Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1998-05-26
2001-02-06
Tate, Christopher (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C514S080000, C514S215000, C540S581000, C540S576000, C424S195110
Reexamination Certificate
active
06184004
ABSTRACT:
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═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
1
, R
2
, R
3
and R
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
1
to R
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
3
═H, contrary to what is disclosed in the prior art discussed above. Particularly preferred precursor compounds are of formula (3) in which R
1
═R
3
═R
4
═H and R
2
═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.
REFERENCES:
patent: 4290862 (1981-09-01), Vlahov et al.
patent: 5428159 (1995-06-01), Shieh et al.
patent: 5633238 (1997-05-01), Snorrason
Szewczyk et al. J. Heterocyclic Chem. vol. 25, pp. 1809-1811, 1988.
Szewczyk et al. J. Heterocyclic Chem. vol. 32, pp. 195-199, 1995.
Kutbay et al. Turkish J. Bot. vol. 17(1), pp. 1-4, abstract enclosed, 1993.
Propavko, S. Apicult. Abstract, vol. 21(3), p. 127, 1970.
Yang et al. J. Chin. Chem. Soc. vol. 15(3), pp. 97-105, abstract enclosed, 1968.
Fuganti, C. La Chimica e L'Industria, vol. 51 (11), p. 1254, 1969.
Hawley, G. Condensed Chemical Dictionary, 8th ed., p. 907, 1971.
Bannister Robin Mark
McCague Raymond
Janssen Pharmaceutica N.V.
Saliwanchik Lloyd & Saliwanchik
Tate Christopher
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