1-Methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

ethyl 1-Methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate2 (5600 mg, 25 mmol) and potassium hydroxide (4740 mg, 30 mmol) were added towater (50 mL). The mixturewas stirred forovernight, then acidified to pH 1 using HCl, to give 3 as a whitesolid thatwas filtered off and dried with yield 59percent, m.p.195e196 °C, 1H NMR (500 MHz, DMSO‑d6), δ: 12.80 (s, 1H, COOH), 8.44 (s, 1H, CH), 3.93 (s, 1H, CH3).Preparation Example V.63-trifluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid (One-Pot Reaction)At -30° C., trifluoroacetyl fluoride (18.3 g, 0.16 mol; 99.5percent) was introduced into a solution of methyl 3-piperidin-1-ylacrylate (97percent, 25 g, 0.14 mol) and KF (12.5 g, 0.51 mol) in toluene (250 ml). The reaction mixture was stirred at -30° C. for 3 h and then, over a period of one hour, warmed to room temperature. The reaction mixture was washed with deionized water (400 ml). After phase separation, the aqueous phase was extracted once with toluene (200 ml). The toluene phases were combined and, under reduced pressure, concentrated to about 600 ml. The reaction solution obtained in this manner was, at -50° C., added dropwise to a solution of methylhydrazine (7.4 g, 0.16 mol) in toluene (150 ml). The reaction mixture was stirred at -50° C. for 2 h and then, over a period of one hour, warmed to room temperature. Aqueous sodium hydroxide solution (10percent strength, 69.4 g, 0.17 mol) was then added, and the reaction mixture was heated under reflux conditions for 2 h. After cooling to room temperature, the phases were separated. The toluene phase was extracted with aqueous sodium hydroxide solution (10percent strength, 100 ml). The aqueous phases were combined, adjusted to pH 1 using hydrochloric acid (conc.) and cooled to 0° C. The precipitated solid was filtered off, washed with cyclohexane and, at 60° C., dried under reduced pressure. 3-trifluoromethyl-1-methyl-1H-pyrazol-4-ylcarboxylic acid was obtained in an amount of 21.8 g and a purity of 98percent (according to 0.50 g of Compound (III) having purity of 98.1percent by weight was dissolved in 4 ml of methanol, followed by further adding 2.0 g of a 32percent by weight aqueous solution of sodium hydroxide, further followed by reacting at an external temperature of 75°C for 4 hours. The reaction solution was observed by HPLC after cooling, and the result showed that the reaction yield of Compound (V) was 99percent or more.To a solution of 1 -methyl-3 -(trifluoromethyl)-li/-pyrazole-4-carboxy lie acid (38.8 mg, 0.200 mmol) in l, 2-dichloroethane (0.90 mL) and dimethyl sulfoxide (0.10 mL) at ambient temperature were added l-hydroxy-7-azabenzotriazole (27.2 mg, 0.200 mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.300 mmol) sequentially and the reaction mixture was allowed to stir for 15 min. (li?)-2, 2-Difluoro-/V-hydroxy-6- sulfamoyl-6-azaspiro[2.5]octane-l-carboximidamide (Intermediate 11) (59.7 mg, 0.210 mmol) was added and the reaction mixture was allowed to stir for 2 h at ambient temperature. The reaction mixture was warmed to 90 C and allowed to stir for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water, the layers separated, and the organic layer purified by silica gel chromatography, eluting with a gradient of hexanes: ethyl acetate - 95:5 to 25:75 to afford the title compound. MS: mz = 443.2 [M+H] 'H NMR (DMSO-fife) d 8.91 (s, 1 H), 6.78 (s, 2 H), 4.03 (s, 3 H), 3.37 - 3.24 (m, 1 H), 3.22 - 3.09 (m, 1 H), 3.10 - 2.97 (m, 2 H), 2.95 - 2.79 (m, 1 H), 2.04 - 1.83 (m, 4 H).

Molecular Weight:194.11
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:194.03031189
Monoisotopic Mass:194.03031189
Topological Polar Surface Area:55.1
Heavy Atom Count:13
Complexity:218
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes