Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1998-07-02
2000-07-11
Barts, Samuel
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D49108
Patent
active
060874953
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to processes for the manufacture of enantiomerically-enriched forms of galanthamine, in free base or salt form.
BACKGROUND TO INVENTION
(-)-Galanthamine and derivatives thereof are useful compounds for the treatment of Alzheimer's disease and related illnesses. Currently galanthamine is usually obtained by extraction from natural sources, such as daffodil or snowdrop bulbs. However, the yields of these extractive procedures are low, resulting in high costs and limited supplies of naturally obtained galanthamine.
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. ##STR1##
Several procedures have been developed for the resolution of galanthamine. One procedure involves formation of a diastereomeric salt with di-p-toluoyl tartaric acid and separation of the mixture by recrystallisation; see Kametani et al, Heterocycles, 1976, 1111. However, the need for the unnatural form of tartaric acid to access the desired, therapeutically-active, (-)-galanthamine renders this process costly.
Another resolution procedure involves the formation of diastereomeric esters with (-)-camphanic chloride and separation of the mixture by recrystallisation; see Szewczyk et al, J Het. Chem. (1995) 32: 195. The resultant product is then converted into (-)-galanthamine by reduction in a process which destroys the chiral auxiliary group, so rendering this process impractical for economic production.
SUMMARY OF THE INVENTION
The present invention is based on the surprising discovery of processes for the separation of the enantiomers of galanthamine by direct crystallisation techniques.
According to a first aspect of the present invention, a process for the preparation of an enantiomerically-enriched galanthamine salt, in which the counterion is achiral, comprises seeding a supersaturated solution of the racemic salt with an enantiomerically-enriched form of the salt, and recovering the salt form that crystallises out of solution.
According to a second aspect of the present invention, a process for increasing the enantiomeric excess of an enantiomerically-enriched galanthamine salt, in which the counterion is achiral, comprises crystallisation of a solution of the said enantiomerically-enriched salt, and recovery of the salt form that crystallises out of solution. Optionally, the solution can be seeded with an enantiomerically-enriched form of the salt. Advantageously, this process for enhancing enantiomeric enrichment can be used subsequent to any process capable of producing enantiomerically-enriched galanthamine, to achieve very high enantiomeric excess.
Both the processes of the present invention have the advantage of simplicity and cost effectiveness. Preferably, the processes are employed to manufacture salt forms enriched in (-)-galanthamine, which can then be used directly in pharmaceutical formulations, provided of course that the salt counterion is pharmaceutically-acceptable, or converted to the free base form of galanthamine, eg. by reaction with an appropriate base. However, both processes can adequately be used to prepare salt forms enriched in (+)-galanthamine, or the free base thereof, if this is desired.
DESCRIPTION OF THE INVENTION
In the context of the present Application, by enantiomerically-enriched typically we mean at least 10% ee, more typically at least 20% ee, upto what may be considered substantially single enantiomer form, for instance at least 80
Barts Samuel
Janssen Pharmaceutica N.V.
LandOfFree
Process for the preparation of galanthamine does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of galanthamine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of galanthamine will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-543469