Preparation background and overview of 2-chloro-4-amino-5-nitropyridine
2-Chloro-4-amino-5-nitropyridine is an intermediate of benzimidazole derivatives, used to treat bone development disorders and other diseases; it is also an intermediate of a PLK1 recombinant protein inhibitor, used to treat Cell proliferative diseases, especially cancer.
4-Amino-2-chloro-3-nitropyridine and 2-chloro-4-amino-5-nitropyridine are very important pharmaceutical intermediates, with huge market demand and good market prospects. Therefore, how to synthesize 4-amino-2-chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine and achieve their separation is of great significance.
2-Chloro-4-amino-5-nitropyridine
Preparation of 2-chloro-4-amino-5-nitropyridine
There are some reports on the preparation method of 2-chloro-4-amino-5-nitropyridine in the prior art, but the yield of the product is low. For example, the world patent WO2007047793 is a cyclopentenol core The method for synthesizing glycoside compound intermediates and treating viral infections uses 2-chloro-4-aminopyridine as raw material, 70% fuming nitric acid and concentrated sulfuric acid as mixed acid to perform nitration reaction, and uses silica gel column chromatography to separate the product. 70% of 4-amino-2-chloro-3-nitropyridine and 25% of 4-amino-2-chloro-5-nitropyridine were obtained, as well as 5% of impurities.
World patent WO200684281 is a preparation of an E1 active formaldehyde-based furanase inhibitor nucleoside derivative, using 2-chloro-4-aminopyridine as raw material, 90% fuming nitric acid and concentrated sulfuric acid as mixed acid. Nitrification reaction, the product obtained is a mixture of 4-amino-2-chloro-3-nitropyridine and 2-chloro-4-amino-5-nitropyridine, which is separated by flash column chromatography, using the mobile phase The ratio of dichloromethane:ethyl acetate is 1:4, and 44% of 4-amino-2-chloro-3-nitropyridine is obtained, but the yield of the product is low. Moreover, dichloromethane in the mobile phase is highly volatile in the air, which may cause the ratio of the mobile phase to change and the separation effect to be poor. Column chromatography cannot separate a large number of products, and fuming nitric acid is highly active. , but its price is relatively expensive, which greatly limits its industrial production.
Use 2-chloro-4-aminopyridine as raw material, 65% nitric acid and concentrated sulfuric acid as mixed acid to carry out nitration reaction to prepare 2-chloro-4-amino-5-nitropyridine, and simultaneously generate 2-chloro-4- Amino-3-nitropyridine, the corresponding pure product was obtained after recrystallization and purification.
The synthesis method follows the following steps:
1) Dissolve 200g of 2-chloro-4-aminopyridine in 1200mL of concentrated sulfuric acid at 0℃, add dropwise 1000mL of 65% nitric acid, after the addition is completed, react at 15℃ for 2h, then Pour into ice water, stir at 0°C, add NH3 to adjust pH to 3, precipitate white powdery solid I, filter;
2) Dissolve the white powdery solid I in 2000 mL of concentrated sulfuric acid, heat to 80°C for 3 hours, stir at room temperature overnight, then pour into ice water, add NH3 at 0°C to first adjust the pH to 1.5, An orange precipitate is generated, filtered, and the precipitate is discarded. The filtrate is continued to pass through NH3 until the pH is 3, and filtered to obtain a yellow powdery solid II, which is the isomer 2-chloro-4-amino-5-nitropyridine and 2-chloro. The mixture of -4-amino-3-nitropyridine, the yield of isomers is 98%, and the purity is 98%. Among them, the yield of 2-chloro-4-amino-5-nitropyridine is 75%.
Among them, there are two purposes of stirring overnight at room temperature after the reaction: the first is to fully react; the second is to fully cool down; because the temperature of concentrated sulfuric acid in the reaction system is very high, the internal temperature may not be sufficiently cooled down in a short period of time. Concentrated sulfuric acid itself will generate heat when added to water. If the temperature is not completely cooled and added to ice water, it will generate heat violently and be dangerous, so stir overnight to fully cool down.
3) Recrystallize the yellow powdery solid II (where: the recrystallization reagents are ethyl acetate and petroleum ether, the total dosage is 3 times the volume of the yellow powdery solid II, the volume ratio of ethyl acetate to petroleum ether (1:5), heated to reflux, and then lowered to 30°C to precipitate yellow powdery solid III;
Filter, and the solid is pure 2-chloro-4-amino-5-nitropyridine; the yield is 78%, and the purity is 97%; the solvent is removed from the filtrate under reduced pressure, and the residue is recrystallized with 95% ethanol to obtain The light yellow powdery solid IV is pure 2-chloro-4-aminomethylbenzeneboronic acid-3-nitropyridine, with a yield of 22% and a purity of 98%.
