Method for preparing 2-amino-4, 6-dichloropyridine by catalyzing amination of 2, 4, 6-trichloropyridine

Abstract

The invention discloses a method for preparing 2-amino-4, 6-dichloropyridine by catalyzing amination of 2, 4, 6-trichloropyridine, which comprises the following steps: adding 2, 4, 6-trichloropyridine, stronger ammonia water and a Pd / N-C-ZnCl composite catalyst into a high-pressure reaction kettle, sealing, stirring and reacting, tracking by HPLC (High Performance Liquid Chromatography) until the raw materials basically disappear, cooling the reaction liquid to room temperature, filtering and recovering the catalyst, and drying to obtain the 2-amino-4, 6-dichloropyridine. Collecting filtrate for later use; slowly dropwise adding a hydrochloric acid solution into the filtrate in an ice-water bath to adjust the pH value, standing to remove impurities, adding a sodium carbonate solution into the system to adjust the pH value of the system again, carrying out precipitation treatment, filtering, washing a filter cake I, and carrying out next-step treatment; mixing the filter cake I, cyclopentyl methyl ether and water, heating until solids are dissolved, slowly cooling to room temperature, cooling again, filtering crystallized feed liquid, and drying a filter cake II to obtain the high-purity 2-amino-4, 6-dichloropyridine. The catalyst adopted by the invention is high in catalytic activity, mild in reaction condition and high in production efficiency, and the yield and the purity of the prepared product are obviously improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for catalytically aminating 2,4,6-trichloropyridine to prepare 2-amino-4,6-dichloropyridine. BACKGROUND

[0002] 2-amino-4,6-dichloropyridine is an important pharmaceutical and pesticide intermediate, which is widely used in the synthesis of various biologically active compounds, such as herbicides, insecticides and drug molecules. The molecular structure of 2-amino-4,6-dichloropyridine contains two different chlorine atoms and an amino group, which enables it to undergo further precise functionalization, thus playing a crucial role in the synthesis of high-value fine chemicals.

[0003] Currently, the industrial preparation method of 2-amino-4,6-dichloropyridine is mainly achieved by selective amination of 2,4,6-trichloropyridine. The core challenge of the above reaction lies in how to selectively replace the chlorine atom at the 2-position with an amino group while keeping the chlorine atoms at the 4- and 6-positions stable and unreactive. However, the existing technical route mainly has the following limitations in practical application: 1. Due to the differences in electronic effect and steric hindrance of the three chlorine atoms on the pyridine ring, the chlorine atom at the 2-position usually has the highest reactivity. However, under traditional amination conditions, there is a lack of effective selective regulation means, which easily leads to over-amination or poor regioselectivity, thereby reducing the yield and purity of the target product and bringing great difficulties to subsequent separation and purification; 2. Although homogeneous palladium catalysts have been applied in the above amination reaction, there are problems such as difficulty in catalyst recovery, noble metal residue and high cost. Although some heterogeneous catalysts have been developed, their activity and selectivity are often unsatisfactory. Many catalysts cannot achieve high conversion rate under mild conditions, or have poor selectivity, which makes it difficult to meet the requirements of economic efficiency and efficiency for industrial production.

[0004] 3. In order to promote the reaction, high-pressure ammonia gas or liquid ammonia is often used as the amination reagent in the existing methods. The above two media have very high requirements for reaction equipment, and there are high-pressure operation risks and ammonia leakage hazards. In addition, the process flow is complex, which limits its wide application in conventional production facilities; 4. After the reaction is completed, the reaction liquid usually contains unreacted raw materials, positional isomers, over-amination by-products and catalyst residues, etc. in addition to the target product. Traditional purification methods are inefficient, consume a large amount of solvent, and it is difficult to achieve the high purity required for pharmaceutical intermediates, resulting in unstable yield and quality of the final product.

[0005] In summary, there is an urgent need in the art to develop a new type of catalytic amination method to solve the above technical problems. SUMMARY

[0006] Therefore, the technical problem to be solved by the present application is to provide a method for preparing 2-amino-4,6-dichloropyridine by catalyzing amination of 2,4,6-trichloropyridine, which has high catalytic activity of the catalyst, mild reaction conditions, high production efficiency, and significantly improved yield and purity of the prepared product.

[0007] To solve the above technical problems, the present application adopts the following technical solutions: A method for preparing 2-amino-4,6-dichloropyridine by catalyzing amination of 2,4,6-trichloropyridine, comprising the following steps: (1) In a high-pressure reaction kettle, 2,4,6-trichloropyridine, concentrated ammonia water and Pd / N-C-ZnCl2 composite catalyst are added, sealed, stirred and reacted, and the reaction is tracked by HPLC until the raw material is basically consumed. The reaction solution is cooled to room temperature, the catalyst is recovered by filtration, and the filtrate is collected for use; (2) The above filtrate is slowly added with hydrochloric acid solution under ice water bath to adjust the pH, and after standing and removing impurities, sodium carbonate solution is added to the system to adjust the pH of the system again, and then the system is precipitated, filtered, and the filter cake is washed and then subjected to the next step; (3) The filter cake I and cyclopentyl methyl ether, water are mixed, heated to dissolve the solid, then slowly cooled to room temperature, and then cooled again. The crystallization liquid is filtered, and the filter cake II is dried to obtain high-purity 2-amino-4,6-dichloropyridine.

[0008] Preferably, in step (1), the concentration of the concentrated ammonia water is 25-30% v / v, and the mass ratio of 2,4,6-trichloropyridine, concentrated ammonia water and Pd / N-C-ZnCl2 composite catalyst is 1:10:(0.05-0.15).

[0009] Preferably, in step (1), the stirring reaction temperature is 55-65°C, and the time is 2-3h.

[0010] Preferably, in step (1), the preparation method of the Pd / N-C-ZnCl2 composite catalyst comprises the following steps: Zinc acetate dihydrate is dissolved in methanol to obtain solution A; 2-methyl imidazole is dissolved in methanol to obtain solution B; under vigorous stirring, solution A is quickly poured into solution B, and the reaction is continued under stirring at room temperature. After the reaction is completed, the precipitate is washed and dried after centrifugal treatment to obtain ZIF-8 powder; The ZIF-8 powder is placed in a tube furnace and subjected to calcination treatment under nitrogen atmosphere to obtain a nitrogen-doped carbon carrier; Sodium chloropalladate is dissolved in deionized water to obtain a palladium solution; the palladium solution is slowly added to the nitrogen-doped carbon carrier under stirring, and then dried and finally subjected to heat treatment to obtain a palladium-loaded carrier; The anhydrous zinc chloride is dissolved in methanol to obtain a zinc-containing solution, the above-mentioned palladium-loaded carrier is added for impregnation treatment, then the solvent is removed by rotary evaporation, and finally activation treatment is performed to obtain a Pd / N-C-ZnCl2 composite catalyst.

[0011] Preferably, at least one of the following characteristics is included when preparing the nitrogen-doped carbon carrier: The mass ratio of the zinc acetate dihydrate and 2-methylimidazole is 5:(10-12); the stirring reaction time is 5-6h; The flow rate of the nitrogen is 100 sccm; the heating rate during calcination is 3-5 ℃ / min, the calcination temperature is 900℃, and the calcination time is 1-3h.

[0012] Preferably, at least one of the following characteristics is included when preparing the palladium-loaded carrier: The mass ratio of the sodium chloropalladate and the nitrogen-doped carbon carrier is (0.1-0.2):1; The heat treatment atmosphere is nitrogen, the temperature is 300℃, and the time is 2-3h.

[0013] Preferably, at least one of the following characteristics is included when loading the zinc chloride: The mass ratio of the anhydrous zinc chloride and the palladium-loaded carrier is (0.4-0.6):1; The impregnation treatment conditions are: ultrasonic treatment at room temperature and a power of 200-300W for 20-30min, followed by stirring for 3-4h; The activation treatment conditions are: 150℃, 3-4h.

[0014] Preferably, in step (2), the concentration of the hydrochloric acid solution is 1M, the pH of the system is adjusted to 2-3 by dropping the hydrochloric acid solution; the concentration of the sodium carbonate solution is 10% w / w, the pH of the system is adjusted to 7-8 again by dropping the sodium carbonate solution, the precipitation treatment temperature is 0-5℃, and the time is 0.5-1.5h.

[0015] Preferably, in step (3), the volume ratio of the cyclopentyl methyl ether and water is 4:1; the temperature for heating to dissolve the solid is 65-75℃.

[0016] Preferably, in step (3), the process of slowly cooling to room temperature is: cooling at a rate of 0.5-1.0℃ / min, the temperature for re-cooling is 0-5℃, and the time is 1-2h.

[0017] The technical solution provided by the application has at least the following advantages: The application provides a method for preparing 2-amino-4,6-dichloropyridine by catalyzing amination of 2,4,6-trichloropyridine, which promotes the smooth progress of the reaction by introducing a specific catalyst in the amination reaction. Pd in the catalyst is the core active center of the catalytic amination reaction, can efficiently activate chlorine atoms, and promote the nucleophilic substitution of ammonia molecules; N-C, as a carrier, is obtained by high-temperature calcination of ZIF-8, has a high specific surface area, a rich pore structure and a large number of nitrogen-doped sites, these nitrogen sites not only can stably anchor palladium nanoparticles and prevent them from aggregating and losing, but also can adjust the electron cloud density of palladium through the electronic effect, further improving the catalytic activity of palladium. ZnCl2, as a Lewis acid, can strongly adsorb and activate the nitrogen atoms on the pyridine ring, thereby polarizing and weakening the 2-position chlorine atom, making it more easily replaced by ammonia, which realizes the site-selective activation of the 2-position chlorine and improves the purity of the product. In summary, Pd, N-C and ZnCl2 form a synergistic catalytic system, which simultaneously activates the reactants and precisely locates the reaction site, realizing high conversion rate and high regioselectivity of the raw materials. The catalyst has high catalytic activity, mild amination reaction conditions and high production efficiency.

[0018] The application realizes efficient separation of the target product through acid-base precipitation and crystallization purification. The recrystallization is carried out using a cyclopentyl methyl ether and water mixed solvent. The cyclopentyl methyl ether is a green solvent, which has the advantages of good chemical stability, moderate boiling point, partial mutual solubility with water and easy layering. Its specific polarity and solubility can realize efficient purification of 2-amino-4,6-dichloropyridine. During the cooling crystallization, the temperature is slowly reduced at a rate of 0.5-1.0 ℃ / min, so that the crystals with uniform size and higher purity are formed, effectively improving the product purity. DETAILED DESCRIPTION

[0019] The technical solutions of the application will be described below clearly and completely. Obviously, the described embodiments are part of the embodiments of the application, rather than all the embodiments. EMBODIMENT

[0020] A method for preparing 2-amino-4,6-dichloropyridine by catalyzing amination of 2,4,6-trichloropyridine, comprising the following steps: (1) Preparation of Pd / N-C-ZnCl2 composite catalyst: a. 5.0 g of zinc acetate dihydrate is dissolved in 150 mL of methanol to obtain solution A; 11.0 g of 2-methylimidazole is dissolved in 150 mL of methanol to obtain solution B, and solution A is quickly poured into solution B under vigorous stirring, and the reaction is continued to stir at room temperature for 5 hours; b. After the reaction is completed, the reaction liquid is centrifuged, the centrifugal precipitate is washed with methanol for three times, and then dried in a vacuum drying box at 80℃ for 12 hours to obtain white ZIF-8 powder; c. The ZIF-8 powder was placed in a tube furnace and heated to 900 °C at a rate of 5 °C / min under a nitrogen atmosphere with a flow rate of 100 seem, and calcined for 2 hours. After calcination, the nitrogen-doped carbon support was obtained after natural cooling to room temperature; d. 0.15 g of sodium chloropalladate was dissolved in 20 mL of deionized water to obtain a palladium solution. The palladium solution was slowly added to 1.0 g of the above-mentioned nitrogen-doped carbon support under stirring to ensure sufficient infiltration, and then dried at 80 °C for 12 hours; e. The dried solid was heat-treated at 300 °C for 2 hours under a nitrogen atmosphere to obtain a palladium-loaded support; f. 0.5 g of anhydrous zinc chloride was dissolved in 30 mL of methanol to obtain a zinc-containing solution. 1.0 g of the above-mentioned Pd / N-C support was added to the zinc-containing solution, and ultrasonic treatment was performed at room temperature for 25 minutes at a power of 250 W, followed by continuous stirring for 3.5 hours; g. The methanol solvent was removed by a rotary evaporator, and then the obtained solid was activated at 150 °C for 3.5 hours to obtain a Pd / N-C-ZnCl2 composite catalyst; (2) Synthesis and purification of 2-amino-4,6-dichloropyridine: a. 50.0 g of 2,4,6-trichloropyridine, 500 g of concentrated ammonia water with a concentration of 28% v / v, and 5.0 g of the above-prepared Pd / N-C-ZnCl2 composite catalyst (mass ratio of 1:10:0.1) were added to a 500 mL high-pressure reaction kettle. The reaction kettle was sealed, stirring was started, and the temperature was raised to 60 °C for 2.5 hours. HPLC tracking was performed until the peak area of the raw material 2,4,6-trichloropyridine disappeared; b. The reaction liquid was cooled to room temperature, the catalyst was recovered by filtration, and the filtrate was collected; c. The filtrate was cooled in an ice water bath, and 1M hydrochloric acid solution was slowly added under stirring to adjust the pH of the system to 2.5. After standing for 0.5 hours, 10% w / w sodium carbonate solution was slowly added to adjust the pH of the system to 7.5. The system was allowed to stand at 0-5 °C for 1 hour; d. Filtration was performed to obtain a filter cake which was washed twice with a small amount of ice water; e. The filter cake I, 200 mL of cyclopentyl methyl ether, and 50 mL of water (volume ratio of 4:1) were added to a 500 mL flask, and heated to 70 °C to completely dissolve the solid; f. After the solid was dissolved, the temperature was lowered to room temperature at a rate of 0.8 °C / min, and then transferred to an ice water bath at 0-5 °C for continued crystallization for 1.5 hours; g.The crystallized solution was filtered to obtain filter cake II, which was washed once with a small amount of pre-cooled cyclopentyl methyl ether, and the washed filter cake II was dried in a vacuum drying oven at 50°C for 6 hours to obtain high-purity white solid 2-amino-4,6-dichloropyridine. The purity of the product was 99.5% by HPLC analysis, and the yield was 92% based on 2,4,6-trichloropyridine. Example

[0021] A method for catalyzing the amination of 2,4,6-trichloropyridine to prepare 2-amino-4,6-dichloropyridine, comprising the following steps: (1) Preparation of Pd / N-C-ZnCl2 composite catalyst: a. The preparation process is the same as a-c in step (1) of Example 1; b. 0.10 g of sodium chloropalladate was dissolved in 20 mL of deionized water to obtain a palladium solution, which was added dropwise to 1.0 g of nitrogen-doped carbon carrier and dried; then it was heat-treated at 300°C for 3 hours under a nitrogen atmosphere to obtain Pd / N-C; c. 0.4 g of anhydrous zinc chloride was dissolved in 30 mL of methanol, and 1.0 g of the above Pd / N-C carrier was added, and then it was ultrasonically treated at 200W power for 30 minutes at room temperature, followed by stirring for 4 hours; after removing the solvent by rotary evaporation, it was activated at 150°C for 4 hours to obtain a Pd / N-C-ZnCl2 composite catalyst; (2) Synthesis and purification of 2-amino-4,6-dichloropyridine: a. 50.0 g of 2,4,6-trichloropyridine, 500 g of concentrated ammonia water with a concentration of 25% v / v, and 2.5 g of the above catalyst (mass ratio of 1:10:0.05) were added to a high-pressure reaction kettle, the kettle was sealed, and the reaction was stirred at 55°C for 3 hours, and the reaction was followed by HPLC until completion; b. The subsequent steps are the same as b-g in step (2) of Example 1; c. After drying, the product was analyzed by HPLC and the purity was 99.2%, and the yield was 90%. Example

[0022] A method for catalyzing the amination of 2,4,6-trichloropyridine to prepare 2-amino-4,6-dichloropyridine, comprising the following steps: (1) Preparation of Pd / N-C-ZnCl2 composite catalyst: a. The preparation process is the same as a-c in step (1) of Example 1; b. 0.20 g of sodium chloropalladate was dissolved in 20 mL of deionized water to obtain a palladium solution, which was added dropwise to 1.0 g of nitrogen-doped carbon carrier and dried; it was heat-treated at 300°C for 2 hours under a nitrogen atmosphere to obtain Pd / N-C; c. 0.6 g of anhydrous zinc chloride was weighed into 30 mL of methanol, 1.0 g of the Pd / N-C carrier described above was added, and the mixture was ultrasonically treated at room temperature for 20 minutes at a power of 300 W, and then stirred for 3 hours. After the solvent was removed by rotary evaporation, the Pd / N-C-ZnCl2 composite catalyst was obtained by activation at 150°C for 3 hours; (2) Synthesis and purification of 2-amino-4,6-dichloropyridine: a. 50.0 g of 2,4,6-trichloropyridine, 500 g of concentrated ammonia water with a concentration of 30% v / v, and 7.5 g of the catalyst described above (mass ratio of 1:10:0.15) were added to a high-pressure reaction kettle, the kettle was sealed, and the reaction was stirred at 65°C for 2 hours. The reaction was tracked by HPLC until it was complete; b. The subsequent steps were the same as b-g of step (2) of Example 1; c. After drying, the product was analyzed by HPLC and had a purity of 99.4% and a yield of 91%.

[0023] Comparative Example 1 The difference between this comparative example and Example 1 is that the Pd / N-C-ZnCl2 composite catalyst is not used, and the other steps and conditions are the same as in Example 1.

[0024] After 3 hours of reaction, HPLC monitoring showed that more than 85% of the raw material 2,4,6-trichloropyridine remained, and almost no reaction occurred. This proves that under the mild conditions, without the specific catalyst of the present application, the amination reaction is difficult to proceed.

[0025] Comparative Example 2 The difference between this comparative example and Example 1 is that the zinc chloride loading and activation steps (1) f and g are not performed during the preparation of the catalyst, i.e., the Pd / N-C is used directly as the catalyst.

[0026] Under the same reaction conditions as in Example 1, using this catalyst, the reaction was carried out for 3 hours, HPLC showed that the conversion rate of the raw material was 78%, and the final product yield was 70% with a purity of 98.0%. The results show that the lack of ZnCl2 component reduces the catalytic activity and selectivity.

[0027] In summary, the Pd / N-C-ZnCl2 composite catalyst provided by the present application exhibits high activity and high selectivity in the selective amination reaction of 2,4,6-trichloropyridine. Combined with a specific purification process, high-purity 2-amino-4,6-dichloropyridine products can be efficiently and highly-yield obtained.

[0028] Obviously, the above described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments of the present application, other different forms of changes or variations can be made by those skilled in the art without making any creative labor, and all should belong to the protection scope of the present application.

Claims

1. A method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine, characterized in that, Includes the following steps: (1) In a high-pressure reactor, add 2,4,6-trichloropyridine, concentrated ammonia and Pd / NC-ZnCl2 composite catalyst, seal and stir the reaction. Track the reaction by HPLC until the raw materials are basically gone. Cool the reaction solution to room temperature, filter to recover the catalyst, and collect the filtrate for later use. (2) The above filtrate was slowly added dropwise with hydrochloric acid solution under ice water bath to adjust the pH. After standing to remove impurities, sodium carbonate solution was added to the system to adjust the pH of the system again. After precipitation treatment, the filtrate was filtered. After washing the filter cake, the next step of processing was carried out. (3) Mix filter cake one with cyclopentylmethyl ether and water, heat until the solid dissolves, then slowly cool to room temperature and cool again, filter the crystallization liquid, and dry filter cake two to obtain high-purity 2-amino-4,6-dichloropyridine.

2. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 1, characterized in that, In step (1), the concentration of the concentrated ammonia is 25-30% v / v, and the mass ratio of 2,4,6-trichloropyridine, concentrated ammonia and Pd / NC-ZnCl2 composite catalyst is 1:10:(0.05-0.15).

3. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 1, characterized in that, In step (1), the temperature of the stirring reaction is 55-65℃ and the time is 2-3h.

4. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 1, characterized in that, In step (1), the preparation method of the Pd / NC-ZnCl2 composite catalyst includes the following steps: Zinc acetate dihydrate was dissolved in methanol to obtain solution A; 2-methylimidazole was dissolved in methanol to obtain solution B; solution A was quickly poured into solution B under vigorous stirring, and the reaction was continued to be stirred at room temperature. After the reaction was completed, the solution was centrifuged, the precipitate was washed and dried to obtain ZIF-8 powder. ZIF-8 powder was placed in a tube furnace and calcined under a nitrogen atmosphere to obtain a nitrogen-doped carbon support. Sodium chloropalladium was dissolved in deionized water to obtain a palladium solution; the palladium solution was slowly added dropwise to a nitrogen-doped carbon support under stirring, then dried, and finally heat-treated to obtain a palladium-loaded support. Anhydrous zinc chloride was dissolved in methanol to obtain a zinc-containing solution. The above-mentioned palladium-supported carrier was added, and the solution was impregnated. Then, the solvent was removed by rotary evaporation, and finally, the solution was activated to obtain the Pd / NC-ZnCl2 composite catalyst.

5. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 4, characterized in that, When preparing nitrogen-doped carbon supports, at least one of the following characteristics must be included: The mass ratio of zinc acetate dihydrate to 2-methylimidazole is 5:(10-12); the stirring reaction time is 5-6 hours. The nitrogen flow rate is 100 sccm; the heating rate during calcination is 3-5 ℃ / min, the calcination temperature is 900℃, and the calcination time is 1-3h.

6. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 4, characterized in that, When preparing a support for palladium loading, at least one of the following characteristics must be included: The mass ratio of sodium chloropalladium to nitrogen-doped carbon support is (0.1-0.2):1; The heat treatment atmosphere is nitrogen, the temperature is 300℃, and the time is 2-3 hours.

7. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 4, characterized in that, When zinc chloride is loaded, it must include at least one of the following characteristics: The mass ratio of anhydrous zinc chloride to the palladium-supported carrier is (0.4-0.6):1; The conditions for impregnation treatment are: sonication at room temperature and 200-300W power for 20-30 minutes, followed by stirring for 3-4 hours; The activation conditions are: 150℃, 3-4h.

8. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 1, characterized in that, In step (2), the concentration of the hydrochloric acid solution is 1M, and the pH of the system is adjusted to 2-3 by adding hydrochloric acid solution dropwise; the concentration of the sodium carbonate solution is 10%w / w, and the pH of the system is adjusted to 7-8 by adding sodium carbonate solution dropwise again; the precipitation treatment temperature is 0-5℃, and the time is 0.5-1.5h.

9. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 1, characterized in that, In step (3), the volume ratio of cyclopentylmethyl ether to water is 4:1; the temperature at which the solid dissolves is 65-75℃.

10. The method for preparing 2-amino-4,6-dichloropyridine by catalytic amination of 2,4,6-trichloropyridine according to claim 1, characterized in that, In step (3), the process of slowly cooling down to room temperature is as follows: the temperature is reduced at a rate of 0.5-1.0℃ / min, the temperature of the second cooling is 0-5℃, and the time is 1-2h.