Pyridine → 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]butan-1-one

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Reaction Steps

2-[2-Methyl-4-(trifluoromethyl)imidazol-1-yl]butyric acid (149 mg, 0.632 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Oxalyl chloride (110 μL, 1.26 mmol) and a catalytic amount of dimethylformamide (1 μL) was added and the reaction was stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the acid chloride was dried under vacuum. The crude acid chloride was dissolved in acetonitrile (1.5 mL). To a portion of this solution (0.5 mL, 0.21 mmol) was added 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (38.7 mg, 0.178 mmol) and pyridine (55 μL, 0.68 mmol) at room temperature and the reaction mixture was stirred for 2 h. Water and ethyl acetate were then added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 50˜80% ethyl acetate in hexanes with 0.1% aqueous ammonium hydroxide) to afford the desired product contaminated with some 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]butyric acid. The product was dissolved in ethyl acetate and washed once with 1N aqueous sodium hydroxide solution. Drying over anhydrous sodium sulfate followed by filtration and removal of solvent under reduced pressure and drying under vacuum afforded the desired product as a white solid (60.4 mg, 0.139 mmol, 78%). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.58 (ddd, J=9.2, 5.2, 2.0 Hz, 2H), 7.35 (ddd, J=9.2, 8.4, 0.8 Hz, 2H), 5.47 (dd, J=9.2, 5.6 Hz, 1H), 3.81-3.98 (m, 2H), 2.84 (t, J=6.2 Hz, 2H), 2.34 (s, 3H), 2.03-2.11 (m, 2H), 1.96-2.01 (m, 2H), 0.85 (t, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C21H21N5OF4 [M+H]+ 436, found 436.

Provenance & Evidence