5-BROMO-1H-INDAZOLE-3-CARBOXYLICACID

Step 1 A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120°C to get a clear solution. The solution was cooled to 90°C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90°C. The solution was further heated 16 h at 90°C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-lH-indazole-3-carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5percent yield). NMR (DMSO-dBenzopyrazole-3-carboxylic acid (81.1 g, 0.5 mol) was added to anhydrous acetic acid (4 L).Heat to 90°C and stir until the solids completely dissolve.A mixture solution of liquid bromine (160 g, 1 mol) and anhydrous acetic acid (300 mL) was slowly added dropwise. Control the dropping rate so that liquid bromine will not evaporate out of the condenser as much as possible. The system was incubated at 90°C and stirred overnight. The next day, a large amount of solids precipitated in the system. After the reaction was monitored by HPLC, the reaction was cooled to room temperature and allowed to stand for more than 3 hours, and suction filtered. The solid was washed with a little ethyl acetate, diethyl ether and dried. The resulting solid was refluxed with ethanol (500 mL) for 1 h, cooled, and the white solid was filtered off with suction and dried. 102.2 g of 5-bromobenzopyrazole-3-carboxylic acid was obtained in a yield of 84.8percent.5-Bromo-1H-indazole-3-carboxylic acid (96a) A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120°C to get a clear solution. The solution was cooled to 90°C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90°C. The solution was further heated 16 h at 90°C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-lH- indazole-3-carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5percent yield). 1H NMR (DMSO-dThe intermediate XIX was prepared according to the method reported (J Heterocyclic Chemistry, 1964, 1(5), 239-241). To a solution of 0.55 g of sodium hydroxide in 10 mL of water, 3.2 g of 5-bromoisatin (16.9 mmol) was added. After stirring for one hour the EPO (a) Step 1 Step 1 A suspension of indazole-3-carboxylic acid (CXXXI) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120 C. to get a clear solution. The solution was cooled to 90 C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90 C. The solution was further heated 16 h at 90 C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-1H-indazole-3-carboxylic acid (CXXXII) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-d6) delta ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J=1.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H); ESIMS found for C8H4BrN2O2 m/z 242.0 (M+H).A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120C to get a clear solution. The solution was cooled to 90C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90C. The solution was further heated 16 h at 90C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-lH-indazole-3-carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). NMR (DMSO-d6) delta ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.56 (dd, J = 7.0, 1.2 Hz, 1H); ESIMS found for Cs^BrNaOa mlz 242.0 (M+H).A suspension of indazole-3-carboxylic acid (XLIX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120 C. to get a clear solution. The solution was cooled to 90 C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90 C. The solution was further heated 16 h at 90 C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-1H-indazole-3-carboxylic acid (L) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-d6) delta ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J=1.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H); ESIMS found for C8H4BrN2O2 m/z 242.0 (M+H).A suspension of indazole-3-carboxylic acid (LII) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120oC to get a clear solution. The solution was cooled to 90oC. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90oC. The solution was further heated 16 h at 90oC. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-1H-indazole-3-carboxylic acid (LIII) as a white solid (1.30 g, 5.39 mmol, 87.5% yield).1H NMR (DMSO-d6) d ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.56 (dd, J = 7.0, 1.2 Hz, 1H); ESIMS found for C8H4BrN2O2 m/z 242.0 (M+H).Benzopyrazole-3-carboxylic acid (81.1 g, 0.5 mol) was added to anhydrous acetic acid (4 L).Heat to 90C and stir until the solids completely dissolve.A mixture solution of liquid bromine (160 g, 1 mol) and anhydrous acetic acid (300 mL) was slowly added dropwise. Control the dropping rate so that liquid bromine will not evaporate out of the condenser as much as possible. The system was incubated at 90C and stirred overnight. The next day, a large amount of solids precipitated in the system. After the reaction was monitored by HPLC, the reaction was cooled to room temperature and allowed to stand for more than 3 hours, and suction filtered. The solid was washed with a little ethyl acetate, diethyl ether and dried. The resulting solid was refluxed with ethanol (500 mL) for 1 h, cooled, and the white solid was filtered off with suction and dried. 102.2 g of 5-bromobenzopyrazole-3-carboxylic acid was obtained in a yield of 84.8%.A suspension of indazole-3- carboxylic acid (5.0 g, 30.8 mmol) in glacial acetic acid (250 mL) was heated at 120 C to get a clear solution. The solution was cooled to 90 C and added a solution of bromine (3.17 mL, 61.7 mmol) in glacial acetic acid (50 mL) drop wise and the reaction mixture was heated at 90 C for 16 h. The reaction mixture was cooled to room temperature, poured into ice water, the precipitated solid was filtered, washed with water and n-pentane and dried in high vacuum to give the title compound as off white solid m/z 241.0 [M + H]+ ; Yield (6 g, 81%).5-Bromo-1H-indazole-3-carboxylic acid (96a) Indazole-3-carboxylic acid (8.57 g, 51.9 mmol) was suspended in glacial acetic acid (500 mL) in a 3-neck 1 L round-bottomed flask fitted with overhead stirrer. Upon heating to 90 C. the starting material went into solution. Bromine (5.3 mL, 104 mmol) was added in acetic acid (50 mL) via addition funnel. The orange mixture was stirred 16 h at 90 C., then cooled to 5 C. in an ice bath. The yellow precipitate was collected by vacuum filtration, washed with EtOAc and Et2O, and dried under vacuum to afford 96a (9.24 g, 74%) as a pale yellow crystalline solid: 1H NMR (300 MHz, DMSO-d6) delta 8.20 (d, J=1.88 Hz, 1H), 7.64 (d, J=8.86 Hz), 7.55 (dd, J=1.88, 8.86 Hz, 1H).A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120C to get a clear solution. The solution was cooled to 90C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90C. The solution was further heated 16 h at 90C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-lH- indazole-3-carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-d6) delta ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.56 (dd, J = 7.0, 1.2 Hz, 1H); ESIMS found for C8H4BrN202 mlz 242.0 (M+H).A heterogeneous mixture of General procedure: To a solution of 5-bromo-1 /-/-indazole-3-carboxylic acid II (1 eq.) in dry DMF under Ar atmosphere, the proper amine (III, 1.2 eq.), DIPEA (4.5 eq.) and HATU (1.2 eq.) were added. After stirring at room temperature overnight, the solvent was evaporated under reduced pressure. The residue was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous Na2S04, filtered and evaporated under reduced pressure to give the intermediate compound having general formula IV. Purification by flash chromatography was performed when required.General procedure: A mixture of 5-bromo-1 /-/-indazole-3-carboxylic acid (II, 1 eq.), the proper amine (III, 1 - 1.2 eq.), HOBt (1.2 eq.) and EDC.HCI (1.2 eq.) in DMF was stirred at room temperature overnight. The reaction was checked by HPLC/MS. The mixture was concentrated and then diluted with EtOAc. The solution was washed with aqueous 2N NaOH solution and with brine. The organic phase was dried over anhydrous MgS04, filtered and evaporated under reduced pressure to give the intermediate compound having general formula IV. Purification by flash chromatography was performed when required.

Molecular Weight:241.04
XLogP3:2.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:239.95344
Monoisotopic Mass:239.95344
Topological Polar Surface Area:66
Heavy Atom Count:13
Complexity:224
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes