Background and overview of the synthesis method of 2-amino-4-bromopyridine
2-Amino-4-bromopyridine, also known as 4-bromo-2-aminopyridine, because the bromine atoms and amino groups in the molecule can continue to biochemically introduce other functional groups, many novel and diverse heterocyclic compounds can be designed and synthesized. , 2-amino-4-bromopyridine is a widely used pharmaceutical intermediate.
Synthetic method of 2-amino-4-bromopyridine
CN201510652275.8 provides a new synthesis method of 2-amino-4-bromopyridine, which has low raw material cost, high yield, simple reaction operation, convenient three waste treatment, and easy industrialization.
Includes the following steps:
(1) Esterification reaction: 4-bromopyridine hydrochloride is esterified to obtain crude 4-bromopyridine-2-carboxylic acid ethyl ester;
(2) Amination reaction: The crude 4-bromopyridine-2-carboxylic acid ethyl ester is ammoniated to obtain 4-bromopyridine-2-carboxamide;
(3) Hofmann degradation reaction: 4-bromopyridine-2-carboxamide is subjected to Hofmann degradation to obtain 2-amino-4-bromopyridine;
Step 1: Add ethyl pyruvate to a 20-liter three-neck bottle, cool it to 0 degrees, mechanically stir the tetrahydrofuran and add hydrogen peroxide dropwise, control the temperature during the dripping process to be below 0 degrees, and leave it aside after the dripping is completed; at 200 Add dichloromethane and the free dichloromethane solution of 4-bromopyridine hydrochloride into the reaction kettle (for example, take 5 kg of 4-bromopyridine hydrochloride, dissolve it in 30 liters of water, and adjust the pH to 8 with sodium bicarbonate , extracted three times with 50 liters of methylene chloride), ferrous sulfate and a sulfuric acid aqueous solution with a concentration of 50wt%, stir and lower the temperature to minus 10 degrees, add dropwise the reagent prepared in the 20-liter reaction bottle, and control the temperature during the dropwise addition Between minus 10 degrees and 0 degrees, keep stirring for one hour after dripping. TCL detects that the reaction is complete. Add the reaction system to 100 liters of water, stir thoroughly for 30 minutes, separate the liquids, and repeat this operation until the water phase is colorless and the organic phase is colorless. Concentrate to obtain 8.5 kilograms of crude product, which is brown-red liquid A. It is used directly in the next step without purification.
Second step: Add 8.5 kg of A in batches to 35 liters of ammonia water, stir with methane overnight, and centrifuge to obtain the crude product. Wash with ethyl acetate and centrifuge to obtain 4.5 kg of amide;
The third step: Add water, sodium hydroxide and dichlorotetrahydrofuran to the 50-liter reaction kettle, stir and lower the temperature to 0 degrees, add bromine dropwise, cool to minus 10 degrees after dripping, add amide in batches, and finish adding Keep stirring for one hour, then heat to 80 degrees and react for one hour. TCL is detected until the reaction is completed. Lower to room temperature and centrifuge to obtain crude product. Crystallize with toluene to obtain 1.5 kilograms of pure product.
