Patent US 8324,411
|Inventors||Annibale Salvi, Antonio Nardi, Stefano Maiorana, Mara Sada|
|Original Assignee||Laboratorio Chimico Internazionale S.P.A.|
aReagents and conditions: (a) (i) K2CO3, KI, Bu4NBr, DMF, 60 °C; (ii) 80 °C, 1 h; (iii) BnCl, 50 °C, 1 h; (iv) 80 °C, 1 h; (v) add MeOH at 50 °C; (vi) cool to <25 °C, filter; (vii) evaporate, add THF; (viii) wash at 60 °C with aq NaOH, H2O, brine; (ix) evaporate, add EtOAc, concentrate; (x) cool <4 °C, 1 h; (xi) filter, wash, dry. (b) (i) TEMPO, aq NaH2PO4, aq Na2HPO4, MeCN, 35 °C; (ii) add aq NaClO2, 35 °C, 50 min; (iii) add aq NaOCl, 65 °C, 3 h; (iv) cool rt, add H2O; (v) add H3PO4, pH 3; (vi) filter, H2O wash, dry; (vii) Et3N, DMF, EtOAc, 60 °C, 0.5 h; (viii) filter hot; (ix) add H2O, separate; (x) extract H2O phase at 60 °C with EtOAc (×6); (xi) cool organic phases to rt, add HCl to pH 2; (xii) cool <5 °C, 1 h; (xiii) filter, H2O wash, MeCN wash, dry. (c) (i) FeCl3, Ac2O, 65 °C, 1.5 h; (ii) cool <4 °C, 1 h; (iii) filter, wash in Ac2O, EtOAc wash, dry.
Example 1 Preparation of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone (dibenzyl aloe-emodin)483 g (3.5 moles) of potassium carbonate, 16 g (0.1 moles) of potassium iodide and 16 g (0.05 moles) of tetrabutylammonium bromide are added to a solution of 270 g (1 mole) of 1,8-dihydroxy-3-(hydroxymethyl)anthraquinone (aloe-emodin) in 3500 ml of DMF at 60° C.; the reaction mixture is heated at 80° C. for 1 h. It is cooled to 50° C. and 443 g (3.5 moles) of benzyl chloride are added dropwise in approximately one hour. At the end of the dripping, the reaction mixture is brought back to 80° C. and left at that temperature under stirring for 45-60 minutes. It is then cooled to 50° C. and 200 ml of methyl alcohol are added. It is cooled to 20-25° C. and the inorganic salts are removed by filtering. The organic solvent is distilled at 60-70° C. at reduced pressure and the residue is dissolved in 3200 ml of tetrahydrofuran at 60° C. Maintaining the temperature at 50-60° C., the organic phase is washed twice with 1200 ml of 2.5 molar aqueous sodium hydroxide and once with 1000 ml of a saturated solution of sodium chloride in water. The organic phase is concentrated at reduced pressure at 60° C. and the residue is recovered with 2700 ml of ethyl acetate. The suspension thus obtained is concentrated to approximately ⅓ of the initial volume by distillation of the solvent at reduced pressure. It is gradually cooled to 0-4° C. and kept at that temperature for 1 hour. The solid is filtered and washed with ethyl acetate (100 ml×2). The damp product is dried at 45° C. at reduced pressure for 12-14 hours, providing 334 g (yield 74%) of dibenzyl aloe-emodin having a purity of 98% (HPLC).
melting point: 170-171° C.
IR cm−1: 1655, 1612, 1232
Example 2 Synthesis of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)10 g (0.06 moles) of radical 2,2,6,6-tetramethyl-1-piperidinyl-oxyl (TEMPO) and 1160 ml of an aqueous solution of 120 g (1 mole) of sodium dihydrogen phosphate and 180 g (1 mole) of disodium hydrogen phosphate are added in sequence to a suspension of 333 g (0.74 moles) of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone in 1660 ml of acetonitrile. The reaction mixture is heated to 35° C. and a solution of 167 g (1.5 moles) of sodium chlorite 80% in 513 ml of water is added dropwise in 40-50 minutes, maintaining the temperature around 35-40° C. 20 ml of aqueous sodium hypochlorite 10-12% are then dripped in and the reaction is heated to 60-65° C. for three hours. It is cooled to room temperature and 1400 ml of water are added. Phosphoric acid 85% is dripped in until reaching a pH of 2.8-3.2. The solid obtained is filtered and washed with water (350 ml×2). The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 337 g (yield 98%) of crude dibenzylrhein.
Example 3 Purification of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)337 g (0.72 moles) of crude 1,8-dibenzyloxyanthraquinone-3-carboxylic acid are dissolved in a solution of 134 ml of triethylamine in 900 ml of dimethylformamide DMF and 1800 ml of ethyl acetate, heating to 60° C. for 20-30 min. Any undissolved elements are removed by hot filtering and 2700 ml of water are added. The organic phase is separated and the aqueous phase is washed 6 times with 800 ml of ethyl acetate each time, maintaining the temperature at 60° C. The organic phase is cooled to room temperature and acidified with hydrochloric acid 33% until pH 2 is reached; the suspension thus obtained is cooled to 0-5° C. for approximately 1 hour. The product is filtered, washing it thoroughly with water (1200 ml) and then with 200 ml of acetonitrile. After drying at 50° C. at reduced pressure for 14-16 hours, 256 g of dibenzylrhein are obtained with a yield of 76%.
melting point: 250-251° C.
IR cm−1: 1666, 1621, 1587, 1524
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) δ: 2.4 (6H, s); 7.6 (1H, dd); 7.9 (1H, t); 8.0 (1H, d); 8.1 (1H, dd); 8.5 (1H, d).
IR cm−1: 1763, 1729, 1655, 1619, 1591, 1183.
Chromium: not detectable (<1 ppm)
Genotoxic impurities (aloe emodin and acetyl derivatives)≦2 ppm.
/////////Diacerein, US 8324411, PATENT