Preparation method of amino-substituted quinoline nitrogen heterocyclic ring

Abstract

The invention relates to a preparation method of an amino-substituted quinoline nitrogen heterocyclic ring. The amino-substituted quinoline nitrogen heterocyclic ring is prepared through a specifically-made reaction kettle, the reaction kettle is provided with a kettle body (1) made of glass, and the kettle body is provided with a kettle cover (11), a lower flange (12) and a cylinder (13); the reaction kettle further comprises an air inlet combination (2), an air outlet combination (3), a fixing device (4) and a stirring part (5). The method comprises the steps that 8-bromoquinoline is dissolved in N,N-dimethylformamide for preparing 8-quinolinecarbonitrile, then the 8-quinolinecarbonitrile reacts with a sulfuric acid aqueous solution to obtain 2quinoline-8-formic acid, the 2quinoline-8-formic acid is dissolved in methyl alcohol, and thionyl chloride is dropwise added to obtain quinoline-8-methyl formate; the quinoline-8-methyl formate is dissolved in carbon tetrachloride, pyridine is added, and bromine is dropwise added to obtain 3-bromoquinoline-8-methyl formate; the 3-bromoquinoline-8-methyl formate reacts with lithium hydroxide to prepare 3-bromoquinoline-8-formic acid; through transition of 3-bromine-8-Boc-aminoquinoline, a product 3-bromine-8-aminoquinoline is obtained.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a synthesis method of the pharmaceutical intermediate 3-bromo-8-aminoquinoline. Background technique [0002] Aminoquinoline and its derivatives are an important class of compounds with strong biological activity and are widely used in medicine, pesticides and other fields. Therefore, the synthesis of aminoquinoline derivatives has received extensive attention, especially among pharmaceutical intermediates. are widely used in. A glycosylated 3-aminoquinoline compound and its preparation method are given in CN201710229123.6, which is an example of the application and synthesis of aminoquinoline derivatives, but the 3-bromo-8-amino Quinoline rarely has applications or preparation methods as pharmaceutical intermediates, or has literature or information published. [0003] Due to the properties of this molecule, this method cannot be extended to the synthesis of other s...

AI Technical Summary

Problems solved by technology

A glycosylated 3-aminoquinoline compound and its preparation method are given in CN201710229123.6, which is an example of the application and synthesis of aminoquinoline derivatives, but the 3-bromo-8-amino Quinoline rarely has applications or preparation methods as pharmaceutical intermediates, or has literature or information published

[0003] Due to the properties of this molecule, the method cannot be extended to the synthesis of other similar structures

This is determined by the ingenuity of the preparation method, the higher yield and the non-reproducibility of the shorter reaction time obtained from numerous experiments. Other routes basically cannot have higher yield or acceptable reaction time.

[0004] In addition, there is also such a problem in the prior art, that is, the existing four-necked bottle has a significant deficiency as a reaction vessel. Generally, this type of laboratory preparation uses a four-necked bottle as a reaction vessel, and several disadvantages are prominent: one. Insufficient performance, when the mixture in the four-necked bottle needs to be stirred, because the four-necked bottle generally clamps the main bottleneck to achieve high-speed stirring, but the bottom of the four-necked bottle is uneven, so that the stirring rod cannot go deep, and it is difficult to achieve high-speed stirring. The most stable stirring speed is 350-400 rpm. If it is higher, the overall vibration of the device is too severe, and there is a risk of damage to the whole bottle. Due to the uneven bottom of the bottle, the material In many cases, it is also difficult to obtain effective and sufficient stirring, which affects the full progress of the reaction; 2. The deficiency of the existing nitrogen protection method, the existing nitrogen protection is to feed nitrogen from one mouth of the four-necked bottle, and lead the bottle from the other mouth. However, due to the limitation of the shape of the four-necked bottle in this way, a large dead volume or a volume that does not participate in convection will be generated in the bottle. According to infrared video detection, the occurrence of such a dead volume is a high probability event. And the current simple way of nitrogen ventilation is difficult to overcome; 3. The problem of large loss of the reaction mixture, the multiple ports of the four-necked bottle, and the small problem of the main port make it difficult for the reaction mixture to be properly processed during each step. In practice, a large amount or most of them are lost, and often each step will reduce the product quantity by 1-20% due to operational problems, which not only affects the actual product quantity obtained, but also makes the yield of each step The calculation deviates from the actual situation, which cannot be overcome by using the four-necked bottle system

There is also the need for heating and reflux. When the four-necked bottle is heated and refluxed, the condenser tube and the four-necked bottle are rigidly combined, and the gap in the middle cannot be ignored, and the overall device is not well integrated. The center of gravity is biased during high-speed stirring, and the shaking is obvious. , there is a risk of device breakdown

In addition, when there are many steps, in the traditional four-necked bottle preparation method, when the reaction mixture is removed after each step, because the four-necked bottle is not easy to operate with a spoon or the like, it is difficult to remove the reaction product completely, and a part of it is often lost. , especially when the product is viscous and the quantity is small, the problem is particularly prominent

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