Report on the preparation method of 3-amino-4-methylpyridine_Industrial additives

Background and overview of the preparation method of 3-amino-4-methylpyridine

3-Amino-4-methylpyridine is an important pharmaceutical and chemical intermediate. It is widely used in the synthesis and research and development of medicines, pesticides, and veterinary drugs. It has high application value and market value.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor developed by the German company Boehringer Ingelheim. It binds near the catalytic site of the enzyme and directly acts on the reverse transcriptase, inhibiting its activity and thereby inhibiting HIV replication. It is used clinically To inhibit mother-to-child viral transmission of AIDS. Tofacitinib is a drug for the treatment of rheumatoid arthritis developed by Pfizer Pharmaceuticals of the United States. It was approved by the U.S. Food and Drug Administration (FDA) on November 6, 2012 for patients with inadequate response to or intolerance to methotrexate treatment. Adult patients with moderately to severely active rheumatoid arthritis (RA). 3-Amino-4-methylpyridine is an important intermediate for the preparation of nevirapine and tofacitinib.

The preparation method of 3-amino-4-methylpyridine is reported

Report on the preparation method of 3-amino-4-methylpyridine 1.

Add 57g of 2-chloro-3-amino-4-methylpyridine (0.4mol), 33g of sodium acetate (0.4mol), mL of methanol, and 5% palladium carbon (moisture content 54.13%) 0.95 into the high-pressure reaction kettle. g Synthesize fluorphlogopite, seal the kettle, replace the air in the kettle with high-purity hydrogen, the pressure is 0.4MPa, heat and stir, control the temperature at 60°C, and react for 8 hours. When the pressure is less than 0.15MPa, hydrogen needs to be added. After the reaction is completed, cool to room temperature, open the kettle, and perform suction filtration to obtain a gray solid. Recover the palladium carbon. The filtrate is decompressed under reduced pressure, and 100 mL of water is added to dissolve it. It will turn into an orange-yellow or light yellow-green liquid. Adjust the solution with 30% potassium hydroxide solution. The pH value is alkaline, extract with an organic solvent, combine the organic phases, dry over anhydrous magnesium sulfate, filter, and remove the solution under reduced pressure to obtain 41.1g of 3-amino-4-methylpyridine as a light yellow solid, yield 97.6%, purity 99.1%.

Report on the preparation method of 3-amino-4-methylpyridine 2.

Step 1, preparation of 4-methyl-3-nitropyridine

To a 500 ml four-necked flask connected to a stirrer, thermometer and reflux condenser, add 10.6 g (0.1 mol) 3-chlorocrotonaldehyde, 50 g methylene chloride, and 12.0 g (0.2 mol) nitromethane. 0.4 grams of DBU, stir and react at 40-45°C for 3 hours. After the gas phase detection reaction is completed, add 23.5 grams (0.2 mol) of N,N-dimethylformamide dimethyl acetal, raise the temperature to 100-105°C and stir for 4 hours. At the same time, dichloromethane and excess nitromethane are evaporated and recovered. After the gas phase detection reaction is completed, cool to 30°C, add 40.0 grams of 15% ammonia methanol solution, stir and react at 45-50°C for 4 hours, and distill under reduced pressure to recover methanol. Cool to 20°C, add 100 grams of water and 50 grams of methylene chloride, separate the layers, extract the water layer three times with 20 grams of methylene chloride each time, combine the organic phases, and dry with 3.0 grams of anhydrous sodium sulfate for 3 hours. , filter, and distill the filtrate to recover the solvent to obtain 12.8 grams of viscous liquid 4-methyl-3-nitropyridine, with a yield of 92.8% and a gas phase purity of 99.9%.

Step 2, preparation of 3-amino-4-methylpyridine

Into a 250 ml stainless steel pressure kettle, add 13.8 grams (0.1 mol) 4-methyl-3-nitropyridine, 80 grams methanol, 0.07 grams 5% palladium on carbon, replace it with nitrogen three times, and fill with hydrogen to a pressure of 0.2-0.3MPa, 50-55℃ catalytic hydrogenation reaction for 4 hours. After the hydrogenation reaction is completed, it is lowered to room temperature, the palladium carbon is separated by filtration, the solvent is recovered by distillation, and the residue is recrystallized with 30 grams of methyl tert-butyl ether to obtain 1. Pyridineboronic acid: 0.6 g of off-white solid 3-amino-4-methylpyridine, yield 98.5%, gas phase purity 99.9%.

The NMR data of the product are as follows: 1HNMR (CDCl3, δ, ppm): 8.52 (s, 1H), 8.22 (d, 1H), 7.28 (m, 1H), 4.1 (b, 2H), 2.31 (s, 3H)

References

[1] [Chinese invention, Chinese invention authorization] CN201110239922.4 A method for preparing 3-amino-4-methylpyridine

[2] [Chinese invention, Chinese invention authorization] CN201810023740.5 A simple preparation method of low-cost 3-amino-4-methylpyridine [Public]/A kind of 3-amino-4-methylpyridine Preparation method【Authorization】