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Synthesis of racemic [methyl‐d 3 ]‐iabeled cis ‐ and trans ‐3′‐hydroxycotinine
Author(s) -
Ravard Alain,
Crooks Peter A.
Publication year - 1994
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/jlcr.2580341102
Subject(s) - chemistry , acetone , methyl acrylate , organic chemistry , diastereomer , yield (engineering) , medicinal chemistry , materials science , copolymer , metallurgy , polymer
A method is described for the synthesis of the racemic [methyl‐d 3 ] forms of the nicotine metabolites cis ‐3′‐hydroxycotinine and trans ‐3′‐hydroxycotinine. The key intermediate was [methyl‐d 3 ]‐N‐methylhydroxylamine, obtained from a selective hydrogenation of d 3 ‐nitro‐methane. This intermediate was converted to [methyl‐d 3 ]‐α‐3‐pyridyl‐N‐methylnitrone, which was condensed with methyl acrylate to give a mixture of isomeric isoxazolidines. The hydrogenolysis of this mixture afforded a 70:30 mixture of [methyl‐d 3 ] cis ‐ and trans ‐3′‐hydroxycotinine, from which the pure cis ‐ isomer could be isolated by recrystallization from acetone. [Methyl‐d 3 ]‐ trans ‐3′‐hydroxycotinine could be prepared in high yield from the cis ‐isomer via chiral inversion utilizing a Mitsunobu reaction, or by chromatographic separation from a mixture of the cis ‐ and trans ‐3′‐benzoyloxycotinine, followed by O‐debenzoylation in methanolic NaOH.