Method for synthesizing 2, 3, 4, 5-tetrachloropyridine by using 2, 5-dichloropyridine

Abstract

The invention relates to the technical field of synthesis of chlorine-containing pyridine intermediates, and discloses a method for synthesizing 2, 3, 4, 5-tetrachloropyridine by using 2, 5-dichloropyridine, which comprises the following steps: step 1, preparation of 2, 5-dichloropyridine nitrogen oxide: taking 2, 5-dichloropyridine as a raw material, reacting in the presence of a catalyst and acetic acid, and then filtering to remove the catalyst to obtain 2, 5-dichloropyridine nitrogen oxide; adding an acetic acid solution of 2, 5-dichloropyridine nitrogen oxide; step 2, nitration reaction: adding sulfuric acid and nitric acid, and reacting to obtain 2, 5-dichloro-4-nitropyridine nitrogen oxide; step 3, nitrogen and oxygen removal reaction: adding acetyl chloride to replace 4-position nitro to obtain 2, 4, 5-trichloropyridine nitrogen oxide, and then adding phosphorus trichloride to remove nitrogen and oxygen to obtain 2, 4, 5-trichloropyridine; and 4, chlorination and refining: adding Lewis acid into the 2, 4, 5-trichloropyridine, reacting to obtain a 2, 3, 4, 5-tetrachloropyridine crude product, and refining the crude product to obtain the finished product 2, 3, 4, 5-tetrachloropyridine. The invention solves the problems of more byproducts and unsatisfactory product purity and yield in the prior art.

Description

Technical Field

[0001] This invention relates to the field of chloropyridine intermediate synthesis technology, specifically to a method for synthesizing 2,3,4,5-tetrachloropyridine using 2,5-dichloropyridine. Background Technology

[0002] 2,3,4,5-Tetrachloropyridine is a chloropyridine-based fine chemical intermediate. It is a key intermediate for the synthesis of various pesticides and pharmaceutical compounds and can be used to construct complex heterocyclic structures, providing basic material support for the research and development and production of related products.

[0003] Currently, the synthesis of 2,3,4,5-tetrachloropyridine mainly uses 2-chloropyridine as a starting material and Sn-AC as a supported catalyst, through a catalytic chlorination reaction. However, in the catalytic chlorination reaction using 2-chloropyridine as a starting material, the target product constitutes a very low proportion of the final product, accompanied by large amounts of dichloropyridine, 2,3,5-trichloropyridine, and other byproducts. Furthermore, the chlorinated products of pyridine compounds have similar properties, making efficient separation and purification difficult using conventional methods such as distillation and crystallization. Additionally, the distillation process, due to the easy polymerization and coupling of chloropyridine, generates a large amount of tar at high temperatures, increasing subsequent processing steps and costs, and potentially further reducing the final product yield. Therefore, developing a highly selective synthetic route for 2,3,4,5-tetrachloropyridine is of great significance. Summary of the Invention

[0004] The present invention aims to provide a method for synthesizing 2,3,4,5-tetrachloropyridine using 2,5-dichloropyridine, in order to solve the problems of excessive by-products, unsatisfactory product purity and yield in the prior art.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: a method for synthesizing 2,3,4,5-tetrachloropyridine using 2,5-dichloropyridine, comprising the following steps: Step 1: Preparation of 2,5-dichloropyridine nitrogen oxides: Using 2,5-dichloropyridine as a raw material, the reaction is carried out under the conditions of catalyst and acetic acid. The catalyst is then removed by filtration to obtain an acetic acid solution of 2,5-dichloropyridine nitrogen oxides. Step 2, nitration reaction: Sulfuric acid and nitric acid are added to the acetic acid solution of 2,5-dichloropyridine oxide to obtain 2,5-dichloro-4-nitropyridine oxide; Step 3, Denitrification reaction: Acetyl chloride is added to 2,5-dichloro-4-nitropyridine oxynitride to replace the nitro group at the 4-position to obtain 2,4,5-trichloropyridine oxynitride, and then phosphorus trichloride is added to remove nitrogen and oxygen to obtain 2,4,5-trichloropyridine. Step 4, Chlorination and Purification: Lewis acid is added to 2,4,5-trichloropyridine to react and obtain crude 2,3,4,5-tetrachloropyridine. The crude product is then purified to obtain the finished product, 2,3,4,5-tetrachloropyridine.

[0006] Preferably, as an improvement, in step one, the catalyst is TS-1 catalyst, and the mass ratio of the catalyst to 2,5-dichloropyridine is 1:15~30.

[0007] Preferably, as an improvement, in step one, the mass ratio of acetic acid solvent to 2,5-dichloropyridine is 1:1~4, and the reaction conditions are 60-80℃ for 2h.

[0008] Preferably, as an improvement, in step two, the addition rate of the mixture of sulfuric acid and acetic acid solution of 2,5-dichloropyridine nitrogen oxides is 5~8 g / min, and the nitric acid is fuming nitric acid, with an addition rate of 0.8~1.3 g / min.

[0009] Preferably, as an improvement, in step two, the nitration reaction conditions are 80-100℃ for 50-70s, and the product is purified with methanol after the nitration reaction is completed.

[0010] Preferably, as an improvement, in step three, the molar ratio of acetyl chloride to 2,5-dichloro-4-nitropyridine nitrogen oxide is 2~5:1, and the mixture is refluxed for 5-8 hours after the addition of acetyl chloride.

[0011] Preferably, as an improvement, in step three, the denitrification conditions for adding phosphorus trichloride are: 2-3 hours at room temperature or 5-8 hours at 30-40°C.

[0012] Preferably, as an improvement, in step four, the Lewis acid is ferric chloride, and the amount of ferric chloride added is 0.8 to 1.5% of the mass of 2,4,5-trichloropyridine.

[0013] Preferably, as an improvement, in step four, the chlorination reaction conditions are chlorination at 150~170℃ for 25~40h; or chlorination at 100-120℃ for 12-18h.

[0014] Preferably, as an improvement, in step four, the refining method is to add methanol for refining.

[0015] The principle and advantages of this scheme are as follows: In practical applications, this technical scheme addresses the problems of numerous chlorination products, complex composition, and difficult separation in the synthesis of 2,3,4,5-tetrachloropyridine in existing technologies. Utilizing the structural characteristics of 2,5-dichloropyridine, a nitrogen-oxygen group is first introduced through TS-1 catalytic oxidation to enhance molecular reactivity. Then, the mixed acid nitration conditions are controlled using a microchannel reactor to achieve selective nitration of the carbon atom at position 4, laying the foundation for subsequent substitution reactions. Acetyl chloride is specifically used to replace the nitro group at position 4, introducing a chlorine atom to form a 2,4,5-trichloropyridine structure. Due to the conjugation effect of the chlorine atom on the ring and steric hindrance, the chlorine at position 3 exhibits excellent selectivity and conversion rate. The nitrogen-oxygen group is then removed using phosphorus trichloride to avoid side reactions. The electron-withdrawing effect of the chlorine atom at positions 2 and 4 activates the reactivity of the carbon atom at position 3, achieving highly selective chlorination under Lewis acid catalysis and avoiding over-chlorination or misaligned chlorination at other sites.

[0016] During the technology development phase, the selection and optimization of catalysts in the nitrogen oxidation process was one of the key challenges and difficulties of this technical solution. The inventors had previously attempted to use catalysts such as molybdenum trioxide and copper acetylacetonate, but the results showed incomplete reactions and unsatisfactory product conversion rates. Furthermore, the inventors optimized Lewis acids, trying aluminum trichloride and copper salts, but these methods resulted in the formation of aluminum complex salts after the reaction, leading to severe emulsification of the system and environmental pollution from heavy metals such as copper salts. In contrast, this technical solution utilizes ferric chloride, which not only achieves highly efficient catalytic reactions but also, after hydrolysis, acts as an excellent flocculant, meeting environmental protection requirements and demonstrating unexpected technological advantages.

[0017] In summary, the beneficial effects of this technical solution are as follows: 1. This technical solution uses site-guided design to achieve extremely high selectivity for chlorination at the 3-position, directly obtaining high-purity products. This avoids the problem of traditional methods where the products contain multiple impurities such as 2,3,5-trichloropyridine and 2,3,5,6-tetrachloropyridine, which are difficult to purify.

[0018] 2. This technical solution does not require a complex distillation process; the product purity can be increased to 99% simply by recrystallizing methanol, which greatly reduces the difficulty and cost of post-processing.

[0019] 3. This technical solution has a high overall product yield and mild reaction conditions, further avoiding the problem of excessive by-products in high-temperature reactions. Attached Figure Description

[0020] Figure 1 This is a chromatogram of 2,4,5-trichloropyridine in Example 1 of the present invention.

[0021] Figure 2 The chromatogram is of 2,3,4,5-tetrachloropyridine prepared in Example 1 of this invention. Detailed Implementation

[0022] The following detailed description provides further details on specific embodiments, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art; the experimental methods used are all conventional methods; and the materials and reagents used are all commercially available.

[0023] Overview of the plan: A method for synthesizing 2,3,4,5-tetrachloropyridine from 2,5-dichloropyridine includes the following steps: Step 1: Preparation of 2,5-dichloropyridine nitrogen oxides: 2,5-dichloropyridine (2,5-dichloropyridine is commercially available or prepared using the method in CN118530168) is added to TS-1 catalyst and acetic acid solvent, and reacted at 60-80℃ for 2 hours. The catalyst is removed by filtration to obtain an acetic acid solution of 2,5-dichloropyridine nitrogen oxides; the mass ratio of catalyst to 2,5-dichloropyridine is 1:15~30; the mass ratio of acetic acid solution to 2,5-dichloropyridine is 1:1~4.

[0024] Step 2, Nitration reaction: The nitration reaction is carried out in a microreactor (microreactor equipment reference patent CN103183620B). A mixture of sulfuric acid and acetic acid solution of 2,5-dichloropyridine nitrogen oxides is injected at a rate of 5~8 g / min, and fuming nitric acid is injected at a rate of 0.8~1.3 g / min. The mixture is held at 80-100℃ for 50-70 s. The reaction solution is dripped into an ice-water bath to precipitate solids. After purification with 3 times the amount of methanol, 2,5-dichloro-4-nitropyridine nitrogen oxides with a purity of over 98% are obtained.

[0025] Step 3: Substitution and Denitrification Reaction: Acetyl chloride was added to the dry product of 2,5-dichloro-4-nitropyridine oxide and refluxed for 5-8 hours to substitute the 4-nitro group and obtain 2,4,5-trichloropyridine oxide; the molar ratio of acetyl chloride to 2,5-dichloro-4-nitropyridine oxide was 2~5:1; then phosphorus trichloride was added in a one-pot process, with excess phosphorus trichloride added, and the denitrification reaction was carried out at room temperature for 2-3 hours. After passing the HPLC control, ice water was added dropwise for hydrolysis, and the lower layer was separated to obtain 2,4,5-trichloropyridine.

[0026] Alternatively, after obtaining 2,4,5-trichloropyridine nitride, it is added to ice water to obtain a yellow solid. After drying, the product is dissolved in toluene, and phosphorus trichloride is added to remove oxygen atoms. The mixture is reacted at 30-40℃ for 5-8 hours, hydrolyzed, separated, dried with anhydrous sodium sulfate, and distilled from toluene to obtain 2,4,5-trichloropyridine.

[0027] Step 4, Chlorination and Purification: Lewis acid (ferric chloride) is added to 2,4,5-trichloropyridine and reacted at 150-170℃ to obtain 2,3,4,5-tetrachloropyridine. The amount of ferric chloride added is 0.8-1.5% of the mass of 2,4,5-trichloropyridine. After the reaction is complete, the mixture is washed with water and separated at 30℃ to obtain the 2,3,4,5-tetrachloropyridine product. Three times the mass of methanol is added and stirred. The mixture is cooled to -5 to 0℃ and filtered to obtain 99% pure 2,3,4,5-tetrachloropyridine.

[0028] Alternatively, 2,4,5-trichloropyridine can be added to Lewis acid and chlorinated at 100-120℃ for 12-18 hours to obtain 2,3,4,5-tetrachloropyridine; then, it can be hydrolyzed with water at 35-40℃, separated into layers, the pH of the organic phase can be adjusted to 7-8, 3 times the mass of methanol can be added, and the temperature can be lowered to 5-8℃ for recrystallization to obtain 99% pure 2,3,4,5-tetrachloropyridine.

[0029] Example 1 A method for synthesizing 2,3,4,5-tetrachloropyridine from 2,5-dichloropyridine includes the following steps: Step 1: Preparation of 2,5-dichloropyridine nitrogen oxides: 100g of 2,5-dichloropyridine (2,5-dichloropyridine is commercially available or prepared using the method in CN118530168) is added to 4g of TS-1 catalyst and acetic acid solvent, and reacted at 60-80℃ for 2h. The catalyst is removed by filtration to obtain an acetic acid solution of 2,5-dichloropyridine nitrogen oxides.

[0030] Step 2, Nitration reaction: The nitration reaction is carried out in a microreactor (microreactor equipment reference patent CN103183620B). A mixture of sulfuric acid and acetic acid solution of 2,5-dichloropyridine nitrogen oxides is injected at a rate of 7 g / min, and fuming nitric acid is injected at a rate of 1 g / min. The mixture is held at 80-100℃ for 50-70 s. The reaction solution is dripped into an ice-water bath to precipitate 140 g of solid. After purification with 3 times the amount of methanol, 2,5-dichloro-4-nitropyridine nitrogen oxides with a purity of over 98% are obtained.

[0031] Step 3: Substitution and Denitrification Reaction: 160 g of acetyl chloride was added to the dried 2,5-dichloro-4-nitropyridine oxide and refluxed for 5-8 h to substitute the nitro group at the 4-position, yielding 2,4,5-trichloropyridine oxide. Subsequently, 300 g of phosphorus trichloride was added in a one-pot reaction, and the denitrification reaction was carried out at room temperature for 2-3 h. After passing HPLC control, ice water was added dropwise for hydrolysis. The lower layer was separated to obtain 115 g of 2,4,5-trichloropyridine (chromatogram shown). Figure 1 (As shown).

[0032] Step 4, Chlorination and Purification: 1.5g of Lewis acid (ferric chloride) is added to 2,4,5-trichloropyridine and reacted at 150-170℃ to obtain 2,3,4,5-tetrachloropyridine. After the reaction is complete, the mixture is washed with water and separated at 30℃ to obtain the 2,3,4,5-tetrachloropyridine product. Three times its weight of methanol is added and stirred. The mixture is cooled to -5 to 0℃ and filtered to obtain 100g of 99% pure 2,3,4,5-tetrachloropyridine (chromatogram shown). Figure 2 (As shown).

[0033] Example 2 The difference between this embodiment and Embodiment 1 is that this embodiment is a method for synthesizing 2,3,4,5-tetrachloropyridine using 2,5-dichloropyridine. Steps one and two are the same as in Embodiment 1. Step three, substitution and deoxygenation reaction: After obtaining 2,4,5-trichloropyridine oxide, it is added to ice water to obtain a yellow solid. After drying, the product is dissolved in toluene, and phosphorus trichloride is added to remove oxygen atoms. The molar ratio of phosphorus trichloride to 2,4,5-trichloropyridine oxide is 1.2~2. The reaction is carried out at 30-40℃ for 5-8 hours, followed by hydrolysis, separation, drying with anhydrous sodium sulfate, and distillation of toluene to obtain 2,4,5-trichloropyridine.

[0034] Step 4, Chlorination and Purification: 2,4,5-Trichloropyridine is added to Lewis acid (the amount of ferric chloride added is 0.8% of the mass of 2,4,5-trichloropyridine), and chlorinated at 100-120℃ for 12-18h to obtain 2,3,4,5-tetrachloropyridine; then hydrolyzed with water at 35-40℃, separated into layers, the pH of the organic phase is adjusted to 7-8, 3 times the mass of methanol is added, and recrystallization is carried out at 5-8℃ to obtain 99% pure 2,3,4,5-tetrachloropyridine.

[0035] Comparative Example 1 The difference between this comparative example and Example 1 is that 2,3,4,5-tetrachloropyridine is prepared using a conventional process, namely, using 2-chloropyridine as a raw material and Sn-AC as a supported catalyst, and is prepared by catalytic chlorination reaction.

[0036] Comparative Example 2 The difference between this comparative example and Example 1 is that the catalyst in this comparative example is molybdenum trioxide.

[0037] Comparative Example 3 The difference between this comparative example and Example 1 is that the catalyst in this comparative example is copper acetylacetone.

[0038] Comparative Example 4 The difference between this comparative example and Example 1 is that the amount of ferric chloride added in this comparative example is 2% of the mass of 2,4,5-trichloropyridine.

[0039] Experiment 1 The purity, yield, selectivity, and conversion of the 2,3,4,5-tetrachloropyridine synthesized in the above embodiments and comparative examples were tested by gas chromatography. The conversion rate was the ratio of the amount of feedstock reduced in gas chromatography to the initial amount of feedstock; the selectivity was the ratio of the amount of target product detected in the gas chromatography results to the amount of feedstock converted. The test results are shown in Table 1 below: Table 1

[0040] The results showed that Examples 1-2 of the present invention could balance the purity, selectivity and conversion rate of the product, and the product yield was also relatively ideal. Comparative Example 1 used a traditional preparation process, which resulted in more byproducts and an unsatisfactory product yield. Adjusting the catalyst type in Comparative Examples 2-3 led to a significant decrease in the product yield, selectivity and conversion rate. In Comparative Example 4, excessive addition of ferric chloride produced a similar catalytic effect to the examples, but excessive ferric chloride led to an increase in the flocculent matter produced by the reaction, which was not conducive to production and processing.

[0041] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A method for synthesizing 2,3,4,5-tetrachloropyridine using 2,5- dichloropyridine, characterized in that, Comprising the following steps: Step one, preparation of 2,5-dichloropyridine N-oxide: 2,5-dichloropyridine as raw material, under the condition of catalyst and acetic acid, and then remove the catalyst by filtration to obtain 2,5-dichloropyridine N-oxide acetic acid solution; Step two, nitration reaction: adding sulfuric acid and nitric acid to the 2,5-dichloropyridine N-oxide acetic acid solution, and reacting to obtain 2,5-dichloro-4-nitropyridine N-oxide; Step three, denitrogenation reaction: adding acetyl chloride to 2,5-dichloro-4-nitropyridine N-oxide to replace the 4-nitro group to obtain 2,4,5-trichloropyridine N-oxide, and then adding phosphorus trichloride to obtain 2,4,5-trichloropyridine; Step four, chlorination and purification: adding Lewis acid to 2,4,5-trichloropyridine to obtain 2,3,4,5-tetrachloropyridine crude product, and purifying the crude product to obtain finished product 2,3,4,5-tetrachloropyridine.

2. The method for synthesizing 2, 3, 4, 5-tetrachloropyridine by using 2, 5-dichloropyridine according to claim 1, characterized in that: In step one, the catalyst is TS-1 catalyst, and the mass ratio of catalyst to 2,5-dichloropyridine is 1:15-30.

3. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 2, characterized in that: In step one, the mass ratio of acetic acid solvent to 2,5-dichloropyridine is 1:1-4, and the reaction condition is 60-80℃ for 2h.

4. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 3, characterized in that: In step two, the addition rate of the mixture of sulfuric acid and 2,5-dichloropyridine N-oxide acetic acid solution is 5-8g / min, and the nitric acid is fuming nitric acid, and the addition rate of fuming nitric acid is 0.8-1.3g / min.

5. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 4, characterized in that: In step two, the nitration reaction condition is 80-100℃ for 50-70s, and after the nitration reaction is completed, methanol is used for purification.

6. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 5, characterized in that: In step three, the molar ratio of acetyl chloride to 2,5-dichloro-4-nitropyridine N-oxide is 2-5:1, and after adding acetyl chloride, it is refluxed for 5-8h.

7. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 6, characterized in that: In step three, the denitrogenation condition of adding phosphorus trichloride is 2-3h at room temperature or 5-8h at 30-40℃.

8. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 6, characterized in that: In step four, the Lewis acid is ferric chloride, and the addition amount of ferric chloride is 0.8-1.5% of the mass of 2,4,5-trichloropyridine.

9. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 8, characterized in that: In step four, the chlorination reaction condition is 150-170℃ for 25-40h; or 100-120℃ for 12-18h.

10. The method for synthesizing 2,3,4,5-tetrachloropyridine by using 2,5- dichloropyridine according to claim 9, characterized in that: In step four, the purification method is to add methanol for purification.

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