Preparation method of difluoromethoxy polysubstituted nitrogen-containing heterocyclic compound

Abstract

The invention discloses a preparation method of a difluoromethoxy polysubstituted nitrogen-containing heterocyclic compound. The difluoromethoxy polysubstituted nitrogen-containing heterocyclic compound is prepared by using a special reaction kettle, the reaction kettle is provided with a glass body (1), the body is provided with a kettle cover (11), a lower flange (12) and a cylinder body (13) and further comprises an air intake assembly (2), an air outlet assembly (3), a fixing device (4), a stirring part (5) and a cooling pump tank (6); 2-bromo-3-fluoropyridine is used as a starting point to obtain 2-bromo-3-fluoropyridine-4-boronic acid, and 2-bromo-3-fluoropyridine-4-boronic acid is used for preparing 2-bromo-3-fluoro-4-hydroxypyridine; transition of 2-bromo-3-fluoro-4-difluoromethoxypyridine is performed; 3-fluoro-4-difluoromethoxypyridine-2-ethyl formate is prepared; a low temperature reaction under nitrogen protection is performed under protection of nitrogen to obtain 3-fluoro-4-di Fluoromethoxypyridine-2-methanol, a reaction is performed at a room temperature to obtain a final product of 3-fluoro-4-difluoromethoxypyridine-2-formaldehyde.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a synthesis method of the pharmaceutical intermediate 3-fluoro-4-difluoromethoxypyridine-2-carbaldehyde. Background technique [0002] Pyridine 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 benzaldehyde derivatives has received extensive attention, especially among pharmaceutical intermediates. application. CN201710892085.2 provides a synthetic method of 2-chloro-5-chloromethylpyridine, CN201710670517.5 provides a synthetic method of 2,3-dichloropyridine, and CN201710292322.1 provides a 2 The preparation method of -(2-alkylphenoxy)pyridine derivatives is an example of the application and synthesis of pyridine derivatives, but the 3-fluoro-4-difluoromethoxypyridine-2- Formaldehyde seldom has the application or preparation method as a phar...

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Problems solved by technology

CN201710892085.2 provides a synthetic method of 2-chloro-5-chloromethylpyridine, CN201710670517.5 provides a synthetic method of 2,3-dichloropyridine, and CN201710292322.1 provides a 2 The preparation method of -(2-alkylphenoxy)pyridine derivatives is an example of the application and synthesis of pyridine derivatives, but the 3-fluoro-4-difluoromethoxypyridine-2- Formaldehyde is rarely used as a pharmaceutical intermediate or a preparation method, or there are 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

There is another problem. Although in many organic reactions, it is not necessary to heat up to 100°C or boil / reflux, but the boiling point of organic matter is low, and it is more obvious to volatilize above 40°C. When there is less material, it will volatilize. There are many substances, and they cannot directly contact the liquid / substance near the reflux condenser, which is often not easy to condense, and a large amount of them adheres to the wall of the vessel, especially when there is less material, which has a great impact on the expectation that the reaction will be performed according to the expected proportion.

When the low temperature needs to be controlled, the existing four-necked bottle can also be applied with a low-temperature cooling liquid circulation device, but due to its shape problem, the cooling contact area is small, and because the four-necked bottle is usually fixed on the test bench, it is not easy to erect. Fearing that the four-neck bottle will be brittle, the coolant usually only touches a small area at the bottom of the four-necked bottle

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