| 51% |
With hydrazine hydrate; In ethylene glycol; |
6-Methoxy-3-methyl-1H-indazole To a stirred solution of 2'-fluoro-4'-methoxyacetophenone (0.5 g, 3.0 mmol) in ethylene glycol (10 mL) was added dropwise hydrazine hydrate (0.1 g, 3.1 mmol). The mixture was stirred for 24 h and partitioned between dichloromethane (20 mL) and water (3*20 mL). The organic layer was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give an orange oil. The oil was dissolved in ethylene glycol (10 mL) and heated at 165 C. for 24 h. The solution was cooled to room temperature and partitioned between dichloromethane (20 mL) and water (3*20 mL). The organic extract was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)] to give the product (0.25 g, 51%) as a colourless solid: IR numax (Nujol/cm-1) 1624, 1519, 1458, 1295, 1208, 1170, 1024 and 821; NMR deltaH (400 MHz, CDCl3) 2.54 (3H, s), 3.86 (3H, s), 6.78-6.81 (2H, m) and 7.52 (1H, d, J 9 Hz). |
| 32% |
With hydrazine hydrate; for 48h;Reflux; |
Acid Preparation 14; 3-Methyl-1 H-indazole-5-carboxvlic acid; A solution of 2-fluoro-4-methoxyactophenone (2.0 g, 12 mmol) in hydrazine hydrate (30 mL) was heated at reflux for two days. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3x). The organic extracts were concentrated, dissolved in a minimal amount of CH2CI2 and filtered to afford 6-methoxy-3-methyl-1 H- <n="51"/>indazole (370 mg, 19%). The filtrate was refiltered to provide additional product (250 mg, 13%). |
| 32% |
With hydrazine; for 48h;Heating / reflux; |
A solution of 2-fluoro-4-methoxyacetophenone (2.0 g, 12 mmol) in hydrazine (30 mL) was heated at reflux for 2 days. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3x). The combined organic extracts were concentrated, dissolved in a minimum amount of CH2CI2, filtered to provide 6-methoxy-3-methyl-1 H-indazole as a yellow solid (620 mg, 32%).To a solution of 6-methoxy-3-methyl-1 H-indazole (620 mg, 3.82 mol) in CH2CI2 (25 mL) at 0 0C was added a dichloromethane solution of boron tribromide (17 mL of 1 M solution). The mixture was stirred at room temperature overnight. The solution was carefully quenched by pouring slowly into iced saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic extracts were concentrated and the crude material was purified by Biotage chromatography (4OS column, acetone/heptane 45% 500 mL and 60% 150 mL) to provide 3-methyl-1H- . indazoJr6-ol as an orange, solid (458 mg, 81%).A solution of 3-methyl-1 H-indazol-6:l (458 mg73.1 "mmol) in THF (30 mL) was treated with sodium hydride (0.50 g of 60% oil dispersion). After the initial effervescence had subsided, the solution was heated to 50 0C for 1 hour before cooling to room temperature and adding N-phenyltrifluoromethane- sulphonimide (2.50 g, 7.0 mmol). The mixture was stirred at room temperature for 2 hours before pouring " into water.TheraqueTjus phase was extracted with EtOAc (3x). The combined organic extracts were concentrated and the crude material was purified by Biotage chromatography (4OM column, 12% acetone/heptane). To provide 3-methyl-1-(trifluoromethylsulfonyi)-1H-indazol-6-yl trifluoromethanesulfonate (1.13 g, 89%).A solution of 3-methyl-1-(trifluoromethylsulfonyl)-1 H-indazol-6-yl trifluoromethanesulfonate (0.61 g, 1.5 mmol) in DMF (6 mL) was flushed with carbon dioxide for 5 minutes. To this was added palladium acetate (68 mg, 0.30 mmol), 1,1 -bis(diphenylphosino)ferrocene (167 mg, 0.30 mmol), triethylamine (0.33 g, 0.45 mL, 3.2 mmol), and methanol (4 mL). The solution was stirred at room temperature overnight under one atmosphere of CO. The solution was poured into water and extracted with EtOAc (3x). The combined organic extracts were concentrated and purified by Biotage chromatography (4OS column, 8% EtOAc/heptanes) to provide methyl 3-methyl-1-(trifluoromethylsulfonyl)-1 H-indazole-6-carboxylate (330 mg, 69%). <n="32"/>To a solution of 3-methyl-1-(trifluoromethylsulfonyl)-1 H-indazole-6-carboxylate (590 mg, 1.83 mmol) in MeOH/water (3:1 , 72 mL) was added potassium carbonate (1.01 g, 7.31 mmol) and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature and methanol was removed under reduced pressure. The aqueous solution was acidified with KHSO4 to pH 3 - 3.5. The white precipitate that formed was isolated by vacuum filtration, dissolved in EtOAc and washed with water. The organic extract was dried over MgSO4, filtered, concentrated and dried to yield the title compound as a white solid (259 mg, 80%). |
|
With hydrazine; In ethylene glycol; at 20 - 150℃; for 52h; |
100 g of fluoro-acetophenone in 400 ML of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4h after which the reaction mixture was heated to 150 C for 48h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave indazole. |
|
With hydrazine; |
REFERENCE EXAMPLE 49 6-methoxy-3-methyl-1 H-indazole 2-fluoro-4-methoxyacetophenone (5.0 g) was treated with hydrazine (75 ml) under argon and the mixture was heated to reflux for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (200 ml) then extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluding with a mixture of ethyl acetate and hexane (1:3, v/v) to yield the title compound (4.05 g). |
| 4.2 g |
With hydrazine hydrate; at 140℃; for 20h; |
To 2'-fluoro-4'-methoxyacetophenone (5.24 g) was added hydrazine monohydrate (20 mL) at room temperature, and then the reaction mixture was stirred at 140C for 20 hours. The precipitated solid was filtered to give the titled compound (4.20 g) as a red solid. 1H-NMR (400 MHz, CDCl3) delta:7.52 (1H, d, J=9.3 Hz), 6.80-6.78 (2H, m), 3.86 (3H, s), 2.54 (3H, s). |
|
With hydrazine; In ethylene glycol; at 20 - 150℃; for 52h; |
[0111] 100 g of 2-fluoro-4-methoxy-acetophenone in 400 mL of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4 h after which the reaction mixture was heated to 150 C. for 48 h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave 6-methoxy-3-methyl-1H-indazole. [0112] 1H NMR (CDCL3): 7.5 (1H, d, 7.5 Hz); 6.8 (2H, m); 3.8 (3H, s); 2.55 (3H, s) LCMS [M+H]=163 |
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