Synthesis of racemic [methyl-d3]-iabeled cis- and trans-3′-hydroxycotinine

✍ Scribed by Alain Ravard; Peter A. Crooks

• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: French
• Weight: 361 KB
• Volume: 34
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580341102

✦ Synopsis

Abstract

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.