WO2009106908A1 - Processus de préparation de rhéine - Google Patents

Processus de préparation de rhéine Download PDF

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Publication number
WO2009106908A1
WO2009106908A1 PCT/IB2008/000447 IB2008000447W WO2009106908A1 WO 2009106908 A1 WO2009106908 A1 WO 2009106908A1 IB 2008000447 W IB2008000447 W IB 2008000447W WO 2009106908 A1 WO2009106908 A1 WO 2009106908A1
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WO
WIPO (PCT)
Prior art keywords
rhein
emodin
aloe
process according
diacerein
Prior art date
Application number
PCT/IB2008/000447
Other languages
English (en)
Inventor
Guido Di Napoli
Alessandro Di Napoli
Original Assignee
Laboratoire Medidom S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoire Medidom S.A. filed Critical Laboratoire Medidom S.A.
Priority to PCT/IB2008/000447 priority Critical patent/WO2009106908A1/fr
Priority to ARP090100512A priority patent/AR072769A1/es
Publication of WO2009106908A1 publication Critical patent/WO2009106908A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds

Definitions

  • the present invention relates to a process for preparing rhein and diacerein from aloe-emodin.
  • Diacerein, and its active metabolite rhein are known compounds having anti- arthritic, anti-inflammatory, antipyretic and analgesic activity.
  • rhein is the bio-active compound diacerein, the acetylated derivative of rhein, enhances bio-availability and is the preferred form for therapeutic administration.
  • Diacerein is known as being useful in the treatment of diseases associated with an abnormal degeneration of the connective tissue and is most known for use in the treatment of arthritic diseases such as rheumatoid arthritis and osteoarthritis.
  • Diacerein may be prepared by a number of known processes.
  • the most known process for preparing diacerein comprises the acetylation of aloin to obtain acetylbarbaloin, followed by chromic oxidation of the acetyl derivative to obtain diacerein (R. Robinson and G. L. Simonsen, Journal of the Chemical Society, Transactions, 1909, 95,. 1085-1095), for example as described in EP 0 636 602.
  • chromic oxidation occurs only if aloin used as the starting material has a high degree of purity.
  • hexevalent chromium compounds such as chromic anhydride (Cr ⁇ 3) is subject to stringent regulations in view of a very high toxicity and carcinogenicity, as well as the harmful effects on the environment, and it is expected that the use of such chromium compounds will be restricted in the industry in the near future.
  • diacerein obtained by chromic oxidation of acetylbarbaloin must be subjected to specific, often complex, purification processes to obtain a diacerein substantially free from any traces of chromium.
  • Objects of the present invention are obtained by a process for the preparation of rhein or diacerein from aloe-emodin according to claim 1.
  • a process for preparing rhein or diacerein from aloe-emodin comprising oxidizing aloe-emodin with hydrogen peroxide or an alkali metal peroxide in a basic reaction medium, optionally in the presence of an organic solvent, to obtain rhein.
  • a basic reaction medium optionally in the presence of an organic solvent
  • acetylating the rhein thus obtained using an acetylating agent to obtain diacerein.
  • the oxidizing agent used is preferably hydrogen peroxide.
  • the aloe-emodin is advantageously dissolved in an alkali or alkaline-earth metal hydroxide solution as reaction medium, preferably aqueous sodium hydroxide or potassium hydroxide, before addition of the peroxide oxidizing agent.
  • an alkali or alkaline-earth metal hydroxide solution as reaction medium, preferably aqueous sodium hydroxide or potassium hydroxide, before addition of the peroxide oxidizing agent.
  • the oxidation is carried out in the presence of an organic solvent, preferably an ether or an alcohol.
  • the oxidation of aloe-emodin to rhein is carried out at a temperature ranging from 40 0 C to 100 0 C.
  • the aloe-emodin used has a purity of at least 50%.
  • the rhein obtained is acetylated by treatment with an acetylating agent, preferably acetic anhydride, to obtain diacerein.
  • an acetylating agent preferably acetic anhydride
  • rhein and diacerein may be obtained by the process of the present invention by oxidation of aloe-emodin, with good yield and good level of purity, without using any chromium compounds, and without the need for complex purification processes.
  • the process according to the invention is also economical since inexpensive reagent and solvents may be used in the process, and since aloe-emodin with a purity of as low as 70% may be effectively used. Moreover the process is simple and easy to carry out even on an industrial scale.
  • the process of the present invention comprises oxidizing aloe-emodin represented by the following formula (I):
  • aloe-emodin starting material may be used aloe-emodin having a purity of from 50% to 100% pure aloe-emodin.
  • the process of the present invention allows rhein to be obtained with a good yield and a good level of purity even using aloe-emodin of relatively low purity.
  • rhein may be obtained by the oxidation of aloe-emodin according to the process of the present invention with a good yield and at a good level of purity starting from aloe-emodin having a purity as low as 70%.
  • aloe-emodin starting material having an aloe-emodin purity of 70% to 90% may be advantageously used from the point of view of production costs.
  • the starting aloe-emodin may be obtained by any known process.
  • the starting aloe-emodin may be obtained by the oxidation of aloin using iron (III) chloride with a hydrochloric acid catalyst using known processes, such as described in US 5,652,265.
  • the aloe-emodin starting material may be obtained by a process involving oxidation of aloin by treatment with an oxygen-containing gas.
  • aloe-emodin may be prepared by oxidizing aloin dissolved in a polyhydric alcohol by concerted treatment with air or oxygen gas in the presence of an acid, e.g. nitric or sulphuric acid, as described in WO 2006/051400, of the applicant.
  • aloe-emodin may be advantageously obtained by the oxidation of aloin by the treatment of aloin with air or oxygen gas in an acid reaction medium, in the presence of a copper-salt catalyst.
  • the acid reaction medium preferably comprises a mineral acid, for example aq. hydrochloric acid or sulphuric acid.
  • the copper salt may be a copper (I) salt or a copper (II) salt, for instance chloride, sulphate, bromide or nitrate salts, preferably chloride or sulphate salts, particularly copper (I), chloride or copper (II) chloride.
  • the reaction mixture comprising the aloin starting material in acid reaction media is subjected to a gas over-pressure of air or oxygen gas in the presence of the copper salt catalyst.
  • the oxidation of aloin may be carried out by introducing the oxygen-containing gas in a continuous way, for example at a gas flow rate of 5 to 50 L/h into the heated reaction mixture, or be performed in a pressure reactor, for example at a pressure of 1.1 to 5.0 bar.
  • the oxidation is carried out at a temperature in the range from 40 0 C to 125 0 C, preferably at a temperature in the range from 80 0 C to 90 0 C.
  • the reaction time will depend on the reaction conditions and will usually lie in a range from about 3 to 12 hours.
  • the oxidation reaction may be followed by a conventional treatment to isolate the crude aloe-emodin.
  • Recovery of the aloe-emodin may, for example, be carried out by extraction using an organic solvent, such as toluene or dichloromethane.
  • the extraction of crude aloe-emodin product may be followed by purification of the crude aloe-emodin by conventional processes, e.g. by crystallization, to obtain aloe-emodin in pure form.
  • aloe-emodin may be effectively prepared, with a good yield and purity, from aloin having a purity as low as 5%.
  • the aloe-emodin starting material is dissolved in a basic reaction medium.
  • a basic reaction medium any suitable base may be used.
  • a suitable basic reaction medium includes any base with which aloe-emodin forms a stable aqueous solution.
  • Suitable basic reaction medium include alkali metal and alkaline-earth metal hydroxide aqueous solutions. According to a preferred embodiment of the invention, the reaction medium is sodium hydroxide or potassium hydroxide.
  • the hydroxide basic reaction medium is preferably in the form of an aqueous solution of the hydroxide at a concentration of 10% to 70% w/w, preferably aqueous sodium hydroxide or potassium hydroxide aqueous solution having a concentration ranging from 20% to 40% w/w is used, for instance potassium hydroxide or sodium hydroxide solution having a concentration of about 25%.
  • the aloe-emodin is preferably dissolved in 2 to 15 parts (w/w) of hydroxide.
  • the oxidation of aloe- emodin to rhein is carried out in the presence of an organic solvent.
  • Any suitable organic solvent may be envisaged.
  • a suitable organic solvent includes any solvent that is compatible with the basic reaction medium and which is stable with respect to peroxide oxidation in the reaction conditions.
  • the organic solvent may be an ether or a tertiary alcohol.
  • suitable organic solvents include specifically, but not exclusively, 1 ,2-dimethoxyethane, tetrahydrofuran, 1 ,4-dioxane, isopropyl ether, tertiary butyl methyl ether or tertiary alcohols such as tert-butanol.
  • the organic solvent may be used in an amount of 2 to 15 parts (w/w) with respect to aloe-emodin.
  • the aloe-emodin may be first partially dissolved in the organic solvent and then dissolved by addition of the basic reaction medium, or may be dissolved in the basic reaction medium before addition of the organic solvent, or preferably a mixture of the basic reaction and the organic solvent may be first prepared before addition of the aloe-emodin.
  • the inorganic peroxide may be hydrogen peroxide, or may be a metal peroxide, particularly an alkali metal peroxide, or alternatively an alkaline-earth metal peroxide, such as sodium peroxide.
  • hydrogen peroxide is used as the oxidizing agent.
  • the use of hydrogen peroxide as oxidant is advantageous with respect to environmental impact since there are no metallic or other chemical residues formed on its use as oxidant, and it is decomposed to oxygen and water.
  • Hydrogen peroxide is inexpensive and widely commercially available.
  • Aqueous hydrogen peroxide solution having a hydrogen peroxide concentration of 30% to 60%, for example around 50%, may be advantageously used.
  • the peroxide oxidizing agent is used in a molar excess with respect to aloe- emodin.
  • a ratio of 4 parts or more hydrogen peroxide with respect to aloe-emodin is generally required for complete oxidation.
  • the oxidation of aloe- emodin to rhein is carried out at a temperature in the range of 40 0 C to 100 0 C, preferably a temperature between 50 0 C and 70 0 C, for example around 55 ° to 65 0 C.
  • the basic reaction media optionally with the presence of organic solvent, is heated to a temperature in a range between 40 ° and 100 0 C before addition of the aloe-emodin starting product.
  • the aloe-emodin may be dissolved in the basic reaction medium, optionally in the presence of an organic solvent, and the resulting solution then heated to reaction temperature.
  • the concentration of the basic reaction medium solution is advantageously maintained during the peroxide addition process by simultaneous addition of additional base.
  • the reaction time of the oxidation will depend on the reaction conditions and the peroxide employed. Determination of the reaction time and the degree of conversion of aloe-emodin to rhein may be performed by conventional techniques of analysis, for example HPLC. Oxidation of aloe-emodin with hydrogen peroxide may generally be carried out over 1 to 10 hours, for instance 2 to 5 hours.
  • the oxidation reaction will usually be followed by a conventional treatment of the reaction mixture to isolate the thus produced rhein. This may comprise for example addition of an acid, for example hydrochloric acid, acetic acid or phosphoric acid, to precipitate rhein, followed by filtering and washing the crude rhein with water and drying.
  • the purity of the crude rhein obtained by the chromium-free oxidation of aloe- emodin of the present invention is dependent on the purity of the starting aloe- emodin.
  • rhein may be obtained with a purity of greater than 80% starting from aloe- emodin having a purity as low as 70%.
  • rhein obtained by the chromium-free oxidation process according to the present invention from aloe- emodin having a purity of 80% or more, has a purity of around 90% to 95%.
  • the crude rhein thus obtained may be advantageously converted into diacerein by acetylation with an acetylating agent, without the need for any purification of the crude rhein.
  • crude rhein obtained from the above-oxidation process may be optionally purified using conventional purification processes known to the persons in the art, such as crystallization or liquid-liquid partioning processes.
  • rhein may be purified by crystallization from a solvent selected from N.N-dimethylacetamide, N,N-dimethylformamide, or 1- methyl-2-pyrrolidone and at a yield of higher than 75%.
  • Rhein obtained according to the above-oxidation process may be acetylated according to an optional acetylation step to obtain diacerein, represented by the following formula (IV):
  • the acetylation of rhein may be carried out by treatment of rhein with an acetylating agent which can be chosen from those known to the persons skilled in the art.
  • the acetylating agent is acetic anhydride.
  • the acetylation may be carried out in various organic solvents, provided that they are inert, or in any case compatible with the reaction conditions, such as glacial acetic acid.
  • acetic anhydride is used as the reaction solvent.
  • Acetylation of rhein with acetic anhydride is preferably carried out in the presence of an acid as a catalyst.
  • the acid catalyst may be for example acetic acid, methanesulphonic acid, trifluoro methyl sulphonic acid, sulphuric acid.
  • concentrated sulphuric acid is used as catalyst.
  • Acetylation of rhein with acetic anhydride is preferably carried out at a temperature ranging from 20 0 C to 50 0 C for 3 to 6 hours.
  • the acetylation reaction will usually be followed by a conventional treatment of the reaction mixture to isolate diacerein. This may comprise for example, pouring the reaction mixture into water at 2 0 C to 5 0 C, filtering diacerein, washing diacerein with water and drying diacerein. If needed, the crude diacerein may be further purified by re-crystallization in a solvent such as ethanol, acetone, isopropanol or any other appropriate solvent.
  • rhein and diacerein may be prepared from aloe-emodin without the need for chromium compounds, or other toxic or harmful substances, and without the need for any complex purification processes to remove residual oxidant. According to the process described herein, rhein may be obtained, at a good yield and a good level of purity, starting from aloe-emodin having a purity as low as 70%.
  • rhein produced according to the process of the present invention may be converted to diacerein, by acetylation with an acetylating agent, without requiring any purification of the crude rhein.
  • the process according to the invention is also economical since aloe-emodin of relatively low purity may be used as starting product, and since inexpensive reagent and solvents may be used in the process. Moreover the process is simple and easily applied on an industrial scale.
  • KOH (9.6 ml) and H202 (12 ml) were added simultaneously over 30 minutes, maintaining the temperature between 63 0 C - 65 0 C.
  • a second portion of aloe-emodin (82%, 10g) was added.
  • KOH (9.6 ml) and H202 (12 ml) were added simultaneously over 30 minutes maintaining the temperature between 63 0 C - 65 0 C.
  • aloe-emodin 82%, 1Og was added.
  • Hydrochloric acid 37% (210 ml) was added over 1.5 hours until pH 3.5 - 3.0, maintaining the temperature between 55 0 C - 60 0 C, whereby and a yellow / orange solid was formed.
  • the suspension was cooled to 35 0 C - 40 0 C, and then filtered and washed with water (20Og).
  • Potassium hydroxide 50 % (317g) and hydrogen peroxide 50% (317g, 264 ml) were added simultaneously over 4 hours maintaining the temperature between 63 0 C - 65 0 C.
  • the reaction was followed by HPLC.
  • hydrochloric acid 37% (380 ml) was added over 1.5 - 2 hours until pH 2.0, maintaining the temperature between 55 0 C - 60 0 C, whereby a yellow / orange solid was formed.
  • the suspension was cooled to 35 0 C - 40 0 C, and then filtered and washed with water (28Og).
  • Rhein obtained according to Example 2 was purified by crystallization using N,N-dimethylacetamide (DMA) (8 parts). Crude rhein was dissolved at 80 0 C - 100 0 C and then cooled at 15 0 C - 20 0 C. The product was refluxed in acetone (5 - 10 parts) to minimize the DMA content. The purified rhein had a purity of 98-100%, and the overall yield was higher than 75%.
  • DMA N,N-dimethylacetamide

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un processus de préparation de rhéine ou de diacéréine qui consiste à oxyder de l'émodine d'aloès avec du peroxyde d'hydrogène ou un oxydant peroxyde de métal alcalin dans un milieu de réaction basique, éventuellement en présence d'un solvant organique afin d'obtenir de la rhéine. Ce processus est éventuellement suivi par l'acétylation de la rhéine ainsi obtenue au moyen d'un agent acétylant pour obtenir de la diacéréine.
PCT/IB2008/000447 2008-02-29 2008-02-29 Processus de préparation de rhéine WO2009106908A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IB2008/000447 WO2009106908A1 (fr) 2008-02-29 2008-02-29 Processus de préparation de rhéine
ARP090100512A AR072769A1 (es) 2008-02-29 2009-02-13 Procesopara preparar reina

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102875369A (zh) * 2011-07-15 2013-01-16 台州海辰药业有限公司 大黄酸的新合成方法
CN106966891A (zh) * 2017-02-07 2017-07-21 刘瀚文 一种大黄酸的全合成工艺

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0636602A1 (fr) 1993-07-30 1995-02-01 Laboratoire Medidom S.A. Procédé de préparation de la diacérein
US5652265A (en) 1995-03-29 1997-07-29 Wisconsin Alumni Research Foundation Production of rhein and rhein derivatives
EP0928781A1 (fr) 1997-12-30 1999-07-14 Laboratoire Medidom S.A. Procédé de préparation de rhéine et de ses dérivés diacylés
WO2006051400A1 (fr) 2004-11-12 2006-05-18 Laboratoire Medidom S.A. Procede pour l'elaboration d'aloe-emodine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0636602A1 (fr) 1993-07-30 1995-02-01 Laboratoire Medidom S.A. Procédé de préparation de la diacérein
US5652265A (en) 1995-03-29 1997-07-29 Wisconsin Alumni Research Foundation Production of rhein and rhein derivatives
EP0928781A1 (fr) 1997-12-30 1999-07-14 Laboratoire Medidom S.A. Procédé de préparation de rhéine et de ses dérivés diacylés
WO2006051400A1 (fr) 2004-11-12 2006-05-18 Laboratoire Medidom S.A. Procede pour l'elaboration d'aloe-emodine
EP1666446A1 (fr) * 2004-11-12 2006-06-07 Laboratoire Medidom S.A. Procédé pour préparation du rhéine et diacerhéine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Pharmazeutische Wirkstoffe, Synthesen, Patente and Anwedungen", 1982, GEORGE THIEME VERLAG
BARAK G ET AL: "Selective Oxidation of Alcohols by a H202-RuCl3 System under Phase-Transfer Conditions", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 53, no. 15, 1 January 1988 (1988-01-01), pages 3553 - 3555, XP002498721, ISSN: 0022-3263 *
LEI ET AL: "Oxidation of alcohols using H2O2 as oxidant catalyzed by AlCl3", CATALYSIS COMMUNICATIONS, ELSEVIER SCIENCE, AMSTERDAM, NL, vol. 9, no. 5, 4 February 2008 (2008-02-04), pages 740 - 742, XP022453432, ISSN: 1566-7367 *
R. LONGO: "Sostanze Farmaceutiche", ITALIAN TRANSLATION AND REVIEW, 1998, pages 596
R. ROBINSON; G. L. SIMONSEN, JOURNAL OF THE CHEMICAL SOCIETY, TRANSACTIONS, vol. 95, 1909, pages 1085 - 1095

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102875369A (zh) * 2011-07-15 2013-01-16 台州海辰药业有限公司 大黄酸的新合成方法
CN106966891A (zh) * 2017-02-07 2017-07-21 刘瀚文 一种大黄酸的全合成工艺

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Publication number Publication date
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