Quinuclidine chemistry. 3. Beta-cis-2-(4'-Chlorobenzhydryl)-3-quinuclidinol, a new central nervous system stimulant. Importance of the benzhydryl configuration.
The 1,4 addition of p-chlorophenylmagnesium bromide to 2-benzylidene-3-quinuclidinone gave 2-(4-chlorobenzhydryl)-3-quinuclidinone as two diastereoisomers. Selective reduction of this ketone with aluminum isopropoxide gave the two cis-2-(4-chlorobenzhydryl)-3-quinuclidinols, which differ only in the configuration of the benzhydryl group, designated alpha and beta in order of their elution on chromatography. Reduction with NaBH4 gave a mixture of four isomeric alcohols, of which the two cis isomers were selectively oxidized. The two trans-2-(4-chlorobenzhydryl)-3-quinuclidinols were chromatographically separated and desingated alpha and beta in order of elution. Only the beta-cis and beta-trans alcohols showed CNS stimulant properties. The beta-cis isomer was shown to be related both qualitatively and quantitatively more to methylphenidate (Ritalin) than to d-amphetamine.
D000818:Animals; D001066:Appetite / Q000187:drug effects; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D000882:Haplorhini; D007928:Lethal Dose 50; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013268:Stimulation, Chemical
D001067:Appetite Depressants; D001559:Benzhydryl Compounds; D011812:Quinuclidines; D008774:Methylphenidate; D003913:Dextroamphetamine