A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397), the first non-peptide ORL-1 receptor antagonist

An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-pi peridyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) 1, the first non -peptide ORL-1 receptor antagonist described in literature, is outlined. Af ter construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, conden sation with o-phenylendiamine produced the beta -enamino ester 2. which has been conveniently used to construct the benzimidazolone substituent at C-4 . Catalytic hydrogenation of intermediate II followed by base-promoted cis- trans isomerization of the key compound 12 led to the formation of ester 13 , which was converted to the racemic title compound by LiAlH4 reduction. Th e pure enantiomers were obtained by chiral preparative HPLC separation usin g a derivatized cellulose-based stationary phase, (C) 2001 Elsevier Science Ltd. All rights reserved.