4-aminopyridine based on Hofmann degradation and supercritical/subcritical fluid, and preparation method of 4-aminopyridine

Abstract

The invention provides 4-aminopyridine based on Hofmann degradation and a supercritical / subcritical fluid, and a preparation method of the 4-aminopyridine. The preparation method comprises the following steps: adding ethyl isonicotinate into a reaction kettle, pressing liquid ammonia into the reaction kettle, carrying out pressurizing and heating to enable the liquid ammonia to reach a supercritical state, rapidly carrying out cooling to stop the reaction to obtain isonicotinamide; continuing introducing bromine water into the isonicotinamide, carrying out heating and pressurizing until the bromine water reaches a subcritical state, cooling the reaction system to room temperature under a stirring condition, and transferring the reaction system out, adjusting the pH value of the system to alkalinity to stop the reaction to obtain a 4-aminopyridine crude product; carrying out reduced pressure distillation on the 4-aminopyridine crude product to remove a part of water, then adding the crude product into a benzene solvent, carrying out microwave heating and uniform mechanical stirring, carrying out cooling and recrystallization, carrying out filtering, and carrying out vacuum drying toobtain the 4-aminopyridine based on Hofmann degradation and the supercritical / subcritical fluid. According to the invention, the supercritical fluid technology is applied to preparing the 4-aminopyridine by using the Hofmann degradation, production efficiency is improved, and the yield of the product is remarkably improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a 4-aminopyridine based on Hoffmann degradation and super / subcritical fluid and a preparation method thereof. Background technique [0002] Aminopyridine compounds are ammonia-containing substances with a heterocyclic structure. Among them, 4-aminopyridine, also known as p-aminopyridine, is an important intermediate for the preparation of medicine, organic synthesis and dye synthesis, especially 4-aminopyridine can Stimulating the central nervous system and producing excitatory effects have good application prospects in the preparation of potassium ion inhibitors, but at present 4-aminopyridine mainly relies on imports, and the domestic preparation technology is still not mature enough. [0003] The traditional 4-aminopyridine uses pyridine as the starting material, which is oxidized by hydrogen peroxide to obtain pyridine nitrogen oxide, and then nitrated by mixed ...

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Problems solved by technology

[0002] Aminopyridine compounds are ammonia-containing substances with a heterocyclic structure. Among them, 4-aminopyridine, also known as p-aminopyridine, is an important intermediate for the preparation of medicine, organic synthesis and dye synthesis, especially 4-aminopyridine can Stimulates the central nervous system and produces excitatory effects. It has a good application prospect in the preparation of potassium ion inhibitors. However, at present, 4-aminopyridine mainly relies on imports, and the domestic preparation technology is still not mature enough.

[0003] The traditional 4-aminopyridine uses pyridine as the starting material, which is oxidized by hydrogen peroxide to obtain pyridine nitrogen oxide, and then nitrated by mixed acid and reduced by iron powder to obtain 4-aminopyridine. This method has mature technology and high product yield. However, post-processing is troublesome and the pollution is heavy

It is also reported that palladium-carbon (Pd / C) is used as a catalyst to prepare, but the system needs to be acidic, or titanium tetrachloride-lithium aluminum hydride (TiCl4-LiAlH4) is prepared as a reducing agent, but it needs to be prepared under anhydrous conditions. Under the conditions of these reactions, the operating conditions are relatively harsh, the cost is high and it is difficult to industrialize production

Chinese patent CN 1319947C discloses a preparation method of 4-aminopyridine, which uses iodine or alkali metal iodide, sodium hydroxide or potassium hydroxide, and an aqueous solution of bromine as a catalyst to make isonicotinamide Hoffman degradation reaction occurs to prepare high-purity 4-aminopyridine. The catalyst selected in this method is cheap, which greatly reduces the cost of synthesizing 4-aminopyridine, and the reaction conditions are mild, there is no pollution to the environment, and there are few "three wastes", but The preparation method of metal salt catalyst is relatively complicated

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