Process for production of diacetylrhein

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai

Reexamination Certificate

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C552S262000

Reexamination Certificate

active

06624192

ABSTRACT:

The present invention is concerned with a process for obtaining diacetylrhein of pharmaceutically usable purity with a residual content of undesired aloe-emodin derivatives of, in all, less than 20 ppm, the diacetylrhein obtainable according to this process and a pharmaceutical composition which contains this compound.
Diacetylrhein of the formula:
is a medicinally-active compound which possesses antiarthritic, anti-inflammatory, antipyretic and analgesic activity. Therefore, diacetylrhein is used for the treatment of arthritic diseases (cf., for example DE-A-27 11 493 and U.S. Pat. No. 4,244,968).
Diacetylrhein can be prepared, for example, by the acetylation of barbaloin and oxidation of the peracetylated barbaloin obtained with chromium trioxide. Furthermore, diacetylrhein can be prepared by the acetylation of rhein which can be obtained, for example, from senna drug.
Diacetylrhein obtained according to these processes contains undesired accompanying aloe-emodin derivatives which result from an incomplete oxidation with chromium trioxide or are co-extracted in the case of the extraction of senna drug. These accompanying materials are present in relatively small amounts and can, therefore, only be separated with great difficulty by means of well-known purification procedures. Furthermore, in the case of the first of the above-mentioned processes, chromium residues are present which have to be removed in appropriate manner.
Therefore, it is an object of the present invention to provide a process for obtaining diacetylrhein which is simple to carry out and gives high yields and in which diacetylrhein is obtained of pharmaceutically usable purity with a residual content of undesired aloe-emodin derivatives of, in all, less than 20 ppm.
Thus, according to the present invention, there is provided a process for obtaining diacetylrhein, wherein diacetylrhein containing aloe-emodin derivatives (i.e. aloe-emodin and/or derivatives thereof) is subjected to a liquid—liquid partitioning between a polar organic solvent which is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5 and the diacetylrhein is recovered and optionally recrystallised.
A diacetylrhein containing aloe-emodin can be used in the process according to the present invention. Important sources of diacetylrhein are the senna drug-containing sennosides, as well as the rhein-9-anthrone-8-glucoside obtainable from the sennosides.
Therefore, a preferred embodimental form of the present invention is a process for the preparation of diacetylrhein which is substantially free from aloe-emodin derivatives, wherein
a) rhein-9-anthrone-8-glucoside containing aloe-emodin components is oxidised to the corresponding anthraquinone compounds,
b) the glucose residue in the 8-position of the anthraquinone compounds is split off in an acid medium,
c) the 1,8-dihydroxyanthraquinone compounds obtained are acetylated and
d) a liquid—liquid partitioning of the product obtained is carried out between a polar organic solvent which is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5 and the diacetylrhein is recovered and optionally recrystallised.
Another preferred embodiment of the present invention is a process for the preparation of diacetylrhein which is substantially free from aloe-emodin derivatives, wherein
a) a sennoside mixture is subjected to a reduction to the corresponding anthrone compounds,
b) the anthrone compounds obtained are oxidised to the corresponding anthraquinone compounds,
c) the glucose residue in the 8-position of the anthraquinone compounds is split off in an acid medium,
d) the 1,8-dihydroxyanthraquinone compounds obtained are acetylated and
e) a liquid—liquid partitioning of the product obtained is carried out between a polar organic solvent which is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5 and the diacetylrhein is recovered and optionally recrystallised.
In the following, the individual steps of the process according to the present invention are explained in more detail:
Reduction of the Sennoside Mixture to the Corresponding Anthrone Compounds
The sennoside mixture used as starting material can be obtained, for example, from senna drug. The senna drug consists of the dried leaves and fruits of the senna plant, for example of the Indian senna (Cassia angustifolia) and Egyptian senna (Cassia acutifolia). The senna drug contains dianthrone glucosides of rhein and aloe-emodin. The most important ones are sennosides A, B, Al, C, D and Dl. The sennosides correspond to the general formula:
In the case of sennosides A, B and Al, R stands for COOH and in the case of sennosides C, D and Dl, R stands for CH
2
OH. The sennosides A, B and Al and the sennosides C, D and Dl are stereoisomers and differ from one another by the configuration on carbon atoms 10 and 10′.
The obtaining of sennosides from senna drug is described, for example, in DE-A-32 00 131, reference to which is here made to the complete specification. According to this, the senna drug is first extracted with aqueous methanol. The concentrate remaining after complete removal of the methanol contains the sennosides in the form of alkali metal salts, preferably potassium salts. The concentrate is purified by liquid—liquid extraction with alcohols or ketones, for example butan-2-ol or butan-2-one, which are partly soluble in water (raffinate). The raffinate is acidified to a pH value of about 1.5 to 2.0 and the sennosides are crystallised by seeding out. The crude sennoside mixture obtained can be used as starting material for the process according to the present invention. If desired, the crude sennoside mixture can also be recrystallised.
Alternatively, the concentrate mixed with an alcohol which is only partly soluble in water, especially butan-2-ol, can be used as starting material for the process according to the present invention.
In the case of the extraction of the senna drug, the ratio of drug to extraction agent is preferably 1:4 to 1:15 and especially 1:4 to 1:10.
The extraction is preferably carried out in the presence of a buffer, for example trisodium citrate, glycine, sodium bicarbonate or saccharose.
According to the process of the present invention, these starting materials are reduced to give rhein-9-anthrone-8-glucoside (R=COOH) and aloe-emodin-9-anthrone-8-glucoside (R=CH
2
OH) of the general formula:
wherein R is COOH or CH
2
OH.
Reducing agents with an appropriate reducing potential include stannous chloride, sulphur dioxide, alkali metal borohydrides and preferably alkali metal dithionites, especially sodium dithionite. The reducing agent is used in large excess. In general, a dithionite and especially sodium dithionite is used in a 1 to 4 fold amount by weight, referred to the content of sennosides in the starting material.
For carrying out the reduction, the starting material can be present in aqueous solution or suspension and the reducing agent added thereto in solid form or dissolved in water. It is preferred to work in a two-phase mixture by adding thereto a polar organic solvent which, at most, is only partly miscible with water, especially butan-2-ol.
The reaction is preferably carried out at a temperature of 40 to 60° C. and especially of 50 to 55° C. and at a pH of 7 to 9. The reduction is preferably carried out several times and especially 2 to 10 times.
The 9-anthrone-8-glucosides formed are precipitated out by the addition of an acid, for example of sulphuric acid, to a pH value of 4 to 4.5. The temperature should thereby preferably be not more than 40° C. In the case of the precipitating out of the anthrone glucosides and in the case of the isolation thereof, for example by filtration, it is preferable to work under an atmosphere of nitrogen in order to avoid an uncontrolled oxidation of these compounds.
Oxidation of the Anthrone Compounds to the Anthraquinone Compounds
The anthrone compounds obtained are now oxidised to the corresponding anthraquinone compounds of the general formula:
wherein R is COOH or CH
2
OH. Oxidation agents appropria

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