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A kind of preparation method of difluoromethoxy multi-substituted nitrogen-containing heterocyclic compound

A technology of flanges and reactors, applied in chemical instruments and methods, chemical/physical processes, chemical/physical/physical-chemical processes, etc., can solve problems such as difficult to achieve high-speed stirring, device collapse, center of gravity offset, etc., to achieve Good heating/cooling effect, stable stirring, and pressure-reducing effect

Active Publication Date: 2021-07-30
北京六合宁远医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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  • A kind of preparation method of difluoromethoxy multi-substituted nitrogen-containing heterocyclic compound
  • A kind of preparation method of difluoromethoxy multi-substituted nitrogen-containing heterocyclic compound
  • A kind of preparation method of difluoromethoxy multi-substituted nitrogen-containing heterocyclic compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] A reaction kettle, which has a body 1 made of glass, the body is equipped with a kettle cover 11, a lower flange 12, and a cylinder body 13. It is characterized in that: the reaction kettle also includes an air inlet combination 2, an air outlet combination 3, and a fixing device 4. Stirring section 5. Cooling liquid tank. The reaction kettle has improved the overall problems of the current four-neck bottle system as a whole: it is not stable enough, the bottom contact area is small, the heating and cooling are slow, the stirring speed cannot be increased, the nitrogen protection effect is not good, and the feeding must be completely opened, and it is very difficult to remove the reaction mixture. Troublesome and difficult to solve the problem.

[0041] The center of kettle lid 11 has middle hole 14, and middle hole 14 is the circular through hole that the center is positioned at kettle lid 11 centers, and its inner side surface is frosted shape, is used for bonding wit...

Embodiment 2

[0052] 1) Get a reaction kettle as claimed in claim 2, wash and dry, fix the body (1) on the fixture (4), open the lid (11), add 350ml of tetrahydrofuran, and then add 70g of diisopropylamine , close the kettle cover (11), feed nitrogen gas at a speed of 140ml / min, and after 5 minutes, set the cooling liquid tank (6) in the cooling liquid circulation tank on the low-temperature cooling liquid circulation device, and make the body (1 ) is supported by the middle part of the middle tank, and an appropriate amount of cooling liquid is filled in the cooling liquid circulation tank, and the temperature is lowered to about minus 35°C. With continuous stirring at a speed of 80 rpm, the cooling liquid is slowly dripped from the feeding hole (18). Add 2.2eq of n-butyllithium, close the feed hole (18) after the dropwise addition, raise the temperature to about minus 25°C, continue stirring for 45min, cool down to minus 78°C, and drop in slowly from the feed hole (18). Contain the THF so...

Embodiment 3

[0059] 1) Get a reaction kettle as claimed in claim 2, wash and dry, fix the body (1) on the fixture (4), open the lid (11), add 360ml of tetrahydrofuran, and then add 72g of diisopropylamine , close the kettle cover (11), feed nitrogen gas at a speed of 150ml / min, and after 5 minutes, set the cooling liquid tank (6) in the cooling liquid circulation tank on the low-temperature cooling liquid circulation device, and make the body (1 ) is supported by the middle part of the middle tank, and an appropriate amount of cooling liquid is filled in the cooling liquid circulation tank, and the temperature is lowered to about minus 38°C. While stirring at a speed of 100 r / min, drip from the feeding hole (18) at a slow speed Add 2.2eq of n-butyllithium, close the feed hole (18) after the dropwise addition, raise the temperature to about minus 27°C, continue stirring for 55min, cool down to minus 79°C, and drop in slowly from the feed hole (18) Contain the THF solution of the 2-bromo-3-f...

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Abstract

A method for preparing difluoromethoxy multi-substituted nitrogen-containing heterocyclic compounds, which is prepared by using a special reactor, the reactor has a glass body (1), the body is equipped with a lid (11), a lower convex Edge (12), barrel (13), and the reactor also includes an air inlet combination (2), an air outlet combination (3), a fixing device (4), a stirring part (5), and a cooling pump tank (6); ‑Bromo‑3‑fluoropyridine is used as a starting point for synthesis to obtain 2‑bromo‑3‑fluoropyridine‑4‑boronic acid, which is then prepared to obtain 2‑bromo‑3‑fluoro‑4‑hydroxypyridine; and then through 2‑bromo‑3 Transition of fluoro-4-difluoromethoxypyridine; 3-fluoro-4-difluoromethoxypyridine-2-formic acid ethyl ester; low temperature reaction under nitrogen protection to obtain 3-fluoro-4-difluoromethoxy base pyridine-2-methanol, and react at room temperature to obtain the final product 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): B01J19/18B01J19/14B01J19/02C07D213/68
CPCB01J19/02B01J19/14B01J19/18B01J2219/00103B01J2219/0254C07D213/68
Inventor 邢立新
Owner 北京六合宁远医药科技股份有限公司
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