Process for the preparation of galanthamine and its derivatives

The subject invention pertains to a process for preparing a compound having a formula (4) or (5), in either optically-enriched or racemic form, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from hydrogen, alkyl, aryl, alkaryl, aralkyl and acyl groups. In one embodiment, the process of the invention comprises mixing with a plant extract obtained from crushed daffodil bulbs or crushed snowdrop bulbs an oxidative cyclisation precursor of the compound. ##STR1##

FIELD OF THE INVENTION
 The present invention relates to a process for producing galanthamine
 and/or its derivatives from plant extracts.
 BACKGROUND OF THE INVENTION
 Galanthamine (and its derivatives) are useful compounds for the treatment
 of Alzheimer's disease and related illnesses. Currently galanthamine,
 nor-galanthamine and the oxidised precursors thereof, narwedine and
 nor-narwedine, are usually obtained by extraction from particular types of
 bulbs, such as daffodils or snowdrops. The yields of these extractive
 procedures are extremely low, resulting in product(s) which are expensive
 and in short supply.
 Studies have shown that the biosynthesis of such compounds probably
 proceeds by a pathway similar to that shown in Scheme 1 below, where the
 key step is an oxidative cyclisation. These studies have also indicated
 that when the cyclisation precursor lacks a methyl group on the amine
 nitrogen (i.e. R.dbd.H) the biosynthesis to narwedine and galanthamine is
 disfavoured, and instead proceeds down other pathways, e.g. to
 pyrrolo(de)phenanthridine and ethanophenanthridine alkaloids (see Barton
 and Kirby, J. Chem. Soc. (1961) 806 and Fuganti et al, Tetrahedron Lett.
 (1974) 2261).
 SUMMARY OF THE INVENTION
 According to the present invention, a process for preparing a compound
 having a formula (4) or (5), in either optically-enriched or racemic form,
 wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected
 from hydrogen, alkyl, aryl, alkaryl, aralkyl and acyl groups, comprises
 mixing with a plant extract an oxidative cyclisation precursor of the said
 compound. All formulae are depicted below.
 Surprisingly, the process of the present invention is capable of achieving
 higher yields of the desired compounds than simple extraction from bulbs,
 and has the further advantage of its own simplicity. The process is
 particularly useful for the preparation of such compounds in
 optically-enriched form, more particularly (-)-galanthamine or
 (-)-narwedine.
 DESCRIPTION OF THE INVENTION
 Whether the process of the invention results in an optically-enriched or
 racemic form of a desired compound may depend upon the choice of the
 precursor to be mixed with the plant extract. Typically, however, an
 optically-enriched form is achieved. This is particularly advantageous
 when the product is (-)-galanthamine, or a derivative thereof, on account
 of its therapeutic activity. However, if the product is racemic or
 optically-enriched narwedine, or a derivative thereof, it can be readily
 converted to optically-enriched, eg. (-), galanthamine by a process such
 as that described by Shieh et al, J. Org. Chem. (1994) 59: 5463.
 By optically-enriched typically we mean mixtures of enantiomers having an
 enantiomeric excess of at least 50%, and more typically at least 80%, or
 90% or higher, thereby including single enantiomer form.
 The groups R.sup.1 to R.sup.4 have been defined above, and typically
 include up to 20 carbon atoms. The preferred precursor compound for the
 preparation of (-)-galanthamine has surprisingly been found to be a
 secondary amine having the formula (3), below, in which the nitrogen atom
 is unsubstituted, ie. R.sup.3.dbd.H, contrary to what is disclosed in the
 prior art discussed above. Particularly preferred precursor compounds are
 of formula (3) in which R.sup.1.dbd.R.sup.3.dbd.R.sup.4.dbd.H and
 R.sup.2.dbd.alkyl, preferably methyl.
 The plant extract is typically derived from daffodils or snowdrops,
 although other plants may give suitable extracts, and is preferably
 derived from the bulb of the plant. The extract is typically used in
 fragmented form, for instance by crushing with a pestle and mortar, and is
 then suspended in a liquid medium. Typically, the liquid medium comprises
 an aqueous buffer, optionally including an additive such as an organic
 solvent or a surfactant. The precursor compound is then added to the
 liquid mixture, and preferably stirred for a period. The mixture is then
 extracted in a conventional manner.
 The present invention is now further illustrated by the following Example.

EXAMPLE
 Daffodil bulbs which had been stored in a refrigerator were allowed to warm
 to room temperature over night. The bulbs were crushed with a pestle and
 mortar and a 1 g sample of this material was stirred with 10 mg of a
 secondary amine of formula (3) below, in which
 R.sup.1.dbd.R.sup.3.dbd.R.sup.4.dbd.H and R.sup.2.dbd.Me, in aqueous
 phosphate buffer (20 ml) and ethanol (10 ml) for 18 hours. The mixture was
 then extracted with ethyl acetate and then concentrated in vacuo. Gas
 chromatographic analysis of the residue indicated that three times the
 amount of (-)-galanthamine was produced in comparison with a control
 reaction, which was run under identical conditions but without the
 addition of the amine (3).
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