Method of producing betulinic acid

Details Method of producing betulinic acid Method of producing betulinic acid

1999-05-10

2001-01-16

Lilling, Herbert J. (Department: 1651)

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

Organic compounds

Carboxylic acid esters

C424S195110, C514S169000, C552S502000

Reexamination Certificate

active

06175035

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention, in general, relates to the production of betulinic acid and, more particularly, to a novel method of producing betulinic acid from plant fibers.
2. The Prior Art
Betulinic acid otherwise known as 3b-hydroxy-lup-20(29)-en-28-acid (C
30
H
48
O
3
) is a natural substance with a triterpene molecular structure and has been found in many plants. A specific effect of betulinic acid against the growth of cancer cells was described in 1995 by Pisha et al. in Nature Medicine 1, pp. 1046 seq. Amides of betulinic acid have been described as anti-HIV-agents with a new kind of effective mechanism in 1996 by Evers et al. in J. Med. Chem. 39, pp. 1056 seq. and by Soler et al. in J. Med. Chem. 39, pp. 1069 seq. This has led to a substantial increase in the demand for betulinic acid.
Methods of its production, for instance from the bark of
picramnia pentandra
(
simaroubaceae
) have been described by Herz et al. in Photochemistry, Vol. 11, 1972, pp. 3061 seq., and, from the bark of
arbutus menziesii
(
ericaceae
), by Robinson et al. in Photochemistry, Vol. 9, 1970, pp. 907 seq., and, from the bark of
ziziphus Mauritania
(
rhamnaceae
), by Pisha et al. In Nature Medicine, Vol. 1, pp. 1046 seq.
These starter materials are difficult to obtain, however. They require complex isolation processes, as the betulinic acid can be extracted only in admixture with other substances and it constitutes but a small proportion of the total abstract. Its separation requires multiple-stage cleaning by complex procedures, usually chromatographically. Thus, such production of betulinic acid is correspondingly expensive.
OBJECT OF THE INVENTION
It is an object of the invention to produce betulinic acid from readily available plant materials.
Another object of the invention resides in a method of producing betulinic acid from a plant material having a high betulinic acid content.
Moreover, it is an object of the invention to produce betulinic acid by a simple process.
BRIEF SUMMARY OF THE INVENTION
In accordance with the invention betulinic acid is produced by extraction from the bark of plane trees (sycamores) with solvents of medium polarity such as, for instance, dichloromethane, chloroform or diethylether, inspissation and recrystallization, preferably from methanol. While the bark of plane trees of the species
platanus acerifolia
is the currently preferred source, the bark of other species of the genus platanus may be equally useful for practicing the instant invention. In the event, extracts obtained with dichloromethane are contaminated by only a few accompanying substances. The advantage derived from the invention is that the bark of plane trees is easily obtainable. The trees are peculiar in that during the fall or autumn season the bark separates from, and is shed by, the trees so that it need only be collected. Unlike the gathering of the bark of other trees, there is no need for felling plane trees. A tree of a height of about 10 m supplies several kilograms of bark annually.
Moreover, because of the favorable component mixture of plane tree bark and the selected solvents, the process in accordance with the invention yields a pure product in a few stages without chromatography. The solvents may be recovered. This renders the process ecologically sound, quick and cost efficient. The process may be practiced with simple apparatus and on any scale.
In accordance with a further advantageous embodiment of the invention the betulinic acid can even from the first fractions of extraction be obtained with but insignificant contamination, by inspissation to about one fifth of its volume, recovering of the extraction medium. Double or treble recrystallization leads to a pure uncolored product. In another advantageous embodiment of the invention, further fractions of extraction are inspissated to a completely dry state and need be recrystallized only once.
Additional betulinic acid is obtained by adding hydrochloric acid to the methanolic original solution.


REFERENCES:
patent: 4072570 (1978-02-01), Williams
patent: 5658947 (1997-08-01), Dasgupta et al.
patent: 5750578 (1998-05-01), Carlson et al.
patent: 5804575 (1998-09-01), Pezzuto et al.
patent: 6048847 (2000-04-01), Ramadoss et al.

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