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With acetic acid; sodium nitrite; In water; at 20.0℃;Cooling with ice;
First Step [Show Image] To a glacial acetic acid solution (120 mL) of 2,3-dimethyl-5-nitroaniline [which can be synthesized, for example, by the method described in WO2005117819] (1.0 g, 6.02 mmol), an aqueous solution (3 mL) of sodium nitrite (0.42 g, 6.14 mmol) was added under ice cooling. The mixed solution was stirred under ice cooling for one hour, and then stirred at room temperature for 2 days. Acetic acid was distilled off under reduced pressure and water was added to the resulting residue, followed by stirring under ice cooling for 30 minutes. The precipitate was collected by filtration to obtain 1.14 g of 6-nitro-4-methylindazole. 1H-NMR (500 MHz, DMSO-d6) d: 2.67 (s, 3H), 7.75 (s, 1H), 8.27 (s, 1H), 8.37 (s, 1H).
With iron; ammonium chloride; In ethanol; for 1.0h;Reflux;
Second Step [Show Image] To an aqueous 80% ethanol solution (75 mL) of the product (0.80 g, 4.52 mmol) of the first step, ammonium chloride (0.12 g, 2.26 mmol) and iron (2.56 g, 45.2 mmol) were added, followed by reflux for one hour. The reaction mixture was cooled to room temperature and insoluble substances were filtered through cerite, followed by washing in turn with ethanol and ethyl acetate. The filtrate was concentrated under reduced pressure and water was added to the resulting residue, and then the precipitated solid was collected by filtration to obtain 0.43 g of 6-amino-4-methylindazole. 1H-NMR (500 MHz, DMSO-d6) d: 2.37 (s, 3H), 5.09 (s, 2H), 6.25 (s, 1H), 6.31 (s, 1H), 7.74 (s, 1H), 12.19 (s, 1H).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20.0℃; for 0.25h;
(Step 1) [0324] Iodoethane (1.2 mL) and sodium hydride (60% in oil; 600 mg) were added to a solution of <strong>[885520-77-4]4-methyl-6-nitro-1H-indazole</strong> (1.77 g), which can be synthesized by the method described in Patent No. WO 2009/084695, in DMF (17 mL), and the reaction solution was stirred at room temperature for 15 minutes. After dilution with ethyl acetate, the reaction solution was washed with water twice and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent: hexane/ethyl acetate) to obtain 1-ethyl-<strong>[885520-77-4]4-methyl-6-nitro-1H-indazole</strong> and 2-ethyl-4-methyl-6-nitro-2H-indazole as a light yellow solid, respectively.