* 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.
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].
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 7, p. 817 - 822
[2] Patent: WO2005/85170, 2005, A1, . Location in patent: Page/Page column 9-10
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7582 - 7587
[4] Journal of the Chemical Society, 1909, vol. 95, p. 1088
[5] Patent: US5480873, 1996, A,
[6] Patent: EP2196450, 2010, A1, . Location in patent: Page/Page column 6-7
2
[ 481-74-3 ]
[ 478-43-3 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With chromium(VI) oxide In acetic anhydride; acetic acid at 65℃; for 8 h; Stage #2: With sodium carbonate In water
6g of chrysophanol was added to 150ml of mixed solution of anhydride and pyridine (1:1), overnight at room temperature. The reaction mixture was put into cold water for crystallization , then filtered and dried, was put into 300 ml of acetic anhydride and glacial acetic acid mixture (1:1). Chromium trioxide solution was dropped at 45°C, and then was stirred for 8 hours at 65°C. The reaction mixture was put into water, crystallized, filtered, added into 1000 ml of 25percent sodium carbonate solution, extracted by chloroform for three times. Sodium carbonate solution was heated to boiling, cooled, added into hydrochloric acid for acidification. Until a large amount of gas is drained off, the solution was heated to boiling for 1 hour, cooled, crystallized, filtered and washed by water, recrystallized with glacial acetic acid, thus 2g of rhein was obtained. The product yield was above 98percent.
98%
Stage #1: at 20℃; Stage #2: With chromium(VI) oxide; acetic anhydride; acetic acid In water at 45 - 65℃; for 8 h;
6 g of chrysophanol was added to 150 ml of mixed solution of anhydride and pyridine (1:1), overnight at room temperature. The reaction mixture was put into cold water for crystallization, then filtered and dried, was put into 300 ml of acetic anhydride and glacial acetic acid mixture (1:1). Chromium trioxide solution was dropped at 45° C., and then was stirred for 8 hours at 65° C. The reaction mixture was put into water, crystallized, filtered, added into 1000 ml of 25percent sodium carbonate solution, extracted by chloroform for three times. Sodium carbonate solution was heated to boiling, cooled, added into hydrochloric acid for acidification. Until a large amount of gas is drained off, the solution was heated to boiling for 1 hour, cooled, crystallized, filtered and washed by water, recrystallized with glacial acetic acid, thus 2 g of rhein was obtained. The product yield was above 98percent.
Example 3; Oxidizing medium was prepared by dissolving sodium nitrite (255 g) in sulphuric acid (1.2 I). The oxidizing medium was heated to 1200C and then aloe-emodin (100 g) was added slowly thereto. After completion of the oxidation reaction (3 hours), the reaction mixture was poured into distilled water (7.2 I) at 2°C to precipitate rhein, and rhein is filtered and dried. Rhein having a degree of purity of 90 - 95 percent was obtained in a yield of more than 85 percent.
62%
With water; pyridinium chlorochromate In N,N-dimethyl-formamide at 20℃; for 24 h;
A mixture of compound A1 (1 mmol, 0.27 g), PCC (2 mmol, 0.45 g), DMF (100 ml) and 2 mL of water were stirred at room temperature for 24 h, monitored by TLC. After the completion of reaction, 100 mL of ice water was added under stirring to afford orange precipitate. The orange precipitate was filtered, washed and dried. Recrystallization of the orange precipitate from ethanol gave compound B7 as brown acicular crystals, yield 62percent; mp 310–313 °C; IR νmax cm−1: 3432, 3059, 2930, 1695, 1628, 1270, 1192, 757; 1H NMR (DMSO-d6): δ = 7.58 (d, 1H, J = 8.2 Hz, 1H, H-C(6)), 7.85 (s, 1H, H-C(1)), 7.97 (dd, 1H, J1 = 8.2 Hz, J2 = 7.5 Hz, H-C(7)), 8.01 (s, 1H, H-C(3)), 8.45 (d, 1H, J = 7.5 Hz, H-C(8)), 11.87 (s, 1H, HO-C(1)), 11.94 (s, 1H, HO-C(8)), 13.90 (s, 1H, COOH); ESI-MS m/z: 285.04 [M+H]+.
62%
With pyridinium chlorochromate In water; N,N-dimethyl-formamide at 20℃; for 24 h;
A mixture of compound 1 (1 mmol, 0.27 g), PCC (2 mmol, 0.45 g), DMF (100 ml) and 2 mL of water were stirred at room temperature for 24 h, monitored by TLC. After the completion of reaction, 100 mL of ice water was added under stirring to afford orange precipitate. The orange precipitate was filtered, washed and dried. Recrystallization of the orange precipitate from ethanol gave compound A4 as brown acicular crystals, yield 62percent; m.p. 310-313 °C; IR νmax cm-1: 3432, 3059, 2930, 1695, 1628, 1270, 1192, 757; 1H NMR (d6-DMSO): δ = 7.58 (d, 1H, J = 8.2 Hz, 1H, H-C(6)), 7.85 (s, 1H, H-C(1)), 7.97 (dd, 1H, J1 = 8.2 Hz, J2 = 7.5 Hz, H-C(7)), 8.01 (s, 1H, H-C(3)), 8.45 (d, 1H, J = 7.5 Hz, H-C(8)), 11.87 (s, 1H, HO-C(1)), 11.94 (s, 1H, HO-C(8)), 13.90 (s, 1H, COOH); HRMS (ESI): calcd for [M + H]+ (C15H9O6) m/z 285.0399, found 285.0403.
Reference：
[1] Green Chemistry, 2018, vol. 20, # 13, p. 3038 - 3043
[2] Patent: WO2006/51400, 2006, A1, . Location in patent: Page/Page column 18
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 5, p. 1064 - 1073
[4] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 289 - 296
[5] Patent: WO2009/106908, 2009, A1, . Location in patent: Page/Page column 12-13
[6] Patent: CN108218701, 2018, A,
4
[ 1402610-53-0 ]
[ 478-43-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
With sulfuric acid In water
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 60-65°C 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.(R). (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 20percent/80percent and the two last elutions are performed by using ethanol/water mixture 60percent/40percent. The fraction containing the Rhein is then brought to pH 4.5-5 with 10percent sulphuric acid. The suspension is cooled to 5-10°C, 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 87percent.
In a three-necked flask equipped with a magnetic stirrer and reflux condenser, intermediate product IV and toluene were added,Heating to reflux, dropping 30percent hydrobromic acid, dropping complete, keep reflux for 10 hours, vacuum distillation of toluene, filtration, filter cake alkali solution, filter to remove insoluble impurities, the filtrate and hydrochloric acid precipitation products,Filtration, filter cake drying to rhein, the yield of 56percent.
Reference：
[1] Patent: CN106966891, 2017, A, . Location in patent: Paragraph 0038-0039
6
[ 154658-30-7 ]
[ 478-43-3 ]
Yield
Reaction Conditions
Operation in experiment
15.5 g
With sodium chlorite; sodium dihydrogenphosphate In water; dimethyl sulfoxide at 5 - 25℃; for 4.5 h;
DMSO (300 g) was added to the reactor.Formula II (33.5 g, 125 mmol),Stir for 30 minutes,The internal temperature is controlled at 5 °C.Rapid dropwise addition of sodium dihydrogen phosphate solution(anhydrous sodium dihydrogen phosphate 45g, 0.375mol, 28.9g purified water),Control the dropping temperature below 20 °C,Sodium chlorite solution (sodium chlorite 45.2 g, 0.5 mol, 180 g water) was added dropwise.Control the dropping temperature below 10 °C,After the addition is completed, the temperature is raised to 25 ° C.Stir for 4.5 hours,HPLC detection,The residual of 3.4percent of formula II is complete.Cool down to 15 ° C,Quickly add 550mL of water,The internal temperature does not exceed 40 °C during the addition process.After the addition is completed,Stir for 2 hours,The reaction solution is filtered,The filter cake ethanol (210g) is beaten once,Drying at 60 ° C for 8 hours,15.5 g of a yellow solid were obtained.98.3percent purity,The calculated yield is based on aloe-emodin.The yield was 82.9percent.
Reference：
[1] Patent: CN108218701, 2018, A, . Location in patent: Paragraph 0035-0037; 0046-0048; 0057-0059; 0068; 0069; 0070
7
[ 6155-37-9 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, p. 383 - 384
8
[ 1019637-61-6 ]
[ 478-43-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2009, # 35, p. 6205 - 6210
9
[ 820243-51-4 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
10
[ 13739-02-1 ]
[ 478-43-3 ]
[ 875535-36-7 ]
[ 875535-35-6 ]
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2014, vol. 127, p. 355 - 360
11
[ 109650-18-2 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7906 - 7912
12
[ 820243-52-5 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
13
[ 820243-54-7 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
14
[ 820243-55-8 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
15
[ 1026688-54-9 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
16
[ 2161-90-2 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7906 - 7912
17
[ 152039-11-7 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7906 - 7912
18
[ 152039-20-8 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7906 - 7912
19
[ 65131-09-1 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, p. 383 - 384
20
[ 80301-53-7 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, p. 383 - 384
21
[ 80301-52-6 ]
[ 478-43-3 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, p. 383 - 384
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%.
With dmap; triethylamine; In acetic anhydride; at 20℃; for 1h;
a. Dissolve rhein (10g, 0.035mmol) in acetic anhydride solution and slowly add DMAP (2.15g, 0.018mmol) under stirring at room temperature. Solid appears in the reaction solution, and then slowly add triethylamine 9.7 mL, 0.07 mmol),The solid was dissolved and after rapid stirring at room temperature for 1 h, 1 M HCl was added dropwise. Another solid appeared in the solution and the reaction was quenched with water.The reaction solution was suction filtered, washed to obtain a crude product, the crude product was recrystallized to give a yellow powder compound B, a yield of 95%;
> 90%
With sulfuric acid; at 0 - 30℃; for 4 - 5h;
Example 5; Purified rhein (90 g) obtained in example 4 was dissolved in acetic anhydride (6.48 I) and the solution was cooled at 0C. Then sulphuric acid (64.8 ml) was added thereto and the reaction mixture was warmed at 300C. After completion of the reaction (4 - 5 hours), the reaction mixture was poured into distilled water at 40C and the precipitated diacerein was filtered, washed with distilled water and dried. Diacerein was obtained in a yield of more than 90 %. The diacerein was recrystallized in ethanol. The diacerein obtained was more than 98% pure.
85.4%
With sulfuric acid; at 5 - 35℃; for 3h;Inert atmosphere;
The reactor was charged with acetic anhydride (140.0 g) and the finished product of formula III (14.0 g).Stir well,Nitrogen protection,Prevent moisture from entering,Start to cool down to 5 C,Start adding 18.0 g of concentrated sulfuric acid,Control the dropping temperature below 10 C,After the addition is completed,Warming up to 35 C,Stir for 3 hours,HPLC detection of the residual of formula III 2.1%,Investing in another clean reactorPurified water (300 mL),Stir and cool to 5 C,Add the reaction solutionIn a reactor containing purified water,Control temperature below 20 C,Stir for 3 hours.The reaction solution is filtered,The filter cake is washed and beaten twice with water in the reactor.320g per time,Beat it again with 160.0g of ethanol,Stir for 0.5 hours,The filter cake was blast dried at 60 C for 11 hours.Obtained 17.0 g of crude (yellow),Input in the reactor190 g of N,N-dimethylformamide and 17.0 g of crude formula I,Raise to 80 C and stir for 2 hours.The solids are all dissolved,High temperature pressure filtration,The filtrate is kept warmed to another dry reactor,Slowly cool to 20 C with stirring.After filtration, the filter cake was washed twice with ethanol and beaten twice.80g each time,The filter cake is air dried for 8 hours.Drying temperature 70 C,This gave 15.5 g of product (yellow).99.6% purity,Single impurity is less than 0.1%,The yield was 85.4%.
With pyridine;
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%.
With zinc trifluoromethanesulfonate; at 130℃; for 2h;
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 4,5-diacetoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid 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.
With zinc trifluoromethanesulfonate; at 130℃; for 2h;
The rhein (284 mg, 1 mmol) was dissolved in acetic anhydride (612 mg, 6 mmol)Then, zinc trifluoromethanesulfonate (2 mg, 0.005 mmol) was added and then reacted at 130 C for 2 h,After completion of the reaction, the mixture was cooled to room temperature,filter,The crude product was recrystallized from acetic acid to give 4,5-acetoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid.4,5-acetoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (368 mg, 1 mmol) was dissolved in dichloromethane (5 mL)Oxalyl chloride (254 mg, 2 mmol) was added,A further drop of N, N-dimethylformamide,Stirred at room temperature for 1 hour,After the solvent was spin dried,Dissolved in methylene chloride,Was added 2-chloro-4-trifluoromethyl-aniline (200mg, 1.1mmol) and triethylamine (1mL),Stirred at room temperature for 4 hours,The reaction was quenched with saturated sodium chloride solution,And extracted three times with dichloromethane,Combine organic phase,Saturated brine washing,Filter spin dry,The product was 420 mg (yield 77%) by column chromatography.
Stage #1: Chrysophanol With chromium(VI) oxide In acetic anhydride; acetic acid at 65℃; for 8h;
Stage #2: With sodium carbonate In water
2
6g of chrysophanol was added to 150ml of mixed solution of anhydride and pyridine (1:1), overnight at room temperature. The reaction mixture was put into cold water for crystallization , then filtered and dried, was put into 300 ml of acetic anhydride and glacial acetic acid mixture (1:1). Chromium trioxide solution was dropped at 45°C, and then was stirred for 8 hours at 65°C. The reaction mixture was put into water, crystallized, filtered, added into 1000 ml of 25% sodium carbonate solution, extracted by chloroform for three times. Sodium carbonate solution was heated to boiling, cooled, added into hydrochloric acid for acidification. Until a large amount of gas is drained off, the solution was heated to boiling for 1 hour, cooled, crystallized, filtered and washed by water, recrystallized with glacial acetic acid, thus 2g of rhein was obtained. The product yield was above 98%.
98%
Stage #1: Chrysophanol With pyridine at 20℃;
Stage #2: With chromium(VI) oxide; acetic anhydride; acetic acid In water at 45 - 65℃; for 8h;
2
6 g of chrysophanol was added to 150 ml of mixed solution of anhydride and pyridine (1:1), overnight at room temperature. The reaction mixture was put into cold water for crystallization, then filtered and dried, was put into 300 ml of acetic anhydride and glacial acetic acid mixture (1:1). Chromium trioxide solution was dropped at 45° C., and then was stirred for 8 hours at 65° C. The reaction mixture was put into water, crystallized, filtered, added into 1000 ml of 25% sodium carbonate solution, extracted by chloroform for three times. Sodium carbonate solution was heated to boiling, cooled, added into hydrochloric acid for acidification. Until a large amount of gas is drained off, the solution was heated to boiling for 1 hour, cooled, crystallized, filtered and washed by water, recrystallized with glacial acetic acid, thus 2 g of rhein was obtained. The product yield was above 98%.
4,5-bis(tetrahydropyran-4-carbonyloxy)-9,10-dioxo-dihydroanthracene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
4, 5-Dihydroxy-9, 10-dioxoanthracene-2-carboxylic acid (168 g) was stirred in pyridine (5 L) at RT resulting in a brown suspension. The acid chloride (209 g, 1.41 mol) was added over 10 min and the reaction was stirred at RT for 48 h. The reaction mixture was split into 5 equal batches and each was added slowly to 3M HCI solution (3.75 L) with ice-cooling giving a yellow precipitate. The mixtures were filtered and the combined solid was triturated with acetone (2 x 600 ml). The resulting solid was dried in a vac-oven at 50 C (173 g, 83%). 'H NMR (400 MHz, DMSO): 1.78-1. 86 (4H, m), 1.97-2. 01 (4H, m), 2.91-2. 93 (2H, m), 3.43-3. 46 (4H, m), 3.92-3. 96 (4H, m), 7.59 (1 H, d J=7.6 Hz), 7.85-7. 91 (1H, t J=7. 6 Hz), 8.00 (1 H, s), 8.10 (1H, d J=7.6 Hz), 8.52 (1H, s). ESI : 509 (M + H+).
With sulfuric acid; sodium nitrite at 120℃; for 3h;
3
Example 3; Oxidizing medium was prepared by dissolving sodium nitrite (255 g) in sulphuric acid (1.2 I). The oxidizing medium was heated to 1200C and then aloe-emodin (100 g) was added slowly thereto. After completion of the oxidation reaction (3 hours), the reaction mixture was poured into distilled water (7.2 I) at 2°C to precipitate rhein, and rhein is filtered and dried. Rhein having a degree of purity of 90 - 95 % was obtained in a yield of more than 85 %.
62%
With water; pyridinium chlorochromate In N,N-dimethyl-formamide at 20℃; for 24h;
4.1.12 4,5-Dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (B7)
A mixture of compound A1 (1 mmol, 0.27 g), PCC (2 mmol, 0.45 g), DMF (100 ml) and 2 mL of water were stirred at room temperature for 24 h, monitored by TLC. After the completion of reaction, 100 mL of ice water was added under stirring to afford orange precipitate. The orange precipitate was filtered, washed and dried. Recrystallization of the orange precipitate from ethanol gave compound B7 as brown acicular crystals, yield 62%; mp 310-313 °C; IR νmax cm-1: 3432, 3059, 2930, 1695, 1628, 1270, 1192, 757; 1H NMR (DMSO-d6): δ = 7.58 (d, 1H, J = 8.2 Hz, 1H, H-C(6)), 7.85 (s, 1H, H-C(1)), 7.97 (dd, 1H, J1 = 8.2 Hz, J2 = 7.5 Hz, H-C(7)), 8.01 (s, 1H, H-C(3)), 8.45 (d, 1H, J = 7.5 Hz, H-C(8)), 11.87 (s, 1H, HO-C(1)), 11.94 (s, 1H, HO-C(8)), 13.90 (s, 1H, COOH); ESI-MS m/z: 285.04 [M+H]+.
62%
With pyridinium chlorochromate In water; N,N-dimethyl-formamide at 20℃; for 24h;
4 Synthesis of 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid
A mixture of compound 1 (1 mmol, 0.27 g), PCC (2 mmol, 0.45 g), DMF (100 ml) and 2 mL of water were stirred at room temperature for 24 h, monitored by TLC. After the completion of reaction, 100 mL of ice water was added under stirring to afford orange precipitate. The orange precipitate was filtered, washed and dried. Recrystallization of the orange precipitate from ethanol gave compound A4 as brown acicular crystals, yield 62%; m.p. 310-313 °C; IR νmax cm-1: 3432, 3059, 2930, 1695, 1628, 1270, 1192, 757; 1H NMR (d6-DMSO): δ = 7.58 (d, 1H, J = 8.2 Hz, 1H, H-C(6)), 7.85 (s, 1H, H-C(1)), 7.97 (dd, 1H, J1 = 8.2 Hz, J2 = 7.5 Hz, H-C(7)), 8.01 (s, 1H, H-C(3)), 8.45 (d, 1H, J = 7.5 Hz, H-C(8)), 11.87 (s, 1H, HO-C(1)), 11.94 (s, 1H, HO-C(8)), 13.90 (s, 1H, COOH); HRMS (ESI): calcd for [M + H]+ (C15H9O6) m/z 285.0399, found 285.0403.
Stage #1: 1,8-dihydroxy-3-hydroxymethyl-9,10-anthracenedione With dihydrogen peroxide; potassium hydroxide In 1,2-dimethoxyethane; water at 60 - 65℃;
Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 55 - 60℃;
2; 3
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 rheinRhein 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%
Multi-step reaction with 2 steps
1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide / 4 h / 30 °C
2: sodium dihydrogenphosphate; sodium chlorite / dimethyl sulfoxide; water / 4.5 h / 5 - 25 °C
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.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 5h;
50ml of methanol was added to a 100ml round bottom flask, placed in a cold trap 15min, a thermometer measuring the flask of methanol keeping the temperature below -10 . Weigh 1.5gL- aspartic acid, into a round bottom flask. Monitoring at any time along the sidewall, times slowly added thionyl chloride 1.5eq liquid, the bottle during the temperature kept below 0 . After stirring in the cold trap and then to aspartate dissolved, stirring was continued IH, then transferred to room temperature and stirred overnight. Drained under reduced pressure to give a yellow viscous liquid. Quantitative dichloromethane was added to give a quantitative solution. 50ml round bottomed flask was added 40mg rhein, 38.4mgEDC · HCl, 20mgHOBt, an appropriate amount of aspartic acid methyl ester, and then adding an appropriate amount of dichloromethane, then added 4-5 eq of triethylamine, stirred and dissolved, to purple, clear liquid. At room temperature was stirred 5h, TCL (chloroform as eluant) to monitor the reaction. Through the column, eluted with chloroform, collecting the second strip, rhubarb spin done aspartate ester. Rhubarb aspartic acid methyl ester to the acid, the solution was added 1MNaOH, IH After stirring for 45 , 10% hydrochloric acid was added dropwise, shallow purple solution, to precipitate a pale yellow solid, add two drops, to the solution was stirred for longer purple. Filtered, washed twice with water, ethanol and rinsed again, and dried to give a yellow solid rhubarb aspartate. TCL (toluene: ethyl acetate: formic acid = 7.5:2:0.5) have only one large polar than the starting material rhein yellow dot. Yield 28.9%,
N-(2-chloro-4-(trifluoromethyl)phenyl)-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
The rhein (284 mg, 1 mmol) was dissolved in dichloromethane (5 mL) Oxalyl chloride (254 mg, 2 mmol) was added, A further drop of N, N-dimethylformamide, Stirred at room temperature for 1 hour, After the solvent was spin dried, Dissolved in dichloromethane, Was added 2-chloro-4-trifluoromethylaniline (200mg, 1.1mmol) and triethylamine (1mL), Stirred at room temperature for 4 hours, The reaction was quenched with saturated sodium chloride solution, And extracted three times with dichloromethane, Combine organic phase, Saturated brine washing, Filter spin dry, The product was 380 mg (yield 82percent) by column chromatography.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 3h; Inert atmosphere;
21 Example 21
Under an argon atmosphere, Rhein (0 · 28g, 1 · 0mmol), EDCI (1 · 05g, 5 · 5mmol), H0Bt (0 · 61g,4.5 mmol) and bridging ligand 2- (1-imidazolyl) ethylamine (0.56 g, 5.0 mmol) dissolved in DMF, 100yL of TEA (triethylamine) was added dropwise, and stirred for 3 hours under ice bath, the crude product was separated and purified by column chromatography to obtain an organic compound L4 modified by a bridging ligand, the yield was 42%.
1
In this example, the rhein-isoquinoline alkaloid self-assembled nanoparticles were prepared by a method including the following steps.Taking the rhein-berberine complex as an example, weigh the rhein and berberine in a molar ratio of 10:1 to 1:10 and dissolve them in DMSO and methanol, and mix the two solutions to adjust the pH=8 -10, react for 20 minutes.Subsequently, the above-mentioned mixed solution was slowly added dropwise to PBS at 60° C., and incubated for 1 hour in an ultrasonic environment.Next, the above product is dialyzed to obtain the rhein-berberine nanoparticles.The preparation methods of the other two complexes are the same.The complex prepared in Example 1 was further analyzed by mass spectrometry.The conditions of mass spectrometry analysis are as follows: set the ion source to positive ion detection mode, capillary voltage 3.5kV, cone voltage 40V, ion source temperature 120, collision energy 35eV, cone gas flow rate 50L/h, desolvent gas flow rate 800L /h, mass spectrum collection range: 502000.No need for column separation and purification before mass spectrometry analysis.The molecular ion peaks and molecular structures of the nanoparticles obtained by mass spectrometry are shown in Table 1.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 10h;
(1) Add 1 eq of sunitinib and 1 eq of rhein to the reaction flask, and add 100ml of dichloromethane to dissolve;(2) After the above reaction system is cooled to normal temperature, add 1.1eq of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.1eq of 1-hydroxybenzotriazole in turn, add After completion, the reaction system was stirred at room temperature for 10 hours;(3) Add water to the reaction system to quench the reaction, then extract with 50 ml of ethyl acetate, wash the organic phase with 100 ml of saturated NaCl, dry over anhydrous NaSO4, filter, and remove the solvent to obtain the product.
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