5-amino-2-bromophenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-amino-2-bromo-phenol (35.2 g, 0.187 mol) in N,N-dimethylformamide (350 mL) was added potassium tert-butoxide (22.9 g, 0.204 mol). After 15 min, benzyl chloride (25.5 mL, 0.222 mol) was added within 2 min. The reaction was stirred during 4 h and then poured onto an aqueous solution of sodium hydrogenocarbonate and extracted with ethyl acetate. The combined organic phases were washed with brine and water then dried over sodium sulfate, filtered, and evaporated under vacuum. 55.6 g of the title compound were obtained. Black solid, ISP-MS: m/e=279.1 ([M+H]+). extracted with ethyl acetate The combined organic phases were washed with brine and water then dried over sodium sulfate filtered evaporated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-amino-2-bromo-phenol (35.2 g, 0.187 mol) in N,N-dimethylformamide (350 mL) was added potassium tert-butoxide (22.9 g, 0.204 mol). After 15 min, benzyl chloride (25.5 mL, 0.222 mol) was added within 2 min. The reaction was stirred during 4 h and then poured onto an aqueous solution of sodium hydrogenocarbonate and extracted with ethyl acetate. The combined organic phases were washed with brine and water then dried over sodium sulfate, filtered, and evaporated under vacuum. 55.6 g of the title compound were obtained. Black solid, ISP-MS: m/e=279.1 ([M+H]+). extracted with ethyl acetate The combined organic phases were washed with brine and water then dried over sodium sulfate filtered evaporated under vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 4-bromo-3-methoxy-phenylamine (37.6 g, 0.186 mol) and tetrabutylammonium iodide (96 g, 0.260 mol) in dichloromethane (1.2 L) was cooled down to −78° C. A 1M solution of boron trichloride in dichloromethane (520 mL, 0.521 mol) was added dropwise, within 20 min. The cooling bath was removed. After 3 hours, the reaction mixture was poured onto ice water (4.5 kg). The organic layer was extracted with water. The combined aqueous layers were washed with dichloromethane. The pH was adjusted to 9 using sodium hydrogencarbonate. Sodium chloride was added until saturation. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents were evaporated. The solid was washed with dichloromethane and dried under vacuum. 35.2 g of the title compound were obtained. Brown solid, ISP-MS: m/e=189.1 ([M+H]+). The cooling bath was removed the reaction mixture was poured onto ice water (4.5 kg) The organic layer was extracted with water The combined aqueous layers were washed with dichloromethane Sodium chloride was added until saturation The aqueous layer was extracted with ethyl acetate The combined organic layers were dried over sodium sulfate filtered the solvents were evaporated The solid was washed with dichloromethane dried under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 131.7 mg (1.1 mmol) of pyridine hydrochloride and 286.7 mg (1.3 mmol) of 4-bromo-3-hydroxy-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 374.1 mg (88.6%) of the product as a pink solid, m.p. 146° C. (dec.), mass spectrum (electrospray, m/e): M+H 369.9.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.2 g, 6.7 mmol) in N,N-dimethylformamide (60 mL) were added 5-amino-2-bromophenol (1.9 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The solvent was evaporated under reduced pressure and the obtained solid was washed with diisopropyl ether to give the title compound (0.79 g, 31%) as a yellow powder. After cooling the mixture to room temperature extracted with ethyl acetate The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine dried over anhydrous sodium sulfate filtrated The solvent was evaporated under reduced pressure the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) The solvent was evaporated under reduced pressure the obtained solid was washed with diisopropyl ether

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.2 g, 6.7 mmol) in N,N-dimethylformamide (60 mL) were added 5-amino-2-bromophenol (1.9 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The solvent was evaporated under reduced pressure and the obtained solid was washed with diisopropyl ether to give the title compound (0.79 g, 31%) as a yellow powder. After cooling the mixture to room temperature extracted with ethyl acetate The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine dried over anhydrous sodium sulfate filtrated The solvent was evaporated under reduced pressure the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) The solvent was evaporated under reduced pressure the obtained solid was washed with diisopropyl ether

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-3-methoxyaniline (5.0 g, 25 mmol) was added to 48% hydrobromic acid (20 mL), and the reaction mixture was stirred at 80° C. for 16 hr. After completion of the reaction, the mixture was allowed to cool to room temperature, and adjusted to pH 7-8 by adding 8N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→100/0) to give the title compound (2.0 g, 43%) as a white powder. After completion of the reaction to cool to room temperature The mixture was extracted with ethyl acetate the obtained organic layer was washed with water and saturated brine dried over anhydrous sodium sulfate filtrated The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→100/0)