Synthesis of ($\pm$)-Methyl-(1-aryl-4-pyridin-3-yl-but-3-enyl)-amines

  • Jang, Jin-Hee (College of Pharmacy, Kangwon National University) ;
  • Sin, Kwan-Seog (College of Pharmacy, Kangwon National University) ;
  • Park, Hae-Il (College of Pharmacy, Kangwon National University)
  • Published : 2001.12.01

Abstract

trans-Metanicotine, a subtype (${\alpha}_4{\beta}_2$)-selective ligand for neuronal nicotinic acetylcholine receptor, is under clinical phase for Alzheimer's disease. An efficient synthetic route for ($\pm$)-methyl-(1-aryl-4-pyridin-3-yl-but-3-enyl)-am ices, derivatives of tracts-metanicotine, was explored. Allylation reaction of aryl aldimines with allylmagnesium bromide in THF gave ($\pm$)-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 ($\pm$)-methyl-(1-aryl-4-pyridin-3-yl-but-3-enyl)-carbamic acid tert-butyl esters. Deprotection of the N-Boc group in aqueous 1 N-HCI solution gave the titled amines in good yields. Thus, trans-metanicotine analogues modified at the ${\alpha}-position$ of the methylamino group with amyl groups were obtained in 5 steps.

Keywords

References

  1. Psycopharmacology: fourth generation of progress Neuronal acetylcholine receptors: novel targets for CNS therapeutics Arneric,S.P.;Sullivan,J.P.;Williams,M.;Bloom,F.E.(ed.);Kupfer,D.J.(ed.)
  2. Science v.217 The cholinergic hypothesis of geriatric memory dysfunction Bartus,R.T.;Dean,R.L.I.;Beer,B.;Lippa,A.S.
  3. J. Pharmcol. Exp. Ther. v.279 RJR-2403: A nicotinic agonist with CNS selectiveity 1. In vitro characterization Bencherfif,M.;Lovette,M.E.;Fowler,K.W.;Arrington,S.R.;Reeves,L.K.;Caldwell,W.S.;Lippello,P.M.
  4. J. Heterocyclic Chem. v.35 Synthesis of Oxazolyl- and Furanyl-substituted Imidazole Hydrochlorides and Methiodides Boulos,J.;Schulman,J.;
  5. Med. Chem. Res. v.2 Nicotine addiction: considerations in the therapeutic use of nicotine Corrigal,W.
  6. J. Org. Chem. v.43 Palladium-catalyzed vinylic substitutionreactions with heterocyclic bromides Frank,W.C.;Kim,Y.C.;Heck,R.F.
  7. Neuropharmacology v.34 Neuronal nicotinic receptors; Molecular organization and regulations Galzi,J.L.;Changeux,J.P.
  8. J. Med. Chem. v.40 Neuronal nicotinic acetylcholine receptors as targets for drug discovery Halloday,M.W.;Dart.M.J.;Lynch,J.K.
  9. Med. Chem. Res. v.2 Nicotine as a potential therapeutic agent: and overview and clinical perspective Karan,L.D.
  10. Am. Heart J. v.127 Cardiovascular effects of nicotine: relation to deterious effects of cigarette smoking Khosla,S.;Laddu,A.;Ehrenpreis,S.;Somberg,J.C.
  11. Med. Chem. Res. v.2 Nicotine involvement in cognitive function: possible therapeutic applications Levin,E.D.
  12. Alzheimer's disease: From molecular biology to therapy RJR-2403: A CNS-selective nicotinic agonist with therapeutic potential Lippello,P.M.;Bencherif,M.;Caldwell,Arrington,S.R.;Fowler,K.W.;Lovette,M.E.;Reeves,L.K.;Becker,R.(ed.);Giacobini,E.(ed.)
  13. N. Engl. J. Med. v.319 Pharmacologic aspects of cigarette smoking and nicotine addiction Oates,J.A.;Wood,A.J.J.;Benowitz,N.L.
  14. Arch. Pharm. Res. v.23 A Concise Synthetic Pathway for trans-Metanicotine Analogues Park.H.;Jang,J.;Sin,K.S.
  15. Acta Neurol. Scand. Suppl. v.149 Cholinergic therpy in dementia Whitehouse,P.J.
  16. Drug News & Perspectives v.7 Neuronal nicotinic acetylcholine receptors Williams,M.;Sullivan,J.P.;Arneric,S.P.
  17. Chem. Rev. v.93 Selective Reactions Using Allylic Metals Yamamoto,Y.;Asao,N.