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In methanol; diethyl ether; dichloromethane;Heating / reflux;
A solution of 3-methoxy-6-methyl-2-nitro-pyridine (2.25 g, 13.4 mmol) in H2O containing MgSO4 (5.24 g, 43.7 mmol) was heated to reflux. A solution of KMnO4 (5.72 g, 36.2 mmol) was added slowly over a period of 1 h and reflux was maintained for an additional 5 h. The reaction mixture was cooled to room temperature and concentrated ammonia was added (6 mL). The brown solid was filtered and washed twice with water. The filtrate was concentrated and the new precipitate formed, composed mostly of starting material, was removed by filtration. The filtrate was acidified and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4, filtered and concentrated. The residue was taken up in MeOH-DCM (40 mL, 1:1 ratio) and a solution of diazomethane in Et2O was added until a persisting yellow color was observed. The solution was then concentrated to dryness and purified by flash column chromatography, using a gradient of hexane/EtOAc from 6/4 to 4/6 as the eluent, to give 5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester (585 mg, 20% yield).
5-Cyclohexylamino-6-nitro-pyridine-2-carboxylic acid methyl ester: A solution of <strong>[390816-44-1]5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester</strong> (0.585 g, 2.75 mmol) and cyclohexylamine (0.636 mL, 5.51 mmol) in DMF (8mL) was heated at 70 C. for 20 h. The mixture was poured on brine (5OmL) while mixing vigorously. The solid formed was filtered, washed with water and then dissolved in EtOAc. The solution was washed with water, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-cyclohexylamino-6-nitro-pyridine-2-carboxylic acid methyl ester as a brown oil (0.558 g) which was used in the subsequent step without purification.
In DMF (N,N-dimethyl-formamide); at 70℃; for 20.0h;Heating / reflux;
A solution of <strong>[390816-44-1]5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester</strong> (0.585 g, 2.75 mmol) and cyclohexylamine (0.636 mL, 5.51 mmol) in DMF (8 mL) was heated at 70 C. for 20 h. The mixture was poured on brine (50 mL) while mixing vigorously. The solid formed was filtered, washed with water and then dissolved in EtOAc. The solution was washed with water, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-cyclohexylamino-6-nitro-pyridine-2-carboxylic acid methyl ester as a brown oil (0.558 g) which was used in the subsequent step without purification.
With ammonia; In diethyl ether; water; magnesium sulfate;
5-Methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester: A solution of 3-methoxy-6-methyl-2-nitro-pyridine (2.25 g, 13.4 mmol) in H2O containing MgSO4 (5.24 g, 43.7 mmol) was heated to reflux. A solution of KMnO4 (5.72 g, 36.2 mmol) was added slowly over a period of 1 h and reflux was maintained for an additional 5 h. The reaction mixture was cooled to room temperature and concentrated ammonia was added (6 mL). The brown solid formed was filtered and washed twice with water. The filtrate was concentrated and the new precipitate formed, composed mostly of starting material, was removed by filtration. The filtrate was acidified and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4, filtered and concentrated. The residue was taken up in MeOH-DCM (40 mL, 1:1 ratio) and a solution of diazomethane in Et2O was added until a persisting yellow color was observed. The solution was then concentrated to dryness and purify by flash column chromatography, using a gradient of hexane/EtOAc from 6/4 to 4/6 as the eluent, to give 5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester (585 mg).
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 48.0h;
Preparation 3 .(compound 203); Methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester; <n="25"/>S-Methoxy-e-nitro-pyridine-Z-carboxylic acid obtained in preparation 2 (2.54 g, 12.8 mmol) in DMF (25 mL) was treated with K2CO3 (2.2 g, 15.9 mmol) and MeI (1.2 mL, 19.2 mmol). The orange suspension was heated to 500C for 48 hours. After evaporation of the solvent in vacuo the crude mixture was treated with water (50 mL) and extracted with EtOAc (2x50 mL) the combined organic phases were washed with brine (2x 50 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 2.75 g crude. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent. 5-Methoxy-6-nitro- pyridine-2-carboxylic acid methyl ester was obtained as a slightly yellow solid.1H NMR (CDCI3) delta = 8.36 (IH, d), 7.59 (IH, d), 4.05 (3H, s), 4.00 (3H, s).
Preparation 4 (compound 204); 6-Amino-5-methoxy-pyridine-2-carboxylic acid methyl ester; 5-Methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester obtained in preparation 3 (1.11 g, 5.25 mmol) and Fe (1.76 g, 31.5 mmol) were mixed in acetic acid (20 mL). The reaction reaction mixture was heated to 1000C for 30 min. After cooling of the yellow reaction mixture to rt the solvent was removed in vacuo and then added to NaHCO3 (sat., 100 mL). The product was extracted <n="26"/>with EtOAc (5x 60 mL) and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. 6-Amino-5-methoxy-pyridine-2- carboxylic acid methyl ester was obtained as a white solid.1H NMR (DMSO-de) delta = 7.33 (IH, d), 7.09 (IH, d), 6.07 (2H, s), 3.84 (3H, s), 3.77 (3H, s).13 C NMR (DMSO-de) delta = 165.8, 150.8, 145.7, 136.6, 115.7, 114.6, 55.9, 51.9.
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