Synthesis, stereochemistry, and opioid receptor binding activity of heterocyclic analogues of BW373U86

The synthesis of a series of heterocyclic analogues of (±)‐4‐((α R *)‐α‐((2 S *,5 R *)‐4‐allyl‐2,5‐dimethyl‐1‐piperazmyl)‐3‐hydroxybenzyl)‐ N,N ‐diethylbenzarrude (BW373U86) for screening against opioid receptors is described. The intermediate α‐heterocyclic benzyl alcohols 24 were synthesized either by low temperature reaction of lithioheterocycles with 3‐(( tert ‐butyldimethylsilyl)oxy)benzaldehyde ( 10 ) or by reaction of 3‐(( tert ‐butyldimethylsilyl)oxy)phenylmagnesium bromide ( 19 ) with heterocyclic carbaldehydes. The α‐heterocyclic benzyl alcohols 24 were converted to chloromethines ( 25 ) with thionyl chloride and used to alkylate with trans ‐1‐allyl‐2,5‐dimethylpiperazine ( 5 ) to give diastereomeric pairs of the target compounds. The bromoheterocycles were then derivatized to produce amides. Compounds that are potent and selective for the 5 or μ opioid receptors and some mixed δ/μ analogues are reported.