4-Chloro-3-nitropyridine

Snuff color to brown powder

N-(3- { [2- (4-amino-furazan-3-yl)-1-phenyl-lH-imidazo [4, 5-c] pyridin-6- yl] oxy} phenyl) acetamide Step 1. 4-Chloro-3-nitropyridine To a suspension of 3-nitro-4-pyridinol (20 g, 143 mmol) in toluene (300 mL) was added phosphorous oxychloride (65.7g, 429mmol) at 0 °C. The resulting mixture was warmed to room temperature, then heated to reflux (110 °C) for 16 hours. After cooling to rt, the solvent was removed in vacuo and the residue was poured on ice, then basified with K2CO3 to pH = 10. The mixture was extracted with ethyl acetate and the organic phase was washed twice with water, followed by once with brine before concentrating to a brown oil which solidified on standing (22. 5g, 99percent). MS (ES+) m/e 159 [M+H] +.Step 1. 4-Chloro-3-nitropyridine To a suspension of 3-nitro-4-pyridinol (20g, 143mmol) in toluene (300ml) was added phosphorous oxychloride (65.7g, 429mmol) at 0 °C. The resulting mixture was warmed to room temperature, then heated to reflux (110 °C) for 16 hours. After cooling to rt, the solvent was removed in vacuo and the residue was poured on ice, then basified by K2CO3 to pH = 10. The mixture was extracted with ethyl acetate and the organic phase was washed twice with water, followed by once with brine before concentrating to a brown oil which solidified on standing (22. 5g, 99percent)To a solution of 4-hydroxy-3-nitro-pyridine (2 g, 14 mmol) in POC13 (6 mL) was added PC15 (2.5 g, 12 mmol). The mixture was heated to reflux for 3 hours. The solvent was evaporated and the residue was cooled with ice-water and vigorously stirred with water (3 mL) and CHC13 (6 mL). The aqueous was extracted CHC13 (5x5 mL). The organic phase was combined and dried over MgSO4. After filtration, the solvent was removed to afford the product 4-Chloro-3-nitro-pyridine (2.24g, 99percent). 1H NMR (CDC13, 400 Hz) 8 9.13 (s, 1H), 8. 70 (d, J=5.2Hz, 1H), 7.55 (d, J=5.6Hz, 1H). MS (ESI+) [M+H] + 159.N-(3- { [2- (4-amino-furazan-3-yl)-1-phenyl-lH-imidazo [4, 5-c] pyridin-6- yl] oxy} phenyl) acetamide Step 1. 4-Chloro-3-nitropyridine To a suspension of 3-nitro-4-pyridinol (20 g, 143 mmol) in toluene (300 mL) was added phosphorous oxychloride (65.7g, 429mmol) at 0 °C. The resulting mixture was warmed to room temperature, then heated to reflux (110 °C) for 16 hours. After cooling to rt, the solvent was removed in vacuo and the residue was poured on ice, then basified with K2CO3 to pH = 10. The mixture was extracted with ethyl acetate and the organic phase was washed twice with water, followed by once with brine before concentrating to a brown oil which solidified on standing (22. 5g, 99percent). MS (ES+) m/e 159 [M+H] +.Step 1. 4-Chloro-3-nitropyridine To a suspension of 3-nitro-4-pyridinol (20g, 143mmol) in toluene (300ml) was added phosphorous oxychloride (65.7g, 429mmol) at 0 °C. The resulting mixture was warmed to room temperature, then heated to reflux (110 °C) for 16 hours. After cooling to rt, the solvent was removed in vacuo and the residue was poured on ice, then basified by K2CO3 to pH = 10. The mixture was extracted with ethyl acetate and the organic phase was washed twice with water, followed by once with brine before concentrating to a brown oil which solidified on standing (22. 5g, 99percent)a) (a) 4-Hydroxy-3-nitropyridine ( 10.0 g, 71.38 mmol) was added to 100 ml of phosphorus oxychloride, which was then refluxed under stirring for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to 500 ml of ice water, which was then neutralized with 2N sodium hydroxide solution. The reaction mixture was extracted with methylene chloride (300 ml). The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound of a pale yellow solid (9.2 g, 92.0percent).[50] TLC: n-hexane/ethyl acetate=2/l(v/v): Rf=O.5[51] * H-NMR (CDCl ) δ 9.12(s, IH), 8.69(d, IH), 7.55(d, IH)4-Hydroxy-3-nitropyridine (10 g, 71.38 mmol) was added to 100 ml of phosphorus oxychloride. The reaction mixture was refluxed for 1 hour and then concentrated under reduced pressure. The resulting residue was added to 500 ml of ice water and then neutralized with 2N sodium hydroxide solution. The reaction mixture was extracted with 300 ml of methylene chloride. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound (9.2 g, 92.0 percent) as a pale yellow solid.[145] Rf (n-hexane/ethyl acetate = 2/1 , v/v) = 0.5[146] Example 4 2-{1-[4-(2-methoxy-5-nitropyridin-4-ylamino)phenyl]azetidin-3-yloxy}ethanol (4a) 4-chloro-3-nitropyridine To phosphorus pentachloride (16.3 g, 78.6 mmol) was added phosphorus oxychloride (16.2 mL, 173 mmol), 3-nitropyridin-4-ol (10.0 g, 71.4 mmol) was separately added at 60° C. over 15 min, and the mixture was stirred at 140° C. for 3.5 hr. The solvent was evaporated under reduced pressure, and the residue was poured into ice water, and neutralized with potassium carbonate. The mixture was extracted twice with chloroform, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1, V/V). The solvent of the object fraction was evaporated under reduced pressure to give the title object compound as a pale-yellow powder (10.1 g, yield 89percent). Example 37 7- (2, 4-DICHLORO-PHENYL)-2-METHYL-2H-PYRAZOLO [4, 3-B] pyridine H N - NOZ O Cl Ar 103 104 =3w Br H2 NHZ NAcz X Ar Ar Ar 107 108 ste 110 N, -, 1 NHR Ar Ar Ar 111 113 Ar = 4-dichlorophenyl step 1 A mixture OF POC13 (22 mL) and PC15 (15 g) was warmed to 70° C and 4-hydroxy-3- nitropyridine (103, 10 g) was added in small portions. A white solid formed and evolution of gas occurred. After the addition was completed the reaction was warmed to 140° C and the reaction stirred for 5 h. The reaction mixture was cooled and concentrated in vacuo. To the residue was added carefully H20 (50 ML) and the pH adjusted to 7.5 with solid NA2CO3. DCM was added and the two-phase mixture stirred for 30 min. The phases were separated and the aqueous phase washed twice with DCM (50 mL). The combined organic phases were dried (MgS04), filtered and evaporated to afford 104 (8.72 g, 77percent theory) which was sufficiently pure to use in the next step.To a suspension of 3-nitropyridin-4-ol (4.342 g, 31 mmol) in toluene (60 mL) was added POCl3-Nitropyridin-4-ol (334.4g, 2.37mol, 1.0wt) was charged to a 20000mL flask under nitrogen followed by toluene (5000mL, 15vol). Phosphorous oxychloride (1800mL, 5.4vol) was added slowly. N, N'-Dimethylformamide (1.73g, 0.024mol, 1molpercent) was added and the mixture heated at reflux for 2 hours. 4-Hydroxy-3-nitropyridine (10.0 g, 71.4 mmol) is added portionwise to a mechanically stirred mixture of phosphorous pentachloride (16.32 g, 78.6 mmol) and phosphorous oxychloride (16.2 mL) at 55-60° C. After the addition is complete, the temperature is raised to 130-140° C. for 4 hr. After cooling to room temperature, the phosphorous oxychloride is removed and the residue is cautiously treated with ice/water, made basic with sodium carbonate and extracted with ether. The combined extract is dried, filtered and concentrated to yield 4-chloro-3-nitropyridine (5.1 g, 45percent yield) as a pale yellow solid.

Molecular Weight:158.54
XLogP3:1.3
Hydrogen Bond Acceptor Count:3
Exact Mass:157.9883050
Monoisotopic Mass:157.9883050
Topological Polar Surface Area:58.7
Heavy Atom Count:10
Complexity:136
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes