Narcissus and Daffodil

Narcissus patents 411
and bulbs of the ‘sunflower Galanthus Kzasnovii’ (sic) are said to give an extraction
galanthamine yield of 0.5% (dry weight) (Asoyeva, 1968).
Galanthamine can also be extracted from the summer snowflake Leucojum aestivum
(Proskurnina, 1961), using an 8% ammonium aqueous solution plus dichloroethane
or other organic solvents followed by a sulphuric acid treatment, with
subsequent crystalline precipitation of other alkaloids such as lycorine and thebaine.
Further treatment of the liquor with chloroform allows for extraction of the
galanthamine itself by vacuum distillation.
The snowdrop (Proskyrni, 1960) is the starting material in another patent, the
final liquor being treated with a solution of hydrobromic acid and acetone to form
galanthamine hydrobromide. Ground, fresh amaryllis bulbs are moistened with
7% ammonium hydroxide and extracted with dichloroethane in another patent
process file that leads to a yellow oily liquid which crystallises on standing
(Asoyeva, 1963). Another variant of the Leucojum aestivum source involves treatments
with aluminium oxide in the final stages of extraction (Ordzhonikidze
Chem-Pharm, 1962).
A Japanese patent file describes the production of galanthamine, utilising clay
or ion-exchange resins, from Lycoris squamigera (Shionogi & Co. Ltd., 1960). Extraction
from the leaves and flowers of Galanthus nivalis (the common snowdrop) is the
subject of another patent, but the practicalities of isolating from plants that are not
available commercially in sufficient biomass limit the value of such approaches
(Chimiko Pharmazetitschen Zavod, 1968). Production from Ungernia victoris
(Aleksandrova et al., 1994) in tissue culture is also cited as a commercially viable
process. The claim that by first bringing the extract of bulb derived material to
pH4 can lead to a pure form of the alkaloid galanthamine, is made in yet another
publication (Hille et al., 1996).
Production of synthetic galanthamine
The chiral nature of the galanthamine molecule with its three asymmetric carbon
atoms has led to considerable problems in synthetic manufacture. Even though
processes have been described several decades ago, commercialisation has, until
recently, been severely limited by low yields. Obtaining an optimal starting point
for (–)-galanthamine has been the subject of much research. In particular, narwedine
has been the subject of several patent filings as a potential means of addressing
the problem. For example, the preparation of a single (–)-narwedine enantiomer
by seeding a solution of racemic narwedine with single enantiomer (–)-narwedine
in the absence of amine base, plus the reduction of the resultant (–)-narwedine to
the single (–)-galanthamine enantiomer is claimed, with the advantage that such
(–)-narwedine prepared by this method is configurationally stable to racemisation
in the solid state and can be produced on a large scale with very high purity (Potter
and Tiffen, 1998).
Another approach has sought to limit the problems of possible contamination
with unwanted epi-galanthamine compounds by incorporating specific reducing
agents in the process of converting (–)-narwedine to (–)-galanthamine (Carlsson
and Shieh, 1995).
Attempts to increase the yields in the phenolic coupling stage of the preparation
of new and known narwedine derivatives include a method in which oxidation