FIELD OF THE INVENTION
The present invention is a process for the synthesis of the pharmaceutical compound
Diacerein.
BACKGROUND AND PRIOR ART

The product patent, GB 1578452, filed in March 1977, discloses Diacerein and Rhein
(compound of Formula II).

Diacerein or diacetyl Rhein is used as a medicament for the treatment of Rheumatoid arthritis
and Osteoarthritis. It has also been patented for the treatment of Psoriasis and its associated
diseases. Diacerein bears the anthraquinone nucleus and is chemically known as 4,5-
bis(acetyloxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, CAS number [13739-
02-1]. It can be represented by the below formula.
Rhein performs the functions of inhibiting NADH-linked oxidations, i.e. mitochondrial
oxidations, assisting in the formation of cross-links with tropocollagen and chelating with
calcium and copper ions in vivo to form a water-soluble complex. These functions are
pertinent to the alleviation of pain that afflicts persons suffering from rheumatoid arthritis or
osteoarthritis. In light of this pharmacology Rhein was formulated into a composition for the
treatment of these diseases. Later, it was discovered that the intestinal mucosa strongly binds
Rhein, thus affecting its bioavailability. In order to increase the plasma concentration of Rhein
the phenolic hydroxyl groups were protected, thereby converting the compound into its estei
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derivative. This ester would be the pro-drug and would hydrolyze in vivo to liberate Rhein.
Diacerein is such an ester pro-drug.
GB 1578452 describes a method for the synthesis of Diacerein, which comprises extraction of
Sennosides A and B from the Senna plant, treating it with concentrated hydrochloric acid and
then with ferric chloride and glacial acetic acid and finally isolating Rhein. This Rhein is then
acetylated using acetic anhydride in the presence of concentrated sulphuric acid to obtain
Diacerein.
There are various other processes also for the synthesis of Diacerein starting from chemical
compounds and from naturally occurring substances. Diacerein is usually prepared from
suitable reactants by Diels-Alder reaction {Chemistry and Industry, 1988, 4, 124) or by
organometallic routes {Tetrahedron Letters 2007, 48, 7117). A publication from J. of Org.
Chem., 2004, 69, 8982 even describes a synthesis of Diacerein by Fries rearrangement.
Tetrahedron Letters, 1993, 34, 7447 reports the synthesis of anthraquinone compounds that
are similar to Rhein by Friedel-Craft's acylation.
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Scheme of synthesis from Tetrahedron Letters, 1993,34, 7447


Diacerein is also synthesized from substances of plant origin like Sennosides A, B, C, D
(isolated from the Senna plant) - US 5,391,775, Aloin (isolated from plants belonging to the
genus Aloe) - US 5,670,695, WO2006/051400 and Chrysophanol or Chrysophanic acid
(isolated from plants belonging to the genus Cassia). All these substances bear the
anthraquinone skeleton.

Another process for the synthesis of Diacerein is from Aloe-emodine triacetate - Journal of
Organic Chemistry, 1961, 26 (3), 979.

Diacerein that is obtained from these naturally occurring substances is often found to be
contaminated with structurally related compounds. Aloe-emodine is one such compound that
is frequently found with Rhein and Diacerein. It is the reduced form of Rhein; it has a
hydroxyl group. It has the below formula and can be isolated from plants of the genus Aloe.

Aloe-emodine offers special cause for concern because, apart from having cathartic properties,
it is suspected of being mutagenic. It is thus imperative that Diacerein be substantially free of
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Aloe-emodine derivatives, which, if consumed with Diacerein, could hydrolyze in vivo to
form Aloe-emodine.
There are a number of methods that have been reported for the purification of Diacerein
extending from the operationally simple to the most elaborate. Purification of crude Diacerein
by crystallization from 2-methoxyethanol or N,N-dimethylacetamide is described in
US5670695 and crystallization from acetic anhydride or its mixture with acetic acid is
described in WO2001/096276. Another method for purification that is used is liquid-liquid
partitioning, as described in EP520414 and WO2006/051400. EP1177164 elucidates the
crystallization of Diacerein from acetic anhydride or its mixture with acetic acid, further
dissolution in acetone/triethylamine mixture and re-precipitation with aqueous phosphoric
acid.
OBJECT OF THE INVENTION
Accordingly, an object of the present invention is to provide a novel process for the
preparation of Diacerein from a commercially available starting material.
Another object is to provide a novel intermediate, namely, the diacyl derivative of Rhein.
SUMMARY OF THE INVENTION
In one aspect of the present invention a new method for the synthesis of Diacerein, starting
from the natural product Aloe-emodine, is provided. According to this method, Aloe-emodine
is oxidized to Rhein, which is then converted into its diacyl derivative. This compound is
isolated, purified to remove the non-polar impurities, hydrolyzed back to Rhein and then
acetylated to yield Diacerein.
According to another aspect there is provided a novel diacyl derivative of Rhein. This diacyl
Rhein intermediate is purified by solvent precipitation and then taken forward to Diacerein.
The purification of the diacyl Rhein from tetrahydrofuran and toluene forms another aspect of
the invention.
According to a further aspect there is provided a method for the purification of Diacerein by
using N-methyl pyrrolidone.
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DETAILED DESCRIPTION OF THE INVENTION
During the synthesis of Diacerein from Aloe-emodine by oxidation and subsequent
acetylation, the major problem that was encountered by the inventors was in its purification. It
was observed while purifying Diacerein that certain non-polar impurities always remained
closely associated with it. This was due to the very slight difference in solubility between
Diacerein and the impurities. These impurities, being formed as by-products during Diacerein
synthesis, are expected to be structurally very similar and it was difficult to separate these
compounds by taking advantage of the polarity difference between them. When the
purification steps were reiterated it was found that the marginal improvement in purity did not
justify the loss in yield and economy of the process on an industrial scale. Further, the large
volumes of solvents used would be an additional burden on the environment.
Another suitable method for purification that was considered was separation by
chromatography. Chromatographic separation by appropriate choice of stationary and mobile
phases is still possible although it is neither economical nor feasible on an industrial scale.
To overcome this difficulty related to the purification of Diacerein, the present inventors
proposed to remove the impurities at an intermediary stage. During routine experimentation it
was fortuitously discovered that diacyl derivatives, other than diacetyl, differ considerably
from the impurities in terms of solubility. For this reason acyl derivatives (other than acetyl)
were envisaged as intermediates and the solubility profiles of these derivatives were found to
be significantly different from that of the undesired compounds. Thus, one aspect of the
present invention is a novel intermediate for the synthesis of Diacerein. The technical
advancement in the art resides in the use of this diacyl derivative of Rhein to prepare
Diacerein that renders it substantially free of non-polar impurities. Accordingly the process for
the synthesis of Diacerein is as shown below.
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Synthesis of Diacerein
Thus to synthesize Diacerein, Aloe-emodine, which is commercially available, is oxidized to
Rhein using chromic acid. This Rhein is then acylated with the anhydride of the chosen
organic acid, for example anhydride of valeric acid, to form the corresponding diacyl
derivative. The diacyl derivative is separated from the reaction mixture and purified in order to
remove the non-polar impurities. After purification it is subjected to alkaline hydrolysis to
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obtain Rhein. The final step in the synthesis is the acetylation of Rhein using acetic anhydride
under acidic conditions and is as per the prior art procedure.
Purification
The purification of the diacyl Rhein forms another aspect of the invention. The diacyl
intermediate is dissolved in tetrahydrofuran (THF) at about 65°C. To this hot solution toluene
is added at the same temperature to re-precipitate the intermediate. The THF is then removed
from the reaction mixture by distillation and the slurry left behind is allowed to cool to room
temperature. The pure product is isolated by filtration and carried forward for the remaining
synthetic steps.
The final aspect of the present invention is the purification of Diacerein. Diacerein that is
obtained at the end of the above process is crude and is subjected to a final purification. It is
dissolved in N-methyl pyrrolidone (NMP) at about 70°C. The filtrate obtained is contacted
with methanol at about 60°C to precipitate the product. If required this operation may be
repeated before dissolving Diacerein in NMP again and precipitating it with water. At the end
of these purification steps Diacerein is substantially pure and free of the non-polar impurities
also. The impurity profile of the final product is:
• Monoacetyl Rhein - 1: less than 0.15%
• Monoacetyl Rhein - 2: less than 0.15%
. Rhein: less than 0.15%
• Any unknown impurity: less than 0.1 %
Diacerein that is obtained is 99.5% pure as analyzed by HPLC.
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The invention is now described by the following non-limiting examples. The process of the
invention can be illustrated by the use of dipropionyl Rhein (of Formula III) as the diacyl
intermediate in the synthesis of Diacerein.


Example 1
To the solution of Aloe-emodine (200 gm) in Tetrahydrofuran (2000ml) Chromic acid was
added at 0-40°C. The reaction was maintained at 25-40°C and monitored by HPLC. After the
completion of the reaction THF was distilled off completely, the reaction mass was diluted
with water (2000ml) and the solid was filtered off. The solid was washed first with water
(200ml) and then with acetone (200 ml). The wet solid (Rhein) was dried under vacuum at 60-
65°C.
Dry wt of the product: 160 gm
Preparation of Chromic Acid: 500 gm of Na2Cr207 was dissolved in water (1500ml) and
cone. H2SO4 (333 ml) was added to this solution at 0-10°C. This solution was used as such.
Example 2
To the mixture of Rhein (160 gm) in propionic anhydride (1600 ml) sulphuric acid (48 ml)
was added drop-wise at 25-40°C. After the addition the reaction was maintained at 25-40°C
and monitored by HPLC. After completion the reaction mass was quenched in water at 5-
10°C, the product was isolated by filtration and washed with excess of water and then with
acetone (160 ml). The Dipropionyl Rhein was dried under vacuum at 25-30°C.
Dry wt of product: 210 gm.
Physical Data:
Melting Point: 221°C
IR(inKBr): 1148 cm-1, 1255 cm"1, 1594 cm"1, 1685 cm"1, 1766 cm"1, 2941 cm"1.
lH NMR (DMSO-D6): 8 1.23-1.81 (6H), 2.54-2.81 (4H), 7.66-7.7 (1H), 7.9-8.2 (3H), 8.5
(1H).
Example 3
To the clear solution of dipropionyl Rhein (210 gm) in THF (1600 ml) at 60-65°C, toluene
(1680 ml) was added. The reaction mixture was cooled to 25-30°C and solid was filtered off.
Its purity was confirmed by HPLC. [The related substance purity should be not less than 95%
and any individual impurity should be not more than 0.15%.]
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80g of NaOH was dissolved in 2L of water and wet dipropionyl Rhein was added to it at room
temperature. The solution turned dark red. Hydrolysis was carried out at 60-65°C. At the end
of the reaction, the reaction mass was cooled to 25-30°C and acidified with cone.
Hydrochloric acid (160.5 ml) till pH = 1. The solid was filtered off, washed with water and
dried under vacuum at 60-65°C.
Dry wt Rhein: 111 gm.
Example 4
To the mixture of Rhein (111 gm) in acetic anhydride (1100 ml) sulphuric acid (33.3 ml) was
added drop-wise while maintaining the temperature between 25-45°C. When the addition was
complete the reaction temperature was maintained at 25-40°C and monitored by HPLC. After
completion of the reaction, the reaction mass was quenched in water at 5-10°C. The product
was isolated by filtration and washed with excess of water. The wet solid was subjected to
charcoal treatment in N-methyl-2-Pyrrolidone (charcoal removed by filtration) and methanol
(1100 ml) was added to it at 60-65°C. The reaction mass was cooled to 25-30°C and the solid
was filtered off. The wet solid was again dissolved in NMP (880 ml) at 70-80°C and to this
clear solution methanol was added (880 ml) at 60-65°C. The solution was cooled to 25-30°C
to precipitate the solid, which was then filtered off. This purification was repeated till the
monoacetyl impurities were below the desired limit.
This wet solid was further dissolved in N-methyl-2-Pyrrolidone (640 ml) at 70-80°C and the
clear solution was slowly added over preheated water (3200 ml) at 80-90°C. The slurry
obtained was cooled to 25-30°C, the solid was filtered off and dried under vacuum at 50-55°C.
Dry wt of Diacerein: 55 gm.
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WE CLAIM
1. A process for the preparation of Diacerein comprising:
[a] oxidation of aloe-emodine to obtain Rhein;
[b] preparing the diacyl derivative of Rhein;
[c] optionally purifying the diacyl derivative of Rhein;
[d] hydrolysis of diacyl derivative of Rhein;
[e] acetylation of Rhein to Diacerein.

2. A process of claim 1, wherein the Diacerein obtained is further purified.
3. A process of claim 1, wherein aloe-emodine is oxidized to Rhein with hexavalent
Chromium.
4. A process of claim 1, wherein the hydrolysis of the diacyl derivative of Rhein is
carried out under alkaline conditions.
5. A process of claim 1, wherein acetylation of Rhein is carried out using acetic
anhydride in the presence of an acid.
6. A process according to claim 5, wherein the acid used is sulphuric acid.
7. A process of claim 1, wherein the diacyl derivative is dipropionyl Rhein.
8. A process according to claim 1, wherein the diacyl derivative of Rhein is purified by
solvent precipitation.
9. A process according to claim 1, wherein the diacyl derivative of Rhein is purified
using Tetrahydrofuran.
10. A process for the purification of diacyl derivative of Rhein comprising:

[a] dissolving said diacyl derivative of Rhein in Tetrahydrofuran,
[b] contacting it with toluene and
[c] isolating the diacyl Rhein.
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11. A process for the purification of Diacerein comprising:
[a] dissolving Diacerein in N-methyl pyrrolidone and dissolving it at a higher
temperature;
[b] adding an alcohol, water or mixtures thereof;
[c] cooling the solution to room temperature;
[d] isolating Diacerein as a solid product.
12. A process of claim 11 further comprising
[a] dissolving Diacerein in N-methyl pyrrolidone at a higher temperature,
[b] contacting this solution with water that is at a temperature between 80°C and 90°C,
[c] cooling the resulting solution to room temperature,
[d] isolating the product.
13. A process for the purification of Diacerein according to claim 11, comprising:
[a] dissolving Diacerein in N-methyl pyrrolidone and dissolving it at a higher
temperature;
[b] adding methanol;
[c] cooling the solution to room temperature;
[d] isolating Diacerein as a solid product.
14. The dipropionyl Rhein of Formula III, and salts thereof, as an intermediate in the
synthesis of Diacerein.

Dated this 20th day of February 2008
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A process for the preparation of the pharmaceutical ingredient Diacerein, of Formula I,
by oxidation of aloe-emodine, acylation of resulting Rhein followed by hydrolysis and
final acetylation.