A device and method for continuous flow synthesis of aromatic azide compounds

Abstract

The present invention provides an apparatus and method for continuous flow synthesis of aromatic azide compounds, and relates to the field of organic synthesis technology. The method of the present invention comprises the following steps: preparing a solution of an aromatic halogenated compound and an organic solvent, delivering the solution to a continuous flow reactor via a metering pump, and then subjecting the solution to a mixing reaction, and then entering a continuous flow quenching reactor. The quenching extraction solvent is delivered to the continuous flow quenching reactor via a metering pump for quenching extraction, and then passing through a continuous liquid separator to obtain an aromatic azide compound solution, which is then concentrated and crystallized to obtain a solid. The organic solution can also be directly put into the next step of reaction. The preparation of aromatic azide compounds using the continuous flow synthesis apparatus and synthesis method of the present invention has the advantages of precise control conditions, good selectivity, simple and safe operation, a wide controllable range of explosiveness and leakage, and a fast reaction rate. It has great practical value in improving production efficiency, improving production safety, and reducing environmental pollution.

Description

Technical Field

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

[0002] Aryl azide compounds are an important class of chemical synthesis intermediates and are widely used in many fields such as organic synthesis, chemical biology, functional materials and clinical medicine. Currently, there are many methods for the synthesis of aryl azide compounds: (1) primary aryl amines react with inorganic acids and sodium nitrite to generate diazo compounds, which react with sodium azide to obtain aryl azide compounds through displacement reaction; (2) halogenated benzenes react with azides to obtain aryl azide compounds through coupling reaction; (3) phenylhydrazine reacts with triphenylphosphine, bromine water and tetrabutylnitrosamine to generate aryl azide compounds; (4) aryl borate and sodium azide react with Cu(I) catalysis to generate aryl azide compounds. However, the above preparation methods have many defects, such as high pH requirements during diazotization, difficulty in control, high raw material toxicity, easy generation of by-products, low yield, limited application range, large limitations and harsh conditions, which limit their further application.

[0003] Patent Publication No. CN103012195B discloses a method for preparing aryl azide compounds. Using porous copper as a catalyst, the method involves mixing an iodinated aryl compound, sodium azide, an alkaline substance, and a ligand in a solvent and reacting them, resulting in a one-pot preparation of the aryl azide compound. Patent Publication No. CN106588693B also discloses a method for synthesizing aryl azide compounds. An iodinated aryl compound, sodium azide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and a copper source catalyst are mixed in a solvent and reacted to obtain the target compound. Both patents utilize copper-containing (copper or copper salt) catalysts. The MSDS for sodium azide states that it forms highly sensitive compounds with heavy metals and base salts. This means that sodium azide forms copper azide when in contact with copper or copper salts. Copper azide is a high-energy-density energetic material with high electrostatic and mechanical sensitivity, making it a powerful detonating agent. The synthesis methods involved in these two patents are only at the milligram scale stage, and there are high safety risks if they are to be scaled up for production.

[0004] At the same time, the vast majority of azidation reactions currently performed domestically and internationally are conducted in autoclaves, which presents numerous challenges. These include high requirements for industrial equipment during production, the risk of explosion and leakage during the production process, the large batch size of azide compounds required in traditional autoclave production methods, and the heavy weight of azide compounds, which cannot be suspended in solvents and transported using industrial pumps. The dosing process requires lengthy manual weighing, posing significant safety risks. Most processes strictly require anhydrous conditions, but under traditional methods, some water inevitably enters the autoclave during the dosing, reaction, and in-process control stages, thus impacting the reaction.

[0005] Continuous flow reaction is a high-efficiency, energy-saving, safe, low-carbon and environmentally friendly continuous synthesis production method. It has the following advantages: (1) It can achieve instantaneous mixing of reaction materials and precise control of reaction process parameters, which can improve the yield and selectivity of the reaction; (2) It can achieve continuous and automated control of the process, thereby improving process stability and ensuring product quality; (3) The small reaction volume ensures the safety of the chemical reaction.

[0006] Current continuous flow methods for synthesizing aryl azides using halogenated aryls do not directly utilize powdered solid azides for continuous synthesis. Instead, they employ sodium azide solutions (prepared in water or a water-based mixed solvent) for continuous flow reactions, which cannot guarantee the absence of water in the reaction system. However, during the preparation of aryl azides, carboxylate groups on the aromatic rings of the substrates are easily hydrolyzed upon contact with water, so water is not permitted in the reaction system. While sodium azide has good solubility in water, no anhydrous solvent can effectively dissolve it. Therefore, a continuous flow method for synthesizing aryl azides using solid sodium azide as a raw material is needed. However, a reaction system using solid sodium azide as a raw material is inevitably a solid-liquid heterogeneous system. Achieving continuous flow synthesis in such a system inevitably raises challenges, such as how to safely store the solid sodium azide, how to accurately meter and deliver it, and how to address the problem of solids clogging the continuous flow pipeline. Further research is needed to address these issues. Summary of the Invention

[0007] In order to solve the problems of high requirements for reactors and high risks of explosion and leakage when synthesizing aromatic azide compounds from aromatic halide compounds, the present invention provides an apparatus and method for continuous flow synthesis of aromatic azide compounds.

[0008] The present invention provides a device for continuous flow synthesis of aromatic azide compounds, comprising:

[0009] The raw material liquid storage tank 1, the feed pipe 21, multiple continuous flow azide reaction modules, the discharge pipe 22, the reaction liquid storage tank 6, the quenching and extraction continuous flow reaction module 23, and the continuous phase separation module are connected in sequence, and the metering pumps 9 and 10 are connected to the quenching and extraction continuous flow reaction module 23;

[0010] Each of the continuous flow azide reaction modules includes a solid feeding funnel, a reaction liquid discharge valve, a raw material liquid inlet valve, and a solid feeding funnel feeding controller;

[0011] Multiple continuous flow azide reaction modules are arranged in parallel, and the continuous flow azide reaction modules are connected by pipes. The first continuous flow azide reaction module has a whole system circulating water inlet 19, and the last continuous flow azide reaction module has a whole system circulating water outlet 20;

[0012] The continuous phase separation module is connected to the organic phase outlet 35 and the aqueous phase outlet 36 .

[0013] Furthermore, the raw liquid storage tank 1 and the feed pipe 21 are connected via a metering pump 7;

[0014] And / or, the feed pipe 21 is connected to the raw material liquid inlet valve in each continuous flow azide reaction module; the discharge pipe 22 is connected to the reaction liquid discharge valve in each continuous flow azide reaction module;

[0015] And / or, the discharge pipe 22 is connected to the reaction liquid storage tank 6;

[0016] And / or, the reaction liquid storage tank 6 and the quenching extraction continuous flow reaction module 23 are connected via a metering pump 8;

[0017] And / or, the quenching extraction continuous flow reaction module 23 is connected to the continuous phase separation module.

[0018] Furthermore, the number of the continuous flow azide reaction modules is 1 to 10; preferably 4 to 9;

[0019] And / or, each continuous flow azide reaction module is connected to a motor, and a driving end of the motor is connected to a turbine stirrer;

[0020] And / or, the continuous phase-splitting module includes a continuous phase-splitting module 24, a continuous phase-splitting module 25 and a continuous phase-splitting module 26 connected in series.

[0021] The present invention also provides use of the aforementioned device in continuous flow synthesis of aromatic azide compounds.

[0022] The present invention also provides a method for continuous flow synthesis of aromatic azide compounds, which is carried out in the aforementioned apparatus;

[0023] Preferably, it comprises the steps of:

[0024] S1: adding an organic solution A prepared by dissolving an aryl halide compound in an organic solvent into a raw material liquid storage tank 1;

[0025] S2: adding the azide compound to the solid addition funnel of each continuous flow azide reaction module;

[0026] S3: Using the quenching solvent as the organic solution B, connect the metering pump 9;

[0027] S4: Using the extraction solvent as the organic solution C, connect the metering pump 10;

[0028] S5: The organic solution A is passed through the metering pump 7 through the feed pipe 21 and is added to the continuous flow azide reaction module through the raw material liquid inlet valve of the continuous flow azide reaction module; the azide compound in the solid feeding funnel is added to the continuous flow azide reaction module by controlling the solid feeding funnel feeding controller; the organic solution A and the azide compound are mixed and reacted to obtain a reaction solution;

[0029] S6: The obtained reaction solution, organic solution B and organic solution C are passed into the quenching and extraction continuous flow reaction module 23 for quenching and extraction, and then enter the continuous phase separation module for phase separation to obtain an organic phase containing aromatic azide compounds.

[0030] Further,

[0031] In step S1, the organic solvent is an anhydrous organic solvent;

[0032] And / or, in step S1, the mass ratio of the aryl halide compound to the organic solvent is 1:(5-10);

[0033] And / or, in step S2, the azide compound is sodium azide;

[0034] And / or, in step S2, the mass ratio of the azide compound in each continuous flow azide reaction module to the aryl halide compound in step S1 is (0.1-1):1;

[0035] And / or, in step S3, the quenching solvent is a saturated sodium chloride solution or water;

[0036] And / or, in step S3, the mass ratio of the quenching solvent to the aryl halide compound in step S1 is (5-10):1;

[0037] and / or, in step S4, the extraction solvent is methyl tert-butyl ether, toluene, dichloromethane, ethyl acetate, or isopropyl acetate;

[0038] And / or, in step S4, the mass ratio of the extraction solvent to the aryl halogenated compound in step S1 is (1-10):1.

[0039] Further,

[0040] In step S1, the organic solvent is N,N-dimethylacetamide;

[0041] And / or, in step S2, the mass ratio of the azide compound in each continuous flow azide reaction module to the aryl halide compound in step S1 is (0.1-0.5):1;

[0042] And / or, in step S3, the quenching solvent is a saturated sodium chloride solution;

[0043] And / or, in step S4, the extraction solvent is methyl tert-butyl ether.

[0044] Further,

[0045] In step S1, the aryl halide compound is a compound represented by formula I:

[0046]

[0047] in,

[0048] n is 0, 1, 2, 3, 4 or 5;

[0049] 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 or halogenated C1-C6 alkoxy;

[0050] R2 is selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl;

[0051] R3 is selected from hydrogen;

[0052] R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy;

[0053] R5 is selected from halogen;

[0054] X is selected from CR6 or N;

[0055] R6 is selected from -SR7 or -OR8;

[0056] R7 and R8 are independently selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl;

[0057] And / or, in step S6, the aromatic azide compound is a compound represented by formula II:

[0058]

[0059] in,

[0060] n is 0, 1, 2, 3, 4 or 5;

[0061] 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 or halogenated C1-C6 alkoxy;

[0062] R2 is selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl;

[0063] R3 is selected from hydrogen;

[0064] R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy;

[0065] X is selected from CR6 or N;

[0066] R6 is selected from -SR7 or -OR8;

[0067] R7 and R8 are independently selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl;

[0068] Preferably,

[0069] The aryl halide compounds are methyl 3-(tert-butyl mercaptan)-4-fluoro-2-(2-fluorophenylamino)benzoate, methyl 6-chloro-2-(2-fluorophenylamino)nicotinate, and benzyl 3-(benzyloxy)-4-fluoro-2-(2-fluorophenylamino)benzoate;

[0070] And / or, the aromatic azide compound is methyl 4-azido-3-(tert-butylthio)-2-(2-fluorophenylamino)benzoate, methyl 6-azido-2-(2-fluorophenylamino)nicotinate, or benzyl 4-azido-3-benzyloxy-2-(2-fluorophenylamino)benzoate.

[0071] Further,

[0072] In step S5, the circulation temperature of each continuous flow azide reaction module is 65-70°C;

[0073] And / or, in step S5, the flow rate of adding the organic solution A to the continuous flow azide reaction module is 20 to 200 ml / min;

[0074] And / or, in step S5, the addition of the azide compound is completed before the addition of the organic solution A is completed;

[0075] And / or, in step S5, the organic solution A is first added to the first continuous flow azide reaction module, and after 30 to 40 minutes of adding the organic solution A, the raw material inlet valve is controlled to allow the organic solution A to enter the other continuous flow azide reaction modules in sequence;

[0076] And / or, in step S5, the reaction temperature is 60°C to 85°C, and the reaction time is 90 to 120 minutes;

[0077] and / or, in step S6, the circulation temperature of the quenching extraction continuous flow reaction module is 20° C.;

[0078] Preferably,

[0079] In step S5, the volume of each continuous flow azide reaction module is 1 to 5 L;

[0080] And / or, in step S5, the flow rate of adding the organic solution A to the continuous flow azide reaction module is 20 ml / min;

[0081] And / or, in step S6, the volume of the quenching extraction continuous flow reaction module is 10-20 ml.

[0082] Further,

[0083] In step S6, the flow rate of the reaction solution into the quenching extraction continuous flow reaction module is 20 to 200 ml / min; the flow rate of the organic solution B into the quenching extraction continuous flow reaction module is 15 to 200 ml / min; the flow rate of the organic solution C into the quenching extraction continuous flow reaction module is 20 to 200 ml / min;

[0084] Preferably, the ratio of the flow rate of the reaction solution entering the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added to the continuous flow azide reaction module in step S5 is 1 to 1.2:1;

[0085] The ratio of the flow rate of the organic solution B entering the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added to the continuous flow azide reaction module in step S5 is 0.6 to 0.9:1;

[0086] The ratio of the flow rate of the organic solution C entering the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added to the continuous flow azide reaction module in step S5 is 0.8-1.2:1.

[0087] The present invention provides an apparatus and method for the continuous flow synthesis of aromatic azide compounds. The method comprises the following steps: adding an aromatic halide compound and an azide compound to a continuous flow azide reaction module via a metering pump and a solid feeding funnel, performing a mixing reaction, continuous quenching and extraction, obtaining an aromatic azide solution via a continuous liquid separator, and then concentrating and crystallizing to obtain a solid. Alternatively, the organic solution can be directly used in the next reaction.

[0088] Compared with the prior art, the advantages of the present invention are:

[0089] (1) When the present invention adopts a continuous flow reaction, since the continuous flow reactor is small in size and large in number, production efficiency is guaranteed while improving safety;

[0090] (2) During the reaction, the materials are quickly and effectively mixed together in a precise fixed ratio to react, which increases safety and reduces the risk of explosion and leakage;

[0091] (3) The continuous flow azide reactor of the present invention is a turntable continuous flow azide reactor, which continuously flows throughout the entire process from feeding, mixing and reaction, avoiding the accumulation, explosion and leakage caused by the need for additional configuration and transfer in conventional batch reactions, thereby improving environmental safety and production efficiency.

[0092] (4) The present invention uses solid azide as a raw material, which avoids the introduction of water and effectively prevents the hydrolysis of the carboxylate group on the aromatic ring of the substrate.

[0093] In summary, the continuous flow synthesis device and synthesis method of the present invention are used to prepare aromatic azide compounds, which have the advantages of precise control conditions, good selectivity, simple and safe operation, a wide controllable range of explosiveness and leakage, and a fast reaction rate. They have great practical value in improving production efficiency, improving production safety, and reducing environmental pollution.

[0094] 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.

[0095] 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

[0096] Figure 1 The present invention provides a modular design of a continuous flow reaction device and a process flow chart for synthesizing aromatic azide compounds.

[0097] Figure 2Schematic diagram of the device for continuous flow synthesis of aromatic azide compounds of the present invention. DETAILED DESCRIPTION

[0098] 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.

[0099] The synthetic route of the continuous flow synthesis of aromatic azide compounds of the present invention is as follows:

[0100]

[0101] in,

[0102] n is 0, 1, 2, 3, 4 or 5;

[0103] R1 is a substituent on the phenyl ring, each R1 is independently selected from halogen (such as fluorine, chlorine, bromine), C1-C6 alkyl (such as methyl), C1-C6 alkoxy (such as methoxy), halogenated C1-C6 alkyl (such as trifluoromethyl) or halogenated C1-C6 alkoxy (such as trifluoromethoxy);

[0104] R2 is selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl;

[0105] R3 is selected from hydrogen;

[0106] R4 is selected from hydrogen, halogen (such as fluorine, chlorine, bromine), C1-C6 alkyl (such as methyl), C1-C6 alkoxy (such as methoxy), halogenated C1-C6 alkyl (such as trifluoromethyl) or halogenated C1-C6 alkoxy (such as trifluoromethoxy);

[0107] R5 is selected from halogen;

[0108] X is selected from CR6 or N;

[0109] R6 is selected from -SR7 or -OR8;

[0110] R7 and R8 are independently selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl.

[0111] The modular design of the continuous flow reaction device of the present invention and the process flow chart for synthesizing aromatic azide compounds are shown in FIG. Figure 1 As shown; the schematic diagram of the device is as follows Figure 2 shown.

[0112] The continuous flow reaction device of the present invention ( Figure 2 ) includes the following components:

[0113] (1) Raw material liquid storage tank 1, reaction liquid storage tank 6, quenching extraction continuous flow reaction module 23, continuous phase separation module 24, continuous phase separation module 25, continuous phase separation module 26, organic phase outlet 35, aqueous phase outlet 36; wherein the quenching extraction continuous flow reaction module 23 corresponds to Figure 1 The continuous quenching extraction reactor, the continuous phase separation module 24, the continuous phase separation module 25, the continuous phase separation module 26, the organic phase outlet 35, and the aqueous phase outlet 36 correspond to Figure 1 The serial dispenser section in.

[0114] (2) metering pumps 7, 8, 9 and 10; metering pumps 7, 9 and 10 correspond to Figure 1 Metering pump 1, metering pump 2 and metering pump 3.

[0115] (3) The solid feeding funnel 11, the reaction liquid discharge valve 15, the raw material inlet valve 31, the solid feeding funnel feeding controller 27, and the whole system circulating water inlet 19 constitute the continuous flow azide reaction module 2; the solid feeding funnel 12, the reaction liquid discharge valve 16, the raw material inlet valve 32, and the solid feeding funnel feeding controller 28 constitute the continuous flow azide reaction module 3; the solid feeding funnel 13, the reaction liquid discharge valve 17, the raw material inlet valve 33, and the solid feeding funnel feeding controller 29 constitute the continuous flow azide reaction module 4; the solid feeding funnel 14, the reaction liquid discharge valve 18, the raw material inlet valve 34, the solid feeding funnel feeding controller 30, and the whole system circulating water outlet 20 constitute the continuous flow azide reaction module 5. Continuous flow azide reaction modules 2, 3, 4 and 5 constitute Figure 1 The continuous flow azide reactor in the embodiment can also increase the number of continuous flow azide reaction modules according to actual needs.

[0116] (4) Feed pipe 21 and discharge pipe 22.

[0117] The method for continuous flow synthesis of aromatic azide compounds of the present invention comprises the following steps:

[0118] S1: Add solution A prepared by dissolving an aryl halide compound in an organic solvent into a raw material liquid storage tank 1, and connect the metering pump 7.

[0119] S2: Add the azide compound of each batch into the solid addition funnels 11, 12, 13, and 14.

[0120] S3: Label the quenching solvent as solution B and connect it to metering pump 9.

[0121] S4: The extraction solvent is labeled as solution C and connected to the metering pump 10.

[0122] S5: The solution A described in S1 is added to the continuous flow azide reaction modules 2, 3, 4, and 5 via the metering pump 7. The solid addition funnels 11, 12, 13, and 14 containing the azide compound are also added to the continuous flow azide reaction modules 2, 3, 4, and 5 via the controllers 27, 28, 29, and 30. The solution A reacts with the azide compound at 60°C to 85°C in the continuous flow azide reaction module to generate a mixed reaction liquid containing an azide group. The reaction liquid enters the reaction liquid storage tank 6 through the reaction liquid discharge valves 15, 16, 17, and 18 and the discharge pipe 22, and then enters the quenching and extraction continuous flow reaction module 23 through the metering pump 8 for quenching and extraction at 20°C to 30°C. After continuous quenching and extraction, the solution is passed through the continuous phase separation modules 24, 25, and 26 to obtain an aromatic azide solution. The solid is obtained by concentration and crystallization. The organic solution can also be directly used for the next reaction.

[0123] The present invention adds an aryl halide compound and an azide compound to a continuous flow azide reaction module via a metering pump, undergoes a mixing reaction, and undergoes continuous quenching and extraction. The aryl azide solution is then concentrated and crystallized to obtain a solid. The organic solution can also be directly used in the next reaction. The present invention achieves solid azide compound feeding, avoiding the introduction of water during the reaction. The method for preparing aryl azide compounds using the apparatus of the present invention has the advantages of precise control conditions, high safety, short reaction time, reduced explosion and leakage risks, simple operation, and environmental friendliness. It has great practical value in improving production safety and increasing production efficiency.

[0124] Example 1: Synthesis of the aryl azide compounds of the present invention

[0125] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0126] 1. Raw material preparation

[0127] Solution A: A mixed solution of 100 g of methyl 3-(tert-butyl mercaptan)-4-fluoro-2-(2-fluorophenylamino)benzoate and 500 g of N,N-dimethylacetamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0128] Reagent A: 21 g of sodium azide from each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0129] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0130] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0131] 2. The specific parameters of the module are as follows:

[0132] Continuous flow azide reaction modules 2, 3, 4, and 5: The circulation temperature reaches 65-70°C and reaches stability, with a volume of 1L*9;

[0133] Quenching extraction continuous flow reaction module 23: circulation temperature 20°C, volume 15 ml.

[0134] 3. The specific operations are as follows:

[0135] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 20 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0136] The subsequent continuous flow azide reaction modules are fed and reacted sequentially according to the above method. When the feeding of continuous flow azide reaction module 2 is completed, the raw material liquid inlet valve 31 is closed and the raw material liquid inlet valve 32 is opened at the same time, and so on. As needed, when the last continuous flow azide reaction module is fed, the first reaction module is completed and discharged. After the last reaction module is fed, the first reaction module can be fed again, thereby achieving a continuous flow reaction. Figure 2 Only four continuous flow azide reaction modules are shown, but the number of continuous flow azide reaction modules can be expanded as needed. In this embodiment, there are nine continuous flow azide reaction modules.

[0137] Directly conducting a large-scale reaction in one reaction module carries the risk of explosion and leakage, while dividing the reaction into several small reaction modules can reduce the risk coefficient of explosion and leakage of the azide compound. At the same time, when reacting in one reaction module, the amount of azide compound added in each batch is very large. The azide compound has a heavy specific gravity and cannot be suspended by adding a solvent and transported using an industrial pump. A large amount of azide compound cannot be added at once during the feeding process, and manual weighing and batch addition are required for a long time, which poses a great safety risk. Moreover, most processes strictly require to be carried out under anhydrous conditions. When a reaction module reacts, the amount of feed is large. It is inevitable that some water will enter the reactor during the feeding, reaction, and intermediate control stages, thereby affecting the reaction.

[0138] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the metering pump 8 is opened, with a flow rate of 20 ml / min. The metering pumps 9 and 10 are started at the same time, with a flow rate of 16.6 ml / min and a flow rate of 20 ml / min for the metering pump 10. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing methyl 4-azido-3-(tert-butylsulfide)-2-(2-fluorophenylamino)benzoate solution is obtained, which can be concentrated to a large amount of solid precipitated and then cooled and crystallized to obtain a solid product. The organic solution can also be directly put into the next step of the reaction.

[0139] In this example, 100.1 g of methyl 4-azido-3-(tert-butylthio)-2-(2-fluorophenylamino)benzoate was prepared, with a total yield of 94% and a purity of 96%.

[0140] Example 2: Synthesis of the aryl azide compounds of the present invention

[0141] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0142] 1. Raw material preparation

[0143] Solution A: A mixed solution of 100 g of methyl 3-(tert-butyl mercaptan)-4-fluoro-2-(2-fluorophenylamino)benzoate and 500 g of N,N-dimethylacetamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0144] Reagent A: 26 g of potassium azide in each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0145] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0146] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0147] 2. The specific parameters of the module are as follows:

[0148] Continuous flow azide reaction modules 2, 3, 4, and 5, with a circulation temperature of 65-70°C and a stable temperature, and a volume of 1L*9;

[0149] The quenching extraction continuous flow reaction module 23 has a circulation temperature of 20° C. and a volume of 15 ml.

[0150] 3. The specific operations are as follows:

[0151] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 20 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0152] The subsequent continuous flow azide reaction modules are fed with materials in sequence for reaction according to the above method. When the continuous flow azide reaction module 2 is fed with materials, the raw material inlet valve 31 is closed and the raw material inlet valve 32 is opened at the same time, and so on.

[0153] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the metering pump 8 is opened, with a flow rate of 20 ml / min. The metering pumps 9 and 10 are started at the same time, with a flow rate of 16.6 ml / min and a flow rate of 20 ml / min for the metering pump 10. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing methyl 4-azido-3-(tert-butylsulfide)-2-(2-fluorophenylamino)benzoate solution is obtained, which can be concentrated to a large amount of solid precipitated and then cooled and crystallized to obtain a solid product. The organic solution can also be directly put into the next step of the reaction.

[0154] In this example, 98 g of methyl 4-azido-3-(tert-butylthio)-2-(2-fluorophenylamino)benzoate was prepared with a total yield of 92% and a purity of 94%.

[0155] Example 3: Synthesis of the aryl azide compounds of the present invention

[0156] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0157] 1. Raw material preparation

[0158] Solution A: A mixed solution of 100 g of methyl 3-(tert-butyl mercaptan)-4-fluoro-2-(2-fluorophenylamino)benzoate and 500 g of N,N-dimethylformamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0159] Reagent A: 21 g of sodium azide from each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0160] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0161] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0162] 2. The specific parameters of the module are as follows:

[0163] Continuous flow azide reaction modules 2, 3, 4, and 5: The circulation temperature reaches 65-70°C and reaches stability, with a volume of 1L*9;

[0164] Quenching extraction continuous flow reaction module 23: circulation temperature 20°C, volume 15 ml.

[0165] 3. The specific operations are as follows:

[0166] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 18.5 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0167] The subsequent continuous flow azide reaction modules are fed with materials in sequence for reaction according to the above method. When the continuous flow azide reaction module 2 is fed with materials, the raw material inlet valve 31 is closed and the raw material inlet valve 32 is opened at the same time, and so on.

[0168] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the delivery pump 8 is opened, with a flow rate of 18.5 ml / min. The metering pumps 9 and 10 are started at the same time, with a flow rate of 16.6 ml / min and a flow rate of 20 ml / min for the metering pump 9. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing methyl 4-azido-3-(tert-butylsulfide)-2-(2-fluorophenylamino)benzoate solution is obtained, which can be concentrated to a large amount of solid precipitated and then cooled and crystallized to obtain a solid product. The organic solution can also be directly put into the next step of the reaction.

[0169] In this example, 85.2 g of methyl 4-azido-3-(tert-butylthio)-2-(2-fluorophenylamino)benzoate was prepared, with a total yield of 80% and a purity of 89%.

[0170] Example 4: Synthesis of the aryl azide compounds of the present invention

[0171] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0172] 1. Raw material preparation

[0173] Solution A: A mixed solution of 100 g of methyl 6-chloro-2-(2-fluorophenylamino)nicotinate and 500 g of N,N-dimethylacetamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0174] Reagent A: 27 g of sodium azide in each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0175] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0176] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0177] 2. The specific parameters of the module are as follows:

[0178] Continuous flow azide reaction modules 2, 3, 4, and 5: The circulation temperature reaches 65-70°C and reaches stability, with a volume of 1L*9;

[0179] Quenching extraction continuous flow reaction module 23: circulation temperature 20°C, volume 15 ml.

[0180] 3. The specific operations are as follows:

[0181] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 20 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0182] The subsequent continuous flow azide reaction modules are fed with materials in sequence for reaction according to the above method. When the continuous flow azide reaction module 2 is fed with materials, the raw material inlet valve 31 is closed and the raw material inlet valve 32 is opened at the same time, and so on.

[0183] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the delivery pump 8 is started at a flow rate of 20 ml / min. At the same time, the metering pumps 9 and 10 are started, and the flow rate of the metering pump 9 is 16.6 ml / min and the flow rate of the metering pump 10 is 20 ml / min. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and then enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing (6-azido-2-(2-fluorophenylamino)nicotinate) solution is obtained, which can be concentrated until a large amount of solid is precipitated and then cooled and crystallized to obtain a solid product. The organic solution can also be directly used in the next reaction.

[0184] 97.2 g of (6-azido-2-(2-fluorophenylamino)nicotinate) methyl ester prepared in this example has a total yield of 95% and a purity of 96%.

[0185] Example 5: Synthesis of the aryl azide compounds of the present invention

[0186] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0187] 1. Raw material preparation

[0188] Solution A: A mixed solution of 100 g of methyl 6-chloro-2-(2-fluorophenylamino)nicotinate and 500 g of N,N-dimethylacetamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0189] Reagent A: 37.5 g of potassium azide in each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0190] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0191] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0192] 2. The specific parameters of the module are as follows:

[0193] Continuous flow azide reaction modules 2, 3, 4, and 5: The circulation temperature reaches 65-70°C and reaches stability, with a volume of 1L*9;

[0194] Quenching extraction continuous flow reaction module 23: circulation temperature 20°C, volume 15 ml.

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

[0196] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 20 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0197] The subsequent continuous flow azide reaction modules are fed with materials in sequence for reaction according to the above method. When the continuous flow azide reaction module 2 is fed with materials, the raw material inlet valve 31 is closed and the raw material inlet valve 32 is opened at the same time, and so on.

[0198] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the delivery pump 8 is started at a flow rate of 20 ml / min. At the same time, the metering pumps 9 and 10 are started, and the flow rate of the metering pump 9 is 16.6 ml / min and the flow rate of the metering pump 10 is 20 ml / min. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and then enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing (6-azido-2-(2-fluorophenylamino)nicotinate) solution is obtained, which can be concentrated until a large amount of solid is precipitated and then cooled and crystallized to obtain a solid product. The organic solution can also be directly used in the next reaction.

[0199] 92.0 g of (6-azido-2-(2-fluorophenylamino)nicotinate) methyl ester was prepared in this example, with a total yield of 90% and a purity of 95%.

[0200] Example 6: Synthesis of the Aryl Azide Compounds of the Present Invention

[0201] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0202] 1. Raw material preparation

[0203] Solution A: A mixed solution of 100 g of benzyl 3-(benzyloxy)-4-fluoro-2-(2-fluorophenylamino)benzoate and 500 g of N,N-dimethylacetamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0204] Reagent A: 16.6 g of sodium azide in each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0205] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0206] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0207] 2. The specific parameters of the module are as follows:

[0208] Continuous flow azide reaction modules 2, 3, 4, and 5: The circulation temperature reaches 65-70°C and reaches stability, with a volume of 1L*9;

[0209] Quenching extraction continuous flow reaction module 23: circulation temperature 20°C, volume 15 ml.

[0210] 3. The specific operations are as follows:

[0211] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 20 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0212] The subsequent continuous flow azide reaction modules are fed with materials in sequence for reaction according to the above method. When the continuous flow azide reaction module 2 is fed with materials, the raw material inlet valve 31 is closed and the raw material inlet valve 32 is opened at the same time, and so on.

[0213] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the delivery pump 8 is started at a flow rate of 20 ml / min. At the same time, the metering pumps 9 and 10 are started, and the flow rate of the metering pump 9 is 16.6 ml / min and the flow rate of the metering pump 10 is 20 ml / min. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and then enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing 4-azido-3-benzyloxy-2-(2-fluorophenylamino)benzoic acid benzyl ester is obtained. The solution can be concentrated until a large amount of solid is precipitated and then cooled and crystallized to obtain a solid product. The organic solution can also be directly used in the next reaction.

[0214] 96.7 g of benzyl 4-azido-3-benzyloxy-2-(2-fluorophenylamino)benzoate was prepared in this example with a total yield of 92% and a purity of 96%.

[0215] Example 7: Synthesis of the aryl azide compounds of the present invention

[0216] use Figure 2 The apparatus shown is used to synthesize aromatic azide compounds.

[0217] 1. Raw material preparation

[0218] Solution A: A mixed solution of 100 g of benzyl 3-(benzyloxy)-4-fluoro-2-(2-fluorophenylamino)benzoate and 500 g of N,N-dimethylacetamide is placed in a raw material liquid storage tank 1 and connected to a metering pump 7;

[0219] Reagent A: 23.7 g of potassium azide in each continuous flow azide reaction module, divided into solid addition funnels 11, 12, 13, and 14;

[0220] Solvent B: 500 g of saturated brine (sodium chloride aqueous solution) connected to metering pump 9;

[0221] Solvent C: 444 g of methyl tert-butyl ether was connected to metering pump 10.

[0222] 2. The specific parameters of the module are as follows:

[0223] Continuous flow azide reaction modules 2, 3, 4, and 5: The circulation temperature reaches 65-70°C and reaches stability, with a volume of 1L*9;

[0224] The quenching extraction continuous flow reaction module 23 has a circulation temperature of 20° C. and a volume of 15 ml.

[0225] 3. The specific operations are as follows:

[0226] The automatic feeding system is turned on, and solution A is delivered to the continuous flow azide reaction module 2 by the metering pump 7 through the feeding pipe 21. At the same time, the solid feeding funnel feeding controller 27 is controlled to control the solid feeding funnel 11 to add sodium azide to the continuous flow azide reaction module 2. Solution A and sodium azide react in the continuous flow azide reaction module 2 for 90 minutes to obtain a reaction liquid. The flow rate of solution A is 20 ml / min. After 30 minutes of feeding, the feed is controlled by controlling the raw material liquid inlet valve, thereby automatically switching solution A to other continuous flow azide reaction modules. Nine continuous flow azide reaction modules are added in this way.

[0227] The subsequent continuous flow azide reaction modules are fed with materials in sequence for reaction according to the above method. When the continuous flow azide reaction module 2 is fed with materials, the raw material inlet valve 31 is closed and the raw material inlet valve 32 is opened at the same time, and so on.

[0228] While adding the materials to the rear reaction module, the reaction in the reaction module 2 is monitored by an online monitor. After the raw materials react, the reaction liquid discharge valve 15 at the bottom of the reaction module is automatically opened and the delivery pump 8 is started at a flow rate of 20 ml / min. At the same time, the metering pumps 9 and 10 are started, and the flow rate of the metering pump 9 is 16.6 ml / min and the flow rate of the metering pump 10 is 20 ml / min. The mixture enters the quenching extraction continuous flow reaction module 23, stays for 16 seconds, and then enters the continuous phase separation modules 24, 25, and 26. After treatment, an organic phase containing 4-azido-3-benzyloxy-2-(2-fluorophenylamino)benzoic acid benzyl ester solution is obtained. The solution can be concentrated until a large amount of solid precipitates and then cooled and crystallized to obtain a solid product. The organic solution can also be directly used in the next reaction.

[0229] 90.4 g of benzyl 4-azido-3-benzyloxy-2-(2-fluorophenylamino)benzoate was prepared in this example with a total yield of 86% and a purity of 90%.

[0230] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0231] Test Example 1: Process Safety Assessment of the Synthesis Method of the Aryl Azide Compounds of the Present Invention

[0232] 1. Evaluation Method

[0233] Test conditions

[0234] 1.1 Reaction Calorimeter RC1mx AP01-1.0 Test Conditions

[0235] (1) Test instrument: RC1mx AP01-1.0 reaction calorimeter

[0236] (2) Reactor material: atmospheric pressure glass reactor

[0237] (3) Maximum volume of reactor: 1000mL

[0238] (4) Calorimetric mode: heat flow method

[0239] 1.2 Differential Scanning Calorimetry (DSC)

[0240] (1) Testing instrument: DSC differential scanning calorimeter

[0241] (2) Test environment: nitrogen purge

[0242] (3) Purge rate: 50ml / min

[0243] (4) Temperature range: 25-400℃ / min

[0244] (5) Temperature rise rate: 10.0℃ / min

[0245] (6) Test crucible: high pressure sealed gold crucible

[0246] 1.3 Adiabatic Accelerating Rate Calorimeter ARC Test Conditions

[0247] (1) Test instrument: ARC adiabatic accelerating calorimeter

[0248] (2) Test mode: Heat-Search-Wait (HWS)

[0249] (3) Temperature rise detection threshold: 0.02℃ / min

[0250] (4) Temperature limit: 350.0℃

[0251] (5) Step heating rate: 5.0℃ / min

[0252] (6) Waiting time: 15.0 min

[0253] (7) Test ball: stainless steel, titanium alloy, resistant to 20MPa pressure

[0254] 1) Description of the experimental process

[0255] (1) Clean the reactor and make sure there are no impurities; purge with nitrogen to ensure there is no oxygen;

[0256] (2) Methyl 3-(tert-butylmercaptan)-4-fluoro-2-(2-fluorophenylamino)benzoate (48.00 g) and N,N-dimethylacetamide (240.00 g) were added to a reaction kettle, heated to Tr = 25.00 ° C, and stirred at 180 rpm to dissolve;

[0257] (3) Tr = 25.00 °C, calibration measurement U / Cpr;

[0258] (4) Sodium azide (9.60 g) was added to the reaction vessel, and the temperature was controlled not to exceed 30.00°C;

[0259] (5) After the addition is completed, keep the temperature at Tr = 60.00 ° C and the reaction time is 2 h;

[0260] (6) Tr = 60.00°C, calibrate and measure U / Cpr.

[0261] (7) After the reaction is completed, water is added to quench the mixture, and then MTBE is added for extraction. The phases are then separated, and the aqueous phase is reacted with sodium hypochlorite to destroy the reaction and discharged as waste water. The organic phase is concentrated to a large amount of solids, and then n-heptane is added for crystallization.

[0262] 2. Evaluation Conclusion

[0263] The process operating temperature Tp of the present invention is 60.0 °C. The reaction is carried out under atmospheric pressure, and the maximum technical temperature MTT is the boiling point of N,N-dimethylacetamide, which is 166.10 °C. The temperature TD24 corresponding to the time to reach the maximum reaction rate TMRad of the runaway system is 60.7 °C in 24 hours, and after the system runs away and the feeding is stopped in time, the maximum temperature MTSR that the system may reach is 105.78 °C. It is obtained that Tp < TD24 < MTSR < MTT. According to the process hazard assessment criteria in Table 1, the process hazard assessment level of the HLTNA04 azide reaction can be determined to be level 5. It can be seen that the risk of preparing aryl azide compounds using a reaction kettle is very high. However, using the device and method of the present invention can make the reaction safer.

[0264] Table 1. Process Hazard Assessment Results

[0265]

[0266] Due to certain safety hazards in the post-treatment of the reaction product, the present invention attempts to select a suitable solvent for extraction. After phase separation, it is directly used for the next reaction, and good results are obtained. The appropriate dosage is selected according to the solubility of the aryl azide compound in the solvent, and then the solvent recovery rate, the ease of phase separation, and the energy consumption are comprehensively evaluated. The relevant results are shown in Table 2. After evaluation, methyl tert-butyl ether is the preferred solvent.

[0267] Table 2. Comprehensive Evaluation Results of Different Solvents

[0268]

[0269] In summary, using the continuous flow synthesis device and synthesis method of the present invention to prepare aryl azide compounds has the advantages of precise control conditions, good selectivity, simple and safe operation, a large controllable range of explosiveness and leakage, and fast reaction rate, and has great practical value in improving production efficiency, production safety and reducing environmental pollution.

Claims

1. A device for continuous flow synthesis of aromatic azide compounds, characterized in that: It includes: The raw liquid storage tank (1), the feed pipe (21), a plurality of continuous flow azide reaction modules, the discharge pipe (22), the reaction liquid storage tank (6), the quenching and extraction continuous flow reaction module (23), and the continuous phase separation module are connected in sequence, and the metering pump 2 (9) and the metering pump 3 (10) are connected to the quenching and extraction continuous flow reaction module (23); Each of the continuous flow azide reaction modules includes a solid feeding funnel, a reaction liquid discharge valve, a raw material liquid inlet valve, and a solid feeding funnel feeding controller; Multiple continuous flow azide reaction modules are arranged in parallel, and the continuous flow azide reaction modules are connected by a circulating water pipeline, the first continuous flow azide reaction module has a circulating water inlet (19) for the entire system, and the last continuous flow azide reaction module has a circulating water outlet (20) for the entire system; The continuous phase separation module is connected to the organic phase outlet (35) and the aqueous phase outlet (36).

2. The device according to claim 1, characterized in that: The raw liquid storage tank (1) and the feed pipe (21) are connected via a metering pump (7); And / or, the feed pipe (21) is connected to the raw material inlet valve in each continuous flow azide reaction module; the discharge pipe (22) is connected to the reaction liquid discharge valve in each continuous flow azide reaction module; and / or, the discharge pipe (22) is connected to the reaction liquid storage tank (6); And / or, the reaction liquid storage tank (6) and the quenching extraction continuous flow reaction module (23) are connected via a metering pump four (8); And / or, the quenching extraction continuous flow reaction module (23) is connected to a continuous phase separation module.

3. The device according to claim 1 or 2, characterized in that: The number of the continuous flow azide reaction modules is 4 to 9; And / or, each continuous flow azide reaction module is connected to a motor, and a driving end of the motor is connected to a turbine stirrer; And / or, the continuous phase-splitting module comprises a first continuous phase-splitting module (24), a second continuous phase-splitting module (25), and a third continuous phase-splitting module (26) connected in series.

4. Use of the device according to any one of claims 1 to 3 in the continuous flow synthesis of aromatic azide compounds.

5. A method for continuous flow synthesis of aromatic azide compounds, characterized in that: It is carried out in the apparatus according to claim 2 or 3.

6. The method according to claim 5, characterized in that: It includes the following steps: S1: adding an organic solution A prepared by dissolving an aryl halide compound in an organic solvent into a raw material liquid storage tank (1); S2: adding the azide compound to the solid addition funnel of each continuous flow azide reaction module; S3: Use the quenching solvent as organic solution B and connect to metering pump 2 (9); S4: Using the extraction solvent as the organic solution C, connect metering pump three (10); S5: The organic solution A is passed through the feed pipe (21) by a metering pump (7) and is added to the continuous flow azide reaction module through the raw material inlet valve of the continuous flow azide reaction module; the azide compound in the solid feeding funnel is added to the continuous flow azide reaction module by controlling the solid feeding funnel feeding controller; the organic solution A and the azide compound are mixed and reacted to obtain a reaction solution; S6: The obtained reaction solution, organic solution B and organic solution C are passed into the quenching and extraction continuous flow reaction module (23) for quenching and extraction, and then enter the continuous phase separation module for phase separation to obtain an organic phase containing aromatic azide compounds.

7. The method according to claim 6, characterized in that: In step S1, the organic solvent is an anhydrous organic solvent; And / or, in step S1, the mass ratio of the aryl halide compound to the organic solvent is 1:(5-10); And / or, in step S2, the azide compound is sodium azide; And / or, in step S2, the mass ratio of the azide compound in each continuous flow azide reaction module to the aryl halide compound in step S1 is (0.1-1):1; And / or, in step S3, the quenching solvent is a saturated sodium chloride solution or water; And / or, in step S3, the mass ratio of the quenching solvent to the aryl halide compound in step S1 is (5-10):1; and / or, in step S4, the extraction solvent is methyl tert-butyl ether, toluene, dichloromethane, ethyl acetate or isopropyl acetate; And / or, in step S4, the mass ratio of the extraction solvent to the aryl halogenated compound in step S1 is (1-10):

1.

8. The method according to claim 7, wherein: In step S1, the organic solvent is N,N-dimethylacetamide; And / or, in step S2, the mass ratio of the azide compound in each continuous flow azide reaction module to the aryl halide compound in step S1 is (0.1-0.5):1; And / or, in step S3, the quenching solvent is a saturated sodium chloride solution; And / or, in step S4, the extraction solvent is methyl tert-butyl ether.

9. The method according to claim 6, wherein: In step S1, the aryl halide compound is a compound represented by 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 or halogenated C1-C6 alkoxy; R2 is selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl; R3 is selected from hydrogen; R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy; R5 is selected from halogen; X is selected from CR6 or N; R6 is selected from -SR7 or -OR8; R7 and R8 are independently selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl; And / or, in step S6, the aromatic azide compound is a compound represented by 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 or halogenated C1-C6 alkoxy; R2 is selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl; R3 is selected from hydrogen; R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy; X is selected from CR6 or N; R6 is selected from -SR7 or -OR8; R7 and R8 are independently selected from benzyl, benzyl substituted with 1 to 3 methyl groups, and C1 to C5 alkyl.

10. The method according to claim 9, characterized in that: The aryl halide compounds are methyl 3-(tert-butyl mercaptan)-4-fluoro-2-(2-fluorophenylamino)benzoate, methyl 6-chloro-2-(2-fluorophenylamino)nicotinate, and benzyl 3-(benzyloxy)-4-fluoro-2-(2-fluorophenylamino)benzoate; And / or, the aromatic azide compound is methyl 4-azido-3-(tert-butylthio)-2-(2-fluorophenylamino)benzoate, methyl 6-azido-2-(2-fluorophenylamino)nicotinate, or benzyl 4-azido-3-benzyloxy-2-(2-fluorophenylamino)benzoate.

11. The method according to claim 6, wherein: In step S5, the organic solution A is added to the continuous flow azide reaction module at a flow rate of 20 to 200 ml / min; And / or, in step S5, the addition of the azide compound is completed before the addition of the organic solution A is completed; And / or, in step S5, the organic solution A is first added to the first continuous flow azide reaction module, and after 30 to 40 minutes of adding the organic solution A, the raw material inlet valve is controlled to allow the organic solution A to enter the other continuous flow azide reaction modules in sequence; And / or, in step S5, the reaction temperature is 60° C. to 85° C., and the reaction time is 90 to 120 min.

12. The method according to claim 11, wherein: In step S5, the volume of each continuous flow azide reaction module is 1 to 5 L; And / or, in step S5, the flow rate of adding the organic solution A to the continuous flow azide reaction module is 20 ml / min; And / or, in step S6, the volume of the quenching extraction continuous flow reaction module is 10-20 ml.

13. The method according to claim 6, wherein: In step S6, the flow rate of the reaction liquid into the quenching extraction continuous flow reaction module is 20 to 200 ml / min; the flow rate of the organic solution B into the quenching extraction continuous flow reaction module is 15 to 200 ml / min; the flow rate of the organic solution C into the quenching extraction continuous flow reaction module is 20 to 200 ml / min.

14. The method according to claim 13, wherein: The ratio of the flow rate of the reaction solution passing into the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added to the continuous flow azide reaction module in step S5 is 1 to 1.2:1; The ratio of the flow rate of the organic solution B entering the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added to the continuous flow azide reaction module in step S5 is 0.6 to 0.9:1; The ratio of the flow rate of the organic solution C entering the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added to the continuous flow azide reaction module in step S5 is 0.8-1.2:1.

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