Diacerein or diacetylrein (1,8-diacetoxy-3- carboxyanthraquinone) is a known antiarthritic medicament used for some time in clinical practice.

Different processes for the preparation of diacerein are known: for example, FR-A-2508798 describes the acetylation of rein (1,8-dihydroxyanthraquinone-3- carboxylic acid), with an acetic anhydride excess in the presence of sulfuric acid.

EP-A-636602 discloses a preparation process characterized by purificating the crude diacerein by crystallization from 2-methoxyethanol or N,N- dimethylacetamide. The methods described above, as well as other known ones, suffer anyway from some drawbacks (use of expensive, toxic solvents, difficulty of purification, unsatisfactory yields) which restrict its industrial use.

More precisely, the purification step of crude diacerein is particularly critical.

It has now been found a process for the preparation of diacerein which is advantageous compared with the known methods.

The process of the invention comprises: a) acetylation of aloin, of formula (I):

to give acetyl-barbaloin (II) b) oxidation of acetyl-barbaloin (II) to give crude diacerein; c) salification of the crude diacerein with an organic amine in aqueous or aqueous-acetonic solution, precipitation of the alkali salt by addition of an organic acid alkali salt and treatment with a diluted acid to give acid diacerein, of formula (III)

Step a) is preferably effected using acetic anhydride as acetylating agent.

The reaction is typically carried out using an acetic anhydride excess in the presence of bases such as potassium acetate, at a temperature of about 1300-1400C.

Step b) is preferably carried out using chromic anhydride in acetic acid solution.

Chromic anhydride is used in excess to the stoichiometric, for example in molar ratios ranging from 5:1 to 10:1 compared with the starting aloin. The reaction temperature usually ranges from 40 to 60"C.

The oxidation is preferably carried out without previous recovery of the compound (II).

In step c), organic amines such as triethylamine, trimethylamine and the like can be used. Preferably, triethylamine in acetone solution is used, which is added to an acetone aqueous solution of crude diacerein.

The organic acid alkali salt is preferably 2-sodium ethylhexanoate, added in acetone/isopropanol solution.

The sodium salt is filtered, washed with acetone and dried.

Any organic or inorganic acid, such as hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, phosphoric acid, can be used for the conversion to acid diacerein. Particularly preferred is the use of diluted phosphoric acid, at concentrations ranging from 1 to about 30%.

The following examples illustrate the invention in greater detail.

Example 1 A) A 1000 it reactor is loaded with 25 kg of aloin,

8.8 kg of anhydrous potassium acetate and 125 kg of acetic anhydride. The mixture is heated to 135~C, keeping said temperature for 60 minutes, after that is cooled to about 50"C and added with 250 kg of acetic anhydride. Keeping the temperature at 55"C, a solution of 30 kg of chromic anhydride dissolved in 100 kg of acetic acid is added in about 4 hours.

At the end of the addition, temperature is kept at 55"C for 30 minutes, then 210 kg of water are added. After cooling at 15"C, the reaction mixture is centrifuged and washed to neutrality with water, finally dried at 70"C. The yield in crude diacerein is 15 kg with a K.F. lower than 0.5%.

B) A 600 lt reactor is loaded with 15 kg of crude diacerein and 110 kg of acetone/water 90:10. The suspension is added with a solution of 5.3 kg of triethylamine in 65 kg of acetone to obtain the complete dissolution of the reaction mixture.

Separately, a solution of 9.7 kg of sodium 2-ethyl- hexanoate in 46 kg of an acetone-isopropanol 1:1 mixture is prepared. Diacerein sodium salt precipitates, which is centrifuged and dried at 70"C. The yield is 14.5 kg.

C) A 600 it reactor is loaded with 15 kg of diacerein sodium salt and 300 kg of water to obtain a complete dissolution. Separately, a solution of 28 kg of 85% phosphoric acid and 160 kg of water is prepared, which is added to the reactor containing sodium diacerein in about 4 hours. A fine yellow crystal precipitates which is centrifuged, washed to neutrality with water and dried at 70"C. Yield

in pure diacerein 13 kg.

Example 2 A) A 1000 lt reactor is loaded with 25 kg of aloin, 9 kg of anhydrous potassium acetate and 130 kg of acetic anhydride. The mixture is heated to 138"C keeping said temperature for 60 minutes, after that is cooled to about 50"C and added with 260 kg of acetic anhydride. Temperature is brought to 45"C, then a solution of 31 kg of chromic anhydride dissolved in 105 1 of acetic acid is added in about 5 hours, keeping said temperature. At the end of the addition, temperature is kept for 30 minutes, then 220 kg of water are added. After cooling at 15"C, the reaction mixture is centrifuged, washing the cake with water to neutrality, then dried at 70"C. 15 kg of crude diacerein are obtained, having a 0.5% maximum K.F.

B) A 600 lt reactor is loaded with 15 kg of crude diacerein and 110 kg of acetone/water 90:10. The suspension is added with a solution of 5.2 kg of triethylamine in 60 kg of acetone to obtain the complete dissolution of the reaction mixture.

Separately, a solution of 9.5 kg of sodium-2-ethyl- hexanoate in 45 kg of an acetone-isopropanol 1:1 mixture is prepared. Diacerein sodium salt precipitates, which is centrifuged and dried at 70"C. The yield is 14.3 kg.

C) A 600 lt reactor is loaded with 15 kg of diacerein sodium salt and 300 kg of water then, after dissolution, a solution of 29 kg of 85% phosphoric acid and 170 kg of water is added in about 4 hours.

The resulting yellow product is centrifuged, washed to neutrality with water and dried at 70~C. 12.9 kg of pure diacerein are obtained.