Method, device and application for hydroxylation of benzoic acid or benzoic acid derivatives

Abstract

The present invention discloses a method, device and application for hydroxylation of benzoic acid or benzoic acid derivatives, and relates to the technical field of organic chemical engineering. The hydroxylation method comprises: mixing a first mixture including benzoic acid or benzoic acid derivatives, an oxidant and a photoinitiator with oxygen, and performing a hydroxylation reaction under photocatalysis to obtain a hydroxylation reaction liquid containing a compound represented by formula (2). In the present invention, benzoic acid or benzoic acid derivatives are used as raw materials, and hydroxylation is performed under photocatalysis, which does not rely on precious metal catalysts while maintaining a high reaction efficiency and relatively small environmental pollution.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical engineering, and in particular to a method, a device and application for hydroxylating benzoic acid or a benzoic acid derivative. Background Art

[0002] 2-Acetoxybenzoic acid and its derivatives are widely used in the fields of medicine, materials and organic synthesis. In medicine, it is an important intermediate for anti-inflammatory, analgesic and antibacterial drugs; in organic synthesis, it participates in acylation and substitution reactions; in materials science, it is used as a stabilizer for coatings and polymer materials to improve heat resistance and mechanical strength. Therefore, they are of great value in the development of functional materials and drugs.

[0003] The method for synthesizing 2-acetoxybenzoic acid and its derivatives is usually based on 2-hydroxybenzoic acid and its derivatives as starting materials, and acetic anhydride or acetyl chloride is used for acetylation under concentrated sulfuric acid catalysis. However, the method has problems such as equipment corrosion, acidic waste liquid pollution and low yield. Therefore, the development of environmentally friendly and highly active catalysts to replace traditional protonic acid catalysis has become a research focus. In recent years, there are methods using benzoic acid and its derivatives as starting materials, and the efficiency of hydroxylation reaction is significantly improved by direct functionalization of CH bonds, but it usually depends on precious metal catalysts (such as palladium, ruthenium, rhodium), which is not conducive to the reduction of cost. Therefore, the development of efficient, environmentally friendly and low-cost synthesis processes has become an important research direction.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The object of the present invention is to provide a method, device and application for hydroxylation of benzoic acid or benzoic acid derivatives, avoiding the use of noble metal catalysts while ensuring the efficiency of hydroxylation.

[0006] The present invention is achieved in that:

[0007] In a first aspect, the present invention provides a method for hydroxylating benzoic acid or a benzoic acid derivative, comprising:

[0008] Hydroxylation, mixing a first mixture including a compound represented by formula (3), an oxidant and a photoinitiator with oxygen, and performing a hydroxylation reaction under photocatalysis to obtain a hydroxylation reaction liquid containing a compound represented by formula (2); wherein the structures of the compound represented by formula (3) and the compound represented by formula (2) are as follows:

[0009]

[0010] Wherein, R is hydroxyl, alkoxy, halogen or alkyl acyl.

[0011] The compound of formula (3) is used as a raw material and hydroxylated under photocatalysis to synthesize the compound of formula (2). This method does not rely on precious metal catalysts and can maintain a high reaction efficiency, and has relatively little environmental pollution.

[0012] In an optional embodiment, the hydroxylation reaction comprises at least one of the following:

[0013] (1) The reaction temperature is 25°C to 60°C;

[0014] (2) The duration is 0.5 to 20 minutes;

[0015] (3) The reaction pressure is 0 to 1.0 MPa;

[0016] (4) The wavelength of the light source used for catalysis is 390nm-600nm;

[0017] (5) The molar ratio of the compound represented by formula (3), the oxidant, the photoinitiator and the oxygen is 1:(0.01-1):(0.01-0.5):(1.8-2.2).

[0018] Carrying out the hydroxylation reaction under this condition is beneficial to improving the conversion rate of the hydroxylation reaction while taking into account the reaction efficiency.

[0019] In an optional embodiment, the oxidant is selected from at least one of titanium dioxide, cupric chloride, sodium chlorate, o-benzoquinone, p-benzoquinone, dicyanoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, benzoyl peroxide, hydrogen peroxide, potassium permanganate, chromium chloride, and chlorine dioxide; preferably, the oxidant is selected from at least one of o-benzoquinone, p-benzoquinone, dicyanoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, benzoyl peroxide, and hydrogen peroxide;

[0020] There are many kinds of oxidants in the prior art, among which titanium dioxide, copper chloride, sodium chlorate, etc. have strong oxidizing properties, but the reaction conditions and side reactions are limited; o-benzoquinone, p-benzoquinone, dicyanoquinone, etc. have high selectivity and reactivity, can effectively promote the reaction and reduce by-products, and are better than improving the reaction efficiency. Oxidants such as benzoyl peroxide and hydrogen peroxide show stability and good environmental friendliness under mild conditions.

[0021] In an optional embodiment, the photoinitiator is selected from at least one of tert-butyl nitrite, ethyl nitrite, isopropyl nitrite, n-butyl nitrite, tert-butyl hydroperoxide, 1-hydroxycyclohexyl phenyl ketone, (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide, coumarin, and diazetidin; preferably, the photoinitiator is selected from at least one of tert-butyl nitrite, ethyl nitrite, isopropyl nitrite, and n-butyl nitrite;

[0022] Nitrite photoinitiators (such as tert-butyl nitrite, ethyl nitrite, etc.) have strong absorption peaks in the 390-600nm ultraviolet visible light band, can efficiently absorb light energy and excite to a high energy state, generate highly reactive free radicals or excited state substances, and promote subsequent chemical reactions. In addition, the synthesis process of nitrite photoinitiators is mature, the cost is low, and it has strong industrial application potential, can achieve excellent initiation performance, and has obvious advantages in cost and operation.

[0023] In an optional embodiment, the first mixture also includes an organic solvent, and the organic solvent is selected from at least one of methanol, ethanol, isopropanol, water, acetonitrile, ethyl acetate, dichloromethane, chloroform, acetone, N,N-dimethylformamide, and N,N-dimethylacetamide; preferably, the organic solvent is selected from at least one of water, acetonitrile, acetone, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0024] The hydroxylation reaction can have a high conversion rate and efficiency without the use of precious metal catalysts, which is beneficial to reducing production costs.

[0025] In a second aspect, the present application provides a method for synthesizing 2-acetoxybenzoic acid and its derivatives, comprising:

[0026] Synthesize the compound represented by formula (2) according to any one of the methods described in the above embodiments;

[0027] Acylation, placing the second mixture of the compound represented by formula (2) and the acylating agent in the presence of microwaves and a catalyst for acylation reaction, cooling and crystallizing the liquid after the acylation reaction to obtain the compound represented by formula (1), wherein the structure of the compound represented by formula (1) is as follows:

[0028]

[0029] In the present invention, the acylation reaction is carried out in the presence of microwaves and a catalyst to prepare the 2-acetoxybenzoic acid and its derivatives described in formula (1), which can improve the yield of 2-acetoxybenzoic acid and its derivatives.

[0030] In an alternative embodiment, the acylation step comprises at least one of the following:

[0031] (1) The reaction time is 0.5 min to 5 min;

[0032] (2) The reaction pressure is 0 to 1.5 MPa;

[0033] (3) Microwave output power is 100W to 300W;

[0034] (4) The molar ratio of the compound represented by formula (2), the acylating agent and the catalyst is 1:(1-3):(0.01-1).

[0035] Carrying out the acylation reaction under this condition is conducive to improving the conversion rate of the acylation reaction while taking into account the conversion efficiency.

[0036] In an optional embodiment, the acylating agent is at least one of carboxylic acids, acid anhydrides, acid halides, amides, esters and aromatic compounds; preferably at least one of acetic acid, acetic anhydride, trifluoroacetic anhydride, acetyl chloride, acetamide, N-methylacetamide, N-acetyl-2,2-dimethylpropionamide, ethyl acetate, vinyl acetate, isopropenyl acetate, trimethylsilyl acetate, 2,3-butanedione, 2,2-dimethyl-1,3-dioxane-4,6-dione, acetanilide, 2-acetyl-4,5-dichloro-3(2H)-pyridazine, 2-acetylbenzimidazole and N-acetylphthalimide; more preferably at least one of acetic acid, acetic anhydride, acetyl chloride, acetamide, ethyl acetate, vinyl acetate and trimethylsilyl acetate;

[0037] In the acylation reaction, highly reactive acylating agents such as acetic acid, acetic anhydride and acetyl chloride are preferred, as they can react quickly with nucleophiles and greatly improve the reaction efficiency. In addition, acetates such as ethyl acetate are widely used in various reaction conditions because the ester products they generate have high stability and adaptability.

[0038] In an optional embodiment, the catalyst is at least one of an ion exchange resin, a solid acid catalyst, a solid base catalyst, a metal oxide catalyst, a transition metal catalyst and a molecular sieve; preferably a cation exchange resin or a molecular sieve; more preferably at least one of Dowex50WX2-100 cation exchange resin, D061 cation exchange resin, D072 cation exchange resin, IR120 cation exchange resin, NKC-9 cation exchange resin, 732-resin cation exchange resin, Amberlyst-15 cation exchange resin, ZSM-5 molecular sieve and MCM-41 molecular sieve.

[0039] There are many types of catalysts to choose from in the acylation reaction, which are easy to recycle and do not require the introduction of traditional proton acids as acylation reaction catalysts, thus avoiding the problems of proton acid corrosion to equipment and environmental pollution.

[0040] In a third aspect, an embodiment of the present application provides a device for hydroxylating benzoic acid or a benzoic acid derivative, comprising a first micromixer, wherein the inlet of the first micromixer is connected to a first storage tank and an oxygen source, and the outlet of the first micromixer is sequentially connected to a photocontinuous flow reactor, a gas-liquid separator and a liquid-liquid separator; wherein the first storage tank is used to hold a first mixture including a compound represented by formula (3), an oxidant and a photoinitiator; wherein the structure of the compound represented by formula (3) is as follows:

[0041]

[0042] Wherein, R is hydroxyl, alkoxy, halogen or alkyl acyl.

[0043] The hydroxylation reaction is carried out in a photocontinuous flow reactor, which has high photon utilization rate, good reaction reproducibility, is independent of precious metal catalysts, and is easy to scale up for production.

[0044] In a fourth aspect, an embodiment of the present application provides a synthesis device for 2-acetoxybenzoic acid and its derivatives, comprising the device for hydroxylating benzoic acid or benzoic acid derivatives described in the aforementioned embodiment and a second micromixer, wherein the inlet of the second micromixer is connected to an acylating agent storage tank and an organic phase outlet of the liquid-liquid separator, the outlet of the second micromixer is connected to a microwave continuous flow reactor, the outlet of the microwave continuous flow reactor is sequentially connected to a third micromixer, a mixed continuous flow reactor and a solid-liquid separator, the solid phase outlet of the solid-liquid separator is provided with a collection pipeline for the compound of formula (1), and the inlet of the third micromixer is also connected to a water tank; wherein the structure of the compound represented by formula (1) is as follows:

[0045]

[0046] The microwave continuous flow reactor has excellent mass transfer, heat transfer and molecular mixing performance, which can shorten the reaction time from dozens of hours in the traditional intermittent reactor method to about 5 minutes, and can significantly improve the reaction efficiency. The micro mixer is used in conjunction with the microwave continuous flow reactor to ensure the mixing efficiency of the raw materials and thus ensure the stable operation of the equipment.

[0047] In an optional embodiment, the optical continuous flow reactor comprises a first continuous reaction device, an integrated light source device and a thermostat, wherein the integrated light source device is used to provide a wavelength-adjustable light source, and the thermostat is used to adjust and control the reaction temperature of the first continuous reaction device;

[0048] And / or, the microwave continuous flow reactor comprises a second continuous reaction device and a microwave generator integrated on the second continuous reaction device;

[0049] And / or, a pulser is further arranged between the first micro-mixer and the first storage tank.

[0050] In an optional embodiment, the first continuous reaction device, the second continuous reaction device and the mixed continuous flow reactor are one of a continuous flow reactor, a static tubular continuous flow reactor, a dynamic oscillating tubular continuous flow reactor, a fixed bed reactor or a plate-type oscillating continuous flow reactor; in some optional embodiments, the inner diameter of the static tubular continuous flow reactor or the dynamic oscillating tubular continuous flow reactor is 1 mm to 10 cm; the inner diameter of the channel of the plate-type oscillating continuous flow reactor is 10 cm to 50 cm; the inner diameter of the fixed bed reactor is 0.5 cm to 2.0 cm, and the length is 5 cm to 20 cm.

[0051] And / or, the first micromixer, the second micromixer and the third micromixer are each independently selected from any one of a static mixer, a T-type micromixer, a Y-type micromixer, a cross mixer, a coaxial flow micromixer, a dynamic continuous stirring mixer and a flow focusing micromixer.

[0052] The synthesis device of 2-acetoxybenzoic acid and its derivatives provided in the embodiment of the present application can realize the fully continuous synthesis of the raw material compound of formula (3) to 2-acetoxybenzoic acid and its derivatives of formula (1). The process has a high degree of automation, no intermediate intervention is required, the time and space efficiency is high, manual operation is reduced, and the labor intensity and production cost are reduced. The fully continuous flow microchannel process can realize the simultaneous multiphase mixing, mass transfer and reaction, the operating conditions are mild and simple, no stirring equipment is required, the process energy consumption is greatly reduced, and industrial production can be quickly realized.

[0053] The present invention has the following beneficial effects:

[0054] In the present invention, benzoic acid or a benzoic acid derivative is used as a raw material, and hydroxylation is carried out under the action of photocatalysis, which does not rely on precious metal catalysts and can maintain a high reaction efficiency while causing relatively little environmental pollution.

[0055] The acylation reaction is carried out in the presence of microwaves and a catalyst to prepare the 2-acetoxybenzoic acid and its derivatives described in formula (1), which can improve the yield of 2-acetoxybenzoic acid and its derivatives.

[0056] The hydroxylation reaction is carried out in a photocontinuous flow reactor, which has high photon utilization rate, good reaction reproducibility, is independent of precious metal catalysts, and is easy to scale up for production.

[0057] The microwave continuous flow reactor has excellent mass transfer, heat transfer and molecular mixing performance, which can shorten the reaction time from dozens of hours in the traditional intermittent reactor method to about 5 minutes, and can significantly improve the reaction efficiency. The micro mixer is used in conjunction with the microwave continuous flow reactor to ensure the mixing efficiency of the raw materials and thus ensure the stable operation of the equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0059] Figure 1 Schematic diagram of the synthesis device of 2-acetoxybenzoic acid and its derivatives in Example 1.

[0060] Illustration: 1-first storage tank; 2-feed pump; 3-pulser; 4-first micro mixer; 5-gas flow meter; 6-integrated light source device; 7-first continuous reaction device; 8-thermostat; 9-first back pressure valve; 10-gas-liquid separator; 11-liquid-liquid separator; 12-microwave generator; 13-second continuous reaction device; 14-second back pressure valve; 15-third micro mixer; 16-mixed continuous flow reactor; 17-continuous filter; 18-control valve; 19-filtrate collection pipeline; 20-formula (1) compound collection pipeline; 21-second micro mixer; 22-acylating agent storage tank; 23-water tank; 24-oxygen source. DETAILED DESCRIPTION

[0061] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0062] An embodiment of the present invention provides a method for hydroxylating benzoic acid or a benzoic acid derivative, comprising:

[0063] Hydroxylation, mixing a first mixture including a compound represented by formula (3), an oxidant and a photoinitiator with oxygen, and performing a hydroxylation reaction under photocatalysis to obtain a hydroxylation reaction liquid containing a compound represented by formula (2); wherein the structures of the compound represented by formula (3) and the compound represented by formula (2) are as follows:

[0064]

[0065]

[0066] Wherein, R is hydroxyl, alkoxy, halogen or alkyl acyl.

[0067] In this embodiment, a mixed solution of the compound represented by formula (3), an oxidant and a photoinitiator is mixed with oxygen, and then a hydroxylation reaction is carried out. After the reaction is completed, gas-liquid separation and liquid-liquid separation can be carried out in sequence to obtain a solution containing the compound represented by formula (2). The compound represented by formula (3) is used as a raw material, and hydroxylation is carried out under photocatalysis to synthesize the compound represented by formula (2). It does not need to rely on a precious metal catalyst while maintaining a high reaction efficiency and relatively small environmental pollution.

[0068] In an optional embodiment, the hydroxylation reaction comprises at least one of the following:

[0069] (1) The reaction temperature is 25°C to 60°C;

[0070] (2) The duration is 0.5 to 20 minutes;

[0071] (3) The reaction pressure is 0 to 1.0 MPa;

[0072] (4) The wavelength of the light source used for catalysis is 390nm-600nm;

[0073] (5) The molar ratio of the compound represented by formula (3), the oxidant, the photoinitiator and the oxygen is 1:(0.01-1):(0.01-0.5):(1.8-2.2).

[0074] In an optional embodiment, the temperature of the hydroxylation reaction is 25°C to 60°C, specifically 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C or any value between 25°C and 60°C; the time is 0.5min to 20min, specifically 0.5min, 1min, 5min, 10min, 15min, 20min or any value between 0.5min and 20min; the pressure is 0 to 1.0MPa, specifically 0.1MPa, 2MPa a, 4MPa, 6MPa, 8MPa, 1.0MPa or any value between 0 and 1.0MPa; the wavelength of the light source used for catalysis is 390nm-600nm, specifically 390nm, 450nm, 500nm, 550nm, 600nm or any value between 390nm and 600nm; preferably, the temperature of the hydroxylation reaction is 25°C to 40°C, the time is 2min to 15min, the pressure is 0 to 0.5MPa, and the wavelength of the light source used for catalysis is 390nm-460nm.

[0075] Carrying out the hydroxylation reaction under this condition is conducive to improving the conversion rate of the hydroxylation reaction while taking into account the reaction efficiency. Among them, the reaction temperature and pressure will affect the reaction efficiency and conversion rate. Too low or too high will lead to a decrease in conversion rate or reaction efficiency; the wavelength of the light source needs to be compatible with the photoinitiator, otherwise the photocatalytic effect will be reduced.

[0076] In an optional embodiment, in the hydroxylation reaction, the molar ratio of the compound represented by formula (3), the oxidant, the photoinitiator and the oxygen is 1:(0.01-1):(0.01-0.5):(1.8-2.2), specifically, it can be any value between 1:0.01:0.5:1.8, 1:0.05:0.3:1.9, 1:0.1:0.2:2.0, 1:0.5:0.1:2.1, 1:1:0.01:2.2 or 1:(0.01-1):(0.01-0.5):(1.8-2.2), preferably 1:(0.02-0.5):(0.02-0.3):(1.8-2.2).

[0077] Among them, the compound shown in formula (3), the oxidant, and oxygen are used as reactants. If any one of the reactants is used in excessive amounts, the conversion rate of the excess reactants will be reduced, thereby causing a waste of raw materials; the amount of photoinitiator used will affect the selectivity of the reaction. If the amount of photoinitiator used is too small, it will lead to an increase in side reactions, thereby causing a decrease in yield. However, if the amount of photoinitiator is excessive, it will also cause a waste of catalysts. Carrying out the hydroxylation reaction under the above conditions is conducive to improving the conversion rate of the hydroxylation reaction while taking into account the reaction efficiency.

[0078] In an optional embodiment, the oxidant is selected from at least one of titanium dioxide, cupric chloride, sodium chlorate, o-benzoquinone, p-benzoquinone, dicyanoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, benzoyl peroxide, hydrogen peroxide, potassium permanganate, chromium chloride, and chlorine dioxide; preferably, the oxidant is selected from at least one of o-benzoquinone, p-benzoquinone, dicyanoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, benzoyl peroxide, and hydrogen peroxide;

[0079] There are many kinds of oxidants in the prior art, among which titanium dioxide, copper chloride, sodium chlorate, etc. have strong oxidizing properties, but the reaction conditions and side reactions are limited; o-benzoquinone, p-benzoquinone, dicyanoquinone, etc. have high selectivity and reactivity, can effectively promote the reaction and reduce by-products, and are better than improving the reaction efficiency. Oxidants such as benzoyl peroxide and hydrogen peroxide show stability and good environmental friendliness under mild conditions.

[0080] In an optional embodiment, the photoinitiator is selected from at least one of tert-butyl nitrite, ethyl nitrite, isopropyl nitrite, n-butyl nitrite, tert-butyl hydroperoxide, 1-hydroxycyclohexyl phenyl ketone, (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide, coumarin, and diazetidin; preferably, the photoinitiator is selected from at least one of tert-butyl nitrite, ethyl nitrite, isopropyl nitrite, and n-butyl nitrite;

[0081] Nitrite photoinitiators (such as tert-butyl nitrite, ethyl nitrite, etc.) have strong absorption peaks in the 390-600nm ultraviolet visible light band, can efficiently absorb light energy and excite to a high energy state, generate highly reactive free radicals or excited state substances, and promote subsequent chemical reactions. In addition, the synthesis process of nitrite photoinitiators is mature, the cost is low, and it has strong industrial application potential, can achieve excellent initiation performance, and has obvious advantages in cost and operation.

[0082] In an optional embodiment, the first mixture also includes an organic solvent, and the organic solvent is selected from at least one of methanol, ethanol, isopropanol, water, acetonitrile, ethyl acetate, dichloromethane, chloroform, acetone, N,N-dimethylformamide, and N,N-dimethylacetamide; preferably, the organic solvent is selected from at least one of water, acetonitrile, acetone, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0083] The hydroxylation reaction can have a high conversion rate and efficiency without the use of precious metal catalysts, which is beneficial to reducing production costs.

[0084] The present invention also provides a method for synthesizing 2-acetoxybenzoic acid and its derivatives, comprising:

[0085] Synthesize the compound represented by formula (2) according to any one of the methods described in the above embodiments;

[0086] Acylation, placing the second mixture of the compound represented by formula (2) and the acylating agent in the presence of microwaves and a catalyst for acylation reaction, cooling and crystallizing the liquid after the acylation reaction to obtain the compound represented by formula (1), wherein the structure of the compound represented by formula (1) is as follows:

[0087]

[0088] In this embodiment, a solution containing the compound represented by formula (2) is mixed with an acylating agent, and then transferred to a microwave reactor in the presence of a catalyst to perform an acylation reaction. After the acylation reaction is completed, the acylation reaction liquid can be mixed with water to cool down, so that the compound represented by formula (1) is cooled and crystallized, and then solid-liquid separation is performed to obtain the compound represented by formula (1). In the present invention, an acylation reaction is performed in the presence of microwaves and a catalyst to prepare 2-acetoxybenzoic acid and its derivatives represented by formula (1), which can improve the yield of 2-acetoxybenzoic acid and its derivatives.

[0089] In an alternative embodiment, the acylation step comprises at least one of the following:

[0090] (1) The reaction time is 0.5 min to 5 min;

[0091] (2) The reaction pressure is 0 to 1.5 MPa;

[0092] (3) Microwave output power is 100W to 300W;

[0093] (4) The molar ratio of the compound represented by formula (2), the acylating agent and the catalyst is 1:(1-3):(0.01-1).

[0094] In an optional embodiment, the acylation reaction time is 0.5 min to 5 min, specifically 0.5 min, 1 min, 2 min, 3 min, 4 min, 5 min or any value between 0.5 min and 5 min; the reaction pressure is 0 to 1.5 MPa, specifically 0.3 MPa, 0.6 MPa, 0.9 MPa, 1.2 MPa, 1.5 MPa or any value between 0 and 1.5 MPa; the microwave output power is 100 W to 300 W, specifically 100 W, 150 W, 200 W, 250 W, 300 W or any value between 100 W and 300 W; preferably, the acylation reaction time is 0.5 min to 3 min, the reaction pressure is 0.5 MPa to 1.5 MPa, and the microwave output power is 150 W to 300 W;

[0095] Among them, the reaction temperature and pressure will affect the reaction efficiency and conversion rate. Too low or too high will lead to a decrease in conversion rate or reaction efficiency; microwave power will affect the reaction temperature and, at the same time, can provide energy for the reaction, which is beneficial to increase the reaction rate of the acylation reaction relative to the side reaction, and is beneficial to further increase the yield of 2-acetoxybenzoic acid and its derivatives.

[0096] In an optional embodiment, in the acylation reaction, the molar ratio of the compound represented by formula (2), the acylating agent and the catalyst is 1:(1-3):(0.01-1), specifically, it can be any value between 1:1:1, 1:1.5:0.75, 1:2:0.5, 1:2.5:0.25, 1:3:0.01 or 1:(1-3):(0.01-1); preferably, it is 1:(1.2-2):(0.01-0.5).

[0097] Wherein, the compound represented by formula (2) and the acylating agent are used as reactants. If any one of the reactants is used in excessive amounts, the conversion rate of the excess reactants will be reduced, thereby causing a waste of raw materials. The amount of catalyst used will affect the selectivity of the reaction. If the catalyst is used in too little amount, side reactions will increase, thereby causing a decrease in yield. However, if the catalyst is used in excessive amounts, it will also cause a waste of the catalyst. Carrying out the acylation reaction under the above conditions is conducive to improving the conversion rate of the acylation reaction while taking into account the conversion efficiency.

[0098] In an optional embodiment, the acylating agent is at least one of carboxylic acids, acid anhydrides, acid halides, amides, esters and aromatic compounds; preferably at least one of acetic acid, acetic anhydride, trifluoroacetic anhydride, acetyl chloride, acetamide, N-methylacetamide, N-acetyl-2,2-dimethylpropionamide, ethyl acetate, vinyl acetate, isopropenyl acetate, trimethylsilyl acetate, 2,3-butanedione, 2,2-dimethyl-1,3-dioxane-4,6-dione, acetanilide, 2-acetyl-4,5-dichloro-3(2H)-pyridazine, 2-acetylbenzimidazole and N-acetylphthalimide; more preferably at least one of acetic acid, acetic anhydride, acetyl chloride, acetamide, ethyl acetate, vinyl acetate and trimethylsilyl acetate;

[0099] In the acylation reaction, highly reactive acylating agents such as acetic acid, acetic anhydride and acetyl chloride are preferred, as they can react quickly with nucleophiles and greatly improve the reaction efficiency. In addition, acetates such as ethyl acetate are widely used in various reaction conditions because the ester products they generate have high stability and adaptability.

[0100] In an optional embodiment, the catalyst is at least one of an ion exchange resin, a solid acid catalyst, a solid base catalyst, a metal oxide catalyst, a transition metal catalyst and a molecular sieve; preferably a cation exchange resin or a molecular sieve; more preferably at least one of Dowex50WX2-100 cation exchange resin, D061 cation exchange resin, D072 cation exchange resin, IR120 cation exchange resin, NKC-9 cation exchange resin, 732-resin cation exchange resin, Amberlyst-15 cation exchange resin, ZSM-5 molecular sieve and MCM-41 molecular sieve.

[0101] There are many types of catalysts to choose from in the acylation reaction, which are easy to recycle and do not require the introduction of traditional proton acids as acylation reaction catalysts, thus avoiding the problems of proton acid corrosion to equipment and environmental pollution.

[0102] In an optional embodiment, the temperature of the cooling crystallization step is -10°C to 25°C, specifically -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or any value between -10°C and 25°C, preferably -10°C to 0°C.

[0103] In some embodiments, in the cooling crystallization step, the acylation reaction liquid is mixed with deionized water and then passed through a continuous flow reactor for cooling crystallization, and then filtered through a continuous filter 17 to obtain a compound of formula (1), wherein the residence time of the material in the continuous flow reactor is 1 min to 5 min, specifically 1 min, 2 min, 3 min, 4 min, 5 min or any value between 1 min and 5 min, preferably 2 min to 5 min.

[0104] The embodiment of the present invention also provides a device for hydroxylating benzoic acid or a benzoic acid derivative, comprising a first micromixer 4, wherein the inlet of the first micromixer 4 is connected to a first storage tank 1 and an oxygen source 24, and the outlet of the first micromixer 4 is sequentially connected to a photocontinuous flow reactor, a gas-liquid separator 10 and a liquid-liquid separator 11; wherein the first storage tank 1 is used to contain a first mixture including a compound represented by formula (3), an oxidant and a photoinitiator; wherein the structure of the compound represented by formula (3) is as follows:

[0105]

[0106] Wherein, R is hydroxyl, alkoxy, halogen or alkyl acyl.

[0107] In this embodiment, the mixed solution of the compound represented by formula (3), the oxidant and the photoinitiator and the oxygen are respectively transported to the first micro mixer 4 for mixing, and then enter the photocontinuous flow reactor for hydroxylation reaction. After the reaction is completed, online continuous gas-liquid separation and online continuous liquid-liquid separation are sequentially performed to obtain a solution containing the compound represented by formula (2).

[0108] The hydroxylation reaction is carried out in a photocontinuous flow reactor, which has high photon utilization rate, good reaction reproducibility, is independent of precious metal catalysts, and is easy to scale up for production.

[0109] The embodiment of the present invention also provides a synthesis device of 2-acetoxybenzoic acid and its derivatives, comprising the device for hydroxylating benzoic acid or benzoic acid derivatives described in the above embodiment and a second micro-mixer 21, the inlet of the second micro-mixer 21 is connected to the acylating agent storage tank 22 and the organic phase outlet of the liquid-liquid separator 11, the outlet of the second micro-mixer 21 is connected to a microwave continuous flow reactor, the outlet of the microwave continuous flow reactor is sequentially connected to a third micro-mixer 15, a mixing continuous flow reactor 16 and a solid-liquid separator, the solid phase outlet of the solid-liquid separator is provided with a collection pipeline 20 of the compound of formula (1), and the inlet of the third micro-mixer 15 is also connected to a water tank 23; wherein the structure of the compound represented by formula (1) is as follows:

[0110]

[0111] In this embodiment, a solution containing the compound represented by formula (2) is mixed with an acylating agent in a second micro-mixer 21, and then transferred to a microwave continuous flow reactor in the presence of a catalyst to carry out an acylation reaction. After the acylation reaction is completed, the acylation reaction liquid can be mixed with water in a third micro-mixer 15 and then transferred to a mixing continuous flow reactor 16 to cool and crystallize the compound represented by formula (1), and then solid-liquid separation is carried out in a solid-liquid separator to obtain the compound represented by formula (1).

[0112] The microwave continuous flow reactor has excellent mass transfer, heat transfer and molecular mixing performance, which can shorten the reaction time from dozens of hours in the traditional intermittent reactor method to about 5 minutes, and can significantly improve the reaction efficiency. The micro mixer is used in conjunction with the microwave continuous flow reactor to ensure the mixing efficiency of the raw materials and thus ensure the stable operation of the equipment.

[0113] In an optional embodiment, the photocontinuous flow reactor includes a first continuous reaction device 7, an integrated light source device 6 and a thermostat 8, wherein the integrated light source device 6 is used to provide a light source with adjustable wavelength, and the thermostat 8 is used to adjust and control the reaction temperature of the first continuous reaction device 7.

[0114] In an optional embodiment, the light source is a Visible Light-LED, and the wavelength of the light source is 390nm-600nm, specifically, it can be 390nm, 450nm, 500nm, 550nm, 600nm or any value between 390nm-600nm;

[0115] In an optional embodiment, the microwave continuous flow reactor comprises a second continuous reaction device 13 and a microwave generator 12 integrated on the second continuous reaction device 13. In an optional embodiment, the power of the microwave generator 12 is 100W to 300W, specifically, it can be 100W, 150W, 200W, 250W, 300W or any value between 100W and 300W;

[0116] In an optional embodiment, a pulser 3 is further provided between the first micro-mixer 4 and the first storage tank 1 to improve the mixing efficiency of the reaction mixer.

[0117] In an optional embodiment, the first continuous reaction device 7, the second continuous reaction device 13 and the mixed continuous flow reactor 16 are one of a continuous flow reactor, a static tubular continuous flow reactor, a dynamic oscillating tubular continuous flow reactor, a fixed bed reactor or a plate oscillating continuous flow reactor. In an optional embodiment, the inner diameter of the static tubular continuous flow reactor or the dynamic oscillating tubular continuous flow reactor is 1mm to 10cm; the inner diameter of the channel of the plate oscillating continuous flow reactor is 10cm to 50cm; the inner diameter of the fixed bed reactor is 0.5cm to 2.0cm, and the length is 5cm to 20cm;

[0118] And / or, the first micromixer 4, the second micromixer 21 and the third micromixer 15 are each independently selected from any one of a static mixer, a T-type micromixer, a Y-type micromixer, a cross mixer, a coaxial flow micromixer, a dynamic continuous stirring mixer and a flow focusing micromixer; preferably any one of a static mixer, a T-type micromixer and a dynamic continuous stirring mixer.

[0119] The synthesis device of 2-acetoxybenzoic acid and its derivatives provided in the embodiment of the present application can realize the fully continuous synthesis of the raw material compound of formula (3) to 2-acetoxybenzoic acid and its derivatives of formula (1). The process has a high degree of automation, no intermediate intervention is required, the time and space efficiency is high, manual operation is reduced, and the labor intensity and production cost are reduced. The fully continuous flow microchannel process can realize the simultaneous multiphase mixing, mass transfer and reaction, the operating conditions are mild and simple, no stirring equipment is required, the process energy consumption is greatly reduced, and industrial production can be quickly realized.

[0120] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0121] Example 1

[0122] This embodiment provides a synthesis device for 2-acetoxybenzoic acid and its derivatives, specifically as follows Figure 1As shown, it includes a first storage tank 1, a feed pump 2, a pulser 3, a first micromixer 4, a light continuous flow reactor, a first back pressure valve 9, a gas-liquid separator 10, a liquid-liquid separator 11, a second micromixer 21, a microwave continuous flow reactor, a second back pressure valve 14, a third micromixer 15, a mixed continuous flow reactor 16 and a continuous filter 17, which are connected in sequence. The inlet of the first micromixer 4 is also connected to an oxygen source 24, and the outlet of the oxygen source 24 is provided with a gas flow meter 5; the inlet of the second micromixer 21 is also connected to an acylating agent storage tank 22; the inlet of the third micromixer 15 is also connected to a water tank 23. The first storage tank 1 is used to store reaction materials, including the compound shown in formula (3), an oxidant and a photoinitiator; the feed pump 2 is used to adjust and control the liquid flow rate, and the pulser 3 is used to improve the mixing efficiency of the reaction mixer; the gas flow meter 5 is used to measure and control the gas flow; the optical continuous flow reactor includes an integrated light source device 6, a plate-type oscillating continuous flow reactor and a thermostat 8, wherein the integrated light source device 6 is used to adjust and control the wavelength of the light source, and the thermostat 8 is used to adjust and control the reaction temperature of the plate-type oscillating continuous flow reactor; the microwave continuous flow reactor includes a microwave The generator 12 and the fixed bed reactor, the first back pressure valve 9 and the second back pressure valve 14 are used to adjust and control the reaction pressure in the micro-reaction system, the gas-liquid separator 10 is used to separate gas from liquid, the liquid-liquid separator 11 is used to separate liquids, the continuous filter 17 is used to continuously separate solid-liquid mixtures, the continuous filter 17 is provided with a control valve 18 on the discharge port and is connected to a filtrate collection pipeline 19 and a formula (1) compound collection pipeline 20, the control valve 18 is used to change the flow direction of the fluid and help switch the fluid flow path between different pipelines or equipment.

[0123] Example 2

[0124] This embodiment provides a method for synthesizing 2-acetoxybenzoic acid and its derivatives, and the synthesis path is as follows:

[0125]

[0126] The device used is as shown in Example 1, and the synthesis method specifically comprises the following steps:

[0127] (i) Benzoic acid (3), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and tert-butyl nitrite were mixed with acetonitrile / water (V) at a molar ratio of 1:0.1:0.02. 乙腈 / V 水=9 / 1, 2.23M) composed of a mixed solution, in which the molar ratio of benzoic acid (3) to oxygen is 1:2, and the oxygen introduction pressure is calculated according to the ideal gas state equation so that oxygen is continuously introduced into the mixed solution during the hydroxylation reaction) are respectively transported to a T-type mixer for mixing, and then enter a photocontinuous flow reactor (volume is 15 ml, inner diameter is 2 mm, wavelength is 390 nm), the back pressure during the reaction is 0.5 MPa, the temperature in the photocontinuous flow reactor is controlled to be 25° C. After reacting for 5 minutes (i.e., the residence time of the mixed reaction material in the photocontinuous flow reactor is 5 minutes), the solution containing the compound salicylic acid (2) flows out from the outlet of the photocontinuous flow reactor, passes through a gas-liquid separator 10 and a liquid-liquid separator in sequence, and the organic phase containing salicylic acid (2) flows out from the outlet of the liquid-liquid separator;

[0128] (ii) The organic phase containing salicylic acid (2) obtained in the previous step and acetic acid are respectively conveyed to a T-shaped micromixer for mixing according to a molar ratio of salicylic acid (2) to acetic acid of 1:1.5, and the mixed solution is conveyed to a microwave continuous flow reactor (reaction volume of 2 ml, output power of 150 W, and filled with Amberlyst-15 cation exchange resin). The back pressure during the reaction is 1.0 MPa. After 1 minute of reaction (i.e., the residence time of the mixed reaction materials in the fixed bed reactor is 1 minute), the acetonitrile solution containing the acylated product (1) flows out from the outlet of the fixed bed reactor.

[0129] (iii) mixing the acetonitrile solution containing the acylated product (1) obtained in the previous step with deionized water (V 乙腈溶液 / V 去离子水 =1 / 2) are respectively transported to an online stirring micro mixer for mixing, and the mixed solution is transported to a coil microchannel reactor (with a volume of 4 ml and an inner diameter of 0.8 mm). The temperature in the microchannel reactor is controlled to be 25° C., and continuous cooling and crystallization is performed for 3 min (i.e., the residence time of the mixed reactants in the microchannel reactor is 3 min). After the reaction is completed, online filtration is continued in a continuous filter 17, and the filtrate is collected through a filtrate collecting pipeline 19 for subsequent recycling. After the product is dried, the purity of 2-acetoxybenzoic acid is detected to be 98.8%, and the total separation yield is 88%.

[0130] Example 3

[0131] The only difference between this embodiment and embodiment 1 is that the plate-type oscillating continuous flow reactor in embodiment 1 is replaced by a coil-type microchannel reactor, and the purity of the obtained product 2-acetoxybenzoic acid is 98.8%, and the total separation yield is 73%.

[0132] Compared with Example 2, Example 3 shows that the plate-type oscillating continuous flow reactor is more conducive to improving the yield of the product than the coil-type microchannel reactor.

[0133] Example 4

[0134] The only difference between this example and Example 2 is that the oxidant in the hydroxylation reaction is hydrogen peroxide. The purity of the obtained product 2-acetoxybenzoic acid is 99%, and the total isolated yield is 90%.

[0135] Compared with Example 2, Example 4 shows that hydrogen peroxide is more conducive to improving the yield and purity of the product than 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

[0136] Example 5

[0137] The only difference between this embodiment and embodiment 2 is that the photoinitiator in the hydroxylation reaction is n-butyl nitrite. The purity of the obtained product 2-acetoxybenzoic acid is 98.8%, and the total isolated yield is 75%.

[0138] Compared with Example 2, Example 5 shows that n-butyl nitrite is more conducive to improving the purity of the product than tert-butyl nitrite, but the yield is significantly reduced.

[0139] Example 6

[0140] The only difference between this example and Example 2 is that the acylating agent in the acylation reaction is acetic anhydride. The purity of the obtained product 2-acetoxybenzoic acid is 98.8%, and the total isolated yield is 84%.

[0141] Compared with Example 2, Example 6 shows that acetic anhydride reduces the yield of the synthesized product and does not improve the purity compared with acetic acid.

[0142] Example 7

[0143] The only difference between this example and Example 2 is that the acylating agent in the acylation reaction is acetyl chloride. The purity of the obtained product 2-acetoxybenzoic acid is 99%, and the total isolated yield is 81%.

[0144] Compared with Example 2, Example 7 shows that compared with acetic acid, the yield of the synthesized product of acetyl chloride is lower and the purity is only slightly improved.

[0145] Example 8

[0146] The only difference between this embodiment and embodiment 2 is that the Amberlyst-15 cation exchange resin is replaced by ZSM-5 molecular sieve, and the purity of the obtained product 2-acetoxybenzoic acid is 98.8%, the total separation yield is 83%, and the yield of the synthetic product is lower.

[0147] Example 9

[0148] The only difference between this example and Example 2 is that the Amberlyst-15 cation exchange resin is replaced by the NKC-9 cation exchange resin. The purity of the obtained product 2-acetoxybenzoic acid is 98.8%, the total separation yield is 87%, and the yield of the synthetic product is slightly lower.

[0149] Example 10

[0150] The only difference between this example and Example 2 is that benzoic acid is replaced by benzoate. In this example, the substrate benzoate is completely converted, and the purity of the obtained product 2-(acetoxy)benzoic acid methyl ester is 99%, and the total isolated yield is 91%, and the yield of the synthetic product is slightly improved.

[0151] Embodiment 11

[0152] The only difference between this embodiment and embodiment 2 is that benzoic acid is replaced by ethyl benzoate. In this embodiment, the substrate ethyl benzoate is completely converted, and the purity of the obtained product ethyl 2-(acetoxy)benzoate is 99%, the total separation yield is 83%, and the yield of the synthetic product is lower.

[0153] Example 12

[0154] The only difference between this example and Example 2 is that benzoic acid is replaced by benzamide. In this example, the substrate benzamide is completely converted, and the purity of the obtained product 2-(aminocarbonyl)phenyl acetate is 99%, and the total isolated yield is 80%. The yield of the synthetic product is lower.

[0155] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for hydroxylating benzoic acid or a benzoic acid derivative, characterized in that: include: Hydroxylation, mixing a first mixture including a compound represented by formula (3), an oxidant and a photoinitiator with oxygen, and performing a hydroxylation reaction under photocatalysis to obtain a hydroxylation reaction liquid containing a compound represented by formula (2); wherein the structures of the compound represented by formula (3) and the compound represented by formula (2) are as follows: Wherein, R is hydroxyl, alkoxy, halogen or alkyl acyl.

2. The method for hydroxylating benzoic acid or a benzoic acid derivative according to claim 1, characterized in that: The hydroxylation reaction comprises at least one of the following: (1) The reaction temperature is 25°C to 60°C; (2) The duration is 0.5 min to 20 min; (3) The reaction pressure is 0 to 1.0 MPa; (4) The wavelength of the light source used for catalysis is 390nm-600nm; (5) The molar ratio of the compound represented by formula (3), the oxidant, the photoinitiator and the oxygen is 1:(0.01-1):(0.01-0.5):(1.8-2.2).

3. The method for hydroxylating benzoic acid or a benzoic acid derivative according to claim 1, characterized in that: The oxidant is selected from at least one of titanium dioxide, cupric chloride, sodium chlorate, o-benzoquinone, p-benzoquinone, dicyanoquinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, benzoyl peroxide, hydrogen peroxide, potassium permanganate, chromium chloride, and chlorine dioxide; And / or, the photoinitiator is selected from at least one of tert-butyl nitrite, ethyl nitrite, isopropyl nitrite, n-butyl nitrite, tert-butyl hydroperoxide, 1-hydroxycyclohexyl phenyl ketone, (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide, phenyl bis (2,4,6-trimethylbenzoyl) phosphine oxide, coumarin, and diazetidin; And / or, the first mixture also includes an organic solvent, and the organic solvent is selected from at least one of methanol, ethanol, isopropanol, water, acetonitrile, ethyl acetate, dichloromethane, chloroform, acetone, N,N-dimethylformamide, and N,N-dimethylacetamide.

4. A method for synthesizing 2-acetoxybenzoic acid and its derivatives, characterized in that: include: Synthesize the compound represented by formula (2) according to any one of claims 1 to 3; Acylation, placing the second mixture of the compound represented by formula (2) and the acylating agent in the presence of microwaves and a catalyst for acylation reaction, cooling and crystallizing the liquid after the acylation reaction to obtain the compound represented by formula (1), wherein the structure of the compound represented by formula (1) is as follows:

5. The method for synthesizing 2-acetoxybenzoic acid and its derivatives according to claim 4, characterized in that: The acylation step comprises at least one of the following: (1) The reaction time is 0.5 min to 5 min; (2) The reaction pressure is 0 to 1.5 MPa; (3) Microwave output power is 100W to 300W; (4) The molar ratio of the compound represented by formula (2), the acylating agent and the catalyst is 1:(1-3):(0.01-1); (5) The acylating agent is at least one of carboxylic acids, acid anhydrides, acid halides, amides, esters and aromatic compounds; (6) The catalyst is at least one of an ion exchange resin, a solid acid catalyst, a solid base catalyst, a metal oxide catalyst, a transition metal catalyst and a molecular sieve.

6. The method for synthesizing 2-acetoxybenzoic acid and its derivatives according to claim 5, characterized in that: The acylating agent is at least one of acetic acid, acetic anhydride, trifluoroacetic anhydride, acetyl chloride, acetamide, N-methylacetamide, N-acetyl-2,2-dimethylpropionamide, ethyl acetate, vinyl acetate, isopropenyl acetate, trimethylsilyl acetate, 2,3-butanedione, 2,2-dimethyl-1,3-dioxane-4,6-dione, acetanilide, 2-acetyl-4,5-dichloro-3(2H)-pyridazine, 2-acetylbenzimidazole, and N-acetylphthalimide; And / or, the catalyst is a cation exchange resin or a molecular sieve.

7. A device for hydroxylating benzoic acid or a benzoic acid derivative, characterized in that: The invention comprises a first micro mixer (4), wherein the inlet of the first micro mixer (4) is connected to a first storage tank (1) and an oxygen source (24), and the outlet of the first micro mixer (4) is connected to a photocontinuous flow reactor, a gas-liquid separator (10) and a liquid-liquid separator (11) in sequence; wherein the first storage tank (1) is used to contain a first mixture comprising a compound represented by formula (3), an oxidant and a photoinitiator; wherein the structure of the compound represented by formula (3) is as follows: Wherein, R is hydroxyl, alkoxy, halogen or alkyl acyl.

8. A synthesis device for 2-acetoxybenzoic acid and its derivatives, characterized in that: The invention comprises the device for hydroxylating benzoic acid or a benzoic acid derivative according to claim 7 and a second micro mixer (21), wherein the inlet of the second micro mixer (21) is connected to an acylating agent storage tank (22) and an organic phase outlet of the liquid-liquid separator, the outlet of the second micro mixer (21) is connected to a microwave continuous flow reactor, the outlet of the microwave continuous flow reactor is sequentially connected to a third micro mixer (15), a mixing continuous flow reactor (16) and a solid-liquid separator, the solid phase outlet of the solid-liquid separator is provided with a collection pipeline (20) of the compound of formula (1), and the inlet of the third micro mixer (15) is also connected to a water tank (23); wherein the structure of the compound represented by formula (1) is as follows:

9. The synthesis device of 2-acetoxybenzoic acid and its derivatives according to claim 8, characterized in that: The optical continuous flow reactor comprises a first continuous reaction device (7), an integrated light source device (6) and a thermostat (8), wherein the integrated light source device (6) is used to provide a light source with adjustable wavelength, and the thermostat (8) is used to adjust and control the reaction temperature of the first continuous reaction device (7); And / or, the microwave continuous flow reactor comprises a second continuous reaction device (13) and a microwave generator (12) integrated on the second continuous reaction device (13); And / or, a pulser (3) is further provided between the first micro-mixer (4) and the first storage tank (1).

10. The synthesis device of 2-acetoxybenzoic acid and its derivatives according to claim 9, characterized in that: The first continuous reaction device (7), the second continuous reaction device (13) and the mixed continuous flow reactor (16) are one of a continuous flow reactor, a static tubular continuous flow reactor, a dynamic oscillating tubular continuous flow reactor, a fixed bed reactor or a plate oscillating continuous flow reactor; And / or, the first micromixer (4), the second micromixer (21) and the third micromixer (15) are each independently selected from any one of a static mixer, a T-type micromixer, a Y-type micromixer, a cross mixer, a coaxial flow micromixer, a dynamic continuous stirring mixer and a flow focusing micromixer.

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