THE SYNTHESIS OF NOVEL GABA UPTAKE INHIBITORS .2. SYNTHESIS OF 5-HYDROXYTIAGABINE, A HUMAN METABOLITE OF THE GABA REUPTAKE INHIBITOR TIAGABINE

(R)-1-(4-(2,5-Dihydro-3-methyl-5-oxothien-2-ylidene)-4-(3-methyl-2-thienyl)butyl)-3- piperidinecarboxylic acid (5-hydroxytiagabine) 13, has been prepared in 8 steps from 2-bromo-3-methylthiophene 3. Key steps are Grignard reactions, displacement of heteroaromatic chlorine with methoxy, and simultaneously demethylation and opening of a hydroxymethylcyclopropane with bromotrimethylsilane. An alternative approach involving acylation of 2-lithio-3-methylthiophene 17a was found less satisfying. A metalloporphyrin assisted hydroxylation of tiagabine 1 also yielded the target metabolite. The structure of 5-hydroxytiagabine was confirmed by NMR-data including COSY, ROESY, HMQC and HMBC experiments.