WO1998056750A1 - A process for the preparation of diacerein - Google Patents

A process for the preparation of diacerein Download PDF

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Publication number
WO1998056750A1
WO1998056750A1 PCT/EP1998/003221 EP9803221W WO9856750A1 WO 1998056750 A1 WO1998056750 A1 WO 1998056750A1 EP 9803221 W EP9803221 W EP 9803221W WO 9856750 A1 WO9856750 A1 WO 9856750A1
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WIPO (PCT)
Prior art keywords
diacerein
acid
crude
process according
solution
Prior art date
Application number
PCT/EP1998/003221
Other languages
German (de)
French (fr)
Inventor
Monica Sinistri
Roberta Sinistri
Original Assignee
Synteco S.R.L.
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Filing date
Publication date
Application filed by Synteco S.R.L. filed Critical Synteco S.R.L.
Priority to AU85356/98A priority Critical patent/AU8535698A/en
Publication of WO1998056750A1 publication Critical patent/WO1998056750A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00Systems 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.

Abstract

A process for the preparation of diacerein characterized by purification of crude diacerein by salificating it with an organic acid alkali salt and subsequent conversion to the acid form with diluted acids.

Description

A PROCESS FOR THE PREPARATION OF DIACEREIN
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.
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):
Figure imgf000004_0001
to give acetyl-barbaloin (II)
Figure imgf000004_0002
b) oxidation of acetyl-barbaloin (II) to give crude diacerein; c) salification of the crude diacerein with an organic a ine 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)
Figure imgf000004_0003
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°-140βC.
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 50βC and added with 250 kg of acetic anhydride. Keeping the temperature at 55βC, 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 It 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 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 138βC 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 It 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 It 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.

Claims

1. A process for the preparation of diacerein, which comprises : a) acetylation of aloin, of formula (I):
Figure imgf000009_0001
to give acetyl-barbaloin (II)
Figure imgf000009_0002
b) oxidation of acetyl-barbaloin (II) to give crude diacerein; c) salification of the crude diacerein with an organic a ine 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)
Figure imgf000010_0001
2. A process as claimed in claim 1, wherein acetylation is carried out using an acetic anhydride excess in the presence of potassium acetate.
3. A process as claimed in claim 1 or 2 , wherein step b) is effected using chromic anhydride in acetic acid solution.
4. A process according to any one of the above claims, wherein the crude diacerein is salified with triethylamine.
5. A process according to any one of the above claims, wherein 2-sodium ethylhexanoate is used as organic acid alkali salt.
6. A process according to any one of the above claims, wherein the precipitation of the salt takes place in a isopropanol-acetone 1:1 mixture.
7. A process according to any one of the above claims, wherein sodium diacerein is converted to acid diacerein by treatment with diluted aqueous phosphoric acid.
PCT/EP1998/003221 1997-06-11 1998-05-29 A process for the preparation of diacerein WO1998056750A1 (en)

Priority Applications (1)

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Applications Claiming Priority (2)

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ITMI97A001375 1997-06-11
IT97MI001375A IT1292132B1 (en) 1997-06-11 1997-06-11 PROCEDURE FOR THE PREPARATION OF DIACEREIN

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000068179A1 (en) * 1999-05-07 2000-11-16 Synteco S.P.A. A process for the purification of diacerein
WO2001044144A2 (en) * 1999-12-17 2001-06-21 Ranbaxy Laboratories Limited Process for the preparation of sodium salts of statins
CN101696164A (en) * 2009-10-19 2010-04-21 黄再新 Method for synthesizing diacerein crude product by using barbaloin by one-step method
WO2011030350A1 (en) 2009-09-08 2011-03-17 Lupin Limited Eco-friendly method for catalytic aerial oxidation of aloe-emodin to rheinal
WO2011099834A2 (en) * 2010-02-15 2011-08-18 Interquim, S.A. De C.V. Procedure for the purification of crude diacerein via potassium salt/dimethylformamide
EP2497761A1 (en) 2011-02-11 2012-09-12 ICROM S.p.A. Process for the purification of anthraquinone derivatives
CN115521205A (en) * 2022-09-22 2022-12-27 北京百奥药业有限责任公司 Crystal form of diacerein sodium salt and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0636602A1 (en) * 1993-07-30 1995-02-01 Laboratoire Medidom S.A. A process for the preparation of diacerein
WO1996024572A1 (en) * 1995-02-07 1996-08-15 Steba Beheer B.V. Method for purifying diacetyl rhein

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0636602A1 (en) * 1993-07-30 1995-02-01 Laboratoire Medidom S.A. A process for the preparation of diacerein
WO1996024572A1 (en) * 1995-02-07 1996-08-15 Steba Beheer B.V. Method for purifying diacetyl rhein

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100700687B1 (en) * 1999-05-07 2007-03-27 신테코 에스.피.아. A process for the purification of diacerein
WO2000068179A1 (en) * 1999-05-07 2000-11-16 Synteco S.P.A. A process for the purification of diacerein
AU772845B2 (en) * 1999-05-07 2004-05-06 Synteco S.P.A. A process for the purification of diacerein
JP2002544183A (en) * 1999-05-07 2002-12-24 シンテコ エッセ.ピ.ア. Purification method of diacerein
WO2001044144A3 (en) * 1999-12-17 2001-11-15 Ranbaxy Lab Ltd Process for the preparation of sodium salts of statins
US6756507B2 (en) 1999-12-17 2004-06-29 Ranbaxy Laboratories Limited Process for the preparation of sodium salts of statins
WO2001044144A2 (en) * 1999-12-17 2001-06-21 Ranbaxy Laboratories Limited Process for the preparation of sodium salts of statins
WO2011030350A1 (en) 2009-09-08 2011-03-17 Lupin Limited Eco-friendly method for catalytic aerial oxidation of aloe-emodin to rheinal
CN101696164A (en) * 2009-10-19 2010-04-21 黄再新 Method for synthesizing diacerein crude product by using barbaloin by one-step method
WO2011099834A2 (en) * 2010-02-15 2011-08-18 Interquim, S.A. De C.V. Procedure for the purification of crude diacerein via potassium salt/dimethylformamide
WO2011099834A3 (en) * 2010-02-15 2013-01-03 Interquim, S.A. De C.V. Procedure for the purification of crude diacerein via potassium salt/dimethylformamide
EP2497761A1 (en) 2011-02-11 2012-09-12 ICROM S.p.A. Process for the purification of anthraquinone derivatives
CN115521205A (en) * 2022-09-22 2022-12-27 北京百奥药业有限责任公司 Crystal form of diacerein sodium salt and preparation method thereof
CN115521205B (en) * 2022-09-22 2023-11-10 北京百奥药业有限责任公司 Crystal form of diacerein sodium salt and preparation method thereof

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ITMI971375A1 (en) 1998-12-11
ITMI971375A0 (en) 1997-06-11
IT1292132B1 (en) 1999-01-25
AU8535698A (en) 1998-12-30

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