CN115837261A - Device and method for continuous flow synthesis of aryl azide compound - Google Patents

Abstract

The invention provides a device and a method for continuously synthesizing aryl azide compounds, and relates to the technical field of organic synthesis. The method comprises the following steps: preparing a solution from an aryl halogenated compound and an organic solvent, conveying the solution to a continuous flow reactor through a metering pump, carrying out mixing reaction, introducing the solution into a continuous flow quenching reactor, conveying a quenching extraction solvent to the continuous flow quenching reactor through the metering pump for quenching extraction, obtaining an aryl azide compound solution through a continuous liquid separator, concentrating and crystallizing to obtain a solid, or directly putting the organic solution into the next reaction. The aryl azide compound prepared by the continuous flow synthesis device and the synthesis method has the advantages of precise control of conditions, good selectivity, simple and safe operation, large controllable range of explosiveness and leakage property and high reaction rate, and has great practical value in the aspects of improving the production efficiency, improving the production safety and reducing the environmental pollution.

Description

Device and method for continuous flow synthesis of aryl azide compound

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a device and a method for continuously synthesizing aryl azide compounds.

Background

The aryl azide compounds are important chemical synthesis intermediates and are widely applied to a plurality of fields of organic synthesis, chemical biology, functional materials, clinical medicine and the like. There are many methods for synthesizing aryl azide compounds: (1) Under the action of inorganic acid and sodium nitrite, the generated diazo compound and sodium azide are subjected to displacement reaction to obtain aryl azide; (2) The aryl azide is obtained by coupling reaction of halogenated benzene and azide; (3) Phenylhydrazine reacts under the action of triphenylphosphine, bromine water and tetrabutyl ammonium nitrite to generate aryl azide; (4) Aryl borate and sodium azide generate aryl azide under the catalysis of Cu (I). However, the preparation method has many defects, such as high requirement on pH during diazotization, difficulty in control, high raw material toxicity, easiness in generating byproducts, low yield, low application range, high limitation and harsh conditions, so that further application of the method is limited.

The publication No. CN103012195B discloses a preparation method of aryl azide compounds, which comprises the steps of selecting porous copper as a catalyst, mixing iodo aryl compounds, sodium azide, alkaline substances and ligands in a solvent, reacting, and completing the preparation of the aryl azide compounds by a one-pot method; the patent publication No. CN106588693B also discloses a synthesis method of aryl azide, iodo-aryl compound, sodium azide, 1, 8-diazabicyclo [5.4.0] undec-7-ene and copper source catalyst are mixed in solvent and then react to obtain the target compound. The 2 patents mentioned above all use a copper (copper or copper salt) containing catalyst, described in sodium azide MSDS: form very sensitive compounds with heavy metals and basic salts, i.e. contact of sodium azide with copper or copper salts results in copper azide formation. Copper azide is an energetic material with high energy density, has very high electrostatic and mechanical sensitivity and is a powerful initiating explosive. The synthesis method involved in these 2 patents only stays in the milligram scale stage, and there is a high safety risk if a production scale-up is to be achieved.

Meanwhile, most of the azide reactions at home and abroad are carried out in a reaction kettle, so that a plurality of problems exist. Such as: the requirement on equipment is high during industrial production; the risk of explosion and leakage during production; in the traditional kettle type production mode, the amount of the azide is large in each batch, but the azide is heavy in specific gravity, cannot be added with a solvent for suspension and conveyed by an industrial pump, and needs to be weighed manually for a long time in the feeding process, so that the safety risk is high; most processes are carried out under the strict requirement of water-free conditions, but in the traditional mode, partial water enters a reaction kettle inevitably in the feeding, reaction and control stages, so that the reaction is influenced.

The continuous flow reaction is a continuous synthesis production method with high efficiency, energy conservation, safety, low carbon and environmental protection, and has the following advantages: (1) The instantaneous mixing of reaction materials and the accurate control of reaction process parameters can be realized, and the yield and the selectivity of the reaction can be improved; (2) The process is continuously and automatically controlled, so that the process stability is improved and the product quality is ensured; and (3) the safety of the chemical reaction is ensured due to the small reaction volume.

At present, a continuous flow method for synthesizing aryl azide compounds by using halogenated aryl does not directly adopt powdery solid azide compounds to continuously synthesize the aryl azide compounds, and sodium azide solution (prepared by dissolving water or mixed solvent of water) is adopted to carry out continuous flow reaction, so that the reaction system cannot be ensured to contain no water, but in the process of preparing the aryl azide compounds, carboxylic ester groups on aromatic rings of substrates are easy to hydrolyze when meeting water, so that the reaction system cannot contain water, and sodium azide has better solubility in water, so that an anhydrous solvent which can well dissolve the sodium azide cannot be found out, and a method for synthesizing the aryl azide compounds by using the continuous flow of the solid sodium azide as a raw material needs to be researched. A reaction system adopting solid sodium azide as a raw material is necessarily a solid-liquid heterogeneous system, and continuous flow synthesis of the solid-liquid heterogeneous system is necessarily achieved by solving the problems that the solid sodium azide is safely stored, the solid sodium azide is accurately metered and conveyed, and a continuous flow pipeline is easily blocked by solids in the system. Further research is needed to solve the above problems.

Disclosure of Invention

In order to solve the problems of high requirements on a reaction kettle and high explosion and leakage risks in the process of synthesizing aryl azide compounds from aryl halogenated compounds, the invention provides a device and a method for synthesizing the aryl azide compounds by continuous flow.

The invention provides a device for continuously synthesizing aryl azide compounds, which comprises:

the raw material liquid storage tank 1, the feeding pipe 21, the continuous flow azide reaction modules, the discharging pipe 22, the reaction liquid storage tank 6, the quenching extraction continuous flow reaction module 23 and the continuous phase splitting module are sequentially connected, and the metering pump 9 and the metering pump 10 are connected with the quenching extraction continuous flow reaction module 23;

each continuous flow azide reaction module comprises a solid feeding funnel, a reaction liquid discharging valve, a raw material inlet valve and a solid feeding funnel feeding controller;

a plurality of continuous flow nitrine reaction modules are arranged in parallel, the continuous flow nitrine reaction modules are connected through pipelines, a circulating water inlet 19 of the whole system is arranged on the first continuous flow nitrine reaction module, and a circulating water outlet 20 of the whole system is arranged on the last continuous flow nitrine reaction module;

the continuous phase separation module is connected with an organic phase outlet 35 and a water phase outlet 36.

Further, the raw material liquid storage tank 1 is connected with the feeding pipe 21 through a metering pump 7;

and/or the feeding pipe 21 is connected with a raw material liquid inlet valve in each continuous flow azide reaction module; the discharge pipe 22 is connected with a reaction liquid tapping valve in each continuous flow azide reaction module;

and/or the discharge pipe 22 is connected with 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 through a metering pump 8;

and/or the quenching extraction continuous flow reaction module 23 is connected with the continuous phase separation module.

Further, the number of the continuous flow azide reaction modules is 1-10; preferably 4 to 9;

and/or each continuous flow azide reaction module is connected with a motor, and the driving end of the motor is connected with a turbine stirrer;

and/or the sequential phase separation modules include a sequential phase separation module 24, a sequential phase separation module 25, and a sequential phase separation module 26 connected in series.

The invention also provides application of the device in continuous flow synthesis of the aryl azide compounds.

The invention also provides a method for continuously synthesizing the aryl azide compound, which is carried out in the device;

preferably, it comprises the following steps:

s1: adding an organic solution A prepared by dissolving aryl halogenated compounds in an organic solvent into a raw material solution storage tank 1;

s2: adding an azide compound to the solid addition funnel of each continuous flow azide reaction module;

s3: connecting a quenching solvent serving as an organic solution B with a metering pump 9;

s4: taking an extraction solvent as an organic solution C, and connecting a metering pump 10;

s5: the organic solution A passes through a feeding pipe 21 through a metering pump 7, is controlled by a raw material liquid inlet valve of the continuous flow azide reaction module, and is added into the continuous flow azide reaction module; adding the azide compound contained in the solid feeding funnel into the continuous flow azide reaction module by controlling a feeding controller of the solid feeding funnel; mixing the organic solution A and the azide for reaction to obtain a reaction solution;

s6: and introducing the obtained reaction liquid, the organic solution B and the organic solution C into a quenching extraction continuous flow reaction module 23 for quenching and extraction, and then entering a continuous phase separation module for phase separation to obtain an organic phase containing the aryl azide compounds.

Further, the air conditioner is provided with a fan,

in the step S1, the organic solvent is an anhydrous organic solvent;

and/or in the step S1, the mass ratio of the aryl halogenated compound to the organic solvent is 1: (5-10);

and/or, in the step S2, the azide compound is sodium azide;

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

and/or, in the step S3, the quenching solvent is a saturated sodium chloride solution or water;

and/or in the step S3, the mass ratio of the quenching solvent to the aryl halogenated compound in the 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 the step S4, the mass ratio of the extraction solvent to the aryl halogenated compound in the step S1 is (1-10): 1.

further, the air conditioner is provided with a fan,

in the step S1, the organic solvent is N, N-dimethylacetamide;

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

and/or, in the step S3, the quenching solvent is a saturated sodium chloride solution;

and/or, in the step S4, the extraction solvent is methyl tert-butyl ether.

Further, the air conditioner is provided with a fan,

in step S1, the aryl halogenated compound is a compound represented by formula I:

wherein the content of the first and second substances,

n is 0, 1, 2, 3, 4 or 5;

R ₁ is a substituent on the phenyl ring, each R ₁ Independently selected from halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

R ₂ selected from benzyl, benzyl substituted by 1-3 methyl groups, C ₁ ～C ₅ An alkyl group;

R ₃ selected from hydrogen;

R ₄ selected from hydrogen, halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

R ₅ selected from halogens;

x is selected from CR ₆ Or N;

R ₆ is selected from-SR ₇ OR-OR ₈ ；

R ₇ 、R ₈ Are respectively and independently selected from benzyl, benzyl substituted by 1-3 methyl, C ₁ ～C ₅ An alkyl group;

and/or in the step S6, the aryl azide compound is a compound shown as a formula II:

wherein the content of the first and second substances,

n is 0, 1, 2, 3, 4 or 5;

R ₁ is a substituent on the phenyl ring, each R ₁ Independently selected from halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

R ₂ selected from benzyl, benzyl substituted by 1-3 methyl groups, C ₁ ～C ₅ An alkyl group;

R ₃ selected from hydrogen;

R ₄ selected from hydrogen, halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

x is selected from CR ₆ Or N;

R ₆ is selected from-SR ₇ OR-OR ₈ ；

R ₇ 、R ₈ Are respectively and independently selected from benzyl, benzyl substituted by 1-3 methyl, C ₁ ～C ₅ An alkyl group;

preferably, the first and second electrodes are formed of a metal,

the aryl halogenated compound is methyl 3- (tert-butyl mercaptan) -4-fluoro-2- (2-fluorophenylamino) benzoate, 6-chloro-2- (2-fluorophenylamino) nicotinic acid methyl ester, and 3- (benzyloxy) -4-fluoro-2- (2-fluorophenylamino) benzyl benzoate;

and/or the aryl azide compound is methyl 4-azide-3- (tert-butyl sulfide) -2- (2-fluorophenylamino) benzoate, methyl 6-azide-2- (2-fluorophenylamino) nicotinate and benzyl 4-azide-3-benzyloxy-2- (2-fluorophenylamino) benzoate.

Further, the air conditioner is provided with a fan,

in the step S5, the circulating temperature of each continuous flow azide reaction module is 65-70 ℃;

and/or in the step S5, the flow rate of adding the organic solution A into the continuous flow azide reaction module is 20-200 ml/min;

and/or in the step S5, the addition of the azide compound is completed before the addition of the organic solution A is finished;

and/or in the step S5, adding the organic solution A into a first continuous flow azide reaction module, and after feeding the organic solution A for 30-40 min, controlling a raw material liquid inlet valve to enable the organic solution A to sequentially enter other continuous flow azide reaction modules;

and/or in the step S5, the reaction temperature is 60-85 ℃, and the reaction time is 90-120 min;

and/or in step S6, the circulation temperature of the quenching extraction continuous flow reaction module is 20 ℃;

preferably, the first and second electrodes are formed of a metal,

in the step S5, the volume of each continuous flow azide reaction module is 1-5L;

and/or in the step S5, the flow rate of adding the organic solution A into the continuous flow azide reaction module is 20ml/min;

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

Further, the air conditioner is provided with a fan,

in the step S6, the flow rate of introducing the reaction liquid into the quenching extraction continuous flow reaction module is 20-200 ml/min; the flow rate of the organic solution B introduced into the quenching extraction continuous flow reaction module is 15-200 ml/min; the flow rate of the organic solution C introduced into the quenching extraction continuous flow reaction module is 20-200 ml/min;

preferably, the ratio of the flow rate of the reaction liquid introduced into the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added into the continuous flow azide reaction module in the step S5 is 1-1.2: 1;

the flow rate of the organic solution B introduced into the quenching extraction continuous flow reaction module and the flow rate of the organic solution A added into the continuous flow azide reaction module in the step S5 are in a ratio of 0.6-0.9: 1;

the ratio of the flow speed of the organic solution C introduced into the quenching extraction continuous flow reaction module to the flow speed of the organic solution A added into the continuous flow azide reaction module in the step S5 is 0.8-1.2: 1.

the invention provides a device and a method for continuously synthesizing aryl azide compounds. The method comprises the following steps: and adding the aryl halogenated compound and the azide compound into the continuous flow azide reaction module through a metering pump and a solid feeding funnel, performing mixed reaction and continuous quenching extraction, obtaining an aryl azide solution through a continuous liquid distributor, concentrating and crystallizing to obtain a solid, or directly putting the organic solution into the next reaction.

Compared with the prior art, the invention has the advantages that:

(1) When the continuous flow reactor is used for continuous flow reaction, the production efficiency is ensured on the premise of improving the safety because the continuous flow reactor has small volume and more number;

(2) During reaction, materials are quickly and effectively mixed together at an accurate fixed ratio for reaction, so that the safety is improved, and the risks of explosion and leakage are reduced;

(3) The continuous flow azide reactor is a rotating disc type continuous flow azide reactor, continuous flow reaction is carried out in the whole process of feeding, mixing and reaction, accumulation, explosion and leakage in the process of needing additional configuration and transfer in the conventional batch reaction are avoided, the environmental protection and safety are improved, and the production efficiency is high.

(4) The method adopts the solid azide as the raw material, avoids the introduction of water, and effectively avoids the hydrolysis of the carboxylate group on the aromatic ring of the substrate.

In conclusion, the aryl azide compound prepared by the continuous flow synthesis device and the synthesis method has the advantages of precise control of conditions, good selectivity, simple and safe operation, large controllable range of explosiveness and leakage property and high reaction rate, and has great practical value in the aspects of improving the production efficiency, improving the production safety and reducing the environmental pollution.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is a block diagram of the modular design of the continuous flow reactor of the present invention and a process for the synthesis of aryl azides.

FIG. 2 is a schematic diagram of the apparatus for continuous flow synthesis of aryl azide compounds according to the present invention.

Detailed Description

The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.

The synthetic route of the aryl azide compound synthesized by continuous flow is as follows:

wherein the content of the first and second substances,

n is 0, 1, 2, 3, 4 or 5;

R ₁ is a substituent on the phenyl ring, each R ₁ Independently selected from halogen (e.g. fluorine, chlorine, bromine), C ₁ ～C ₆ Alkyl (e.g. methyl), C ₁ ～C ₆ Alkoxy (e.g. methoxy), halo C ₁ ～C ₆ Alkyl (e.g. trifluoromethyl) or halo C ₁ ～C ₆ Alkoxy (e.g., trifluoromethoxy);

R ₂ selected from benzyl, benzyl substituted by 1-3 methyl groups, C ₁ ～C ₅ An alkyl group;

R ₃ selected from hydrogen;

R ₄ selected from hydrogen, halogen (e.g. fluorine, chlorine, bromine), C ₁ ～C ₆ Alkyl (e.g. methyl), C ₁ ～C ₆ Alkoxy (e.g. methoxy), halo C ₁ ～C ₆ Alkyl (e.g. trifluoromethyl) or halo C ₁ ～C ₆ Alkoxy (e.g., trifluoromethoxy);

R ₅ selected from halogens;

x is selected from CR ₆ Or N;

R ₆ is selected from-SR ₇ OR-OR ₈ ；

R ₇ 、R ₈ Are respectively and independently selected from benzyl, benzyl substituted by 1-3 methyl, C ₁ ～C ₅ An alkyl group.

The module design of the continuous flow reaction device and the process flow chart of the synthesis of the aryl azide compound are shown in figure 1; the schematic diagram of the device is shown in fig. 2.

The continuous flow reaction device (figure 2) of the present invention comprises the following components:

(1) The device comprises a raw material liquid storage tank 1, a reaction liquid storage tank 6, a quenching and extracting continuous flow reaction module 23, a continuous phase separation module 24, a continuous phase separation module 25, a continuous phase separation module 26, an organic phase outlet 35 and a water phase outlet 36; wherein the quenching extraction continuous flow reaction module 23 corresponds to the continuous quenching extraction reactor in fig. 1, and 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 the continuous liquid separator in fig. 1.

(2) A metering pump 7, a metering pump 8, a metering pump 9 and a metering pump 10; wherein the metering pumps 7, 9 and 10 correspond to the first metering pump, the second metering pump and the third metering pump in fig. 1, respectively.

(3) The solid feeding funnel 11, the reaction liquid discharging valve 15, the raw material liquid inlet valve 31, the solid feeding funnel feeding controller 27 and the circulating water inlet 19 of the whole system form a continuous flow azide reaction module 2; the solid feeding funnel 12, the reaction liquid discharging valve 16, the raw material liquid inlet valve 32 and the solid feeding funnel feeding controller 28 form a continuous flow azide reaction module 3; the solid feeding funnel 13, the reaction liquid discharging valve 17, the raw material liquid inlet valve 33 and the solid feeding funnel feeding controller 29 form a continuous flow azide reaction module 4; the solid feeding funnel 14, the reaction liquid discharging valve 18, the raw material inlet valve 34, the solid feeding funnel feeding controller 30 and the circulating water outlet 20 of the whole system form a continuous flow azide reaction module 5. The continuous flow azide reaction modules 2, 3, 4 and 5 form the continuous flow azide reactor shown in fig. 1, and the number of the continuous flow azide reaction modules can be increased according to actual requirements.

(4) An inlet pipe 21 and an outlet pipe 22.

The method for continuously synthesizing the aryl azide compounds comprises the following steps:

s1: a solution A prepared by dissolving aryl halogenated compounds in an organic solvent is added into a raw material liquid storage tank 1 and is connected with a metering pump 7.

S2: the charge of azide per batch was added to solid addition funnels 11, 12, 13, 14.

S3: the quench solvent is labeled solution B and is connected to metering pump 9.

S4: the extraction solvent is designated as solution C and is connected to a metering pump 10.

S5: adding the solution A in the S1 into continuous flow azide reaction modules 2, 3, 4 and 5 through a metering pump 7, adding solid feeding funnels 11, 12, 13 and 14 filled with azide compounds into the continuous flow azide reaction modules 2, 3, 4 and 5 through controllers 27, 28, 29 and 30, reacting the solution A and the azide compounds in the continuous flow azide reaction modules at 60-85 ℃ to generate mixed reaction liquid containing azide groups, feeding the reaction liquid into a reaction liquid storage tank 6 through reaction liquid bleeder valves 15, 16, 17, 18 and a discharge pipe 22, feeding the reaction liquid into a quenching extraction continuous flow reaction module 23 through a metering pump 8 to quench and extract at 20-30 ℃, obtaining aryl azide solution through continuous phase separation modules 24, 25 and 26 after continuous quenching and extracting, concentrating and crystallizing to obtain solid, and also directly feeding the organic solution into the next step of reaction.

According to the invention, aryl halogenated compounds and azide compounds are added into a continuous flow azide reaction module through a metering pump, mixed reaction and continuous quenching extraction are carried out, an aryl azide solution is obtained through a post-continuous liquid distributor, then the aryl azide solution is concentrated and crystallized to obtain a solid, and the organic solution can also be directly put into the next reaction. The method for preparing the aryl azide compound by adopting the device disclosed by the invention has the advantages of accurate control of conditions, high safety, short reaction time, reduction of explosion and leakage risks, simplicity in operation and environmental friendliness, and has great practical value in the aspects of improving the production safety and improving the production efficiency.

Example 1 Synthesis of aryl Azide Compounds of the invention

The aryl azide compound was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: placing a mixed solution of 100g of methyl 3- (tert-butylmercaptan) -4-fluoro-2- (2-fluorophenylamino) benzoate and 500g of N, N-dimethylacetamide into a raw material liquid storage tank 1, and connecting a metering pump 7;

reagent A: 21g of sodium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated saline (sodium chloride aqueous solution) is connected with a metering pump 9;

solvent C: 444g of methyl tert-butyl ether was connected to the metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4, 5: the circulation temperature reaches 65-70 ℃ and reaches a stable volume 1L 9;

quenching extraction continuous flow reaction module 23: the circulation temperature was 20 ℃ and the volume was 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction liquid, controlling the flow rate of the solution A to be =20ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like. When the materials are fed to the last continuous flow azide reaction module according to requirements, the first reaction module finishes the reaction and discharges the materials, and the feeding of the first reaction module can be carried out after the feeding of the last reaction module is finished, so that the continuous flow reaction is realized; fig. 2 only shows 4 continuous flow azide reaction modules, but the number of continuous flow azide reaction modules can be expanded according to requirements, and in this embodiment, the number is 9.

The risk of explosion and leakage exists in a large number of reactions directly in one reaction module, and the reaction module is divided into a plurality of small reaction modules, so that the risk coefficients of explosion and leakage of the azide can be reduced; meanwhile, when the reaction is carried out in one reaction module, the amount of the azide compound fed in each batch is large, the specific gravity of the azide compound is heavy, the azide compound cannot be added into a solvent for suspension and conveyed by using an industrial pump, a large amount of the azide compound cannot be added at one time in the feeding process, the azide compound needs to be manually weighed for a long time and added in batches, and the safety risk is high; most processes are carried out under the strict requirement of anhydrous condition, the feeding amount of a reaction module is large, and partial water is inevitably fed into a reaction kettle in the feeding, reaction and central control stages, so that the reaction is influenced.

When a reaction module is fed, a reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a metering pump 8 is opened, the flow rate is =20ml/min, the metering pump 9 and the metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the raw materials enter a quenching extraction continuous flow reaction module 23, the raw materials stay for 16S and then enter continuous phase separation modules 24, 25 and 26, an organic phase containing methyl 4-azido-3- (tert-butyl sulfide) -2- (2-fluorophenyl amino) methyl benzoate solution is obtained through treatment, the organic phase containing methyl 4-azido-2- (tert-butyl sulfide) -methyl benzoate solution can be concentrated to a large amount of solids and then cooled and crystallized to obtain a solid product, and the organic solution can also be directly put into the next reaction for use.

Methyl 4-azido-3- (tert-butylthio) -2- (2-fluorophenylamino) benzoate 100.1g, obtained in this example, was in a total yield of 94% and a purity of 96%.

Example 2 Synthesis method of aryl Azide Compound of the invention

The aryl azide compound was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: placing a mixed solution of 100g of methyl 3- (tert-butylmercaptan) -4-fluoro-2- (2-fluorophenylamino) benzoate and 500g of N, N-dimethylacetamide into a raw material liquid storage tank 1, and connecting a metering pump 7;

reagent A: 26g of potassium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated brine (sodium chloride aqueous solution) is connected with a metering pump 9;

solvent C: 444g of methyl tert-butyl ether was connected to the metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4 and 5, wherein the circulating temperature reaches 65-70 ℃ and reaches the stable volume 1L 9;

the extraction continuous flow reaction module 23 is quenched, the circulation temperature is 20 ℃, and the volume is 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction liquid, controlling the flow rate of the solution A to be =20ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like.

When a reaction module is fed, a reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a metering pump 8 is opened, the flow rate is =20ml/min, the metering pump 9 and the metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the raw materials enter a quenching extraction continuous flow reaction module 23, the raw materials stay for 16S and then enter continuous phase separation modules 24, 25 and 26, an organic phase containing methyl 4-azido-3- (tert-butyl sulfide) -2- (2-fluorophenyl amino) methyl benzoate solution is obtained through treatment, the organic phase containing methyl 4-azido-2- (tert-butyl sulfide) -methyl benzoate solution can be concentrated to a large amount of solids and then cooled and crystallized to obtain a solid product, and the organic solution can also be directly put into the next reaction for use.

Methyl 4-azido-3- (tert-butylthio) -2- (2-fluorophenylamino) benzoate 98g, prepared in this example, was in a total yield of 92% and purity of 94%.

Example 3 Synthesis method of aryl Azide Compound of the invention

The aryl azide compound was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: placing a mixed solution of 100g of methyl 3- (tert-butylmercaptan) -4-fluoro-2- (2-fluorophenylamino) benzoate and 500g of N, N-dimethylformamide into a raw material liquid storage tank 1, and connecting a metering pump 7;

reagent A: 21g of sodium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated saline (sodium chloride aqueous solution) is connected with a metering pump 9;

and (3) solvent C: 444g of methyl tert-butyl ether was connected to the metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4, 5: the circulation temperature reaches 65-70 ℃ and reaches a stable volume 1L 9;

quenching extraction continuous flow reaction module 23: the circulation temperature was 20 ℃ and the volume was 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction liquid, controlling the flow rate of the solution A to be 18.5ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like.

When a reaction module behind the material is added, the reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a conveying pump 8 is started, the flow rate is =18.5ml/min, a metering pump 9 and a metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the reaction liquid enters a quenching extraction continuous flow reaction module 23, the reaction liquid stays for 16S and then enters continuous phase separation modules 24, 25 and 26, and after treatment, a solution containing methyl 4-azido-3- (tert-butyl sulfide) -2- (2-fluorophenylamino) methyl benzoate in an organic phase is obtained, the solution can be concentrated until a large amount of solid is separated out, a solid product is obtained through cooling crystallization, and the organic solution can also be directly put into the next reaction for use.

Methyl 4-azido-3- (tert-butylthio) -2- (2-fluorophenylamino) benzoate 85.2g, total yield 80%, purity 89% was prepared in this example.

Example 4 Synthesis method of aryl Azide Compound of the invention

The aryl azide was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: putting a mixed solution of 100g of 6-chloro-2- (2-fluorophenyl amino) methyl nicotinate and 500g of N, N-dimethylacetamide into a raw material liquid storage tank 1, and connecting a metering pump 7;

reagent A: 27g of sodium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated saline (sodium chloride aqueous solution) is connected with a metering pump 9;

solvent C: 444g of methyl tert-butyl ether was connected to the metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4, 5: the circulation temperature reaches 65-70 ℃ and reaches a stable volume 1L 9;

quenching extraction continuous flow reaction module 23: the circulation temperature was 20 ℃ and the volume was 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction liquid, controlling the flow rate of the solution A to be =20ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like.

When a reaction module is fed, a reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a conveying pump 8 is started, the flow rate is =20ml/min, a metering pump 9 and a metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the raw materials enter a quenching extraction continuous flow reaction module 23, the raw materials stay for 16S and then enter continuous phase separation modules 24, 25 and 26, an organic phase solution containing (6-azido-2- (2-fluorophenylamino) methyl nicotinate) is obtained after treatment, the organic phase solution can be concentrated until a large amount of solids are separated out, a solid product is obtained through cooling crystallization, and the organic solution can also be directly put into the next step of reaction for use.

97.2g of methyl (6-azido-2- (2-fluorophenylamino) nicotinate) prepared in this example was obtained in 95% overall yield and 96% purity.

Example 5 Synthesis of aryl Azide Compounds of the invention

The aryl azide compound was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: putting a mixed solution of 100g of 6-chloro-2- (2-fluorophenylamino) methyl nicotinate and 500g of N, N-dimethylacetamide into a raw material liquid storage tank 1, and connecting a metering pump 7;

reagent A: 37.5g of potassium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated saline (sodium chloride aqueous solution) is connected with a metering pump 9;

solvent C: 444g of methyl tert-butyl ether was connected to the metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4, 5: the circulation temperature reaches 65-70 ℃ and reaches a stable volume 1L 9;

quenching extraction continuous flow reaction module 23: the circulation temperature was 20 ℃ and the volume was 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction liquid, controlling the flow rate of the solution A to be =20ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like.

When a reaction module is fed, a reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a conveying pump 8 is started, the flow rate is =20ml/min, a metering pump 9 and a metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the raw materials enter a quenching extraction continuous flow reaction module 23, the raw materials stay for 16S and then enter continuous phase separation modules 24, 25 and 26, an organic phase (6-azido-2- (2-fluorophenylamino) methyl nicotinate) solution is obtained after treatment, the organic phase can be concentrated until a large amount of solids are precipitated, a solid product is obtained through cooling and crystallization, and the organic solution can also be directly put into the next step of reaction for use.

92.0g of methyl (6-azido-2- (2-fluorophenylamino) nicotinate) prepared in this example was obtained in 90% overall yield and 95% purity.

Example 6 Synthesis of aryl Azide Compounds of the invention

The aryl azide was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: putting 100g of 3- (benzyloxy) -4-fluoro-2- (2-fluorophenylamino) benzyl benzoate and 500g of N, N-dimethylacetamide mixed solution into a raw material liquid storage tank 1, and connecting with a metering pump 7;

reagent A: 16.6g of sodium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated saline (sodium chloride aqueous solution) is connected with a metering pump 9;

and (3) solvent C: 444g of methyl tert-butyl ether was connected to a metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4, 5: the circulation temperature reaches 65-70 ℃ and reaches a stable volume 1L 9;

quenching extraction continuous flow reaction module 23: the circulation temperature was 20 ℃ and the volume was 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction solution, controlling the flow rate of the solution A to be =20ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, and thus automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like.

When a reaction module is fed, a reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a conveying pump 8 is started, the flow rate is =20ml/min, a metering pump 9 and a metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the raw materials enter a quenching extraction continuous flow reaction module 23, the raw materials stay for 16S and then enter continuous phase separation modules 24, 25 and 26, the raw materials are treated to obtain a solution of an organic phase containing 4-azido-3-benzyloxy-2- (2-fluorophenyl amino) benzyl benzoate, the solution can be concentrated until a large amount of solids are separated out, a solid product is obtained through cooling crystallization, and the organic solution can also be directly put into the next reaction for use.

96.7g of benzyl 4-azido-3-benzyloxy-2- (2-fluorophenylamino) benzoate was prepared in this example in 92% overall yield and 96% purity.

Example 7 Synthesis of aryl Azide Compounds of the invention

The aryl azide compound was synthesized using the apparatus shown in FIG. 2.

1. Raw material preparation

Solution A: putting 100g of 3- (benzyloxy) -4-fluoro-2- (2-fluorophenylamino) benzyl benzoate and 500g of N, N-dimethylacetamide mixed solution into a raw material liquid storage tank 1, and connecting with a metering pump 7;

reagent A: 23.7g of potassium azide in each continuous flow azide reaction module is subpackaged into solid addition funnels 11, 12, 13 and 14;

solvent B: 500g of saturated saline (sodium chloride aqueous solution) is connected with a metering pump 9;

solvent C: 444g of methyl tert-butyl ether was connected to the metering pump 10.

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

continuous flow azide reaction modules 2, 3, 4, 5: the circulation temperature reaches 65-70 ℃ and reaches a stable volume 1L 9;

and a quenching extraction continuous flow reaction module 23 with circulation temperature of 20 ℃ and volume of 15ml.

3. The specific operation is as follows:

starting an automatic feeding system, conveying the solution A into the continuous flow azide reaction module 2 through a feeding pipe 21 by a metering pump 7, controlling a solid feeding funnel 11 to add sodium azide into the continuous flow azide reaction module 2 by controlling a solid feeding funnel feeding controller 27, reacting the solution A and the sodium azide in the continuous flow azide reaction module 2 for 90min to obtain a reaction liquid, controlling the flow rate of the solution A to be =20ml/min, controlling feeding by controlling a raw material liquid inlet valve after feeding for 30min, automatically switching the solution A into other continuous flow azide reaction modules, and adding 9 continuous flow azide reaction modules by analogy.

And the subsequent continuous flow nitrine reaction modules are sequentially fed for reaction according to the method, after the feeding of the continuous flow nitrine reaction module 2 is finished, the raw material liquid inlet valve 31 is closed, and meanwhile, the raw material liquid inlet valve 32 is opened, and the like.

When a reaction module is fed, a reaction in the reaction module 2 is monitored by an online monitor, after the reaction of raw materials is finished, a reaction liquid discharging valve 15 at the bottom of the reaction module is automatically opened, a conveying pump 8 is started, the flow rate is =20ml/min, a metering pump 9 and a metering pump 10 are simultaneously started, the flow rate of the metering pump 9 is =16.6ml/min, the flow rate of the metering pump 10 is =20ml/min, the raw materials enter a quenching extraction continuous flow reaction module 23, the raw materials stay for 16S and then enter continuous phase separation modules 24, 25 and 26, an organic phase containing 4-azido-3-benzyloxy-2- (2-fluorophenyl amino) benzyl benzoate solution is obtained after treatment, the organic phase can be concentrated until a large amount of solids are separated out, a solid product is obtained through cooling crystallization, and the organic solution can also be directly put into the next reaction for use.

90.4g of benzyl 4-azido-3-benzyloxy-2- (2-fluorophenylamino) benzoate was prepared in this example in 86% overall yield and 90% purity.

The advantageous effects of the present invention are demonstrated by specific test examples below.

Test example 1 evaluation of Process safety of the Synthesis method of aryl Azide Compound of the present invention

1. Evaluation method

Test conditions

1.1 reaction calorimeter RC1mx AP01-1.0 test condition

(1) Testing an instrument: RC1mx AP01-1.0 reaction calorimeter

(2) The material quality of the reaction kettle: normal pressure glass reaction kettle

(3) Maximum volume of the reaction kettle: 1000mL

(4) Calorimetric mode: heat flow method

1.2 differential scanning calorimeter DSC

(1) Testing an instrument: DSC differential scanning calorimeter

(2) And (3) testing environment: nitrogen purging

(3) Purge rate: 50ml/min

(4) Temperature range: 25-400 ℃/min

(5) Rate of temperature rise: 10.0 ℃/min

(6) Testing the crucible: high-pressure closed gold crucible

1.3 adiabatic accelerated calorimeter ARC test conditions

(1) Testing an instrument: ARC adiabatic acceleration calorimeter

(2) And (3) a test mode: heat-seek-wait (HWS)

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

(4) Upper limit of temperature: 350.0 deg.C

(5) Step temperature rise rate: 5.0 ℃/min

(6) Waiting time: 15.0min

(7) Testing the pellets: stainless steel, titanium alloy, resisting 20MPa pressure

1) Description of the Experimental procedures

(1) Cleaning the reaction kettle and confirming that no impurities exist; nitrogen purging to ensure no oxygen;

(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 vessel, and the mixture was heated to Tr =25.00 ℃ and dissolved with stirring at 180 rpm;

(3) Tr =25.00 ℃, calibration measurement U/Cpr;

(4) Adding sodium azide (9.60 g) into a reaction kettle, and controlling the temperature to be not more than 30.00 ℃;

(5) After the feeding is finished, keeping the temperature at Tr =60.00 ℃ and reacting for 2h;

(6) Tr =60.00 ℃, calibration measurement U/Cpr.

(7) After the reaction is finished, adding water for quenching, then adding MTBE for extraction, then splitting phases, adding sodium hypochlorite into a water phase for reaction and destruction, then discharging wastewater, concentrating an organic phase to a large amount of solids, and then adding n-heptane for crystallization.

2. Evaluation conclusion

The process operating temperature Tp of the invention is 60.0 ℃. The reaction is carried out under normal pressure, and the technical maximum temperature MTT is 166.10 ℃ of the boiling point of N, N-dimethylacetamide. The maximum reaction rate reaching time TMRad of the runaway system is 60.7 ℃ corresponding to the temperature TD24 of 24 hours, the feeding is stopped in time after the system is out of control, and the maximum temperature MTSR which the system can possibly reach is 105.78 ℃. Tp < TD24< MTSR < MTT, and the evaluation grade of the process risk of HLTNA04 azide reaction can be determined to be grade 5 according to the process risk evaluation standard in Table 1. Therefore, the danger of preparing the aryl azide compound by adopting the reaction kettle is very high. The device and the method can ensure that the reaction is safer.

TABLE 1 evaluation results of Process Risk

Because reaction products have certain potential safety hazard in post-treatment, the invention tries to select proper solvent for extraction, and after phase separation, the reaction products are directly used for the next reaction, thereby obtaining good effect. The appropriate amount of the aryl azide is selected according to the solubility of the aryl azide in the solvent, and then the recovery rate of the solvent, the phase separation difficulty and the energy consumption are comprehensively evaluated, and the related results are shown in a table 2. Methyl tert-butyl ether was evaluated as a preferred solvent.

TABLE 2 comprehensive evaluation results of different solvents

In conclusion, the aryl azide compound prepared by the continuous flow synthesis device and the synthesis method has the advantages of precise control of conditions, good selectivity, simple and safe operation, large controllable range of explosiveness and leakage property and high reaction rate, and has great practical value in the aspects of improving the production efficiency, improving the production safety and reducing the environmental pollution.

Claims (10)

1. A continuous flow synthesis device of aryl azide compounds is characterized in that: it includes:

the device comprises a raw material liquid storage tank (1), a feeding pipe (21), a plurality of continuous flow azide reaction modules, a discharging pipe (22), a reaction liquid storage tank (6), a quenching and extracting continuous flow reaction module (23) and a continuous phase separation module which are sequentially connected, wherein a metering pump (9) and a metering pump (10) are connected with the quenching and extracting continuous flow reaction module (23);

each continuous flow azide reaction module comprises a solid feeding funnel, a reaction liquid discharging valve, a raw material inlet valve and a solid feeding funnel feeding controller;

a plurality of continuous flow nitrine reaction modules are arranged in parallel, the continuous flow nitrine reaction modules are connected through pipelines, a circulating water inlet (19) of the whole system is arranged on the first continuous flow nitrine reaction module, and a circulating water outlet (20) of the whole system is arranged on the last continuous flow nitrine reaction module;

the continuous phase separation module is connected with an organic phase outlet (35) and a water phase outlet (36).

2. The apparatus of claim 1, wherein: the raw material liquid storage tank (1) is connected with the feeding pipe (21) through a metering pump (7);

and/or the feeding pipe (21) is connected with a raw material liquid inlet valve in each continuous flow azide reaction module; the discharge pipe (22) is connected with a reaction liquid discharge valve in each continuous flow azide reaction module;

and/or the discharge pipe (22) is connected with a reaction liquid storage tank (6);

and/or the reaction liquid storage tank (6) is connected with the quenching extraction continuous flow reaction module (23) through a metering pump (8);

and/or the quenching extraction continuous flow reaction module (23) is connected with the continuous phase separation module.

3. The apparatus of claim 1 or 2, wherein: the number of the continuous flow azide reaction modules is 1-10; preferably 4 to 9;

and/or each continuous flow azide reaction module is connected with a motor, and the driving end of the motor is connected with a turbine stirrer;

and/or the sequential phase separation modules comprise serially connected sequential phase separation modules (24), sequential phase separation modules (25) and sequential phase separation modules (26).

4. Use of the device of any one of claims 1 to 3 for continuous flow synthesis of aryl azide compounds.

5. A method for continuous flow synthesis of aryl azide compounds is characterized in that: it is carried out in an apparatus according to any one of claims 1 to 3;

preferably, it comprises the following steps:

s1: dissolving aryl halogenated compounds in an organic solvent to prepare an organic solution A, and adding the organic solution A into a raw material liquid storage tank (1);

s2: adding an azide compound to the solid addition funnel of each continuous flow azide reaction module;

s3: connecting a metering pump (9) by taking the quenching solvent as an organic solution B;

s4: connecting an extraction solvent serving as an organic solution C with a metering pump (10);

s5: the organic solution A passes through a feeding pipe (21) through a metering pump (7), is controlled by a raw material liquid inlet valve of the continuous flow azide reaction module, and is added into the continuous flow azide reaction module; adding the azide compound contained in the solid feeding funnel into the continuous flow azide reaction module by controlling a feeding controller of the solid feeding funnel; mixing the organic solution A and the azide for reaction to obtain a reaction solution;

s6: and introducing the obtained reaction liquid, the organic solution B and the organic solution C into a quenching extraction continuous flow reaction module (23) for quenching and extraction, and then entering a continuous phase separation module for phase separation to obtain an organic phase containing the aryl azide compounds.

6. The method of claim 5, wherein:

in the step S1, the organic solvent is an anhydrous organic solvent;

and/or in the step S1, the mass ratio of the aryl halogenated compound to the organic solvent is 1: (5-10);

and/or in the step S2, the azide compound is sodium azide;

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

and/or, in the step S3, the quenching solvent is a saturated sodium chloride solution or water;

and/or in the step S3, the mass ratio of the quenching solvent to the aryl halogenated compound in the 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 the step S4, the mass ratio of the extraction solvent to the aryl halogenated compound in the step S1 is (1-10): 1.

7. the method of claim 6, wherein:

in the step S1, the organic solvent is N, N-dimethylacetamide;

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

and/or, in the step S3, the quenching solvent is a saturated sodium chloride solution;

and/or, in the step S4, the extraction solvent is methyl tert-butyl ether.

8. The method of claim 5, wherein:

in step S1, the aryl halogenated compound is a compound represented by formula I:

wherein the content of the first and second substances,

n is 0, 1, 2, 3, 4 or 5;

R ₁ is a substituent on the phenyl ring, each R ₁ Independently selected from halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

R ₂ selected from benzyl, benzyl substituted by 1-3 methyl groups, C ₁ ～C ₅ An alkyl group;

R ₃ selected from hydrogen;

R ₄ selected from hydrogen, halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

R ₅ selected from halogens;

x is selected from CR ₆ Or N;

R ₆ is selected from-SR ₇ OR-OR ₈ ；

R ₇ 、R ₈ Are respectively and independently selected from benzyl, benzyl substituted by 1-3 methyl, C ₁ ～C ₅ An alkyl group;

and/or in the step S6, the aryl azide compound is a compound shown as a formula II:

wherein the content of the first and second substances,

n is 0, 1, 2, 3, 4 or 5;

R ₁ is a substituent on the phenyl ring, each R ₁ Independently selected from halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

R ₂ selected from benzyl, benzyl substituted by 1-3 methyl groups, C ₁ ～C ₅ An alkyl group;

R ₃ selected from hydrogen;

R ₄ selected from hydrogen, halogen, C ₁ ～C ₆ Alkyl radical, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl or halo C ₁ ～C ₆ An alkoxy group;

x is selected from CR ₆ Or N;

R ₆ is selected from-SR ₇ OR-OR ₈ ；

R ₇ 、R ₈ Are respectively and independently selected from benzyl, benzyl substituted by 1-3 methyl, C ₁ ～C ₅ An alkyl group;

preferably, the first and second electrodes are formed of a metal,

the aryl halogenated compound is methyl 3- (tert-butyl mercaptan) -4-fluoro-2- (2-fluorophenylamino) benzoate, 6-chloro-2- (2-fluorophenylamino) nicotinic acid methyl ester and 3- (benzyloxy) -4-fluoro-2- (2-fluorophenylamino) benzyl benzoate;

and/or the aryl azide compound is methyl 4-azide-3- (tert-butyl sulfide) -2- (2-fluorophenylamino) benzoate, methyl 6-azide-2- (2-fluorophenylamino) nicotinate and benzyl 4-azide-3-benzyloxy-2- (2-fluorophenylamino) benzoate.

9. The method of claim 5, wherein:

in the step S5, the circulating temperature of each continuous flow azide reaction module is 65-70 ℃;

and/or in the step S5, the flow rate of adding the organic solution A into the continuous flow azide reaction module is 20-200 ml/min;

and/or in the step S5, the addition of the azide compound is completed before the addition of the organic solution A is finished;

and/or in the step S5, adding the organic solution A into a first continuous flow azide reaction module, and after feeding the organic solution A for 30-40 min, controlling a raw material liquid inlet valve to enable the organic solution A to sequentially enter other continuous flow azide reaction modules;

and/or in the step S5, the reaction temperature is 60-85 ℃, and the reaction time is 90-120 min;

and/or in step S6, the circulation temperature of the quenching extraction continuous flow reaction module is 20 ℃;

preferably, the first and second electrodes are formed of a metal,

in the step S5, the volume of each continuous flow azide reaction module is 1-5L;

and/or in the step S5, the flow rate of adding the organic solution A into the continuous flow azide reaction module is 20ml/min;

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

10. The method of claim 5, wherein:

in the step S6, the flow rate of introducing the reaction liquid into the quenching extraction continuous flow reaction module is 20-200 ml/min; the flow rate of the organic solution B introduced into the quenching extraction continuous flow reaction module is 15-200 ml/min; the flow rate of the organic solution C introduced into the quenching extraction continuous flow reaction module is 20-200 ml/min;

preferably, the ratio of the flow rate of the reaction liquid introduced into the quenching extraction continuous flow reaction module to the flow rate of the organic solution A added into the continuous flow azide reaction module in the step S5 is 1-1.2: 1;

the flow rate of the organic solution B introduced into the quenching extraction continuous flow reaction module and the flow rate of the organic solution A added into the continuous flow azide reaction module in the step S5 are in a ratio of 0.6-0.9: 1;

the flow rate of the organic solution C introduced into the quenching extraction continuous flow reaction module and the flow rate of the organic solution A added into the continuous flow azide reaction module in the step S5 are in a ratio of 0.8-1.2: 1.

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