Synthesis method of 2, 3-dichloropyridine

Abstract

The invention discloses a synthesis method of 2, 3-dichloropyridine, which comprises the following specific steps: carrying out a chlorination reaction by using pyridine as a starting raw material, zinc chloride as a catalyst, anhydrous dichloromethane as a solvent and N-chloro-N-methylbenzenesulfonamide as a chlorination reagent, washing an organic phase with water after the reaction is finished, drying anhydrous sodium sulfate, and distilling to obtain 2, 3-dichloropyridine. And 3, 3-dichloropyridine is obtained. According to the method, key parameters such as reaction temperature, time and reagent dosage are optimized, so that the problems of poor selectivity, more byproducts and the like in a traditional chlorination method are effectively avoided. Under the optimal condition, the separation yield of the target product is stably maintained to be 90% or above. The method is simple and convenient to operate, mild in condition, safe and reliable, is suitable for kilogram-scale reaction, can keep stable reaction efficiency in amplified production, has good industrial application potential, and provides a feasible technical scheme for large-scale preparation of 2, 3-dichloropyridine.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical technology, specifically relating to a method for synthesizing 2,3-dichloropyridine. Background Technology

[0002] 2,3-Dichloropyridine is an important fine chemical intermediate widely used in the synthesis of pesticides, pharmaceuticals, and functional materials, especially as a key intermediate for the novel insecticide chlorantraniliprole, exhibiting significant market demand. Current synthetic routes for 2,3-dichloropyridine mainly involve using pyridine, nicotinamide, 3-aminopyridine, or 2,3,6-trichloropyridine as raw materials, followed by chlorination, hydrogenation reduction, or diazotization reactions; however, all of these methods have certain limitations.

[0003] For example, Chinese patent CN110818621B discloses a synthetic method using 2-piperidinone as a raw material. This involves chlorination to generate 1,3,3-trichloro-2-piperidinone, followed by an elimination reaction to obtain 3-chloro-2-hydroxypyridine, which is then reacted with a chlorinating agent (such as thionyl chloride or phosphorus oxychloride) to produce 2,3-dichloropyridine. This method has low raw material costs and relatively simple operation, but the chlorinating agent used (such as chlorine or trichloroisocyanuric acid) is too reactive, easily generating polychlorinated byproducts, leading to insufficient selectivity. Simultaneously, the high chloride ion content in the wastewater increases the burden of post-treatment. Chinese patent CN103145609A describes a preparation method using 2,3,6-trichloropyridine as a raw material. In an alcohol solvent, in the presence of a palladium-on-carbon catalyst, selective hydrogenation-reduction dechlorination is performed using formate as a hydrogen donor to generate 2,3-dichloropyridine. However, this method requires a large amount of high-cost palladium-on-carbon catalyst (accounting for 7–9% of the raw material mass), limiting its industrial application. Furthermore, patents and related literature (such as *Shandong Chemical Industry*, 2015, No. 23, pp. 26–27) using nicotinamide as a raw material, followed by Hoffmann degradation to produce 3-aminopyridine, and then chlorination, diazotization, and Sandmeier reaction to synthesize 2,3-dichloropyridine, with an overall yield of only 50.1%–69%. Other methods also have their own shortcomings: for example, the photochlorination process proposed by Chinese patent CN101830845A requires a dedicated photochemical reactor, which is costly and limited by the transparency of the reaction system; the metal-catalyzed chlorination method reported by patent US2012019080A1 improves some selectivity, but still requires the use of highly toxic chlorine gas and the catalyst is expensive; and the electrochemical chlorination method is difficult to scale up due to electrode corrosion and complex processes.

[0004] In summary, existing technologies have significant shortcomings in terms of reaction selectivity, raw material cost, process safety, environmental friendliness, and industrial feasibility. In particular, traditional chlorination methods, represented by chlorine gas, have low yields in kilogram-scale production, severely hindering their widespread application. Therefore, a green and efficient synthesis process for 2,3-dichloropyridine urgently needs to be proposed. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 2,3-dichloropyridine. This method employs an innovative chlorinating reagent, N-chloro-N-methylbenzenesulfonamide (NCMB), to achieve highly selective chlorination at room temperature or low temperature. The reaction process is mild, produces minimal waste, and is suitable for kilogram-scale production.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0007] This invention provides a method for synthesizing 2,3-dichloropyridine, the specific steps of which are as follows:

[0008] Using pyridine as the starting material, zinc chloride as the catalyst, anhydrous dichloromethane as the solvent, and N-chloro-N-methylbenzenesulfonamide as the chlorinating agent, a chlorination reaction was carried out. After the reaction was completed, the organic phase was washed with water, dried with anhydrous sodium sulfate, and distilled to obtain 2,3-dichloropyridine.

[0009] Preferably, the preparation process of the N-chloro-N-methylbenzenesulfonamide is as follows:

[0010] N-methylbenzenesulfonamide was dissolved in dichloromethane and sodium bicarbonate was added. Under ice bath conditions, tert-butyl hypochlorite was added dropwise. After the reaction was completed, the solid was removed by filtration, the organic phase was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain N-chloro-N-methylbenzenesulfonamide.

[0011] Preferably, the molar ratio of N-methylbenzenesulfonamide, sodium bicarbonate, and tert-butyl hypochlorite is 1:1.2~1.5:1~1.5.

[0012] Preferably, the ice bath temperature is 0-5℃, the dropping time is 30-35 minutes, and the reaction time is 1-1.5 hours.

[0013] Preferably, the amount of solvent is 1 L per kilogram of pyridine.

[0014] Preferably, the zinc chloride is 0.1 to 0.15 times the mass of 2,3-dichloropyridine.

[0015] Preferably, the mass of the N-chloro-N-methylbenzenesulfonamide is 2 to 3 times that of pyridine.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] 1. This invention uses a novel chlorination reagent, N-chloro-N-methylbenzenesulfonamide (NCMB), to replace the traditional chlorine source. It can achieve highly selective chlorination of the pyridine ring at room temperature or low temperature. The reaction conditions are mild, the safety is high, and there are few by-products. It avoids the insufficient selectivity and environmental pollution problems existing in the traditional chlorination process and has good green chemical characteristics.

[0018] 2. The process of this invention is simple, the operating conditions are controllable, and the yield of the product 2,3-dichloropyridine is high and suitable for kilogram-scale production. Furthermore, this invention also provides a simple method for preparing N-chloro-N-methylbenzenesulfonamide (NCMB), further reducing reagent costs and improving the economics and industrial application potential of the process. Attached Figure Description

[0019] Figure 1 This is a diagram showing the results of the chlorination reactions of pyridine with different chlorination reagents and catalysts according to the present invention. Detailed Implementation

[0020] 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 for illustration and explanation only and are not intended to limit the present invention.

[0021] Example 1: Production process steps of N-chloro-N-methylbenzenesulfonamide (NCMB).

[0022] N-methylbenzenesulfonamide (0.1 mol) was dissolved in 100 mL of anhydrous dichloromethane, and sodium bicarbonate (0.12 mol) was added as an acid binder; (2) tert-butyl hypochlorite (t-BuOCl, 0.11 mol) was slowly added dropwise at 0-5 °C for about 30 minutes; (3) after the addition was complete, the mixture was stirred for 1 hour. After the reaction was completed, the solid was removed by filtration, the organic phase was washed with water, and dried with anhydrous sodium sulfate; (4) the solvent was evaporated to obtain N-chloro-N-methylbenzenesulfonamide (NCMB) with a yield of 95%. The preparation process of N-chloro-N-methylbenzenesulfonamide (NCMB) is safe and simple, the raw materials are readily available, and there are few by-products, making it suitable for industrial production.

[0023] Example 2: Laboratory-scale production process of 2,3-dichloropyridine (NCMB dosage 2 equivalents, ZnCl2 dosage 0.1 equivalents, reaction time 3 hours).

[0024] In a 50 mL round-bottom flask, pyridine (10 g), zinc chloride (1 g), and 10 mL of anhydrous dichloromethane were added sequentially. N-chloro-N-methylbenzenesulfonamide (NCMB) (20 g) was slowly added dropwise over 1 hour in an ice bath (0–5 °C). After the addition was complete, the mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, the organic phase was washed with water, dried over anhydrous sodium sulfate, and distilled to obtain 2,3-dichloropyridine with a yield of 92% and a purity of 99.1% (purity determined by HPLC).

[0025] Example 3: Laboratory-scale production process of 2,3-dichloropyridine (NCMB dosage 2.5 equivalents, ZnCl2 dosage 0.125 equivalents, reaction time 4 hours).

[0026] In a 50 mL round-bottom flask, pyridine (10 g), zinc chloride (1.25 g), and 10 mL of anhydrous dichloromethane were added sequentially. N-chloro-N-methylbenzenesulfonamide (NCMB) (25 g) was slowly added dropwise over 1 hour in an ice bath (0–5 °C). After the addition was complete, the mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, the organic phase was washed with water, dried over anhydrous sodium sulfate, and distilled to obtain 2,3-dichloropyridine with a yield of 95% and a purity of 99.4% (purity determined by HPLC).

[0027] Example 4: Laboratory-scale production process of 2,3-dichloropyridine (NCMB dosage 3 equivalents, ZnCl2 dosage 0.15 equivalents, reaction time 5 hours).

[0028] In a 50 mL round-bottom flask, pyridine (10 g), zinc chloride (1.5 g), and 10 mL of anhydrous dichloromethane were added sequentially. N-chloro-N-methylbenzenesulfonamide (NCMB) (30 g) was slowly added dropwise over 1 hour in an ice bath (0–5 °C). After the addition was complete, the mixture was heated to room temperature and stirred for 5 hours. After the reaction was complete, the organic phase was washed with water, dried over anhydrous sodium sulfate, and distilled to obtain 2,3-dichloropyridine with a yield of 93% and a purity of 99.2% (purity determined by HPLC).

[0029] Example 5: Process steps for the production of 2,3-dichloropyridine at a kilogram scale (optimized based on intermediate values).

[0030] In a 2L round-bottom flask, pyridine (1 kg), zinc chloride (125 g), and 1 L of anhydrous dichloromethane were added sequentially. Under ice bath conditions (0–5°C), N-chloro-N-methylbenzenesulfonamide (NCMB) (2.5 kg) was slowly added dropwise in batches over 1 hour. After the addition was complete, the mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, the organic phase was washed with water, dried over anhydrous sodium sulfate, and distilled to obtain 2,3-dichloropyridine with a yield of 92% and a purity of 99.0% (purity determined by HPLC).

[0031] Comparative Example 1: Traditional chlorination method, highlighting the mild conditions of the present invention.

[0032] 10 g of pyridine was dissolved in chloroform, and excess chlorine gas (flow rate controlled at 0.05 L / min) was introduced at 0°C. A small amount of FeCl3 was added as a catalyst, and the reaction temperature was gradually increased to 80°C with continuous stirring for 8 hours. After the reaction, the mixture was washed with water, purified by distillation, and yielded a mixture of 2,3-dichloropyridine (containing polychlorinated byproducts). The yield was only 68%, and the purity was 87% (HPLC detection). A large amount of HCl waste gas and byproducts were generated, requiring an additional waste gas treatment system. This method involves high temperature (80°C), long reaction time (8 hours), numerous byproducts, and poor selectivity. Compared with the mild conditions of this invention (droplet addition at 0-5°C followed by room temperature, 3-5 hours, no HCl waste gas), it is less efficient and has a heavier environmental burden.

[0033] Comparative Example 2: Traditional NCS chlorination method, highlighting the mild conditions of the present invention.

[0034] 10 g of pyridine was dissolved in acetonitrile, and 30 g of N-chlorosuccinimide (NCS) was added as a chlorinating agent. Without a catalyst, the mixture was heated to 90 °C and refluxed for 6 hours. After the reaction, the mixture was filtered and distilled to obtain 2,3-dichloropyridine. The yield was 75%, and the purity was 91% (HPLC detection). Succinimide byproducts and organic waste liquid were produced. This method requires high temperature (90 °C) and a long reaction time (6 hours). Compared with this invention, the conditions are harsher, energy consumption is higher, and selectivity is generally lower.

[0035] Comparative Example 3: Chlorination reaction of pyridine with different chlorination reagents and catalysts.

[0036] The rest is the same as in Example 3, except for the chlorination reagent and catalyst. Finally, the reaction products were qualitatively and quantitatively analyzed by gas chromatography. Specific experimental data and reaction conditions are shown in Table 1 and... Figure 1As shown in the figure. Experimental results show that different chlorination reagents have significant differences in reactivity, selectivity and yield. N-chloro-N-methylbenzenesulfonamide (NCMB) as a chlorination reagent exhibits excellent chemoselectivity and regioselectivity in the chlorination reaction of pyridine. This reaction not only shows high atom economy, but also the product separation and purification operation is simple.

[0037] Table 1: Results of chlorination reactions of pyridine with different chlorination reagents and catalysts.

[0038]

[0039] This invention uses pyridine as a raw material and employs a novel chlorination reagent, N-chloro-N-methylbenzenesulfonamide (NCMB), to replace traditional chlorine sources (such as liquid chlorine, chlorine gas, or NCS) to achieve regioselective chlorination of the 2- and 3-positions of the pyridine ring under mild conditions. This process not only boasts high reaction selectivity and a stable yield exceeding 90%, but also avoids the formation of polychlorinated byproducts, exhibiting significant advantages in safety, economy, and environmental friendliness. Overall, this method is simple to operate, environmentally friendly, and possesses excellent potential for industrial application, aligning with the development concept of green chemistry in modern organic synthesis.

[0040] Finally, it should be noted that the above descriptions 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 synthesizing 2,3-dichloropyridine, characterized in that, The specific steps are as follows: Using pyridine as the starting material, zinc chloride as the catalyst, anhydrous dichloromethane as the solvent, and N-chloro-N-methylbenzenesulfonamide as the chlorinating agent, a chlorination reaction was carried out. After the reaction was completed, the organic phase was washed with water, dried with anhydrous sodium sulfate, and distilled to obtain 2,3-dichloropyridine.

2. The method for synthesizing 2,3-dichloropyridine according to claim 1, characterized in that, The preparation process of the N-chloro-N-methylbenzenesulfonamide is as follows: N-methylbenzenesulfonamide was dissolved in dichloromethane and sodium bicarbonate was added. Under ice bath conditions, tert-butyl hypochlorite was added dropwise. After the reaction was completed, the solid was removed by filtration, the organic phase was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain N-chloro-N-methylbenzenesulfonamide.

3. The method for synthesizing 2,3-dichloropyridine according to claim 2, characterized in that, The molar ratio of N-methylbenzenesulfonamide, sodium bicarbonate, and tert-butyl hypochlorite is 1:1.2~1.5:1~1.

5.

4. The method for synthesizing 2,3-dichloropyridine according to claim 2, characterized in that, The ice bath temperature is 0-5℃, the dropping time is 30-35 minutes, and the reaction time is 1-1.5 hours.

5. The method for synthesizing 2,3-dichloropyridine according to claim 1, characterized in that, The amount of solvent is 1 L per kilogram of pyridine.

6. The method for synthesizing 2,3-dichloropyridine according to claim 1, characterized in that, The zinc chloride is 0.1 to 0.15 times the mass of 2,3-dichloropyridine.

7. The method for synthesizing 2,3-dichloropyridine according to claim 1, characterized in that, The mass of the N-chloro-N-methylbenzenesulfonamide is 2 to 3 times that of pyridine.

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