5-Bromo-3-nitro-2(1H)-pyridinone

Yellow Solid

General procedure: 2-Amino-3-nitropyridine 8 (0.015 mol) was dissolved, on cooling with ice, in 70percent sulfuric acid and treated with a solution of NaNO2 (1.24 g) in water (8 mL), which was added dropwise so as to maintain the reaction temperature in 0-5 °C range. The reaction was allowed to warm up to rt and stirred at that temperature for 3 h. The precipitate formed was isolated by filtration, washed with water and dried at 60 °C overnight.Intermediate 12; N-[(R)-1-(5-Bromo-3-fluoro-pyridin-2-yl)-ethyl]-acetamide Step A: 2, 5-Dibromo-3-nitro-pyridine To a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90 C. (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90 C. and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous 1N NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2SO4 and evaporated obtain the title compound as yellow solid (25.2 g, 97%).Step A: 2, 5-Dibromo-3-nitro-pyridineTo a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90C (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90C and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous IN NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2S04 and evaporated obtain the title compound as yellow solid (25.2 g, 97%).To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr3 (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 12O0C for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3 x 200 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (10.30 g, 80.03%).2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N, N- dimethylformamide (0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1. 2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 C and the reaction was aged for about 14 h at 90 C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with 1N NaOH (2 x 10 vol) and H20 (5 vol). The batch was concentrated under reduced pressure to yield the desired product.REFERENCE EXAMPLE1. N-[I -(5-Bromo-3 -fluoropyridin-2-yl)vinyl] acetamideStep 1. 2, 5-Dibromo-3-nitropyridine.2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N1N- dimethylformamide (DMF, 0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1.2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 0C and the reaction was aged for about 14 h at 90 0C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with IN NaOH (2 x 10 vol) and H2O (5 vol). The batch was concentrated under reduced pressure to yield the desired product.REFERENCE EXAMPLES; 1. Lambda^[l-(5-Bromo-3-fluoropyridin-2-yl)vinyI]acetamide; Step 1; 2, 5-Dibromo-3-nitropyridine; 2-Hydroxy-3-nitro-5-bromopyridine (1 eq) was suspended in toluene (3 vol) and N;N-dimethylformamide (0.1 eq) was added. The mixture was protected from light. A solution of phosphorus oxybromide (1.2 eq) in toluene (2 vol) was added to the pyridine mixture over 1.5 h at about 90 0C and the reaction was aged for about 14 h at 90 0C. The reaction mixture was cooled to room temperature and water (10 vol) and toluene (5 vol) were added. The layers were cut and the organic layer was washed with IN NaOH (2 x 10 vol) and H2O (5 vol). The batch was concentrated under reduced pressure to yield the desired product.N, N'-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82%) as a yellow solid. 1H-NMR delta (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.70 (d, J=3.0 Hz, 1H).N, N'-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82%) as a yellow solid. 1H-NMR delta (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.70 (d, J=3.0 Hz, 1H).A mixture of 5-bromo-2-hydroxy-3-nitropyridine (14) (28.8 g, 131.5 mmol), POCl3 (288 mL) and anhydrous DMF (30 mL) was stirred and heated at reflux for 3 h. After removal of POCl3, the residue was poured into ice water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1 hexanes/EtOAc) to afford 15 (25.4 g, 81%) as a pale yellow solid, mp 66-67 C (lit32 68 C). 1H NMR (CDCl3) delta 8.70 (d, J = 2.0 Hz, 1H, Ar-H), 8.37 (d, J = 2.5 Hz, 1H, Ar-H).General procedure: 2-Hydroxy-3-nitropyridine 5 (0.015 mol) was suspended in POCl3 (15 mL). Anhydrous DMF (2 mL) was added and the resulting mixture was heated at reflux for 12 h. The excess of POCl3 was removed by distillation, the residue was taken up in a mixture of DCM with ice and the mixture was stirred for 30 min. The organic layer was separated, washed with water (3 x), dried over anhydrous Na2SO4, filtered and concentrated to yield analytically pure product.Example 7 Synthesis of 7-(4-amino-naphthalen-1-yl)-1H-pyrido [2, 3-b][1, 4]oxazin-2-one Hydrochloride 2-Hydroxy-3-nitro-5-bromopyridine (10 g) was combined with 25 mL of phosphorus oxychloride and 5 g of phosphorus pentachloride. The mixture was heated to 110 C. for 2 h, then cooled to room temperature and poured into ice-water and stirred 30 min. The mixture was extracted with CHCl3, then the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by chromatography through a short plug of SiO2, eluding with 4:1 hexanes:EtOAc afforded 6.72 g of 5-bromo-2-chloro-3-nitro-pyridine.A mixture of I-100 (8.0 g, 36.7 mmol) and N, N-diethylaniline (7 mL) in POCl3(30 mL) was refluxed for 4 hours. The reaction mixture was cooled to room temperature, poured onto ice and stirred for additional 30 minutes. A yellow precipitate was filtered off used in the following step without further purification (7.2 g, 83%). MS (ESI): m/z 238 (M+1)+.A suspension of 5-bromo-2-hydroxy-3-nitro-pyridine (10g;ex.Maybridge) in phosphorus oxychloride (10ml) was heated at 130C to give a red solution. The solution was heated at 130Cfor 2.5. The reaction mixture was poured onto iced water and then neutralised by the portionwise addition of solid sodium bicarbonate. The aqueous was extracted twice with ethyl acetate and the combined organics were dried (MgS04), filtered and evaporated to give the title compound as a yellow solid (10.28g). NMR (d6-DMSO) 8 8.93 (2H, s). LC/MS t = 2.6min, [MH(at)] + acetonitrile 279 consistent with molecular formula CSH2g'Br35C1N20aA suspension of 5-bromo-2-hydroxy-3-nitro-pyridine (19.2g;ex.Maybridge) in phenyl dichlorophosphate (40ml) was heated at 180C for 30 minutes to give a red oil. The reaction mixture was then purified as described in Method 1 (a) to give the title compound as a pale yellow solid (20.4g). NMR (CDCI3) 8 8.36 (1H, d), 8.69 (1H, d). LC/MS t = 2.6min, [MH(at)J 239 consistent with molecular formula CsHz8lBr3sCINzOzTo a round-bottom flask charged with 5-Bromo-3-nitro-pyridin-2-ol (976 mg, 4.0 mmol) was added 6.0 mL of phosphoryl chloride, the resulting suspension was heated to 105 0C and kept for 12 hrs. Then the excess POCI3 was removed under reduced pressure, the residue then was dissolved in anhydrous 10 mL of DCM, 1 mL of 3-aminopropyl-1-ol was then added. The resulting mixture was stirred for 30 min., DCM was then removed under reduced pressure to give a oil residue which was stirred at 45 0C for 12 hrs. Then the reaction was quenched with water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was obtained as a yellow solid 3-(5-bromo-3-nitro-pyridin-2-ylamino)-propan-1-ol and was used for next step without further purification. 1H NMR (400 MHz, CDCI3) delta 1.90 (2H, m), 2.60 (1 H, br.), 3.71 (2H, m), 3.78 (2H, m), 8.42 (1 H, d, J = 2.4 Hz), 8.55 (1 H, d, J = 2.4 Hz); MS m/z (MH)+: 276, 278A mixture of 5-bromo-3-nitropyridin-2-ol (1.26 g, 4.6 mmol) and tin chloride dihydrate (3.91 g, 17.3 mmol) in ethyl acetate (19.3 mL) was heated at 50 C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with brine. The aqueous layer was separated and extracted with ethyl acetate (5*50 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to give a black solid 580 mg (53%), which was used without further purification.(1) Dissolving 2-hydroxy-3-nitro-5-bromopyridine in water and stirring, adding a mixture of iron powder and hydrochloric acid thereto, reacting for 50 minutes, and then treating to obtain 2-hydroxy-3-amino-5- BromopyridineGeneral procedure: 2-Amino-3-nitropyridine 8 (0.015 mol) was dissolved, on cooling with ice, in 70% sulfuric acid and treated with a solution of NaNO2 (1.24 g) in water (8 mL), which was added dropwise so as to maintain the reaction temperature in 0-5 C range. The reaction was allowed to warm up to rt and stirred at that temperature for 3 h. The precipitate formed was isolated by filtration, washed with water and dried at 60 C overnight.

Molecular Weight:218.99
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:217.93270
Monoisotopic Mass:217.93270
Topological Polar Surface Area:74.9
Heavy Atom Count:11
Complexity:276
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes