WO2009106908A1

WO2009106908A1 - Process for preparing rhein

Info

Publication number: WO2009106908A1
Application number: PCT/IB2008/000447
Authority: WO
Inventors: Guido Di Napoli; Alessandro Di Napoli
Original assignee: Laboratoire Medidom S.A.
Priority date: 2008-02-29
Filing date: 2008-02-29
Publication date: 2009-09-03
Also published as: AR072769A1

Abstract

Process for the preparation of rhein or diacerein comprising oxidising aloe-emodin with hydrogen peroxide or an alkali-metal peroxide oxidant in a basic reaction medium, optionally in the presence of an organic solvent, to obtain rhein. Optionally followed by acetylating the rhein thus obtained using an acetylating agent to obtain diacerein.

Description

PROCESS FOR PREPARING RHEIN

Background of the invention

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. Although 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.

In such a process, the chromic oxidation occurs only if aloin used as the starting material has a high degree of purity. Further, use of hexevalent chromium compounds, such as chromic anhydride (Crθ3) 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.

Still further, to reach a purity acceptable for pharmaceutical application, 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.

As an alternative to preparing diacerein from aloin by the acetylation of aloin to obtain acetylbarbaloin, there have been proposed in the literature processes for the preparation of diacerein starting from aloe-emodin. For example, there has been described the preparation of diacerein by the oxidation of aloe-emodin with hexevalent chromium. ("Sostanze Farmaceutiche", Italian translation and review by R. Longo, OEMF, Milan, 1998, P. 596, of "Pharmazeutische Wirkstoffe, Synthesen, Patente and Anwedungen", George Thieme Verlag,

Stuttgart-New York, 1982-1987).

An alternative process for preparing diacerein from aloe-emodin is disclosed in EP 0 928 781 , whereby aloe-emodin is oxidized to rhein with a salt of nitrous acid in an acid reaction medium. The rhein so-obtained is then acetylated with an acetic anhydride to give diacerein.

Summary of the invention

There is an ongoing need for processes for preparing rhein and diacerein from aloin which do not comprise chromic oxidation, and/or require the use of other toxic or harmful substances, and which provide rhein with a good yield and level of purity.

It is an object of the invention to provide a process for preparing rhein which does not require the use of chromium compounds or other toxic or harmful substances.

It would be advantageous to provide a process for the preparation of rhein from aloe-emodin which provides rhein with a good yield and level of purity, and which does not require complex purification processes. It would be advantageous to provide a process for the preparation of rhein and diacerein which is simple, economic and which can be easily scaled up to industrial level.

Objects of the present invention are obtained by a process for the preparation of rhein or diacerein from aloe-emodin according to claim 1.

According to the present invention, there is provided 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. Optionally followed by 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.

In a preferred embodiment of the present invention, the oxidation is carried out in the presence of an organic solvent, preferably an ether or an alcohol.

Preferably, the oxidation of aloe-emodin to rhein is carried out at a temperature ranging from 40 ⁰C to 100 ⁰C.

In one preferred embodiment of the present invention, the aloe-emodin used has a purity of at least 50%.

In a preferred embodiment of the present invention, the rhein obtained is acetylated by treatment with an acetylating agent, preferably acetic anhydride, to obtain diacerein. Advantageously, 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.

Other objects and advantageous features of the present invention will be apparent from the claims and the following detailed description and example.

Detailed description of the invention

The process of the present invention comprises oxidizing aloe-emodin represented by the following formula (I):

to obtain rhein represented by the following formula (II):

(H) The aloe-emodin is oxidized to rhein with an inorganic peroxide in a basic reaction medium.

As the aloe-emodin starting material, may be used aloe-emodin having a purity of from 50% to 100% pure aloe-emodin. Advantageously, 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. Particularly, 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%. For example 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. For instance, 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.

Advantageously, the aloe-emodin starting material may be obtained by a process involving oxidation of aloin by treatment with an oxygen-containing gas. Particularly, 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.

Alternatively 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.

In this process 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. Preferably 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 40⁰C to 125 ⁰C, preferably at a temperature in the range from 80⁰C to 90 ⁰C. 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. If desired 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.

According to the described process aloe-emodin may be effectively prepared, with a good yield and purity, from aloin having a purity as low as 5%.

In the process of the present invention, the aloe-emodin starting material is dissolved in a basic reaction medium. As the 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.

In a preferred embodiment of the present invention, 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. Advantageously, the organic solvent may be an ether or a tertiary alcohol. Examples of 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.

Preferably, the organic solvent may be used in an amount of 2 to 15 parts (w/w) with respect to aloe-emodin.

Where a mixture of basic reaction medium and organic solvent is used, 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. Preferably 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. For example, where hydrogen peroxide is used as oxidant, a ratio of 4 parts or more hydrogen peroxide with respect to aloe-emodin is generally required for complete oxidation.

According to a preferred embodiment of the process, the oxidation of aloe- emodin to rhein is carried out at a temperature in the range of 40 ⁰C to 100 ⁰C, preferably a temperature between 50 ⁰C and 70 ⁰C, for example around 55 ° to 65 ⁰C.

According to a preferred embodiment of the invention, the basic reaction media optionally with the presence of organic solvent, is heated to a temperature in a range between 40 ° and 100 ⁰C before addition of the aloe-emodin starting product. Alternatively 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. Advantageously, according to the process of the present invention, rhein may be obtained with a purity of greater than 80% starting from aloe- emodin having a purity as low as 70%. For instance, 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.

If desired, 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. According to one embodiment, 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. In a preferred embodiment, 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. In a preferred embodiment 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. In a preferred embodiment, concentrated sulphuric acid is used as catalyst.

Acetylation of rhein with acetic anhydride is preferably carried out at a temperature ranging from 20 ⁰C to 50 ⁰C 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 ⁰C to 5 ⁰C, 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. According to the present invention 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%.

Advantageously, 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.

Examples

Example 1 :

Into a round bottom flask equipped with a mechanical stirrer and two addition funnels, 100g of KOH 25% (w/w) and 198g of DME (dimethoxyethane) were poured. The mixture was heated to 60 ⁰C. Reagents were added into the two addition funnels, 43.2g (36 ml) of hydrogen peroxide 50% was added into one funnel, and 43.2g (28.8 ml) of potassium hydroxide 50% was added into the second funnel. The first portion of aloe-emodin (82%, 10g) (Laboratoire Medidom, Switzerland) was added, whereby a deep red solution was formed. KOH (9.6 ml) and H202 (12 ml) were added simultaneously over 30 minutes, maintaining the temperature between 63⁰C - 65 ⁰C. 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 ⁰C - 65 ⁰C.

A third portion of aloe-emodin (82%, 1Og) was added. KOH (9.6 ml) and H202 (12 ml) were added simultaneously over 30 minutes maintaining the temperature between 63 - 65 ⁰C.

Additional amounts of reagents were added until the reaction was completed; KOH (115.2 ml) and H202 (144 ml) were added simultaneously over 3 hours maintaining the temperature between 63 ⁰C - 65 ⁰C. The reaction was followed by HPLC.

Hydrochloric acid 37% (210 ml) was added over 1.5 hours until pH 3.5 - 3.0, maintaining the temperature between 55 ⁰C - 60 ⁰C, whereby and a yellow / orange solid was formed. The suspension was cooled to 35 ⁰C - 40 ⁰C, and then filtered and washed with water (20Og).

21.5g of crude rhein was obtained as an orange solid after drying at 70 ⁰C. The crude rhein had a purity of 92 % and was obtained with a 78% yield.

Example 2:

Into a round bottom flask equipped with a mechanical stirrer and two addition funnels were poured, 40Og of KOH 25% (w/w) and 264g of DME (dimethoxyethane). The mixture was heated to 60 ° C. 4Og aloe-emodin (87%) (Laboratoire Medidom, Switzerland) was added, whereby a deep red solution was formed.

Potassium hydroxide 50 % (317g) and hydrogen peroxide 50% (317g, 264 ml) were added simultaneously over 4 hours maintaining the temperature between 63 ⁰C - 65 ⁰C. The reaction was followed by HPLC. When the reaction was complete, hydrochloric acid 37% (380 ml) was added over 1.5 - 2 hours until pH 2.0, maintaining the temperature between 55 ⁰C - 60 ⁰C, whereby a yellow / orange solid was formed. The suspension was cooled to 35 ⁰C - 40 ⁰C, and then filtered and washed with water (28Og).

33 g of crude rhein was obtained as an orange solid after drying at 70 ⁰C, with a purity of 92%, yield 83%. The rhein thus obtained had aloe-emodin content <0.25% determined by HPLC.

Example 3: Purification of rhein

Rhein obtained according to Example 2 was purified by crystallization using N,N-dimethylacetamide (DMA) (8 parts). Crude rhein was dissolved at 80 ⁰C - 100 ⁰C and then cooled at 15 ⁰C - 20 ⁰C. 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%.

Claims

1. A process for the preparation of rhein or diacerein comprising oxidising aloe-emodin with hydrogen peroxide or an alkali-metal peroxide oxidant in a basic reaction medium, optionally in the presence of an organic solvent, to obtain rhein, optionally followed by acetylating the rhein thus obtained using an acetylating agent to obtain diacerein.

2. A process according to claim 1 wherein the oxidant is hydrogen peroxide.

3. A process according to claim 1 or 2 wherein the aloe-emodin is dissolved in an aqueous alkali metal or alkaline-earth metal hydroxide as the basic reaction medium.

4. A process according to claim 3 wherein the alkali-metal or alkaline-earth metal hydroxide aqueous solution has a concentration in the range from 10% to 60% (w/w).

5. A process according to claim 3 or 4 wherein the basic reaction medium is selected from sodium hydroxide or potassium hydroxide.

6. A process according to any one of claims 1 to 5 wherein the oxidation is carried out in the presence of an organic solvent.

7. A process according to claim 6 wherein the organic solvent is one or more organic solvents selected from the group consisting of 1 ,2- dimethoxyethane, tetrahydrofuran, 1 ,4-dioxane, isopropyl ether, tertiary butyl methyl ether or tert-butanol.

8. A process according to claims 2 to 7 wherein hydrogen peroxide is used in an amount of at least 4 parts w/w with respect to aloe-emodin.

9. A process according to any one of claims 1 to 8 wherein the oxidation is performed at a temperature in the range of from 40 ⁰C to 100 ⁰C.

10. A process according to any one of claims 1 to 9 wherein the aloe-emodin is prepared by oxidation of aloin by treatment with an oxygen-containing gas, optionally in the presence of a copper salt.

11. A process according to any one of claims 1 to 10 wherein the aloe-emodin has a purity of from 50% to 90%.

12. A process according to any one of claims 1 to 11 comprising a step of purifying rhein by crystallization from a solvent selected from N₁N- dimethylacetamide, N,N-dimethylformamide or 1-methyl-2-pyrrolidone.

13. A process according to any one of claims 1 to 12 comprising a step of acetylating the rhein using an acetylating agent to obtain diacerein.

14. A process according to claim 13 wherein the acetylating agent is acetic anhydride.