Selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis

Abstract

The invention discloses a selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis. According to the method, tetrachloroglycoluril is adopted as a chlorine source, iron trifluoromethanesulfonate is adopted as a catalyst, and pyridine is adopted as a starting raw material to carry out selective chlorination reaction. Due to the unique electronic structure of the Ag-NPs catalyst, the high-regioselectivity chlorination of the pyridine site 2 is realized. By systematically optimizing reaction parameters including key factors such as reaction temperature, time and reagent stoichiometric ratio, the technical problems of excessive chlorination, by-product formation and the like in the traditional synthesis path are solved. Under the optimal condition, the separation yield of the target product is stably maintained to be 93% or above, and the regioselectivity reaches 98%. The process has the remarkable advantages of mild reaction conditions, easily available raw materials, simplicity and convenience in operation and the like. As the mild chlorination reagent is adopted, special anti-corrosion equipment is not needed, and the reaction is carried out in a homogeneous system, the process flow is simple, and the production cost is remarkably reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine chemical engineering, and particularly relates to a method for selectively synthesizing 2-chloropyridine based on Ag-NPs catalysis. Background Art

[0002] As a key organic synthesis intermediate, 2-chloropyridine has wide application value in the fields of agrochemicals and fine chemical engineering, and particularly plays an important role in the preparation of pesticides and additives for daily chemicals. Its derivatives exhibit good biological activity and low toxicity characteristics, making it an important compound in the field of organic synthesis.

[0003] Existing 2-chloropyridine synthesis strategies can be mainly divided into two categories: functional group transformation and direct chlorination. The functional group transformation method uses 2-aminopyridine or 2-hydroxypyridine as precursors, but is limited by the difficulty of obtaining raw materials and economic considerations. The direct chlorination method uses chlorine gas to react with the pyridine ring, including process routes such as thermal chlorination, catalytic chlorination, and photo-chlorination. However, due to the inert characteristics of the pyridine ring, traditional thermal chlorination needs to be carried out under harsh conditions above 300 °C, resulting in a complex product distribution and difficult to control. To overcome this dilemma, researchers have developed a multi-step synthesis route using pyridine N-oxide as an intermediate, but this method has deficiencies such as cumbersome processes and large environmental loads.

[0004] The invention patent with the publication number CN1110481C discloses a new process for synthesizing 2-chloropyridine from pyridine and chlorine gas, and has developed a reactive distillation coupling process, significantly improving the process efficiency of the direct chlorination method. The invention patents with the publication numbers CN103554013A and CN103554014A propose an organic solvent method and a solvent-free method, achieving a total yield of 90-98%. The invention patent with the publication number CN101830844A adopts an ultraviolet photocatalytic system and optimizes the reaction selectivity by adding an activator, but this method is affected by multiple factors and is difficult to control the process.

[0005] In addition to chlorine gas, researchers have also explored various chlorinating reagents. Jung et al. (Synth. Commun., 2001) achieved the synthesis of 2-chloropyridine with a 90% yield using phosphorus oxychloride in the presence of triethylamine. The hydrochloric acid-hypochlorite system developed by the invention patent with the publication number CN105418493A exhibits a selectivity of 83%. However, traditional chlorinating reagents generally have environmental and safety risks, especially the use of phosgene has been restricted in many regions. Therefore, the development of green chlorination methods has important research value for promoting the sustainable synthesis of pyridine compounds. Summary of the Invention

[0006] To solve the defects existing in the prior art, the present invention provides a method for selectively synthesizing 2-chloropyridine based on Ag-NPs catalysis.

[0007] To solve the above technical problems, the present invention provides the following technical solutions:

[0008] The present invention provides a method for selectively synthesizing 2-chloropyridine based on Ag-NPs catalysis, and its synthetic route is as follows:

[0009]

[0010] The specific synthesis steps are as follows:

[0011] Mix pyridine, Ag-NPs catalyst and an appropriate amount of anhydrous dichloromethane, and slowly drop the tetrachloroglycoluril dissolved in dichloromethane into the mixed reaction system within 60 minutes. Control the reaction temperature at 50-80 °C, stir and react for 2 hours, and monitor the reaction process by TLC or HPLC; after the reaction is completed, cool the mixture to room temperature, quench with water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product; finally, obtain high-purity 2-chloropyridine by vacuum distillation.

[0012] Preferably, the preparation process of the Ag-NPs is as follows:

[0013] S11. Under the low-temperature condition of 0-5 °C, dissolve silver nitrate in water, add PEG as a stabilizer, and slowly drop the NaBH 4 solution as a reducing agent under stirring conditions. After the reaction is completed, prepare silver nanoparticles, and during this period, the solution changes from colorless to yellow or gray;

[0014] S12. Mix the carrier pre-ultrasonically dispersed in absolute ethanol with the ethanol dispersion of silver nanoparticles, and let it stand at room temperature to achieve uniform loading of silver nanoparticles;

[0015] S13. Filter the product, wash it with ethanol and dry it to obtain a supported silver nanoparticle catalyst with high catalytic activity, namely Ag-NPs.

[0016] Preferably, the concentration of silver nitrate in step S11 is 0.1 M, and the reaction time is 1-2 hours.

[0017] Preferably, the dispersion time in step S12 is 0.5-0.8 hours, the carrier is any one of SBA-15, alumina, and activated carbon, and the standing time is 12-16 hours.

[0018] Preferably, the drying temperature in step S13 is 120-150 °C, and the drying time is 6-8 hours.

[0019] Preferably, the preparation process of the tetrachloroglycoluril is as follows:

[0020] Dissolve glycoluril in deionized water and stir to completely dissolve it. Then control the solution temperature at 5 - 10 °C. Under continuous stirring, slowly add the newly prepared sodium hypochlorite solution, and at the same time adjust and maintain the pH value between 8 - 9 with sodium hydroxide solution. The reaction process needs to be carried out in the dark and stirred continuously for 6 - 8 hours. During this period, white solids can be observed to gradually precipitate. After the reaction is completed, cool the reaction solution to 0 - 5 °C and continue stirring for 1 hour to promote crystallization. Collect the precipitated white crystals by suction filtration and wash them 3 - 4 times with pre-cooled deionized water to remove unreacted raw materials and by-products. Finally, vacuum dry the obtained product at 45 - 50 °C for 10 - 12 hours to obtain the tetrachloroglycoluril product.

[0021] Preferably, the amount of anhydrous dichloromethane is 0.1 L of anhydrous dichloromethane per kilogram of chloropyridine.

[0022] Preferably, the mass of Ag - NPs is 0.1 - 0.2 times that of pyridine.

[0023] Preferably, the mass of tetrachloroglycoluril is 0.25 times that of pyridine.

[0024] Preferably, the stirring reaction time is 2 - 4 hours.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) In the present invention, Ag - NPs, as a Lewis acid, can effectively activate pyridine molecules. By forming a coordination bond with the pyridine nitrogen atom, it significantly enhances the electron deficiency at the C - 2 position of the pyridine ring, thereby promoting the electrophilic chlorination reaction at the C - 2 position. In addition, tetrachloroglycoluril, as a chlorinating reagent, can provide a highly efficient and mild chlorination environment. The chloride ions released during the reaction process selectively attack the C - 2 position of pyridine under the synergistic action of Ag - NPs. Compared with traditional chlorinating reagents, this system not only significantly improves the yield of 2 - chloropyridine but also avoids the formation of by - products (such as 3 - chloropyridine or poly - chlorinated pyridines), thus improving the selectivity of the reaction.

[0027] (2) Compared with the pyridine chlorination reaction carried out under traditional high - temperature, high - pressure or strong - acid conditions, the synergistic effect of the present invention can significantly reduce the energy input required for the reaction. As an efficient catalyst, Ag - NPs can not only activate the substrate at a relatively low temperature but also accelerate the reaction rate by stabilizing the intermediate. The solid form of tetrachloroglycoluril has high chemical stability and can release Cl + under mild conditions, reducing the dependence on strong oxidants or highly corrosive reagents. This beneficial effect makes the reaction process more environmentally friendly and suitable for large - scale production, meeting the requirements of energy conservation and consumption reduction in industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a schematic diagram of the effects catalyzed by different catalysts in the present invention;

[0029] Figure 2 It is a schematic diagram of the effects of using different chlorinating reagents in the present invention. Specific Embodiments

[0030] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not intended to limit the present invention.

[0031] Example 1: Process steps for the production of Ag-NPs.

[0032] Under low-temperature (0 - 5°C) conditions, silver nitrate (0.1M) is dissolved in water, PEG is added as a stabilizer, and NaBH 4 solution is slowly added dropwise as a reducing agent under stirring conditions. Silver nanoparticles are prepared by reacting for 1 hour, during which the solution changes from colorless to yellow or gray; the second step is to mix the carrier (such as SBA-15, alumina, or activated carbon) that has been ultrasonically dispersed in absolute ethanol for 30 minutes with the ethanol dispersion of silver nanoparticles, and let it stand at room temperature for 12 hours to achieve uniform loading of silver nanoparticles. Finally, the product is filtered, washed with ethanol, and dried at 120°C for 6 hours to obtain a supported silver nanoparticle catalyst with high catalytic activity.

[0033] Example 2: Process steps for the production of tetrachloroglycoluril.

[0034] Glycoluril is dissolved in deionized water and stirred until completely dissolved. Subsequently, the temperature of the solution is controlled at 5 - 10°C; under continuous stirring conditions, a newly prepared sodium hypochlorite solution is slowly added dropwise, and the pH value is adjusted and maintained between 8 - 9 with sodium hydroxide solution; the reaction process needs to be carried out in the dark and with continuous stirring for 6 - 8 hours, during which white solids can be observed to gradually precipitate; after the reaction is completed, the reaction solution is cooled to 0 - 5°C and stirred for another 1 hour to promote crystallization; the precipitated white crystals are collected by suction filtration and washed 3 - 4 times with pre-cooled deionized water to remove unreacted raw materials and by-products; finally, the obtained product is vacuum dried at 45 - 50°C for 10 - 12 hours to obtain a tetrachloroglycoluril product with relatively high purity.

[0035] Example 3: Process steps for the production of 2-chloropyridine.

[0036] In a dry three-necked flask, add pyridine (0.5 kg), Ag-NPs (0.05 kg, catalyst), and 0.05 L of anhydrous dichloromethane. Slowly add tetrachloroglycoluril (0.125 kg, chlorinating reagent) dissolved in dichloromethane to the reaction system within 60 minutes. Control the reaction temperature at 50 °C and stir the reaction for 2 hours. Monitor the reaction progress by TLC or HPLC. After the reaction is completed, cool the mixture to room temperature, quench with water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Finally, obtain 2-chloropyridine by vacuum distillation with a yield of 97% and a purity of 99.3% (purity detected by HPLC).

[0037] Subsequently, the scale-up reaction and different metal nanoparticle catalysts were systematically investigated. The reaction products were qualitatively and quantitatively analyzed by gas chromatography. The specific experimental data and reaction conditions are shown in Table 1 and Figure 1 、 2 as follows.

[0038] Table 1: Scale-up reaction experiments.

[0039]

[0040] Through systematic experimental studies and data analysis, the present invention elucidates the catalytic performance of tetrachloroglycoluril in the Ag-NPs catalytic system. This system not only exhibits excellent chemoselectivity and regioselectivity but also has advantages such as high atom utilization efficiency and simple product separation. More importantly, when the reaction is scaled up to the kilogram scale, the catalytic system still shows reaction activity and selectivity comparable to those at the small-scale level, which fully confirms the good industrial application prospects of this catalytic system.

[0041] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not used 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 recorded in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis, characterized in that: Its synthetic route is as follows: The specific synthesis steps are as follows: Pyridine, Ag-NPs catalyst and an appropriate amount of anhydrous dichloromethane are mixed, tetrachloroglycoluril dissolved in dichloromethane is slowly added dropwise to the mixed reaction system within 60 minutes, the reaction temperature is controlled at 50-80°C, the reaction is stirred, and the reaction progress is monitored by TLC or HPLC; after the reaction is completed, the mixture is cooled to room temperature, quenched with water, extracted with dichloromethane, the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product; finally, high-purity 2-chloropyridine is obtained by vacuum distillation.

2. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 1, characterized in that: The preparation process of the Ag-NPs is as follows: S11, dissolving silver nitrate in water at a low temperature of 0-5°C, adding PEG as a stabilizer, and slowly dropping a NaBH4 solution as a reducing agent under stirring. After the reaction is completed, silver nanoparticles are prepared, during which the solution changes from colorless to yellow or gray; S12, mixing the carrier ultrasonically dispersed in anhydrous ethanol in advance with the ethanol dispersion of silver nanoparticles, and letting it stand at room temperature to achieve uniform loading of the silver nanoparticles; S13, filtering the product, washing with ethanol and drying it to obtain a supported silver nanocatalyst with high catalytic activity, namely, Ag-NPs.

3. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 2, characterized in that: The concentration of silver nitrate in step S11 is 0.1 M, and the reaction time is 1-2 hours.

4. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 2, characterized in that: In the step S12, the dispersion time is 0.5-0.8 hours, the carrier is any one of SBA-15, alumina, and activated carbon, and the standing time is 12-16 hours.

5. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 2, characterized in that: In step S13, the drying temperature is 120-150° C., and the drying time is 6-8 hours.

6. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 1, characterized in that: The preparation process of the tetrachloroglycoluril is: Dissolve glycoluril in deionized water, stir to completely dissolve, and then control the solution temperature at 5-10°C; slowly drop a freshly prepared sodium hypochlorite solution under continuous stirring, and adjust and maintain the pH value between 8 and 9 with sodium hydroxide solution; the reaction process needs to be protected from light and continuously stirred for 6-8 hours, during which white solid can be observed to gradually precipitate; after the reaction is completed, cool the reaction solution to 0-5°C, and continue stirring for 1 hour to promote crystallization; collect the precipitated white crystals by suction filtration, and wash them with pre-cooled deionized water for 3-4 times to remove unreacted raw materials and by-products; finally, vacuum dry the obtained product at 45-50°C for 10-12 hours to obtain a tetrachloroglycoluril product.

7. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 1, characterized in that: The amount of the anhydrous dichloromethane is 0.1 L per kilogram of chloropyridine.

8. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 1, characterized in that: The mass of the Ag-NPs is 0.1 to 0.2 times that of pyridine.

9. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 1, characterized in that: The mass of the tetrachloroglycoluril is 0.25 times that of pyridine.

10. The selective synthesis method of 2-chloropyridine based on Ag-NPs catalysis according to claim 1, characterized in that: The stirring reaction time is 2-4 hours.

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