Cl.[CH2:2]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11]C)=[O:10])[C:5]=1[CH3:13])[CH3:3].CC(C)([O-])C.[K+].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[Li+].[OH-].Cl>C(O)C.O>[CH2:2]([C:4]1[N:8]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)[N:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[CH3:13])[CH3:3]To a mechanically stirred solution of methyl 5-ethyl-4-methyl-1H-pyrazole-3-carboxylate hydrochloride (Step 1, 825 mg, 4.03 mmol) in dry ethanol (20 mL) was added potassium tert-butoxide (1.18 g, 10.5 mmol) and a solution of 4-methylbenzyl bromide (1.12 g, 6.05 mmol) in dry ethanol (20 mL). The reaction mixture was stirred at 60° C. over night. After being cooled to rt, LiOH (0.5N aq., 40.3 mL, 20.1 mmol) was added, and the mixture was stirred at 40° C. for additional 3 h. After being cooled to RT again, the reaction mixture was diluted with water (200 mL) and acidified with HCl (2N aq., 12.1 mL, 24.2 mmol). Extraction with dichloromethane, drying over anhydrous magnesium sulfate, filtration, evaporation of the solvent and subsequent purification by preparative HPLC afforded the title compound as a white solid (183 mg, 18%): 1H NMR (400 MHz, CDCl3) δ 7.12 (d, 2H), 7.01 (d, 2H), 5.30 (s, 2H), 2.53 (quart, 2H), 2.32 (s, 3H), 2.22 (s, 3H), 0.98 (t, 3H); ES-MS m/z 259 (MH)+; HPLC RT (Method D) 2.13 min.
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