Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1998-08-20
2000-07-25
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
A61K 3155
Patent
active
060938153
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the discovery of a novel process for the manufacture of galanthamine and related compounds, in racemic or in optically-enriched form, and to novel intermediates in that process.
BACKGROUND OF THE INVENTION
(-)-Galanthamine (and related compounds) are useful compounds for the treatment of Alzheimer's disease and related illnesses. Currently galanthamine is usually obtained by extraction from particular types of bulbs, such as daffodils or snowdrops.
It is known that single enantiomer galanthamine (2) can be prepared from racemic narwedine (1) through resolution followed by reduction of the enone function, as depicted in Scheme 1, below. Usefully, since the enantiomers of narwedine (1) readily equilibrate (racemise) by way of reversible ring opening to a dienone, coupled to the fact that crystals of racemic (1) exist as a conglomerate of enantiomers, a dynamic resolution of (1) can be carried out by crystallisation with entrainment by crystals of the desired isomer (see Barton and Kirby, J. Chem. Soc. (C) (1962) 806). However, in respect of a total synthesis, racemic narwedine itself is not readily available.
Numerous processes have been based on the biomimetic approach pioneered by Barton and Kirby in 1962, in which the key oxidative cyclisation step proceeded in only 1.4% yield. In later studies it was found that the yields of the phenolic coupling could be increased substantially by deactivation of the basic amine as either an amide or sulphonamide group, and by blocking the para-position with a removable group (i.e. replaceable by hydrogen) such as bromine, e.g. as in compound (3) in Scheme 2 below; see for instance Franck and Lubs, Liebigs. Ann. Chem. (1968) 720: 131; Kametani et al., J. Chem. Soc., Chem. Comm. (1969) 425 and J. Chem. Soc.(C) (1969) 2602-2605 and Szewczyk et al., J. Heterocyclic Chem. (1988) 1809).
However, processes operating on this strategy are cumbersome owing to the need to remove the amine protecting group from the product of the phenolic coupling (compound (4) in Scheme 2) by reduction. This invariably leads to concomitant reduction of the narwedine carbonyl group, and possibly other functional groups, producing racemic galanthamine and/or epigalanthamine, or derivatives thereof, as depicted by compound (5) in Scheme 2. To obtain racemic narwedine (1) from the latter compounds then requires a separate reoxidation step.
SUMMARY OF THE INVENTION
Surprisingly, it has now been discovered that phenolic coupling of the general type described above can be carried out with acceptable yield without the need to render non-basic the amine functionality in the cyclisation precursor. This discovery is particularly advantageous because the product of the phenolic coupling does not need to undergo the cumbersome reduction-oxidation procedure to afford narwedine.
Accordingly, in one aspect of the present invention a process for preparing an optically-enriched compound having the formula (11), below, comprises oxidative cyclisation of a tertiary amine having the formula (12), below, wherein X.sup.1 is a removable functionality, X.sup.2 is hydrogen or a removable functionality, R.sup.1 is selected from hydrogen and alkyl, aryl, alkaryl, aralkyl groups having up to 20 carbon atoms, and R.sup.2 and R.sup.3 are independently selected from hydrogen and alkyl, aryl, alkaryl, aralkyl and acyl groups having up to 20 carbon atoms. Resolution and reduction of the resulting compounds leads to optically-enriched compounds having the galanthamine structure as depicted by formula (10), below.
According to other aspects of the present invention, novel compounds having the formulae (10), (11) and (12 ) and are defined in the claims. Of particular interest are the optically-enriched forms of compounds (10) and (11), and in particular when enriched in the enantiomer which has the stereochemical configuration of (-)-galanthamine, which therefore allow ready access to (-)-galanthamine per se. By optically-enriched typically we mean an enantiomeric excess of at
REFERENCES:
Shimzu et al. (Heterocycles (1977), 8, 277-82), 1977.
Heinsch et al. (Monatsch. Chem., 102 (1971), 530-537), 1971.
Shimizu, K. et al. (1978) Stereochemical Studies. LIV. A Biogenetic-type Asymmetric Synthesis of optically Active Galanthamine from L-Tyrosine. Chem. Pharm. Bull. 26(12): 3765-3771.
Szewczyk, J. Lewin, A.H., Carroll, F.I. (1988) An Improved Synthesis of Galanthamine. J. Heterocyclic Chem. 25: 1809-1811.
Kametani, T. et al. (1969) Studies on the Syntheses of Heterocyclic Compounds. Part CCCXV. Modified Total Synthesis of (+/-)--Galanthamine through Phenol Oxidation. J. Chem. Soc. (C): 2602-2605.
Vlahov, R. et al. (1989) Synthesis of Galanthamine and Related Alkaloids. Tetrahedron 45(11): 3329-3345.
Chaplin David Andrew
Fraser Neil
Tiffin Peter David
Janssen Pharmaceutica N.V.
Kifle Bruck
Shah Mukund J.
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