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

This report describes the synthesis of cis 5-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-p-fluorophenyl-1-methylpiperidine (1a) and the analogous cis and trans 1-benzylpiperidines 2a,b. Key steps in the synthesis were the alpha-chlorination of the lactams 5 and 6 (1-methyl-and 1-benzyl-6-p-fluorophenyl-2-piperidinone), and nucleophilic substitution of the resulting cis and trans 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 piperidine 1a, a conformational equilibrium was observed. This was shifted to the [2ax,5eq]form for the cis N-benzyl analogue 2a.