Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1999-06-28
2002-02-12
Coleman, Brenda (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06346618
ABSTRACT:
CROSS-REFERENCE TO A RELATED APPLICATION
This application is a national stage entry under 35 U.S.C §371 of PCT/GB97/01425, filed May 23, 1997.
FIELD OF THE INVENTION
This invention relates to a crystallisation-induced asymmetric transformation, or dynamic resolution, of narwedine-type compounds, and reduction of the resulting diastereomeric salts to galanthamine-type compounds.
BACKGROUND TO THE INVENTION
(−)−Galanthamine is an amaryllidaceae alkaloid which is currently under investigation for the treatment of Alzheimer's disease. Galanthamine is extracted from daffodil bulbs, a process both expensive and time consuming. (−)−Galanthamine has been synthesised by resolution of narwedine to obtain (−)−narwedine, and subsequent reduction to (−)−galanthamine.
Barton and Kirby, J. Chem. Soc. (1962) 806, disclose the first synthetic route to (−)−galanthamine from racemic narwedine which had been prepared in very low yield from N-(3-hydroxy-4-methoxy-benzyl)-N-methyl-2-(4-hydroxyphenyl)-ethylamine. They found that (−)−narwedine crystallised preferentially when (+)−galanthamine or a mixture of (+)−galanthamine and (+)−epigalanthamine was present, and used this to resolve racemic narwedine.
Shieh and Carlson, J. Org. Chem. (1994) 59: 5463, disclose crystallising racemic narwedine in the present of (+)−galanthamine from a solvent/amine base mixture, to give (−)−narwedine in good yield. They also disclose that seeding a solution of racemic narwedine in ethanol/triethylamine mixture with (−)−narwedine results in the crystallisation-induced asymmetric transformation of (−)−narwedine in 84% yield.
However, a problem with using the prior art processes for the resolution of narwedine on a large scale is that narwedine has a tendency to self-seed, sometimes giving material of poor enantiomeric excess, or even the opposite enantiomer of narwedine. For the purpose of industrial manufacture these factors compromise the reproducibility of the process.
The reduction of narwedine to galanthamine requires reagents that show 1,2- rather than 1,4 - regioselectivity, and that also give the required diastereoselectivity in the product, so that galanthamine is formed rather than epigalanthamine. There are several examples in the literature of reagents that favour the 1,2- reduction over the 1,4- reduction of enones and which can diastereo-selectively reduce the carbonyl function in the desired manner. Such examples include LiAlH
4
(see G. Schroder et al, Ber. (1971) 104: 3406; aluminium isopropoxide (seed. H. Picker et al, Syn. Comm. (1975) 5: 451); NaBH
4
with catalytic amounts of rare earth metal halides (see J. L. Luche, J. Am. Chem. Soc. (1978) 100: 2226 and M. M. Abelman et al, J. Am. Chem. Soc, (1990) 112: 6959); lithium aluminium tributoxy hydride (see H. Haubenstock, J. Org. Chem. (1972) 37: 656,); DIBAL (see K. E. Wilson et al, J. Chem. Soc., Chem Comm (1970), 213); REDAL (see C. Iwata et al, Chem. Pharm. Bull. (1988) 36: 14581); superhydride (see Y. Hitotsuyanagi et al, J. Chem. Soc., Chem Comm. (1994) 2707); and bulky trialkyl-borohydrides such as L-selectride (see W. G. Dauben et al, Tet. Lett. (1978) 4487 and A. M. P. Koskinen et al, Tet Lett. (1993) 34: 6765). Many of these reagents have been used for the reduction of narwedine and narwedine-type enones.
In particular, Barton and Kirby, J. Chem. Soc. (1962) 806, disclose that LiAlH
4
reduces narwedine regioselectively and with some diastereoselectivity to give galanthamine with contaminant epigalanthamine. Other workers have observed similar diastereoselectivity in this reaction; see T. Kametani et al, J. Chem. Soc. C (1969) 2602 and T. Kametani et al, J. Org. Chem. (1971) 36: 1295). Also Shieh and Carlson, in WO-A-9527715, disclose the use of LiAlH
4
/AlCl
3
to increase this diastereoselectivity.
Barton and Kirby (as above) also disclose that NaBH
4
is less regioselective than LiAlH
4
and obtain a mixture of 1,2- and 1,4- reduction products from narwedine, while Shieh and Carlson, in WO-A-9527715, disclose the use of the reagent NaBH
4
/CeCl
3
, known to be selective for 1,2-reduction over 1,4-reduction, to obtain galanthamine. NaBH
4
has also been found to give good diastereoselectivity on reduction of a highly substituted narwedine derivative to a galanthamine derivative; see K. Shimizu et al, Chem. Phar. Bull. (1973) 3765).
Shieh and Carlson, J. Org. Chem. (1994) 59: 5463, disclose the use of L-selectride to reduce narwedine to galanthamine without producing epigalanthamine. L-selectride has also been used to effect 1,2-reduction of the carbonyl function of N-formylbromonarwedine diastereoselectively, followed by LiAlH
4
to reduce the N-formyl group and remove the bromine to obtain galanthamine; see J. Szewczyk et al, J. Heterocyclic Chem. (1995) 32: 195.
SUMMARY OF THE INVENION
According to a first aspect of the present invention, a process for the asymmetric transformation of a racemic compound of formula (I), below (relative stereochemistry, shown), in which R
1
is H or an alkyl group having up to 20 carbon atoms, R
2
is H or an alkyl, aryl, alkaryl, aralkyl group having up to 20 carbon atoms, and X is H, a halogen, tert-butyl, or any other removable substituent, comprises reaction of racemic compound (I) with an enantiomerically-enriched acid HY*, wherein Y* is a chiral group, to form a diastereomeric salt of compound (I) having Y* as a counterion.
According to a second aspect of the present invention, a diastereomeric salt of compound (I) has as a counterion a chiral group Y* derived from an enantiomerically-enriched acid HY*.
Preferably, both R
1
and R
2
are, independently, an alkyl group having up to 4 carbon atoms, more preferably with one or both of them being methyl.
The crystallisation-induced asymmetric transformation of the present invention is advantageous over prior art entrainment procedures for a number of reasons. Firstly, the formation of the diastereomeric salt controls the stereochemistry of the product and eliminates any problem of self-seeding which may occur in entrainment procedures. This makes possible a dynamic one pot procedure, whereby all the substrate is converted into a single diastereomeric salt, giving a maximum theoretical yield of 100% instead of the normal 50% maximum yield from a normal classical resolution. This is unexpected, since in situ racemisation of narwedine-type compounds are reported to be catalysed by added base (see Shieh and Carlson, above), and yet in this dynamic process the racemisation occurs in the presence of a chiral acid.
Secondly, the process of the present invention is a general process for a range of compounds of the formula (I), not just for narwedine, provided that an appropriate acid is used as the resolving agent. Previous methods for resolution of narwedine rely on the fact that narwedine has a conglomerate crystal structure, and are therefore not general for other narwedine-type compounds which are not conglomerates.
Moreover, and also surprisingly, we have discovered that the diastereomeric salts produced by the process outlined above can be reduced directly to enantiomerically-enriched or enantiomerically-pure galanthamine without requiring the salt to be cracked.
According to a third aspect of the invention, therefore, a process for the preparation of a compound of formula (III), below (relative stereochemistry shown), comprises asymmetric transformation of a racemic compound of formula (I) using the process according to the first aspect of the invention, followed by reduction of the salt obtained.
This combined asymmetric transformation/reduction procedure represents a convenient and economical process for the preparation of enantiomerically-enriched or enantiomerically-pure galanthamine, or derivatives thereof.
DESCRIPTION OF THE INVENTION
The overall asymmetric transformation/reduction process is shown in Scheme 1, below. The invention is not limited to the stereochemistry shown.
The term asymmetr
Chaplin David Andrew
Johnson Nicholas Bernard
Paul Jane Marie
Potter Gerard Andrew
Coleman Brenda
Janssen Pharmaceutica N.V.
Saliwanchik Lloyd & Saliwanchik
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