SYNTHESIS OF 2,5-SUBSTITUTED PIPERIDINES - TRANSPOSITION OF 1,4-SUBSTITUTION PATTERN FOR THE ANALGESIC DRUG R6582

This report describes the synthesis of cis imidazol-1-yl)-2-p-fluoroph enyl-1-methylpiperidine (1a) and the analogous cis and trans 1-benzylp iperidines 2a,b. Key steps in the synthesis were the alpha-chlorinatio n of the lactams 5 and 6 (1-methyl-and 1-benzyl-6-p-fluorophenyl-2-pip eridinone), and nucleophilic substitution of the resulting cis and tra ns 3-chloro lactams 8a,b and 9a,b. H-1 NMR analysis for the epimeric 3 ,6-substituted lactam compounds revealed a preferred axial orientation for the 3-chloro substituent and an equatorial orientation for the 3- (oxobenzimidazolyl) group. For the reduced compound, cis N-methyl pipe ridine 1a, a conformational equilibrium was observed. This was shifted to the [2ax,5eq]form for the cis N-benzyl analogue 2a.