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C) 2-chloro-3-nitro-6-(trifluoromethyl)pyridine To 3-nitro-6-(trifluoromethyl)pyridin-2-ol (5.5 g) was added phosphorous pentachloride (25.0 g) at room temperature. The reaction mixture was stirred at 170°C for 2.5 hr, cooled to room temperature, and slowly poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated brine and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.0 g). 1H NMR (300 MHz, CDCl3) δ 7.84 (1H, d, J = 8.1 Hz), 8.38 (1H, d, J = 8.1 Hz).
With hydrogenchloride; piperdinium acetate; In methanol; water;
a 2-(Ethylamino)-3-nitro-6-(trifluoromethyl)pyridine To a solution of 2-nitroacetamide ammonium salt (4 g, 33 mmol) in water (165 mL) was added piperidinium acetate (33 mmol) in water followed by slow addition of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (6.1 mL, 43 mmol) in MeOH (11 mL). The reaction was stirred for 2 h at room temperature and at reflux for 3 h. The reaction mixture was allowed to cool to 45 C. and aqueous HCl (1N) was added until the pH was acidic. After 1 h at room temperature, the reaction mixture was extracted with CH2Cl2 (3*). The combined organic layer was successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc, then EtOAC:MeOH, 9:1)to give 3-nitro-6-(trifluoromethyl)-2(1H)-pyridinone (2.7 g, 40% yield as a yellow solid.
45.B B) 3-nitro-6-(trifluoromethyl)pyridin-2-ol
B) 3-nitro-6-(trifluoromethyl)pyridin-2-ol To a solution of 2-nitroacetamide (16.9 g) and (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (30.0 g) in ethanol (700 mL) was slowly added sodium ethoxide (22.1 g) at room temperature. The reaction mixture was stirred at 90°C for 2 hr, the pH of the mixture was adjusted to 2 with 1 M hydrochloric acid, and the mixture was stirred at room temperature for additional 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.5 g). 1H NMR (400 MHz, CDCl3) δ 7.46 (1H, d, J = 8.0 Hz), 8.69 (1H, d, J = 8.0 Hz), 11.02 (1H, brs).
C) 2-chloro-3-nitro-6-(trifluoromethyl)pyridine To 3-nitro-6-(trifluoromethyl)pyridin-2-ol (5.5 g) was added phosphorous pentachloride (25.0 g) at room temperature. The reaction mixture was stirred at 170C for 2.5 hr, cooled to room temperature, and slowly poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated brine and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.0 g). 1H NMR (300 MHz, CDCl3) delta 7.84 (1H, d, J = 8.1 Hz), 8.38 (1H, d, J = 8.1 Hz).
ethyl (E)-5,5,5-trifluoro-4-oxopent-2-enoate[ No CAS ]
[ 117519-07-0 ]
Yield
Reaction Conditions
Operation in experiment
1.5 g
With sodium ethanolate In ethanol at 90℃; for 2h;
113.a Step-a:
Step-a: Synthesis of 3-nitro-6-(trifluoromethyl)pyridin-2-ol To a solution of 2-nitroacetamide (5.0 g, 47.8 mmol) in ethanol (25 mL) at RT was added ethyl (E)-5,5,5-trifluoro-4-oxopent-2-enoate (11.24 g, 57.3 mmol) and 25% sodium ethoxide in ethanol (25.9 mL, 95.3 mmol). The reaction mixture was stirred at 90° C. for 2 h. Reaction mixture was cooled to RT, diluted with water (50 mL), acidified with 1N HCl and extracted with EtOAc (2*150 mL). The combined organic layers were washed brine solution (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to get the residue which was purified by combiflash chromatography using 50% EtOAc in hexanes as eluent to afford the title compound (1.5 g); 1H NMR (400 MHz, DMSO-d6): δ 8.58 (d, J=8.4 Hz, 1H), 7.84 (bs, 1H), 7.51 (d, J=7.6 Hz, 1H).
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