2-bromo-4-chloro-6-nitro-phenol

The reaction flask was successively added with acetic acid (7.5 L) 4-chloro-2-bromophenol (1500.0 g, 7.2 mol) was stirred well;Sodium nitrate was added dropwise at room temperature(1229.0 g, 14.5 mol)And concentrated sulfuric acid(1418.0 g, 14.5 mol) in water (1.4 L);After the drop, the temperature control 25-30°C reaction about 20-30min;The reaction was stopped and poured into ice water (7.5 L) and stirred for 20 min.The filter cake was washed with water until the filtrate was near neutral (pH 6-7). The filter cake was dried to obtain a yellow solid: 1742 g, yield: 95percent.(a) Example 116; 1-[6-Chloro-8-(1H-pyrazol-4-yl)-3, 4-dihydro-2H-benzo[1, 4]oxazine-2-carbonyl]-4-(4-fluoro-benzyl)-piperidine-4-carbonitrile Step-1: 2-Bromo-4-chloro-6-nitro-phenolTo a solution of 4-chloro-2-nitrophenol (1 g, 5.76 mmol) in acetic acid was added bromine (0.32 ml, 6.3 mmol) at 5-10° C. and stirred at 10° C. for half an hour. The temperature of the reaction mixture was raised to room temperature and stireed at RT for 3 hours. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The organic layer was washed with ethyl acetate and dried over sodium sulfate. Concentration of organic layer was afforded 1.3 g (90.9percent) of 2-Bromo-4-chloro-6-nitro-phenol. GCMS [m/z]: 253.0. [0054] A solution of 4-chloro-2-nitrophenol (4) (3.12 g, 18.0 mmol) in acetic acid (25 mL) was cooled to 5-10 °C, and bromine (1.0 mL, 19.7 mmol) was added dropwise. The reaction mixture was stirred for half an hour at 10 °C and then for 3 hours at room temperature. The mixture was then diluted with ice- water and extracted with dichloromethane (DCM) (3x30 mL). The combined organic extracts were washed with brine (30 mL) and dried over anhydrous NaStep 1: 4-chloro-2-nitrophenol (1.0 equiv.) was dissolved in Acetic Acid (0.64 M) and cooled in an ice-bath. To the mixture was then added bromine (1.1 equiv.) and the mixture agitated for 3 h while gradually warming to room temperature. Additional bromine (0.3 equiv.) was added. Then, after additional hour, almost complete conversion to the desired product is observed. At this stage, ice-cold water was added and immediately, a yellowish suspension was observed. The mixture was vigirously agitated and then filtered. The yellowish orange precipitate was washed with water and then with heptane and the yellow powder was placed under high-vacuum for 3 days to afford 2-bromo-4-chloro-6- nilrophenol in 76percent yield. LCMS (rn/z) (M+H) = 291.9, Rt = 1.45 min.

Molecular Weight:252.45
XLogP3:4.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:250.89848
Monoisotopic Mass:250.89848
Topological Polar Surface Area:66
Heavy Atom Count:12
Complexity:186
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes