| 98% |
With hydrogen In methanol at 20℃; for 5 h; |
SYNTHESIS EXAMPLESNo. 1-1: 2-[chloro(difluoro)methyl]-1H-benzimidazole-4-carboxamide; 2-Amino-3-nitrobenzoic acid (3.00 g, 16.47 mmol) was dissolved in dimethoxyethane (15 ml), thionyl chloride was added (2.61 g, 21.91 mmol), and the mixture was stirred at 50° C. for 12 h. Subsequently, the reaction mixture was concentrated under reduced pressure, the solvent was removed and then toluene was added, and the mixture was concentrated again. Thereafter, aqueous saturated ammonia solution (40 ml) was initially charged in a round-bottom flask and cooled to 10° C., and the acid chloride (3.30 g, 16.45 mmol) from the first step, which had not been purified any further, was added dropwise while stirring vigorously. In the course of this, the temperature of the reaction mixture was kept below 40° C. After the end of the addition, the reaction mixture was stirred at 50° C. for one hour, then diluted with water and stirred at room temperature. By filtering off the orange precipitate which formed with suction, washing with water and drying, 2-amino-3-nitrobenzamide (2.60 g, 87percent) was obtained. 2-Amino-3-nitrobenzamide (2.60 g, 14.35 mmol) was then added in a metal vessel to palladium on carbon (water-moist catalyst, 10percent Pd, 0.05 equiv., 0.072 mmol) in methanol (80 ml). In a laboratory reactor, hydrogen was introduced into the metal vessel and the resulting reaction mixture was stirred at room temperature at a pressure of 2 bar for 5 h. After complete conversion, the catalyst was filtered off through Celite and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was extracted with water and ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product did not need any further purification and contained 2,3-diaminobenzamide (2.15 g, 98percent) in a purity of >95percent. 2,3-Diaminobenzamide (200 mg, 1.32 mmol) was dissolved in chlorodifluoroacetic acid (3 ml) with vigorous stirring. The resulting reaction mixture was subsequently stirred under reflux for 3 h. After cooling to room temperature, NaHCO3 solution was added. In the course of this, the 2-[chloro(difluoro)methyl]-1H-benzimidazole-4-carboxamide target product (190 mg, 58percent) precipitated out as a colorless solid, which was filtered off with suction, washed with water and finally dried. 1H NMR (400 MHz, d6-DMSO δ, ppm) 14.40 (br. s, 1H, NH), 8.72 (br. s, 1H, NH), 8.02 (m, 1H, NH), 7.92 (m, 1H), 7.74 (m, 1H), 7.55 (m, 1H); 13C NMR (150 MHz, d6-DMSO δ, ppm) 165.5, 147.9, 139.1, 134.2, 124.9, 124.5, 123.9, 118.4-122.2 (t, CF2Cl), 116.6. |
| 98% |
With palladium 10% on activated carbon; hydrogen In methanol; water at 20℃; for 5 h; |
2-Amino-3-nitrobenzoic acid (3.00 g, 16.47 mmol) was dissolved in dimethoxyethane (15 ml), thionyl chloride was added (2.61 g, 21.91 mmol), and the mixture was stirred at 50°C for 12 h. Subsequently, the reaction mixture was concentrated under reduced pressure, the solvent was removed and then toluene was added, and the mixture was concentrated again. Thereafter, aqueous saturated ammonia solution (40 ml) was initially charged in a round-bottom flask and cooled to 10°C, and the acid chloride (3.30 g, 16.45 mmol) from the first step, which had not been purified any further, was added dropwise while stirring vigorously. In the course of this, the temperature of the reaction mixture was kept below 40°C. After the end of the addition, the reaction mixture was stirred at 50°C for one hour, then diluted with water and stirred at room temperature. By filtering off the orange precipitate which formed with suction, washing with water and drying, 2-amino-3-nitrobenzamide (2.60 g, 87percent) was obtained. 2-Amino-3-nitrobenzamide (2.60 g, 14.35 mmol) was then added in a metal vessel to palladium on carbon (water-moist catalyst, 10percent Pd, 0.05 equiv., 0.072 mmol) in methanol (80 ml). In a laboratory reactor, hydrogen was introduced into the metal vessel and the resulting reaction mixture was stirred at room temperature at a pressure of 2 bar for 5 h. After complete conversion, the catalyst was filtered off through Celite and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was extracted with water and ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product did not need any further purification and contained 2,3-diaminobenzamide (2.15 g, 98percent) in a purity of > 95percent. 2,3-Diaminobenzamide (200 mg, 1.32 mmol) was dissolved in chlorodifluoroacetic acid (3 ml) with vigorous stirring. The resulting reaction mixture was subsequently stirred under reflux for 3 h. After cooling to room temperature, NaHCO3 solution was added. In the course of this, the 2-[chloro(difluoro)methyl]-1H-benzimidazole-4-carboxamide target product (190 mg, 58percent) precipitated out as a colorless solid, which was filtered off with suction, washed with water and finally dried. 1H NMR (400 MHz, d6-DMSO δ, ppm) 14.40 (br. s, 1H, NH), 8.72 (br. s, 1H, NH), 8.02 (m, 1H, NH), 7.92 (m, 1H), 7.74 (m, 1H), 7.55 (m, 1H); 13C NMR (150 MHz, d6-DMSO δ, ppm) 165.5, 147.9, 139.1, 134.2, 124.9, 124.5, 123.9, 118.4-122.2 (t, CF2Cl), 116.6. |
| 53% |
With ammonium formate In methanol at 40℃; for 2 h; |
Pd/C (200 mg) is added to a stirred mixture of 2-amino-3- nitrobenzamide (1.81 g, 10.0 mmoles) or 2-AMINO-3-NITRO- (N- substituted) -benzamide and ammonium-formiate (3.78 g, 0.06 mol) in methanol (40 mL) or some other appropriate solvent and the mixture is stirred at 40 °C for 2 hours. The mixture is then filtered through Cellite, washed with methanol (40 mL) or the used solvent, evaporated and the residue is purified by way of crystallyzation or flash column chromatography to give 2,3-diaminobenzamide as a pale brown light sensitive solid (800 mg, 53 percent), MP 103-105 °C ; v max (CM-1) 3330,3170, 1630, 1600, MS m/z (percent) : 151 (M+, 70), 134 (72), 106 (100) 79 (38). The same method can be used for 2, 3-DIAMINO- (N-SUBSTITU- ted) benzamides |
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