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Enantiomers of the muscarinic antagonist 1‐cyclohexyl‐1‐(4‐fluorophenyl)‐4‐piperidino‐1‐butanol ( p ‐fluoro‐hexahydro‐difenidol): Synthesis, absolute configuration, and enantiomeric purity
Author(s) -
Strohmann Carsten,
Bauerecker Sigurd,
Cammenga Heiko K.,
Jones Peter G.,
Mutschler Ernst,
Lambrecht Günter,
Tacke Reinhold
Publication year - 1991
Publication title -
liebigs annalen der chemie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 0170-2041
DOI - 10.1002/jlac.199119910196
Subject(s) - chemistry , enantiomer , stereochemistry , absolute configuration , stereoselectivity , methiodide , muscarinic acetylcholine receptor , enantiomeric excess , enantioselective synthesis , medicinal chemistry , receptor , catalysis , organic chemistry , biochemistry
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 LiCCCH 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).