was determined by mass spectrometry and calculated to be 97.6 atom % deuterium. Copyright © 1998 John Wiley & Sons, Ltd.