The synthesis of [14C]-3S,4R-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine hydrochloride (BRL 29060A), and mechanistic studies using carbon-13 labelling

Paroxetine, BRL 29060A 1 has been labelled with both carbon-14 and carbon-13. Hydroxymethylation of 4-(4-fluorophenyl)-1-methyl-1,2,5,6-tetrahydropyridine, using [14C]formaldehyde, produced an enantiomeric mixture of products which was taken without separation through a multistage sequence. Resolution of the mixture of stereoisomers at the penultimate step gave [14C]BRL 29060A with the required configuration. The overall radiochemical yield was 8%. At some stage in this process, as shown by C-13 labelling studies, scrambling of the label took place to give BRL 29060A with the majority of the label in the C-2 position of the piperidine ring and the remainder at the expected 7-methylene position. Further investigations of this route using carbon-13 as the label are described. When sesamol, (3,4-methylenedioxyphenol) was reacted with the O-benzene sulphonate of (±)-cis-4-(4-fluorophenyl)-3-(hydroxy[13C]methyl)-l-methylpiperidine, an inversion of configuration resulted via the previously described 1-aza[3.1.1]bicycloheptane ring system. It is also shown that the corresponding (±)-trans-substituted piperidine, under similar conditions, does not undergo this inversion.