5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester

A mixture of compound 14-3 (1 g, 5.37 mmol) and hydrazine hydrate (10.7 mmol, 9.64 mol/L) in ethanol (20 mL) was stirred at 75 °C under N2 for 1 hour. After the reaction was complete, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V: V) = 2 : ito afford a pale yellow solid 14-4 (0.55 g, 56percent). MS (ESI, pos.ion) m/z: i83.i[M+1] and a) Ethyl 5-isopropyl-lH-pyrazole-3-carboxylate To a solution of ethyl 4-methyl-3-oxopentanoate (4 g, 21.6 mmol, CAS: 7152-15-0) in ethanol (100 mL), was added acetic acid (1.9 g, 32.4 mmol) and hydrazine monohydrate (1.7 g, 0.032 mol, CAS: 7803-57-8). The reaction mixture was stirred for 12 hours until LCMS analysis indicated the completion of the reaction. The reaction solution was concentrated under reduced pressure and diluted with water. The mixture was extracted twice with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine(40 mL), dried over Naa) Ethyl 5-isopropyl- 1 H-pyrazole-3-carboxylateTo a solution of CH3CH2ONa (23 g, 0.34 mol) in anhydrous EtOH (500 mL) were added diethyl oxalate (50 g, 0.34 mol, CAS: 95-92-1) and 3-methyl-2-butanone (29 g, 0.34 mol, CAS: 563-80- 4) at 0°C. The solution was stuffed at 50°C overnight. The mixture was cooled to O-5°C, and acetic acid (20.4 g, 0.34 mol) was added, followed by hydrazine monohydrate (17.2 g, 0.34 mol, CAS: 7803-57-8). The mixture was stirred at 30°C overnight and cooled to room temperature afterwards. Volatiles were removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (500 mL) and extracted with ethyl acetate (1 L). The organic layer was washed with brine and concentrated under reduced pressure to give the desired crude product. Purification by flash chromatography (silica gel, CH2C12/MeOH = 200/1-80/1 by vol)gave crude ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (30 g, 48percent yield) as a yellow solid. MS (ESI): 183.1 ([M+H]j.Preparation 6 5-ISOPROPYL-1 H-PVRAZOLE-3-CARBOXYLIC acid ethyl ester 5-ISOPROPYL-1 H-PYRAZOLE-3-CARBOXYLIC acid (WO 03/035065, page. 485, example 17b) (1. 00G, 6. 49mmol) was dissolved in a mixture of concentrated sulphuric acid (1.5mL) and ethanol (25mL) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was cooled, poured into water, basified with 0. 88 ammonia then extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield the title product, 514mg (43percent). 1HNMR (CDCI3, 400MHZ) : 1.30 (d, 6H), 1.38 (t, 3H), 3.64 (m, 1H), 4.38 (m, 2H), 6.63 (s, 1 H).General procedure: To a solution of ethyl 5-ethyl-1H-pyrazole-3-carboxylate (32.0 mg, 0.190 mmol) in DMF (0.4 mL) was added sodium hydride (7.0 mg, 0.17 mmol, 60percent oil suspension) at 0 oC. After being stirred at room temperature for 10 minutes, a solution of 7-(bromomethyl)-5-chloro-2-phenylpyrazolo[1, 5-a]pyridine (50.0 mg, 0.155 mmol) in DMF (0.4 mL) was added to the mixture at 0 oC. After being stirred at 0 oC for 1 h, saturated aq. ammonium chloride was added to the mixture. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, and then dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (Hexane:AcOEt = 4:1) to give the title compound 28c as a yellow oil (34.0 mg, 52percent).a) Ethyl 5-isopropyl- 1 H-pyrazole-3-carboxylateTo a solution of CH3CH2ONa (23 g, 0.34 mol) in anhydrous EtOH (500 mL) were added diethyl oxalate (50 g, 0.34 mol, CAS: 95-92-1) and 3-methyl-2-butanone (29 g, 0.34 mol, CAS: 563-80- 4) at 0°C. The solution was stuffed at 50°C overnight. The mixture was cooled to O-5°C, and acetic acid (20.4 g, 0.34 mol) was added, followed by hydrazine monohydrate (17.2 g, 0.34 mol, CAS: 7803-57-8). The mixture was stirred at 30°C overnight and cooled to room temperature afterwards. Volatiles were removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (500 mL) and extracted with ethyl acetate (1 L). The organic layer was washed with brine and concentrated under reduced pressure to give the desired crude product. Purification by flash chromatography (silica gel, CH2C12/MeOH = 200/1-80/1 by vol)gave crude b) Ethyl 4-fluoro-5-isopropyl- 1 H-pyrazole-3-carboxylateTo a solution of b) Ethyl 5-isopropyl-2-(2, 2, 2-trifluoroethyl)pyrazole-3-carboxylate To a solution of ethyl 5-isopropyl-lH-pyrazole-3-carboxylate (1 g, 5.5 mmol) in DMF (10 mL), were added 2, 2, 2-trifluoroethyl iodide (1.7 g, 8.3 mmol, CAS: 353-83-3) and Cs2C03 (2.1 g, 11 mmol). The reaction mixture was stirred at 50°C for 12 hours. Then the reaction solution was concentrated under reduced pressure and diluted with water. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered through a thin silica pad, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give ethyl 5-isopropyl-2-(2, 2, 2- trifluoroethyl)pyrazole-3-carboxylate (500 mg, 36percent yield) as a white solid. MS (ESI): 265.2 (M+H)+.NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under 2 atmosphere at 0 °C. To this solution was added NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under N2 atmosphere at 0° C. To this solution was added

Molecular Weight:182.22
XLogP3:1.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:182.105527694
Monoisotopic Mass:182.105527694
Topological Polar Surface Area:55
Heavy Atom Count:13
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes