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5.1 1-Methylpyrazol-5-yl 1-Methylbenzotriazole-5-carboxylate 1.5 g of 1-methylbenzotriazole-5-carboxylic acid (8.5 mmol) and 0.87 g of 1-methyl-5-hydroxypyrazole (8.9 mmol) were dissolved in 70 ml of abs. acetonitrile and admixed with 1.62 g of EDC (8.5 mmol), 2 ml of triethylamine and a catalytic amount of DMAP. After the reaction had ended, the solution was poured into water and the mixture was extracted with ethyl acetate. The organic phase was washed and dried, and the product was then purified by crystallization. Yield: 0.77 g (35%). 1H NMR (CDCl3, TMS): δ=3.82 (s, 3H); 4.40 (s, 3H); 6.28 (d, 1H); 7.48 (d, 1H); 7.67 (d, 1H); 8.36 (d, 1H); 8.98 (s, 1H) ppm.
In methanol; at 0℃; for 4.66667h;Heating / reflux;
3-Methoxyacrylic acid methyl ester (4 g, 34.45 mmol) was dissolved in methanol (50 ml) and cooled to O0C. Methyl hydrazine (1.75 g, 37.9 mmol) in methanol (20ml) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 10 minutes then heated to reflux for 4 hours. The reaction was then concentrated and purified by silica gel column chromatography eluted with ethyl acetate/methanol = 100/0 to 80/20 to recover the title product as a white solid (2.5 g, 73% yield). 1H NMR (400 MHz, DMSO-de) delta 3.463.47(3H s) 5.28-5.29(1H d) 7.06-7.08(1 H d) 10.75-10.81(1H bs)
In methanol; for 8h;Reflux; Inert atmosphere;
A magnetically stirred solution of methyl 3-methoxyacrylate (20.0g, 172.2mmol) in methanol (100mL) was treated slowly with N-methylhydrazine (10.0mL, 189.4mmol) then heated at reflux for 8h. The resulting mixture was cooled to room temperature then concentrated under a stream of nitrogen followed by high vacuum pump to afford an orange solid that was dissolved in DMF (19.9mL, 258.4mmol) and cooled to 0C. The resulting mixture was treated dropwise with phosphoryl chloride (48.1mL, 516.6mmol) then heated at 80C for 12h before being cooled and neutralised via the slow addition of ice cold NaOH (10M, 300mL). The aqueous solution was then extracted with a dichloromethane/isopropanol mixture (9:1, 5×100mL) and the combined organic phases were washed with chilled water (3x100mL), brine (1×100mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to afford an orange solid. Recrystallisation (dichloromethane/hexane) afforded the title pyrazole 8 (16.31g, 66%) as yellow crystals
In methanol; water; for 2h;Cooling with ice;
To a 1000 mL four-necked flask was placed 170 g of methanol under ice-water bath.At the same time, 116 g of methyl 3-methoxyacrylate and 262.8 g (35%) of an aqueous methylhydrazine solution were added dropwise to the flask.After the addition was completed, the reaction was continued for 2 hours.After the reaction was completed, methanol, water and methylhydrazine were distilled off under reduced pressure.That is, the product 1-methyl-5-hydroxypyrazole.
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