A continuous process for the synthesis of 2-chloro-4-amino-5-methylpyridine

Abstract

The application discloses a continuous synthesis method of 2-chloro-4-amino-5-methylpyridine, which is prepared from 2-chloro-5-methylpyridine as a starting material, and the continuous synthesis of 2-chloro-5-methylpyridine N-oxide is first carried out in a fixed bed reactor by using titanium silicalite catalyst, then the continuous nitration synthesis of 2-chloro-4-nitro-5-methylpyridine N-oxide is carried out in a microreactor by using SO3 / concentrated nitric acid, and the continuous hydrogenation synthesis of 2-chloro-4-amino-5-methylpyridine is carried out in a continuous stirred tank reactor by using Raney nickel catalyst. Through the above three-step continuous reaction, the total yield of 2-chloro-4-amino-5-methylpyridine can reach more than 80%, and the synthesis method is simple, three-waste is less, and has good economic effect and environmental effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate preparation technology, specifically relating to a novel method for the continuous synthesis of 2-chloro-4-amino-5-methylpyridine. Background Technology

[0002] Finerenone (BAY 94-8862, structural formula is...) (Is) is a nonsteroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the harmful effects of mineralocorticoid receptor overactivation. In diabetes, mineralocorticoid receptor overactivation is thought to contribute to the progression of chronic kidney disease and cardiovascular damage, which may be driven by factors such as metabolism, hemodynamics, or inflammation and fibrosis.

[0003] 2-Hydroxy-4-amino-5-methylpyridine (also known as 4-amino-5-methylpyridinone, its structural formula is...) 2-hydroxy-4-amino-5-methylpyridine is a key intermediate in the synthesis of fenelitone. Currently, the preparation method of 2-hydroxy-4-amino-5-methylpyridine generally uses 2-chloro-5-methylpyridine as the starting material, and goes through three steps of oxidation, nitration and hydrogenation to obtain 2-chloro-4-amino-5-methylpyridine. Finally, it undergoes a high-temperature and high-pressure alkaline hydrolysis reaction to obtain the final product.

[0004] Chinese patent CN 103193704A and Hristen L et al. (HETEROCYCLES, Vol. 78, No. 11, 2009, pp. 2811-2826) disclose a method for synthesizing 2-chloro-5-methylpyridine nitrogen oxides. The former uses sulfuric acid and sodium tungstate as catalysts and hydrogen peroxide as an oxidant. After the reaction, neutralization and extraction are required to obtain the product. Not only is the catalyst difficult to recover, but it also generates a large amount of waste, which is not conducive to industrial production.

[0005] .

[0006] The latter method uses the in-situ peracetic acid process, where hydrogen peroxide and acetic acid react to form peracetic acid, which then oxidizes 2-chloro-5-methylpyridine to produce pyridine nitrogen oxides. However, due to the highly corrosive nature of acetic acid, the equipment requirements are demanding, and the recovery of acetic acid is difficult and complex, which is also unfavorable for industrial production.

[0007] .

[0008] Chinese patent CN 115340492A discloses a method for preparing 2-chloro-4-nitro-5-methylpyridine nitrogen oxides. Because the nitration of pyridine heterocycles is quite difficult, the traditional mixed acid nitration method requires far greater quantities of nitric acid and sulfuric acid. Furthermore, neutralization and quenching are necessary after the reaction. Therefore, not only are the raw material costs high, but a large amount of waste is also generated.

[0009] .

[0010] Patent WO 2020 / 178175 reports the reduction of 2-chloro-4-nitropyridine nitrogen oxides using a platinum-molybdenum bimetallic catalyst supported on activated carbon at 20-50°C and 3 MPa hydrogen atmosphere for 30 h. This method has a long hydrogenation time, low efficiency, high pressure, and demanding equipment requirements, making industrial scale-up difficult.

[0011] . Summary of the Invention

[0012] To address the aforementioned technical problems, this invention develops a continuous and efficient method for synthesizing 2-chloro-4-amino-5-methylpyridine. Compared to previously reported batch processes, this method improves production efficiency and significantly reduces the generation of waste while ensuring the same raw material consumption and maintaining the same target product yield, thus enabling large-scale production.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] A continuous synthesis method for 2-chloro-4-amino-5-methylpyridine, using 2-chloro-5-methylpyridine as the starting material, firstly involves the continuous synthesis of 2-chloro-5-methylpyridine oxides catalyzed by titanium silicate molecular sieves in a fixed-bed reactor, then the continuous nitration synthesis of 2-chloro-4-nitro-5-methylpyridine oxides using SO3 / concentrated nitric acid in a microreactor, and finally the continuous hydrogenation synthesis of 2-chloro-4-amino-5-methylpyridine using Raney nickel catalyst in a continuous stirred tank reactor; the specific steps include:

[0015] 1) Continuous synthesis of 2-chloro-5-methylpyridine nitride:

[0016] 2-Chloro-5-methylpyridine, solvent A, and 27.5 vol% hydrogen peroxide solution were mixed and catalytically oxidized in a fixed-bed reactor at 50-100 °C in the presence of a catalyst. The resulting product was cooled by a condenser, separated by a gas-liquid separator, and the liquid phase was quenched of residual hydrogen peroxide before being sent to a concentration system for concentration to obtain 2-chloro-5-methylpyridine nitrogen oxides.

[0017] 2) Continuous synthesis of 2-chloro-4-nitro-5-methylpyridine nitride:

[0018] The synthesized 2-chloro-5-methylpyridine nitrogen oxides were prepared into a reaction solution with concentrated sulfuric acid (98%), and then mixed sequentially with sulfur trioxide and concentrated nitric acid (98%) through a static mixer before being introduced into a microreactor. The reaction was carried out at 30-60℃. After the reaction, the product was diluted by cooling, subjected to countercurrent extraction, and the organic phase was concentrated to obtain 2-chloro-5-methylpyridine nitrogen oxides. The obtained acid phase was concentrated and reused.

[0019] 3) Continuous synthesis of 2-chloro-4-amino-5-methylpyridine:

[0020] The synthesized 2-chloro-4-nitro-5-methylpyridine nitride was mixed with solvent B and a dechlorination inhibitor and reacted in a continuous stirred tank reactor at 50-60°C, hydrogen pressure of 0.5-2 MPa, and in the presence of Raney nickel catalyst. After filtration, the resulting clear liquid was concentrated in a concentration system to obtain the target product. The solid catalyst used was reused after post-treatment.

[0021] Further, in step 1), the mass ratio of 2-chloro-5-methylpyridine, solvent A, and hydrogen peroxide solution is 1:(1~3):(0.90~1.5).

[0022] Further, solvent A in step 1) is one or more of water, methanol, ethanol, and acetonitrile.

[0023] Furthermore, the catalyst mentioned in step 1) is a titanium-silicon molecular sieve such as TS-1 or Ti-MWW, with a space velocity of 0.08-0.1 min. -1 .

[0024] Furthermore, in step 1), the mixed reaction solution remains in the fixed-bed reactor for 10-120 minutes to carry out the reaction.

[0025] Furthermore, in step 2), the molar ratio of 2-chloro-5-methylpyridine nitrogen oxides to concentrated sulfuric acid, sulfur trioxide, and concentrated nitric acid is 1:(0.5~3):(0.5~2):(2~5).

[0026] Furthermore, in step 2), the mixed reaction solution is kept in the microreactor for 5-60 minutes to react.

[0027] Furthermore, the microreactor mentioned in step 2) is any one of a tubular reactor, a microchannel reactor, and a bundled microreactor.

[0028] Furthermore, in step 3), the mass ratio of 2-chloro-4-nitro-5-methylpyridine, solvent B, dechlorination inhibitor and Raney nickel catalyst is 1:(2~10):(0.1%-1%):(2%-10%).

[0029] Further, solvent B in step 3) is one or more of water, methanol, ethanol, tetrahydrofuran, and dichloromethane.

[0030] Further, the dechlorination inhibitor mentioned in step 3) is one or more of morpholine, dicyandiamide, diethylamine, and ammonium acetate.

[0031] Furthermore, in step 3), the mixed reaction solution is kept in the continuous batch reactor for 1-6 hours for reaction.

[0032] The beneficial effects of this invention are as follows:

[0033] 1. The process of this invention enables fully continuous production, greatly improving the production efficiency and product quality stability of 2-chloro-4-amino-5-methylpyridine;

[0034] 2. The oxidation reaction of 2-chloro-5-methylpyridine in this invention uses a molecular sieve catalyst instead of a peroxy acid process, which reduces process costs and avoids the problem of waste acid recovery;

[0035] 3. The nitration process of this invention can increase the reaction rate, achieve a lower reaction temperature, a smaller reaction liquid holdup, and improve reaction safety, while solving the problem of sulfuric acid recovery and reuse;

[0036] 4. The hydrogenation process of this invention uses Raney nickel hydrogenation to replace traditional iron powder reduction, realizing a low-cost, green, continuous hydrogenation process.

[0037] 5. When produced according to the process of this invention, the total yield of 2-chloro-4-amino-5-methylpyridine can reach over 80%. Attached Figure Description

[0038] Figure 1 This is a process flow diagram of the continuous synthesis of 2-chloro-4-amino-5-methylpyridine according to the present invention. Detailed Implementation

[0039] A continuous synthesis method for 2-chloro-4-amino-5-methylpyridine, specifically comprising the following steps:

[0040] 1) Continuous synthesis of 2-chloro-5-methylpyridine nitride:

[0041] 2-Chloro-5-methylpyridine, solvent A, and 27.5 vol% hydrogen peroxide solution were mixed at a mass ratio of 1:(1~3):(0.90~1.5). The mixture was then passed through a catalyst-packed atmosphere (space velocity 0.08-0.1 min) at 50-100 °C. -1 In a fixed-bed reactor, the catalytic oxidation reaction is carried out for 10-120 min. After that, the product is cooled by a condenser and separated by a gas-liquid separator. The liquid material is then quenched of residual hydrogen peroxide and sent to a concentration system for concentration to obtain 2-chloro-5-methylpyridine nitrogen oxides.

[0042] 2) Continuous synthesis of 2-chloro-4-nitro-5-methylpyridine nitride:

[0043] The synthesized 2-chloro-5-methylpyridine nitrogen oxides were prepared into a reaction solution with concentrated sulfuric acid (98%), and then mixed sequentially with sulfur trioxide and concentrated nitric acid (98%) through a static mixer before being introduced into a microreactor. The reaction was carried out at 30-60℃ for 5-60 min. After the reaction, the product was diluted by cooling, extracted countercurrently, and the organic phase was concentrated to obtain 2-chloro-5-methylpyridine nitrogen oxides. The obtained acid phase was concentrated and reused. The molar ratio of 2-chloro-5-methylpyridine nitrogen oxides to concentrated sulfuric acid, sulfur trioxide, and concentrated nitric acid was 1:(0.5~3):(0.5~2):(2~5).

[0044] 3) Continuous synthesis of 2-chloro-4-amino-5-methylpyridine:

[0045] The synthesized 2-chloro-4-nitro-5-methylpyridine nitride oxide was mixed with solvent B, dechlorination inhibitor and Raney nickel catalyst at a mass ratio of 1:(2~10):(0.1%-1%):(2-10%). The mixture was then introduced into a continuous stirred tank reactor at 50-60℃ and hydrogen pressure of 0.5-2MPa for 1-6 hours to carry out the reaction. After filtration, the resulting clear liquid was concentrated in a concentration system to obtain the target product. The solid catalyst used was reused after post-treatment.

[0046] In step 1), solvent A is one or more of water, methanol, ethanol, and acetonitrile. The catalyst is a titanium-silicon molecular sieve such as TS-1 or Ti-MWW.

[0047] The microreactor mentioned in step 2) is any one of a tubular reactor, a microchannel reactor, and a bundled microreactor.

[0048] In step 3), solvent B is one or more of water, methanol, ethanol, tetrahydrofuran, and dichloromethane. The dechlorination inhibitor is one or more of morpholine, dicyandiamide, diethylamine, and ammonium acetate.

[0049] To make the content of this invention easier to understand, the technical solution of this invention will be further described below with reference to specific embodiments, but this invention is not limited thereto.

[0050] Example 1: Continuous preparation of 2-chloro-5-methylpyridine nitride:

[0051] Using 2-chloro-5-methylpyridine as raw material, a reaction solution was prepared by mixing 2-chloro-5-methylpyridine, methanol, and 27.5 vol% hydrogen peroxide solution at a mass ratio of 1:3:1.15. 100 g of catalyst TS-1 was then packed into the column of a fixed-bed reactor. The fixed-bed reactor was then heated to 70°C, and the reaction solution was pumped into the fixed-bed reactor using a horizontal flow pump. The flow rate was adjusted to a residence time of 40 min, and the reactor was run continuously for 72 h. The resulting liquid product was cooled by a condenser, separated by a gas-liquid separator, and then quenched with 1% granular manganese dioxide by heating to remove residual hydrogen peroxide. The product was then sent to a concentration system for concentration to obtain the 2-chloro-5-methylpyridine nitrogen oxide product, with a yield of 93.2% and a purity of 98%.

[0052] Example 2 Continuous preparation of 2-chloro-5-methylpyridine nitride:

[0053] Using 2-chloro-5-methylpyridine as raw material, a reaction solution was prepared by mixing 2-chloro-5-methylpyridine, methanol, and 27.5 vol% hydrogen peroxide solution at a mass ratio of 1:3:1.15. 100 g of catalyst TS-1 was then packed into the column of a fixed-bed reactor. The fixed-bed reactor was then heated to 70°C, and the reaction solution was pumped into the fixed-bed reactor using a horizontal flow pump. The flow rate was adjusted to a residence time of 20 min, and the reactor was run continuously for 72 h. The resulting liquid product was cooled by a condenser, separated by a gas-liquid separator, and then quenched with 1% granular manganese dioxide to remove residual hydrogen peroxide. Finally, it was sent to a concentration system for concentration to obtain the 2-chloro-5-methylpyridine nitrogen oxide product, with a yield of 96.9% and a purity of 98%.

[0054] Example 3 Continuous preparation of 2-chloro-5-methylpyridine nitride:

[0055] Using 2-chloro-5-methylpyridine as raw material, a reaction solution was prepared by mixing 2-chloro-5-methylpyridine, methanol, and 27.5 vol% hydrogen peroxide solution at a mass ratio of 1:3:1.15. 100 g of catalyst TS-1 was then packed into the column of a fixed-bed reactor. The fixed-bed reactor was then heated to 70°C, and the reaction solution was pumped into the fixed-bed reactor using a horizontal flow pump. The flow rate was adjusted to a residence time of 30 min, and the reactor was run continuously for 72 h. The resulting liquid product was cooled by a condenser, separated by a gas-liquid separator, and then quenched with 1% granular manganese dioxide to remove residual hydrogen peroxide. Finally, the product was sent to a concentration system for concentration to obtain the 2-chloro-5-methylpyridine nitrogen oxide product, with a yield of 95.5% and a purity of 98%.

[0056] Example 4 Continuous preparation of 2-chloro-5-methylpyridine nitride:

[0057] Using 2-chloro-5-methylpyridine as raw material, a reaction solution was prepared by mixing 2-chloro-5-methylpyridine, methanol, and 27.5 vol% hydrogen peroxide solution at a mass ratio of 1:3:1.15. 100 g of Ti-MWW catalyst was then packed into the column of a fixed-bed reactor. The fixed-bed reactor was then heated to 70°C, and the reaction solution was pumped into the fixed-bed reactor using a horizontal flow pump. The flow rate was adjusted to a residence time of 40 min, and the reactor was run continuously for 72 h. The resulting liquid product was cooled by a condenser, separated by a gas-liquid separator, and then quenched with 1% granular manganese dioxide by heating to remove residual hydrogen peroxide. The product was then sent to a concentration system for concentration to obtain the 2-chloro-5-methylpyridine nitrogen oxide product with a yield of 97.2% and a purity of 98%.

[0058] Example 5: Continuous preparation of 2-chloro-4-nitro-5-methylpyridine nitride:

[0059] Using 2-chloro-5-methylpyridine nitride as a raw material, a reaction solution was prepared by mixing any of the 2-chloro-5-methylpyridine nitrides prepared in Examples 1-4 with 98% concentrated sulfuric acid. The reaction solution was then first pumped with sulfur trioxide to a static mixer using a co-current pump, and then mixed with 98% concentrated nitric acid in another static mixer. The molar flow rates of 2-chloro-5-methylpyridine nitride, 98% concentrated sulfuric acid, sulfur trioxide, and concentrated nitric acid were all 1 mol / min, 1 mol / min, and 3 mol / min, respectively. The mixed reaction solution was then passed through a microreactor and held at 50°C for 30 min. After the product was discharged, it was diluted with ice water and subjected to multi-stage countercurrent extraction with dichloromethane. The resulting organic phase extract was concentrated to obtain 2-chloro-4-nitro-5-methylpyridine nitride with a yield of 85.1% and a purity of 98%.

[0060] Example 6: Continuous preparation of 2-chloro-4-nitro-5-methylpyridine nitride:

[0061] Using 2-chloro-5-methylpyridine nitride as a raw material, a reaction solution was prepared by mixing any of the 2-chloro-5-methylpyridine nitrides prepared in Examples 1-4 with 98% concentrated sulfuric acid. The reaction solution was then first pumped with sulfur trioxide to a static mixer using a co-current pump, and then mixed with 98% concentrated nitric acid in another static mixer. The molar flow rates of 2-chloro-5-methylpyridine nitride were 1 mol / min, 98% concentrated sulfuric acid were 2 mol / min, sulfur trioxide were 1 mol / min, and concentrated nitric acid were 3 mol / min. The mixed reaction solution was passed through a microreactor and held at 50°C for 30 min. After the product was discharged, it was diluted with ice water and subjected to multi-stage countercurrent extraction with dichloromethane. The resulting organic phase extract was concentrated to obtain 2-chloro-4-nitro-5-methylpyridine nitride with a yield of 87.5% and a purity of 98%.

[0062] Example 7 Continuous preparation of 2-chloro-4-nitro-5-methylpyridine nitride:

[0063] Using 2-chloro-5-methylpyridine nitride as a raw material, a reaction solution was prepared by mixing any of the 2-chloro-5-methylpyridine nitrides prepared in Examples 1-4 with 98% concentrated sulfuric acid. The reaction solution was then first pumped with sulfur trioxide to a static mixer using a co-current pump, and then mixed with 98% concentrated nitric acid in another static mixer. The molar flow rates of 2-chloro-5-methylpyridine nitride were 1 mol / min, 98% sulfuric acid were 1 mol / min, sulfur trioxide was 0.5 mol / min, and concentrated nitric acid was 3 mol / min. The mixed reaction solution was then passed through a microreactor and held at 50°C for 30 min. After the product was discharged, it was diluted with ice water and subjected to multi-stage countercurrent extraction with dichloromethane. The resulting organic phase extract was concentrated to obtain 2-chloro-4-nitro-5-methylpyridine nitride with a yield of 71.3% and a purity of 98%.

[0064] Example 8 Continuous preparation of 2-chloro-4-amino-5-methylpyridine:

[0065] 2-Chloro-4-nitro-5-methylpyridine nitride, morpholine, and methanol prepared in any of Examples 5-7 were added to a 5L autoclave at a mass ratio of 1:0.005:6 to prepare a 3L reaction solution. 5% (by mass) of Raney nickel catalyst (based on the mass of 2-chloro-4-nitro-5-methylpyridine nitride) was then added. After purging with nitrogen and hydrogen three times, the reaction solution was continuously pumped into a continuously stirred tank reactor using a diaphragm pump at a pressure of 1.5 MPa and a temperature of 70°C, with a residence time controlled at 4 hours. The product was cooled, filtered, and the filtrate concentrated to obtain 2-chloro-4-amino-5-methylpyridine with a yield of 97.1% and a purity of 98%.

[0066] Example 9 Continuous preparation of 2-chloro-4-amino-5-methylpyridine:

[0067] 2-Chloro-4-nitro-5-methylpyridine nitride, prepared in any of Examples 5-7, dicyandiamide, and methanol were added to a 5L autoclave at a mass ratio of 1:0.005:6 to prepare a 3L reaction solution. 5% (by mass) of Raney nickel catalyst (based on the mass of 2-chloro-4-nitro-5-methylpyridine nitride) was then added. After purging with nitrogen and hydrogen three times, the reaction solution was continuously pumped into a continuously stirred tank reactor using a diaphragm pump at a pressure of 1.5 MPa and a temperature of 70°C, with a residence time controlled at 4 hours. The product was cooled, filtered, and the filtrate concentrated to obtain 2-chloro-4-amino-5-methylpyridine with a yield of 98.5% and a purity of 98%.

[0068] Example 10 Continuous preparation of 2-chloro-4-amino-5-methylpyridine:

[0069] 2-Chloro-4-nitro-5-methylpyridine nitride, morpholine, and methanol prepared in any of Examples 5-7 were added to a 5L autoclave at a mass ratio of 1:0.005:6 to prepare a 3L reaction solution. 5% (by mass) of Raney nickel catalyst (based on the mass of 2-chloro-4-nitro-5-methylpyridine nitride) was then added. After purging with nitrogen and hydrogen three times, the reaction solution was continuously pumped into a continuously stirred tank reactor using a diaphragm pump at a pressure of 1.5 MPa and a temperature of 60°C, with a residence time controlled at 4 hours. The product was cooled, filtered, and the filtrate concentrated to obtain 2-chloro-4-amino-5-methylpyridine with a yield of 97.1% and a purity of 98%.

[0070] Example 11 Continuous preparation of 2-chloro-4-amino-5-methylpyridine:

[0071] 2-Chloro-4-nitro-5-methylpyridine nitride, morpholine, and methanol prepared in any of Examples 5-7 were added to a 5L autoclave at a mass ratio of 1:0.005:6 to prepare a 3L reaction solution. 5% (by mass) of Raney nickel catalyst (based on the mass of 2-chloro-4-nitro-5-methylpyridine nitride) was then added. After purging with nitrogen and hydrogen three times, the reaction solution was continuously pumped into a continuously stirred tank reactor using a diaphragm pump at a pressure of 1.0 MPa and a temperature of 60°C, with a residence time controlled at 4 hours. The product was cooled, filtered, and the filtrate was concentrated to obtain 2-chloro-4-amino-5-methylpyridine with a yield of 97.6% and a purity of 98%.

[0072] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A continuous synthesis method for 2-chloro-4-amino-5-methylpyridine, characterized in that: Includes the following steps: 1) Continuous synthesis of 2-chloro-5-methylpyridine nitride: 2-Chloro-5-methylpyridine, solvent A, and 27.5 vol% hydrogen peroxide solution were mixed and catalytically oxidized in a fixed-bed reactor at 50-100 °C in the presence of a catalyst. The resulting product was cooled by a condenser, separated by a gas-liquid separator, and the liquid phase was quenched of residual hydrogen peroxide before being sent to a concentration system for concentration to obtain 2-chloro-5-methylpyridine nitrogen oxides. 2) Continuous synthesis of 2-chloro-4-nitro-5-methylpyridine nitride: The synthesized 2-chloro-5-methylpyridine nitrogen oxides were prepared with concentrated sulfuric acid to form a reaction solution. Then, the solution was mixed with sulfur trioxide and concentrated nitric acid in sequence through a static mixer and then introduced into a microreactor. The reaction was carried out at 30-60℃. After the reaction, the product was diluted by cooling, extracted by countercurrent, and the organic phase was concentrated to obtain 2-chloro-4-nitro-5-methylpyridine nitrogen oxides. 3) Continuous synthesis of 2-chloro-4-amino-5-methylpyridine: The synthesized 2-chloro-4-nitro-5-methylpyridine nitrogen oxides were mixed with solvent B and a dechlorination inhibitor and reacted in a continuous stirred tank reactor at 50-60°C, hydrogen pressure of 0.5-2 MPa and in the presence of Raney nickel catalyst. After filtration, the resulting clear liquid was concentrated in a concentration system to obtain the target product. The catalyst mentioned in step 1) is a titanium-silicon molecular sieve; the reaction time of the mixed reaction solution in the fixed-bed reactor is 10-120 min; The molar ratio of 2-chloro-5-methylpyridine nitrogen oxides to concentrated sulfuric acid, sulfur trioxide, and concentrated nitric acid used in step 2) is 1:(0.5~3):(0.5~2):(2~5).

2. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1, characterized in that: The mass ratio of 2-chloro-5-methylpyridine, solvent A, and hydrogen peroxide solution used in step 1) is 1:(1~3):(0.90~1.5).

3. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1, characterized in that: The solvent A mentioned in step 1) is one or more of water, methanol, ethanol, and acetonitrile.

4. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1, characterized in that: In step 1), the catalyst space velocity is 0.08-0.1 min. -1 .

5. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1, characterized in that: In step 2), the mixed reaction solution remains in the microreactor for 5-60 minutes to react. The microreactor can be any one of a tubular reactor, a microchannel reactor, or a bundled microreactor.

6. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1, characterized in that: The mass ratio of 2-chloro-4-nitro-5-methylpyridine, solvent B, dechlorination inhibitor and Raney nickel catalyst used in step 3) is 1:(2~10):(0.1%-1%):(2%-10%).

7. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1 or 6, characterized in that: Solvent B is one or more of water, methanol, ethanol, tetrahydrofuran, and dichloromethane; The dechlorination inhibitor is one or more of morpholine, dicyandiamide, diethylamine, and ammonium acetate.

8. The continuous synthesis method of 2-chloro-4-amino-5-methylpyridine according to claim 1, characterized in that: In step 3), the mixed reaction solution is kept in a continuous stirred tank reactor for 1-6 hours to carry out the reaction.

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