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CAS No. : | 13739-02-1 | MDL No. : | MFCD00468030 |
Formula : | C19H12O8 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TYNLGDBUJLVSMA-UHFFFAOYSA-N |
M.W : | 368.29 | Pubchem ID : | 26248 |
Synonyms : |
Diacerhein;Diacetylrhein;SF 277;4,5-Diacetylrhein;DAR
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 89.71 |
TPSA : | 124.04 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.2 cm/s |
Log Po/w (iLOGP) : | 2.0 |
Log Po/w (XLOGP3) : | 1.9 |
Log Po/w (WLOGP) : | 2.01 |
Log Po/w (MLOGP) : | 1.14 |
Log Po/w (SILICOS-IT) : | 2.91 |
Consensus Log Po/w : | 1.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.32 |
Solubility : | 0.177 mg/ml ; 0.000479 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.13 |
Solubility : | 0.0274 mg/ml ; 0.0000745 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.72 |
Solubility : | 0.00707 mg/ml ; 0.0000192 mol/l |
Class : | Moderately soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.08 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #2: With hydrogenchloride In water |
Diacerein (150 g, 0.41 mol) was stirred in 10percent (w/w) Na2CO3 solution (4 L) resulting in a red mixture. After stirring overnight the mixture was acidified to pH2 with 5M HCI solution to give a yellow precipitate. This was filtered and dried in a vac-oven at 50 °C (168 g, >100percent). 'H NMR (400 MHz, DMSO): 7.40 (1H, d J=8 Hz), 7.71-7. 76 (2H, m), 7.82 (1 H, t J=8 Hz), 8.11 (1 H, d J=1. 6 Hz). |
60% | With sodium hydroxide In water for 0.5 h; | Diacerein (0.012 M, 4.5 g) was dispersed in 80 ml of 10percent aqueous sodium hydroxide solution. The solution was heated on a boiling water bath for 30 min and then poured into 120 mL of 10percent HCl. Rhein was obtained in the form of yellow flakes which were recrystallized twice with pyridine. Rhein. mp 318–319 °C, Rf 0.58 (chloroform: methanol; 3:0.5 v/v),percent yield 60, Log P 0.2402. IR (ν, cm−1, KBr) 3566 (Phenolic OH stretch.), 3100, 2850 (Broad OH stretch. of COOH), 1682 (C=O stretch. of –COOH), 1193 (C–O stretch. of phenol), 1H NMR (δ, ppm, DMSO-d6) 8.57 carboxylic OH [s; 1H], 8.26 benzene CH2 [s; 2H], 8.25 benzene CH2 [s; 2H], 7.32–7.83 benzene CH2 [t; 3H], 3.79 phenolic OH [d; 2H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Diacerein (150 g, 0.41 mol) was stirred in 10% (w/w) Na2CO3 solution (4 L) resulting in a red mixture. After stirring overnight the mixture was acidified to pH2 with 5M HCI solution to give a yellow precipitate. This was filtered and dried in a vac-oven at 50 C (168 g, >100%). 'H NMR (400 MHz, DMSO): 7.40 (1H, d J=8 Hz), 7.71-7. 76 (2H, m), 7.82 (1 H, t J=8 Hz), 8.11 (1 H, d J=1. 6 Hz). | |
60% | With sodium hydroxide; In water; for 0.5h; | Diacerein (0.012 M, 4.5 g) was dispersed in 80 ml of 10% aqueous sodium hydroxide solution. The solution was heated on a boiling water bath for 30 min and then poured into 120 mL of 10% HCl. Rhein was obtained in the form of yellow flakes which were recrystallized twice with pyridine. Rhein. mp 318-319 C, Rf 0.58 (chloroform: methanol; 3:0.5 v/v),% yield 60, Log P 0.2402. IR (nu, cm-1, KBr) 3566 (Phenolic OH stretch.), 3100, 2850 (Broad OH stretch. of COOH), 1682 (C=O stretch. of -COOH), 1193 (C-O stretch. of phenol), 1H NMR (delta, ppm, DMSO-d6) 8.57 carboxylic OH [s; 1H], 8.26 benzene CH2 [s; 2H], 8.25 benzene CH2 [s; 2H], 7.32-7.83 benzene CH2 [t; 3H], 3.79 phenolic OH [d; 2H]. |
In sodium carbonate; | 1 9,10-Dihydro-4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid 4,5-Diacetoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid (5 g) was magnetically stirred in 5% w/v aqueous sodium carbonate (100 ml) at 80 C. for 2 hours 25 minutes. The suspension was allowed to cool, then diluted with water (100 ml) and adjusted to pH 1 by addition of concentrated hydrochloric acid. After filtering and washing with water (200 ml), the collected yellow-brown solid was dried at 64 C. in vacuo, m.p. >260 C. |
5g of raw Diacerein containing about 300 ppm of Aloemodine derivatives is dissolved in 40ml of methanol and, under magnetic agitation, 40ml of water and 5g of KOH are added. In the presence of a condenser, heating to 60-65C is performed for 30 minutes; after this period, 35ml of 6N HCL are added; dilution with about 35ml of water is performed and the solution is boiled for about 30 minutes. After cooling, the suspension is filtered under vacuum, the residue washed with water and dried under vacuum at constant weight. 4.5g of Rhein are thus obtained. 2g of Rhein thus obtained are transformed into the corresponding potassium salt as described for the Diacerein in Example 1. 2g of Potassium Salt of Rhein are dissolved in 200ml of water (final pH of the solution 6.2). This solution, after filtration under vacuum, is percolated through a 7.5cm-diameter 10cm-high column, packed with 180g of Diaion SP207 (Mitsubishi). Washing with a volume corresponding to the volume of the column of acetone and then elution with a water/ethanol mixture are performed until the complete elution of the Rhein. 4 elution steps are performed: the two first elutions are performed by using ethanol/water mixture 20%/80% and the two last elutions are performed by using ethanol/water mixture 60%/40%. The fraction containing the Rhein is then brought to pH 4.5-5 with 10% sulphuric acid. The suspension is cooled to 5-10C, the precipitate recovered by filtration under vacuum, washed with cold water and dried under vacuum. The precipitate, after drying, is acetylated using pyridine and acetic anhydride in a ratio of 1:1 (alternatively, other conventional acetylating agents may be used). After drying under vacuum, 1.5g of Diacerein are obtained which under HPLC analysis are shown to be free of impurities. The yield of the process, from the Potassium Salt of Rhein, is 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; thionyl chloride; In dichloromethane; at 0 - 20℃; | A suspension of <strong>[13739-02-1]diacetylrhein</strong> (0.0032mol, 1.21 g) in 15ml of anhydrous dichloromethane was prepared containingpyridine (0.0035mol, 0.32 g) and cooled at 0C. Freshly redistilledthionyl chloride (0.0034mol, 0.41 g) in dichloromethane(2 ml) was added drop wise to the above suspension.The mixture was stirred at room temperature for 36 h.The product was dried under vacuum and immediately usedin the next step. m. p. 238- 240C (melts with decomposition),Rf = 0.91, methanol: water (2:1 v/v), % yield 92%. |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; | The compound rhein (284mg, 1mmol) in acetic anhydride (612mg, 6mmol) was added with Zn(CF3SO3)2 (2mg, 0.005mmol) and stirred at 130C for 2h. Then the resulting yellow solution was poured into ice water, filtered and dried under reduced pressure, and recrystallized from ethyl acetate to obtain pure <strong>[13739-02-1]4,5-diacetoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid</strong> b. Oxalyl chloride (3mmol) was added to a solution of diacerein b (1mmol) in DCM (20mL) dropwise with stirring and the mixture was added a catalytic amount of DMF. After 1h, the mixture was distilled off under reduced pressure and the produced acid chloride was collected. The acid chloride residue directly reacted with aromatic or aliphatic amine (1.5mmol) and N(Et)3 (2mmol) in DCM (20mL) and stirred at room temperature (RT) for 3h. The mixture was poured into water (30mL), extracted with DCM (20mL×2), washed with brine (10mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was further purified by silica gel chromatography to afford the desired products c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; thionyl chloride; tert-butylamine; In water; toluene; | EXAMPLE 16 4,5-Diacetoxy-9,10-dihydro-N-(1,1-dimethylethyl)-9,10-dioxoanthracene-2-carboxamide To a stirred mixture of <strong>[13739-02-1]4,5-diacetoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid</strong> and thionyl chloride (3.6 liters) was added dry pyridine (267.0 ml) dropwise over 15 minutes. The mixture was heated under reflux for 4 hours and then cooled to 40 C. The excess thionyl chloride was removed by distillation in vacuo and replaced with toluene (6 liters). The mixture was cooled to 15 C. and tert-butylamine (600 ml) was added over 10 minutes. The mixture was left to stir at room temperature over-night. More tert-butylamine (550 ml) was added (550 ml) was added until no more starting material could be detected. The mixture was cooled to 0-5 C. and the solid isolated by filtration and pulled dry on the sinter. The solid was removed from the sinter and slurried in water for 15 minutes. The crude product was isolated and dried in vacuo at 60 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetone; | A suspension of 15.6 kg of crude diacerein, containing about 500 ppm of aloe-emodine, in a mixture of 80 1 of acetone and 80 1 of water is added with 4.27 kg of trietylamine. The resulting solution is extracted with four aliquots of butyl acetate (100 1 each); the organic phases are pooled and butyl acetate is recovered and recycled to the process. The diacerein salt solution is acidified with diluted HC1 ; precipitated diacerein is centrifuged, thoroughly washed with water and dried to afford 14.8 kg of diacerein with an aloe- emodine content not higher than 2 parts per million. Crystallisation from acetic anhydride/acetic acid is subsequently carried out according to what reported above. | |
In dichloromethane; water; butanone; for 2h;Heating / reflux; | A solution of 100 grams of crude diacerein (aloe-emodine content of about 500 ppm) in 500 ml of methyl ethyl ketone, 500 ml of water, 27.5 grams of triethylamine and 50 ml of methylene chloride is loaded in a Soxhlet apparatus suitable for liquid-liquid extraction. 1 Litre of methylene chloride is loaded in the round-bottom flask for the extraction solvent and heated up to reflux temperature. Extraction is continued for about one hour (the extraction solvent, being denser than the aqueous acetone phase, passes up through it and overflows from the body of the Soxhlet, siphoning over to the flask containing methylene chloride, thus removing the extracted aloe-emodine), thereafter the extraction solvent is then replaced with 500 ml of fresh methylene chloride and extraction is continued for another hour. The water-acetone solution of the diacerein salt is allowed to stand, then separated from the methylene chloride phase (containing emodine traces) and acidified to pH 1 with diluted hydrochloric acid to precipitate diacerein. After filtration and drying under vacuum at 60C, diacerein (94 grams) contains less than 4 parts per million of aloe-emodine. The extraction can also be interrupted and addition of fresh methylene chloride can be avoided when aloe-emodine levels sufficiently low for the intended use are reached. Highly pure diacerein can be obtained by crystallization from acetic acid/acetic anhydride (70/9 V/V). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetone; | A suspension of 15.6 kg of crude diacerein, containing about 500 ppm of aloe-emodine, in a mixture of 80 1 of acetone and 80 1 of water is added with 4.27 kg of trietylamine. The resulting solution is extracted with four aliquots of butyl acetate (100 1 each); the organic phases are pooled and butyl acetate is recovered and recycled to the process. The diacerein salt solution is acidified with diluted HC1 ; precipitated diacerein is centrifuged, thoroughly washed with water and dried to afford 14.8 kg of diacerein with an aloe- emodine content not higher than 2 parts per million. Crystallisation from acetic anhydride/acetic acid is subsequently carried out according to what reported above. | |
With hydrogenchloride; In water; butanone;pH 1; | A solution of 100 grams of crude diacerein (aloe-emodine content of about 500 ppm) in 500 ml of methyl ethyl ketone, 500 ml of water, 27.5 grams of triethylamine and 50 ml of methylene chloride is loaded in a Soxhlet apparatus suitable for liquid-liquid extraction. 1 Litre of methylene chloride is loaded in the round-bottom flask for the extraction solvent and heated up to reflux temperature. Extraction is continued for about one hour (the extraction solvent, being denser than the aqueous acetone phase, passes up through it and overflows from the body of the Soxhlet, siphoning over to the flask containing methylene chloride, thus removing the extracted aloe-emodine), thereafter the extraction solvent is then replaced with 500 ml of fresh methylene chloride and extraction is continued for another hour. The water-acetone solution of the diacerein salt is allowed to stand, then separated from the methylene chloride phase (containing emodine traces) and acidified to pH 1 with diluted hydrochloric acid to precipitate diacerein. After filtration and drying under vacuum at 60C, diacerein (94 grams) contains less than 4 parts per million of aloe-emodine. The extraction can also be interrupted and addition of fresh methylene chloride can be avoided when aloe-emodine levels sufficiently low for the intended use are reached. Highly pure diacerein can be obtained by crystallization from acetic acid/acetic anhydride (70/9 V/V). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 kg of crude humid diacerein (equivalent to 62 kg of dry diacerein), are dissolved at a maximum pH between 7.0-7.2 in a mixture of 375.8 kg of water and 441.2 kg of acetone; 16.33 kg of triethylamine dissolved in 186.2 kg of acetone at a temperature of 23-25C for 6-8 hours are required. when diacerein has dissolved completely, 10 extractions are performed with 100 liters of toluene, using 10 liters in every extraction. After that, the water phase is adjusted to a pH of about 2.8 with 80% phosphoric acid and a 91-92.5% weight/weight yield, 8 ppm of aloe-emodin, 23 ppm of chromium, 99.24% purity and a 98.55% concentration is obtained. | ||
In the same procedure of example 1, after the dissolution, 10 extractions with 100 liters of ethyl acetate, using 10 liters in every extraction are performed; after crystallization at a pH of about 2.2, using 80% phosphoric acid, a 88-90% weight/weight yield, 10 ppm of aloe-emodin, 25 ppm of chromium, a purity of 99.16% and a concentration of 98.96% are obtained. | ||
In the same procedure of example 1, after the dissolution, 10 extractions with 100 liters of toluene, using 10 liters in every extraction are performed; after crystallization at a pH of about 2.8, using 10% sulphuric acid, a 90-93% weight/weight yield, 7 ppm of aloe-emodin, 20 ppm of chromium, a purity of 99.31% and a concentration of 99.44% are obtained. |
In the same procedure of example 1, after the dissolution, 10 extractions with 100 liters of isobutyl acetate, using 10 liters in every extraction are performed; after crystallization at a pH of about 2.5, using 10% sulphuric acid, a 92-93% weight/weight yield, 9 ppm of aloe-emodin, 23 ppm of chromium, a purity of 99.24% and a concentration of 98.55% are obtained. | ||
In the same procedure of example 1, after the dissolution, 10 extractions with 100 liters of xylene, using 10 liters in every extraction are performed; after crystallization at a pH of about 2.7, using 10% sulphuric acid, a 91-93% weight/weight yield, 7 ppm of aloe-emodin, 21 ppm of chromium, a purity of 99.31% and a concentration of 99.44% are obtained. | ||
In the same procedure of example 1, after the dissolution, 10 extractions with 100 liters of xylene, using 10 liters in every extraction are performed; after crystallization at a pH of about 3.0, using 30% phosphoric acid, a 90-92% weight/weight yield, 8 ppm of aloe-emodin, 24 ppm of chromium, a purity of 98.76% and a concentration of 98.99% are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; triethylamine; In thionyl chloride; chloroform; benzene; | EXAMPLE 18 Preparation of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid ethylthioethyl ester 7.4 g (0.02 mole) of 4,5-bis(acetyloxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid are dissolved in 40 ml of SOCl2. The reaction mixture is left to react for 2 hours under stirring, then the thionyl chloride excess is evaporated off under vacuum, the residue is washed with anhydrous benzene and solvent is evaporated off under vacuum. The formed chloride is dissolved in 200 ml of chloroform and the obtained solution is dropped into a mixture of 2 g (0.02 mole) of triethylamine and 2.2 g (0.02 mole) of 2-ethyl-thioethyl alcohol in 40 ml of chloroform, at a temperature of 0-10 C. The reaction is almost immediate at room temperature. After that, solvent is evaporated off under vacuum, the residue is taken up into 40 ml of benzene and filtered. The filtrate is treated with 10% NH3 and it is left to react for about 12 hours at room temperature. The solution is acidified to pH 5-6 with diluted HCl. A precipitate is obtained which can be filtered, containing the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; | EXAMPLE 15 Preparation of 4,5-dihydroxy-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid butyl ester 7.4 g (0.02 mole) of 4,5-bis(acetoxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid are dissolved in 150 ml of butanol. Gaseous HCl is bubbled through the obtained solution until saturation. The reaction mixture is left to react for half an hour at room temperature, then it is heated to 60-70 C. for 3 hours, while continuing HCl bubbling. The desired product precipitates, which is cooled, filtered and crystallized from ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; nitrogen; In N-methyl-acetamide; | EXAMPLE 35 N-Benzyloxy-4,5-diacetoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxamide To a stirred solution of <strong>[13739-02-1]4,5-diacetoxy-9,10-dihydro-9,10-dioxoanthracene-2-carboxylic acid</strong> (6.14 g) in dry dimethylformamide (1.1 l) and nitrogen at -15 C. was added dropwise N-methylmorpholine (3.71 g) as a solution in dimethylformamide (20 ml) during 5 minutes. Stirring at -15 C. was continued for 40 minutes before the dropwise addition of isobutylchloroformate (2.51 g) as a solution in dimethylformamide (10 ml) over 10 minutes. The mixture was stirred at -15 C. for 45 minutes when a solution of O-benzylhydroxylamine hydrochloride (2.93 g) in dimethylformamide (20 ml) was added dropwise. Stirring was continued for 5 hours at -15 C. and the mixture was then allowed to warm to room temperature. After 16 hours at room temperature, the dark solution was concentrated in vacuo. The gummy residue was triturated with ethyl acetate to yield a bright yellow solid. This was triturated with tetrahydrofuran and the insoluble material then washed with 5% aqueous sodium bicarbonate solution. The insoluble yellow solid was washed with water and dried in vacuo yielding the title compound, m.p. 192-194 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(6) The diacetyl rhein was then analyzed by TLC and HPLC, revealing a purity exceeding 95%. The diacetyl rhein's final weight was 2.61 g. The percentage yield of conversion of aloe-emodin triacetate to diacetyl rhein was then calculated. | ||
The theoretical yield of pure diacetyl rhein from 3.0 g of pure aloe-emodin triacetate is 2.79 g ([396.3 g aloe-emodin triacetate/368.3 g diacetyl rhein]=[3.0 g aloe-emodin triacetate/X g diacetyl rhein]). Since 2.79 g was the theoretical yield, the efficiency of the oxidation procedure is 93.5% ([2.61 g obtained 2.79 g theoretical yield]*100). NMR analysis (1 H-NMR; frequency=400 MHz.; solvent=DMSO-d6) for diacetyl rhein (FIG. 8) gave the following signals: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; | Release of diacerein from its salt A mixture of dry potassium salt of diacerein (63.4 g), absolute ethanol (632.5 ml) and demineralized water (632.5 ml) is kept at +20-22C until complete dissolution. SA 189 carbon is added (5.0 g), and after approximately 1 hour the product is filtered on a celite bed, washing with an ethanol-water mixture. The diacerein is precipitated by adding to the filtered solution 10% sulphuric acid until pH 4.0 is reached. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
iron(III) chloride; at 65℃; for 1.5h; | Example 4; Synthesis of l,8-diacetoxy-3-carboxyanthraquinone (diacerein); 45 g (0.28 moles) of anhydrous iron trichloride are added in portions to a suspension of 255 g (0.55 moles) of l,8-dibenzyloxyanthraquinone-3- carboxylic acid in 1300 ml of acetic anhydride. The reaction mixture is heated to 650C for one hour and thirty minutes. It is gradually cooled to 2-4C and maintained at that temperature for 1 hour. The solid obtained is filtered and washed with 150 ml of acetic anhydride and then with 400 ml of ethyl acetate. The damp product is dried at 500C at reduced pressure for 14-16 hours, providing 186 g of crude diacerein (yield 92%). The crude diacerein is purified according to the known techniques. <n="11"/>1H NMR (d6-DMSO) delta: 2.4 (6 H, s); 7.6 (1 H, dd); 7.9 (1 H, t); 8.0 (1 H5 d); 8.1(lH,dd);8.5(lH,d). IR cm-1: 1763, 1729, 1655,1619, 1591, 1183. Chromium: not detectable (< 1 ppm)Genotoxic impurities (aloe emodin and acetyl derivatives) < 2 ppm. | |
iron(III) chloride; at 65℃; for 1.5h; | Example 4 Synthesis of 1,8-diacetoxy-3-carboxyanthraquinone (Diacerein); 45 g (0.28 moles) of anhydrous iron trichloride are added in portions to a suspension of 255 g (0.55 moles) of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid in 1300 ml of acetic anhydride. The reaction mixture is heated to 65 C. for one hour and thirty minutes. It is gradually cooled to 2-4 C. and maintained at that temperature for 1 hour. The solid obtained is filtered and washed with 150 ml of acetic anhydride and then with 400 ml of ethyl acetate. The damp product is dried at 50 C. at reduced pressure for 14-16 hours, providing 186 g of crude diacerein (yield 92%). The crude diacerein is purified according to the known techniques.1H NMR (d6-DMSO) delta: 2.4 (6 H, s); 7.6 (1 H, dd); 7.9 (1 H, t); 8.0 (1 H, d); 8.1 (1 H, dd); 8.5 (1 H, d).IR cm-1: 1763, 1729, 1655,1619, 1591, 1183.Chromium: not detectable (<1 ppm)Genotoxic impurities (aloe emodin and acetyl derivatives) 2 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium 2-ethylhexanoate; triethylamine; In 2-methyl-propan-1-ol; water; acetone; at 18℃; for 2h; | 5g of raw Diacerein containing 250 ppm of Aloemodine derivatives are suspended in 75ml of acetone and 5ml of water and, under magnetic agitation, 2.5ml of triethylamine are added. The solution thus obtained is treated at 18C with 18ml of a 1M solution of potassium Ethyl Hexanoate in isobutanol diluted with 26ml of acetone. Salification agent is added over a period of 2 hours. A precipitate is formed which is filtered, washed with acetone and dried under vacuum at 40C for one night. 5g of Potassium Salt of Diacerein are obtained. 2g of this product are dissolved in 200ml of water (final pH of the solution 6.2). This solution, after filtration under vacuum, is percolated through a 7.5cm-diameter 10cm-high column, packed with 180g of SEPABEADS SP207 (Mitsubishi). The typical characteristics of SEPABEADS SP207 are given in the table 2 below: Washing with a volume corresponding to the volume of the column of acetone and then elution with a ethanol/water mixture are performed until the complete elution of the Diacerein. 4 elution steps are performed: the two first elutions are performed by using ethanol/water mixture 20%/80% and the two last elutions are performed by using ethanol/water mixture 60%/40%. The fraction containing the product is then brought to pH 4.5-5 with 10% sulphuric acid. The suspension is cooled to 5-10C, the precipitate recovered by filtration under vacuum, washed with cold water and dried under vacuum. 1.3g of Diacerein are obtained which on HPLC analysis are found to be free of impurities. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In ethanol; water; acetone;pH 4.5 - 5; | 5g of raw Diacerein containing 250 ppm of Aloemodine derivatives are suspended in 75ml of acetone and 5ml of water and, under magnetic agitation, 2.5ml of triethylamine are added. The solution thus obtained is treated at 18C with 18ml of a 1M solution of potassium Ethyl Hexanoate in isobutanol diluted with 26ml of acetone. Salification agent is added over a period of 2 hours. A precipitate is formed which is filtered, washed with acetone and dried under vacuum at 40C for one night. 5g of Potassium Salt of Diacerein are obtained. 2g of this product are dissolved in 200ml of water (final pH of the solution 6.2). This solution, after filtration under vacuum, is percolated through a 7.5cm-diameter 10cm-high column, packed with 180g of SEPABEADS SP207 (Mitsubishi). The typical characteristics of SEPABEADS SP207 are given in the table 2 below: Washing with a volume corresponding to the volume of the column of acetone and then elution with a ethanol/water mixture are performed until the complete elution of the Diacerein. 4 elution steps are performed: the two first elutions are performed by using ethanol/water mixture 20%/80% and the two last elutions are performed by using ethanol/water mixture 60%/40%. The fraction containing the product is then brought to pH 4.5-5 with 10% sulphuric acid. The suspension is cooled to 5-10C, the precipitate recovered by filtration under vacuum, washed with cold water and dried under vacuum. 1.3g of Diacerein are obtained which on HPLC analysis are found to be free of impurities. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxypropyl-beta-cyclodextrin; In aq. phosphate buffer; dimethyl sulfoxide; at 37℃;pH 7.2;Darkness;Kinetics; | A stock solution of DARh (103 M) was prepared in DMSO. Avolume of 2.5 mL of the stock solution was added to the pH 7.2 ± 0.1 phosphate buffered saline (PBS) containing HPbetaCD (range 0-100 mM) to make a final volume of 25 mL (104 MDARh). Samples were kept in the dark thermostatted at 37 ± 0.5 C and thehydrolysis reaction of DARh to Rh was monitorated by UV-vis (forboth DARh and Rh) and fluorescence spectra (only for Rh) [11]. Absorption spectra were recorded on a Perkin Elmer UV-vis Lambda25 spectrophotometer at 344 nm, corresponding to the maximum absorption wavelength of DARh, using 1 cm quartz cell. Fluorescence measurements were carried out by a Perkin-ElmerLS50B fluorimeter using 1 cm quartz cell, slit width was 5, excitation and fluorescence emission wavelength of 435 nm. In both cases, a software was used for data storage and processing. Different calibration curves, for each cyclodextrin concentration, were used to calculate Rh formation and DARh disappearance in solution. The observed first-order rate constant (Kobs) for the degradation was obtained from a non-linear regression analysis of [DARh]/[DARh]0 (where [DARh] is the concentration at a given time t and [DARh]0 is DARh initial concentration) plotted vs. time [12]. All measurements were carried out at least in triplicate. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
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Prevention | |
Code | Phrase |
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
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P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
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Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
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P321 | |
P322 | |
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P378 | |
P380 | Evacuate area. |
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P390 | Absorb spillage to prevent material damage. |
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P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
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P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
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Disposal | |
Code | Phrase |
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
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H205 | May mass explode in fire |
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H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
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H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
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Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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