Preparation method and application of 2-chloro-5-chloromethylpyridine

Abstract

The invention relates to the technical field of organic synthesis, and discloses a preparation method and application of 2-chloro-5-chloromethylpyridine. The method comprises the following steps: mixing 2-chloro-2-chloromethyl-4-cyanobutyraldehyde with a chlorinating agent, carrying out a first-stage reaction, and then reducing the temperature of a reaction system to 65-99% of the temperature of the first-stage reaction, and carrying out a second-stage reaction. The preparation method can improve the yield of the target product 2-chloro-5-chloromethylpyridine, also has the beneficial effects of low cost and small pollution, and can meet the production requirements of the chemical industry.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method and application of 2-chloro-5-chloromethylpyridine. Background Art

[0002] 2-Chloro-5-chloromethylpyridine can be used to produce pesticide intermediates such as imidacloprid, acetamiprid, nitenpyram, and thiacloprid, and is also an intermediate for some pharmaceutical syntheses. The demand in China is more than 30,000 tons, indicating its crucial role in the synthesis of neonicotinoid insecticides and pharmaceuticals.

[0003] The traditional process uses 2-chloro-2-chloromethyl-4-cyanobutyraldehyde as the raw material and phosphorus oxychloride as the chlorinating agent to carry out a cyclization reaction under certain conditions, and then obtains the finished product of 2-chloro-5-chloromethylpyridine through processes such as hydrolysis, alkali neutralization, and rectification separation. This process has the advantages of easily available raw materials, low production cost, and high product purity, but also has the disadvantages of a large amount of three wastes and difficult treatment of wastewater.

[0004] CN109574918B discloses a method for continuously preparing 2-chloro-5-chloromethylpyridine using a microchannel reactor. This method uses 2-chloro-5-methylpyridine and chlorine as raw materials and reacts using a microchannel reactor, having the advantages of good mass and heat transfer, high productivity and purity of the product, and less three wastes. However, the raw material 2-chloro-5-methylpyridine has a high price and no cost advantage.

[0005] CN102796039B discloses a method for continuously preparing 2-chloro-5-chloromethylpyridine in a microchannel. This method uses 2-chloro-5-methylpyridine as the raw material, sulfonyl chloride as the chlorinating reagent, and azobisisobutyronitrile as the initiator, and carries out a chlorination reaction at 80-130 °C to obtain 2-chloro-5-chloromethylpyridine. This invention has the advantages of short reaction time, simple production process, and easy industrial production. However, this reaction uses sulfonyl chloride and azobisisobutyronitrile as reaction raw materials, which will produce some sulfur- and nitrogen-containing wastes and are difficult to treat.

[0006] CN107628989B discloses a synthesis method of 2-chloro-5-chloromethylpyridine. After the raw material 3-methylpyridine is vaporized, it is mixed with chlorine using nitrogen as the carrier gas and then introduced into a tubular reactor filled with a supported palladium chloride catalyst to carry out a chlorination reaction to obtain 2-chloro-5-chloromethylpyridine in one step. This process has the advantages of fast reaction rate, simple process flow, and less generation of three wastes. However, the reaction yield of this method is only about 50%, and still needs to be further optimized. At the same time, a noble metal catalyst is used and needs to be recycled to reduce the production cost.

[0007] At present, no method with high yield, simple and safe operation, low cost and little pollution has been found for the synthesis of 2-chloro-5-methylpyridine. Therefore, those skilled in the art urgently need to develop a more effective process for synthesizing 2-chloro-5-chloromethylpyridine to meet the production needs of the chemical industry. Summary of the Invention

[0008] The object of the present invention is to overcome the problem in the prior art that there is a lack of a method for synthesizing 2-chloro-5-methylpyridine with high yield, simple and safe operation, low cost and little pollution, and to provide a method for preparing 2-chloro-5-chloromethylpyridine and its application.

[0009] To achieve the above object, on the one hand, the present invention provides a method for preparing 2-chloro-5-chloromethylpyridine, which is characterized in that the method comprises: mixing 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde with a chlorinating agent and carrying out a first-stage reaction, and then reducing the temperature of the reaction system to 65-99% of the temperature of the first-stage reaction to carry out a second-stage reaction.

[0010] On the second hand, the present invention provides the application of the method described in the first hand of the present invention in improving at least one of the raw material conversion rate, the yield of the target product, the safety and the stability in the method for preparing 2-chloro-5-chloromethylpyridine.

[0011] Through the above technical solutions, the preparation method provided by the present invention can improve the raw material conversion rate and the yield of the target product 2-chloro-5-chloromethylpyridine, and at the same time has the beneficial effects of low cost, little pollution, safety and stability, and can meet the production needs of the chemical industry. Detailed Embodiments

[0012] As described above, on the one hand, the present invention provides a method for preparing 2-chloro-5-chloromethylpyridine, which is characterized in that the method comprises: mixing 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde (hereinafter referred to as CCC) with a chlorinating agent and carrying out a first-stage reaction, and then reducing the temperature of the reaction system to 65-99% of the temperature of the first-stage reaction to carry out a second-stage reaction.

[0013] In some embodiments of the present invention, preferably, the chlorinating agent is selected from at least one of trichloromethyl chloroformate (solid phosgene), trichloromethyl chloroformate (diphosgene) and oxalyl chloride, preferably selected from trichloromethyl chloroformate (solid phosgene) and / or trichloromethyl chloroformate (diphosgene), and more preferably trichloromethyl chloroformate (solid phosgene).

[0014] In some embodiments of the present invention, preferably, the mass ratio of 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde to the chlorinating agent is 1-4:1, preferably 1-2:1.

[0015] In some embodiments of the present invention, preferably, the temperature of the second-stage reaction is 95-99% of the temperature of the first-stage reaction.

[0016] In some embodiments of the present invention, preferably, the temperature of the first-stage reaction is 80-120°C, preferably 100-115°C; the time is 0.5-5 h, preferably 2-3 h.

[0017] In some embodiments of the present invention, preferably, the time of the second-stage reaction is 0.5-5 h, preferably 2-3 h.

[0018] In some embodiments of the present invention, preferably, the method is carried out in the presence of a solvent.

[0019] In some embodiments of the present invention, preferably, the organic solvent is selected from organic solvents.

[0020] In some embodiments of the present invention, preferably, the solvent is selected from aromatic compounds, preferably toluene.

[0021] In some embodiments of the present invention, preferably, the 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde and the chlorinating agent participate in the reaction in the form of solutions in the organic solvent respectively.

[0022] In some embodiments of the present invention, preferably, in the solution of 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde, the concentration of 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde is 20-50 wt%, preferably 40-45 wt%.

[0023] In some embodiments of the present invention, preferably, in the solution of the chlorinating agent, the concentration of the chlorinating agent is 20-50 wt%, preferably 40-45 wt%.

[0024] In the present invention, the method can be carried out by a continuous synthesis process, and the process can be carried out by a continuous reaction device, such as a two-stage kettle continuous device.

[0025] In the present invention, the continuous reaction device further includes a material circulation device, such as a condensation reflux device.

[0026] In the present invention, the continuous reaction device further includes a separation and purification device, such as a layering kettle.

[0027] In the present invention, the continuous reaction device further includes a material receiver, such as a crude product receiving tank and a tar receiving kettle.

[0028] In the present invention, there is no particular limitation on the capacities of the primary reactor and the secondary reactor in the two-stage continuous kettle-type device, and those skilled in the art can make appropriate adjustments according to the actual production situation.

[0029] In the present invention, compared with a reactor with a volume of 2000 L, the feeding rate of 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde in the primary reactor is 435 - 440 kg / h.

[0030] In the present invention, compared with a reactor with a volume of 2000 L, the feeding rate of the chlorinating agent in the primary reactor is 260 - 270 kg / h.

[0031] In the present invention, the reaction temperature of the primary reactor is the same as the temperature of the first-stage reaction, and the reaction temperature of the secondary reactor is the same as the temperature of the second-stage reaction.

[0032] According to a particularly preferred embodiment of the present invention, the method includes: under the condition of 105 - 108 °C, the weight ratio of the CCC toluene solution to the solid phosgene toluene solution is 1.4 - 1.8:1 for the first-stage reaction for 2.5 - 3.5 h, and then the temperature of the reaction system is reduced to 96 - 99% of the temperature of the first-stage reaction for the second-stage reaction for 2.5 - 3.5 h, which can greatly improve the yield of the target product 5-norbornene-2-carbaldehyde.

[0033] The second aspect of the present invention provides the application of the method according to one aspect of the present invention in improving at least one of the raw material conversion rate, target product yield, safety and stability in the preparation method of 2-chloro-5-(chloromethyl)pyridine.

[0034] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, all raw materials are ordinary commercially available products.

[0035] Conditions for GC analysis:

[0036] Agilent 7820A, equipped with a hydrogen flame ionization detector and a capillary injection system,

[0037] Chromatographic column: AC1 capillary gas chromatographic column (30×0.32×0.25);

[0038] Column oven temperature: programmed temperature rise of 50 °C for 3 min;

[0039] 20 °C / min to 100 °C for 4 min;

[0040] 40 °C / min to 250 °C for 10 min;

[0041] Vaporization chamber temperature: 200 °C; Detection chamber temperature: 300 °C;

[0042] Gas flow rate (ml / min): Hydrogen 30, Air 300

[0043] Make-up gas flow: 25 ml / min; Column flow rate: 1.28 ml / min;

[0044] Split ratio: 20:1;

[0045] Stop time: 12 min; Injection volume: 0.2 μl.

[0046] Example 1

[0047] Open the valves of the overflow pipes of the first-stage synthesis reactor (volume 2 m 3 ) and the second-stage reactor (volume 2 m 3 ). Feed the CCC toluene solution in the CCC (concentration 41.2 wt%) toluene transfer tank and the phosgene toluene solution in the phosgene (concentration 43.2 wt%) toluene transfer tank. Set the feed rate of the CCC toluene solution at 437 kg / h and the feed rate of the phosgene toluene solution at 265 kg / h. The gas-phase material in the first-stage reactor is condensed and refluxed by the first-stage condenser, and the tail gas enters the second-stage reactor. After 2.8 h, the liquid-phase material automatically overflows from the first-stage reactor to the second-stage reactor. The gas-phase material in the second-stage reactor is condensed and refluxed back to the reactor by the second-stage condenser. The reaction temperature of the first-stage reactor is 108 °C, and the reaction temperature of the second-stage reactor is 105 °C. After 2.8 h, when the liquid level in the second-stage reactor reaches the overflow port, the material overflows to the automatic stratification tank. The upper crude product layer is separated into the synthetic crude product receiving tank through the synthetic crude product cooler, and the lower dark tar layer is separated into the stratified tar receiving tank. When the second-stage reactor overflows to the stratification tank through the overflow pipe, a sample is taken from the second overflow pipe for GC analysis, and the CCC content is 0.3%. Continuous feeding for 24 h, 3408 kg of 2-chloro-5-chloromethylpyridine with a content of 97% is obtained from the treatment of the crude product layer, and the yield based on CCC is 85%.

[0048] Example 2

[0049] Open the first-stage synthesis reactor (volume 10 m 3 ) and the second-stage reactor (volume 10 m 3)Overflow pipe valve, which transfers the CCC toluene liquid in the CCC (concentration 41.2 wt%) toluene intermediate tank and the solid light (concentration 43.2 wt%) toluene liquid in the solid light toluene intermediate tank. Set the feed rate of CCC toluene liquid at 2185 kg / h and the feed rate of solid light toluene liquid at 1325 kg / h. The gas-phase material in the first-stage kettle is condensed and refluxed through the first-stage condenser, and the tail gas enters the second-stage kettle. After 2.8 h, the liquid-phase material automatically overflows from the first-stage kettle to the second-stage kettle. The gas-phase material in the second-stage kettle is condensed and refluxed back to the kettle through the second-stage condenser. The reaction temperature of the first-stage reaction kettle is 108 °C, and the reaction temperature of the second-stage reaction kettle is 105 °C; after 2.8 h, when the liquid level in the second-stage kettle reaches the overflow port, the material overflows to the automatic stratification kettle. The upper layer of crude product is separated into the synthetic crude product receiving tank through the synthetic crude product cooler, and the lower layer of dark tar is separated into the stratified tar receiving kettle. When the second-stage kettle overflows to the stratification kettle through the overflow pipeline, a sample is taken from the second overflow pipeline for GC analysis, and the CCC content is 0.3%. After continuous feeding for 24 h, 16840 kg of 2-chloro-5-chloromethylpyridine with a content of 97% is obtained from the crude product layer, and the yield based on CCC is 84%.

[0050] Example 3

[0051] Open the overflow pipe valves of the first-stage synthesis reaction kettle (volume 2 m 3 ) and the second-stage reaction kettle (volume 2 m 3 ) to transfer the CCC toluene liquid in the CCC (concentration 41.2 wt%) toluene intermediate tank and the solid light (concentration 43.2 wt%) toluene liquid in the solid light toluene intermediate tank. Set the feed rate of CCC toluene liquid at 437 kg / h and the feed rate of solid light toluene liquid at 265 kg / h. The gas-phase material in the first-stage kettle is condensed and refluxed through the first-stage condenser, and the tail gas enters the second-stage kettle. After 2.8 h, the liquid-phase material automatically overflows from the first-stage kettle to the second-stage kettle. The gas-phase material in the second-stage kettle is condensed and refluxed back to the kettle through the second-stage condenser. The reaction temperature of the first-stage reaction kettle is 100 °C, and the reaction temperature of the second-stage reaction kettle is 95 °C; after 2.8 h, when the liquid level in the second-stage kettle reaches the overflow port, the material overflows to the automatic stratification kettle. The upper layer of crude product is separated into the synthetic crude product receiving tank through the synthetic crude product cooler, and the lower layer of dark tar is separated into the stratified tar receiving kettle. When the second-stage kettle overflows to the stratification kettle through the overflow pipeline, a sample is taken from the second overflow pipeline for GC analysis, and the CCC content is 2.3%. After continuous feeding for 24 h, 3226 kg of 2-chloro-5-chloromethylpyridine with a content of 97% is obtained from the crude product layer, and the yield based on CCC is 80%.

[0052] Example 4

[0053] Open the first-stage synthesis reaction kettle (volume 2 m 3 ) and the second-stage reaction kettle (volume 2 m 3) The overflow pipe valve pumps the CCC toluene solution in the CCC toluene transfer tank (with a concentration of 41.2 wt%) and the solid light toluene solution in the solid light toluene transfer tank (with a concentration of 43.2 wt%) into the first-stage reactor continuously in a certain proportion. Set the feed rate of the CCC toluene solution (with a concentration of 41.2 wt%) at 437 kg / h and the feed rate of the solid light toluene solution at 265 kg / h. The gas-phase material in the first-stage reactor is condensed and refluxed through the first-stage condenser, and the tail gas enters the second-stage reactor. After 2.8 h, the liquid-phase material automatically overflows from the first-stage reactor to the second-stage reactor. The gas-phase material in the second-stage reactor is condensed and refluxed back to the reactor through the second-stage condenser. The reaction temperature of the first-stage reactor is 95 °C, and the reaction temperature of the second-stage reactor is 90 °C; after 2.8 h, when the liquid level in the second-stage reactor reaches the overflow port, the material overflows to the automatic stratification kettle. The upper crude product layer is separated into the synthetic crude product receiving tank through the synthetic crude product cooler, and the lower dark tar layer is separated into the stratified tar receiving kettle. When the second-stage reactor overflows to the stratification kettle through the overflow pipeline, a sample is taken from the second overflow pipeline for GC analysis, and the CCC content is 2.5%. After continuous feeding for 24 h, 3328 kg of 2-chloro-5-chloromethylpyridine with a content of 97% is obtained from the treatment of the crude product layer, and the yield based on CCC is 83%.

[0054] Example 5

[0055] Open the overflow pipe valves of the first-stage synthesis reactor (volume 2 m 3 ) and the second-stage reactor (volume 2 m 3 ) to pump the CCC toluene solution in the CCC toluene transfer tank (with a concentration of 41.2 wt%) and the solid light toluene solution in the solid light toluene transfer tank (with a concentration of 43.2 wt%) into the first-stage reactor continuously in a certain proportion. Set the feed rate of the CCC toluene solution at 530 kg / h and the feed rate of the solid light toluene solution at 265 kg / h. The gas-phase material in the first-stage reactor is condensed and refluxed through the first-stage condenser, and the tail gas enters the second-stage reactor. After 2.48 h, the liquid-phase material automatically overflows from the first-stage reactor to the second-stage reactor. The gas-phase material in the second-stage reactor is condensed and refluxed back to the reactor through the second-stage condenser. The reaction temperature of the first-stage reactor is 108 °C, and the reaction temperature of the second-stage reactor is 105 °C; after 2.48 h, when the liquid level in the second-stage reactor reaches the overflow port, the material overflows to the automatic stratification kettle. The upper crude product layer is separated into the synthetic crude product receiving tank through the synthetic crude product cooler, and the lower dark tar layer is separated into the stratified tar receiving kettle. When the second-stage reactor overflows to the stratification kettle through the overflow pipeline, a sample is taken from the second overflow pipeline for GC analysis, and the CCC content is 2.5%. After continuous feeding for 24 h, 2906 kg of 2-chloro-5-chloromethylpyridine with a content of 95% is obtained from the treatment of the crude product layer, and the yield based on CCC is 71%.

[0056] Example 6

[0057] It was carried out according to the method of Example 1, except that the temperature of the secondary reactor was 75 °C. When the secondary reactor overflowed to the stratification tank through the overflow pipeline, a sample was taken from the secondary overflow pipeline for GC analysis, and the CCC content was 2.5%. After continuous feeding for 24 h, 2,5-dichloromethylpyridine 2647 kg with a content of 97% was obtained after treatment of the crude product layer, and the yield based on CCC was 66%.

[0058] Example 7

[0059] It was carried out according to the method of Example 1, except that the feeding rate of the CCC toluene solution was set at 265 kg / h and the feeding rate of the triphosgene toluene solution was set at 350 kg / h. When the secondary reactor overflowed to the stratification tank through the overflow pipeline, a sample was taken from the secondary overflow pipeline for GC analysis, and the CCC content was 0%. After continuous feeding for 24 h, 2,5-dichloromethylpyridine 2742 kg with a content of 97% was obtained after treatment of the crude product layer, and the yield based on CCC was 68.4%.

[0060] Example 8

[0061] It was carried out according to the method of Example 1, except that the feeding rate of the CCC toluene solution was set at 437 kg / h and the feeding rate of the triphosgene toluene solution was set at 212 kg / h. When the secondary reactor overflowed to the stratification tank through the overflow pipeline, a sample was taken from the secondary overflow pipeline for GC analysis, and the CCC content was 3.0%. After continuous feeding for 24 h, 2,5-dichloromethylpyridine 2622 kg with a content of 97% was obtained after treatment of the crude product layer, and the yield based on CCC was 65.4%.

[0062] Comparative Example 1

[0063] It was carried out according to the method of Example 1, except that the temperatures of both the primary reactor and the secondary reactor were 120 °C. When the secondary reactor overflowed to the stratification tank through the overflow pipeline, a sample was taken from the secondary overflow pipeline for GC analysis, and the CCC content was 0%. After continuous feeding for 24 h, 2,5-dichloromethylpyridine 1965 kg with a content of 97% was obtained after treatment of the crude product layer, and the yield based on CCC was 49%.

[0064] Comparative Example 2

[0065] It was carried out according to the method of Example 1, except that the temperature of the primary reactor was 75 °C and the temperature of the secondary reactor was 108 °C. When the secondary reactor overflowed to the stratification tank through the overflow pipeline, a sample was taken from the secondary overflow pipeline for GC analysis, and the CCC content was 2.2%. After continuous feeding for 24 h, 2,5-dichloromethylpyridine 1885 kg with a content of 96% was obtained after treatment of the crude product layer, and the yield based on CCC was 47%.

[0066] From the results of the above embodiments and comparative examples, it can be seen that compared with the comparative examples, the embodiments adopting the technical solution of the present invention can improve the yield of the target product 2-chloro-5-chloromethylpyridine, and at the same time have the beneficial effects of low cost and small pollution. At the same time, compared with the prior art, the present invention has the advantages of easily available raw materials, low production cost, high product purity, small amount of three wastes, no generation of sulfur-containing and nitrogen-containing wastes, and easy treatment of wastewater. Moreover, the present invention adopts a continuous reaction process, making the safety and stability of the method relatively high.

[0067] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. A preparation method of 2-chloro-5-chloromethylpyridine, characterized in that, The method comprises: mixing 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde with a chlorinating agent for a first-stage reaction, and then reducing the temperature of the reaction system to 65-99% of the temperature of the first-stage reaction for a second-stage reaction.

2. The method according to claim 1, wherein, The chlorinating agent is selected from at least one of trichloromethyl carbonate, trichloromethyl chloroformate, and oxalyl chloride, preferably selected from trichloromethyl carbonate and / or trichloromethyl chloroformate, and more preferably trichloromethyl carbonate.

3. The method according to claim 1 or 2, wherein The mass ratio of the 2-chloro-2-(chloromethyl)-4-cyanobutyraldehyde to the chlorinating agent is 1-4:1, preferably 1-2:

1.

4. The method according to any one of claims 1 to 3, wherein The temperature of the second-stage reaction is 95-99% of the temperature of the first-stage reaction.

5. The method according to any one of claims 1-4, wherein, The temperature of the first-stage reaction is 80-120 °C, preferably 100-115 °C; the time is 0.5-5 h, preferably 2-3 h.

6. The method according to any one of claims 1-5, wherein, The time of the second-stage reaction is 0.5-5 h, preferably 2-3 h.

7. According to the method as claimed in any one of claims 1-6, wherein The method is carried out in the presence of a solvent.

8. The method according to claim 7, wherein, The solvent is selected from organic solvents.

9. The method according to claim 8, wherein The organic solvent is selected from aromatic compounds, preferably toluene.

10. Use of the method according to any one of claims 1-9 in improving at least one of the raw material conversion rate, target product yield, safety, and stability in the preparation method of 2-chloro-5-(chloromethyl)pyridine.