Preparation methods and uses of 2-amino-4-chloro-pyridine_Industrial additives

Background and overview of preparation methods and uses of 2-amino-4-chloro-pyridine

2-Amino-4-chloro-pyridine is a white solid. 4-chloropyridine-2-amide can be prepared from 2-pyridinecarboxylic acid, and then reacted with calcium hypochlorite to obtain 2-amino- 4-Chloro-pyridine. 2-Amino-4-chloro-pyridine can be used to prepare 4-fluoro-2-aminopyridine, which is used to prepare tyrosine kinase inhibitors, P13K inhibitors, aldosterone synthase inhibitors, etc. An important intermediate for inhibitors, it has broad application prospects.

Preparation methods and uses of 2-amino-4-chloro-pyridine

Preparation method and use report of 2-amino-4-chloro-pyridine 1.

Slowly add 40 grams of 2-pyridinecarboxylic acid to 116 grams of thionyl chloride. After the addition is completed, add 1 gram of N,N-dimethylformamide and reflux the reaction solution for 2-16 hours until the raw materials After the reaction is completed, thionyl chloride is recovered to obtain 46 grams of 4-chloropyridine-2-acyl chloride; 4-chloropyridine-2-acyl chloride is dissolved in 200 ml of 1,4-dioxane, and ammonia gas 5 is passed into it. -16 hours until the reaction is completed, remove most of the solvent, cool to 0-5°C, precipitate a white solid and dry it to obtain 4-chloropyridin-2-amide, 37 grams, yield 93%.

Add 35 grams of 4-chloropyridin-2-amide into the calcium hypochlorite aqueous solution in batches. The calcium hypochlorite aqueous solution is prepared from 78 grams of calcium hypochlorite and 1 liter of water. After addition, the temperature is raised to 60- React at 80°C until the raw materials are consumed, then cool to room temperature. The reaction solution is extracted with dichloromethane until there is no product in the water phase. The organic phase is dried over anhydrous sodium sulfate, the solvent is removed, and the ethanol is recrystallized to obtain a white solid, 30 grams, yield 81%.

Preparation method and use report 2 of 2-amino-4-chloro-pyridine,

Step 1, preparation of 4-chloro-2-pyridinecarboxamide (2)

Add 50.0g 4-chloropyridine hydrochloride and 250mL acetonitrile into a 1L double-neck bottle, slowly add 13.2g 98% H2SO4 while stirring, heat to basic magnesium carbonate 60°C, add 81.8g formamide and 21.1g water of mixture. Raise the temperature to 70°C, slowly add 114.3g of ammonium persulfate to the reaction solution within 2 hours, and then react at 75°C for 80 minutes. Add 350 mL of water, evaporate acetonitrile to dryness, precipitate a light yellow solid, filter under reduced pressure, rinse the filter cake with a small amount of water, and dry to obtain 29.1 g of product, with a yield of 56%. m/z: 157[M+H bromomethylphenylboronic acid pinacol ester]+.

Step 2, preparation of 2-amino-4-chloro-pyridine (3)

Add 540mL water and 107.4gKOH into a 1L double-neck bottle, slowly add 19.8mLBr2 dropwise at 5°C, and finish the dripping in about 1 hour. After the dripping is completed, add 30.0g compound 2, heat to 60°C, stir for 2h, and lower to Add 600 mL of glacial acetic acid dropwise at 15°C, raise the temperature to 55°C and stir for 30 mill, lower to 5°C and adjust the pH to 13 with potassium hydroxide solution, extract with ethyl acetate (500mL×2), combine the organic phases, and dry over anhydrous magnesium sulfate. , the solvent was evaporated to obtain 15.3g of product, yield 62%. m/z: 129[M+H]+.

Preparation methods and uses of 2-amino-4-chloro-pyridine

2-Amino-4-chloro-pyridine can be used to prepare 4-fluoro-2-aminopyridine, the method is as follows:

Add 30.0g of compound 2-amino-4-chloro-pyridine and 240mL of N-methylpyrrolidone into a 1L single-neck bottle, heat to 200°C and stir for 10h. Add 420 mL of water, extract with ethyl acetate (300 mL × 2), combine the organic phases, wash the organic phases with 150 mL of water, dry over anhydrous magnesium sulfate, and evaporate the solvent to obtain 20.5 g of the product 4-fluoro-2-aminopyridine, yield 78 %.

References

[1][Chinese invention] CN201810439022.6 Preparation method of 2-amino-4-fluoropyridine

[2] Zhao Chunshen, Song Wuyan, Wu Changyun, Wu Shengfu, Wang Sidong. Research on the synthesis of 4-fluoro-2-aminopyridine [J]. Guangdong Chemical Industry, 2013, 40(17): 229.