Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings

Definitions

• the present invention relates to a process for the preparation of diacerein.
• Diacerein or diacetylrein (1 ,8-diacetoxy-3- carboxyanthraquinone) is a known antiarthritic medicament used for some time in clinical practice.
• 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.
• the purification step of crude diacerein is particularly critical.
• the process of the invention comprises: a) acetylation of aloin, of formula (I): to give acetyl-barbaloin (II)
• 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 130°-140 ⁇ C.
• 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).
• step c) organic amines such as triethylamine, trimethylamine and the like can be used.
• 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%.
• Example 1 illustrates the invention in greater detail.
• 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%.
• a 1000 It 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.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Cited By (7)

Citations (2)

• 1997
  • 1997-06-11 IT IT97MI001375A patent/IT1292132B1/it active IP Right Grant
• 1998
  • 1998-05-29 WO PCT/EP1998/003221 patent/WO1998056750A1/en active Search and Examination
  • 1998-05-29 AU AU85356/98A patent/AU8535698A/en not_active Abandoned

Patent Citations (2)

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