Ethyl 1-methyl-3-phenyl-1H-pyrazole-5-carboxylate

To a solution of REX-P-INT-2 (1.0 g, 4.5 mmol), methylhydrazine sulfate (1.0 g, 6.8 mmol) and NaOH (0.5 g, 13.6 mmol) in EtOH (50 mL). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was quenched with ice water (100 mL), extracted with EtOAc, washed with brine, dried with anhydrous NaEthyl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate To a stirred solution of 20-1 (2.0 g, 9.24 mmol) in DMF (15.0 mL ) was added KTo a solution of REX-P-INT-2 (1.0 g, 4.5 mmol), methylhydrazine sulfate (1.0 g, 6.8 mmol) and NaOH (0.5 g, 13.6 mmol) in EtOH (50 mL). The reaction mixture was stirred at 70 C. overnight. The reaction mixture was quenched with ice water (100 mL), extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography eluted to give product 1-2 (247.5 mg, 23.9%). MS m/z [ESI]: 231.1 [M+1].To a stirred solution of 20-1 (2.0 g, 9.24 mmol) in DMF (15.0 mL ) was added K2CO3 (2.54 g, 18.4 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. Methyl iodide (855 muL, 13.8 mmol) was added and the reaction mixture was stirred for 4 hours. TLC showed formation of two new spots. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, brine, and dried over sodium sulfate. The solution was concentrated and the crude material was purified by column chromatography (silica, 100-200, gradient 0%-30% ethyl acetate/hexane) to afford 20- 2 (400 mg, 1.73 mmol, 19%) and 20-3 (1.8 g, 7.81 mmol, 85%) as colorless oils.1H NMR (20-2, polar fraction) (400 MHz, CDCl3) delta; 7.47-7.39 (m, 5H), 6.84 (s, 1H), 4.42 (q, J = 14.04, 7.0 Hz, 2H), 3.94 (s, 3H), 1.40 (t, J = 7.08 Hz, 3H).1H NMR (20-3, non-polar fraction) (400 MHz, CDCl3) delta; 7.78 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.24 Hz, 2H), 7.32-7.29 (m, 1H), 7.11 (s, 1H), 4.36 (q, J = 14.16, 7.08 Hz, 2H), 4.22 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H)General procedure: General Procedure for the Pd(OAc)2-Catalyzed Acetoxylation: A mixture of substrate (0.6 mmol), Pd(OAc)2 (0.06 mmol, 13.5 mg) and PhI(OAc)2 (2.4 mmol, 773 mg) in AcOH (6 mL) was stirred under ambient air at 100 oC for 1 h. Upon completion of the reaction, the mixture was first dropped into saturated aqueous NaHCO3 (50 mL), then the solution was extracted with methylene chloride (30 mL 3), and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to give the desired acetoxylated product(s).Ethyl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate To a solution of ethyl 2, 4-dioxo-4-phenylbutanoate (5.4 g, 0.025 mol) in ethanol (40 mL) was added a solution of 1-methylhydrazine (1.15 g, 0.025 mol) in ethanol (10 mL) over 15 min under argon. The resulting solution was refluxed for 2 hr, cooled to room temperature and concentrated under reduced pressure. TLC (EtOAc:Hexanes 1:1) showed two spots for two isomers. The residue was flash chromatographed over silica gel (50 g) with anhydrous sodium sulfate (5 g) on top packed with hexanes and the two isomers were separated. The column was eluted with 25% ethyl acetate in hexanes to give 2.7 g of Intermediate 1 as an oil (47%). 1H NMR (60 MHz, CDCl3): delta 7.3 (s, 5H), 6.1 (s, 1H), 4.3 (q, 2H), 3.9 (s, 3H), 1.4 (t, 3H) ppm.To a mixture of [98-86-2] (50 mL, 0.42 mol) and NaH (60% oil dispersion, 17.5 g, 0.44 mol) in [ETOH] [(1] L) is added diethyloxalate (36.5 mL, 0.42 mol). The reaction mixture is stirred overnight at rt. It is concentrated to give 85 g (92%) of a yellow powder. To a solution of this powder (3.15 g, 14.3 mmol) in a mixture of [ETOH] (50 [ML)] and aqueous 3 M HCl (5 mL) is added methylhydrazine (0.76 mL, 14.3 [MMOL).] The reaction mixture is stirred overnight. It is concentrated, and the residue is purified by silica chromatography to give the two pyrazole products. [[10199-51-6]] : Rf = 0.8 (4: 1 [HEXANES/ETOAC) ; LH] NMR [(CDC13, ] 400 MHz) [8] 7.84 (2H), 7.45 (2H), 7. 35 (1H), 4.42 (2H), 4.28 (3H), 1.45 (3H); MS (ESI+) [M/Z] 231.2. [110250-63-2]] : [RF] = 0.3 (4: 1 [HEXANES/ETOAC) ; 1H] NMR [(CDC13, ] 400 MHz) 8 7.4 [(5H), ] 6.90 (1H), 4.62 (2H), 4.00 (3H), 1.44 (3H); MS (ESI+) m/z 231.4.Production Example 197b) 0.67 g of ethyl-(Z)-4-hydroxy-2-oxo-4-phenyl-3-butanoate was dissolved in 10 ml acetic acid, and 0.17 g of methyl hydrazinewas added. After heating under reflux the reaction solution for 2 hours, the acetic acid was evaporated. The residue was dissolved by adding ethyl acetate and tetrahydrofuran, then washed with aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 0.12 g of ethyl 1-methyl-3-phenyl-1H-5-pyrazolecarboxylate from a fraction of hexane:ethyl acetate (9:1) and 0.55 g of ethyl 1-methyl-5-phenyl-1H-3-pyrazolecarboxylate from a fracton of hexane:ethyl acetate (4:1). Ethyl 1-methyl-3-phenyl-1H-5-pyrazolecarboxylate 1H-NMR(CDCl3) delta:1.42(t, J=8.0Hz, 3H) 4.21(s, 3H) 4.38(q, J=8.0Hz, 2H) 7.11(s, 1H) 7.32(t, J=8.0Hz, 1H) 7.40(t, J=8.0Hz, 2H) 8.79(d, J=8.0Hz, 2H)EXAMPLE 14A 2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid. 2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.32 g, 1.39 mmol) was dissolved in 4.5 mL of tetrahydrofuran, 1.5 mL of methanol and 1.5 mL of water, and treated with lithium hydroxide hydrate (0.12 g, 2.78 mmol). After stirring at room temperature overnight, the mixture was acidified (pH =1) with hydrochloric acid, and extracted with ethyl acetate (3*10 mL) and the combined organic phases washed with 10 mL of brine. The organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford a quantitative yield of the title compound. 1H NMR (CD3OD) delta4.2 (s, 3H), 7.2 (s, 1H), 7.3 (t, 1H), 7.4 (t, 2H), 7.8 (d, 2H).

Molecular Weight:230.26
XLogP3:2.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:230.105527694
Monoisotopic Mass:230.105527694
Topological Polar Surface Area:44.1
Heavy Atom Count:17
Complexity:264
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes