Synthesis device and synthesis method of 2-chloronicotinic acid

Abstract

The invention relates to the technical field of intermediates of pesticides and medicines, in particular to a synthesis device and a synthesis method of 2-chloronicotinic acid. Comprising a first feeding tank (1), a first liquid storage tank (2), a first material pump (3), an oxygen inlet (4), a first tubular reactor (5), a second material pump (6), a third liquid storage tank (7), a third material pump (8), a second feeding tank (9), a second liquid storage tank (10), a fourth material pump (11), a second tubular reactor (12), a fifth material pump (13), a hydrolysis tank (14), an acidification crystallization tank (15), a sixth material pump (16) and a centrifugal device (17). The continuous synthesis method adopted by the invention is simple and convenient to operate, the high synthesis yield up to 95% can be obtained by adjusting the material ratio in each liquid storage tank and the flow speed of each material pump, and the yield is stable.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide and pharmaceutical intermediates, and in particular to a synthesis device and a synthesis method of 2-chloronicotinic acid. Background Art

[0002] 2-Chloronicotinic acid, chemically known as 2-chloro-3-pyridinecarboxylic acid, has become a key intermediate in the pesticide and pharmaceutical fields due to its unique chemical properties and wide range of applications. In pharmaceutical applications, it serves as a building block for the synthesis of numerous important drugs, such as nevirapine, pranoprofen, nicotinic acid, mirtazapine, and niflumic acid. In the pesticide field, 2-chloronicotinic acid is used to synthesize highly effective and safe herbicides, such as nicosulfuron, and fungicides such as boscalid. While the application of 2-chloronicotinic acid in the pharmaceutical and pesticide fields is of great significance, it also faces challenges in environmental protection and cost control. Achieving cleaner and more efficient production through continuous technological innovation and process optimization is an important direction for future research.

[0003] Chinese invention patent application CN117143013A discloses a method for synthesizing 2-chloronicotinic acid, comprising: chlorinating 2-hydroxynicotinaldehyde with a chlorinating agent under the catalytic action of a phosphine oxide catalyst to produce 2-chloronicotinaldehyde; and oxidizing 2-chloronicotinaldehyde with a base and introducing air under the catalytic action of a palladium-carbon catalyst to produce 2-chloronicotinic acid. Although this method uses a phosphorus-free chlorinating agent, it still requires the use of a phosphine oxide catalyst, which still produces phosphorus-containing wastes. Furthermore, the oxidation reaction requires a palladium-carbon catalyst, which is expensive, requires acidification after oxidation, and is complex to operate, making it unsuitable for industrialization and resulting in a low yield. Summary of the Invention

[0004] The first aspect of the present invention provides a synthesis device for 2-chloronicotinic acid, comprising: a first feeding tank (1), a first liquid storage tank (2), a first material pump (3), an oxygen inlet (4), a first tubular reactor (5), a second material pump (6), a third liquid storage tank (7), a third material pump (8), a second feeding tank (9), a second liquid storage tank (10), a fourth material pump (11), a second tubular reactor (12), a fifth material pump (13), a hydrolysis tank (14), an acidification crystallization tank (15), a sixth material pump (16), and a centrifugal device (17); the first feeding tank (1), The first liquid storage tank (2), the first material pump (3), the first tubular reactor (5), the second material pump (6), the third liquid storage tank (7), the third material pump (8), the second tubular reactor (12), the fifth material pump (13), the hydrolysis tank (14), the acidification crystallization tank (15), the sixth material pump (16), and the centrifugal device (17) are sequentially connected through pipelines; the oxygen inlet (4) is connected to the first tubular reactor (5) through a pipeline; and the second feeding tank (9), the second liquid storage tank (10), the fourth material pump (11), and the fifth material pump (13) are sequentially connected through pipelines.

[0005] The second aspect of the present invention provides a method for synthesizing 2-chloronicotinic acid using the device. The synthesis reaction formula is shown in 1, comprising the following steps: 1;

[0007] 2-Hydroxynicotinaldehyde, a first solvent, and a catalyst are subjected to a continuous oxidation reaction in a continuous oxidation preparation unit to obtain 2-hydroxynicotinic acid, and the 2-hydroxynicotinic acid is continuously discharged; 2-hydroxynicotinic acid is subjected to a continuous chlorination reaction with triphosgene to obtain an intermediate 2-chloronicotinyl chloride, and the intermediate 2-chloronicotinyl chloride is continuously discharged; 2-chloronicotinyl chloride is hydrolyzed under the action of liquid alkali to obtain sodium 2-chloronicotinate; the sodium 2-chloronicotinate solution is acidified with hydrochloric acid to obtain 2-hydroxynicotinic acid, and then cooled and crystallized to obtain 2-chloronicotinic acid.

[0008] Optionally, include the following steps:

[0009] S1: 2-hydroxynicotinaldehyde and a first solvent are added to a first feeding tank (1), and the mixture is transported to a first liquid storage tank (2); a first catalyst is loaded and fixed in a first tubular reactor (5); triphosgene and a second solvent are added to a second feeding tank (9), and the mixture is transported to a second liquid storage tank (10); a second catalyst is loaded and fixed in a second tubular reactor (12); an alkaline solution is added to a hydrolysis tank (14); and an acid solution is added to an acidification crystallization tank (15);

[0010] S2: The material in the first liquid storage tank (2) is injected into the first tubular reactor (5) via the first material pump (3), oxygen is introduced from the oxygen inlet (4) to carry out the reaction, and the generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank (7) via the second material pump (6), and the content of 2-hydroxynicotinaldehyde in the solution is sampled and tested. When the content is less than 0.5 wt%, the process proceeds to the next step;

[0011] S3: injecting the materials in the second liquid storage tank (10) and the third liquid storage tank (7) into the second tubular reactor (12) through the third material pump (8) and the fourth material pump (11), respectively, and mixing and reacting to obtain a 2-chloronicotinoyl chloride solution;

[0012] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank (14) via a fifth material pump (13) for hydrolysis. After the hydrolysis is completed, the solution is allowed to stand for stratification, and the lower aqueous layer is transferred to an acidification crystallization tank (15) for crystallization. The crystallized material is then fed to a centrifugal device (17) via a sixth material pump (16) for centrifugal drying to obtain 2-chloronicotinic acid.

[0013] The weight ratio of 2-hydroxynicotinaldehyde to the first solvent in the first liquid storage tank (1) is 1:(1-30); the weight ratio of triphosgene to the second solvent in the second liquid storage tank (10) is 1:(1-20).

[0014] Optionally, the weight ratio of 2-hydroxynicotinaldehyde to the first solvent in the first liquid storage tank (1) is 1:(3-10); and the weight ratio of triphosgene to the second solvent in the second liquid storage tank (10) is 1:(2-10).

[0015] Optionally, the weight ratio of 2-hydroxynicotinaldehyde to the first solvent in the first liquid storage tank (1) is 1:(5-10); and the weight ratio of triphosgene to the second solvent in the second liquid storage tank (10) is 1:(3-5).

[0016] The weight ratios of the 2-hydroxynicotinaldehyde, the first catalyst and the second catalyst are 1:(0.05-0.2) and 1:(0.05-0.15) respectively.

[0017] Optionally, the weight ratios of the 2-hydroxynicotinaldehyde, the first catalyst and the second catalyst are 1:(0.1-0.12) and 1:(0.08-0.1) respectively.

[0018] The first solvent and the second solvent are both selected from at least one of chloroform, dichloromethane, dichloroethane, 1,1,2-trichloroethane, and carbon tetrachloride.

[0019] The first catalyst includes at least one of cobalt chloride, cobalt acetate, manganese acetate, palladium carbon, and platinum carbon.

[0020] The second catalyst includes at least one of silver chloride, copper chloride, nickel chloride, zinc chloride, cobalt chloride, and cobalt phthalocyanine.

[0021] The molar ratio of the 2-hydroxynicotinaldehyde to triphosgene, liquid alkali and hydrochloric acid is 1:(1-1.5):(2-4):(2.5-5).

[0022] Optionally, the molar ratio of the 2-hydroxynicotinaldehyde to triphosgene, liquid alkali and hydrochloric acid is 1:(1.1-1.3):(2.5-3):(3.5-4), respectively.

[0023] The temperature inside the first tubular reactor (5) is 30-80°C, and the temperature inside the second tubular reactor (12) is 40-80°C.

[0024] Optionally, the temperature inside the first tubular reactor (5) is 55-80°C, and the temperature inside the second tubular reactor (12) is 55-80°C.

[0025] Optionally, the temperature inside the first tubular reactor (5) is 70-80°C, and the temperature inside the second tubular reactor (12) is 60-70°C.

[0026] The injection speed in S2 is 0.5-50 mL / min.

[0027] Optionally, the injection speed in S2 is 10 to 15 mL / min.

[0028] The material in the second liquid storage tank (10) is injected into the second tubular reactor (12) at a rate of 0.5 to 50 mL / min, and the material in the third liquid storage tank (7) is injected into the second tubular reactor (12) at a rate of 0.5 to 50 mL / min.

[0029] Optionally, the rate at which the material in the second liquid storage tank (10) is injected into the second tubular reactor (12) is 15 to 20 mL / min, and the rate at which the material in the third liquid storage tank (7) is injected into the second tubular reactor (12) is 5 to 10 mL / min.

[0030] The temperature in the hydrolysis tank (14) is 60-80°C.

[0031] The temperature in the acidification crystallization tank (15) is -20 to -10°C.

[0032] Beneficial effects

[0033] 1. The present invention can achieve a product purity greater than 99% by adjusting the ratio of components and process conditions.

[0034] 2. The present invention synthesizes 2-chloronicotinic acid by continuous reaction, so that during the reaction process, the reaction raw materials can be input and the reaction product can be output simultaneously, so that the subsequent reaction process is not affected by the previous reaction product. That is, the degree of back mixing of the reaction liquid is small, the by-products are small, the yield is high, and the product purity is good.

[0035] 3. Compared with the traditional intermittent tank reaction, the present invention greatly reduces the reaction time, has high reaction efficiency and low safety risk.

[0036] 4. The present invention adopts a continuous synthesis reaction to achieve continuous and automated reaction, reduce labor intensity, improve operating conditions, reduce production of finished products, and has good industrial prospects.

[0037] 5. The continuous synthesis method adopted by the present invention is simple to operate. By adjusting the material ratio in each liquid storage tank and the flow rate of each material pump, a high synthesis yield of up to 95% can be obtained, and the yield is stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The present invention is a flow chart of the synthesis method of 2-chloronicotinic acid in an embodiment of the present invention, wherein: 1. first feeding tank; 2. first liquid storage tank; 3. first material pump; 4. oxygen inlet; 5. first tubular reactor; 6. second material pump; 7. third liquid storage tank; 8. third material pump; 9. second feeding tank; 10. second liquid storage tank; 11. fourth material pump; 12. second tubular reactor; 13. fifth material pump; 14. hydrolysis tank; 15. acidification crystallization tank; 16. sixth material pump; 17. centrifugal device.

[0039] Figure 2 For the 2-chloronicotinic acid in Example 1 1 HNMR spectrum. DETAILED DESCRIPTION

[0040] In the following examples and comparative examples, the alkaline solution is a 30 wt % sodium hydroxide solution; and the acid solution is a 30 wt % hydrochloric acid aqueous solution.

[0041] Example 1

[0042] A synthesis device for 2-chloronicotinic acid, such as Figure 1As shown, it includes: a first feeding tank 1, a first liquid storage tank 2, a first material pump 3, an oxygen inlet 4, a first tubular reactor 5, a second material pump 6, a third liquid storage tank 7, a third material pump 8, a second feeding tank 9, a second liquid storage tank 10, a fourth material pump 11, a second tubular reactor 12, a fifth material pump 13, a hydrolysis tank 14, an acidification crystallization tank 15, a sixth material pump 16, and a centrifugal device 17; the first feeding tank 1, the first liquid storage tank 2, the first material pump 3, the first tubular reactor 5, the second material pump 6, the third liquid storage tank 7, the third material pump 8, the second tubular reactor 12, the fifth material pump 13, the hydrolysis tank 14, the acidification crystallization tank 15, the sixth material pump 16, and the centrifugal device 17 are connected in sequence through pipelines; the oxygen inlet 4 is connected to the first tubular reactor 5 through a pipeline; the second feeding tank 9, the second liquid storage tank 10, the fourth material pump 11, and the fifth material pump 13 are connected in sequence through pipelines.

[0043] A method for synthesizing 2-chloronicotinic acid according to the device of claim 1, wherein the synthesis reaction formula is shown below, and the specific steps are as follows:

[0044]

[0045] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 677.1 g dichloromethane) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (13.5 g cobalt acetate) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (385.7 g triphosgene, 384.3 g dichloroethane) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (10.5 g cobalt chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (346.7 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (437.5 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0046] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 70-75° C.) via the first material pump 3 at a rate of 10 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the content of 2-hydroxynicotinaldehyde. If the content reaches 0.35 wt %, the next step is performed.

[0047] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 at flow rates of 15 mL / min and 5.5 mL / min for reaction, and the temperature of the second tubular reactor 12 is controlled at 60-65° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0048] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0049] Example 2

[0050] The specific implementation method is the same as that of Example 1; the difference is that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0051] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 738.6 g 1,1,2-trichloroethane) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (13.5 g cobalt acetate) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (341.2 g triphosgene, 474.8 g 1,1,2-trichloroethane) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (10.5 g nickel chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (360 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (449.7 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0052] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 70-75° C.) via the first material pump 3 at a rate of 10 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the content of 2-hydroxynicotinaldehyde. If the content reaches 0.39 wt %, the solution is transferred to the next step.

[0053] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 at flow rates of 15 mL / min and 5.8 mL / min for reaction, and the temperature of the second tubular reactor 12 is controlled at 60-65° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0054] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0055] Example 3

[0056] The specific implementation method is the same as that of Example 1; the difference is that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0057] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 738.6 g dichloromethane) were added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (14.4 g platinum carbon) was loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (385.7 g triphosgene, 457.5 g dichloromethane) were added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (11.1 g cobalt phthalocyanine) was loaded and fixed in a second tubular reactor 12; an alkaline solution (386.7 g liquid caustic soda) was added to a hydrolysis tank 14; and an acid solution (474 ​​g hydrochloric acid) was added to an acidification crystallization tank 15;

[0058] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 70-75° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 0.44 wt %, the next step is performed.

[0059] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 at flow rates of 20 mL / min and 8.2 mL / min for reaction, and the temperature of the second tubular reactor 12 is controlled at 60-65° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0060] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0061] Example 4

[0062] The specific implementation is the same as that of Example 1; except that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0063] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 615.5 g ethylene dichloride) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (14.7 g cobalt chloride) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (370.9 g triphosgene, 457.5 g ethylene dichloride) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (12.3 g nickel chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (400 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (486.1 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0064] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 75-80° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 0.41 wt %, the solution is transferred to the next step.

[0065] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 at flow rates of 20 mL / min and 8.2 mL / min for reaction, and the temperature of the second tubular reactor 12 is controlled at 65-70° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0066] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0067] Example 5

[0068] The specific implementation is the same as that of Example 1; except that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0069] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 738.6 g dichloroethane) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (14.4 g platinum carbon) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (341.2 g triphosgene, 457.5 g dichloromethane) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (11.1 g nickel chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (400 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (486.1 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0070] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 75-80° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the content of 2-hydroxynicotinaldehyde. If the content reaches 0.4 wt %, the solution proceeds to the next step.

[0071] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 enter the second tubular reactor 12 at flow rates of 15 mL / min and 7 mL / min, respectively, and the temperature of the second tubular reactor 12 is controlled at 65-70° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0072] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0073] Example 6

[0074] The specific implementation method is the same as that of Example 1; the difference is that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0075] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 640.1 g dichloroethane) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (14.4 g cobalt acetate) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (341.2 g triphosgene, 467.8 g dichloromethane) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (11.1 g cobalt chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (366.7 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (455.8 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0076] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 70-75° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 0.46 wt %, the solution is transferred to the next step.

[0077] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 enter the second tubular reactor 12 at flow rates of 15 mL / min and 7 mL / min, respectively, and the temperature of the second tubular reactor 12 is controlled at 60-65° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0078] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0079] Example 7

[0080] The specific implementation method is the same as that of Example 1; the difference is that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0081] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 640.1 g 1,1,2-trichloroethane) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (13.5 g platinum carbon) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (341.2 g triphosgene, 467.8 g 1,1,2-trichloroethane) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (10.5 g cobalt chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (366.7 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (455.8 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0082] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 75-80° C.) via the first material pump 3 at a rate of 10 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 0.48 wt %, the solution is transferred to the next step.

[0083] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 at flow rates of 15 mL / min and 5.5 mL / min for reaction, and the temperature of the second tubular reactor 12 is controlled at 65-70° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0084] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 60-65° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0085] Comparative Example 1

[0086] The specific implementation is the same as that of Example 1; except that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0087] S1: 2-hydroxy-nicotinaldehyde and a first solvent (123.1 g 2-hydroxy-nicotinaldehyde, 369.3 g 1,1,2-trichloroethane) were added into the first feeding tank 1 and delivered to the first liquid storage tank 2; the first catalyst (8.5 g cobalt acetate) was loaded and fixed in the first tubular reactor 5; triphosgene and a second solvent (296.7 g triphosgene, 593.5 g 1,1,2-trichloroethane) were added into the second feeding tank 9 and delivered to the second liquid storage tank 10; the second catalyst (7.6 g nickel chloride) was loaded and fixed in the second tubular reactor 12; a base solution (200 g liquid alkali) was added into the hydrolysis tank 14; an acid solution (243.1 g hydrochloric acid) was added into the acidification crystallization tank 15;

[0088] S2: the material in the first liquid storage tank 2 was injected into the first tubular reactor 5 at a speed of 15 mL / min (the temperature was kept at 55-60 °C) through the first material pump 3, oxygen was introduced from the oxygen inlet 4 for reaction, and the generated 2-hydroxy-nicotinic acid solution was delivered to the third liquid storage tank 7 through the second material pump 6 and sampled to detect the content of 2-hydroxy-nicotinaldehyde in the solution, and the content reached 2.27 wt% to enter the next step;

[0089] S3: the materials in the second liquid storage tank 10 and the third liquid storage tank 7 were mixed and reacted in the second tubular reactor 12 through the third material pump 8 and the fourth material pump 11 respectively (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 were injected into the second tubular reactor 12 at a flow rate of 15 mL / min and 7 mL / min respectively, and the temperature of the second tubular reactor 12 was controlled at 50-55 °C), to obtain a 2-chloronicotinoyl chloride solution;

[0090] S4: after reaction, the 2-chloronicotinoyl chloride solution was input into the hydrolysis tank 14 through the fifth material pump 13 for hydrolysis, and the temperature was controlled at 60-65 °C during the hydrolysis process; after the hydrolysis was completed, the layers were separated, the lower water layer was discharged to the acidification crystallization tank 15 for crystallization, the temperature was controlled at -20 to -10 °C during the crystallization process, and the material after crystallization was delivered to the centrifugal device 17 through the sixth material pump 16 for centrifugal drying, to obtain 2-chloronicotinic acid.

[0091] Comparative Example 2

[0092] The specific implementation is the same as that of Example 1; the difference is that the method for synthesizing 2-chloronicotinic acid is as follows:

[0093] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 800 g ethylene dichloride) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (16.7 g platinum carbon) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (311.6 g triphosgene, 593.5 g ethylene dichloride) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (15.3 g cobalt chloride) is loaded and fixed in a second tubular reactor 12; an alkaline solution (200 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (243.1 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0094] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 60-65° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 1.87 wt %, the next step is performed.

[0095] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 enter the second tubular reactor 12 at flow rates of 15 mL / min and 7 mL / min, respectively, and the temperature of the second tubular reactor 12 is controlled at 50-55° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0096] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 50-55° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0097] Comparative Example 3

[0098] The specific implementation is the same as that of Example 1; except that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0099] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 800 g dichloromethane) are added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (6.2 g cobalt chloride) is loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (281.9 g triphosgene, 593.5 g dichloromethane) are added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (4.9 g cobalt phthalocyanine) is loaded and fixed in a second tubular reactor 12; an alkaline solution (200 g liquid caustic soda) is added to a hydrolysis tank 14; and an acid solution (243.1 g hydrochloric acid) is added to an acidification crystallization tank 15;

[0100] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 60-65° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 7.6 wt %, the next step is performed.

[0101] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 enter the second tubular reactor 12 at flow rates of 15 mL / min and 7 mL / min, respectively, and the temperature of the second tubular reactor 12 is controlled at 50-55° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0102] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 50-55° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0103] Comparative Example 4

[0104] The specific implementation is the same as that of Example 1; except that the method for synthesizing 2-chloronicotinic acid is specifically the following steps:

[0105] S1: 2-hydroxy-nicotinaldehyde and a first solvent (123.1 g 2-hydroxy-nicotinaldehyde, 677.1 g carbon tetrachloride) were added into the first feeding tank 1 and delivered to the first liquid storage tank 2; the first catalyst (14.4 g cobalt chloride) was loaded and fixed in the first tubular reactor 5; triphosgene and a second solvent (281.9 g triphosgene, 384.3 g carbon tetrachloride) were added into the second feeding tank 9 and delivered to the second liquid storage tank 10; the second catalyst (4.9 g cobalt phthalocyanine) was loaded and fixed in the second tubular reactor 12; a base solution (200 g liquid alkali) was added into the hydrolysis tank 14; an acid solution (243.1 g hydrochloric acid) was added into the acidification and crystallization tank 15;

[0106] S2: the materials in the first liquid storage tank 2 were injected into the first tubular reactor 5 at a speed of 15 mL / min (the temperature was kept at 50-55 °C) through the first material pump 3, oxygen was introduced from the oxygen inlet 4 for reaction, and the generated 2-hydroxy-nicotinic acid solution was delivered to the third liquid storage tank 7 through the second material pump 6 and sampled for detection of the content of 2-hydroxy-nicotinaldehyde in the solution, and the content of 8.8 wt% entered the next step;

[0107] S3: the materials in the second liquid storage tank 10 and the third liquid storage tank 7 were mixed and reacted in the second tubular reactor 12 through the third material pump 8 and the fourth material pump 11 respectively (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 entered the second tubular reactor 12 at a flow rate of 15 mL / min and 4 mL / min respectively, and the temperature of the second tubular reactor 12 was controlled at 50-55 °C), to obtain a 2-chloronicotinoyl chloride solution;

[0108] S4: after reaction, the 2-chloronicotinoyl chloride solution was input into the hydrolysis tank 14 through the fifth material pump 13 for hydrolysis, and the temperature was controlled at 50-55 °C during the hydrolysis process; after the hydrolysis was completed, the layers were separated, the lower water layer was discharged to the acidification and crystallization tank 15 for crystallization, the temperature was controlled at -20 to -10 °C during the crystallization process, and the crystallized material was delivered to the centrifugal device 17 through the sixth material pump 16 for centrifugal drying, to obtain 2-chloronicotinic acid.

[0109] Comparative Example 5

[0110] The specific implementation is the same as that of Example 1; the difference is that the method for synthesizing 2-chloronicotinic acid is as follows:

[0111] S1: 2-hydroxynicotinaldehyde and a first solvent (123.1 g 2-hydroxynicotinaldehyde, 677.1 g carbon tetrachloride) were added to a first feeding tank 1 and transported to a first liquid storage tank 2; a first catalyst (14.4 g palladium carbon) was loaded and fixed in a first tubular reactor 5; triphosgene and a second solvent (281.9 g triphosgene, 384.3 g carbon tetrachloride) were added to a second feeding tank 9 and transported to a second liquid storage tank 10; a second catalyst (10.5 g copper chloride) was loaded and fixed in a second tubular reactor 12; an alkaline solution (200 g liquid caustic soda) was added to a hydrolysis tank 14; and an acid solution (243.1 g hydrochloric acid) was added to an acidification crystallization tank 15;

[0112] S2: The material in the first liquid storage tank 2 is injected into the first tubular reactor 5 (maintained at 50-55° C.) via the first material pump 3 at a rate of 15 mL / min. Oxygen is introduced from the oxygen inlet 4 to carry out the reaction. The generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank 7 via the second material pump 6. The solution is sampled and tested for the 2-hydroxynicotinaldehyde content. If the content reaches 9.3 wt %, the solution is transferred to the next step.

[0113] S3: The materials in the second liquid storage tank 10 and the third liquid storage tank 7 are respectively introduced into the second tubular reactor 12 by the third material pump 8 and the fourth material pump 11 for mixing and reaction (the materials in the second liquid storage tank 10 and the third liquid storage tank 7 enter the second tubular reactor 12 at flow rates of 15 mL / min and 7 mL / min, respectively, and the temperature of the second tubular reactor 12 is controlled at 50-55° C.) to obtain a 2-chloronicotinoyl chloride solution;

[0114] S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank 14 via a fifth material pump 13 for hydrolysis. The temperature is controlled at 50-55° C. during the hydrolysis process. After the hydrolysis is completed, the solution is allowed to stand and separate into layers. The lower aqueous layer is transferred to an acidification crystallization tank 15 for crystallization. The temperature is controlled at -20 to -10° C. during the crystallization process. The crystallized material is then fed to a centrifuge 17 via a sixth material pump 16 for centrifugal drying to obtain 2-chloronicotinic acid.

[0115] Performance testing methods

[0116] 1. Perform nuclear magnetic resonance testing on the 2-chloronicotinic acid synthesized in Example 1. 1 H NMR spectrum is shown in Figure 2 ,analyze Figure 2 It can be seen that: 1 HNMR (400MHz, DMSO) δ13.79 (s, 1H), 8.94–8.41 (m, 1H), 8.26 (t, J = 19.3Hz, 1H), 7.54 (dd, J = 7.5, 4.9Hz, 1H).

[0117] 2. Purity (HPLC-external standard method) and yield tests of the examples and comparative examples. The yield was calculated based on 2-hydroxynicotinaldehyde.

[0118] Performance test data

[0119] Table 1

[0120] purity% Yield % Example 1 99.5 95.0 Example 2 99.1 94.7 Example 3 99.3 95.4 Example 4 99.6 96.2 Example 5 99.7 95.7 Example 6 99.6 95.3 Example 7 99.5 94.6 Comparative Example 1 98.5 89.2 Comparative Example 2 98.9 90.1 Comparative Example 3 98.6 84.6 Comparative Example 4 99.0 84.5 Comparative Example 5 98.2 81.1

Claims

1. A synthesis device for 2-chloronicotinic acid, characterized in that: include: A first feeding tank (1), a first liquid storage tank (2), a first material pump (3), an oxygen inlet (4), a first tubular reactor (5), a second material pump (6), a third liquid storage tank (7), a third material pump (8), a second feeding tank (9), a second liquid storage tank (10), a fourth material pump (11), a second tubular reactor (12), a fifth material pump (13), a hydrolysis tank (14), an acidification crystallization tank (15), a sixth material pump (16), and a centrifugal device (17); the first feeding tank (1), the first liquid storage tank (2), the first material pump (3), an oxygen inlet (4), a first tubular reactor (5), a second material pump (6), a third liquid storage tank (7), a third material pump (8), a second feeding tank (9), a second liquid storage tank (10), a fourth material pump (11), a second tubular reactor (12), a fifth material pump (13), a hydrolysis tank (14), an acidification crystallization tank (15), a sixth material pump (16), and a centrifugal device (17); The pump (3), the first tubular reactor (5), the second material pump (6), the third liquid storage tank (7), the third material pump (8), the second tubular reactor (12), the fifth material pump (13), the hydrolysis tank (14), the acidification crystallization tank (15), the sixth material pump (16), and the centrifugal device (17) are sequentially connected through pipelines; the oxygen inlet (4) is connected to the first tubular reactor (5) through a pipeline; the second feeding tank (9), the second liquid storage tank (10), the fourth material pump (11), and the fifth material pump (13) are sequentially connected through pipelines.

2. A method for synthesizing 2-chloronicotinic acid according to the device of claim 1, characterized in that: The synthesis reaction formula is shown in 1, comprising the following steps: 1； S1: 2-hydroxynicotinaldehyde and a first solvent are added to a first feeding tank (1), and the mixture is transported to a first liquid storage tank (2); a first catalyst is loaded and fixed in a first tubular reactor (5); triphosgene and a second solvent are added to a second feeding tank (9), and the mixture is transported to a second liquid storage tank (10); a second catalyst is loaded and fixed in a second tubular reactor (12); an alkaline solution is added to a hydrolysis tank (14); and an acid solution is added to an acidification crystallization tank (15); S2: The material in the first liquid storage tank (2) is injected into the first tubular reactor (5) via the first material pump (3), oxygen is introduced from the oxygen inlet (4) to carry out the reaction, and the generated 2-hydroxynicotinic acid solution is transported to the third liquid storage tank (7) via the second material pump (6), and the content of 2-hydroxynicotinaldehyde in the solution is sampled and tested. When the content is less than 0.5 wt%, the process proceeds to the next step; S3: injecting the materials in the second liquid storage tank (10) and the third liquid storage tank (7) into the second tubular reactor (12) through the third material pump (8) and the fourth material pump (11), respectively, and mixing and reacting to obtain a 2-chloronicotinoyl chloride solution; S4: After the reaction, the 2-chloronicotinoyl chloride solution is fed to a hydrolysis tank (14) via a fifth material pump (13) for hydrolysis. After the hydrolysis is completed, the solution is allowed to stand for stratification, and the lower aqueous layer is transferred to an acidification crystallization tank (15) for crystallization. The crystallized material is then fed to a centrifugal device (17) via a sixth material pump (16) for centrifugal drying to obtain 2-chloronicotinic acid.

3. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The temperature inside the first tubular reactor (5) is 55-80°C.

4. The method for synthesizing 2-chloronicotinic acid according to claim 2, wherein The temperature inside the second tubular reactor (12) is 55-80°C.

5. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The weight ratio of 2-hydroxynicotinaldehyde to the first solvent in the first liquid storage tank (1) is 1:(3-10); the weight ratio of triphosgene to the second solvent in the second liquid storage tank (10) is 1:(2-10).

6. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The weight ratios of the 2-hydroxynicotinaldehyde, the first catalyst and the second catalyst are 1:(0.05-0.2) and 1:(0.05-0.15) respectively.

7. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The injection speed in S2 is 10-15 mL / min.

8. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The material in the second liquid storage tank (10) is injected into the second tubular reactor (12) at a rate of 15 to 20 mL / min, and the material in the third liquid storage tank (7) is injected into the second tubular reactor (12) at a rate of 5 to 10 mL / min.

9. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The temperature in the hydrolysis tank (14) is 60-80°C.

10. The method for synthesizing 2-chloronicotinic acid according to claim 2, characterized in that: The temperature in the acidification crystallization tank (15) is -20 to -10°C.

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