A device and method for preparing aromatic amine compounds by continuous flow reduction of aromatic azide compounds

Abstract

The present invention provides an apparatus and method for the continuous flow reduction of aromatic azide compounds to prepare aromatic amine compounds, relating to the technical field of organic synthesis. The continuous flow synthesis apparatus and method of the present invention for reducing aromatic azide compounds to prepare aromatic amine compounds offer the advantages of precise control of conditions, high safety, short reaction time, and reduced explosiveness and flammability. Furthermore, the method is simple to operate, requires minimal equipment and site requirements, and is environmentally friendly, possessing significant practical value in improving production safety and efficiency.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a device and method for preparing aromatic amine compounds by continuous flow reduction of aromatic azide compounds. Background Art

[0002] Aromatic amines are key raw materials and intermediates for synthetic rubber, dyes, pigments, chemical reagents, and pharmaceutical pesticides, and are widely used. Reduction of aryl azides to prepare them is currently a primary method. Hydrogenation is commonly used in the reduction of aryl azides.

[0003] However, hydrogenation reduction production requires a production permit, carries the risk of explosion and leakage, and requires improved safety. Furthermore, hydrogenation reduction reactions are extremely demanding on equipment, site, and operator skills, resulting in high costs. Furthermore, the small batch size used in traditional production precludes scalability, reducing production efficiency.

[0004] How to provide a safe, low-cost and suitable method for the synthesis of aromatic amine compounds requires further research. Summary of the Invention

[0005] Currently, the synthesis of arylamine compounds from aryl azide compounds has the problems of high requirements for the reactor, high explosion risk and flammability. In order to solve the above problems, the present invention provides an apparatus and method for preparing arylamine compounds by continuous flow reduction of aryl azide compounds.

[0006] The present invention provides a device for preparing aromatic amine compounds by continuous flow reduction of aromatic azide compounds, which comprises:

[0007] Metering pump 1, metering pump 2, metering pump 3, metering pump 6, metering pump 8, continuous flow reactor 27, continuous filter 10, continuous phase separator 20, storage tank 11, continuous scrubber 21, continuous phase separator 26;

[0008] The metering pump 1 is connected to the continuous flow reactor 27 through the feed port 28, and the metering pump 2 and the metering pump 3 are connected to the continuous flow reactor 27 through the feed port 15; the continuous flow reactor 27, the continuous filter 10, the continuous phase separator 20, the continuous washer 21, and the continuous phase separator 26 are connected in sequence.

[0009] Furthermore, the continuous flow reactor 27 further includes a heated circulating water inlet 14 , a mixed reaction gas and liquid outlet 16 , an exhaust port 17 , a liquid outlet 18 , and a heated circulating water outlet 19 .

[0010] Furthermore, the continuous flow reactor 27 is connected to the continuous filter 10 through the liquid outlet 18; the continuous filter 10 is connected to the continuous phase separator 20 through the metering pump 4; the continuous phase separator 20 is connected to the storage tank 11 and the storage tank 12; the storage tank 11 is connected to the continuous scrubber 21 through the metering pump 5, and the continuous scrubber 21 is connected to the metering pump 6; the continuous scrubber 21 is also connected to the continuous phase separator 26; the continuous phase separator 26 has an organic phase outlet 24 and an aqueous phase outlet 25, and the aqueous phase outlet 25 is connected to the storage tank 13; the storage tank 12 is connected to the continuous disruptor 22 through the metering pump 7, and the storage tank 13 is connected to the continuous disruptor 22 through the metering pump 9, and the metering pump 8 is also connected to the continuous disruptor 22, and the continuous disruptor 22 is also connected to the waste acid water outlet 23.

[0011] The present invention also provides the use of the aforementioned device in the continuous flow reduction of aromatic azide compounds to prepare aromatic amine compounds.

[0012] The present invention also provides a method for preparing aromatic amine compounds by continuous flow reduction of aromatic azide compounds, comprising the following steps:

[0013] S1: dissolving an aromatic azide compound in an organic solvent to prepare solution A, and connecting to metering pump 1;

[0014] S2: dissolve the catalyst in the solvent to prepare solution B, which is connected to metering pump 2;

[0015] S3: dissolving the reducing agent in the solvent to prepare suspension C, which is connected to metering pump 3;

[0016] S4: The solution A described in S1 is added to the continuous flow reactor through the metering pump 1 via the feed port 28, and the solution B and the suspension C are added to the continuous flow reactor through the metering pump 2 and the metering pump 3 respectively. The solution A, the solution B and the suspension C react in the continuous flow reactor 27, and the reaction liquid enters the continuous filter 10 through the liquid outlet 18. The organic phase obtained by passing through the continuous phase separator 20 enters the continuous washer 21 together with the water in the metering pump 6. After washing, it is passed into the continuous phase separator 26 for phase separation. The organic phase is the organic phase containing aromatic amine compounds.

[0017] Furthermore, the aqueous phases obtained by phase separation in the continuous phase separator 20 and the continuous phase separator 26 enter the continuous disruptor 22 and are treated with acid in the metering pump 8 to become wastewater;

[0018] Preferably, the temperature of the continuous destroyer 22 is 10-20°C.

[0019] Further,

[0020] In step S1, the mass volume ratio of the aromatic azide compound to the organic solvent is 1:(5-10);

[0021] and / or, in step S2, the mass volume ratio of the catalyst to the solvent is 1:(1-5);

[0022] And / or, in step S2, the mass ratio of the catalyst to the aromatic azide compound in step S1 is 1:(1-5);

[0023] and / or, in step S3, the mass volume ratio of the reducing agent to the solvent is 1:(1-5);

[0024] And / or, in step S3, the mass ratio of the reducing agent to the aromatic azide compound in step S1 is 1:(1-5).

[0025] Further,

[0026] In step S4, when adding the liquid into the continuous flow reactor, the flow rate of metering pump 1 is 4 to 200 ml / min; the flow rate of metering pump 2 is 2 to 120 ml / min; and the flow rate of metering pump 3 is 2 to 120 ml / min.

[0027] And / or, in step S4, the reaction time is 30 to 35 minutes;

[0028] and / or, in step S4, the temperature in the continuous flow reactor 27 is 20° C. to 35° C.;

[0029] and / or, in step S4, the temperature in the continuous filter 10 is 20-30°C;

[0030] and / or, in step S4, the temperature in the continuous phase separators 20 and 26 is 20-30° C.;

[0031] and / or, in step S4, the temperature in the continuous scrubber 21 is 20-30°C;

[0032] Preferably,

[0033] The flow rate ratio of metering pump 1 to metering pump 2 is 1:0.5-0.6;

[0034] And / or, the flow rate ratio of the metering pump 1 to the metering pump 3 is 1:0.5-0.6.

[0035] Further,

[0036] In step S1, the organic solvent is methyl tert-butyl ether, n-heptane, toluene or methyl acetate;

[0037] And / or, in step S2, the catalyst is ammonium formate, ammonium chloride or ammonium sulfate;

[0038] and / or, in step S3, the reducing agent is iron powder or zinc powder;

[0039] Preferably, in step S1, the organic solvent is methyl tert-butyl ether.

[0040] Further,

[0041] In step S1, the structure of the aromatic azide compound is shown in Formula I:

[0042]

[0043] in,

[0044] n is 0, 1, 2, 3, 4 or 5;

[0045] R1 is a substituent on the benzene ring, and each R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy;

[0046] R2 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl;

[0047] R3 is selected from hydrogen;

[0048] R4 is selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy;

[0049] X is selected from CR5 or N;

[0050] R5 is selected from -OR6 or -SR6;

[0051] R6 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl;

[0052] And / or, in step S4, the structure of the aromatic amine compound is as shown in Formula II:

[0053]

[0054] in,

[0055] n is 0, 1, 2, 3, 4 or 5;

[0056] R1 is a substituent on the benzene ring, and each R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy;

[0057] R2 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl;

[0058] R3 is selected from hydrogen;

[0059] R4 is selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy;

[0060] X is selected from CR5 or N;

[0061] R5 is selected from -OR6 or -SR6;

[0062] R6 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl;

[0063] Preferably, in step S1, the aromatic azide compound is methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate;

[0064] And / or, in step S4, the aromatic amine compound is methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate.

[0065] Compared with the prior art, the present invention has the following beneficial effects:

[0066] (1) The present invention provides a method for preparing aromatic amines by reducing aromatic azide compounds using a continuous flow reaction technology. The method has a short reaction time and can be completed within 30 to 35 minutes, significantly improving the reaction efficiency.

[0067] (2) The present invention adopts continuous flow reaction technology, which allows materials to be quickly and effectively mixed together in a precise fixed ratio to react, thereby increasing the safety of the reaction and reducing the risk of explosion and leakage.

[0068] (3) The continuous flow reaction device occupies a small space, so it has low requirements for site and equipment.

[0069] (4) The present invention adopts a continuous flow reaction from the feeding, mixing and reaction process, which avoids the accumulation, explosion and leakage caused by the additional configuration and transfer required in conventional batch reactions, thereby improving environmental safety and production efficiency.

[0070] In summary, the continuous flow synthesis device and synthesis method of the present invention are used to reduce aromatic azide compounds to prepare aromatic amine compounds, which has the advantages of precise control of conditions, high safety, short reaction time, reduced explosiveness and flammability, simple operation, low equipment requirements, low site requirements, and environmental friendliness. It has great practical value in improving production safety and increasing production efficiency.

[0071] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0072] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 The present invention provides a modular design of a continuous flow reactor and a process flow chart for reducing aromatic azide compounds to prepare aromatic amine compounds.

[0074] Figure 2 Schematic diagram of the apparatus for the continuous flow reduction of aromatic azide compounds to prepare aromatic amine compounds. DETAILED DESCRIPTION

[0075] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0076] The reaction scheme of the present invention is as follows:

[0077]

[0078] in,

[0079] n is 0, 1, 2, 3, 4 or 5;

[0080] R1 is a substituent on the benzene ring, and each R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy;

[0081] R2 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl;

[0082] R3 is selected from hydrogen;

[0083] R4 is selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy;

[0084] X is selected from CR5 or N;

[0085] R5 is selected from -OR6 or -SR6;

[0086] R6 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl.

[0087] The modular design of the continuous flow reactor of the present invention and the process flow chart of reducing aromatic azide compounds to prepare aromatic amine compounds are shown in FIG. Figure 1 As shown; the device diagram is as follows Figure 2 shown.

[0088] The continuous flow reaction device of the present invention ( Figure 2 ) includes the following components:

[0089] Metering pumps 1, 2, 3, 4, 5, 6, 7, 8, 9, continuous filter 10, storage tanks 11, 12, 13, heating circulating water inlet 14, reagent 1 and reagent 2 mixed liquid feed inlet 15, mixed reaction gas and liquid outlet 16, exhaust port 17, liquid outlet 18, heating circulating water outlet 19, continuous phase separator 20, continuous scrubber 21, continuous destroyer 22, waste acid water outlet 23, organic phase outlet 24, aqueous phase outlet 25, continuous phase separator 26, continuous flow reactor 27, raw material liquid inlet 28.

[0090] The method for preparing aromatic amine compounds of the present invention comprises the following steps:

[0091] S1: dissolving the aromatic azide compound in a solvent to prepare solution A, which is connected to metering pump 1 as a raw material;

[0092] S2: Dissolve the catalyst in the solvent to prepare solution B, which is connected to metering pump 2 as reagent 1;

[0093] S3: dissolving the reducing agent in the solvent to prepare a suspension C, which is connected to the metering pump 3 as the reagent 2;

[0094] S4: The solution A in S1 is added to the continuous flow reactor 27 through the raw liquid inlet 28 by the metering pump 1, and the solution B and the suspension C are mixed by the metering pump 2 and the metering pump 3 respectively and added to the continuous flow reactor 27 through the mixed liquid feed port 15. The solution A reacts with the solution B and the suspension C in the continuous flow reactor 27 at 20°C to 35°C to generate a mixed reaction liquid containing amino groups. The reaction liquid flows into the continuous filter 10 through the liquid outlet 18, and after filtration, it is pumped into the continuous phase separator 20 through the metering pump 4. After phase separation, the upper organic phase enters the storage tank 1 1, the lower aqueous phase enters the storage tank 12; the organic phase enters the storage tank 11 and is pumped into the continuous scrubber 21 through the pump 5. At the same time, the metering pump 6 delivers water to the continuous scrubber 21. After washing, it enters the continuous phase separator 26. After phase separation, the upper organic phase is subjected to conventional post-treatment to obtain the aromatic amine product. The lower aqueous phase enters the storage tank 13 through the aqueous phase outlet 25 and is then pumped into the continuous disruptor 22 by the metering pump 9. At the same time, the aqueous phase separated in the previous step is pumped into the continuous flow disruptor 22 through the metering pump 7. At the same time, acid is pumped into the metering pump 8. After destruction, the aqueous phase is treated as waste liquid.

[0095] The present invention adds an aryl azide compound, a reducing agent, and a catalyst to a continuous flow reactor via a metering pump, undergoes a mixing reaction, and produces an arylamine solution. The arylamine product is then obtained through conventional post-processing. The present invention features precise control of conditions, high safety, a short reaction time, reduced explosiveness and flammability, simple operation, low equipment and site requirements, and environmental friendliness, offering significant practical value in improving production safety and efficiency.

[0096] Example 1. Preparation of aromatic amine compounds

[0097] The specific synthesis method of this embodiment is as follows:

[0098] 1. Preparation of solution

[0099] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 500 g of methyl tert-butyl ether is connected to metering pump 1;

[0100] Solution B: A mixed solution of 280 g purified water and 67 g ammonium formate is connected to metering pump 2;

[0101] Suspension C: A suspension of 35.6 g of iron powder and 120 g of purified water is connected to metering pump 3;

[0102] Solvent D: 1 kg purified water connected to metering pump 6;

[0103] Solvent E: 123 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0104] 2. The specific parameters of the module are as follows:

[0105] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0106] Continuous filter 10: maintain room temperature;

[0107] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0108] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0109] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0110] 3. The specific operations are as follows:

[0111] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 88.87g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid metering pump 8 is turned on at the same time to be added to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0112] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 95.5% and a purity of 94%.

[0113] Example 2: Preparation of aromatic amine compounds

[0114] The specific synthesis method of this embodiment is as follows:

[0115] 1. Preparation of solution

[0116] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 500 g of methyl tert-butyl ether is connected to metering pump 1;

[0117] Solvent B: A mixed solution of 280 g purified water and 67 g ammonium formate is connected to metering pump 2;

[0118] Suspension C: A suspension of 41.7 g zinc powder and 110 g purified water is connected to metering pump 3;

[0119] Solvent D: 1.0 kg purified water connected to metering pump 6;

[0120] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0121] 2. The specific parameters of the module are as follows:

[0122] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0123] Continuous filter 10: maintain room temperature;

[0124] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0125] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0126] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0127] 3. The specific operations are as follows:

[0128] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 90.26 g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and is combined with the aqueous phase in the previous step storage tank 12 by the metering pump 7 to enter the continuous destroyer 22, and the hydrochloric acid metering pump 8 is turned on at the same time to be added to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0129] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 97% and a purity of 95%.

[0130] Example 3: Preparation of aromatic amine compounds

[0131] The specific synthesis method of this embodiment is as follows:

[0132] 1. Preparation of solution

[0133] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 500 g of methyl tert-butyl ether is connected to metering pump 1;

[0134] Solvent B: A mixed solution of 290 g purified water and 56.8 g ammonium chloride is connected to metering pump 2;

[0135] Suspension C: A suspension of 35.6 g of iron powder and 120 g of purified water is connected to metering pump 3;

[0136] Solvent D: 1 kg purified water connected to metering pump 6;

[0137] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0138] 2. The specific parameters of the module are as follows:

[0139] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0140] Continuous filter 10: maintain room temperature;

[0141] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0142] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0143] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0144] 3. The specific operations are as follows:

[0145] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 89.8 g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid metering pump 8 is turned on at the same time to be added to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0146] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 96.5% and a purity of 94%.

[0147] Example 4. Preparation of aromatic amine compounds

[0148] The specific synthesis method of this embodiment is as follows:

[0149] 1. Preparation of solution

[0150] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 500 g of methyl tert-butyl ether is connected to metering pump 1;

[0151] Solvent B: A mixed solution of 290 g purified water and 56.8 g ammonium chloride is connected to metering pump 2;

[0152] Suspension C: A suspension of 41.7 g zinc powder and 110 g purified water is connected to metering pump 3;

[0153] Solvent D: 1 kg purified water connected to metering pump 6;

[0154] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0155] 2. The specific parameters of the module are as follows:

[0156] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0157] Continuous filter 10: maintain room temperature;

[0158] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0159] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0160] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0161] 3. The specific operations are as follows:

[0162] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 90.7 g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid pump 8 is turned on at the same time to add it to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0163] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 97.5% and a purity of 97%.

[0164] Example 5. Preparation of aromatic amine compounds

[0165] The specific synthesis method of this embodiment is as follows:

[0166] 1. Preparation of solution

[0167] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 500 g of methyl tert-butyl ether is connected to metering pump 1;

[0168] Solvent B: A mixed solution of 290 g purified water and 56.8 g ammonium sulfate is connected to metering pump 2;

[0169] Suspension C: A suspension of 41.7 g zinc powder and 110 g purified water is connected to metering pump 3;

[0170] Solvent D: 1 kg purified water connected to metering pump 6;

[0171] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0172] 2. The specific parameters of the module are as follows:

[0173] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0174] Continuous filter 10: maintain room temperature;

[0175] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0176] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0177] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0178] 3. The specific operations are as follows:

[0179] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 88.9 g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid metering pump 8 is turned on at the same time to be added to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0180] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 96% and a purity of 93%.

[0181] Example 6. Preparation of aromatic amine compounds

[0182] The specific synthesis method of this embodiment is as follows:

[0183] 1. Preparation of solution

[0184] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 500 g of n-heptane is connected to metering pump 1;

[0185] Solvent B: A mixed solution of 290 g purified water and 56.8 g ammonium chloride is connected to metering pump 2;

[0186] Suspension C: A suspension of 41.7 g zinc powder and 110 g water is connected to metering pump 3;

[0187] Solvent D: 1 kg purified water connected to metering pump 6;

[0188] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0189] 2. The specific parameters of the module are as follows:

[0190] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0191] Continuous filter 10: maintain room temperature;

[0192] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0193] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0194] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0195] 3. The specific operations are as follows:

[0196] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 88.4 g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid metering pump 8 is turned on at the same time to be added to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0197] The aromatic amine compound prepared in this example is methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate, with a total yield of 95% and a purity of 93%.

[0198] Example 7. Preparation of aromatic amine compounds

[0199] The specific synthesis method of this embodiment is as follows:

[0200] 1. Preparation of solution

[0201] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 590 g of toluene is connected to metering pump 1;

[0202] Solvent B: A mixed solution of 290 g purified water and 56.8 g ammonium chloride is connected to metering pump 2;

[0203] Suspension C: A suspension of 41.7 g zinc powder and 110 g water is connected to metering pump 3;

[0204] Solvent D: 1 kg purified water connected to metering pump 6;

[0205] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0206] 2. The specific parameters of the module are as follows:

[0207] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0208] Continuous filter 10: maintain room temperature;

[0209] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0210] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0211] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0212] 3. The specific operations are as follows:

[0213] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 through the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 86.5g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid pump 8 is turned on at the same time to add it to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0214] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 93% and a purity of 90%.

[0215] Example 8. Preparation of aromatic amine compounds

[0216] The specific synthesis method of this embodiment is as follows:

[0217] 1. Preparation of solution

[0218] Solution A: A mixed solution of 100 g of methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate and 630 g of methyl acetate was connected to metering pump 1;

[0219] Solvent B: A mixed solution of 290 g purified water and 56.8 g ammonium chloride is connected to metering pump 2;

[0220] Suspension C: A suspension of 41.7 g zinc powder and 110 g water is connected to metering pump 3;

[0221] Solvent D: 1 kg purified water connected to metering pump 6;

[0222] Solvent E: 80.3 g of hydrochloric acid solution (the concentration of the hydrochloric acid solution is 10%) is connected to the metering pump 8.

[0223] 2. The specific parameters of the module are as follows:

[0224] Continuous flow reactor 27: The circulation temperature reaches 25-35°C and reaches stability, with a volume of 1.2 L;

[0225] Continuous filter 10: maintain room temperature;

[0226] Continuous phase separators 20 and 26: maintained at room temperature, volume 3 L;

[0227] Continuous scrubber 21: circulation temperature 20-30°C, volume 50ml;

[0228] Continuous disruptor 22: Circulating temperature 10-20°C, and reaching stability, volume 50ml.

[0229] 3. The specific operations are as follows:

[0230] The automatic feeding system is turned on, solution A is transported to the continuous flow reactor 27 by the metering pump 1, while solution B is transported to the continuous flow reactor 27 by the metering pump 2, and suspension C is transported to the continuous flow reactor 27 by the metering pump 3. The flow rate of solution A is 23 ml / min, the flow rate of solution B is 11 ml / min, and the flow rate of suspension C is 5 ml / min. Solution A, solution B and suspension C react in the continuous flow reactor 27. After 30 minutes of feeding, the reaction liquid enters the continuous filter 10 from the discharge port 18, and the generated gas is discharged into the absorption tower from the exhaust port 17. The reaction solution after filtering through the continuous filter 10 is pumped into the continuous phase separator 20 through the metering pump 4, the upper organic phase flows into the storage tank 11, and the lower aqueous phase flows into the storage tank 12. The organic phase in the storage tank 11 is transported to the continuous washer 21 by the metering pump 5, and the water metering pump 6 is turned on at the same time to enter the continuous washer 21. After washing, it enters the continuous phase separator 26, and the upper organic phase enters the post-processing device (the post-processing device includes concentration, crystallization, filtration, and drying) through the organic phase outlet 24 to obtain 83.7 g of purified solid, or the organic phase can be directly put into the next reaction; the aqueous phase enters the storage tank 13, is transported by the metering pump 9 and the aqueous phase in the previous step storage tank 12 is transported by the metering pump 7 to merge into the continuous destroyer 22, and the hydrochloric acid metering pump 8 is turned on at the same time to be added to the continuous destroyer 22 for destruction. After destruction, the aqueous phase enters the waste liquid pool through the liquid outlet pipe 23.

[0231] The aromatic amine compound prepared in this example is (methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate), with a total yield of 90% and a purity of 94%.

[0232] Comparative Example 1: Preparation of aromatic amine compounds

[0233] Methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate (100 g) was dissolved in tetrahydrofuran / methanol (1:1, v:v) at room temperature. Under a nitrogen atmosphere, 10% palladium-on-carbon catalyst (1 g) was added. The nitrogen was then replaced three times with hydrogen. The reaction mixture was stirred at room temperature for 7 hours, during which the hydrogen was continuously replaced (every 0.5 hours). After the reaction, the palladium-on-carbon catalyst was filtered off, the mixture was concentrated under reduced pressure, and the methanol was removed by evaporation with n-heptane. The purified product (88.4 g) was obtained with a yield of 95% and a purity of 96%.

[0234] According to the summary of Examples 1 to 8 and Comparative Example 1, the information shown in Table 1 can be obtained.

[0235] Table 1. Reaction results of Examples 1 to 8 and Comparative Example 1

[0236] Group solvent Reagent 1 (catalyst) Reagent 2 (reducing agent) Yield purity Comparative Example 1 Tetrahydrofuran / methanol 10% palladium on carbon hydrogen 95％ 96％ Example 1 Methyl tert-butyl ether Ammonium formate die-hard fans 95.5％ 94％ Example 2 Methyl tert-butyl ether Ammonium formate zinc powder 97％ 95％ Example 3 Methyl tert-butyl ether Ammonium chloride die-hard fans 96.5％ 94％ Example 4 Methyl tert-butyl ether Ammonium chloride zinc powder 97.5％ 97％ Example 5 Methyl tert-butyl ether ammonium sulfate zinc powder 96％ 93％ Example 6 n-heptane Ammonium chloride zinc powder 95％ 93％ Example 7 Toluene Ammonium chloride zinc powder 93％ 90％ Example 8 Methyl acetate Ammonium chloride zinc powder 90％ 94％

[0237] To address the challenges of prior art methods using hydrogen as a reducing agent to prepare aromatic amine compounds, the present invention provides a continuous flow synthesis method for aromatic amine compounds. The product obtained by the present method exhibits high yield and purity. Furthermore, as shown in Table 1, even higher yields and purities are achieved using methyl tert-butyl ether as a solvent and iron or zinc powder as a reducing agent in the presence of a catalyst. Comprehensive analysis indicates that Example 4 represents the optimal process.

[0238] In summary, the continuous flow synthesis device and synthesis method of the present invention are used to reduce aromatic azide compounds to prepare aromatic amine compounds, which has the advantages of precise control of conditions, high safety, short reaction time, reduced explosiveness and flammability, simple operation, low equipment requirements, low site requirements, and environmental friendliness. It has great practical value in improving production safety and increasing production efficiency.

Claims

1. A device for preparing aromatic amine compounds by continuous flow reduction of aromatic azide compounds, characterized in that: It includes: Metering pump 1 (1), metering pump 2 (2), metering pump 3 (3), metering pump 6 (6), metering pump 8 (8), continuous flow reactor (27), continuous filter (10), continuous phase separator 1 (20), storage tank 1 (11), continuous scrubber (21), continuous phase separator 2 (26); The metering pump 1 (1) is connected to the continuous flow reactor (27) through the feed port 1 (28), and the metering pump 2 (2) and metering pump 3 (3) are connected to the continuous flow reactor (27) through the feed port 2 (15); the continuous flow reactor (27), the continuous filter (10), the continuous phase separator 1 (20), the continuous washer (21), and the continuous phase separator 2 (26) are connected in sequence; The continuous flow reactor (27) further includes a heating circulating water inlet (14), a mixed reaction gas and liquid outlet (16), an exhaust port (17), a liquid outlet (18), and a heating circulating water outlet (19); The continuous flow reactor (27) is connected to the continuous filter (10) through the liquid outlet (18); the continuous filter (10) is connected to the continuous phase separator (20) through the metering pump (4); the continuous phase separator (20) is connected to the storage tank (11) and the storage tank (12); the storage tank (11) is connected to the continuous scrubber (21) through the metering pump (5), and the continuous scrubber (21) is connected to the metering pump (6); the continuous scrubber (21) is also connected to the continuous The continuous phase separator 2 (26) is connected; the continuous phase separator 2 (26) has an organic phase outlet (24) and an aqueous phase outlet (25), and the aqueous phase outlet (25) is connected to the storage tank 3 (13); the storage tank 2 (12) is connected to the continuous disruptor (22) through the metering pump 7 (7), and the storage tank 3 (13) is connected to the continuous disruptor (22) through the metering pump 9 (9), and the metering pump 8 (8) is also connected to the continuous disruptor (22), and the continuous disruptor (22) is also connected to the waste acid water outlet (23).

2. Use of the device according to claim 1 in the continuous flow reduction of aromatic azide compounds to prepare aromatic amine compounds.

3. A method for preparing aromatic amine compounds by continuous flow reduction of aromatic azide compounds, characterized in that: The following steps are involved: S1: dissolve the aromatic azide compound in an organic solvent to prepare solution A, and connect the metering pump (1); S2: dissolve the catalyst in a solvent to prepare solution B, and connect it to metering pump 2 (2); S3: dissolving the reducing agent in the solvent to prepare suspension C, and connecting it to metering pump three (3); S4: The solution A described in S1 is added to the continuous flow reactor through the metering pump one (1) via the feed port one (28), and the solution B and the suspension C are added to the continuous flow reactor through the metering pump two (2) and the metering pump three (3) respectively. The solution A, the solution B and the suspension C react in the continuous flow reactor (27), and the reaction liquid enters the continuous filter (10) through the liquid outlet (18), and the organic phase obtained by the continuous phase separator one (20) and the water in the metering pump six (6) enter the continuous washer (21), and after washing, it is passed into the continuous phase separator two (26) for phase separation. The organic phase is the organic phase containing aromatic amine compounds.

4. The method according to claim 3, wherein: The aqueous phases obtained after phase separation in the continuous phase separator 1 (20) and the continuous phase separator 2 (26) enter the continuous destroyer (22) and are treated with acid in the metering pump 8 (8) to become wastewater.

5. The method according to claim 4, characterized in that: The temperature of the continuous destroyer (22) is 10-20°C.

6. The method according to claim 3, wherein: In step S1, the mass volume ratio of the aromatic azide compound to the organic solvent is 1:(5-10); And / or, in step S2, the mass volume ratio of the catalyst to the solvent is 1:(1-5); And / or, in step S2, the mass ratio of the catalyst to the aromatic azide compound in step S1 is 1:(1-5); And / or, in step S3, the mass volume ratio of the reducing agent to the solvent is 1:(1-5); And / or, in step S3, the mass ratio of the reducing agent to the aromatic azide compound in step S1 is 1:(1-5).

7. The method according to claim 3, wherein: In step S4, when adding the liquid into the continuous flow reactor, the flow rate of metering pump 1 (1) is 4-200 ml / min; the flow rate of metering pump 2 (2) is 2-120 ml / min; the flow rate of metering pump 3 (3) is 2-120 ml / min; And / or, in step S4, the reaction time is 30-35 min; and / or, in step S4, the temperature in the continuous flow reactor (27) is 20°C to 35°C; and / or, in step S4, the temperature in the continuous filter (10) is 20-30°C; and / or, in step S4, the temperature in the continuous phase separator 1 (20) and the continuous phase separator 2 (26) is 20-30°C; And / or, in step S4, the temperature in the continuous scrubber (21) is 20-30°C.

8. The method according to claim 7, wherein: The flow rate ratio of metering pump 1 (1) to metering pump 2 (2) is 1:0.5~0.6; And / or, the flow rate ratio of metering pump one (1) to metering pump three (3) is 1:0.5~0.

6.

9. The method according to claim 3, wherein: In step S1, the organic solvent is methyl tert-butyl ether, n-heptane, toluene or methyl acetate; And / or, in step S2, the catalyst is ammonium formate, ammonium chloride or ammonium sulfate; And / or, in step S3, the reducing agent is iron powder or zinc powder.

10. The method according to claim 9, characterized in that: In step S1, the organic solvent is methyl tert-butyl ether.

11. The method according to claim 3, wherein: In step S1, the structure of the aromatic azide compound is shown in Formula I: Formula I in, n is 0, 1, 2, 3, 4 or 5; R1 is a substituent on the benzene ring, each R1 is independently selected from halogen, C1~C6 alkyl, C1~C6 alkoxy, halogenated C1~C6 alkyl, halogenated C1~C6 alkoxy; R2 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl; R3 is selected from hydrogen; R4 is selected from hydrogen, halogen, C1~C6 alkyl, trifluoromethyl, trifluoromethoxy; X is selected from CR5 or N; R5 is selected from -OR6 or -SR6; R6 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl; And / or, in step S4, the structure of the aromatic amine compound is as shown in Formula II: Formula II in, n is 0, 1, 2, 3, 4 or 5; R1 is a substituent on the benzene ring, each R1 is independently selected from halogen, C1~C6 alkyl, C1~C6 alkoxy, halogenated C1~C6 alkyl, halogenated C1~C6 alkoxy; R2 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl; R3 is selected from hydrogen; R4 is selected from hydrogen, halogen, C1~C6 alkyl, trifluoromethyl, trifluoromethoxy; X is selected from CR5 or N; R5 is selected from -OR6 or -SR6; R6 is selected from benzyl, benzyl substituted by 1 to 3 methoxy groups, and C1 to C5 alkyl.

12. The method according to claim 11, wherein: In step S1, the aromatic azide compound is methyl 4-azido-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate; And / or, in step S4, the aromatic amine compound is methyl 4-amino-3-(tert-butylmercapto)-2-(2-fluorophenylamino)benzoate.

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