* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 4h;
To a suspension of indazole-3-carboxylic acid 16AP (10.5g, 64.8mmol) in concentrated sulfuric acid (125ml) at OC was added KNO3 (64.8mmol, 6.55g). The reaction mixture was warmed up to r.t. After stirring for 4hr at r.t, it was poured into a 525ml of ice/water. Solid was collected by filtration and washed with water to give desired 5-nitro-1 H-indazole-3-carboxylic acid 17AP (10.74g, 80%).
63%
With sulfuric acid; nitric acid; at 10 - 20℃; for 1h;
At 10 C., indazole-3-carboxylic acid (0.3 g, 0.18) was dissolved in sulfuric acid (4 mL). Then a mixture of conc. sulfuric acid (2 mL) and 64% HNO3 (0.3 mL) was added and the mixture was allowed to warm to room temperature. After 1 h, the mixture was poured onto ice and water (30 mL). The resulting precipitate was filtered off and washed with cold H2O (2×20 mL). The crude product was recrystallized from AcOH to yield 0.17 g (63%). m.p. 189-194 C. 1H NMR (400 MHz, DMSO-d6) delta 14.3 (s, 1H), 9.37 (s, 1H), 8.38 (d, 1H), 7.69 (d, 1H), 6.9 (s, 1H).
With sulfuric acid; potassium nitrate; at 0 - 20℃;Product distribution / selectivity;
To a suspension of indazoIe-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 ml_ of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer.; Step iTo a suspension of indazole-3-carboxylic acid (3.0 g, 18 rnmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate (90 mL total). The combined organic layer was washed with brine, dried and concentrated to give (54) (2.9 g) as the major product.; Step iTo a suspension of indazoIe-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer.
Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and the reaction mixture was cooled to 0 C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 h. The mixture was stirred for an additional 1 h at 0 C and was poured onto of crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL acetonitrile and the mixture was heated at reflux for 2 h. The mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo to provide ethyl 5- nitroindazole-3-carboxylate (53%) as a colorless solid. The acid, obtained by basic hydrolysis, was coupled with the bicyclobase according to procedure A.
6
[ 75-03-6 ]
[ 78155-76-7 ]
[ 1021389-35-4 ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 54h;
Example 26; 1-ethyl-5-(3-propyl-ureido)-1H-indazole-3-carboxylic acid (thiophen-2-ylmethyl)-amide; The title compound was prepared according to the procedure illustrated in schemes 3 and 6. Step 1. Iodoethane (11.6 mL, 145 mmol) was added to a suspension of <strong>[78155-76-7]5-nitro-1H-indazole-3-carboxylic acid</strong> (10.0 g, 48 mmol) and K2CO3 (20.3 g, 145 mmol) in dimethylformamide (100 mL). The reaction mixture was shaken at room temperature for 18 hours. Again, iodoethane (11.6 mL, 145 mmol) and K2CO3 (20.3 g, 145 mmol) were added to the reaction mixture and shaken for another 18 hours, then heated at 80 C. for a further 18 hours. The reaction mixture was saturated with water (300 mL) and extracted with dichloromethane (3×300 mL). The organic phases were combined and washed with brine (300 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (10% to 50% ethyl acetate/heptane) to afford 1-ethyl-<strong>[78155-76-7]5-nitro-1H-indazole-3-carboxylic acid</strong> ethyl ester, 4.45 g (35%). LC(at)215 nm; Rt 1.41: 94%, m/z (ES+): 264.2 (M+H).
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