2-AMINO-4-CHLORO-5-NITROPYRIDINE

Brown Solid

4-Chloro-3-nitropyridin-2-amine(Aust. J. Chem. 1982, 35, 2025.)4-Chloro-2-aminopyridine (10 g, 77.5 mmol) was dissolved in concentrated sulfuric acid (10OmL) and using a salt-ice bath, was cooled to ca. -8 To a 100 ml round-bottomed flask containing 2-amino-4-chloropyridine (0.480g, 3.75 mmol) cooled in an ice bath was added concentrated sulphuric acid (5.4 g). Thereaction mixture was stirred for 5 min and then nitric acid (70percent; 0.36 g) was addeddropwise. The reaction mixture was stirred at 0 °C for 10 min, then heated to 55 °C andstirred at this temperature for 1 h. It was cooled to room temperature and diluted with ice-1 0 water. The pH was carefully adjusted to ~ 7.5 with 10percent aqueous NaOH whereupon ayellow precipitate formed. This was filtered off, washed with water and dried in vacuoover P205. The product was purified by silica column chromatography (elution withdichloromethane) to provide in order of elution: 4-Chloro-3-nitropyridin-2-amine as ayellow solid (0.21 0 g, 32percent), 1 H-NMR (500 MHz, DMSO-d6) 6.87 (d, J = 5.2 Hz, 1 H, 15 pyridine C-H), 7.21 (s, 2H, NH2), 8.11 (d, J = 5.2 Hz, 1 H, pyridine C-H). [00118] 4-chloro-5-nitropyridin-2-amine (0.080 g, 12percent): 1H-NMR (500 MHz, DMSO-d6)6.58 (s, 1 H, pyridine C-H) 7.58 (s, 2H, NH2), 8.79 (s, 1 H, pyridine C-H).4-Chloropyridin-2-amine (4) (5.2g, 40.6mmol) was carefully dissolved in conc. sulfuric acid (25mL). The reaction mixture was cooled to 0°C and then fuming nitric acid (1.5mL) was added dropwise with stirring. The reaction mixture was allowed to stand for overnight at room temperature, or until a drop mixed with water, gave no precipitate (the nitro-amine is insoluble in dilute acid). The red reaction mixture was then poured into crushed ice and bought to pH 5–6 by adding ammonia solution (28percent). The separated yellow precipitate was removed by filtration, washed well with ice water and dried. The solids were impregnated onto silica gel and purified by flash chromatography (EtOAc : petroleum ether=1:1) to give compound 4-chloro-5-nitropyridin-2-amine (5) as a yellow solid [28, 29]. Yield: 2.88g, 41percent, mp: 257–259°C. To 4-chloro-3-nitropyridine (10.0 g, 63.1 mmol) in 500 ml of liquid ammonium was added potassium permanganate (19.9 g, 126.1 mmol). The reaction was stirred at this temperature (-33 The compounds were prepared as described in the literature with major modifications. To a solution of 4-chloropyridin-2-amine 9 (2.60 g, 0.02 mol) in sulfuric acid (96percent, 40 mL) was slowly added fuming nitric acid (20 mL) under intensively stirring at 0 C over a period of 6 h. The reaction mixture was allowed to stay at 0-5 C for 3 days and then poured into ice water (120 g).The mixture was adjusted to pH 3-5 with ammonium hydroxide (25percent, 160 mL) and the yellow precipitate filtered, washed with cooled water, and dried at room temperature to give 4-chloro-2-nitraminopyridine intermediate (3.46 g, 99percent) as yellow crystals; mp 204-205 C. The crude nitramine (2.73 g, 0.016 mol) was carefully dissolved in small portions into cooled sulfuric acid (96percent, 54 mL) under constant stirring. The solution was allowed to warm to room temperature and stirred for further 3 h. After that, the reaction mixture was poured into ice water (60 g) and adjusted topH 6-7 with ammonium hydroxide (25percent, 150 mL) until a yellow crystalline precipitate was formed. The cooled product (mixture of 3- and 5-nitro isomers) was filtered under normal pressure, dried at room temperature over night, and washed several times with ethyl acetate (170 mL) until the color of the crystalline precipitate had turned to a slight yellow. The residue left after filtration was dissolved in ethanol (100 mL), boiled for 15 min, filtered to removethe insoluble precipitate, and recrystallized from dichloromethane/petroleum ether (50percent, 50 mL) to give the pure product 11 (Fraction 1). The combined ethyl acetate layers were evaporated to dryness and purified by repeated column chromatography on silica gel using 50percent dichloromethane/ethyl acetate as eluent. Chromatographically purified products were additionally recrystallized from dichloromethane/petroleum ether (50percent, each 50 mL), evaporated, and dried at 70 C to give pure product 10 (Fractions 2and 4) and 11 (Fraction 3, for details, see Supplementary data, Fig. S2).4.2.1. 4-Chloro-3-nitropyridin-2-amine (10). Slight yellow needles (1.47 g, 42percent over two steps); mp 176-177 C; Rf (50percent CH2Cl2/EtOAc) 0.69; 1H NMR (500 MHz, DMSO-d6) dH: 6.85 (1H, d, J5.36 Hz, H-5), 7.21 (2H, br s, NH2), 8.11 (1H, d, J5.36 Hz, H-6); 13CNMR (125 MHz, DMSO-d6) dC: 113.2 (C5), 129.5 (C3), 136.0 (C4), 152.1 (C6), 152.8 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0, found 171.9 [MH]e, 174.9 [MH].4.2.2. 4-Chloro-5-nitropyridin-2-amine (11).22b Yellow crystals(1.05 g, 30percent over two steps); mp 260-261 C; Rf (50percent CH2Cl2/EtOAc)0.48; 1H NMR (500 MHz, DMSO-d6) dH: 6.58 (1H, s, H-3), 7.59 (2H, br s, NH2), 8.79 (1H, s, H-6); 13C NMR (125 MHz, DMSO-d6) dC: 108.4(C3), 133.5 (C5), 137.1 (C4), 149.7 (C6), 162.7 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0, found 171.9 [MH]After dissolving 4-chloro-5-nitro-2-amine (1.00g, 5.76mmol) was dissolved in tetrahydrofuran (30mL), cooled to 0 , were added dropwise triethylamine (4.00mL, 28.7mmol) and cyclopropyl chloride (0.55mL, 6.06mmol), warmed to room temperature and stirred overnight.Saturated sodium bicarbonate solution (10 mL) The reaction was quenched with ethyl acetate (200mL × 3) was extracted, the organic phase washed with water (150 mL), saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, separated by column chromatography (eluent: PE / EtOAc (v / v) = 10/1), to give the product 1.20g, yield: 86.0percent.

Molecular Weight:173.56
XLogP3:1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:172.9992041
Monoisotopic Mass:172.9992041
Topological Polar Surface Area:84.7
Heavy Atom Count:11
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes