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

xothien-2-ylidene)-4-(3-methyl-2-thienyl)butyl)-3- piperidinecarboxyli c acid (5-hydroxytiagabine) 13, has been prepared in 8 steps from 2-br omo-3-methylthiophene 3. Key steps are Grignard reactions, displacemen t of heteroaromatic chlorine with methoxy, and simultaneously demethyl ation and opening of a hydroxymethylcyclopropane with bromotrimethylsi lane. An alternative approach involving acylation of 2-lithio-3-methyl thiophene 17a was found less satisfying. A metalloporphyrin assisted h ydroxylation of tiagabine 1 also yielded the target metabolite. The st ructure of 5-hydroxytiagabine was confirmed by NMR-data including COSY , ROESY, HMQC and HMBC experiments.