| 87% |
at 132℃; for 2 h; Heating / reflux |
A suspension of 10.65 g (44.5 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one, 7.97 g (52.4 mmol) of 4-hydrazinobenzoic acid and 57.0 ml of propionic acid is heated to the boiling temperature of the reaction mixture and is kept at this temperature (132 0C) for 2 hours. After completion of the reaction, 57 ml of ethyl acetate is added to the suspension after cooling and the suspension is stirred for 30 minutes.The resulting crystalline product is filtered, washed with 30 ml of ethyl acetate on the filter and dried to a constant weight. A white crystalline product weighing 14.38 g is obtained, i.e. 87percent of the theory, with HPLC purity above 99.4percent and a melting temperature of 260 to 265 0C.Precipitation of the raw product is performed in such a way that the raw product is dissolved in a sodium hydroxide solution (6.16 g in 60 ml of water) and extraction with 50 ml of ethyl acetate is carried out. After separation the aqueous layer is filtered with 0.5 g of active carbon and after filtration the solution is acidified with hydrochloric acid to pH = 1 to 2 and the resulting suspension is stirred at the temperature of 20 0C for 30 minutes. The precipitated product is aspirated and washed with water until neutral pH. After drying to a constant weight, 14.3 g are obtained, i.e. 86percent of the theory, with an HPLC purity above 99.8percent and melting temperature of 263 to 265 0C.The precipitated product is stirred up with ethyl acetate by stirring in a suspension with 57 ml of ethyl acetate at a temperature of 20 0C for 30 minutes. The stirred-up product is aspirated and washed with ethyl acetate. After drying to a constant weight, 13.56 g are obtained, i.e. 82percent of the theory, with HPLC purity above 99.8percent. Melting temperature: 264 to 266 0C. |
| 87% |
With propionic acid In toluene at 110℃; for 2 h; Heating / reflux |
A suspension of 0.7 g (2.93 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-liydrazinobenzoic acid in 8.0 ml of toluene and 5 ml of propionic acid is heated to its boiling point and is maintained at this temperature (110 0C) for 2 hours. After completion of the reaction, the reaction mixture is cooled and filtration is carried out. The crystalline product is washed with toluene and dried until dry.0.95 g of white product is obtained (87percent of the theory), which contains 97.1percent of deferasirox having a melting temperature of 256 to 263 0C.Precipitation of the raw product is performed in such a way that raw deferasirox is dissolved in a solution of 0.6 g of sodium hydroxide in 30.0 ml of water and the solution is extracted with ethyl acetate (1 x 30.0 ml). The aqueous phase is filtered with active carbon and the filtrate is acidified with concentrated hydrochloric acid until pH = 1 to 2. The suspension is stirred at the temperature of 20 0C for 1 hour and the precipitated product is filtered and washed with water. After drying, 0.73 g of precipitated deferasirox (67percent of the theory) is obtained with a purity of 98.5 percent and a melting temperature of 260 to 264 0C. |
| 86% |
for 3 h; Reflux |
A solution of compound 4 (2.39 g, 10 mmol) and 4-hydrazinobenzoic acid (1.67g,11 mmol) was heated with stirring in 30 mL ethanol for 3 h at reflux. The reaction mixture was then cooled to room temperature; the precipitated solid was collected and dried under vacuum overnight. Recrystallization and decolorization with activated charcoal in ethanol afforded 3.21 g (86percent yield) of deferasirox (6) as a white solid. All spectroscopic data of product 6 matched those of an authentic sample. |
| 84% |
With propionic acid In ethyl acetate at 92℃; for 2 h; Heating / reflux |
A suspension of 0.7 g (2.92 mmol) of 2-(24iydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml ethyl acetate and 5.0 ml of propionic acid is heated to its boiling point and maintained at this temperature (92 0C) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with ethyl acetate. After drying, 0.92 g of raw deferasirox is obtained, i.e. 84percent of the theory, with an HPLC purity of 99.7percent and a melting temperature of 258 to 263 0C. |
| 82.5% |
Heating / reflux |
2-(2-hydroxyphenyl)benz(e)[l,3]oxazin-4-one (15.0 g) and 4-hydrazino- benzoic acid (10.5 g) are boiled under reflux in ethanol (225 ml). The reaction is checked for completion after 2 hours by Thin Layer Chromatography (TLC). If the reaction is not complete, the reaction mixture is stirred for an additional hour and the conversion is checked again until it is complete. If the reaction is complete, the mixture is cooled to room temperature and the precipitated solid material is filtered off, washed with ethanol and dried in vacuum. Yield: 82.5 percent. |
| 81% |
With propionic acid In N,N-dimethyl-formamide at 150℃; for 1.5 h; |
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N5N- dimethylformamide and 5 ml of propionic acid is heated up to 150 0C. The mixture is maintained at this temperature and stirred for 1.5 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.88 g of raw deferasirox is obtained, i.e. 81percent of the theory, with an HPLC purity of 93percent and a melting temperature of 255 to 262 0C. |
| 80% |
With triethylamine In ethanol for 2 h; Reflux |
2-(2-Hydroxyphenyl)-4H-3,1-benzoxazin-4-one was prepared according to the previous reported procedure with a little modifications (Lattmann and Acklin, 1997; Ryabukhin et al., 1983). 4-Hydrazino-benzoic acid (11.5mmol, 1.75g) and Et3N (11.5mmol, 1.16g) were dissolved in boiling EtOH (80ml). Then, 2-(2-Hydroxyphenyl)-4H-1,3-benzoxazin-4-one (10.45mmol, 2.50g) was added to the clear solution, and the reaction mixture was refluxed for an additional 2h. After the completion of the reaction, the solution was cooled to room temperature, and water was added until the first sign of precipitation was observed. The mixture was concentrated to a total volume of 50percent under reduced pressure and aqueous 6M HCl (40ml) was added. The resulting solid was filtered, washed with water and dried for 24h in vacuo (3.11g, Yield =80percent). (0011) IR (KBr, cm−1) ν 33,317, 2540, 1680 (νC=O), 1607, 1517, 1495, 1431, 1351, 1221, 988, 752. 1H NMR (CD3COCD3, ppm): δ=7.00 (s, 1H), 7.01–7.04 (m, 3H), 7.39 (m, 2H), 7.48 (d, 1H), 7.53 (d, 2H), 8.15 (d, 2H), 8.19 (d, 1H) 10.00 (s, OH), 10.78 (s, OH) ppm. 13C NMR (CD3COCD3, ppm) δ=113.7, 113.9, 116.6 (CH), 117.0 (CH), 119.5 (CH), 119.8 (CH), 124.0 (2 CH), 126.9 (CH), 130.4 (2 CH), 130.5, 130.7 (CH), 131.4 (CH), 132.6, 141.9 (CH), 152.1, 155.6, 156.4, 160.4, 165.7 (C=O) ppm. MS (m/z) for C21H15N3O4=(374) Anal. Calc. for C21H15N3O4: C 67.56, H 4.05, N 11.25; found C 67.16, H 4.09, N 10.86. |
| 79% |
With methanol In dichloromethane at 0 - 70℃; for 7 h; |
Example 2: Preparation of Deferasirox[0018] A mixture of methanol (450.0 ml), 2-(2-hydroxyphenyl)-benz[l ,3]oxazin- 4-one (30.0gm) were stir for 10 min at 25- 30°C. To the above contents 4- hydrazino benzoic acid (20.03gm) was added. The contents were heated to reflux temperature 65-70°C. The contents were maintained for 4 hours at 65-70°C. The reaction mass was cooled slowly to 0-5°C and maintained it for 1 hour at 0-5°C. The reaction mass was filtered and washed with methanol (30.0 ml). Compound was taken into methylene chloride and stir for 10 min 25 -30°C. The contents were heated to reflux temperature (40-45°C) and maintained the contents for 1 hr at reflux temperature. Cool the contents to .25- 30°C and stirred for lhr at 25 - 30°C. The reaction mass was filtered and washed with methylene chloride (30.0ml). Dried the compound at 60-65°C. Yield: 79.0percent. |
| 77% |
Stage #1: at 77℃; for 2 h; Industry scale
Stage #2: at 80℃; Industry scale |
The moist product obtained at the end of example 2 is placed in a reactor, together with 4.88 kg of 4-hydrazinobenzoic acid and 48 kg of a 3 wt.percent toluene/ethanol mixture. The mass is heated under reflux (approximately 77 °C) for 2 hours. To the mass maintained with heating under reflux, 12 kg of DMF is then added, and heating under reflux is continued (at a temperature of approximately 80 °C) until complete dissolution of the components present in the mixture is observed. 400 g of pharmaceutical quality decolourising carbon is then added. The suspension is heated under reflux (approximately 80 °C) with stirring for 30 minutes, then it is cooled to 60 °C and filtered. The filtered solution is placed in a reactor, heated under reflux, and 800 g of 85 wt.percent of phosphoric acid, and 24 kg of distilled water are added. A precipitate is formed, which is heated under reflux (approximately 80 °C) with continuous stirring for 30 minutes, after which the mixture is cooled to 30 °C, centrifuged, and the solid is washed with a mixture consisting of 24 kg of distilled water and 8 kg of 3percent toluene/ethanol.9.6 kg of raw deferasirox, dry equivalent, is obtained, determined by a weight loss test on step of the product, for a yield equal to approximately 77percent in this step. The product is analysed by HPLC, determining a purity of more than 99.8percent. By HPLC analysis it is determined that the 4-hydrazinobenzoic acid content of the product is below 0.5 ppm (which represents the limit of detection, LOD, of the analytical method .). |
| 60% |
at 100℃; for 1 h; |
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of methoxypropionic acid is heated to 100 0C. The mixture is maintained and stirred at this temperature for 1 hour. After completion of the reaction, the mixture is cooled and 5 ml of ethyl acetate are added. The resulting mixture is stirred for 10 minutes, then it is filtered and the crystals are washed with ethyl acetate. After drying, 0.66 g of raw deferasirox is obtained, i.e. 60percent of the theory, with an HPLC content of 99.3percent and a melting temperature of 259 to 263 0C. |
| 55% |
With trichloroacetic acid In toluene at 110℃; for 3 h; |
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 g of trichloroacetic acid and 5 ml of toluene is heated to 110 0C. The mixture is maintained and stirred at this temperature for 3 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water and ethyl acetate. After drying, 0.6 g of raw deferasirox is obtained, i.e. 55percent of the theory, with an HPLC content of 99.56percent and a melting temperature of 258 to 262 0C. |
| 50% |
With propionic acid In 2-methyltetrahydrofuran at 98℃; for 2 h; Heating / reflux |
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml of 2- methyltetrahydrofuran and 5.0 ml of propionic acid is heated to its boiling point and maintained at this temperature (98 0C) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with 2-methyltetrahydrofuran. After drying, 0.55 g of raw deferasirox is obtained, i.e. <n="11"/>50percent of the theory, with an HPLC purity of 95.3percent and a melting temperature of 255 to 262 0C. |
| 49% |
at 115℃; for 2 h; Heating / reflux |
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4- one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of lactic acid is heated to its boiling point and maintained at this temperature (115 0C) for 2 hours. After completion of the reaction the mixture is cooled down, causing separation of the crystalline product. 5 ml of ethyl acetate are added. After drying, 0.53 g of raw deferasirox is obtained, i.e. 49percent of the theory, with an HPLC content of 94percent and a melting temperature of 248 to 260 0C.Precipitation of the raw product is performed in such a way that raw deferasirox is dissolved in a solution of 0.23 g of sodium hydroxide in 20.0 ml of water and the solution is extracted with ethyl acetate (1 x 20.0 ml). The aqueous phase is filtered with active carbon and the filtrate is acidified with 0.75 ml of concentrated hydrochloric acid until pH = 1 to 2. The suspension is stirred at a temperature of 20 0C for 1 hour and the precipitated product is filtered and washed with water. After <n="12"/>drying, 0.31 g of precipitated deferasirox is obtained, i.e. 29percent of the theory, with a purity of 98.5percent and a melting temperature of 261 to 2640C.The precipitated product is stirred up in ethyl acetate by stirring in a suspension with 10 ml of ethyl acetate at a temperature of 20 0C for 30 minutes. The stirred-up product is aspirated and washed with ethyl acetate. After drying to a constant weight, 0.19 g is obtained, i.e. 17percent of the theory, with a purity above 99.0percent. Melting temperature: 258 to 263 0C. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
