A PROCESS FOR THE PURIFICATION OF DIACEREIN

Abstract: A process for the preparation of diacerein in which diacerein is purified by crystallization of the crude product with a mixture of solvents consisting of acetic acid and acetic anhydride, or with only acetic anhydride, followed by treatment of the solution with ethylenediaminotetraacetic acid to remove any chromium traces.

Description: A PROCESS FOR THE PURIFICATION OF DIACEREIN The present invention relates to an improved process for the purification of diacerein. The most known process for the preparation of diacerein comprises acetylation of aloin to form acetylaloin (acetylbarbalom) which is subsequently oxidized with chromic acid. The subsequent purification process aims at obtaining a product substantially free from impurities and m particular at removing aloe-emodm, which is known to have mutagenic properties above 70 p. p.m. threshold values, as well as at obtaining a product having a chromium content below 50 p.p.m. A number of methods for the purification of crude diacerein are known. EP-A- 96900687 discloses a process in which diacerein is suspended m a mixture of organic solvents and water, a solution is obtained by addition of a tertiary amine, impurities are filtered off, diacerein is reprecipitated as an alkali/alkalme-earth metal salt, which is then dissolved m water to obtain diacerein m slightly acidic medium. It has, however, been observed that solubilization of diacerein salt m water, prior to acidification with weak acids, induces partial deacetylation with consequent formation of one/two impurities causing a loss of the product titre of about 0.5 to 5%. The loss of titre (i.e. of purity) is statistically 2%. On the other hand, it is known from chemical literature that the protection of hydroxy groups by acetylation is reversible, as hydrolysis occurs even m only slightly acidic or basic medium. In the case of diacerein, this remains stable when passing from neutral to acidic medium, but it undergoes fast deacetylation m even slightly basic medium: m particular, the basicity produced by diacerein sodium salt is sufficient to induce hydrolysis Any subsequent reacetylation attempts with acetic acid, acetic anhydride or acetyl chloride are complex, incomplete and decrease yields. EP 636,602 discloses a multi-step purification process, which is very complex and makes use of toxic solvents . More precisely, crude diacerein is dried and purified first by dissolution m methylene chloride and triethylamme, then by precipitation by addition of acids. The product is separated by centπfugation, dried and crystallized from methylcellosolve, filtered, dried again and recrystallized from N,N-dιmethylacetamιde, filtered again and repeatedly washed with water to remove the solvent, which is otherwise difficult to remove by drying. It has now been found that highly pure diacerein can be obtained by simple crystallization of crude diacerein from an acetic anhydride/acetic acid mixture, or from only acetic anhydride, m the presence of small amounts of ethylenediammotetraacetic acid (EDTA) to remove any chromium traces from the previous chromic oxidation of acetylbarbalom, said crystallization being followed by dissolution m an acetone/triethylamme mixture and reprecipitation with diluted phosphoric acid, to thoroughly remove acetic acid. According to the invention, crude diacerein is dissolved m 60-100 parts (v/w) of a hot acetic anhydride/acetic acid mixture m a ratio (v/v) ranging from 10:90 to 30:70; or m 10-25 volumes of only acetic anhydride. The hot solution is added with 0.05 to 0.2% by weight of EDTA, compared with diacerein, and the EDTA- chromium complex is filtered off while hot. After that, the precipitate is cooled, filtered or centrifuged, washed with acetic acid, then with water, dissolved m 10-20 parts by volume of acetone/triethylamme m a 25:1 to 35:1 ratio and reprecipitated with a 4-8% phosphoric acid aqueous solution. After washing with water and drying, diacerein is obtained m 80-90% yields, having 99.7% minimum purity, containing less than 70 p.p.m. of aloe-emodm and no more than 15 p. p.m. of chromium, as determined by atomic absorption. The process according to the invention is obviously also suitable for the purification of diacerein obtained by other routes, which do not involve chromic oxidation. In this case, the addition of EDTA is of course superfluous. Example 1 1 Kg of crude diacerein (obtained by chromic oxidation of acetylbarbalom, see PCT/EP/03221) is dissolved in 80 litres of a hot acetic acid/acetic anhydride 88.75/11.25 mixture (v/v) , 1 g of ethylenediammotetraacetic acid is added thereto, insolubles (EDTA-chromium complex) are filtered off while hot, the solution is cooled to room temperature, filtered by suction and washed first with acetic acid, then with water. The precipitate is dissolved in 14 litres of acetone/triethylamme 31/1 (v/v) and reprecipitated by acidification with 130 litres of 6% aqueous phosphoric acid. After thoroughly washing with water and drying, 850 g of diacerein with 99.7% purity are obtained, containing < 50 p. p.m. of aloe-emodm and 15 p. p.m. of chromium. Example 2 The procedure of example 1 is followed, replacing the crystallization solvent with 17 litres of acetic anhydride. Furthermore, after eliminating the EDTA-chromium complex, the mixture is concentrated by distillation under reduced pressure to about 1/3 the starting volume, then it is worked up as described in example 1. A product with the same purity characteristics as the one of example 1 is obtained in an 83.6% yield.

Claims: CLAIMS 1. A process for the purification of crude diacerein, characterized in that diacerein is crystallized from a solvent consisting of acetic anhydride/acetic acid or from the only acetic anhydride, the crystallized diacerein is then dissolved in acetone/triethylamine and reprecipitated with a phosphoric acid aqueous solution. 2. A process as claimed in claim 1, characterized in that diacerein is dissolved in 60-100 parts by volume of acetic anhydride/acetic acid mixture. 3. A process as claimed in claim 2, characterized in that the acetic anhydride/acetic acid ratio in the mixture ranges from 10:90 to 30:70. 4. A process as claimed in claim 1, characterized in that diacerein is dissolved in 10-25 parts by volume of the only acetic anhydride. 5. A process as claimed in the above claims, characterized in that, when crude diacerein has been obtained by chromic oxidation of acetylbarbaloin, the hot solution is added with 0.05 to 0.2% by weight (on diacerein weight) of ethylenediaminotetraacetic acid (EDTA) and that the EDTA-chromium complex is removed by filtration from the hot solution.

Inventors: SINISTRI MONICA, SINISTRI ROBERTA, SINISTRI, MONICA, SINISTRI, ROBERTA
Applicants: SINISTRI MONICA, SINISTRI ROBERTA, SYNTECO S P A, SINISTRI, MONICA, SINISTRI, ROBERTA, SYNTECO S.P.A.
Application year: 2000
Main classification: C07C69
IPC codes: C07C67, C07C69