SYNTHESIS OF RACEMIC [METHYL-D(3)]-LABELED CIS-3'-HYDROXYCOTININE ANDTRANS-3'-HYDROXYCOTININE

A method is described for the synthesis of the racemic [methyl-d(3)] f orms of the nicotine metabolites cis-3'-hydroxycotinine and trans-3'-h ydroxycotinine. The key intermediate was [methyl-d(3)]-N-methylhydroxy lamine, obtained from a selective hydrogenation of d(3)-nitromethane. This intermediate was converted to [methyl-d(3)]-alpha-3-pyridyl-N-met hylnitrone, which was condensed with methyl acrylate to give a mixture of isomeric isoxazolidines. The hydrogenolysis of this mixture afford ed 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 prepare d in high yield from the cis-isomer via chiral inversion utilizing a M itsunobu reaction, or by chromatographic separation from a mixture of the cis- and trans-3'-benzoyloxycotinine, followed by O-debenzoylation in methanolic NaOH.