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3. Preparation of 4-carbomethoxypyrazole (5): To an ice cold saturated solution of HCl in methanol (500 ml), <strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (4) (19.2 g, 0.17 m) was added and the solution stirred at 0° C. for 3 hours and at ambient temperature overnight. The solvent was distilled off and the brown residue was dissolved in water. The aqueous solution was neutralized with NaHCO3 and the product was repeatedly extracted with ether (25*100 ml). The ether extract was dried over Mg SO4 and concentrated to give the methyl ester (5) as a pale yellow solid (13.59 g, 79.6percent).
With sulfuric acid; sodium methylate; In methanol; chloroform;
PREPARATIVE EXAMPLE 6 Synthesis of methyl pyrazole-4-carboxylate <strong>[37718-11-9]4-Pyrazolecarboxylic acid</strong> (514 mg) was dissolved in methanol (10 ml) and sulfuric acid (0.25 ml), and the mixture was stirred at room temperature for 2 hours, followed by refluxing under heating for 4 hours. After cooling, a 28percent solution (0.95 ml) of sodium methylate in methanol was added to the reaction mixture for neutralization and the solvent was distilled away. Chloroform was added to the residue, and the residue was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled away to give 433 mg of the title compound. 1 H-NMR(CDCl3 /ppm) delta3.92(3H, s), 8.08(2H, s), 8.26(1H, br s)
To the stirred solution of lH-pyrazole-4-carboxylic add 19-1 (20 g, 178.43 mmol) in methanol (100 niL) was added H2SO4 (17.50 g, 178.43 mmol, 9.51 rnL) at 0C and the reaction mixture was refluxed for 16 hours at 80C. Solvent was evaporated and the crude material was neutralized by saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and washed with brine. After separation, the organic layer was dried over sodium sulfate and evaporated to obtain methyl lH-pyrazole-4-earboxylate 19-2 (21 g, 166.52 mmol, 93.32% yield) as white solid. LC MS: ES+127.0.
78%
With sulfuric acid; at 70℃; for 20h;
1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (20 g, 178.4 mmol) and sulfuric acid (39.65 ml)in MeOH (200 ml) were heated at 70C for 20 h. The reactbn mixture was cooled to room temperature and concentrated in vacuo. Aqueous NaOH solution was added to adjust the pH to ~6. The aqueous layer was extracted with EtOAc (3 x 200 ml) and the combined organic extracts were dried (MgSQ;), filtered and evaporated in vacuo to afford the title compound (18.5 g , 78%) as a white solid. 1 H-NMR (CDCI3, 500 MHz): d[ppm]= 8.10 (s, 2H), 3.87 (s, 3H) HPLCMS (Method A): [m/z]: 126.85 [M+H]+
5 g
With hydrogenchloride; at 10 - 35℃;
A) methyl 1H-pyrazol-4-carboxylate A mixture of <strong>[37718-11-9]1H-pyrazol-4-carboxylic acid</strong> (4.00 g) and 4 M hydrogen chloride/methanol solution (150 mL) was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure to give the title compound (5.0 g). 1H NMR (400 MHz, DMSO-d6) delta 3.72 (3H, s), 8.09 (2H, s), 11.62 (1H, s).
4.5 g
With sulfuric acid; at 0℃;Reflux;
To a mixture of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (5.00 g, 44.6 mmol) in dry CH3OH (100 mL) was added drop-wise H2S04 (874 mg, 8.92 mmol) at 0C. The mixture was stirred at reflux overnight. A solution of NaOH (3.83 g, 95.7 mmol, 10 N) was added drop- wise to the reaction mixture. The mixture was poured into ice-water and diluted with ethyl acetate. The organic layer was washed with saturated aqueous lithium chloride solution and brine successively, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 10 : 1) to give methyl 1H- pyrazole-4-carboxylate (4.50 g) as a white solid. LC-MS (ESI) found: 127 [M+H]+.
methyl 1-tetrahydrofuran-3-ylpyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.1%
With caesium carbonate; In N,N-dimethyl-formamide;
To a mixture of methyl 1H-pyrazole-4-carboxylate (800 mg, 6.34 mmol, 1 eq) and 3- iodotetrahydrofuran (1.51 g, 7.61 mmol, 1.2 eq) in DMF (8 mL) was added cesium carbonate (4.13 g, 12.7 mmol, 2 eq) at 20 C under nitrogen. The mixture was stirred at 20 C for 4 h. The residue was poured into ice-water (w/w = 1/1) (100 mL). The aqueous phase was extracted with EA (30 mLx3). The combined organic phase was washed with brine (30 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give methyl 1-cyclopentylpyrazole-4-carboxylate as a white solid in 71.1% yield. LC-MS (ES+, m/z): 198.0 [(M+H)+].
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