Process for preparing galanthamine derivatives by asymmetric red

Details Process for preparing galanthamine derivatives by asymmetric red Process for preparing galanthamine derivatives by asymmetric red

1998-02-02

2000-01-25

Shah, Mukund J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

540521, C07D48700

Patent

active

060180439

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to a process for the production of enantio-enriched galanthamine, and derivatives thereof, by way of an asymmetric reduction reaction.


BACKGROUND TO INVENTION

(-)-Galanthamine, and derivatives thereof, are useful for the treatment of Alzheimer's disease and related illnesses. Currently galanthamine is obtained by extraction from natural sources, such as daffodils or snowdrops. 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 (3) can be prepared from racemic narwedine (4) through resolution followed by reduction of the enone function, as depicted in Scheme 1 below. Usefully, since the enantiomers of narwedine (3) readily equilibrate (racemize) by way of reversible ring opening to a dienone, coupled to the fact that crystals of racemic (4) exist as a conglomerate of enantiomers, a dynamic resolution of (4) can be carried out by crystallisation with entrainment by crystals of the desired isomer; see Barton and Kirby, J. Chem. Soc. (C) (1962) p.806. However, in respect of a total synthesis, this route suffers the disadvantage that racemic narwedine itself is not readily available.
Barton described the use of lithium aluminium hydride to effect the above reduction, however significant amounts of epigalanthamine were also produced, which is undesirable. Reduction of narwedine using the Meerwein-Ponndorf-Verley conditions gave exclusively epigalanthamine. Subsequently it was disclosed in U.S. Pat. No. 5,428,159 that the requisite transformation could readily be achieved using L-Selectride; see Brown and Krishnamurthy, JACS (1972) p.7159. However, this reagent is expensive and only available in pilot plant quantities, and is therefore unsuitable for large scale production; see Rittmeyer, Chimica Oggi (1995) p.51. Alternative reagents disclosed in the prior art are either as esoteric as L-Selectride, or do not afford sufficiently high levels of diastereoselection.


SUMMARY OF THE INVENTION

According to a first aspect of the present invention, a process for preparing a compound of formula (3) in enantio-enriched form comprises reducing a compound of formula (4), both formulae being shown below, using an asymmetric reductant, and wherein A.sup.1 .dbd.A.sup.2 .dbd.H or A.sup.1, A.sup.2 .dbd.O; B.sup.1 .dbd.B.sup.2 .dbd.H or B.sup.1, B.sup.2 .dbd.O; Z.dbd.H, C.sub.1-20 alkyl or a precursor thereof, or a removable protecting group for nitrogen, e.g. acyl or alkyloxycarbonyl; Y.dbd.H or a substituent; R.sup.1 .dbd.C.sub.1-20 alkyl; and R is an optional, additional substituent. Also, a further substituent can optionally be included in the aromatic ring.
The process of the invention is capable of preparing enantio-enriched galanthamine, or a derivative thereof, from either racemic or enantio-enriched narwedine, in greater enantiomeric excess than achieved by prior art processes.
According to a second aspect of the present invention, novel compounds have the general formula (3) in substantially single enantiomer form, wherein A.sup.1 .dbd.A.sup.2 .dbd.B.sup.1 .dbd.B.sup.2 .dbd.H, R.sup.1 .dbd.Me, and the other substituents are as defined above.
According to a third aspect of the present invention, bromogalanthamine is provided in substantially single enantiomer form.
Preferably, the above-described compounds have a configuration corresponding to (-)-galanthamine, allowing ready conversion to (-)-galanthamine.


DESCRIPTION OF THE INVENTION

The process of the present invention has two embodiments. A first embodiment proceeds via a kinetic resolution on reduction of a racemic enone precursor to the target compound, as outlined in Scheme 2, below. Through the use of an asymmetric reductant, only one enantiomer (A) of the enone is reduced into the corresponding galanthamine derivative, while the other enantiomer (B) is largely unreacted.
In a preferred case, any starting material that is not reduced by the asymmetric reductant can be recycled thro

REFERENCES:
Szewczyk et al., "An Improved Synthesis of Galanthamine", J. Het. Chem., vol. 25(6), pp. 1809-1811, Nov. 1988.
Shieh et al., J. Org. Chem., "Asymmetric Transformation . . . ", vol. 59(18), pp. 5463-5465, Sep. 9, 1994.

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