5-(4-CHLOROPHENYL)-1H-PYRAZOLE-3-CARBOXYLIC ACID

White solid

General procedure: 4.1.1.1 General procedure: To a solution of compound 29b (2.6 g, 9.1 mmol) in MeOH(30 mL) and H2O (15 mL) was added LiOHH2O (0.5 g, 20.0 mmol) and the mixture was stirred at70 °C for 8 h. The reaction mixture was evaporated and H2O (15 mL) was added, then acidified byhydrochloric acid (1 M) to pH 3. The suspension was filtered and washed by H2O (10 mL), driedat 50 C for 4 h to afford 11b as a white solid (2.1g, 89.5percent yield), General procedure: To a solution of compound 29b (2.6 g, 9.1 mmol) in MeOH(30 mL) and H2O (15 mL) was added LiOHH2O (0.5 g, 20.0 mmol) and the mixture was stirred at70 C for 8 h. The reaction mixture was evaporated and H2O (15 mL) was added, then acidified byhydrochloric acid (1 M) to pH 3. The suspension was filtered and washed by H2O (10 mL), driedat 50 C for 4 h to afford 11b as a white solid (2.1g, 89.5% yield), General procedure: To amixture of 3-(3-chlorophenyl)-1H-pyrazole-5-carboxylic acid (14a, 133 mg, 0.60 mmol) inDMF(4 mL)was added (S)-methyl-4-(2-amino-3-phenylpropanamido)benzoate hydrochloride (12, 200 mg, 0.60 mmol), N, N-diisopropyl-ethylamine (232 mg, 1.80 mmol), 1-hydroxybenzotriazole(161 mg, 1.20 mmol) and N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide hydrochloride (229 mg, 1.20 mmol)and the reaction mixture was stirred at room temperature overnight.Then TLC analysis indicatedreaction was complete, and H2O (40 mL) was added.The mixture was stirred for 10 min and filtered toget crude product 13a as a yellow solid, which was used for next step without further purification.General procedure: 4.1.1.1 5-(4-Methylphenyl)-1H-pyrazole-3-carboxylic acid (1) 0.4 g of 4-(4-methylphenyl)-2, 4-dioxobutanoic acid was dissolved in 20 ml of glacial acetic acid in 50 ml round-bottom flask. In a stirred solution, 280 muL (3 eq.) of hydrazine monohydrate (N2H4·H2O) was added dropwise. The color of solution was changed to pale yellow immediately after addition of first amount of hydrazine. The progress of reaction was monitored by TLC. After completion, reaction mixture was poured in 50 ml H2O and left to stir overnight. White precipitate was collected, dried on air and recrystallized from the mixture of hexane/EtOH (?9:1), giving 0.34 g of product (87% of theoretical yield). 4.1.2.18 5-(4-Chlorophenyl)-1H-pyrazole-3-carboxylic acid (18) Starting from 0.27 g of 4-(4-chlorophenyl)-2, 4-dioxobutanoic acid, 0.23 g of product was obtained (87% of theoretical yield). White solid, mp = 256-257 C (hexane/AcOEt); C10H7ClN2O2, Mw = 222.63; ESI-MS: Calculated for C10H8ClN2O2 [M+H]+: 223.02688, measured: 223.02694; IR (nu, cm-1): 3188 (N-H), 1679 (C=O), 1488, 1271; 1H NMR (200 MHz, DMSO-d6) delta(ppm): 8.47 (s, 1 H) 8.71 (d, J = 8.42 Hz, 2 H) 9.10 (d, J = 8.99 Hz, 2 H); 13C NMR (50 MHz, DMSO-d6) delta(ppm): 105.86, 127.29, 129.18, 130.62, 132.88, 161.76, two low-intensity signals from pyrazole C=N and C-NH not observed.Acid 68 (0.898 mmol), HOBt (0.898 mmol) and N, O-dimethylhydroxylamine hydrochloride (0.898 mmol) were dissolved in CH2Cl2 (5 mL) and stirred for 10 min. EDC (0.898 mmol) in 5 mL of CH2Cl2 was added dropwise over 20 mins in which the colorless reaction mixture was stirred for 48 hrs. at room temperature under nitrogen. The reaction mixture was diluted with 10 mL of CH2Cl2, washed 2 times with water and twice with brine. The organic layer was dried with Na2SO4 and concentrated to give the amide 69 as a light yellow solid, which was used in the next step without further purification.

Molecular Weight:222.63
XLogP3:2.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:222.0196052
Monoisotopic Mass:222.0196052
Topological Polar Surface Area:66
Heavy Atom Count:15
Complexity:242
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes