4-Nitro-1H-indazole

light yellow powder

A. Sodium nitrite (20 grams, 0.29 mol) was dissolved in 50 mL water. This solution was added all at once to 2-methyl-3-nitroaniline (20 grams, 0.13 moles) in glacial acetic acid near zero degrees C. The reaction was stirred vigorously with an overhead stirrer. An immediate precipitate occurred upon addition of sodium nitrite solution. The reaction was allowed to reach room temperature and stirred overnight. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark orange solid was suspended in water, filtered, and dried yielding 14-21 grams dark orange solid (99percent yield).General procedure: Take compound 7 (5.00g, 32.9mmol), was dissolved in glacial acetic acid (235 mL), under stirring, was added at once sodium nitrite (2.50g, 36.2mmol) in water (6mL)solution, keeping the internal temperature not higher than 20 deg. C, the reaction was stirred for 24h, the system under reduced pressure rotary evaporated to remove most of the glacial acetic acid, was added a lot of water, a lot of solid precipitation, after which the resulting solid was suction filtered, washed with water and dried in vacuo to give the title compound, using this method the synthesis of compounds 8a-8d.To a solution of 2-methyl-3-nitroaniline (50 g, 328 mmol) in AcOH (700 mL), a solution of NaN02 (45.4 g, 657 mmol) in water (100 mL) was added at 0 °C. The reaction was stirred at rt for 48h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was poured onto ice water and filtered. The filtrate was washed with water and dried under vacuum to afford 45 g of 4-nitro-1 H-indazole a1. Yield: 84percent. Reference Indazole-4-Boronate Ester (70): Route 1 EPO Reference Example 4:; Indazole-4-Boronate Ester:; (Route 1); (70) (69) EPO To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole (67) (1.98 g, 81percent).To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4- nitro-lH-indazole C (1.98 g, 81percent).To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole C (1.98 g, 81percent).Example 5 4-(4, 4, 5, 5-Tetramethyl-[l, 3, 2]dioxaborolan-2-yl)-lH-indazole7 -route 2 To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite ( 1.13 g, 1.1 eq.) in water (5mL). After 2 hours, the deep red solution was poured onto ice/ water and the precipitate collected by filtration to yield 4-nitro-lH-indazole (1.98g, 81percent).A mixture of 4-nitro-lH-indazole (760mg, 4.68 mmol), palladium on charcoal (10percent, cat.) and ethanol (3OmL) was stirred under a balloon of hydrogen for 4 hours. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield lH-indazol-4-ylamine (631mg, 100percent).An aqueous solution of sodium nitrite (337mg, 4.89mmol) in water (2mL) was added dropwise to a suspension of lH-indazol-4-ylamine (631mg, 4.74mmol) in 6M Example 3 4-(4, 4, 5, 5-Tetramethyl-[l, 3, 2]dioxaborolan-2-yl)-lH-indazole24 - route 2 [0189] To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid(60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, 2-Methyl-3-nitroaniline (4.023 g, 26.44 mmol) was dissolved inglacial acetic acid (200 mL). Afterwards, a solution of NaNOTo a solution of 2 -methyl- 3 -nitro aniline (500 mg, 3.29 mmol) in AcOH (10 mL) was added a solution of sodium nitrite (250 mg, 3.62 mmol) in HStep A: 4-(4, 4, 5, 5-Tetramethyl-[l, 3, 2]dioxaborolan-2-yl)-lH-indazole 1 - route 2[00239] To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98 g, 81percent).; Preparation of 4-nitro-lH-indazole: A mixture of 2-methyl-3-nitro aniline(200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20° C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30° C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 °C and water (8000 ml) was added, cooled to 25-30 °C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 °C for 2 hours, then was taken in 5percent ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5percent ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under Step A: Preparation of 4-nitro-1H-indazole: A mixture of 2-methyl-3-nitro aniline (200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20° C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30° C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 °C and water (8000 ml) was added, cooled to 25-30 °C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 °C for 2 hours, then was taken in 5percent ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5percent ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under vacuum at below 80 °C for 10 -12 h to give 4-nitro-lH-indazole as a brown solid (150 g, 70percent): mp: 200-203 °C; 1H NMR (200 MHz, CDCI3) δ 13.4 (br, 1H), 8.6 (s, 1H), 8.2-7.95 (dd, 2H), 7.4 (m, 1H). ESMS m/z 164 (M+1). Purity: 95percent (HPLC)2-methyl-3-nit.ro aniline (1O g, 0.005 mol) was taken in acetic acid (100 ml, 10 times) and cooled to 2OA solution of 2-methyl-3-nitτo-phenylamine (5.5 g, 36.15 mmol) in glacial acetic acid (250 ml) was stirred at 0° C. Sodium nitrite (2.5 g, 36.15 mmol) dissolved in water (6 ml) was added to the stirred solution all at once and the stirring continued for 15 min. Yellow precipitate was removed by filtration and discarded and the solution stirred at ambient temperature for 4 hr. Solvent was removed in vacuo and water (20 ml) was added. The precipitate was separated by filtration and dried to afford the crude product. Chromatographic purification on silica gel (eluent, hexane:ethyl acetate, 70:30 to 50:50) afforded the title compound (4.0 g, 67.8 percent).General procedure: To a cooled solution of the chosen 2-methylaniline dissolved in HBFStep 1Compound [65] (15.0 g, 0.099 mol) was dissolved in 375 ml glacial acetic acid in a 500 ml round bottom flask. An aqueous solution of sodium nitrite (8.16 g, 0.12 mol, in 35 ml of water) was added to it. The reaction mixture was stirred for 2 hrs at RT. TLC monitoring showed complete consumption of starting material. Reaction was ceased by the addition of ice-cold water, solid thus formed was filtered and dried well to afford yellowish solid [66] (10.0 g, 62 percent).Step 1 Compound [65] ( 15.0 g, 0.099 mol) was dissolved in 375 ml glacial acetic acid in a 500 ml round bottom flask. An aqueous solution of sodium nitrite (8. 16 g, 0. 12 mol, in 35 ml of water) was added to the reaction mixture. The reaction mixture was stirred for 2 hrs at RT. TLC monitoring showed complete consumption of starting material. Reaction was ceased by the addition, of ice-cold water, solid thus formed was filtered and dried well to afford yellowish solid [66] ( 10.0 g, 62 percent).

Molecular Weight:163.13
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:163.038176411
Monoisotopic Mass:163.038176411
Topological Polar Surface Area:74.5
Heavy Atom Count:12
Complexity:192
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes