Preparation method of 2, 5-dibromo-3-methylpyridine

Abstract

The invention discloses a preparation method of 2, 5-dibromo-3-methylpyridine, which comprises the following steps: directly synthesizing an intermediate product from 2-amino-3-methylpyridine and bromine, adding bromine into the intermediate product twice in a hydrobromic acid solution, directly carrying out diazotization reaction, adjusting the pH value by using a sodium hydroxide solution to obtain a crude product, and recrystallizing to obtain high-purity 2, 5-dibromo-3-methylpyridine. The invention relates to a 2, 5-dibromo-3-methylpyridine product. According to the method, an intermediate product is firstly synthesized, and then the intermediate product is subjected to a diazotization route without heavy metal ion catalysis, so that the problems that the traditional synthesis process is complicated and the treatment difficulty of produced wastewater containing heavy metal ions is high are fundamentally solved, and the solvent is recycled and continuously used. The method has the advantages of simple route, high efficiency, high product purity, no generation of wastewater containing heavy metal ions, economy, environmental protection and suitableness for industrial production. The method is of great significance to the technical improvement of the product.

Description

Technical Field

[0001] This invention relates to a method for preparing 2,5-dibromo-3-methylpyridine. Background Technology

[0002] 2,5-Dibromo-3-methylpyridine is an organic compound with a unique chemical structure. It possesses excellent physical and chemical properties, such as a high melting point, low boiling point, and good stability, making it outstanding in various industrial processes. In the pharmaceutical field, 2,5-dibromo-3-methylpyridine serves as a key intermediate in the synthesis of various drugs. It can be used to prepare compounds with antibacterial, anti-inflammatory, or antitumor activities. By modifying and altering its structure, drug molecules with specific pharmacological effects can be obtained, which is of great significance for improving drug quality and efficacy. In the pesticide field, this product can serve as a highly efficient and low-toxicity pesticide intermediate, contributing to the development of green agriculture. It can also derive compounds with highly efficient insecticidal, fungicidal, or herbicidal activities, supporting the development of environmentally friendly, low-toxicity, and highly efficient pesticide varieties. Furthermore, it has applications in the synthesis of organic optoelectronic materials. It can participate in the preparation of organic materials with special optical and electrical properties for use in the manufacture of optoelectronic devices such as organic light-emitting diodes (OLEDs) and organic solar cells, helping to improve the performance and efficiency of these devices.

[0003] Currently available methods for preparing 2,5-dibromo-3-methylpyridine mainly include direct bromination, pyridine derivative conversion, and palladium-catalyzed coupling. The mainstream method is the pyridine derivative conversion method, which involves synthesizing the intermediate 2-amino-3-methyl-5-bromopyridine from 2-amino-3-methylpyridine, acetic anhydride, liquid bromine, and sodium hydroxide. This intermediate is then diazotized under cuprous bromide catalysis to obtain 2,5-dibromo-3-methylpyridine. This route is relatively lengthy, uses acetic anhydride and cuprous bromide catalysis, and produces wastewater containing heavy metals. Summary of the Invention

[0004] The purpose of this invention is to solve the problems of long process routes, difficult wastewater treatment, and low product yield in existing processes. A proposed process route is to obtain an intermediate product through a one-step bromination, followed by a diazotization reaction without heavy metal ion catalysis to obtain 2,5-dibromo-3-methylpyridine, with solvent recovery and reuse. This method is simple, efficient, produces high-purity products, does not generate wastewater containing heavy metal ions, is economical and environmentally friendly, and is suitable for industrial production.

[0005] To achieve the above objectives, the present invention provides a method for preparing 2,5-dibromo-3-methylpyridine, comprising the following steps: (1) Mix 2-amino-3-methylpyridine with an organic solvent, and then add bromine dropwise at -5-10℃. After the addition is complete, continue to react fully at -5-10℃. After the reaction is complete, separate the solid and liquid. Wash the separated solid with an organic solvent to obtain the intermediate product. (2) Mix the intermediate product with hydrobromic acid, and then add bromine dropwise at -5-10℃. After the addition is complete, continue to react fully at -5-10℃. After the reaction is complete, add sodium nitrite aqueous solution dropwise at -5-10℃. After the addition is complete, continue to react fully at -5-10℃. After the reaction is complete, adjust the pH of the system to 8-9 with sodium hydroxide aqueous solution, and obtain crude 2,5-dibromo-3-methylpyridine by phase separation. (3) Mix crude 2,5-dibromo-3-methylpyridine with methanol or ethanol, heat to reflux, and after sufficient reflux, cool down to recrystallize. After recrystallization, separate the solid and liquid, and dry the obtained solid to obtain 2,5-dibromo-3-methylpyridine.

[0006] In step (1), the molar ratio of 2-amino-3-methylpyridine to bromine is 1:1.0-1.2.

[0007] In step (1), the bromine is added over a period of 0.25-0.5 hours; the reaction time after the addition is complete is 1-2 hours.

[0008] In step (1), the organic solvent is dichloromethane or chloroform; the amount of dichloromethane or chloroform used should be limited to the point that it can completely dissolve 2-amino-3-methylpyridine. Of course, the better the fluidity of the system, the better the reaction effect. Considering both cost and reaction effect, the amount of dichloromethane or chloroform used is generally 5-10 times the mass of 2-amino-3-methylpyridine.

[0009] In step (2), the molar ratio of intermediate product to hydrogen bromide is 1:1.6-2.5; the molar ratio of intermediate product to bromine is 1:1.3-1.5; and the molar ratio of intermediate product to sodium nitrite is 1:1.5-1.8.

[0010] In step (2), the bromine is added over a period of 0.25-0.5 hours; the reaction time after the bromine is added is 1-2 hours; the sodium nitrite solution is added over a period of 0.5-1.0 hours; and the reaction time after the sodium nitrite solution is added is 1-2 hours.

[0011] In step (2), the mass concentration of hydrobromic acid is 45%-48%; the mass concentration of sodium nitrite aqueous solution is 30%-35%; and the mass concentration of sodium hydroxide aqueous solution is 15-30%.

[0012] In step (3), the organic solvent is methanol or ethanol; the amount of methanol or ethanol used is limited to completely dissolving the crude 2,5-dibromo-3-methylpyridine; of course, increasing the amount of methanol or ethanol can achieve better purification effect. Considering both cost and purification effect, the amount of methanol or ethanol used should be 1.3-1.5 times the weight of the crude 2,5-dibromo-3-methylpyridine.

[0013] The reaction process of this invention is shown in the following formula:

[0014] This invention uses dichloromethane or trichloromethane as a solvent. First, 2-amino-3-methylpyridine is directly reacted with bromine to synthesize an intermediate. Then, the intermediate is subjected to a second bromination reaction in hydrobromic acid solution followed by diazotization. The pH is then adjusted by adding sodium hydroxide solution to obtain crude 2,5-dibromo-3-methylpyridine. Finally, the crude 2,5-dibromo-3-methylpyridine is recrystallized to obtain a high-purity 2,5-dibromo-3-methylpyridine product. All organic solvents used in the reaction process can be recovered and reused through distillation.

[0015] The invention provides a simple synthetic route for diazotization reaction without the use of heavy metal ions as a catalyst. It has high reaction efficiency, high product purity, and the solvent can be recycled and reused. It does not produce wastewater containing heavy metal ions. The technical solution is economical and environmentally friendly and suitable for industrial production. Detailed Implementation

[0016] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions in the embodiments of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention. Example 1

[0017] (1) Add 200g (2.35mol) of dichloromethane and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to -5-0℃, and add 29.6g (0.185mol) of bromine dropwise over a period of 0.25h. After the addition is complete, continue to keep the temperature for 1h. After the reaction is complete, filter the sample and wash the obtained solid with dichloromethane to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 20.25g (containing 48% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr0. 12 mol), turn on the refrigeration to cool to -5 to 0℃, add 15.6 g (0.0975 mol) of bromine dropwise over 0.25 h; after the addition is complete, keep the temperature and stir for 1 h; after the reaction is complete, control the temperature to -5 to 0℃ and add 22.17 g of sodium nitrite aqueous solution (containing 7.76 g of NaNO2) dropwise over 0.5 h; after the addition is complete, keep the temperature and stir for 2 h; after the reaction is complete, adjust the pH to 8-9 with 20% sodium hydroxide aqueous solution; after the pH is adjusted, let stand and separate the phases, and take the organic phase to obtain crude 2,5-dibromo-3-methylpyridine; (3) Add 20g of crude 2,5-dibromo-3-methylpyridine and 30mL of methanol to a 500mL four-necked flask with stirring function, heat to 60℃ and reflux for 1h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 17g of 2,5-dibromo-3-methylpyridine product with a purity of 99.2%. Example 2

[0018] (1) Add 200g (2.35mol) of dichloromethane and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to 0-10℃, and add 32.64g (0.204mol) of bromine dropwise over a period of 0.25h. After the addition is complete, continue to keep the temperature for 2h. After the reaction is complete, filter the mixture and wash the obtained solid with dichloromethane to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 25.31g (containing 48% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.15 mol) of bromine was added dropwise to 0-10℃, and the temperature was lowered to 0-10℃. The addition time was 0.5 h. After the addition was completed, the mixture was kept at the temperature and stirred for 30 min. After the reaction was completed, the temperature was controlled at 0-10℃, and 25.14 g of sodium nitrite aqueous solution (containing 8.80 g of NaNO2) was added dropwise for 0.5 h. After the addition was completed, the mixture was kept at the temperature and stirred for 2 h. After the reaction was completed, the pH was adjusted to 8-9 with 15% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 20g of crude 2,5-dibromo-3-methylpyridine and 30mL of ethanol to a 500mL four-necked flask with stirring function, heat to 78℃ and reflux for 1h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 18g of 2,5-dibromo-3-methylpyridine product with a purity of 99.0%. Example 3

[0019] (1) Add 100g (1.18mol) of dichloromethane and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to -5-0℃, and add 35.52g (0.222mol) of bromine dropwise over a period of 0.5h. After the addition is complete, continue to keep the temperature for 1h. After the reaction is complete, filter the mixture and wash the obtained solid with dichloromethane to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 31.64g (containing 48% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.1875 mol) of bromine was added dropwise to -5 to 0℃, and the temperature was lowered to -5 to 0℃. The addition time was 0.5 h. After the addition was completed, the mixture was kept at the same temperature and stirred for 2 h. After the reaction was completed, the temperature was controlled at -5 to 0℃, and 26.63 g of sodium nitrite aqueous solution (containing 9.32 g of NaNO2) was added dropwise for 1 h. After the addition was completed, the mixture was kept at the same temperature and stirred for 2 h. After the reaction was completed, the pH was adjusted to 8 to 9 with 30% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 20g of crude 2,5-dibromo-3-methylpyridine and 30mL of methanol to a 500mL four-necked flask with stirring function, heat to 60℃ and reflux for 2h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 17g of 2,5-dibromo-3-methylpyridine product with a purity of 99.2%. Example 4

[0020] (1) Add 100g (1.18mol) of dichloromethane and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to -5-0℃, and add 29.6g (0.185mol) of bromine dropwise over a period of 0.25h. After the addition is complete, continue to keep the reaction at the temperature for 1.5h. After the reaction is complete, filter the mixture and wash the obtained solid with dichloromethane to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 21.6g (containing 45% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.12 mol) was added, and the temperature was lowered to 0-10℃. 15.52 g (0.097 mol) of bromine was added dropwise over 0.25 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 1 h. After the reaction was complete, the temperature was controlled at 0-10℃, and 25.87 g of sodium nitrite aqueous solution (containing 7.76 g of NaNO2) was added dropwise over 0.5 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 1 h. After the reaction was complete, the pH was adjusted to 8-9 with a 30% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 20g of crude 2,5-dibromo-3-methylpyridine and 20mL of methanol to a 500mL four-necked flask with stirring function, heat to 60℃ and reflux for 1h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 17.6g of 2,5-dibromo-3-methylpyridine product with a purity of 99.0%. Example 5

[0021] (1) Add 100g (0.837mol) of chloroform and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to -5-0℃, and add 29.6g (0.185mol) of bromine dropwise over a period of 0.5h. After the addition is complete, continue to keep the temperature for 1h. After the reaction is complete, filter the mixture and wash the obtained solid with chloroform to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 20.25g (containing 48% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.12 mol) was added, and the temperature was lowered to -5 to 0℃. 18 g of bromine (0.1125 mol) was added dropwise over 0.5 h. After the addition was complete, the mixture was kept at the same temperature and stirred for 1 h. After the reaction was complete, the temperature was controlled at -5 to 0℃, and 31.07 g of sodium nitrite aqueous solution (containing 9.32 g of NaNO2) was added dropwise over 1 h. After the addition was complete, the mixture was kept at the same temperature and stirred for 2 h. After the reaction was complete, the pH was adjusted to 8-9 with a 20% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 19g of crude 2,5-dibromo-3-methylpyridine and 20mL of ethanol to a 500mL four-necked flask with stirring function, heat to 78℃ and reflux for 1h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 16.2g of 2,5-dibromo-3-methylpyridine product with a purity of 99.0%. Example 6

[0022] (1) Add 200g (1.674mol) of chloroform and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to -0-5℃, and add 35.56g (0.222mol) of bromine dropwise over a period of 0.5h. After the addition is complete, continue to keep the temperature for 2h. After the reaction is complete, filter the mixture and wash the obtained solid with chloroform to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 31.64g (containing 48% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.1875 mol) was added, and the temperature was lowered to 5-10℃. 15.52 g (0.097 mol) of bromine was added dropwise over 0.5 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 2 h. After the reaction was complete, the temperature was controlled at 5-10℃, and 25.87 g of sodium nitrite aqueous solution (containing 7.76 g of NaNO2) was added dropwise over 0.5 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 1 h. After the reaction was complete, the pH was adjusted to 8-9 with a 30% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 19g of crude 2,5-dibromo-3-methylpyridine and 30mL of methanol to a 500mL four-necked flask with stirring function, heat to 60℃ and reflux for 1h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 16.2g of 2,5-dibromo-3-methylpyridine product with a purity of 99.1%. Example 7

[0023] (1) Add 150g (1.765mol) of dichloromethane and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to 0-5℃, and add 32.6g (0.204mol) of bromine dropwise over a period of 0.35h. After the addition is complete, continue to keep the temperature for 1h. After the reaction is complete, filter the mixture and wash the obtained solid with dichloromethane to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 21.6g (containing 45% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.12 mol) was added, and the temperature was lowered to 0-5℃. 16.72 g (0.105 mol) of bromine was added dropwise over 0.35 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 2 h. After the reaction was complete, the temperature was controlled at 5-10℃, and 25.14 g of sodium nitrite aqueous solution (containing 8.8 g of NaNO2) was added dropwise over 1 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 2 h. After the reaction was complete, the pH was adjusted to 8-9 with a 15% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 19 g of crude 2,5-dibromo-3-methylpyridine and 20 mL of ethanol to a 500 mL four-necked flask with stirring function, heat to 78 °C and reflux for 1 h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 17 g of 2,5-dibromo-3-methylpyridine product with a purity of 99.0%. Example 8

[0024] (1) Add 100g (1.1765mol) of dichloromethane and 20g (0.185mol) of 2-amino-3-methylpyridine to a 500mL four-necked flask with stirring function, then place it in a low temperature bath to cool to -5-0℃, and add 35.56g (0.222mol) of bromine dropwise over a period of 0.5h. After the addition is complete, continue to keep the temperature for 2h. After the reaction is complete, filter the mixture and wash the obtained solid with dichloromethane to obtain the intermediate product. (2) Add 20g (0.075mol) of intermediate product and 33.75g (containing 45% hydrobromic acid) to a 500mL four-necked flask equipped with a stirrer. HBr 0.1875 mol) was added, and the temperature was lowered to -5 to 0℃. 17.91 g (0.112 mol) of bromine was added dropwise over 0.5 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 1 h. After the reaction was complete, the temperature was controlled at 5-10℃, and 26.63 g of sodium nitrite aqueous solution (containing 9.32 g of NaNO2) was added dropwise over 1 h. After the addition was complete, the mixture was kept at the desired temperature and stirred for 1.5 h. After the reaction was complete, the pH was adjusted to 8-9 with a 15% sodium hydroxide aqueous solution. After the pH was adjusted, the mixture was allowed to stand and the phases were separated. The organic phase was taken to obtain crude 2,5-dibromo-3-methylpyridine. (3) Add 20g of crude 2,5-dibromo-3-methylpyridine and 30mL of ethanol to a 500mL four-necked flask with stirring function, heat to 78℃ and reflux for 2h, then cool down to crystallize, filter after crystallization, dry the obtained solid to obtain 16g of 2,5-dibromo-3-methylpyridine product with a purity of 99.0%.

[0025] The purity of the products obtained in the above embodiments was determined by liquid chromatography.

[0026] The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 2,5-dibromo-3-methylpyridine, characterized in that: Includes the following steps: (1) Mix 2-amino-3-methylpyridine with an organic solvent, and then add bromine dropwise at -5-10℃. After the addition is complete, continue to react fully at -5-10℃. After the reaction is complete, separate the solid and liquid. Wash the separated solid with an organic solvent to obtain the intermediate product. (2) Mix the intermediate product with hydrobromic acid, and then add bromine dropwise at -5-10℃. After the addition is complete, continue to react fully at -5-10℃. After the reaction is complete, add sodium nitrite aqueous solution dropwise at -5-10℃. After the addition is complete, continue to react fully at -5-10℃. After the reaction is complete, adjust the pH of the system to 8-9 with sodium hydroxide aqueous solution, and obtain crude 2,5-dibromo-3-methylpyridine by phase separation. (3) Mix crude 2,5-dibromo-3-methylpyridine with an organic solvent, heat to reflux, and then cool down to recrystallize after full reflux. After recrystallization, separate the solid and liquid, and dry the obtained solid to obtain 2,5-dibromo-3-methylpyridine.

2. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (1), the molar ratio of 2-amino-3-methylpyridine to bromine is 1:1.0-1.

2.

3. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (1), the bromine is added over a period of 0.25-0.5 hours; the reaction time after the addition is complete is 1-2 hours.

4. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (1), the organic solvent is dichloromethane or trichloromethane.

5. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (2), the molar ratio of intermediate product to hydrogen bromide is 1:1.0-1.5; the molar ratio of intermediate product to bromine is 1:1.3-1.5; and the molar ratio of intermediate product to sodium nitrite is 1:1.5-1.

8.

6. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (2), the bromine is added over a period of 0.25-0.5 hours; the reaction time after the bromine is added is 1.0-2.0 hours; the sodium nitrite solution is added over a period of 0.5-1.0 hours; and the reaction time after the sodium nitrite solution is added is 1.0-2.0 hours.

7. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (2), the mass concentration of hydrobromic acid is 45%-48%; the mass concentration of sodium nitrite aqueous solution is 30%-35%; and the mass concentration of sodium hydroxide aqueous solution is 15-30%.

8. The method for preparing 2,5-dibromo-3-methylpyridine according to claim 1, characterized in that: In step (3), the organic solvent is methanol or ethanol.

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