Syntheses of heterocyclic compounds CCCXCVI. Alternative total synthesis of (+-)-galanthamine

Abstract

1.2.3.4-Tetrahydro-8-hydroxy-7-methoxy-l-(4-methoxyphenethyl)-2-methylisoquinoline (3).•-A solution of 30 mg of the bromoisoquinoline 9 in 40 ml of ethanol was shaken in a current of hydrogen on 10 mg of Raney nickel at room temperature and atmospheric pressure. After absorption of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was concentrated in vacuo.The residue was basified with 10% ammonia and extracted with chloroform. The extract was washed with water, dried over Na2S04, and evaporated in vacuo to give 20 mg (83.3%) of A-norhomopetaline (3) as a viscous syrup: mass spectrum m/e 327 (M+); ir (CHCls) 3520 cm-1; uv (EtOH) 279.5 and 284 nm (log e 3.41 and 3.40); nmr r

Biomimetic Synthesis of (.+-.)-Galanthamine and Asymmetric Synthesis of (-)-Galanthamine Using Remote Asymmetric Induction

“…However, chemical yields of the coupling could not be increased to more than 50%. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] In addition, the coupling reaction using metal oxidants had the practical disadvantages of releasing toxic chemicals as waste reagents, e.g., cyanides from potassium ferricyanide or heavy metal ions.…”

“…Although the yield (61%; the best record in our experiments) was not satisfactory in comparison with that obtained in the reaction of 20b, it was higher than any other reported reactions using norbelladine derivatives as substrates. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] Because of the high stereoselectivity on forming imidazolidinone and the good chemical yield in the successive phenol coupling, imidazolidinone 29a with benzyl groups as the protecting groups (R 1 ) and a side chain (R 2 ) of a-amino acid is considered to be the most suitable synthetic intermediate (Chart 5).…”

Synthesis of 3H‐, 14C‐, and stable‐isotope‐labelled galantamine

“…[8][9][10][11] In early 2001, the US Food and Drug Administration approved the compound's hydrobromic acid salt as treatment for mild to moderate Alzheimer's disease under the name Reminyl 1 . Pharmacokinetic research in support of the approval extensively used 3 H-, 14 C-, and stable-isotope-labelled galantamine, the synthesis of which is described here.…”

“…However, considering the tedious and time-consuming synthesis, such approach was refrained from. Moreover, since the proposed reaction sequence does not allow the introduction of a 14 C-unit in the elaborated pathway via an easily attainable labelled fragment, the label should be incorporated into one of its precursors. This would increase the number of reaction steps and inevitably lead to substantially diminished yields.…”

“…In order to meet the pharmacokinetic demands, instead of introducing a 14 C-label in the galantamine-skeleton, the introduction of a 14 Clabel in the exterior methyl groups and also the introduction of a tritium label on the phenyl ring system was opted for. This approach would offer the opportunity to start from optically pure material which gives a direct, one-step access to optically pure galantamine.…”