2-Amino-3-nitro-6-(4-fluorobenzylamino)pyridine

Yellow Solid

To a reaction flask, 200 mL of methanol, 52.08 g of compound 1, 37.54 g of p-fluorobenzylamine and 50.0 mL of triethylamine werea added. The reaction mixture was heated to 80 °C for 10 hours, and the reaction solution was added with 10 times of water to give 76.47 g of compound 3 in a yield of 97.2percent and a purity of 99.62percent (HPLC).2-Amino-6-chloro-3-nitropyridine (ACNP, 10.0 kg) was suspended in isopropanol (49 L) under stirring and a nitrogen blanket. 4-Fluorobenzylamine (7.7 kg) and triethylamine (8.4 kg) were added and the mixture was heated to reflux. Stirring at reflux was maintained for 14 h. The reaction mixture was cooled to 50°C and samples were taken for checking completion of the reaction by HPLC (amount of residual ACNP: 0.02percent). Water (163 kg) was added and the mixture was stirred for 5 min, then cooled to 5°C and stirred for 30 minutes. The precipitate was filtered off, washed with water (41 L) and dried under reduced pressure at 50°C. Yield: 14.6 kg (96.8percent of theory).Was added to the reaction kettle 3.04kg and 10kg of isopropanol fluorobenzylamine, with stirring, was added 4kg2- amino-3-nitro-6-chloropyridine and 8.67kg of triethylamine, and heated at reflux temperature for 12h 70-80 , cooled to 60 , reaction was monitored sampling is complete, add 4percent sodium hydroxide aqueous solution prepared 1.07kg, 55 concentrated under reduced pressure until no solvent flows, centrifuged solids, temperature 50-60 , dried 10-12 hours to give flupirtine maleate intermediate (2-amino-3-nitro-6- (p-fluoro-benzylamino) pyridine) 5.86kg, a yield of 96.6percentTo a solution of Intermediate 5 (500 mg, 2.9 mmol) in isopropanol was added 4- fluorobenzylamine (463 iil, 4.06 mmol) and triethylamine (805 iil, 5.8 mmol). This mixture was stirred at 90°C for 40 minutes in the microwave. Water was added to the mixture and the resulting precipitate was filtered off, washed with water and then driedover vacuum for an hour. Intermediate 6 was isolated as a bright yellow solid (661 mg, 88percent).LCMS (m/z): [IVIH] calcd. for C12H11FN4O2, 262.24; found 263.00.100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25°C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25°C. After complete addition, the reaction mass is stirred at 40-45°C for half an hour again the reaction mass is heated to 80-85°C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25°C and stirred at this temperature for 2-3 hours and then stirred at 15-20°C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine.

Intermediate in the preparation of Flupirtine metabolites.

Molecular Weight:262.24
XLogP3:2.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:262.08660377
Monoisotopic Mass:262.08660377
Topological Polar Surface Area:96.8
Heavy Atom Count:19
Complexity:305
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes