Synthesis of (+/-)-methyl-(1-aryl-4-pyridin-3-yl-but-3-enyl)-amines.
trans-Metanicotine, a subtype (alpha4beta2)-selective ligand for neuronal nicotinic acetylcholine receptor, is under clinical phase for Alzheimer's disease. An efficient synthetic route for (+/-)-methyl-(1-aryl-4-pyridin-3-yl-but-3-enyl)-amines, derivatives of trans-metanicotine, was explored. Allylation reaction of aryl aldimines with allylmagnesium bromide in THF gave (+/-)-methyl-(1-aryl-but-3-enyl)-amines. Protection of the amines with the Boc group and following Heck reaction of the N-Boc amines with 3-bromopyridine gave (+/-)-methyl-(1-aryl-4-pyridin-3-yl-but-3-enyl)-carbamic acid tert-butyl esters. Deprotection of the N-Boc group in aqueous 1N-HCI solution gave the titled amines in good yields. Thus, trans-metanicotine analogues modified at the a-position of the methylamino group with aryl groups were obtained in 5 steps.
Jang
J
J
College of Pharmacy, Kangwon National University, Chunchon, Korea.
Sin
K S
KS
Park
H
H
D009538:Nicotine / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D018722:Nicotinic Agonists / Q000138:chemical synthesis*
D018722:Nicotinic Agonists; C012419:metanicotine; D009538:Nicotine