1. 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
- Author
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Ilaria Peretto, Gian Piero Pollini, Silvano Ronzoni, Giuseppe Giardina, Claudio Trapella, and Carmela De Risi
- Subjects
Bicyclic molecule ,Chemistry ,Stereochemistry ,Narcotic Antagonists ,Spectrum Analysis ,Organic Chemistry ,Clinical Biochemistry ,Substituent ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Nociceptin Receptor ,Adduct ,chemistry.chemical_compound ,Piperidines ,Drug Discovery ,Receptors, Opioid ,Molecular Medicine ,Hydroxymethyl ,Benzimidazoles ,Piperidine ,Enantiomer ,Methyl acrylate ,Molecular Biology ,Chromatography, High Pressure Liquid - Abstract
An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) 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 beta-enamino ester 2, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate 11 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 LiAlH(4) reduction. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase.
- Published
- 2001