A kind of preparation method of multi-substituted bromo-fluorine substituted benzoimidazole compound

Abstract

A method for preparing a multi-substituted bromofluorine-substituted benzoimidazole compound, which is prepared by using a special reaction kettle, the reaction kettle has a glass body (1), the body is equipped with a kettle cover (11), a lower flange (12 ), barrel (13), and the reactor also includes an inlet combination (2), an outlet combination (3), a fixture (4), a stirring portion (5); it is based on 2-bromo-5-fluoroaniline as a synthetic starting point , to obtain (E)-N-(2-bromo-5-fluorophenyl)-2-(hydroxylamine) acetamide, and then prepare 7-bromo-4-fluoroindoline-2,3-dione ; Then through 2-amino-3-bromo-6-fluorobenzoic acid transition; 7-bromo-4-fluoro-1H-phenyl [d] imidazole-2-alcohol; add ethyl acetate and phosphorus oxybromide , to obtain the product 2,7-dibromo-4-fluoro-1H-phenyl[d]imidazole.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a synthesis method of the pharmaceutical intermediate 2,7-dibromo-4-fluoro-1H-phenyl[d]imidazole. Background technique [0002] Imidazole 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 imidazole derivatives has received extensive attention, especially in pharmaceutical intermediates. . CN201611006995.8 provides a kind of imidazole benzaldehyde p-phenylenediamine bis-Schiff base and its preparation method, which is an example of the application and synthesis of imidazole derivatives, but the 2,7-dibromo -4-Fluoro-1H-phenyl[d]imidazole 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 t...

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Problems solved by technology

CN201611006995.8 provides a kind of imidazole benzaldehyde p-phenylenediamine bis-Schiff base and its preparation method, which is an example of the application and synthesis of imidazole derivatives, but the 2,7-dibromo -4-Fluoro-1H-phenyl[d]imidazole 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

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, especially when there is less material, which has a great impact on the expectation that the reaction will be carried out in proportion as expected

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