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With sulfuric acid; for 4.0h;Reflux; Inert atmosphere;
General procedure: Concentrated sulfuric acid (1 mL) was added to a suspension of 5- bromo-lH-indazole-3-carboxylic acid (CXV) (1.30 g, 5.39 mmol) in dry MeOH (50 mL) and heated to reflux for 4 h under argon. The solution was cooled to room temperature and the MeOH was evaporated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2S04, filtered and concentrated to afford methyl 5-bromo-lH-indazole-3-carboxylate (CXVI) as a white solid (1.35 g, 5.29 mmol, 98% yield). 1H NMR (DMSO-d6) delta ppm 14.13 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.67 (d, J= 7.2 Hz, 1H), 7.59 (dd, J= 7.2, 1.2 Hz, 1H), 3.92 (s, 3H); ESIMS found for C9H7BrN202 mlz 256.0 (M+H).
64.5%
With sulfuric acid; for 4.0h;Inert atmosphere; Reflux;
General procedure: Concentrated sulfuric acid (1 mL) was added to a suspension of 5-bromo- lH-indazole-3-carboxylic acid (CXV) (1.30 g, 5.39 mmol) in dry MeOH (50 mL) and heated to reflux for 4 h under argon. The solution was cooled to room temperature and the MeOH was evaporated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2SO/t, filtered and concentrated to afford methyl 5-bromo-lH- indazole-3-carboxylate (CXVI) as a white solid (1.35 g, 5.29 mmol, 98% yield). NMR (DMSO-d6) delta ppm 14.13 (s, 1H), 8.21 (d, J= 1.6 Hz, 1H), 7.67 (d, J= 7.2 Hz, 1H), 7.59 (dd, J = 7.2, 1.2 Hz, 1H), 3.92 (s, 3H); ESIMS found for CgHvBrNaOa mlz 256.0 (M+H)
11
[ 1081-04-5 ]
[ 705264-93-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78 - 0℃; for 3.3h;
Step 1 <strong>[1081-04-5]Ethyl 5-bromo-1H-indazole-3-carboxylate</strong> (16.44 g, 61.09 mmol) prepared according to a known method [J. Am. Chem. Soc., volume 74, page 2009 (1952)] was dissolved in tetrahydrofuran (610 mL), a toluene solution of 1.0 mol/L diisobutyl aluminum hydride (305 mL, 305 mmol) was added over 20 minutes period under nitrogen stream at -78 C and temperature thereof was gradually raised up to 0 C while stirring, followed by further stirring for 3 hours. To the reaction solution was added sodium sulfate decahydrate (98.23 g, 304.9 mmol). This was stirred for one night, the mixture was dried over anhydrous sodium sulfate and filtered through Celite, and the filtrate was concentrated in vacuo to give 5-bromo-3-hydroxymethyl-1H-indazole (13.81 g, quantitatively).Rf = 0.5 (chloroform/methanol = 9/1) 1H-NMR (270 MHz, DMSO-d6)delta; 5.04 (d, J = 5.9 Hz, 2H), 5.76 (t, J = 5.9 Hz, 1H), 7.67-7.74 (m, 2H), 8.30 (s, 1H).
A solution of 5-bromo-lH-indazole-3-carboxylic acid ethyl ester (1.5 g, 5.6 mmol, 1.0 eq) in cone. H2S04 (20 mL) was cooled to 0 C. A mixture of 70 percent HN03 (1.1 mL) and cone. H2S04 (3 mL) was added drop wise and the reaction was maintained for 1 h at 0 C. The mixture was poured into 100 mL of ice water and the solid was collected by filtration and dried in vacuo to give 5-bromo-4-nitro-lH-indazole-3-carboxylic acid ethyl ester (1.6 g, 91%) as a yellow solid. [00299] To a solution of 5-bromo-4-nitro-lH-indazole-3-carboxylic acid ethyl ester (1.6 g, 5.1 mmol, 1.0 eq) in EtOH (80 mL) was added Pd/C (320 mg). The reaction mixture was stirred at rt under 50 psi H2 for 5 h. The reaction was filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 50/1, v/v) to give 4-amino-lH-indazole-3-carboxylic acid ethyl ester (255 mg, 24%) as a yellow solid.
86%
With sulfuric acid; nitric acid; In water; at 0℃; for 1.0h;
Ethyl 5-bromo-lH-indazole-3-carboxylate (5.02 mmol) was dissolved in sulfuric acid (20.0 mL) and was cooled to 0 C. A mixture of 70% nitric acid (7/3, nitric acid/water, 1.0 mL) and sulfuric acid (2.0 mL) was added dropwise and the reaction was maintained for 1 hour at 0 C. The reaction mixture was poured onto 100 mL of ice water and the solids collected by filtration, thus providing the product in 86% yield. The ester (3.82 mmol) was diluted with ethanol (10.0 mL) and 5 M sodium hydroxide (10.0 mL) and the reaction mixture was maintained for 4 h at ambient temperature. The reaction mixture was diluted with water (50 mL) and acidified to pH 1 with 6 N hydrochloric acid. The solids were collected by filtration, thus providing the acid in 82% yield
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