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

2-Hydroxy-5-nitropyridine (200 g, 1.42 mol) was added portion wise to 800 ml of concentrated HCl under constant stirring and then heated to 50 C. To this was slowly added a solution of sodium chlorate (80.0 g, 0.75 mol) inwater. The reactionwas maintained at the same temperature for an additional hour, and then cooled to 0 C. The precipitate obtainedwas filtered, washed thoroughly with water and dried to give 2-Hydroxy-3-chloro-5-nitropyridine. Yield: 240 g, 1.37 mmol (96.0percent). M.P.: 195 e197 C. 1H NMR (300 MHz, DMSO-d6): d 8.65 (d, 1H, J ¼ 2.5 Hz), 8.36 (d, 1H, J ¼ 2.5 Hz). 13C NMR (300 MHz, DMSO-d6): d 153.40, 144.29, 143.59, 135.08, 130.44. MS (ES): 175 (M þ H)þ.2-HYDROXY-5-NITROPYRIDINE (50 g, 357 mmol) AND N-CHLOROSUCCINIMIDE (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-CHLORO-5-NITRO- 2-hydroxypyridine (59 g, 95percent yield). 3-CHLORO-5-NITRO-2-HYDROXY-PYRIDINE (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100 °C within 1 hour, stirred at 100 °C for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3 x 200 mL) and the organic layer was dried over MGS04. The solvent was removed under reduced pressure to give 2, 3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid. A solution of 2, 3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100 °C for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 ML) added. The organic phase was separated and washed with water (2 x 100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g). A suspension of copper cyanide (7 g) and 3-CHLORO-2-IODO-5-NITRO-PYRIDINE (7 g) in acetonitrile (200 mL) was heated to 80 °C within 1 hour and stirred at 80 °C for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (4.26 g). A solution of tin chloride (52 g) and 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (10.3 g) was stirred in ethyl acetate (200 ML) at room temperature for 10 minutes and at 70 °C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate (100 g) added in four portions to the mixture within 4 hours. The mixture was stirred vigorously for 20 hours. The suspension was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated to give 5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder. Step (f) Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro- 2-CYANOPYRIDINE (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60°C for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5-AMINO-6-BROMO-3-CHLORO-2-CYANO-PYRIDINE (6.23 g). 5-Amino-6-bromo-3-chloro-2-cyano-pyridine (1.6 g) was dissolved in tetrahydrofuran (5 mL) at room temperature. NN-DIMETHYLAMINOPYRIDINE (0.5 g) followed by di-tert-butyl dicarbonate (3.78 g) in small portions were added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was dissolved in dicloromethane (60 mL). Trifluoroacetic acid (1 g) was added to the solution and the mixture was stirred for 1 hour. The solvent was removed by evaporation and product was purified from the residue by column chromatography (EtOAc/hexanes 1/1) to give tert-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate (1 g). MS (obs. ) : 333 (M + 1)-Chloro-5-nitro-pyridin-2-ol 17 g (121.4 mmol) 2-hydroxy-5-nitropyridine was taken in 80 ml concentrated HCI and warmed up to 50°C. Then, a solution of 4.5 g (42.5 mmol) NaCI015b. 2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 °C. To this was added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0 °C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro- 5-nitro pyridine. Yield: 850 mg (68.2 percent); m.p.: 195-197 °C; H NMR (DMSO-d2-Hydroxy-5-nitropyridine (lg, 7.14 mmol) was added portion wise to concentrated HCl (4.5 mL) under constant stirring and was then heated to 50 °C. To this, a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL) was added. The reaction was maintained at the same temperature for 1 h, and then was cooled to 0 °C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro-5- nitropyridine. Yield: 68.2 percent; *H NMR (DMSO-d2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 To a warm (50°C) solution of 2-hydroxy-5-nitro-pyridine (17 g, 121 mmol) in concentrated HCI (80 mL) was added dropwise NaCI0General procedure: To a solution of N-hydroxysalicylamide (0.5 g, 3.26 mmol) in anhydrous DMF (5 ml) was added 2a or 2b (3.26 mmol) and freshly calcinated K2CO3 (1.35 g, 9.78 mmol) and the mixture was kept, with stirring at the room temperature overnight. DMF was removed in vacuo and the residue was treated with water (10 ml) and then extracted with CH2Cl2 (5 ml). The organic layer was separated, washed with water, dried over anhydrous CaCl2, and purified by flesh chromatography on silica gel using CH2Cl2 as eluent. Dichloromethane was evaporated in vacuo. The resulting residue was benzo[d]oxazol-2(3H)-one 11. The water layer was acidify by hydrochloric acid, filtered and washed with water. The resulting residue was compound 12a(b).2-Hydroxy-5-nitropyridine (200 g, 1.42 mol) was added portion wise to 800 ml of concentrated HCl under constant stirring and then heated to 50 C. To this was slowly added a solution of sodium chlorate (80.0 g, 0.75 mol) inwater. The reactionwas maintained at the same temperature for an additional hour, and then cooled to 0 C. The precipitate obtainedwas filtered, washed thoroughly with water and dried to give 2-Hydroxy-3-chloro-5-nitropyridine. Yield: 240 g, 1.37 mmol (96.0%). M.P.: 195 e197 C. 1H NMR (300 MHz, DMSO-d6): d 8.65 (d, 1H, J ¼ 2.5 Hz), 8.36 (d, 1H, J ¼ 2.5 Hz). 13C NMR (300 MHz, DMSO-d6): d 153.40, 144.29, 143.59, 135.08, 130.44. MS (ES): 175 (M th H)th.2-HYDROXY-5-NITROPYRIDINE (50 g, 357 mmol) AND N-CHLOROSUCCINIMIDE (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-CHLORO-5-NITRO- 2-hydroxypyridine (59 g, 95% yield). 3-CHLORO-5-NITRO-2-HYDROXY-PYRIDINE (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100 C within 1 hour, stirred at 100 C for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3 x 200 mL) and the organic layer was dried over MGS04. The solvent was removed under reduced pressure to give 2, 3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid. A solution of 2, 3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100 C for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 ML) added. The organic phase was separated and washed with water (2 x 100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solvent gave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g). A suspension of copper cyanide (7 g) and 3-CHLORO-2-IODO-5-NITRO-PYRIDINE (7 g) in acetonitrile (200 mL) was heated to 80 C within 1 hour and stirred at 80 C for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (4.26 g). A solution of tin chloride (52 g) and 3-CHLORO-2-CYANO-5-NITRO-PYRIDINE (10.3 g) was stirred in ethyl acetate (200 ML) at room temperature for 10 minutes and at 70 C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate (100 g) added in four portions to the mixture within 4 hours. The mixture was stirred vigorously for 20 hours. The suspension was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated to give 5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder. Step (f) Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro- 2-CYANOPYRIDINE (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60C for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5-AMINO-6-BROMO-3-CHLORO-2-CYANO-PYRIDINE (6.23 g). 5-Amino-6-bromo-3-chloro-2-cyano-pyridine (1.6 g) was dissolved in tetrahydrofuran (5 mL) at room temperature. NN-DIMETHYLAMINOPYRIDINE (0.5 g) followed by di-tert-butyl dicarbonate (3.78 g) in small portions were added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was dissolved in dicloromethane (60 mL). Trifluoroacetic acid (1 g) was added to the solution and the mixture was stirred for 1 hour. The solvent was removed by evaporation and product was purified from the residue by column chromatography (EtOAc/hexanes 1/1) to give tert-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate (1 g). MS (obs. ) : 333 (M + 1)-Chloro-5-nitro-pyridin-2-ol 17 g (121.4 mmol) 2-hydroxy-5-nitropyridine was taken in 80 ml concentrated HCI and warmed up to 50C. Then, a solution of 4.5 g (42.5 mmol) NaCI03 in 70 ml water was added dropwise by keeping the temperature below 60C. The solution was stirred for 15 minutes, cooled to 0C, and the solid was filtered and dried completely to give 19.7 g (1 13.2 mmol, 93% yield) of the title compound. MS: [M-1] Rf = 0.56 (hexane/EtOAc 1 : 1 ).15b. 5-amino-2, 3-dichloropyridine The procedure of Koch and Schnatterer, Synthesis, 1990, 499-501 was followed. To 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12 N hydrochloric acid was added dropwise a solution of potassium chlorate (21.4 g, 0.18 mol) in H2 O (300 mL) at a rate such that the temperature remained '60 C. The mixture was allowed to stir for a further 30 minutes at ca. 50 C., then allowed to cool to ambient temperature, then was further cooled in an ice bath. The yellow solid was collected by filtration, washed with cold H2 O, and dried under vacuum at 50 C. to afford 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellow powder.2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 C. To this was added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0 C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro- 5-nitro pyridine. Yield: 850 mg (68.2 %); m.p.: 195-197 C; H NMR (DMSO-d6) delta: 8.36 (d, 1H, J = 2.5 Hz), 8.65 (d, 1H, J = 2.5 Hz).2-Hydroxy-5-nitropyridine (lg, 7.14 mmol) was added portion wise to concentrated HCl (4.5 mL) under constant stirring and was then heated to 50 C. To this, a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL) was added. The reaction was maintained at the same temperature for 1 h, and then was cooled to 0 C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro-5- nitropyridine. Yield: 68.2 %; *H NMR (DMSO-d6): delta 13.21 (bs, 1H), 8.66 (d, J=2.7Hz, 1H), 8.39 (d, J=2.7Hz, 1H).2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50 0C. To this was added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0 0C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro-5-nitro pyridine.Yield: 850 mg (68.2 %); m.p.: 195-197 0C; 1H NMR (DMSOd6) delta: 8.36 (d, IH, J = 2.5 Hz), 8.65 (d, IH, J = 2.5 Hz).A 5L flask with mechanical stirrer, thermocouple, and addition funnel was charged with 2-hydroxy-5-nitropyridine (200 g, 1.43 mol, Aldrich) and concentrated HCl (890 mL). The mixture was warmed to 50-55 C. and a solution of KClO3 (61.3 g, 0.5 mol) in water (850 mL) was added dropwise over 75 minutes maintaining the reaction temperature at 55-59 C. Following complete addition, the reaction mixture was cooled in an ice-water bath to an internal temperature of <6 C. and then filtered. The filter cake was washed with cold water (700 mL) and dried under vacuum at 50 C. for 12 hours to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 7.43 (d, J=3 Hz, 1H), 7.59 (d, J=3 Hz, 1H).Concentrated hydrochloric acid (239 g) was added to 2-hydroxy-5-nitropyridine (40.0 g). The resulting slurry was heated to 53 C., and stirred until all the solids dissolved. To this was slowly added a solution of potassium chlorate (14.0 g) in water (250 g), while maintaining the temperature between 55 C. and 59 C. The resulting mixture was stirred at 58-62 C. for about 1 hour. The reaction was then cooled to room temperature, stirred for 12 hours and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/DMSO-d6) delta 8.64 (d, J=2.9 Hz, 1H), 8.35 (d, J=2.9 Hz, 1H)Example 2A 3-chloro-5-nitro-2-pyridinol A 5 L flask with mechanical stirrer, thermocouple, and addition funnel was charged with 2-hydroxy-5-nitropyridine (200 g, 1.43 mol, Aldrich) and concentrated HCl (890 mL). The mixture was warmed to 50-55 C. and a solution of KClO3 (61.3 g, 0.5 mol) in water (850 mL) was added dropwise over 75 minutes maintaining the reaction temperature at 55-59 C. Following complete addition, the reaction mixture was cooled in an ice-water bath to an internal temperature of <6 C. and then filtered. The filter cake was washed with cold water (700 mL) and dried under vacuum at 50 C. for 12 hours to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 7.43 (d, J=3 Hz, 1H), 7.59 (d, J=3 Hz, 1H).Step 1 Preparation of 2-hydroxy-3-chloro-5-nitro pyridine 2-Hydroxy-5-nitro-pyridine (1 g, 7.14 mmol) was added in portions to concentrated hydrochloric acid (4.5 mL) with constant stirring and was heated to 50 C. A solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL) was added slowly to this mixture. The reaction was maintained at the same temperature for 1 hour, and was cooled to 0 C. The precipitate obtained was filtered, washed with water and dried to obtain the title compound. Yield: 0.850 g (68.2%); 1H NMR (DMSO-d6, 300 MHz): delta 8.36 (d, 1H), 8.65 (d, 1H).Place 5-nitro-pyridin-2-ol (20 g, 143 mmol) in concentrated HCl (100 mL). Heat to 50 C and then dropwise add potassium chlorate (6.13 g, 50 mmol) dissolved in water (100 mL). Stir at 50 C for 30 min. Cool the reaction in an ice bath. Filter off the solid and wash with water. Dry thoroughly to yield 21.13 g (85%) of 3-chloro-5-nitro-pyridin-2-ol. MS(ES): m/z = 173 [M+H]. 'To a warm (50C) solution of 2-hydroxy-5-nitro-pyridine (17 g, 121 mmol) in concentrated HCI (80 mL) was added dropwise NaCI03(4.5 g, 42.5 mmol) in water (70 mL), keeping the internal temperature below 60C. The reaction mixture was stirred for 15 min and then cooled to 0C. The resulting precipitate was collected by vacuum filtration and dried to provide 19.7 g of the title compound. tR: 5.45 min (HPLC 3); ESI-MS: 173 [M-H](LC-MS 2); Rf= 0.55 (hexane/EtOAc, 1 : 1 ).EXAMPLE 2A 3-chloro-5-nitro-2-pyridinol A 5 L flask with mechanical stirrer, thermocouple, and addition funnel was charged with 2-hydroxy-5-nitropyridine (200 g, 1.43 mol, Aldrich) and concentrated HCl (890 mL). The mixture was warmed to 50-55 C. and a solution of KClO3 (61.3 g, 0.5 mol) in water (850 mL) was added dropwise over 75 minutes maintaining the reaction temperature at 55-59 C. Following complete addition, the reaction mixture was cooled in an ice-water bath to an internal temperature of <6 C. and then filtered. The filter cake was washed with cold water (700 mL) and dried under vacuum at 50 C. for 12 hours to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 7.43 (d, J=3 Hz, 1H), 7.59 (d, J=3 Hz, 1H).(b) 3-chloro-2-hydroxy-5-nitropyridine To a warm (50 C.) mixture of 100.1 g (0.72 mol) of 1a above in 800 ml of concentrated hydrochloric acid was added dropwise with stirring a solution of 70.0 g (0.6 mol) of potassium chlorate in 1300 ml of water causing an exothermic reaction. The rate of addition was adjusted so that the internal temperature was maintained between 48 and 50 C. After the addition was complete, the reaction temperature was maintained at 50 C. for two additional hours. After cooling to about 10 C. and filtering, the filter cake was washed with 500 ml of water and dried to give 92.0 g (59%) of product as a yellow solid; m.p. 195-197 C.To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0 C. was added quinoline (23.6 mL, 0.2 mol), followed by

Molecular Weight:174.54
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:173.9832197
Monoisotopic Mass:173.9832197
Topological Polar Surface Area:74.9
Heavy Atom Count:11
Complexity:276
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes