1-Methylpyrazole-5-carboxylic Acid

1-methyl-pyrazole-5-carboxylic acid is a member of the class of pyrazoles that is N-methylpyrazole substituted by a carboxy group substituents at position 5. It has a role as a metabolite. It is a member of pyrazoles and a monocarboxylic acid. It derives from a N-methylpyrazole.

Under room temperature, the 1-methyl -1H-pyrazole (2.0g, 24.4 mmol) dissolved in THF in (30 ml). Under the protection of the nitrogen of the obtained mixture to lower the temperature to -78 °C, then slowly dripping n-BuLi to the (10.72 ml, 26.8 mmol). Then the resulting mixture at -78 ° C stirring 2 hours, to room temperature, then the stirring is performed for 1 hour. Then to the reaction solution to maintain this temperature in drying COTo a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78°C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78°C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78°C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78°C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 To a stirred solution of 1-methyl-1H-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen was added a solution of n-BuLi in hexane (2.6M, 670 mmol) dropwise at -78oC over a period of 1 h. Dimethyl sulfate (236 g, 177 mL, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20percent aqueous sodium hydroxide (850 mL) at 40 °C. The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HCI, the precipitate filtered, washed with water, and dried under vacuum to yield 1-methylpyrazole-5-carboxylic acid (85 g, 38percent). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid.A stirred solution of 3-methylpyrazole (82.1 g, 1.0 mol) in water (3.5 L) was heated to 70 °C. Potassium permanganate (111 g, 0.70 mol) was added in one portion, keeping the temperature near 70 °C. The reaction mixture was stirred for 1 h at 70 °C, and then a second portion of potassium permanganate (111 g) was added at 70 °C. After 1 h, a final portion of potassium permanganate (111 g) was added at 70 °C. The reaction mixture was stirred a further 2 h at 70 °C, and any unreacted oxidant was reduced by the dropwise addition of isopropanol. The reaction mixture was cooled to room temperature, filtered, the solid was rinsed with water, and the filtrate evaporated to 500 mL. The aqueous was chilled to 0 °C, acidified with concentrated HC1, filtered, the solid product washed with water, and dried under vacuum to provide pyrazole- 3-carboxylic acid as a white solid (64.4 g, 57percent). Dimethyl sulfate (236 g, 177 ML, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20percent aqueous sodium hydroxide (850 ML) at 40 °C. The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HC1, the precipitate filtered, washed with water, and dried under vacuum to yield 1-METHYLPYRAZOLE-5-CARBOXYLIC acid (85 g, 38percent). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid. A suspension of the acid (90 g, 0.71 mol) and DMF (1 drop) in thionyl chloride (250 ML) was stirred at reflux under nitrogen for 2 h. The solvent was evaporated from the reaction mixture, the residue azeotroped with toluene (3X200 mL), diluted into toluene (250 mL), added to a suspension of Pd-C (10 wtpercent, 9.3 g) in toluene (500 ML), and the mixture stirred at reflux for 8 h with a gentle flow of hydrogen gas through the suspension. After cooling to room temperature, the suspension was filtered through celite, washed with toluene, and concentrated in vacuo. The residue was fractionally distilled under vacuum to provide the title compound (50 g, 63percent) as a low melting white solid (bp = 92 °C COMMAT; 8 MMHG).1-Methyl-1H-pyrazole (5.00 g, 60.9 mmol) was dissolved in diethyl ether (anhydrous; 150 mL), n-butyllithium (2.5 M hexane solution, 26.8 mL, 67.0 mmol) was added while cooling to -78°C, and the mixture was stirred for 30 min at -78°C. The reaction mixture was added to finely pulverized dry ice (500 g), the mixture was heated to room temperature, and further stirred at room temperature for 1 hr. To the reaction mixture was added water (200 mL), and the aqueous layer was separated and washed with diethyl ether (3 x 100 mL). The aqueous layer was acidified by adding concentrated hydrochloric acid to pH 3, and the precipitate was collected by filtration, and dried to give the title compound (2.10 g) as a white solid (yield 27percent).

Molecular Weight:126.11
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:126.042927438
Monoisotopic Mass:126.042927438
Topological Polar Surface Area:55.1
Heavy Atom Count:9
Complexity:126
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes