5-Methyl-1H-pyrazole-3-carboxylic acid

White to light yellow solid

5-methyl-pyrazole-3-carboxylic acid is a memebr of the class of pyrazoles that is 1H-pyrazole with methyl and carboxylic acid group substituents at positions 5 and 3 respectively. It has a role as a metabolite. It is a member of pyrazoles and a monocarboxylic acid. It derives from a hydride of a 1H-pyrazole.

General procedure: In a Biotage tube, the relevant trifluoromethylpyrazole (1 mmol) and sodium hydroxide (0.2 g, 5 mmol) were stirred in ethanol/water 1:3 (1.2 mL). The tube was sealed and heated at 120 or 150 °C, as mentioned in the text for 1 h in a microwave oven. The resulting suspension was dissolved in water; the aqueous phase was washed with dichloromethane twice and made acidic with 2 N hydrochloric acid. This was extracted with ethyl acetate twice; the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to dryness to yield the corresponding acid as described below. CAUTION: the reaction conditions used lead to the release of fluorine ions that attack the glass tubes. Never recycle the reaction tubes as their resistance toward pressure and temperature may have been weakened in a process, which is releasing sodium fluoride.To a solution of 5-methylpyrazole-3-carboxylic acid ethyl ester (4.94 g, 32.0 mmol) in abs. EtOH (80 mL) was added NaOH (6.4 g, 160 mmol). The mixture was heated at reflux for 1 h and cooled to 20 C. The mixture was acidified with HC1 (aq., 2 M, 85 mL, 170 mmol) and the pH adjusted to 3 withNaOH (aq., 2 M). The mixture was extracted with EtOAc (200 mL). The organic phase was washed with NaCI (aq, sat, 50 mL) and concentrated to give the title compound (3.54 g, 88 percent) as a white solid. 5 ^ NMR (DMSO-ds, 400 MHz) S 12.83 (br. s, 1H). 6.43 (s, 1H), 2.22 (s, 3H).3, 5-Dimethyl-1H-pyrazole, 78.5 g (0.818 mol), was dissolved in 700 mL of water heated to 70°C, and 517 g (3.271 mol) of potassium permanganate was added to the hot solution, maintaining the temperature no higher than 90°C. The mixture was cooled to room temperature, the precipitate of MnO2 was filtered off and washed with water, and the filtrate was acidified with aqueous HCl to pH 2 and left overnight. The precipitate was filtered off and washed with water. Yield 41.75 g (33percent), white crystals, mp 257–258°C. 1H NMR spectrum: δ 7.07 ppm, s (1H, 4-H). 5-Methyl-1H-pyrazole-3-carboxylic acid (2). The aqueous filtrate obtained after separation of diacid 1, was neutralized to pH 5–6, and the precipitate of 2 was filtered off and washed with water. Yield 18.1 g (18percent), white crystals, mp 210–211°C. 1H NMR spectrum, δ, ppm: 2.25 s (3H, CH3), 6.42 s (1H, 4-H).Hmpca (5mmol, 0.63g) dissolved in 15mL hydrazine hydrate (100%) is mixed with a hot methanolic solution of Co(NO3)26H2O (20mL) (2.25mmol, 0.65g) with constant stirring. The resulting solution is refluxed for 4h and the solid thus obtained is filtered, washed with dry methanol, and dried in vacuum. Yield is 0.54g (71%) for C10H14CoN4O6 (3). Elemental analysis: Calculated: C, 34.76; H, 4.05; N, 16.22 and Found: C, 34.56; H, 3.89; N, 16.57. IR assignments (in cm1): m(CN) (1476), m(C-N) (1271), m(N-N) (1041) and m(C-O) (1697). (Hmpca) was prepared from the hydrolysis of 5methylpyrazole-3-carbohydrazide (mpch) [27]. Aqueous solution of sodium ethyl acetopyruvate (A) (10g, 0.05mol) is taken in a 250mL round bottom flask and allowed to react with hydrazine sulphate (7g, 0.05mol) in the presence of anhydrous Na2CO3 (Scheme 1). A light yellow product ethyl 5-methylpyrazole-3-carboxylate (B) is obtained. The ester (B) separated from the solution is filtered off, washed with water and dried in an oven at 100C. Recrystallization from aqueous ethanol gave the pure ester (B) in colorless form melting at 82C. The dried ester (0.04mol, 6.2g) is allowed to reflux with hydrazine hydrate (100%) (0.06mol, 3.0g) at water bath temperature for 1h. A white crystalline precipitate of 5-methylpyrazole-3-carbohydrazide (mpch) is obtained which is filtered off, washed with aqueous ethanol and dried in a vacuum desiccator. The dried mpch melts at 153C. The yield is 4.2g (75%). The dry mpch(15mmol, 2.1g) is taken in excess hydrazine hydrate (30mL) and refluxed for 5h. The desired ligand (Hmpca) is obtained by removing excess hydrazine by vacuum distillation. The product thus obtained is recrystallized from dry ethanol. Purity of the product was checked by the determination of melting point (M.P. 239C).In similar way, Cu(ClO4)26H2O (2.25mmol, 0.83g) in 20mL dry methanol is mixed with a dry methanolic solution (15mL) of Hmpca (5mmol, 0.63g). The resulting solution is refluxed for 4h; slow evaporation of the solution at room temperature furnished blue crystalline compound which is filtered off, washed with methanol and dried over silica gel. The yield is 0.51g (68%) for [Cu(mpca)2]H2O( 2). Elemental analysis for 2 (when n1) (C10H12CuN4O5): Calculated: C, 36.16; H, 3.61; N, 16.87 and Found: C, 36.29; H, 3.42; N, 16.91. IR assignments (in cm1): m(CN) (1369), m(C-N) (1285), m(N-N) (1034) and m(C-O) (1550).Hmpca (5mmol, 0.63g) dissolved in 15mL in dry methanol is allowed to mix with a methanolic solution of CuCl22H2O (2.25mmol, 0.38g) (20mL) in a 100mL round bottom flask. The resulting blue solution is refluxed for 6h whereupon a blue crystalline product separates. The product is filtered off, washed with methanol and dried over silica gel. The yield is 0.86 (72%) for [Cu(mpca)2(H2O)]3H2O( 1). Elemental analysis for 1 (C10H14CuN4O6): Calculated: C, 31.10; H, 4.66; N, 14.53 and Found: C, 31.05; H, 4.54; N, 14.85. IR assignments (in cm1): m(CN) (1425), m(C-N) (1299), m(N-N) (1041) and m(C-O) (1627).

Molecular Weight:126.11
XLogP3:0.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:126.042927438
Monoisotopic Mass:126.042927438
Topological Polar Surface Area:66
Heavy Atom Count:9
Complexity:126
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes