Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1994-11-10
2003-07-22
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C552S262000
Reexamination Certificate
active
06596764
ABSTRACT:
The present invention is concerned with a process for the preparation of 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 anti-arthritic, 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, is is an object of the present invention to provide a process for the preparation of 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 the preparation of diacetylrhein, wherein
a) rhein-9-anthrone-8-glucoside containing aloe-emodin components (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,
b) the rhein-9-anthrone-8-glucoside contained after the partitioning in the aqueous phase is oxidised to rhein-8-glucoside,
c) the glucose residue in the 8-position of the rhein-8-glucoside is split off in an acidic medium and
d) the rhein obtained is acetylated and diacetylrhein recovered.
Important sources of rhein-9-anthrone-8-glucoside are the sennosides contained in senna drug. A preferred embodiment of the present invention is, therefore, a process for the preparation of diacetylrhein which is substantially free of aloe-emodin components wherein
a) a sennoside mixture is subjected to a reduction to the corresponding rhein-9-anthrone-8-glucoside and aloe-emodin-9-anthrone-8-glucoside compounds,
b) a liquid-liquid partitioning of compounds obtained is carried out between a polar organic solvent which is only partly miscible with water and an aqueous phase,
c) the rhein-9-anthrone-8-glucoside compounds contained in the aqueous phase after partitioning are oxidised to the corresponding anthraquinone compound,
d) the glucose residue in the 8-position of the anthraquinone compound is split off in an acid medium and
e) the 1,8-dihydroxyanthraquinone compound obtained is acetylated and the diacetylrhein recovered.
Reduction of the sennosides
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 the of Egyptian senna (
Cassia acutifolia
). The senna drug contains dianthrone glucosides of rhein and aloe-emodin. The most important ones are sennosides A, B, A1, C, D and D1. The sennosides correspond to the general formula:
In the case of sennosides A, B and A1, R stands for COOH and in the case of sennosides C, D and D1, R stands for CH
2
OH. The sennosides A, B and A1 and the sennosides C, D and D1 are stereoisomers and differ from one another by the configuration of 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 the potassium salts. This concentrate can be used as starting material for the process according to the present invention.
The concentrate can also be purified by liquid extraction with alcohols or ketones which are partly soluble in water, for example butan-2-ol or butan-2-one (raffinate). The raffinate is acidified to a pH of about 1.5 to 2.0 and the sennosides are brought to to crystallisation by seeding.
The crude sennoside mixture obtained can also 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 concentrated mixed with an alcohol or ketone which is partly soluble in water, especially butan-2-ol, can be used as starting material.
In the case of the extraction of the senna drug, the ratio of drug to extraction solvent 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 bicarbonte or saccharose.
According to the process of the present invention, these starting materials are subjected to a complete reduction to give the corresponding rhein-9-anthrone-8-glucoside (R═COOH) and the corresponding 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, for example, stannous chloride, sulphur dioxide, alkali metal borohydrides and preferably alkali metal dithionites, especially sodium dithionite.
For carrying out the reduction, the starting material can be present in aqueous solution or suspension and the reducing agent is added thereto in solid form or dissolved in water. It is also possible to work is a two-phase mixture by adding thereto a polar organic solvent which is partly miscible with water, especially butan-2-ol.
The reduction can be carried out at ambient or higher temperature. The reduction is preferably carried out at 40 to 60° C. and especially at 50 to 55° C. Working is carried out at a weakly acidic to weekly alkaline pH value of the starting sennoside solution or suspension, preferably at pH 7 to 9. If desired, the reduction can be 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 9-anthrone-8-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.
It is important that the reduction proceeds to completion. Therefore, it is preferable to use the reducing agent in large excess. In the case of using sodium dithionite, in general there is employed a 1 to 4 fold amount by weight of sodium dithionite, referred to the content of sennosides in the starting material. Furthermore, the reducing agent is allowed to act for at least 2 hours and preferably for at least 3 hours. In general, the reduction takes place for not more than 10 hours. A post-reduction is preferably carried out under the said conditions.
Before use in the next step, the product obtained is preferably reprecipitated by bringing it into solution by the addition of a base, for example sodium hydroxide or potassium hydroxide, up to a pH of about 6 to 7, the aqueous solution is extracted with butan-2-ol, acetone or butan-2-one and the product is again precipitat
Carcasona Alfons
Grimminger Wolf
Hietala Pentti
Witthohn Klaus
Zaeske Helga
Badio Barbara P.
Fulbright & Jaworski L.L.P.
Laboratoire Medidom S.A.
LandOfFree
Method of preparing diacetyl rhein does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of preparing diacetyl rhein, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of preparing diacetyl rhein will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3100202