3-AMINO-5-BROMO-2-NITROPYRIDINE

To a solution of compound 3 (1.5 g, 5.2 mmol) in THF (10 ml) was added KOH (582 mg, 10.4 mmol) in water (5.0 ml) and stirred at 90° C. overnight. Water was added to the mixture resulting in a precipitate that was collected by filtration, washed with water, and then dried under reduced pressure to give compound 4 (1.1 g, 95percent)To a solution of 5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57 g, 5.4 mmol) in ethanol (2.5 mL) was added KOH (813 mg, 14.5 mmol) in water (12.5 mL) and stirred at 90° C. for 1 hr then at room temperature for 1 hr. Step 3. Synthesis of 224-3. A mixture of 224-2 (4.80 g, 16.7 mmol) and KOH (1.87 g, 33.4 mmol) in EtOH/HPalladium acetate (0.1541 g, 0.69 mmol) and 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene were weighed out(Xantphos, 0.3977 g, 0.69 mmol) was added to a flask, dissolved with 20 mL of dioxane, and stirred at room temperature for 30 minutes.Weighed iodobenzonitrile (3.3g, 14.4mmol) into the flask, stirred for 15 minutes, added cesium carbonate (6.7g, 20.6mmol) and compound 3 (3.0g, 13.8mmol) into the flask under nitrogen protection. , The reaction was stirred for 12 hours in a 100C oil bath. Filter to remove insolubles from the reaction solution.The filtrate was mixed with silica gel and ethyl acetate:petroleum ether=1:5 column chromatography to remove iodobenzonitrileThe crude product was separated by column chromatography on ethyl acetate. Recrystallization, yellow solid 4, yield: 78.6%To the reaction mixture of intermediate 2 (0.55g, 9.8mmol) in 1.5mL EtOH, KOH (0.55g, 9.8mmol) in 8mLH2O was added. After stirring at 90C for 1h, the mixture was stirred at rt for another 1h. Water (20mL) was added, and the precipitate was collected by filtration and dried under reduced pressure to give KOH (0.55 g, 9.8 mmol) was weighed into the flask, dissolved in 8 mL of water, and 1.5 mL of anhydrous ethanol was added to the flask, followed by the addition of 2 (1.0 g, 3.3 mmol). After stirring at 90C for 1 hour, the temperature was lowered to room temperature and stirring was continued for 1 hour. After the reaction was completed, 20 mL of water was added to the flask and filtered. The cake was dried in a vacuum oven at 45C for 24 hours to give a yellow solid 3, yield:94%, Palladium acetate (0.1541g, 0.69mmol) and Xantphos (0.3977g, 0.69mmol) were dissolved in 15mL dioxane and stirred at ambient temperature for 15min. 4-Aminobenzonitrile (3.3g, 14.4mmol), intermediate 3 (3.0g, 13.8mmol) and Cs2CO3 (6.7g, 20.6mmol) were added. Then the reaction flask was evacuated and backfilled with nitrogen for three times, the resulting mixture was stirred at 100C for 12h. The mixture was filtrated, and the filtrate was collected and concentrated. The crude residue was purified by silica gel column chromatography to provide the title product 4 as a yellow solid. Yield: 78.6%, mp: 241-244C. 1H NMR (400MHz, DMSO-d6, ppm) delta: 9.43 (s, 1H, NH), 8.27 (d, J=1.9Hz, pyridine-H), 8.19 (d, J=2.0Hz, pyridine-H), 7.80 (d, J=8.7Hz, Ph-H), 7.41 (d, J=8.7Hz, Ph-H). 13C NMR (100MHz, DMSO-d6, ppm) delta: 145.33, 144.95, 140.96, 135.15, 134.27 (2×C), 132.30, 126.21, 120.77 (2×C), 119.54, 105.37. ESI--MS: m/z 317.2 (M-1), 319.2 (M+1). C12H7BrN4O2 (317.98).

Molecular Weight:218.01
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:216.94869
Monoisotopic Mass:216.94869
Topological Polar Surface Area:84.7
Heavy Atom Count:11
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes