(1H-PYRAZOL-3-YL)ACETICACIDETHYLESTER

A solution of 2-(lH-pyrazol-3-yl)acetic acid (4.0 g, 32 mmol) and cone. HEthyl 2-(1H-pyrazol-3-yl)acetate (180 mg, 1.17 mmol), caesium carbonate (762 mg, 2.34 mmol) and N, N-dimethylformamide (2 mL) were added in a 25 mL single-neck flask. After cooling in an ice bath, methyl iodide (332 mg, 2.34 mmol) was added dropwise, and the reaction was continued for 2 hours in an ice bath. After completion of the reaction monitored by TLC, water (20 mL) was added. Then mixture was extracted with ethyl acetate (3'10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Solvent was removed in vacuo to afford a mixture of ethyl 2-(1-methyl-1H-pyrazol-3-yl)acetate and ethyl 2-(1-methyl-1H-pyrazol-5-yl)acetate (yellow oil, 136 mg). Step 5: 2-(1-Methyl-1H-pyrazol-5-yl)acetic acid and 2-(1-methyl-1H-pyrazol-3-yl)acetic acid (0079) The mixture of ethyl 2-(1-methyl-1H-pyrazol-3-yl)acetate and ethyl 2-(1-methyl-1H-pyrazol-5-yl)acetate (136 mg, 0.81 mmol), lithium hydroxide monohydrate (102 mg, 2.43 mmol) and ethanol/H2O (2 mL/0.5 mL) were added in a 25 mL single-neck flask, and the mixture was reacted at room temperature for 0.5 hour. After completion of the reaction, ethanol was removed under reduced pressure, then water (2 mL) was added. The mixture was adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (3 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove the solvent to give a product (yellow oil, 100 mg).Ethyl 2-(1H-pyrazol-3-yl)acetate (180 mg, 1.17 mmol), caesium carbonate (762 mg, 2.34 mmol) and N, N-dimethylformamide (2 mL) were added in a 25 mL single-neck flask. After cooling in an ice bath, methyl iodide (332 mg, 2.34 mmol) was added dropwise, and the reaction was continued for 2 hours in an ice bath. After completion of the reaction monitored by TLC, water (20 mL) was added. Then mixture was extracted with ethyl acetate (3'10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Solvent was removed in vacuo to afford a mixture of ethyl 2-(1-methyl-1H-pyrazol-3-yl)acetate and ethyl 2-(1-methyl-1H-pyrazol-5-yl)acetate (yellow oil, 136 mg).Ethyl 2-(1H-pyrazol-3-yl)acetate (180 mg, 1.17 mmol), caesium carbonate (762 mg, 2.34 mmol) and N, N-dimethylformamide (2 mL) were added in a 25 mL single-neck flask. After cooling in an ice bath, methyl iodide (332 mg, 2.34 mmol) was added dropwise, and the reaction was continued for 2 hours in an ice bath. After completion of the reaction monitored by TLC, water (20 mL) was added. Then mixture was extracted with ethyl acetate (3'10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Solvent was removed in vacuo to afford a mixture of ethyl 2-(1-methyl-1H-pyrazol-3-yl)acetate and ethyl 2-(1-methyl-1H-pyrazol-5-yl)acetate (yellow oil, 136 mg). Step 5: 2-(1-Methyl-1H-pyrazol-5-yl)acetic acid and 2-(1-methyl-1H-pyrazol-3-yl)acetic acid (0079) The mixture of ethyl 2-(1-methyl-1H-pyrazol-3-yl)acetate and ethyl 2-(1-methyl-1H-pyrazol-5-yl)acetate (136 mg, 0.81 mmol), lithium hydroxide monohydrate (102 mg, 2.43 mmol) and ethanol/H2O (2 mL/0.5 mL) were added in a 25 mL single-neck flask, and the mixture was reacted at room temperature for 0.5 hour. After completion of the reaction, ethanol was removed under reduced pressure, then water (2 mL) was added. The mixture was adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (3 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove the solvent to give a product (yellow oil, 100 mg). Step 6: Synthesis of N-(2, 6-dichloro-3'-cyano-4'-isobutyl-[1, 1'-biphenyl]-4-yl)-2-(1-methyl-1H-pyrazol-3-yl)acetami de (9A) and N-(2, 6-dichloro-3'-cyano-4'-isobutyl-[1, 1'-biphenyl]-4-yl)-2-(1-methyl-1H-pyrazol-5-yl)acetami de (9B) (0080) 4'-Amino-2', 6'-dichloro-4-isobutyl-[1, 1'-biphenyl]-3-carbonitrile (40 mg, 0.13 mmol), the mixture of 2-(1-methyl-1H-pyrazol-5-yl)acetic acid and 2-(1-methyl-1H-pyrazol-3-yl)acetic acid (44 mg, 0.32 mmol), HATU (118 mg, 0.38 mmol), N, N-diisopropylethylamine (50 mg, 0.39 mmol) and dichloromethane (2 mL) were added in a 25 mL single-neck flask, and the mixture was reacted at room temperature for 4 hours. The resulting crude product was separated by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to give N-(2, 6-dichloro-3'-cyano-4'-isobutyl-[1, 1'-biphenyl]-4-yl)-2-(1-methyl-1H-pyrazol-3-yl)acetami de (white aolid, 26 mg), 1H NMR (400 MHz, CDCl3) delta 9.23 (s, 1H), 7.66 (s, 2H), 7.47 (s, 1H), 7.33 (t, J = 7.4 Hz, 4H), 6.19 (s, 1H), 3.93 (s, 3H), 3.75 (s, 2H), 2.75 (d, J = 7.3 Hz, 2H), 2.02 - 1.97 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 441.0 (M+1) and N-(2, 6-dichloro-3'-cyano-4'-isobutyl-[1, 1'-biphenyl]-4-yl)-2-(1-methyl-1H-pyrazol-5-yl)acetami de (white aolid, 27 mg), 1H NMR (400 MHz, CDCl3) delta 8.26 (s, 1H), 7.63 (s, 2H), 7.47 (d, J = 3.3 Hz, 2H), 7.34 (s, 2H), 6.26 (s, 1H), 3.87 (s, 3H), 3.80 (s, 2H), 2.75 (d, J = 7.3 Hz, 2H), 1.97 - 1.88 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 440.9 (M+1).To a mixture of ethyl 2-(lH-pyrazol-3-yl)acetate (1.0 g, 6.5 mmol) and Cs2C03 (4.2 g, 13 mmol) in DMF (5 mL) was added iodomethane (1.84 g, 13.0 mmol). The mixture was stirred at 0 C for 6 h. H20 (20 ml) was then added and the resulting mixture was extracted with EtOAc (20 ml x 3). The organic layers were combined, washed with brine (20 ml), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (600 mg, 55%>) as yellow oil. LC-MS (ESI): m/z = 169 (M+H)+.A solution of 2-(lH-pyrazol-3-yl)acetic acid (4.0 g, 32 mmol) and cone. H2SO4 (1.0 mL) in ethanol (100 mL) was refluxed overnight. After concentration, the residue was treated with aq. NaHC03, extracted with ethyl acetate, dried over Na2S04. Removal of the solvent gave the title compound (4.6 g, 94%) as brown oil. LC-MS (ESI): m/z = 155 (M+H)+.2-(1H-Pyrazol-3-yl)acetic acid (200 mg, 1.59 mmol), anhydrous ethyl alcohol (20 mL) and concentrated sulfuric acid (0.5 mL) were added in a 25 mL single-neck flask, and the mixture was heated to react at 80' overnight. After completion of the reaction, the solution was cooled to room temperature, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate (3'20 mL), and purified by a silica gel column to afford a product (orange oil, 180 mg), with a yield of 73.7%. 1H NMR (400 MHz, CDCl3) delta 7.54 (s, 1H), 6.25 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H). MS (ESI) m/z: 155.1 (M+1).

Molecular Weight:154.17
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:154.074227566
Monoisotopic Mass:154.074227566
Topological Polar Surface Area:55
Heavy Atom Count:11
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes