Preparation of 2-amino-4-methyl-5-nitropyridine_Industrial additives

Preparation background and overview of 2-amino-4-methyl-5-nitropyridine

2-Amino-4-methyl-5-nitropyridine is a 2-aminopyridine derivative. 2-Amino-substituted nitrogen-containing six-membered heterocyclic compounds have important applications in the chemical industry. In particular, 2-aminopyridine and its derivatives are one of the important structures in pharmaceutical and agricultural chemical molecules and are widely present in natural products, In the synthesis and application of drugs, luminescent materials and various fine chemicals.

Preparation of 2-amino-4-methyl-5-nitropyridine

Preparation Report 1 of 2-amino-4-methyl-5-nitropyridine,

Add 2-fluoro-4-methyl-5nitro-pyridine (1mmol), benzamidine hydrochloride (2mmol), sodium tert-butoxide (3mmol), and HO (0.5mL) into a 25 ml reaction tube. ) and toluene (2.5 mL). The reaction was carried out at 130°C for 28 hours. After the reaction was completed, it was cooled to room temperature.

Add 10 mL of ethyl acetate to quench the reaction, add 6 mL of saturated brine to wash, separate the organic phase, and then extract the aqueous phase 3 times with ethyl acetate (the amount of ethyl acetate each time is 6 mL). Combine the organic phases, add no After drying with sodium sulfate, the solvent, including organic solvents and inorganic solvents, was removed by distillation under reduced pressure. The organic solvent was then separated by column chromatography to obtain the target product, with a yield of 95% calcium and magnesium carbonate.

Qualitative characterization by GC-MS and NMR: GC-MS (EI, 70eV) m/z 153, 136, 80. ¹H NMR (600MHz, CDCl₃+d-DMSO) δ8.76 (s, 1H), 7.29 (s, 2H), 6.31 (s, 1H), 2.47 (s, 3H); ¹³C NMR (150MHz, CDCl₃+d-DMSO) δ 160.5, 146.5, 142.2, 133.6, 106.9, 19.2.

Preparation report 2 of 2-amino-4-methyl-5-nitropyridine,

Measure 150ml of concentrated H₂SO₄ into a 500ml round-bottomed flask, place it in a -5°C low temperature cold bath to pre-cool, and add 50g in batches after 20 minutes 2-Amino-4-methylpyridine, the solution gradually changes from a colorless clear solution to a yellow viscous solution, and the internal temperature does not exceed 0°C during the entire process. Prepare a mixed acid of 34 ml concentrated H₂SO₄ and 34 ml concentrated HNO₃, pre-cool it at -5℃, and slowly pass it through a constant pressure dropping funnel. Add to the reaction solution and keep the temperature not exceeding 0°C. After the dripping is completed, place the reaction at room temperature and stir for 20 minutes. Then transfer to an oil bath and slowly heat to 50°C. A large number of bubbles will be generated, and the color of the reaction solution will gradually deepen and turn brown. . After bubbles no longer occur, keep the temperature at 50°C and continue the reaction. The reaction was monitored by TLC. After 24 hours, the reaction was complete and the reaction was stopped. Slowly add the reaction solution into a stirred beaker filled with ice water to avoid exotherming too quickly. Adjust the pH value to alkaline (about 8) with NaOH solution. A large amount of muddy yellow solid will precipitate. Filter and wash the solid with water until the ammonium bicarbonate is medium. property, transferred to a petri dish, dried under an infrared lamp, and then dried under reduced pressure at 50°C for 3 hours to obtain 41.61g of crude yellow solid product. Recrystallize with EA, remove insoluble impurities by hot filtration, remove part of the solvent by rotary evaporation, recrystallize with EA again, crystallize at room temperature, filter after 24 hours to obtain 18.54g of orange solid, yield 37.08%.

References

[1] [Chinese invention] CN201811172047.0 Preparation method of 2-amino-substituted nitrogen-containing six-membered heterocyclic compounds

[2] [Invented in China] CN201610205596.8 Ethanol compounds used as FGFR inhibitors