A kind of synthetic method of 3-bromopyridine

Abstract

The invention belongs to the technical field of organic synthesis, and in particular to a kind of synthetic method of 3-bromopyridines, the steps are as follows: solvent is added to a reaction vessel, 4-bromopyridines, palladium catalysts and phosphine ligands are added in sequence, stirring is turned on, then slowly heated up, insulation and sealing reaction, HPLC detection reaction after terminating, the reaction solution is cooled and filtered, the filtrate is concentrated under reduced pressure, the crude product of 3-bromopyridines is obtained, and the final product 3-bromopyridines is obtained by rectification. Beneficial effects of the present invention: the synthetic method of the 3-bromopyridines is raw material, and reacts with palladium catalysts and phosphine ligands, so that the synthetic method improves the safety of production; and palladium catalysts can be recycled and regenerated, reducing production costs, and reducing pollution to the environment; therefore, the synthetic method of the 3-bromopyridines is high in safety, environmental protection and economy for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3-bromopyridine. Background Art

[0002] 3-Bromopyridine is an important chemical raw material, used as an intermediate in the fields of medicine, pesticides and organic synthesis. 3-Bromopyridine is an important intermediate of the antidepressant drug zimelidine hydrochloride, and is also an important intermediate of the neurological drug propramoxazole. It can also be used in the synthesis of 3-methylaminopiperidine, an intermediate of the balofloxacin drug.

[0003] There are usually two methods for synthesizing 3-bromopyridine. One is to synthesize 3-bromopyridine by reacting pyridine with bromine. This method usually needs to be carried out under high temperature and high pressure due to the lack of electricity of the pyridine ring, and because bromine is a precursor chemical, its use is limited and cannot be mass-produced; the other is to obtain 3-bromopyridine by diazotization of 3-aminopyridine with bromine. This method produces unstable diazonium salts due to diazotization of aminopyridine, so there is a potential explosion hazard in the synthesis process. Therefore, how to design a synthetic method for 3-bromopyridine that can improve the safety and feasibility of large-scale production and have a higher reaction yield and product purity has become a problem to be solved. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for synthesizing 3-bromopyridine.

[0005] The present invention relates to a method for synthesizing 3-bromopyridine, the steps of which are as follows:

[0006] The solvent is added into the reaction vessel, and then 4-bromopyridine, palladium catalyst and phosphine ligand are added in sequence, stirring is started, and then the temperature is slowly increased, the temperature is kept and the reaction is sealed. After the reaction is completed by HPLC detection, the reaction liquid is cooled and filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product of 3-bromopyridine, which is then distilled to obtain the final product 3-bromopyridine.

[0007] Preferably, the palladium catalyst is palladium acetate, palladium chloride, palladium carbon, bistriphenylphosphine palladium dichloride or palladium-aluminum oxide.

[0008] Preferably, the phosphine ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, dimethyldiphenylphosphine, tri(2-pyridyl)phosphine, dichlorodimethylphosphine or triphenylphosphine.

[0009] Preferably, the mass of the palladium catalyst is 1% to 5% of the mass of 4-bromopyridine.

[0010] Preferably, the mass of the phosphine ligand is 3% to 8% of the mass of 4-bromopyridine.

[0011] Preferably, the temperature is slowly increased to 60°C to 100°C.

[0012] Preferably, the reaction is kept warm and sealed for 8 to 12 hours.

[0013] Preferably, the temperature is lowered to 20°C to 25°C.

[0014] Preferably, the solvent is dichloromethane, ethyl acetate, anhydrous ethanol, methanol or isopropanol.

[0015] Preferably, the volume of the solvent is measured in milliliters, the mass of the 4-bromopyridine is measured in grams, and the volume of the solvent is 5 to 10 times the mass of the 4-bromopyridine.

[0016] Compared with the prior art, the advantages and positive effects of the present invention are:

[0017] (1) The synthesis method of 3-bromopyridine uses 4-bromopyridine as a raw material, reacts with a palladium catalyst and a phosphine ligand, thereby improving the safety of production; and the palladium catalyst can be recycled and regenerated, reducing production costs and reducing environmental pollution; therefore, the synthesis method of 3-bromopyridine has high safety, environmental protection and economic efficiency for large-scale industrial production;

[0018] (2) The reaction conditions of the synthesis method of 3-bromopyridine are mild and the operation method is simple, so the reaction process is more stable and easy to control. Scaling up to industrial production scale will not affect the reaction performance, thereby improving the stability and reliability of large-scale production;

[0019] (3) The method for synthesizing 3-bromopyridine has a high reaction yield and the synthesized 3-bromopyridine has a high purity, thereby reducing energy consumption and production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following briefly introduces the drawings required for describing the embodiment.

[0021] Figure 1 is the reaction formula of the compound of the present invention. DETAILED DESCRIPTION

[0022] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0023] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0024] Example 1

[0025] A method for synthesizing 3-bromopyridine, comprising the following steps:

[0026] 100 ml of ethyl acetate was added to a 300 ml pressure-resistant reaction bottle, and then 10 g of 4-bromopyridine, 0.2 g of palladium acetate and 0.5 g of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl were added in sequence, stirring was started, and then the temperature was slowly raised to 80°C, and the reaction was kept warm and sealed for 10 hours. After HPLC detection, the reaction solution was cooled to 20°C, and then filtered. The filtrate was concentrated under reduced pressure to obtain 9.5 g of yellow oily 3-bromopyridine crude product, and then distilled to obtain 6.8 g of colorless 3-bromopyridine; the reaction yield was 68%, and the purity of 3-bromopyridine was 99.2%;

[0027] Example 2

[0028] A method for synthesizing 3-bromopyridine, comprising the following steps:

[0029] 80 ml of anhydrous ethanol was added to a 300 ml pressure-resistant reaction bottle, and then 10 g of 4-bromopyridine, 0.4 g of palladium chloride and 0.6 g of tri(2-pyridyl)phosphine were added in sequence. Stirring was started, and then the temperature was slowly raised to 60°C. The mixture was kept warm and sealed for reaction for 12 hours. After the reaction was completed by HPLC detection, the reaction solution was cooled to 25°C, and then filtered. The filtrate was concentrated under reduced pressure to obtain 9.3 g of yellow oily 3-bromopyridine crude product, which was then distilled to obtain 6.5 g of colorless 3-bromopyridine. The reaction yield was 65%, and the purity of 3-bromopyridine was 99.3%.

[0030] Example 3

[0031] A method for synthesizing 3-bromopyridine, comprising the following steps:

[0032] Add 100 ml of dichloromethane into a 300 ml pressure-resistant reaction bottle, and then add 10 g of 4-bromopyridine, 0.5 g of bistriphenylphosphine palladium dichloride and 0.8 g of dimethyldiphenylphosphine in sequence, start stirring, then slowly heat to 70°C, keep warm and seal the reaction for 11 hours. After HPLC detection, the reaction solution is cooled to 25°C, then filtered, and the filtrate is concentrated under reduced pressure to obtain 9.0 g of yellow oily 3-bromopyridine crude product, which is then distilled to obtain 6.3 g of colorless 3-bromopyridine; the reaction yield is 63%, and the purity of 3-bromopyridine is 99.1%.

[0033] Example 4

[0034] A method for synthesizing 3-bromopyridine, comprising the following steps:

[0035] Add 50 ml of methanol into a 300 ml pressure-resistant reaction bottle, and then add 10 g of 4-bromopyridine, 0.1 g of palladium-alumina and 0.4 g of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl in sequence, start stirring, then slowly heat to 80°C, keep warm and seal the reaction for 8 hours. After HPLC detection, the reaction solution is cooled to 20°C, then filtered, and the filtrate is concentrated under reduced pressure to obtain 9.4 g of yellow oily 3-bromopyridine crude product, which is then distilled to obtain 6.6 g of colorless 3-bromopyridine; the reaction yield is 66%, and the purity of 3-bromopyridine is 99.5%;

[0036] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing 3-bromopyridine, characterized in that: Here are the steps: Add the solvent to the reaction container, then add 4-bromopyridine, palladium catalyst and phosphine ligand in sequence, start stirring, then slowly increase the temperature, keep warm and seal the reaction, after the reaction is completed by HPLC detection, cool the reaction solution and filter it, and concentrate the filtrate under reduced pressure to obtain a crude product of 3-bromopyridine, and then distill it to obtain the final product 3-bromopyridine; The palladium catalyst is palladium acetate, palladium chloride, palladium carbon, bistriphenylphosphine palladium dichloride or palladium-aluminum oxide; The phosphine ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, dimethyldiphenylphosphine, tri(2-pyridyl)phosphine, dichlorodimethylphosphine or triphenylphosphine.

2. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: The added amount of the palladium catalyst is 1% to 5% of the mass of 4-bromopyridine.

3. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: The added amount of the phosphine ligand is 3% to 8% of the mass of 4-bromopyridine.

4. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: Slowly increase the temperature to 60℃~100℃.

5. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: Keep warm and seal the reaction for 8 to 12 hours.

6. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: Cool down to 20℃~25℃.

7. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: The solvent is dichloromethane, ethyl acetate, anhydrous ethanol, methanol or isopropanol.

8. The method for synthesizing 3-bromopyridine according to claim 1, characterized in that: The volume of the solvent is measured in milliliters, the mass of the 4-bromopyridine is measured in grams, and the volume of the solvent is 5 to 10 times the mass of the 4-bromopyridine.

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