WO1998056750A1 - A process for the preparation of diacerein - Google Patents
A process for the preparation of diacerein Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diacerein
- acid
- crude
- process according
- solution
- Prior art date
Links
- 229960004590 diacerein Drugs 0.000 title claims abstract description 33
- TYNLGDBUJLVSMA-UHFFFAOYSA-N 4,5-diacetyloxy-9,10-dioxo-2-anthracenecarboxylic acid Chemical compound O=C1C2=CC(C(O)=O)=CC(OC(C)=O)=C2C(=O)C2=C1C=CC=C2OC(=O)C TYNLGDBUJLVSMA-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- -1 organic acid alkali salt Chemical class 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- AFHJQYHRLPMKHU-XXWVOBANSA-N Aloin Natural products O=C1c2c(O)cc(CO)cc2[C@H]([C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O2)c2c1c(O)ccc2 AFHJQYHRLPMKHU-XXWVOBANSA-N 0.000 claims description 5
- AFHJQYHRLPMKHU-OSYMLPPYSA-N aloin A Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1[C@@H]1C2=CC(CO)=CC(O)=C2C(=O)C2=C(O)C=CC=C21 AFHJQYHRLPMKHU-OSYMLPPYSA-N 0.000 claims description 5
- CPUHNROBVJNNPW-UHFFFAOYSA-N aloin A Natural products OC1C(O)C(O)C(CO)OC1OC1C2=CC(CO)=CC(O)=C2C(=O)C2=C(O)C=CC=C21 CPUHNROBVJNNPW-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- AFHJQYHRLPMKHU-UHFFFAOYSA-N isobarbaloin Natural products OC1C(O)C(O)C(CO)OC1C1C2=CC(CO)=CC(O)=C2C(=O)C2=C(O)C=CC=C21 AFHJQYHRLPMKHU-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- HHAVHBDPWSUKHZ-UHFFFAOYSA-N propan-2-ol;propan-2-one Chemical compound CC(C)O.CC(C)=O HHAVHBDPWSUKHZ-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 3
- 150000007513 acids Chemical class 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FCDLCPWAQCPTKC-UHFFFAOYSA-N Rhein Chemical compound C1=CC=C2C(=O)C3=CC(C(=O)O)=CC(O)=C3C(=O)C2=C1O FCDLCPWAQCPTKC-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU85356/98A AU8535698A (en) | 1997-06-11 | 1998-05-29 | A process for the preparation of diacerein |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT97MI001375A IT1292132B1 (it) | 1997-06-11 | 1997-06-11 | Procedimento per la preparazione di diacereina |
| ITMI97A001375 | 1997-06-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998056750A1 true WO1998056750A1 (en) | 1998-12-17 |
Family
ID=11377340
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1998/003221 WO1998056750A1 (en) | 1997-06-11 | 1998-05-29 | A process for the preparation of diacerein |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU8535698A (forum.php) |
| IT (1) | IT1292132B1 (forum.php) |
| WO (1) | WO1998056750A1 (forum.php) |
Cited By (7)
| 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 |
| WO2001044144A3 (en) * | 1999-12-17 | 2001-11-15 | Ranbaxy Lab Ltd | Process for the preparation of sodium salts of statins |
| CN101696164A (zh) * | 2009-10-19 | 2010-04-21 | 黄再新 | 一步法用芦荟甙合成双醋瑞因粗品的方法 |
| WO2011030350A1 (en) | 2009-09-08 | 2011-03-17 | Lupin Limited | Eco-friendly method for catalytic aerial oxidation of aloe-emodin to rheinal |
| EP2497761A1 (en) | 2011-02-11 | 2012-09-12 | ICROM S.p.A. | Process for the purification of anthraquinone derivatives |
| WO2011099834A3 (es) * | 2010-02-15 | 2013-01-03 | Interquim, S.A. De C.V. | Procedimiento para la purificación de diacereina cruda vía sal de potasio/dimetil formamida |
| CN115521205A (zh) * | 2022-09-22 | 2022-12-27 | 北京百奥药业有限责任公司 | 双醋瑞因钠盐的晶型及其制备方法 |
Citations (2)
| 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 (fr) * | 1995-02-07 | 1996-08-15 | Steba Beheer B.V. | Procede de purification de la diacetylrheine |
-
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)
| 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 (fr) * | 1995-02-07 | 1996-08-15 | Steba Beheer B.V. | Procede de purification de la diacetylrheine |
Cited By (12)
| 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 |
| JP2002544183A (ja) * | 1999-05-07 | 2002-12-24 | シンテコ エッセ．ピ．ア． | ジアセレインの精製方法 |
| AU772845B2 (en) * | 1999-05-07 | 2004-05-06 | Synteco S.P.A. | A process for the purification of diacerein |
| KR100700687B1 (ko) * | 1999-05-07 | 2007-03-27 | 신테코 에스.피.아. | 디아세레인 정제방법 |
| 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 |
| WO2011030350A1 (en) | 2009-09-08 | 2011-03-17 | Lupin Limited | Eco-friendly method for catalytic aerial oxidation of aloe-emodin to rheinal |
| CN101696164A (zh) * | 2009-10-19 | 2010-04-21 | 黄再新 | 一步法用芦荟甙合成双醋瑞因粗品的方法 |
| WO2011099834A3 (es) * | 2010-02-15 | 2013-01-03 | Interquim, S.A. De C.V. | Procedimiento para la purificación de diacereina cruda vía sal de potasio/dimetil formamida |
| EP2497761A1 (en) | 2011-02-11 | 2012-09-12 | ICROM S.p.A. | Process for the purification of anthraquinone derivatives |
| CN115521205A (zh) * | 2022-09-22 | 2022-12-27 | 北京百奥药业有限责任公司 | 双醋瑞因钠盐的晶型及其制备方法 |
| CN115521205B (zh) * | 2022-09-22 | 2023-11-10 | 北京百奥药业有限责任公司 | 双醋瑞因钠盐的晶型及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1292132B1 (it) | 1999-01-25 |
| AU8535698A (en) | 1998-12-30 |
| ITMI971375A1 (it) | 1998-12-11 |
| ITMI971375A0 (forum.php) | 1997-06-11 |
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