7-FLUOROINDAZOLE

Hydrazine monohydrate (3 ml) was added to 2, 3-difluorobenzaldehyde (1.85 g), and the mixture was heated at 180°C with stirring for 10 hr. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with saturated brine, was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under the reduced pressure. The residue was purified by chromatography on silica gel developed with chloroform/acetone to give the title compound (790 mg, yield 45percent). Reference Example 29 [0626] Step 1 [0627] Hydrazine monohydrate (10mL) was slowly added to Compound xii-1 (5g, 35.2mmol), and the mixture was stirred for 3 hours at 150 °C. The reaction mixture was concentrated in vacuo, and water was added to the mixture. The precipitated solids were collected by filtration to give Compound xii-2 (1.98g, Yield 41percent). [0628] General procedure: The title compounds were obtained by modifying a method described by Lukin et al. [63]. To the properly substituted 2-fluorobenzaldehyde (5 g, 35 mmol) was added hydrazine hydrate (12.9 g, 258 mmol, 12.5 ml). After stirring for 12-48 h (TLC control) at reflux water (20 ml) was added and the resulting mixture was cooled to 5 °C. The precipitate was collected by vacuum filtration. The filtrate was extracted with dichloromethane and the residue after evaporation was combined with the precipitate.General procedure: In a 250 mL flask, 1-chloro-2-nitrobenzene (3.5 g, 22.3 mmol), 4-methyl-1H-indazole (3.0 g, 23 mmol), cesium carbonate (7.4 g, 23 mmol), HMTA (0.1 g) and CuI (0.1g) were dissolved in DMF (100 mL). The mixture was heated to reflux for 26 h. After the complete disappearance of the substrates, the reaction was stopped and the mixture was cooled to room temperature. The reaction mixture was passed through a plug of celite and the filtrate was slowly added to the same volume of water, extracted three times with EtOAc and the organic phase was combined. The combinedorganic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to givea crude product. After the organic layer was concentrated, the residue was purified by column chromatography (EtOAc:PE=8:1) on silica gel to give 4-methyl-1-(2-nitrophenyl)-1H-indazole (3.8 g, yellow crystals. yield 68%).General procedure: To a solution of 2-hydroxy-3-methylbenzaldehyde (5 g, 36.7 mmol) inEtOH (30 mL) was added hydrazine hydrochloride (in excess) in a 250 mL flask. The solution was refluxed for 3 h and the solvent was distilled under reduced pressure. Purification of the residue by column chromatography (EtOAc:PE=10:1) on silica gel was performed to give 3.5 g of 7-methyl-1H-indazole, yellow crystals (73% yield).Preparation 50A: 7-Fluoro-5-nitro-lH-indazole and 7-fluoro-4-nitro-lH-indazole To a solution of 7-fluoro-lH-indazole (7.2g, 52.99 mmol) in 98% H2S04 (70 mL) was added KN03 (5.62 g, 55.64 mmol) portionwise at 0 C, allow the reaction mixture to stir for 4 hr at the same temperature; then poured into ice-water, extracted with EA, the combined organic layers were washed by H20, aq NaHC03, and dried over Na2S04, after concentration the residue was purified by flash chromatography on silica gel (PE/EA=3/1) to afford a mixture of 7-fluoro-5-nitro-lH-indazole and 7-fluoro-4-nitro- lH-indazole (8.23 g, 86%).Preparation 50C: 7-Fluoro-2-methylindazol-5-amine and 7-fluoro-2-methylindazol-4- amine To a solution of 7-fluoro-lH-indazole (7.2g, 52.99 mmol) in 98% H2S04 (70 mL) was added KN03 (5.62 g, 55.64 mmol) portionwise at 0 C, allow the reaction mixture to stir for 4 hr at the same temperature; then poured into ice-water, extracted with EA, the combined organic layers were washed by H20, aq NaHC03, and dried over Na2S04, after concentration the residue was purified by flash chromatography on silica gel (PE/EA=3/1) to afford a mixture of 7-fluoro-5-nitro-lH-indazole and 7-fluoro-4-nitro- lH-indazole (8.23 g, 86%). To a solution of a mixture of 7-fluoro-5-nitro-lH-indazole and 7-fluoro-4-nitro-lH- indazole (8.23 g, 45.47 mmol) in EA (100 mL) was added BF4-OMe3 (10.08 g, 68.20 mmol) at r.t. The mixture was stirred for 5 hr at r.t. aq NaHC03 was added to adjust pH = 7-8, the reaction mixture was extracted with EA, the combined organic layers were dried over Na2S04, the solvent was removed in vacuum to afford a mixture of compound 7- fluoro-2-methyl-5-nitroindazole and 7-fluoro-2-methyl-4-nitroindazole (3.2 g, 36%). (0471) A mixture of 7-fluoro-2-methyl-5-nitroindazole and 7-fluoro-2-methyl-4-nitroindazole (3.2 g, 16.41 mol), Fe (9.2 g, 164 mmol), and NH4Cl (439 mg, 8.20 mmol) in 80% EtOH (30 mL) was refluxed for 4 hr. LC/MS showed the reaction was completed. The mixture was filtered and concentrated, the residue was purified by flash chromatography on silica gel (PE/EA=1/1) to afford a mixture of 7-fluoro-2-methylindazol-5 -amine (326 mg) and 7-fluoro-2-methylindazol-4-amine (724 mg). 7-Fluoro-2-methylindazol-5-amine: 1H NMR (400 MHz, DMSO): delta 4.06 (3H, s), 4.96 (2H, s), 6.39 (1H, J= 1.2 Hz, d), 6.53 (1H, J= 13.6 Hz, 1.2 Hz, dd), 7.96 (1H, J= 2.8 Hz, d). [M+H] Calc'd for C8H8FN3, 166; Found, 166. 7-fluoro-2-methylindazol-4-amine: 1H NMR (400 MHz, DMSO): delta 4.12 (3H, s), 5.41 (2H, s), 5.84 (1H, J= 8.0 Hz, 2.8 Hz, dd), 6.67 (1H, J= 12 Hz, 7.6 Hz, dd), 8.32 (1H, J = 2.8 Hz, d). [M+H] Calc'd for C8H8FN3, 166; Found, 166.Preparation 5OB: 7-Fluoro-2-methyl-5-nitroindazole and 7-fluoro-2-methyl-4- nitroindazole To a solution of 7-fluoro-lH-indazole (7.2g, 52.99 mmol) in 98% H2S04 (70 mL) was added KN03 (5.62 g, 55.64 mmol) portionwise at 0 C, allow the reaction mixture to stir for 4 hr at the same temperature; then poured into ice-water, extracted with EA, the combined organic layers were washed by H20, aq NaHC03, and dried over Na2S04, after concentration the residue was purified by flash chromatography on silica gel (PE/EA=3/1) to afford a mixture of 7-fluoro-5-nitro-lH-indazole and 7-fluoro-4-nitro- lH-indazole (8.23 g, 86%). To a solution of a mixture of 7-fluoro-5-nitro-lH-indazole and 7-fluoro-4-nitro-lH- indazole (8.23 g, 45.47 mmol) in EA (100 mL) was added BF4-OMe3 (10.08 g, 68.20 mmol) at r.t. The mixture was stirred for 5 hr at r.t. aq NaHC03 was added to adjust pH = 7-8, the reaction mixture was extracted with EA, the combined organic layers were dried over Na2S04, the solvent was removed in vacuum to afford a mixture of compound 7- fluoro-2-methyl-5-nitroindazole and 7-fluoro-2-methyl-4-nitroindazole (3.2 g, 36%). [M+H] Calc'd for C8H6FN302, 196; Found, 196.

Molecular Weight:136.13
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:136.04367633
Monoisotopic Mass:136.04367633
Topological Polar Surface Area:28.7
Heavy Atom Count:10
Complexity:129
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes