3-Methyl-1H-indazole-6-carboxylic acid synthesis

Yield:201286-96-6 80%

Reaction Conditions:

Stage #1: methyl 3-methyl-1-[(trifluoromethyl)sulfonyl]-1H-indazole-6-carboxylatewith water;potassium carbonate in methanol; for 2 h;Heating / reflux;
Stage #2: with potassium hydrogensulfate in water; pH=3 - 3.5;

Steps:

7

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%). 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%).

References:

WO2008/65508,2008,A1 Location in patent:Page/Page column 30-31