WO2013038424A2

WO2013038424A2 - Process for purifying diacerein

Info

Publication number: WO2013038424A2
Application number: PCT/IN2012/000464
Authority: WO
Inventors: Milind Gharpure; Dnyandev Rane; Manish Chandrakant SHUKLA; Pramod Vitthal PATIL; Girish Tilakchand PATLE; Sachin Mahadeo LAD; Deepak B. BAVISKAR
Original assignee: Glenmark Generics Ltd
Current assignee: Glenmark Generics Ltd
Priority date: 2011-07-13
Filing date: 2012-06-29
Publication date: 2013-03-21
Anticipated expiration: 2014-01-13
Also published as: WO2013038424A3

Abstract

The present invention provides a process for purification of diacerein, compound of Formula I, the process comprising a. reacting diacerein, compound of Formula I with a silylating agent to form a compound of Formula II, silylated diacerein wherein R is alkyl; and [Formula (I)] [Formula (II)] b. deprotecting compound of Formula II, silylated diacerein in presence of a polar solvent.

Description

PROCESS FOR PURIFYING DIACEREIN

PRIORITY

[0001] This application claims the benefit of IN2013/MUM/201 1 , filed on July 13, 201 1, the content of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a new purification method for diacerein. BACKGROUND OF THE INVENTION

[0003] Diacerein, a diacetyl derivative of rhein, is used in the treatment of osteoarthritis. Chemically, diacerein is known as 4,5-bis(aeetyloxy)-9,10-dihydro- 9,10-dioxo-2-anthracenecarboxylic acid and is represented by Formula I.

Formula I

[0004] Diacerein is commercially available as ARTODAR^® in the form of pharmaceutical preparations. United States Patent No. 5652265 discloses process for preparation of diacerein by acetylating aloe emodin, compound of Formula III followed by oxidation with chromium trioxide.

Formula III

[0005] Diacerein obtained by acetylating aloe emodin followed by oxidation with chromium trioxide disadvantageously leads to impurities, which may include-

(a) aloe emodin, which has mutagenic activity even in amounts as low as 70 ppm;

(b) aloe emodin intermediate products or its derivatives (mono, di, triacetate of aloe emodin) which are believed to be incomplete acetylation and oxidation process or degradation diacerein by-products

(c) residual chromium impurities which are hazardous, carcinogenic and highly toxic even at ppm levels. Subsequently, these undesired impurities can be separated, but with considerable difficulty since a method for purifying diacerein which involves use of basic conditions may cause hydrolysis of one or both the acetyl groups of diacerein to give monoacetyl rhein or rhein.

[0006] Processes geared towards diacerein purification are discussed below. [0007] United States Patent No. 5670695 discloses a process for purifying diacerein, wherein the raw diacerein obtained is salified with triethylamine and the insoluble residue is separated and the diacerein is precipitated by adding an aqueous acid such as hydrochloric acid, followed by successive crystallization of diacerein from 2-methoxyethanol and Ν,Ν-dimethylacetamide. Alternatively the raw diacerein is subjected to three successive recrystallization using N,N- dimethylacetamide, optionally in admixture with acetic anhydride. These purification methods disadvantageously, use basic conditions, which may cause hydrolysis of the acetyl groups of diacerein, but also the repeated purification steps which may cause loss in the yield. Furthermore, N, N-dimethylacetamide may be present in residual amounts in the purified diacerein necessitating the use of another solvent, like ethyl alcohol, to eliminate the residual solvent. [0008] United States Patent No. 5756782 discloses a process in which diacerein is suspended in a mixture of organic solvents and water, where a solution is obtained by addition of a tertiary amine, impurities are filtered off, and diacerein is re-precipitated as an alkali/alkaline-earth metal salt, which is then dissolved in water to obtain diacerein in slightly acidic medium. It is noteworthy that the solubilization of diacerein salt in water, prior to acidification with weak acids may induce partial deacetylation and the formation of impurities.

[0009] International Patent Publication WO2001 /96276 discloses a process for purifying diacerein by using a mixture of acetic acid and acetic anhydride or acetic anhydride alone. Even while the level of chromium content is reduced to 13 ppm only, this process disadvantageously uses higher temperatures for purifying diacerein,.

[0010] United States Patent Publication No. US2007/0037992 discloses a method for purifying diacerein by means of repeated extraction with toluene, but only leads to a diacerein with an average purity of 99.17%, aloe emodin content of 7-10 ppm and chromium content of 20-25 ppm.

[0011] Currently, the state of the art of diacerein purification is complex. The hurdles that have to be surmounted, include, but not limited to the solubility of diacerein, the impurities, which may be present in the diacerein processes, are not only structurally similar to diacerein, but are hazardous, carcinogenic and toxic at ppm levels. The prior art teaches methods for the purification of diacerein that require any of the following, use of a base or an acid, repeated recrystallization, use of high temperature to remove the aloe emodin related impurity and chromium impurity. Spawned from this necessity, a simple process for purifying diacerein is warranted. Evidently, there is a need in the art for a process for purification of diacerein which would circumvent the use of acid or basic conditions that lead to the undesirable formation of desacetyl impurities of diacerein (monoacetyl rhein or rhein). Simultaneously, the inventive process should ideally allow removal of the starting material aloe emodin, its intermediate products or its derivatives (mono, di, triacetate of aloe emodin) and the degradation products of diacerein and the chromium impurities.

[0012] The present invention surprisingly presents a commercially and economically viable novel process for purifying diacerein, which circumvents the disadvantages of the prior known processes and provides diacerein in high purity with an aloe emodin content of less than 2 ppm, triacetylated aloe emodin content of less than 2 ppm and chromium content less than l Oppm. It has unexpectedly been found that diacerein can be obtained in high purity by preparing the silylated derivative of diacerein and deprotecting the silylated derivative in a polar solvent.

SUMMARY OF THE INVENTION [0013] The present invention provides a process for purification of diacerein, compound of Formula I, the process comprising

a. reacting diacerein, compound of Formula I with a silylating agent to form a compound of Formula II, silylated diacerein wherein R is alkyl; and

rmula I

Formula II b. deprotecting compound of Formula II, silylated diacerein in presence of a polar solvent.

[0014] The present invention provides a compound of Formula II.

Formula II

[0015] The present invention provides a process for the preparation of compound of Formula II, the process comprising

a. reacting diacerein, compound of Formula I with a silylating agent to form a silylated diacerein, compound of Formula II, wherein R is alkyl ; and

b. isolating the silylated diacerein, compound of Formula II.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES [0016] Fig. 1 : X-ray powder diffraction pattern (XRPD) of diacerein crystalline form prepared by Example 6.

[0017] Fig. 2: Proton nuclear magnetic resonance spectroscopy ('H-NMR)of compound of Formula II A.

DESCRIPTION OF THE INVENTION [0018] The present invention provides a process for purification of diacerein, compound of Formula I, the process comprising

b. deprotecting the compound of Formula II, silylated diacerein in the presence of a polar solvent.

[0019] The term "alkyl" as used herein includes a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.

[0020] The silylating agent in step (a) may be selected from the group consisting of hexamethyldisilylazane, N,0 bis(trimethylsilyl) acetamide, trimethylchlorosilane and the like. Preferably, hexamethyldisilylazane.

[0021] The reaction of diacerein, compound of Formula I with a silylating agent may be carried out in presence of a solvent selected from the group consisting of halogenated hydrocarbons like methylene dichloride, ethylene dichloride and the like; aliphatic hydrocarbons like hexane, cyclohexane and the like; and aromatic hydrocarbon like toluene, ethylbenzene and the like. Preferably, methylene dichloride. [0022] The reaction of diacerein, compound of Formula I with a silylating agent may be carried out at the refluxing temperature of the solvent used. If required, the reaction may be carried out in presence of a catalyst. The catalyst used may be selected from iodine crystals and the like.

[0023] After completion of reaction, the compound of Formula II, silylated diacerein may be isolated from the reaction mixture. [0024] In step (b) the compound of Formula II, silylated diacerein may be deprotected in presence of a polar solvent. The polar solvent may be selected from the group consisting of alcohols, esters, glycols, polyethylene glycol, glycol ether, • sulfolane, N-methyl pyrolidine, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, water and mixtures thereof.

[0025] The alcohol may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and the like. Preferably, methanol.

[0026] The ester may be selected from the group consisting of ethyl acetate, propyl acetate and the like.

[0027] The glycol may be selected from the group consisting of ethylene glycol, propylene glycol and the like. [0028] The glycol ether may be selected from the group consisting of propylene glycol monomethyl ether, tripropylene glycol methyl ether, dipropylene glycol methyl ether, dipropylene glycol dimethyl ether and the like.

[0029] The deprotection in polar solvent may be carried out by stirring the compound of Formula II in a polar solvent at the reflux temperature of the solvent. The reaction may be refluxed for about 1-3 hours. If required the stirring may be continued for about 1-4 hours at room temperature. The purified diacerein, compound of Formula I, may be isolated by conventional methods known in the art, such as filtration. [0030} In one embodiment of the process of the present invention, the compound of Formula II, silylated diacerein formed in the step (a) may be isolated prior to the deprotection step (b).

[0031] If the compound of Formula II, silylated diacerein is precipitated in the reaction mixture then its isolation may be carried out by filtering the solution to separate the compound of Formula II.

[0032] Alternatively, the isolation of the compound of Formula II, silylated diacerein may be carried out by addition of an anti-solvent to the reaction mixture of step (a) to precipitate the compound of Formula II. The precipitated compound of Formula II may be isolated from the reaction mixture by conventional means such as filtration.

[0033] The anti-solvent may be selected from the group consisting of aromatic hydrocarbons like toluene, ethyl benzene; aliphatic hydrocarbon such as hexane, heptanes, cyclohexane and the like; ethers such as diisopropyl ether and the like. Preferably, toluene

[0034] The anti-solvent may be added to the reaction mixture of step (a) with stirring. Preferably the reaction mixture is cooled to at about room temperature and the anti-solvent is added slowly drop wise to the reaction mixture to precipitate the compound of Formula II, silylated diacerein.

[0035] In one embodiment of the present invention in step (a) diacerein, the compound of Formula I is reacted with hexamethyldisilylazane to form a compound of Formula IIA

Formula IIA

[0036] The reaction of diacerein, compound of Formula I with hexamethyldisilylazane may be carried out in a solvent selected from the group consisting of halogenated hydrocarbons like methylene dichloride, ethylene dichloride and the like; aliphatic hydrocarbon like hexane cyclohexane and the like; and aromatic hydrocarbon like toluene, ethylbenzene and the like. Preferably the solvent is methylene dichloride.

[0037] In one embodiment the compound of Formula IIA, may be isolated from the reaction mixture by addition of an anti-solvent. The anti-solvent may be selected from the group consisting of aromatic hydrocarbons like toluene, ethyl benzene; aliphatic hydrocarbon such as hexane, cyclohexane and the like; ethers such as diisopropyl ether and the like. Preferably, toluene.

[0038] In step (b) the isolated compound of Formula IIA, may be deprotected in presence a polar solvent: The polar solvent may be selected from the group consisting of alcohols such as methanol, ethanol, n-propanol isopropanol and the like; esters such as ethyl acetate; polyethylene glycol, glycol ether, sulfolane, N- methyl pyrolidine, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, water and mixtures thereof. Preferably, methanol.

[0039] In one embodiment of the present invention in step (a) diacerein, the compound of Formula I is reacted with hexamethyldisilylazane in a halogenated hydrocarbon to form a compound of Formula IIA.

Formula IIA

[0040] The compound of Formula IIA, is isolated from the reaction mixture by addition of an hydrocarbon antisolvent.

[0041] In step (b) the isolated compound of Formula IIA may be deprotected by an alcoholic solvent or by using dimethylsulfoxide.

[0042] The alcoholic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and the like. Preferably, methanol.

[0043] In one embodiment of the present invention in step (a) diacerein, the compound of Formula I is reacted with hexamethyldisilylazane in methylene dichloride to form a compound of Formula IIA.

Formula IIA

[0044] The compound of Formula IIA is isolated from the reaction mixture by addition of toluene. [0045] In one embodiment in step (b) the isolated compound of Formula IIA, silylated diacerein may be deprotected in presence of methanol.

[0046] In one embodiment in step (b) the isolated compound of Formula IIA, silylated diacerein may be deprotected in presence of dimethylsulfoxide to obtain compound of formula I. If required the compound of formula I thus obtained may be treated with methanol to obtain compound of formula I in purified form.

[0047] In one embodiment, the present invention provides a process for purifying diacerein, compound of Formula I, the process comprising

a. reacting diacerein, compound of Formula I with a silylating agent to form a silylated diacerein, compound of Formula II, wherein R is alkyl;

b. isolating the silylated diacerein, compound of Formula II; and c. converting the silylated diacerein compound of Formula II to diacerein.

[0048] In step (a) the reaction of diacerein, compound of Formula I with a silylating agent may be carried out in a solvent selected from the group consisting of halogenated hydrocarbon like methylene dichloride, ethylene dichloride and the like; aliphatic hydrocarbon like hexane cyclohexane and the like; and aromatic hydrocarbon like toluene, ethylbenzene and the like; preferably halogenated hydrocarbon. Preferably, methylene dichloride. [0049] The reaction may be carried out in the temperature range of about 30- 40° C.

[0050] In step (b) the compound of Formula II, silylated diacerein may be isolated from the reaction mixture by addition of an antisolvent.

[0051] The anti-solvent may be selected from the group consisting of aromatic hydrocarbons like toluene, ethyl benzene; aliphatic hydrocarbon such as hexane, - cyclohexane and the like; ethers such as diisopropyl ether and the like. Preferably, toluene.

[0052] In step c) the compound of Formula II, isolated silylated diacerein is converted to diacerein.

[0053] In one embodiment in step c) the compound of Formula II, isolated silylated diacerein is converted to diacerein in presence of a polar solvent. [0054] The polar solvent may be selected from the group consisting of alcohols such as methanol, ethanol, n-propanol isopropanol and the like; esters such as ethyl acetate, propyl acetate, butyl acetate; polyethylene glycol, glycol ether, sulfolane, N-methyl pyrolidine, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, water and mixtures thereof. Preferably, methanol.

[0055] In one embodiment in step c) the silylated diacerein, compound of Formula II is converted to diacerein in the absence of an acid. The reaction mixture containing the silylated diacerein which is to be converted to diacerein is free of additional acid and when the diacerein crystallizes out from the reaction mixture there is no presence of additional acid.

[0056] In one embodiment in step c) the silylated diacerein, compound of Formula II is converted to diacerein in absence of acid and in presence of a polar solvent.

[0057] The starting material diacerein is crude and has lower chemical purity and higher content of impurities like aloe emodin, triacetyl aloe emodin and chromium. The starting material crude diacerein may be obtained by any method known in the art. The starting material crude diacerein formed by any known method may be present as a solution or suspension in the reaction mixture and can be subjected to purification by reaction with a silylating agent without isolation. For example reaction of triacetylated aloe emodin with chromium oxide gives crude diacerein starting material which is present in the reaction mixture which may not be isolated and may be used for purification by reaction with a silylating agent. Alternatively the crude diacerein starting material may be isolated from the reaction mixture. The isolated diacerein which is crude may be used for purification by reaction with a silylating agent.

[0058] In one embodiment, the present invention provides a process for purifying diacerein comprising recrystallizing diacerein in a solvent selected from the group consisting of dimethyl sulfoxide, dimethylformamide, halogenated hydrocarbon or mixtures thereof.

[0059] In one embodiment, diacerein is treated with dimethylsulfoxide and the reaction mixture heated for a period of about 1-2 hours with stirring. The reaction mixture is cooled and the solid obtained is filtered to obtain diacerein. [0060] In one embodiment, diacerein is treated with a mixture of dimethylformamide and halogenated hydrocarbon and the reaction mixture obtained is heated for a period of about 1-2 hours with stirring. The reaction mixture is cooled and the solid obtained is filtered to obtain diacerein. [0061] The halogenated hydrocarbon may be selected from methylene dichloride, ethylene dichloride and the like.

[0062] In one embodiment, diacerein is treated with a mixture of dimethylformamide and methylene dichloride and the reaction mixture obtained is heated at about 90-100 °C for a period of about 1-2 hours with stirring. The reaction mixture is cooled and the solid obtained is filtered to obtain diacerein.

[0063] In one embodiment, the recrystallization of diacerein with dimethylsulfoxide or dimethyl formamide is carried out before subjecting it to the silylation step.

[0064] In one embodiment, the present invention provides compound of Formula II.

Formula II

[0065] In one embodiment, the present invention provides compound of Formula II isolated in solid state.

[0066] In one embodiment, the present invention provides a process for preparing compound of Formula II, the process comprising

b. isolating the silylated diacerein, compound of Formula II.

[0067] In step (a) the reaction of diacerein, compound of Formula I with a silylating agent may be carried out in a solvent selected from the group consisting of halogenated hydrocarbons like methylene dichloride, ethylene dichloride and the like; aliphatic hydrocarbon like hexane cyclohexane and the like; and aromatic hydrocarbon like toluene^ ethylbenzene and the like; preferably halogenated hydrocarbon.

[0068] The reaction may be carried out in the temperature range of about 30- 40° C.

[0069] In step (b) the compound of Formula II, silylated diacerein may be isolated from the reaction mixture by addition of an antisolvent. [0070] The anti-solvent may be selected from the group consisting of aromatic hydrocarbons like toluene, ethyl benzene; aliphatic hydrocarbon such as hexane, cyclohexane and the like; ethers such as diisopropyl ether and the like. Preferably toluene.

[0071] Specifically the present invention provides compound of Formula II, wherein R is methyl represented by compound of Formula IIA.

[0072] The compound of Formula IIA is characterized by Ή-NMR (CDC1₃ d₆, δρρηι) 0.43 (s) 9H, 2.45 (s) 6H, 7.42 (d) IH, 7.80 (t)lH, 8.01 (s) IH, 8.25 (d) IH, 8.80 (s) lH. [0073] Ή-NMR spectrum was recorded in CDC1₃ d₆ using 300 MHz Varian- NMR mercury 300 spectrometer.

[0074] In one embodiment the diacerein prepared by the process of the present invention has a purity greater than 99.5%. Preferably greater than 99.7%.

[0075] In one embodiment the diacerein obtained by the process of the present invention has aloe emodin content less than 2 ppm.

[0076] In one embodiment the diacerein obtained by the process of the present invention is free of aloe emodin.

[0077] In one embodiment the diacerein obtained by the process of the present invention has a triacetyl aloe emodin content less than 2 ppm [0078] The determination of purity, aloe emodin content and triacetyl aloe emodin content is carried out by HPLC method as disclosed in Pharmaeuropa Vol.22, No.3, July 2010. [0079] In one embodiment the diacerein obtained by the process of the present invention has chromium content less than 10 ppm. Preferably the chromium content is less than 5 ppm; more preferably less than 2 ppm, still more preferably less than 1 ppm. [0080] In one embodiment the diacerein obtained by the process of the present invention is free of chromium.

[0081] The chromium content is determined by AAS method. [0082] In one embodiment the diacerein obtained by the process of the present invention is free of residual organic solvents.

[0083] In one embodiment the present invention provides diacerein with purity greater than 99.5%, aloe emodin content less than 2 ppm, triacetylated aloe emodin content less than 2 ppm, chromium content less than 2 ppm and free of residual solvents.

[0084] In one embodiment the present invention provides crystalline diacerein characterized by an X- ray powder diffraction pattern with characteristic peaks at about 5.22, 10.45, 17.51, 27.89 ± 0.2 degrees two-theta.

[0085] In one embodiment the present invention provides crystalline diacerein characterized by an X- ray powder diffraction pattern with characteristic peaks at about 5.22, 10.45, 10.67, 17.51, 21.03, 21.46, 21.87, 22.17, 22.48, 23.26, 24.88, 25.15, 27.89, 30.84 and 31.19 ± 0.2 degrees two-theta, which is substantially in accordance with Figure 1.

[0086] The characterization of the crystalline form of diacerein of the present invention is analyzed by X-ray powder diffraction performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu Κα1=1.5406θΑ). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded in the 2Θ range of 2- 50", a step size 0.0167° with a "time-per-step" optimized to 1000 seconds. [0087] In one embodiment the present invention provides crystalline diacerein characterized by an X- ray powder diffraction pattern with characteristic peaks at about 5.22, 10.45, 10.67, 17.51, 21.03, 21.46, 21.87, 22.17, 22.48, 23.26, 24.88, 25.15, 27.89, 30.84 and 31.19 ± 0.2 degrees two-theta, which is substantially in accordance with Figure 1 and with purity greater than 99.5%, aloe emodin content less than 2 ppm, triacetylated aloe emodin content less than 2 ppm, chromium content less than 2 ppm and free of residual solvents.

[0088] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

Example 1

Purification of crude Aloe-Emodin:

In a 3 lit 4-neck round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket placed in oil bath.1400ml toluene was charged followed by charging lOOg aloe-emodin and the flask was flushed with 100 ml of toluene. The reaction mass was heated to about reflux temperature and maintained at about that temperature for about 2hours. The reaction mass was cooled to about 25-30°C and further chilled to about 0- 5°C and maintained at the same temperature for about 1 hour. The reaction mass was filtered and washed with 200ml toluene and wet cake was dried at about 65-70°C in a tray dryer to obtain 95 gm of purified diacerein.

Example 2

Preparation of Crude Diacerein:

In a 51it 4-neck round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket placed in oil bath 1592 gm acetic anhydride, 16.2 gm sodium acetate and 1 OOgm aloe-emodin was charged. The reaction mass was heated up to about 125-130°C and maintained at that temperature for about 90 min at about the same temperature. Then mass was cooled to about 65-70°C.In another 5 lit 4-neck round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket placed in water bath 2456 gm acetic acid, 162 gm water and 162 g Chromium trioxide were added. Reaction mass was stirred to get clear solution. Then mass was filtered and filtrate was heated to about 55-65°C for about 30 min. This solution was added slowly into the above acylated mass at about 55-60°C. Further mass was stirred for about 240min at about 60-70°C.The mass was cooled to about 25-30°C. and stirred for about 14 hours. The mass was filtered and wet cake was washed with mix of 200gm Acetic acid and 200g potable water. The wet cake was dried at about 60- 70°C in tray dryer. Result: Dry wt 110 gm.

HPLC Purity 93.60%

Triacetyl aloe emodin content: more than 10000 ppm

Chromium content: 42 ppm Example 3

Purification of crude diacerein

In a 2 lit 4-neck round bottom flask (RBF) equipped with overhead stirrer, double surface condenser, thermowel pocket placed in water bath, 500ml DMSO and 50 gm above crude diacerein was charged. The mass was heated at about 55-65°C for about an hour and cooled to about 25-30°C. The reaction mass was stirred for about an hour at about the same temperature and the reaction mass was filtered and washed with 50 ml DMSO. The wet cake was charged in 2 lit. RBF and 400 ml DMSO was added. The mass was heated at about 55-65°C. The reaction mass was stirred for about an hour and cooled to about 25- 30°C. The mass was stirred for about an hour. The reaction mass was filtered and washed with 40 ml DMSO. The wet material was dried in try dryer at about 65-70 °C. HPLC Purity: 99.39%

Triacetyl aloe emodin content: 400 ppm

Example 4

Purification of crude diacerein

In a 2 lit 4-neck round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket placed in water bath. 780 ml DMF, 260 ml MDC and 52 gm of crude diacerein was charged. The mass was heated at about 90-100°C for about 90- 120 min. and cooled to about 25-30°C. The reaction mass was stirred for about an hour at about the same temperature and the reaction mass was filtered and washed with 50 ml MDC. The wet cake was charged in 2 lit. RBF and 704 ml DMF and 235 ml MDC was added. The mass was heated at about 90-100°C. The reaction mass was stirred for about 90-120 min. and cooled to about 25- 30°C_r The mass was stirred for about an hour. The reaction mass was filtered and washed with MDC. If required this procedure was repeated. The wet material was dried in try dryer at about 65-70 °C.

HPLC Purity: 99.09%

Triacetyl aloe emodin content: 365.7 ppm Example 5

Preparation of silyl ester of diacerein, compound of Formula HA

In a 1.0 lit 4-neck round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket placed in water bath. 200ml MDC and 50 gm of diacerein obtained from example 4 was charged. The mass was heated at about 35-38°C and at about the same temperature 31.25ml HMDS (Hexmethyldisilylazane) was added followed by addition of 0.1 gm iodine crystals. The reaction mass was maintained at about 35-38°C till clear reaction mixture was observed. The clear reaction mixture was stirred at about 35-38°C for about 10-15min and then cooled to about 20-25°C. At about 20-25°C, 150ml toluene was added slowly to the reaction mixture. After addition of toluene the mass was stirred at about 20-25°C for about an hour. The reaction mixture was filtered and washed with 50ml toluene. The solid obtained was dried in a tray drier. Ή-NMR (CDC1₃ d₆, 5ppm): 0.43 (s) 9H, 2.45 (s) 6H, 7.42 (d) 1H, 7.80 (t)lH, 8.01 (s) 1H, 8.25 (d) 1H, 8.80 (s) 1H.

Example 6

Preparation of purified diacerein

Silylated Diacerein 32.5g was charged in 500ml round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket. 500ml methanol was charged and heated to reflux temperature of about 65-70°C. The reaction mass was maintained at about 65-70°C for about an hour and then cooled to about 25-30°C. The reaction mass was and filtered and solid obtained was washed with 50 ml methanol and dried in tray dryer.

Example 7

Preparation of purified diacerein

Silylated Diacerein was charged in 500ml round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket. 280 ml DMSO was charged and heated to temperature of about 65-70°C. The reaction mass was maintained at about 65- 70°C for about an hour and then cooled to about 25-30°C. The reaction mass was stirred for an hour and filtered and solid obtained was washed with methanol. The wet cake was charged in 500ml Round bottom flask equipped with overhead stirrer, double surface condenser, thermowel pocket. 250 ml Methanol was charged and heated to temperature of about 50-55°C. The reaction mass was maintained at about 50-55°C for about 15-30 min and then cooled to about 25-30°C. The reaction mass was stirred for an hour and filtered and solid obtained was washed with methanol and dried in tray dryer.

The wet material was dried in try dryer at about 65-70 °C.

Triacetyl aloe emodin and aloe content: 1.16 ppm

Chromium content: 1.51 ppm

Claims

We claim

1. A process for purification of diacerein, compound of Formula I, the process comprising

b. deprotecting compound of Formula II, silylated diacerein in presence of a polar solvent.

The process as claimed in claim 1 , wherein the compound of Formula II is isolated prior to deprotection.

The process as claimed in claim 1 , wherein the silylating agent is selected from the group consisting of hexamethyldisilylazane, N,0- bis(trimethylsilyl) acetamide, trimethylchlorosilane.

4. The process as claimed in claim 1, wherein in step b the polar solvent is selected from the group consisting of alcohols, esters, glycols, polyethylene glycol, glycol ethers, sulfolane, N-methyl pyrolidine, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, water and mixtures thereof.

5. A process for purifying diacerein comprising recrystallizing diacerein in a solvent selected from the group consisting of dimethyl sulfoxide, dimethylformamide, halogenated hydrocarbon or mixtures thereof.

6. Compound of Form la II, wherein R is alkyl.

Formula II

7. Compound of Formula II, isolated in solid state.

8. The compound as claimed in claim 6, wherein R is methyl.

9. Use of compound of claim 7 or claim 8 in preparation of diacerein.

10. A process for preparation of compound of Formula II comprising

a. reacting diacerein, compound of Formula I with a silylating agent to form a silylated diacerein, compound of Formula II, wherein R is alkyl; and b. isolating the silylated diacerein, compound of Formula II.