Preparation of 2,6-dibromo-4-aminopyridine_Industrial additives

Preparation background and overview of 2,6-dibromo-4-aminopyridine

2,6-dibromo-4-aminopyridine can be used as a pharmaceutical synthesis intermediate. 2,6-dibromopyridine can be used as the reaction raw material to prepare the intermediate 2,6-dibromopyridine nitrogen oxide, which is further mixed with concentrated 4-nitro-2,6-dibromopyridine nitrogen oxide is prepared by reaction with nitric acid, and finally is prepared by reduction reaction with glacial acetic acid and reduced iron powder.

Preparation of 2,6-dibromo-4-aminopyridine

1) Synthesis of 2,6-dibromopyridine nitroxide: Under nitrogen protection, add 100mL dichloromethane and 2,6-dibromopyridine (7.9g, 34mmol) into a 250mL three-neck flask, and cool to 0 ~5℃, add urea peroxide (10.5g, 110mmol), and dropwise add a solution of deuterated tetrahydrofuran trifluoroacetic anhydride (21.2g, 100mmol) in dichloromethane (20mL). After the dropwise addition, keep the reaction at 0~5℃ 2 hours, then slowly raised to room temperature and stirred for 24 hours. The reaction system was then cooled to 0~2°C, 10% Na₂SO₃ aqueous solution (60mL) was added dropwise, filtered, the filtrate was separated, washed with brine, and anhydrous MgSO₄ was dried and concentrated to obtain a light yellow solid, which was recrystallized from acetone to obtain 2,6-dibromopyridine nitroxide (5.1g).

2) Synthesis of 4-nitro-2,6-dibromopyridine nitroxide: Add 2,6-dibromopyridine nitroxide (20g, 80mmol) into a 500 mL three-neck flask, and add 150 mL of concentrated sulfuric acid. Add dropwise a mixed acid of formaldehyde-based furan composed of 30 mL of concentrated sulfuric acid and 27 mL of concentrated nitric acid. Control the temperature during the dropwise addition to 78-80°C. After the dropwise addition, raise the temperature to 90°C and react for 3 hours. After the reaction system dropped to room temperature, the reaction solution was poured into 500g of crushed ice, filtered with suction, washed with water, and dried under vacuum to obtain a light yellow solid 4-nitro-2,6-dibromopyridine nitroxide (19.8g).

3) Synthesis of 2,6-dibromo-4-aminopyridine: Add 4-nitro-2,6-dibromopyridine nitrogen oxide (14.9g, 50mmol) and 150mL glacial acetic acid into a 250mL three-neck flask , newly prepared reduced iron powder (11.2g, 200mmol), stirred at room temperature for 2 hours. The reaction system was diluted with 500 mL of water, extracted with 100 mL of ethyl acetate, washed once with saturated sodium carbonate aqueous solution and brine, the solvent was removed under reduced pressure, and purified by column chromatography (eluent: petroleum ether/ethyl acetate = 2:1 ), 9.5g of 2,6-dibromo-4-aminopyridine white solid was obtained, with a liquid phase normalized content of 98.7%. ¹HNMR (MHz, CHCl₃-d6) δppm4.2~4.5 (s, br, 2H); 6.68 (s, 2H).

References

[1] [Chinese invention, Chinese invention authorization] CN201510009834.3 1,2,3-thiadiazole-5-formamidine compounds containing three nitrogen heterocycles and their synthesis [disclosed]/containing three nitrogen Heterocyclic 1,2,3-thiadiazole-5-formamidine compounds and their synthesis [Authorized]