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

Reminyl® is a newly approved drug, used in the treatment of mild to moderate Alzheimer disease. The active compound, galantamine, was initially isolated from the bulbs of certain Narcissus species, but is at the moment also produced synthetically. In the process leading to the final approval, the synthesis of tritium-, carbon-14- and stable-isotope-labelled galantamine for pharmacokinetic studies was required. Racemic (±)-1-bromonarwedine, a compound available as intermediate from the commercial synthesis, was transformed to racemic 1-bromo-galantamine. Catalytic bromo-tritium exchange, followed by HPLC purification and resolution afforded tritium-labelled galantamine. The [14C]-label was introduced on the nitrogen as well as on the oxygen-methyl position. This was achieved by N- and O-demethylation of galantamine and reaction of the thoroughly purified intermediate with [14C]-methyl iodide. Stable-isotope-labelled galantamine was obtained likewise by 13CD3OD-methylation of O-demethylated galantamine under Mitsunobu conditions. Copyright © 2002 John Wiley & Sons, Ltd.