2,5-dibromo-4-nitro-1H-imidazole

A mixture consisting of 4-nitroimidazole (100 g, 884 mmol), sodium bicarbonate (164 g, 1.94 mol), and water (500 ml) was intensively stirred, and thereafter, bromine (106 ml, 2.07 mol) was added dropwise to the mixture at room temperature (23°C to 25°C) over 6 hours (wherein it intensively foamed during the dropping). The thus obtained mixture was further stirred under heating (50°C to 55°C, 4 hours). Thereafter, water (400 ml) and concentrated hydrochloric acid (80 ml) were added thereto under cooling on ice (10°C or lower), and the obtained mixture was stirred for 1 hours. Crystals were collected by filtration. The obtained crystals were washed with water (on a filter paper, with 400 ml of water), dispersedly washed (with 800 ml of water, twice), and air-dried (50°C, 16 hours). Yield: 213 g (Yield: 88. 9percent), pale yellow crystal IR (KBr): 3074, 1548, 1468, 1392, 1361, 1345, 1310, 1259, 1172, 1066, 975, 830, 667 cm~l.Reference 4-nitroimidazole (25 g, 221 mmol), sodium bicarbonate (37.1 g, 442 mmol) and water (600 mL) for dilution and then bromine (30 mL, 620 mmol) the temperature at the dropwise addition and the reaction mixture was at 40 ° C and reacted for 12 hours. After filtering the solids level of the reaction mixture was washed with toluene three times and dried under reduced pressure to give a yield of 2, 5-dibromo-4-nitroimidazole of 39.8 g (67percent). Prepared 2, 5-di-bromo-4-nitroimidazole (39.8 g, 149 mmol) and water (450 mL) and then diluted to sodium iodide (223 g, 1486 mmol) was added and stirring under reflux was 12 sigan. Lower the temperature to room temperature, then filtered washing the solids in the reaction mixture with water, dried under reduced pressure to yield 2-bromo-5-iodo of 37.6 g (80percent) was obtained a 4-nitroimidazole. Prepared 2-bromo-5-iodo-4- nitroimidazole (20 g, 63 mmol) in ethanol (190 mL) and then diluted in triethylamine (26.5 mL, 190 mmol) and platinum oxide (108 mg, 0.47 mmol) to give the applied wave after reacting for 3 hours under a hydrogen pressure of 3 bar in the reactor was concentrated under a reduced pressure after filtration with a silica gel and celite. Yield of the reaction mixture with 2-ethyl acetate 10percent washed with hydrochloric acid solution to remove the moisture of the obtained organic layer over anhydrous magnesium sulfate, and then the filtrate was concentrated under reduced pressure and isopropyl alcohol and hexane, to obtain 7.9 g (65percent) and then diluted with to give a-bromo-4-nitroimidazole.Reference Preparation of 2, 5-dibromo-1-methoxymethyl-4-nitroimidazole Under an ice-cooling condition, sodium hydride (3.56 g) was added to a N, N-dimethylformamide (100 ml) solution of Reference Example 1Synthesis of l-ethoxymethyl-2, 5-dibromo-4- nitroimidazoleA mixture of 2, 5-dibromo-4-nitroimidazole (20.0 g, 73.8 mmol) , ethylal (100 ml), and methanesulfonic acid (1.42 g, 14.8 mmol) was stirred under heating (bath temperature: 65 to 70C, internal temperature: 60C, 1.5 hours) . Further, the reaction mixture was evaporated under reduced pressure for two hours (fractional distillation column was used) . The residue was allowed to cool to room temperature, and EPO Reference Example 2Synthesis of l-methoxymethyl-2, 5-dibromo-4- nitroimidazoleA mixture of 2, 5-dibromo-4-nitroimidazole (20.0 g, 73.8 mmol) , methylal (100 ml), and methanesulfonic acid (1.42 g, 14.8 mmol) was stirred under water-cooling, and P2O5 (21.0 g, 148 mmol) was added to the mixture at below 42C. Further, the mixture was suspended and refluxed under heating (43C, 3 hours) . The reaction mixture was evaporated under reduced pressure. The residue was allowed to cool to room temperature, and then ice water (200 g) was added, and the mixture was stirred for 10 minutes. The precipitated crystals were filtered, dispersed and washed (cold water 100 ml, 0.5 hour), and air-dried EPO A mixture consisting of 2, 5-dibromo-4- nitroimidazole (27.1 g, 100 mmol) and concentrated hydrochloric acid (434 ml) was stirred under heating (77C to 80C, 16 hours). The reaction mixture was left to cool, and then stirred under cooling on ice (5C to 10C, 2 hours). Thereafter, the precipitated crystals were collected by filtration and air-dried (50C, 5 hours). The yield of the dried product was 8.26 g. The filtrate was further extracted with ethyl acetate (300 ml) and then dried (MgSO4), followed by vacuum concentration and exsiccation. The yield of the exsiccated product was 9.63 g. Thus, 17.9 g (in total) of 2, 5-dichloro-4-nitroimidazole was obtained (yield: 98. 3%). IR (KBr) : 1566, 1475, 1403, 1366, 1332, 1272, 1190, 1091, 996, 834, 679 cm-l. MS (70 eV) m/z (relative intensity): 183 (15, M+), 181 (25), 108 (28), 74 (42), 62 (100).A suspension consisting of 2, 5-dibromo-4- nitroimidazole (27. 1 g, 100 mmol), sodium iodide (150 g, 1. 00 mol), and water (271 ml) was heated to reflux (102C, 15 hours). The reaction mixture was cooled to room temperature. Thereafter, crystals were collected by filtration, washed with water (on a filter paper, 270 ml), and then air-dried (50C, 20 hours). Yield: 29.0 g (Yield: 91. 2%), pale yellow crystal IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm-i MS (70 eV) m/z (relative intensity): 319 (80, M+), 317 (82), 154 (100), 106 (78).A mixture consisting of 2, 5-dibromo-4- nitroimidazole (108.3 g, 400 mmol), ethanol (184 ml), sodium iodide (120 g, 800 mmol) was heated to reflux in an argon stream (65-70C, 26 hours). The reaction mixture was cooled to room temperature and the precipitated inorganic salt was removed by filtration. 78% (234 ml) of the filtrate (300 ml) was concentrated and exsiccated under reduced pressure (25-50C). The residue (brown oil, 172 g) was suspended in chilled water (422 ml), and concentrated hydrochloric acid (10 ml) was added thereto such that the pH of the solution became 1 to 2. The thus obtained solution was further stirred under cooling on ice for 2 hours. Thereafter, the precipitated crystals were collected by filtration and then dried at 50C for 24 hours. Yield: 89.2 g (Yield: 89.9 %), pale yellow crystal IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm~l MS (70 eV) m/z (relative intensity): 319 (80, M+), 317 (82), 154 (100), 106 (78).A suspension consisting of 2, 5-dibromo-4- nitroimidazole (2.71 g, 10.0 mmol), sodium iodide (15.0 g, 100 mmol), tetrabutylammonium iodide (185 mg, 0.50 mmol), and water (27 ml) was stirred under heating (80C to 85C, 27 hours). The reaction mixture was cooled to room temperature. Thereafter, crystals were collected by filtration, washed with water (on a filter paper, 27 ml), and then air-dried (50C, 18 hours). Yield: 2.71 g (Yield: 85. 3%), pale yellow crystal IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm-1 MS (70 eV) m/z (relative intensity): 319 (80, M+), 317 (82), 154 (100), 106 (78).4-nitroimidazole (25 g, 221 mmol), sodium bicarbonate (37.1 g, 442 mmol) and water (600 mL) for dilution and then bromine (30 mL, 620 mmol) the temperature at the dropwise addition and the reaction mixture was at 40 C and reacted for 12 hours. After filtering the solids level of the reaction mixture was washed with toluene three times and dried under reduced pressure to give a yield of A suspension consisting of 2, 5-dibromo-4- nitroimidazole (2.71 g, 10. 0 mmol), water (13.6 ml), and a 57% hydriodic acid aqueous solution (13.6 ml) was stirred under heating (50C to 60C, 36 hours). The reaction mixture was cooled to room temperature. Thereafter, crystals were collected by filtration, washed with water (on a filter paper, 27 ml), and then air-dried (50C, 15 hours). Yield: 1.11 g (Yield: 34. 9%), . pale yellow crystal IR (KBr): 3218, 1537, 1456, 1386, 1336, 1288, 1250, 1156, 1048, 969, 829, 756, 731, 665 cm 1 MS (70 eV) m/z (relative intensity): 319 (80, M+), 317 (82), 154 (100), 106 (78).A mixture consisting of 4-nitroimidazole (100 g, 884 mmol), sodium bicarbonate (164 g, 1.94 mol), and water (500 ml) was intensively stirred, and thereafter, bromine (106 ml, 2.07 mol) was added dropwise to the mixture at room temperature (23C to 25C) over 6 hours (wherein it intensively foamed during the dropping). The thus obtained mixture was further stirred under heating (50C to 55C, 4 hours). Thereafter, water (400 ml) and concentrated hydrochloric acid (80 ml) were added thereto under cooling on ice (10C or lower), and the obtained mixture was stirred for 1 hours. Crystals were collected by filtration. The obtained crystals were washed with water (on a filter paper, with 400 ml of water), dispersedly washed (with 800 ml of water, twice), and air-dried (50C, 16 hours). Yield: 213 g (Yield: 88. 9%), pale yellow crystal IR (KBr): 3074, 1548, 1468, 1392, 1361, 1345, 1310, 1259, 1172, 1066, 975, 830, 667 cm~l.Reference Preparation of 4-nitroimidazole (25 g, 221 mmol), sodium bicarbonate (37.1 g, 442 mmol) and water (600 mL) for dilution and then bromine (30 mL, 620 mmol) the temperature at the dropwise addition and the reaction mixture was at 40 C and reacted for 12 hours. After filtering the solids level of the reaction mixture was washed with toluene three times and dried under reduced pressure to give a yield of Example 3 Synthesis of 2-bromo-4-nitroimidazole Into 1, 4-dioxane (1 ml) solution of tetra-n-butylammonium borohydride (638 mg) was added dropwise 1, 4-dioxane (1 ml) solution of