477352-16-2

Upstream product

• 100-39-0 benzyl bromide 
• 32161-06-1 1-acetyl-4-piperidinone 
• 76360-25-3 1-(4,4-dimethoxypiperidin-1-yl)ethan-1-one 
• 37779-49-0 methyl 3-oxo-4-phenylbutanoate 
• 477352-12-8 ethyl (E)-4-[2-(1-benzyl-4-hydroxypiperidin-4-yl)phenyl]but-2-enoate 
• 477352-13-9 C₂₄H₂₉NO₃ 

Downstream Products

• 477352-18-4 2-(1'-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-3-yl)ethyl methanesulfonate 

Relevant academic research and scientific papers

Oxa-Pictet–Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure

The Oxa-Pictet–Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet–Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ1affinity (Ki20–26?nM) and σ1/σ2selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ1affinity and σ1/σ2selectivity.

Novel σ receptor ligands. Part 2. SAR of spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] with carbon substituents in position 3

Several spiro[[2]benzopyran-1,4′-piperidines] and spiro[[2]benzofuran-1,4′-piperidines] were synthesized and evaluated for their binding properties for σ1 and σ2 receptors. The key step for the introduction of a one carbon residue is the reaction of the cyclic methyl acetals 2a and 3a with trimethylsilyl cyanide to yield the nitriles 5 and 20. The reaction of the lactols 2b and 3b with stabilized phosphoranes affords spiropiperidines with a two carbon residue in position 3. In agreement with previously reported σ1 and σ2 receptor binding data, the investigated spiro compounds display higher affinity for σ1 vs σ2 receptors. Compounds with a cyano group in position 3 of the spirocycle show high σ1 receptor affinity and selectivity. The spirobenzopyran nitrile 5 and the homologous spirobenzofuran nitriles 20 and 23 show almost identical σ1 affinities, whereas the spirobenzopyran nitrile 13 with a methylene spacer is 10-fold less potent. Among the reported compounds, 1′-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4′-piperidinel -3-carbonitrile 5 represents the most potent σ1 receptor ligand with a Ki value of 1.54 nM and a σ1/σ2 selectivity ratio of 1030.