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A suspension of 1.67 g of 60% sodium hydride in 134.0 mL dry DMF was added 7 g <strong>[932041-13-9]methyl 7-fluoro-1H-indazole-3-carboxylate</strong> in 10 mL dry DMF drop wise via syringe at room temperature. The mixture was allowed to stir for approximately 1 h at room temperature and was then added 8.02 g of 4-cyanobenzyl bromide in 56 mL DMF drop wise via syringe. The resulting mixture was then heated to 60 C. and allowed to stir over night. Reaction was allowed to cool to room temperature and was quenched by the careful addition of water (500 mL). The aqueous solution was extracted with ethyl acetate (4×150 mL). The organic solution is washed with brine (2×200 mL), dried (MgSO4), filtered and concentrated to an oil. Crude reaction was purified via MPLC (25%-50% ethyl ether/heptane) to afford 7.68 g (68.8%) of methyl 1-(4-cyanobenzyl)-7-fluoro-1H-indazole-3-carboxylate as a light yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.01 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H, 7.20-7.28 (m, 1H), 7.06-7.14 (m, 1H), 5.85 (s, 2H), 4.06 (s, 3H). MS (ESI) m/z 310 (M+H)+.
A solution of 30 g <strong>[959236-59-0]7-fluoro-1H-indazole-3-carboxylic acid</strong> in 1200 mL dry methanol was added 8 mL concentrated sulfuric acid. The resulting mixture was heated to reflux and was continued over night. Reaction was allowed to cool to room temperature and was diluted with ethyl acetate (1000 mL). Organic solution was washed with saturated NaHCO3 (2×250 mL), brine (2×250 mL), dried (MgSO4), filtered and concentrated to a brown solid. Crude reaction was purified via MPLC (5%-30% ethyl ether/heptane) to afford 20.74 g (64%) of methyl 7-fluoro-1H-indazole-3-carboxylate as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 14.49 (br s, 1H), 7.85-7.83 (m, 1H), 7.28-7.21 (m, 2H), 3.92 (s, 3H). MS (ESI) m/z 195 (M+H)+.
7-Fluoro-lH-indazole-3 -carboxylic acid (8.0 g) was dissolved in methanol (500 ml) . To the solution was added concentrated H2S04 (15 ml) at ice temperature, and the mixed solution was stirred under reflux for 7 hours. The solvent was removed under reduced pressure, chloroform was added to the residue, and the resultant was neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was further washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (column; Hi-Flash, developing solvent: hexane / ethyl acetate) and then purified again by silica-gel chromatography (column; Hi- Flash, developing solvent: chloroform / methanol) to give methyl 7-fluoro-lH-indazole-3-carboxylate (4.15 g) as a white crystal.
Methyl 7-fluoro-lH-indazole-3 -carboxylate (2.4 g) was dissolved in THF (70 ml) , and the solution was cooled to -70C. To the solution was added dropwise CH3MgI / diethyl ether (2.0 M, 21.63 ml) under nitrogen atmosphere. The reaction solution was stirred overnight with heating at 50C. After the reaction was completed, saturated ammonium chloride aqueous solution (100 ml) was added dropwise to the mixture at ice temperature. The mixture was extracted with ethyl acetate, the organic layer was further washed with brine, dried and concentrated under reduced pressure, and the residue was purified by silica-gel chromatography (column; Hi-Flash, developing solvent: hexane / ethyl acetate) to give the title compound (2.06 g) as a white crystal.LC-MS, m/z; 195 [M+H] +
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