Enantiomers of the muscarinic antagonist 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-1-butanol (p-fluoro-hexahydro-difenidol): Synthesis, absolute configuration, and enantiomeric purity

✍ Scribed by Strohmann, Carsten ;Bauerecker, Sigurd ;Cammenga, Heiko K. ;Jones, Peter G. ;Mutschler, Ernst ;Lambrecht, Günter ;Tacke, Reinhold

• Publisher: John Wiley and Sons
• Year: 1991
• Tongue: English
• Weight: 533 KB
• Volume: 1991
• Category: Article
• ISSN: 0947-3440
• DOI: 10.1002/jlac.199119910196

✦ Synopsis

Abstract

The enantiomers of the antimuscarinic agent 1‐cyclohexyl‐1‐(4‐fluorophenyl)‐4‐piperidino‐1‐butanol [(R)‐ and (S)‐p‐fluorohexahydro‐difenidol] [(R)‐ and (S)‐2a] and their methiodides (R)‐3 and (S)‐3 were prepared with high enantiomeric purity. (R)‐2a and (S)‐2a (isolated as hydrochlorides) were obtained by catalytic hydrogenation (Pd/C contact) of the corresponding enantiomers of 1‐cyclohexyl‐1‐(4‐fluorophenyl)‐4‐piperidino‐2‐butyn‐1‐ol [(R)‐ and (S)‐4]. Reaction of (R)‐2a and (S)‐2a with methyl iodide led to (R)‐3 and (S)‐3, respectively. The unsaturated precursors (R)‐ and (S)‐4 (enantiomeric purity ⩾99.80 and ⩾99.94% e.e.; calorimetric analysis) were prepared by resolution of rac‐4 [available from 4‐FC~6~H~4~C(O)C~6~H~11~ by reaction with LiCCCH~2~NC~5~H~10~] using (R)‐ and (S)‐mandelic acid as resolving agents. The absolute configurations of the (R) and (S) enantiomers of 2a, 3, and 4 were determined by an X‐ray crystal‐structure analysis of (S)‐5, the methiodide of (S)‐4. (R)‐2a and (R)‐3 exhibit a higher affinity for muscarinic M1, M2, M3, and M4 receptors (by up to two orders of magnitude) than their corresponding antipodes (S)‐2a and (S)‐3, the degree of stereoselectivity depending on the receptor subtype involved. (R)‐2a represents a useful tool for muscarinic receptor research (affinity profile: M1 ≈ M3 ≈ M4 > M2).