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With phosphorus(V) oxybromide; In N,N-dimethyl-formamide; at 130℃; for 1.0h;
Example 6(b) 2-Bromo-5-chloro-3-fluoropyridine. To solid <strong>[514797-96-7]5-chloro-3-fluoro-2-hydroxypyridine</strong> (75 g, 0.51 mmol) was added melted POBr3 (150 g, 0.52 mmol). DMF (2 mL) was then added by pipet, and the mixture was heated at 130 C. for 1 h. The excess POBr3 was quenched by the careful addition of water to the reaction mixture at 0 C., and the resulting mixture was dissolved in a 2:1 mixture of EtOAc:water. The organic layer was washed three times with water and once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was passed through a plug of silica gel (10% Et2O:90% hexanes) to provide the title compound as a white solid (79.4 g, 74%). The product was characterized by 1H NMR.
Second step Phosphorus oxybromide (100 g) was dissolved in toluene (100 mL), and the mixture was heated and dissolved at 60C. The crude product (129) (25.7 g) was slowly added at the same temperature, and the mixture was stirred at the 110C for 4 hours. After cooled to room temperature, ice water was added at 0C, 10 mol/L sodium hydroxide (174 mL) was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate and a sodium chloride aqueous solution, and dried over sodium sulfate to afford the crude product (130) (40.3 g).
With hydrogen bromide; bromine; at 0℃; for 0.333333h;
Step 1: 2-bromo-5-chloro-3-fluoropyridine [0218] <strong>[246847-98-3]5-chloro-3-fluoropyridin-2-amine</strong> (5.0 g, 34 mmol) was slowly added to 48% HBr solution (20 mL) with stirring at 0C. To the resulting mixture E (5.24 mL, 102.3 mmol) was then added over 20 minutes at 0C. The reaction mixture was cooled to -10C. A solution of NaNC"2 (5.88 g, 85.3 mmol) in water (20 mL) was added over 1.5 hours, and the mixture stirred for additional 30 minutes. A solution of NaOH (12 g, 306 mmol) in water (20 mL) was added over 30 minutes, and the mixture was allowed to warm to room temperature. The mixture was extracted with ether (3x 100 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound as pale yellow solid (6.43 g, 90%). 1H NMR (400 MHz, CDC13) delta 8.23 (d, J = 2.1 Hz, 1H), 7.48 (dd, J= 7.1, 2.1 Hz, 1H).
90%
5-chioro-3-fluoropvridin-2-amine (5.0 g, 34 turned) was slowly added to 48% HBr%oluuon (20 ml) ith snwng ii 0 ( to 1 e iesultnig m11uie 13L ( 24 ml 102 ? mrnob was then added over 20 minute.s at 0 C. The reaction mixture was cooled to 1 0 ?C. A solunon of NaNO2 (5.88 g, 85.3 mmol) in water (20 mL) was added over I .5 hours, and the mixture stirred for additional 30 minutes. A solution of NaOH. (12 g, 306 mmol) in water (20 mL) was added over 30 mmnutesand the mixture was allowed to warm to room temperature. Th.e mixture was extracted with ether (3 x 1 00 rnL). The combined orgamc phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound as a pale yellow solid (6.43 g, 90%). H NMR (400 MHz, CDCh 6 8.23 (d, 12.1 Hz, 111), 7.48 (dd, J? 7.1. 21 Hz, IN).
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