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

Add time:08/16/2019    Source:sciencedirect.com

An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) Figure 1, Scheme 1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, condensation with o-phenylendiamine produced the β-enamino ester Scheme 1, Scheme 3, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate Scheme 3, Scheme 4 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. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase.

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