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[0104] 449 mg (2.00 mmol, 1.0 eq) 2-Chloro-6-trifluoromethyl nicotinamide, 344 mg (4.00 mmol, 2.0 eq) piperazine and 2.0 mL anhydrous acetonitrile (ACN) were combined in a microwave vial and microwaved at 100 C for 2 minutes. The reaction was diluted with 2.0 mL methanol and centrifuged (4,000 rpm, RT, 8 mins). The supernatant was filtered and purified by reverse-phase HPLC (1-25% CH3CN in 0.085% TFA (aq), 50 mL/min, 2 x 2.0 mL injected). The appropriate fractions were concentrated under reduced pressure. The resulting solids were dissolved in 5.0 mL 1.0 N sodium hydroxide and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with brine, dried (Na2S04) and concentrated under reduced pressure. [0105] Yield = 281 mg (51 %) as off-white needles (isolated as the free base) ; Purity = 99+%; (at)H-NMR (400 MHz, DMSO-d6) No. 8.00 (br s, 1H), 7.83 (d, J= 7.5 Hz, 1H), 7.69 (br s, 1 H), 7.2 (d, J = 7.6 Hz, 1 H), 3 . 3 5 (br m, 4H), 2.79 (br m, 4H), 2.38 (br s, 1 H); LC/MS retention time (10-99% CH3CN/0.085%TFA gradient over 5 min): 1.15 min; Theoretical (M+H)+ m/z for C11H13F3N4O = 275.1; Found 275.0.
EXAMPLE 5 Preparation (2) of 2-chloro-6-trifluoromethylnicotinamide To 100 g of 2-chloro-6-trifluoromethylnicotinonitrile, 140 mL of 96 vol% sulfuric acid was added, followed by stirring at 75C for 2 hours. A reaction solution was poured in 500 mL of cooled water, and precipitated crystals were collected by filtration, washed with water and dried to obtain 108 g of 2-chloro-6-trifluoromethylnicotinamide.
With sodium hypochlorite; sodium hydroxide; In water; at 90℃; for 0.5h;Cooling with ice;
EXAMPLE 6 Preparation of 3-amino-2-chloro-6-trifluoromethylpyridine To a mixture of 200 g of 2-chloro-6-trifluoromethylnicotinamide and 1,000 ml of water, 432 ml of a 11.6 wt% aqueous sodium hypochlorite solution and 190 ml of a 10 N aqueous sodium hydroxide solution were dropwise added in order under cooling with ice, followed by stirring at 90C for 30 minutes. The reaction mixture was cooled to 10C, crystals precipitated were collected by filtration, washed three times with 100 ml of cooled water, and then dried at room temperature for 24 hours to obtain 144 g of 3-amino-2-chloro-6-trifluoromethylpyridine (melting point: 96 to 97C). 1H-NMR(CDCl3) delta= 4.47(2H, bs, NH2), 7.09(1H, d, J= 7.8 Hz), 7.42(1H, d, J= 7.8 Hz).
With ammonia; In tetrahydrofuran; water; for 0.5h;Cooling with ice;
Then, to the obtained 2-chloro-6-trifluoromethylnicotinoyl chloride, 50 mL of THF (tetrahydrofuran) was added, and the resulting solution was gradually dropwise added to 250 mL of 28 wt% aqueous ammonia under cooling with ice. After stirring for 30 minutes, water was added thereto, followed by collection by filtration, washing with water and drying to obtain 40.7 g of 2-chloro-6-trifluoromethylnicotinamide (melting point: 215 to 217C). 1H-NMR(DMSO-d6) delta= 7.97(1H, bs), 8.00(1H, d, J= 7.4 Hz), 8.18(1H, bs), 8.18(1H, d, J= 7.4 Hz).
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