FR2927624A1 - Preparing diacerein useful to treat e.g. psoriasis, comprises oxidizing aloe-emodin to obtain rhein, preparing rhein diacyl derivative, optionally purifying and hydrolyzing rhein diacyl derivative, and acetylating the rhein to diacerein - Google Patents

Abstract

Preparation of diacerein comprises oxidizing aloe-emodin to obtain rhein, preparing rhein diacyl derivative, optionally, purifying and hydrolyzing the rhein diacyl derivative, and acetylating the rhein to diacerein. Independent claims are included for: (1) a process for purifying rhein diacyl derivative comprising dissolving the rhein diacyl derivative in tetrahydrofuran, contacting with toluene and isolating the diacyl rhein; (2) a process for purification of diacerein comprising dissolving the diacerein in N-methyl-pyrrolidone, where the dissolving is carried out at a high temperature, adding alcohol and/or water, cooling the solution at ambient temperature, and isolating the diacerein under solid product form; and (3) a dipropionyl rhein and their salts, as an intermediate product in the synthesis of diacerein. ACTIVITY : Antiarthritic; Antirheumatic; Antipsoriatic. MECHANISM OF ACTION : None given.

Description

NOVEL METHOD FOR SYNTHESIZING A PHARMACEUTICALLY USEFUL ANTHRAQUINONE DERIVATIVE. FIELD OF THE INVENTION The present invention relates to a process for the synthesis of the diacerein pharmaceutical compound. BACKGROUND AND PRIOR ART Diacerein or diacetylrhein is used as a medicament for the treatment of rheumatoid arthritis and osteoarthritis. It is also patented for the treatment of psoriasis and its associated diseases. Diacerein carries the anthraquinone nucleus and is chemically known as 4,5-bis (acetyloxy) -9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, CAS number [13739-02-1] . It can be represented by the formula below. Ac • • Ac

OH Diacerein Anthraquinone Product patent GB 1578452, filed March 1977, discloses diacerein and rhein (compound of formula II). Formula II - Rhein The functions of the rhein are to inhibit NADH-related oxidations, namely mitochondrial oxidations, to facilitate the formation of crosslinks with tropocollagen and to chelate with calcium and copper ions in vivo to form a complex water-soluble. These functions help relieve pain in patients with arthritis or osteoarthritis. In view of these pharmacological properties, rhein has been formulated into a composition for treating these diseases. Later, it was discovered that the intestinal mucosa strongly binds rhein, which affects its bioavailability. In order to increase the plasma concentration of rhein, the phenolic hydroxyl groups have been protected, which converts the compound to its ester derivative. This ester is the prodrug and hydrolyzes in vivo to release rhein. Diacerein is such an ester prodrug. GB 1578452 discloses a process for the synthesis of diacerein, which comprises extracting sennosides A and B from the senna plant, treating it with concentrated hydrochloric acid and then with ferric chloride and glacial acetic acid and finally isolating the rhein. This rhein is then acetylated using acetic anhydride in the presence of concentrated sulfuric acid to obtain diacerein.

There are also various other diacerein synthesis processes starting from chemical compounds and natural substances. Diacerein is usually prepared from suitable reactants by Diels-Alder reaction (Chemistry and Industry, 1988, 4, 124) or organometallic routes (Tetrahedron Letters 2007, 48, 7117). A publication of J. of Org. Chem., 2004, 69, 8982 even describes a synthesis of diacerein by Fries rearrangement. Tetrahedron Letters, 1993, 34, 7447 describes the synthesis of anthraquinone compounds that are rhein-like, by Friedel-Craft acylation.

Synthetic scheme from Tetrahedron Letters, 1993, 34, 7447 OMc ~ ,. Friedel-Craft acylation OMe + OMe ring closure reduction Ô Ô Ô OM e e dém dém éthyl éthyl La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La La US 5,391,775, aloin (isolated from plants belonging to the genus Aloe) - US 5,670,695, WO2006 / 051400 and chrysophanol or chrysophanic acid (isolated from plants belonging to the genus Cassia). All these substances carry the anthraquinone skeleton. Another process for synthesizing diacerein from aloe-emodin triacetate - Journal of Organic Chemistry, 1961, 26 (3), 979. Diacerein OH o OAc OAc OAc O OAc Triacetate of Aloe CrO3 OAc AcOH / (CH3CO) Diacerein which is obtained from these natural substances is often contaminated with structurally related compounds. Aloe-emodin is one of those compounds that is commonly found with rhein and diacerein. It is the reduced form of rhein; it has a hydroxyl group. It has the following formula and can be isolated from plants of the genus Aloe. Aloe-emodin Aloe-emodin poses a particular problem because, apart from having cathartic properties, it is suspected of being mutagenic. It is therefore imperative that diacerein be substantially free of aloe-demodine derivatives which, if consumed with diacerein, could hydrolyze in vivo and form aloe-emodin. A number of methods have been described for purifying diacerein, from the simplest operationally to the most complex. Purification of crude diacerein by crystallization from 2-methoxyethanol or N, N-dimethylacetamide is described in US5670695 and crystallization from acetic anhydride or its mixture with acetic acid is described in WO2001 / 096276. Another purification method that is used is the liquid-liquid partition described in EP520414 and WO2006 / 051400. EP1177164 explains the crystallization of diacerein from acetic anhydride or its mixture with acetic acid, followed by dissolution in acetone / triethylamine and reprecipitation with aqueous phosphoric acid.

OBJECTIVE OF THE INVENTION Accordingly, an object of the present invention is to provide a new process for the preparation of diacerein from a commercially available starting material.

Another objective is to provide a new intermediate product, namely the diacylated derivative of rhein. SUMMARY OF THE INVENTION In one aspect of the present invention, a novel diacerein synthesis process, starting from the natural product Aloe-Emodin, is provided. According to this method, aloe-emodin is oxidized to rhein, which is then converted to its diacylated derivative. This compound is isolated, purified to remove nonpolar impurities, rehydrolysed to rhein and then acetylated to give diacerein. In another aspect, there is provided a novel diacylated rhein derivative. This diacylated rhein intermediate product is purified by precipitation in a solvent and then converted into diacerein.

Purification of diacylated rhein from tetrahydrofuran and toluene is another aspect of the invention. In another aspect, there is provided a method of purifying diacerein using N-methylpyrrolidone. DETAILED DESCRIPTION OF THE INVENTION During the synthesis of diacerein from aloe-emodin by oxidation and subsequent acetylation, the main problem encountered by the inventors arises during its purification. It is observed during the purification of diacerein that there are still some non-polar impurities closely associated with it.

This is due to the very small difference in solubility between diacerein and impurities. These impurities, which are by-products formed during the synthesis of diacerein, are structurally very similar and it is difficult to separate these compounds taking advantage of the difference in polarity between them. By repeating the purification steps, it can be seen that the slight improvement in purity does not justify the loss of yield and profitability of the process on an industrial scale. In addition, the large volumes of solvents used are an additional burden on the environment. Another suitable method for the purification which has been envisaged is the separation by chromatography. Chromatographic separation by appropriate choice of stationary and mobile phases is still possible although it is neither economically viable nor feasible on an industrial scale. To overcome this difficulty related to the purification of diacerein, the present inventors propose to remove the impurities at an intermediate stage. During routine experimentation, it was discovered by chance that diacyl derivatives, different from diacetyls, differ considerably from impurities in solubility. This is why acylated derivatives (different from acetylated ones) have been considered as intermediates, and the solubility profiles of these derivatives have proved to be significantly different from those of undesirable compounds. Thus, one aspect of the present invention is a novel intermediate for the synthesis of diacerein. The technical progress lies in the use of this diacylated rhein derivative to prepare diacerein, which makes it substantially free of non-polar impurities. Therefore, the diacerein synthesis process is as follows. Synthesis scheme oxidation o / O OH Aloes-emodin Rhine o o • N o o diacylated derivative O-acylation The diacylated derivative is purified at this stage to remove the non-polar impurities and then re-hydrolysed to rhein. o diacyl derivative 3] Rhine OH hydrolysis OH Ac7O / H2SO4 or ooo Rhine Diacerein Synthesis of diacerein Thus, to synthesize diacerein, aloe, which is commercially available, is oxidized to rhein using chromic acid . This rhein is then acylated with the anhydride of the chosen organic acid, for example a valeric acid anhydride, to form the corresponding diacyl derivative. The diacylated derivative is separated from the reaction mixture and purified to remove non-polar impurities. After purification, it is subjected to alkaline hydrolysis to obtain rhein. The final step of the synthesis is the acetylation of rhein using acetic anhydride under acidic conditions and follows the procedure of the prior art. Purification The purification of diacylated rhein represents another aspect of the invention. The diacylated intermediate is dissolved in tetrahydrofuran (THF) at about 65 ° C. To this hot solution, toluene is added at the same temperature to reprecipitate the intermediate product. The THF is then removed from the reaction mixture by distillation and the remaining slurry is allowed to cool to room temperature. The pure product is isolated by filtration and transported to the remaining synthesis steps.

The final aspect of the present invention is the purification of diacerein. The diacerein which is obtained at the end of the above process is crude and is subjected to a final purification. It is dissolved in N-methylpyrrolidone (NMP) at about 70 ° C. The filtrate obtained is contacted with methanol at about 60 ° C to precipitate the product. If necessary, repeat this procedure before dissolving the diacerein again in NMP and precipitating it with water. At the end of these purification steps, the diacerein is substantially pure and free of non-polar impurities as well. The impurity profile of the final product is: • monoacetylated rhein - 1: less than 0.15% • monoacetylated rhein - 2: less than 0.15% • Rhine: less than 0.15% • Any unknown impurity: less than 0 The diacerein that is obtained is 99.5% pure, as shown by HPLC analysis. The invention is now described by the following nonlimiting examples. The process of the invention can be illustrated by the use of dipropionyl rhein (of formula III) as a diacylated intermediate product in the synthesis of diacerein. EXAMPLE 1 To the solution of aloe-emodin (200 g) in tetrahydrofuran (2000 ml) was added chromic acid at 0-40 ° C. The reaction is maintained at 25-40 ° C and monitored by HPLC. At the end of the reaction, the THF is distilled completely, the reaction mass is diluted with water (2000 ml) and the solid filtered off. The solid is first washed with water (200 ml) and then with acetone (200 ml). The wet solid (rhein) is dried under vacuum at 60-65 ° C. Dry weight of the product: 160 g Preparation of the chromic acid: 500 g of Na2Cr207 are dissolved in water (1500 ml) and H2SO4 conc. (333 ml) is added to this solution at 0-10 ° C. This solution is used as is. EXAMPLE 2 To the mixture of rhein (160 g) in propionic anhydride (1600 ml) is added dropwise sulfuric acid (48 ml) at 25-40 ° C. After the addition, the reaction is maintained at 25-40 ° C and monitored by HPLC. At the end of the reaction, the reaction mass is quenched in water at 5-10 ° C, the product is isolated by filtration and washed with excess water and then with acetone (160 ml). The dipropionyl rhein is dried under vacuum at 25-30 ° C. Dry weight of the product: 210 g. Physical Data: Melting point: 221 ° C IR (in KBr): 1148 cm -1, 1255 cm -1, 1594 cm -1, 1685 cm -1, 1766 cm -1, 2941 cm -1. 1 H NMR (DMSO-d6): δ 1.23-1.81 (6H), 2.54-2.81 (4H), 7.66-7.7 (1H), 7.9-8.2 ( 3H), 8.5 (1H).

EXAMPLE 3 To the clear solution of dipropionyl rhein (210 g) in THF (1600 ml) at 60-65 ° C was added toluene (1680 ml). The reaction mixture is cooled to 25-30 ° C and the solid filtered off. Its purity is confirmed by HPLC. [The purity of related substances shall not be less than 95%, and any individual impurity shall not be more than 0.15%.] 80 g of NaOH are dissolved in 2 liters of water and wet dipropionyl rhein is added at room temperature. The solution turns to dark red. Hydrolysis is carried out at 60-65 ° C. At the end of the reaction, the reaction mass is cooled to 25-30 ° C and acidified with conc. Hydrochloric acid. (160.5 ml) to pH = 1. The solid is filtered off, washed with water and dried under vacuum at 60-65 ° C. Dry weight of rhein: 111 g. EXAMPLE 4 To the mixture of rhein (111 g) in acetic anhydride (1100 ml) was added sulfuric acid (33.3 ml) dropwise while maintaining the temperature between 25-45 ° C. At the end of the addition, the temperature of the reaction is maintained at 25-40 ° C and is followed by HPLC. At the end of the reaction, the reaction mass is quenched in water at 5-10 ° C. The product is isolated by filtration and washed with excess water. The wet solid is treated with charcoal in N-methyl-2-pyrrolidone (charcoal removed by filtration), and methanol (1100 ml) is added at 60-65 ° C. The reaction mass is cooled to 25-30 ° C and the solid filtered off. The wet solid is again dissolved in NMP (880 ml) at 70-80 ° C and to this clear solution methanol (880 ml) is added at 60-65 ° C. The solution is cooled to 25-30 ° C to precipitate the solid, which is then separated by filtration. This purification is repeated until the monoacetylated impurities are below the desired limit. This wet solid is then dissolved in N-methyl-2-pyrrolidone (640 ml) at 70-80 ° C and the clear solution is slowly added to water (3200 ml) preheated to 80-90 ° C. The suspension obtained is cooled to 25-30 ° C, the solid is filtered off and dried under vacuum at 50-55 ° C. Dry weight of diacerein: 55 g.

Claims (14)

A process for preparing diacerein, comprising: [a] oxidizing aloe-emodin to obtain rhein; [b] the preparation of the diacylated rhein derivative; [c] optionally, purifying the diacylated rhein derivative; [d] hydrolysis of the diacylated rhein derivative; [e] acetylation of rhein to diacerein. 2. Method according to claim 1, wherein the diacerein obtained is then purified. The method of claim 1, wherein the aloe-emodin is oxidized to rhein with hexavalent chromium. The process according to claim 1, wherein the hydrolysis of the diacylated rhein derivative is carried out under alkaline conditions. 5. The process according to claim 1, wherein the acetylation of rhein is carried out using acetic anhydride in the presence of an acid. The process of claim 5 wherein the acid used is sulfuric acid. The process of claim 1, wherein the diacyl derivative is dipropionyl rhein. The process according to claim 1, wherein the diacylated rhein derivative is purified by precipitation in a solvent. The process according to claim 1, wherein the diacylated rhein derivative is purified using tetrahydrofuran. A process for purifying a diacylated rhein derivative comprising [a] dissolving said diacylated rhein derivative in tetrahydrofuran, [b] contacting said rhein with toluene, and [c] the isolation of diacylated rhein. 11. A process for purifying diacerein, comprising: [a] dissolving diacerein in N-methylpyrrolidone and dissolving it at a higher temperature; [b] the addition of an alcohol, water or mixtures thereof; [c] cooling the solution to room temperature; [d] isolation of diacerein as a solid product. The method of claim 11, further comprising [a] dissolving the diacerein in N-methylpyrrolidone at a higher temperature, [b] contacting said solution with water which is at a temperature between 80 ° C and 90 ° C, [c] the cooling of the solution obtained at room temperature, [d] the isolation of the product. The diacerein purification process according to claim 11, comprising: [a] dissolving the diacerein in N-methylpyrrolidone and dissolving it at a higher temperature; [b] the addition of methanol; [c] cooling the solution to room temperature; [d] isolation of diacerein as a solid product. 14. Dipropionylated rhein of formula III, and salts thereof, as an intermediate in the synthesis of diacerein Formula III