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To a solution of 4-chloro-5-nitro-benzene-1 ,2-diamine (8.34 g, 44.4 mmol) and THF (625 ml_) was added carbonyl diimidazole (8.65 g, 53.3 mmol) at 0 0C. The reaction mixture was allowed to warm to 23 0C and was stirred for 20 h at this temperature. The reaction mixture was concentrated to a volume of 300 ml_ and 500 ml_ aqueous 1 M HCI was added, followed by water (total volume 2 L). The resulting suspension was cooled at 0 0C for 2 h, and the precipitate was collected and dried on the filter. It was then triturated with cold EtOAc (20 ml_) and rinsed EtOAc (2 x 5 ml_) to yield the titled compound (7.26 g, 76percent yield). MS (ESI/CI): mass calcd. for C7H4CIN3O3, 213.0; m/z found, 214.0 [M+H]+.
4.1. 5-Chloro-6-nitro-1,3-dihydro-2H-benzimidazole-2-one A mixture of 14 g (0.074 mol) of 4-chloro-5-nitro-1,2-benzenediamine and of 13.44 g (0.226 mol) of urea is heated at 180 C. for 4 hours. The reaction mixture is cooled and evaporated to dryness. The residue is taken up in methanol and evaporated again. The residue is triturated in ether and a solid is obtained which is filtered. The product is used as is in the subsequent stages.
To 5-chloro-6-nitro-1 ,3- dihydro-benzoimidazol-2-one (5.63 g, 26.35 mmol) was added phosphorus oxychloride (35 ml_) and the reaction mixture was heated to 85 0C for 36 h. The reaction mixture was concentrated and the residue triturated with cold saturated aqueous sodium bicarbonate (to pH 8, 0.8 L). The resulting precipitate was collected and dried to yield the titled compound (5.43 g, 89% yield). MS (ESI/CI): mass calcd. for C7H3CI2N3O2, 231.0; m/z found, 232.0 [M+H]+. Step C: 2,6-Dichloro-1 -(2-methoxy-ethoxymethyl)-5-nitro-1 /-/-benzoimidazole.
To a solution of 4-chloro-5-nitro-benzene-1 ,2-diamine (8.34 g, 44.4 mmol) and THF (625 ml_) was added carbonyl diimidazole (8.65 g, 53.3 mmol) at 0 0C. The reaction mixture was allowed to warm to 23 0C and was stirred for 20 h at this temperature. The reaction mixture was concentrated to a volume of 300 ml_ and 500 ml_ aqueous 1 M HCI was added, followed by water (total volume 2 L). The resulting suspension was cooled at 0 0C for 2 h, and the precipitate was collected and dried on the filter. It was then triturated with cold EtOAc (20 ml_) and rinsed EtOAc (2 x 5 ml_) to yield the titled compound (7.26 g, 76% yield). MS (ESI/CI): mass calcd. for C7H4CIN3O3, 213.0; m/z found, 214.0 [M+H]+.
In tetrahydrofuran; at 85℃; for 4.0h;
General procedure: Step 1 : 5-Chloro-6-nitro-lH-benzo[ ]imidazol-2(3H)-one A stirred solution of 4-chloro-5-nitro-l ,2-phenylenediamine (2.0 g, 10.66 mmol) and CDI (2.59 g, 16 mmol) in anhydrous THF (50 mL) was heated to 85 C for 4 h. The reaction was allowed to cool and the solvents were removed under reduced pressure. The resulting residue was washed with 2M aqueous hydrochloric acid and recrystallised from methanol to afford 5-chloro-6-nitro-lH-benzo[ ]imidazol-2(3H)-one as a brown solid (1.9 g, 84%), which was taken through to the next step with no further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 1.5h;
Step 2: 5-Chloro-l,3-dimethyl-6-nitro-lH-benzo[JJimidazol-2(3H)-one 5-Chloro-6-nitro-lH-benzo[ ]imidazol-2(3H)-one (1.00 g, 4.7 mmol) was stirred in DMF (50 niL) then potassium carbonate (1.29 g, 9.4 mmol) and iodomethane (2.66 g, 18.7 mmol) were added. The reaction was stirred at 75 C for 1.5 h. The reaction was allowed to cool and solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were through a phase separation cartridge and evaporated to afford a brown solid (1.07 g, 95%), which was taken through to the next step with no further purification.
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