4-(ETHYLAMINO)-3-NITROPYRIDINE

A solution consisting of 4-methoxy-3-nitropyridine (15.0 g, 97.3 MMOL) with ethyl amine (46.5 mL of 70percent aqueous solution, 584 MMOL) in ethanol (30 mL) was stirred at 85 °C in a sealed flask for 2 h. Removal of all VOLATILES IN VACUO afforded the title compound (16.2 g, 99 percent). MS: (M+H) + = m/z 168.A solution consisting of 4-methoxy-3-nitropyridine (15.0 g, 97.3 mmol) with ethyl amine (46.5 mL of 70percent aqueous solution, 584 mmol) in ethanol (30 mL) was stirred at 85 °C in a sealed flask for 2 h. Removal of all volatiles in vacuo afforded the title compound (16.2 g, 99 percent). MS: (M+H) + = m/z 168.A solution consisting of 4-ethoxy-3-nitropyridine (15.0 g, 97.3 MMOL) and EtNH2 (46.5 mL, 70percent aq. solution, 584 MMOL) in ETOH (30 mL) was stirred at 85 °C in a pressure vessel for 2 h. Removal of all VOLATILES IN VACUO afforded the title compound (16.2 g, 99 percent). MS (ES+) m/z 168 (M+H) +.A solution consisting of 4-ethoxy-3-nitropyridine (15.0 g, 97.3 mmol) and EtNH2 (46.5 mL, 70percent aq. solution, 584 mmol) in EtOH (30 mL) was stirred at 85 °C in a pressure vessel for 2 h. Removal of all volatiles in vacuo afforded the title compound (16.2 g, 99 percent). MS (ES+) m/z 168 (M+H) +.Preparation of Ethyl-(3-nitropyridin-4-yl)amine 4-Methoxy-3-nitropyridine hydrochloride (11.2g, 58.9mmol) in ethanol (75ml) was treated with a 70percent solution of ethylamine in water (64ml) and heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and water. The mixture was extracted (x3) with ethyl acetate, washed with water and saturated aqueous sodium chloride solution before drying over magnesium sulfate. Evaporation of the solvent afforded the title compound (11.7g, 96percent).4-Methoxy-3-nitropyridine hydrochloride (11. 2g, 58.9 mmol) in ethanol (75ml) was treated with a 70percent solution of ethylamin in water (32mi) and heated under reflux for 1 hour. Further ethylamin solution (32m1) was added and the mixture heated under reflux for a further 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate, washed (x3) with water and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated in vacuo to afford the title compound (8.7g, 88percent) ; MS (ES+) m/e 168 [M+H] +.Preparation of Ethyl-(3-nitropyridin-4-yl)amine 4-Methoxy-3-nitropyridine hydrochloride (11.2g, 58.9mmol) in ethanol (75ml) was treated with a 70% solution of ethylamine in water (64ml) and heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and water. The mixture was extracted (x3) with ethyl acetate, washed with water and saturated aqueous sodium chloride solution before drying over magnesium sulfate. Evaporation of the solvent afforded the title compound (11.7g, 96%).1H NMR (400 MHz, DMSO-D6) delta ppm 1.18 (t, J=7.14 Hz, 3H), 3.41 (m, 2H), 6.98 (d, J=6.32 Hz, 1 H), 8.24 (d, J=6.32 Hz, 1 H)1 8.39 (br, 1 H), 9.00 (s, 1 H). MS m/z 168 (M+1)+.4-Methoxy-3-nitropyridine hydrochloride (11. 2g, 58.9 mmol) in ethanol (75ml) was treated with a 70% solution of ethylamin in water (32mi) and heated under reflux for 1 hour. Further ethylamin solution (32m1) was added and the mixture heated under reflux for a further 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate, washed (x3) with water and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated in vacuo to afford the title compound (8.7g, 88%) ; MS (ES+) m/e 168 [M+H] +.A mixture consisting of ethyl (3-nitropyridin-4-yl) amine (11.76 g, 70 MMOL) in acetic acid (140 mL) with sodium acetate (28.7 g, 350 MMOL) and bromine (13.44 g, 84 MMOL) was stirred in a sealed flask at 100 C for 18 h. Most of the solvent was removed in vacuo and the residue partitioned between CH2CI2 and water and the aqueous layer basified with NAHCO3. The organic extract was washed with water then brine, dried (NA2SO4) and all volatiles removed in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate: hexane (2: 8) to afford the title compound (10.4 g, 60%). MS: (M+H) + = m/z 246.A mixture of ethyl (3-nitropyridin-4-yl) amine (11.8 g, 70.0 MMOL), acetic acid (140 mL), sodium acetate (28.7 g, 0.35 mol) and bromine (13.4 g, 84.0 MMOL) was stirred in a pressure vessel at 100 C for 18 h. The solvent was removed in vacuo and the residue partitioned between CH2CI2 and water. The aqueous layer was made basic (PH-8) with NAHCO3 and further extracted with CH2CI2. The combined organic extracts were washed with water, brine and dried (NA2SO4). The solvent was removed in vacuo. and the residue subjected to flash chromatography (20% EtOAc/hexanes, silica gel) to give 10.4 g (60%) of the desired compound. MS (ES+) m/z 246 (M+H) +.A mixture consisting of ethyl (3-nitropyridin-4-yl) amine (11.76 g, 70 mmol) in acetic acid (140 ml) with sodium acetate (28.7 g, 350 mmol) and bromine (13.44 g, 84 mmol) was stirred in a sealed flask at 100 oc for 18 h. Most of the solvent was removed in vacuo and the residue partitioned between CH2CI2 and water and the aqueous layer basified with NaHCO3. The organic extract was washed with water then brine, dried (Na2SO4) and all volatiles removed in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate: hexane (2: 8) to afford the title compound (10.4 g, 60%). MS: (M+H) + = m/z 246.; A mixture of ethyl (3-nitropyridin-4-yl) amine (11.8 g, 70.0 mmol), acetic acid (140 mL), sodium acetate (28.7 g, 0.35 mol) and bromine (13.4 g, 84.0 mmol) was stirred in a pressure vessel at 100 C for 18 h. The solvent was removed in vacuo and the residue partitioned between CH2CI2 and water. The aqueous layer was made basic (pH No. 8) with NaHCO3 and further extracted with CH2CI2. The combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was removed in vacuo. and the residue subjected to flash chromatography (20% EtOAc/hexanes, silica gel) to give 10.4 g (60%) of the desired compound. MS (ES+) m/z 246 (M+H) +.; To a solution of the product of 14 (a) (3. 0g, 17. 9mmol) in acetic acid (40ml) was added bromine (3.12g, 1ml, 19. 7mmol) and the mixture was heated at 100C for 20 hours. After cooling the solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was washed with water (x3), dried and evaporated in vacuo. Purification of the residue by silica gel chromatography eluting with 50% dichloromethane in ethyl acetate afforded the title compound (1.9g, 43%).'H NMR (DMSO-d6) 8.73 (1H, s), 8.52 (1H, s), 7.0 (1H, br), 3.25 (2H, m), 1.16 (3H, t, J 7.2Hz).Preparation of N4-ethylpyridine-3, 4-diamineHN.>. '2Ethyl-(3-nitropyridin-4-yl)amine (8.7g, 52.0mmol) in ethanol (150ml) was hydrogenated for 18 hours in the presence of 10% palladium on carbon. After filtration of the catalyst through celite, the filtrate was concentrated in vacuo to afford the title compound (6.7g, 94%). 1H NMR (400 MHz, DMSO-D6) delta ppm 1.19 (m, 3H), 3.09 (m, 2H), 4.53 (br, 2H), 5.21 (br, 1 H), 6.31 (d, J=5.22 Hz, 1 H), 7.57 (d, J=5.36 Hz, 1 H), 7.62 (s, 1 H). MS (ES+) m/e 138 [M+H]+.To a solution of 4-amino-3-nitropyridine (2.0 mmol) in DMF (10 mL), NaH (2.2 mmol) was addedslowly, the mixture was stirred at room temperature for 30 min. Then ethyl iodine (2.0 mmol) wasadded slowly into the mixture until the reaction is finished monitored by TLC. Then the solvent wasevaporated and the residue was purified by silica gel chromatography by DCM/MeOH system toafford 4-ethylamino-3-nitropydine.To a solution of 4-ethylamino-3-nitropydine (1.0 mmol) in EtOH (10 mL), 10% Pd/C was added.Then the mixture was reduced by catalytic hydrogenation. Until the completion of the reaction, the Pd/C was filtered and the solvent was evaporated. The product was used in the next step withoutfurther purification.The solution of substituted 4-ethylamino-3-aminopydine (0.5 mmol), benzaldehyde (0.5 mmol)with sodium pyrosulfite (0.5 mmol) was stirred in DMF (8 mL) under 120 C overnight. On completionof the reaction, the solvent was evaporated and the residue was purified by silica gel chromatographyby DCM/MeOH system to afford the final product. If necessary, the crude product could berecrystallized in DCM to afford pure compound [31].To a solution of 4-amino-3-nitropyridine (2.0 mmol) in DMF (10 mL), NaH (2.2 mmol) was addedslowly, the mixture was stirred at room temperature for 30 min. Then ethyl iodine (2.0 mmol) wasadded slowly into the mixture until the reaction is finished monitored by TLC. Then the solvent wasevaporated and the residue was purified by silica gel chromatography by DCM/MeOH system toafford 4-ethylamino-3-nitropydine.To a solution of 4-ethylamino-3-nitropydine (1.0 mmol) in EtOH (10 mL), 10% Pd/C was added.Then the mixture was reduced by catalytic hydrogenation. Until the completion of the reaction, the Pd/C was filtered and the solvent was evaporated. The product was used in the next step withoutfurther purification.The solution of substituted 4-ethylamino-3-aminopydine (0.5 mmol), benzaldehyde (0.5 mmol)with sodium pyrosulfite (0.5 mmol) was stirred in DMF (8 mL) under 120 C overnight. On completionof the reaction, the solvent was evaporated and the residue was purified by silica gel chromatographyby DCM/MeOH system to afford the final product. If necessary, the crude product could berecrystallized in DCM to afford pure compound [31].

Molecular Weight:167.17
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:167.069476538
Monoisotopic Mass:167.069476538
Topological Polar Surface Area:70.7
Heavy Atom Count:12
Complexity:157
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes