阅读说明：本技术 一种连续流微反应器中合成4-(4-氟苯甲酰基)丁酸及其类似物的方法 (Method for synthesizing 4- (4-fluorobenzoyl) butyric acid and analogue thereof in continuous flow microreactor ) 是由 石利平 何义 叶金星 徐春涛 程瑞华 孙伟振 张维冰 李大伟 万新强 陆梦云 王 于 2020-12-17 设计创作，主要内容包括：本发明涉及一种连续流微反应器中合成4-(4-氟苯甲酰基)丁酸及其类似物的方法,它包括以下步骤：(1)将化合物1与化合物2混合均匀,得到均相A溶液；(2)将三氯化铝、化合物1和有机溶剂混合均匀,得到均相B溶液；(3)将浓盐酸加水稀释制成C溶液；(4)将所述均相A溶液和均相B溶液转移至第一微反应模块中进行傅-克酰基化反应,待反应结束后,将得到的反应液与所述C溶液再转移至第二微反应模块中进行淬灭反应,再进行分液、洗涤、减压浓缩得到目标化合物3；具体合成路线如下。采用本发明的合成方法,能够连续、快速合成目标产物,不需要三氯化铝进行处理,反应条件温和,反应时间短,收率高,达到90％以上。(The invention relates to a method for synthesizing 4- (4-fluorobenzoyl) butyric acid and analogues thereof in a continuous flow microreactor, which comprises the following steps: (1) uniformly mixing the compound 1 and the compound 2 to obtain a homogeneous phase A solution; (2) uniformly mixing aluminum trichloride, a compound 1 and an organic solvent to obtain a homogeneous phase B solution; (3) diluting concentrated hydrochloric acid with water to obtain solution C; (4) transferring the homogeneous phase A solution and the homogeneous phase B solution to a first micro-reaction module for Fourier transformationAfter the reaction is finished, transferring the obtained reaction liquid and the solution C to a second micro-reaction module for quenching reaction, and then carrying out liquid separation, washing and reduced pressure concentration to obtain a target compound 3; the specific synthetic route is as follows. The synthesis method can continuously and rapidly synthesize the target product, does not need aluminum trichloride for treatment, and has the advantages of mild reaction conditions, short reaction time and high yield which is more than 90 percent.)

1. A method for synthesizing 4- (4-fluorobenzoyl) butyric acid and the like in a continuous-flow microreactor, which is characterized by comprising the following steps:

(1) uniformly mixing the compound 1 and the compound 2 to obtain a homogeneous phase A solution;

(2) uniformly mixing aluminum trichloride, a compound 1 and an organic solvent to obtain a homogeneous phase B solution;

(3) diluting concentrated hydrochloric acid with water to obtain solution C;

(4) respectively pumping the homogeneous phase A solution and the homogeneous phase B solution into a first micro-reaction mixer (M1), uniformly mixing, transferring the mixture into a first micro-reaction module (L1) to perform Friedel-crafts acylation reaction at the temperature of 0-25 ℃ for 5-15 min, respectively pumping the reaction liquid obtained after the Friedel-crafts acylation reaction and the solution C solution into a second micro-reaction mixer (M2), uniformly mixing, transferring the mixture into a second micro-reaction module (L2) to perform quenching reaction at the temperature of 0-25 ℃ for 1-10 min, and after the reaction is finished, performing liquid separation, washing and reduced pressure concentration to obtain a target compound 3; the specific synthetic route is as follows:

wherein R represents fluorine, chlorine, bromine, methyl or methoxy; n represents 1 or 2.

2. The method according to claim 1, wherein in step (1), the concentration of compound 2 in the homogeneous phase a solution is 0.5mol/L to 2.0mol/L, preferably 1.5 mol/L.

3. The method according to claim 2, wherein in step (2), the concentration of aluminum trichloride in the homogeneous B solution is 0.5mol/L to 1.0mol/L, preferably 0.75 mol/L; the molar ratio of the aluminum trichloride to the compound 1 is 1: 1.5-2.5, and preferably 1: 1.7.

4. The method according to claim 3, wherein in step (2), the organic solvent is dichloromethane, tetrahydrofuran or diethyl ether.

5. The method according to claim 1, wherein in the step (3), the concentration of the hydrochloric acid in the solution C is 0.5mol/L to 1.5mol/L, preferably 1 mol/L.

6. The method according to claim 1, wherein in the step (4), when the friedel-crafts acylation reaction is carried out, the molar ratio of the compound 2 to the compound 1 is 1: 5-10, and the reaction time is 12 min; when the quenching reaction was carried out, the reaction time was 5 min.

7. The method of claim 3, wherein in step (4), the flow rate at which the homogeneous A solution is pumped is from 0.2mL/min to 10 mL/min; the flow rate of the solution pumped into the homogeneous phase B is 2-6 times of the flow rate of the solution pumped into the homogeneous phase A.

8. The method according to claim 3, wherein in the step (4), the flow rate of the reaction solution obtained after the Friedel-crafts acylation reaction is pumped in is 0.1mL/min to 2mL/min, and the flow rate of the solution C is pumped in is 2 to 5 times of the flow rate of the reaction solution obtained after the Friedel-crafts acylation reaction is completed.

9. The method according to claim 8, wherein the continuous-flow microreactor comprises a material channel (A), a material channel (B) and a material channel (C), wherein the material channel (A) and the material channel (B) are respectively connected with a feed inlet of the first micro-reaction mixer (M1), a discharge outlet of the first micro-reaction mixer (M1) is connected with a feed inlet of the first micro-reaction module (L1), a discharge outlet of the first micro-reaction module (L1) and the material channel (C) are respectively connected with a feed inlet of a second micro-reaction mixer (M2), a discharge outlet of the second micro-reaction mixer (M2) is connected with a feed inlet of the second micro-reaction module (L2), and a discharge outlet of the second micro-reaction module (L2) is connected with a feed inlet of a receiving reaction vessel (R); a first advection pump (P1) is arranged on a channel between the material channel (A) and the first micro-reaction mixer (M1), a second advection pump (P2) is arranged on a channel between the material channel (B) and the first micro-reaction mixer (M1), and a third advection pump (P3) is arranged on a channel between the material channel (C) and the second micro-reaction mixer (M2).

10. The method according to claim 9, wherein the first or second micro-reaction module (L1, L2) has an inner diameter of 0.1 to 10mm and a length of 5 to 20 m.

Technical Field

The invention particularly relates to the technical field of organic synthesis, and particularly relates to a method for continuously, quickly and efficiently synthesizing 4- (4-fluorobenzoyl) butyric acid and analogues thereof by using a continuous-flow microreactor.

Background

Ezetimibe (Ezetimibe), the structure of which is shown in formula (I), is a novel cholesterol absorption inhibitor jointly developed by Schering-Plough pharmaceutical company and Merck company. The first time the product was marketed in 11 months in 2002 in Germany, and in the United states at the same time. Ezetimibe only acts on the small intestine, and reduces intestinal cholesterol transport to the liver and storage thereof by inhibiting cholesterol absorption; can enhance the clearance of cholesterol in the blood, thereby lowering the plasma cholesterol level, and is suitable for treating homozygous familial hypercholesterolemia (HoGH) and homozygous sitosterolemia (or phytosterolaemia).

Due to the wide prospect of the ezetimibe applied to the treatment of the blood fat reducing disease, the market demand in the future is very large. Fluorobenzene and glutaric anhydride are used as initial raw materials, 4- (4-fluorobenzoyl) butyric acid is obtained through Friedel-crafts reaction, the structure is as follows, and a final product ezetimibe is obtained through a series of reactions such as amidation, reduction and the like.

4- (4-fluorobenzoyl) butyric acid is an important intermediate for synthesizing ezetimibe, and in the prior art, fluorobenzene and glutaric anhydride are used as initial raw materials, and anhydrous aluminum trichloride is used as an acylating agent to carry out Friedel-crafts reaction for preparation. However, the requirement on anhydrous aluminum trichloride is severe, the anhydrous aluminum trichloride needs to be ground, sieved and dried before reaction, the production is difficult to be amplified and applied, and meanwhile, the traditional kettle type reaction has the advantages of low efficiency, low reaction temperature, high requirement on equipment, high energy consumption, low yield and high production cost.

Disclosure of Invention

The invention aims to provide a method for synthesizing an ezetimibe intermediate 4- (4-fluorobenzoyl) butyric acid and an analogue thereof by a continuous-flow microreactor on the basis of the prior art, which can continuously, quickly and efficiently synthesize the ezetimibe intermediate 4- (4-fluorobenzoyl) butyric acid and the analogue thereof, does not need aluminum trichloride for treatment, and has the advantages of mild reaction conditions, short reaction time, high yield and low cost.

The technical scheme of the invention is as follows:

a method for synthesizing 4- (4-fluorobenzoyl) butyric acid and analogues thereof in a continuous-flow microreactor, comprising the steps of:

(1) uniformly mixing the compound 1 and the compound 2 to obtain a homogeneous phase A solution;

(2) uniformly mixing aluminum trichloride, a compound 1 and an organic solvent to obtain a homogeneous phase B solution;

(3) diluting concentrated hydrochloric acid with water to obtain solution C;

(4) respectively pumping the homogeneous phase A solution and the homogeneous phase B solution into a first micro-reaction mixer, uniformly mixing, and transferring to a first micro-reaction module for carrying out Friedel-crafts acylation reaction at the reaction temperature of 0-25 ℃ for 5-15 min; pumping the reaction liquid obtained after the Friedel-crafts acylation reaction and the solution C into a second micro-reaction mixer, uniformly mixing, transferring the mixture into a second micro-reaction module for quenching reaction at the reaction temperature of 0-25 ℃ for 1-10 min, and after the reaction is finished, carrying out liquid separation, washing and reduced pressure concentration to obtain a target compound 3; the specific synthetic route is as follows:

wherein R represents fluorine, chlorine, bromine, methyl or methoxy; n represents 1 or 2.

For the purposes of the present invention, compound I is a compound obtained by substituting R for one hydrogen atom in benzene, wherein R represents fluorine, chlorine, bromine, methyl or methoxy, that is, compound I may be specifically fluorobenzene, chlorobenzene, bromobenzene, toluene or anisole.

The compound 2 is cyclic anhydride, when n is 1, the compound 2 is succinic anhydride, and when n is 2, the compound 2 is glutaric anhydride.

In a preferred embodiment, in step (1), compound 2 is glutaric anhydride/succinic anhydride, and when mixed with compound 1, a homogeneous solution A is obtained. The concentration of compound 2 in the homogeneous A solution is 0.5mol/L to 2.0mol/L, and may be, but is not limited to, 0.5mol/L, 0.8mol/L, 1.0mol/L, 1.2mol/L, 1.5mol/L, 1.8mol/L, or 2.0 mol/L. Further preferably, the concentration of the compound 2 is 1.5 mol/L.

The aluminum trichloride mentioned in the invention is generally anhydrous aluminum trichloride.

In a preferred embodiment, in step (2), aluminum trichloride, the compound 1 and an organic solvent are mixed uniformly, and the concentration of aluminum trichloride in the obtained homogeneous B solution is 0.5mol/L to 1.0mol/L, and can be, but is not limited to, 0.5mol/L, 0.6mol/L, 0.7mol/L, 0.8mol/L, 0.9mol/L or 1.0 mol/L. Further preferably, the concentration of aluminum trichloride is 0.75 mol/L.

In step (1) and in step (2), compound I may be specifically fluorobenzene, chlorobenzene, bromobenzene, toluene or anisole.

In a more preferred embodiment, the molar ratio of aluminum trichloride to compound 1 in the homogeneous B solution is 1:1.5 to 2.5, which may be, but is not limited to, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, or 1: 2.5. Further preferably, the molar ratio of aluminum trichloride to compound 1 is 1: 1.7.

Further, in the step (2), the organic solvent used in the present invention is dichloromethane, tetrahydrofuran or diethyl ether, preferably dichloromethane.

In a preferable embodiment, in the step (3), concentrated hydrochloric acid is diluted with water to prepare a solution C, and the concentration of hydrochloric acid in the solution C is 0.5mol/L to 1.5mol/L, and more preferably, the concentration of hydrochloric acid in the solution C is 1 mol/L.

For the invention, in the step (4), the homogeneous phase A solution and the homogeneous phase B solution are respectively pumped into a first micro-reaction mixer, and are transferred into a first micro-reaction module after being uniformly mixed to carry out Friedel-crafts acylation reaction, wherein the flow rate of the homogeneous phase A solution pumped in is 0.2mL/min to 10mL/min, and can be but is not limited to 0.2mL/min, 2mL/min, 4mL/min, 5mL/min, 6mL/min, 8mL/min or 10 mL/min; the flow rate at which the homogeneous phase B solution is pumped is adjusted according to the flow rate at which the homogeneous phase a solution is pumped, in a preferred embodiment the flow rate at which the homogeneous phase B solution is pumped is 2 to 6 times, e.g., 2 times, 3 times, 4 times, 5 times or 6 times the flow rate at which the homogeneous phase a solution is pumped.

In the step (4), the Friedel-crafts acylation reaction is carried out at a reaction temperature of 0-25 ℃, which can be but is not limited to 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃ or 25 ℃; the reaction time is 5-15 min, and can be adjusted according to needs, for example, 5min, 10min, 12min or 15 min. The mixing time in the first micromixer is too short to be generally ignored.

In another scheme, when the Friedel-crafts acylation reaction is carried out in the first micro-reaction module, the molar ratio of the compound 2 (glutaric anhydride/succinic anhydride) to the compound 1 is 1: 5-10.

In a preferred embodiment, in step (4), the quenching reaction is performed at a reaction temperature of 0-25 ℃, which may be, but is not limited to, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃ or 25 ℃; the reaction time is 1-10 min, and can be adjusted according to the needs, for example, 1min, 3min, 5min or 10 min. The mixing time in the second micromixer is too short to be generally ignored.

In the step (4), pumping the reaction solution (labeled as D reaction solution) and the solution C obtained after the friedel-crafts acylation reaction in the first micro-reaction module into a second micro-reaction mixer, mixing uniformly, and transferring to the second micro-reaction module for quenching reaction, wherein the flow rate of the pumped D reaction solution is 0.1mL/min to 2mL/min, which can be but is not limited to 0.1mL/min, 0.5mL/min, 0.8mL/min, 1mL/min, 1.5mL/min or 2 mL/min; the flow rate of the solution C pumped in is 2 to 5 times, for example, 2 times, 3 times, 4 times or 5 times of the flow rate of the reaction solution D pumped in.

The continuous flow microreactor comprises a material channel A, a material channel B and a material channel C, wherein the material channel A and the material channel B are respectively connected with a feed inlet of a first micro-reaction mixer, a discharge outlet of the first micro-reaction mixer is connected with a liquid inlet of a first micro-reaction module, a liquid outlet of the first micro-reaction module and the material channel C are respectively connected with a feed inlet of a second micro-reaction mixer, a discharge outlet of the second micro-reaction mixer is connected with a liquid inlet of the second micro-reaction module, and a liquid outlet of the second micro-reaction module is connected with a liquid inlet of a receiving reaction kettle; a first flat flow pump is arranged on a channel between the material channel A and the first micro-reaction mixer, a second flat flow pump is arranged on a channel between the material channel B and the first micro-reaction mixer, and a third flat flow pump is arranged on a channel between the material channel C and the second micro-reaction mixer.

Further, the inner diameter of the first or second micro-reaction module is 0.1 to 10mm, for example, 0.1mm, 0.3mm, 1mm, 2mm, 3mm, 5mm, 6mm or 10 mm; the length is 5 to 20m, for example, 5m, 5.5m, 8m, 9m, 10m, 12.5m, 13m, 15m or 20 m. The micro-reaction module has the advantages of large specific surface area, large contact area of reaction liquid, high heat and mass transfer speed and the like. The micro-reaction module is adopted for carrying out chemical reaction, the liquid holdup is small, the process is safe and reliable, and continuous operation can be realized. When the method is used for industrial mass production, the production requirement can be achieved through simple number amplification according to the production requirement, and no amplification effect exists.

By adopting the technical scheme of the invention, the advantages are as follows:

(1) the continuous flow micro-reactor provided by the invention has the advantages of small liquid holdup, strong mass transfer and heat transfer capabilities and the like.

(2) The continuous flow microreactor is adopted to synthesize the ezetimibe intermediate 4- (4-fluorobenzoyl) butyric acid and the analogue thereof, the requirement of low-temperature environment required in the existing synthetic method is avoided, the target product can be continuously, quickly and efficiently synthesized, aluminum trichloride is not required for treatment, the reaction condition is mild, the reaction time is short, the yield is high and reaches more than 90%, the cost is low, and various quantity grades of production can be realized according to the requirement without amplification effect.

Drawings

FIG. 1 is a schematic diagram of the synthesis of 4- (4-fluorobenzoyl) butyric acid and its analogues in a continuous-flow microreactor according to the present invention;

the device comprises a material channel A, B, C, a first advection pump P1, a second advection pump P2, a third advection pump P3, a first reaction mixer M1, a first reaction module L1, a second reaction mixer M2, a second reaction module L2, a receiving reaction kettle R and a liquid outlet O.

Detailed Description

The synthesis process of the present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.

The invention provides a continuous flow microreactor, which comprises a material channel A, a material channel B and a material channel C, wherein the material channel A and the material channel B are respectively connected with a feed inlet of a first micro-reaction mixer M1, a discharge outlet of the first micro-reaction mixer M1 is connected with a liquid inlet of a first micro-reaction module L1, a liquid outlet of the first micro-reaction module L1 and the material channel C are respectively connected with a feed inlet of a second micro-reaction mixer M2, a discharge outlet of the second micro-reaction mixer M2 is connected with a liquid inlet of a second micro-reaction module L2, a liquid outlet of the second micro-reaction module L2 is connected with a liquid inlet of a receiving reaction kettle R, and a liquid outlet O is arranged at the lower part of the receiving reaction kettle R, as shown in figure 1.

A first flat flow pump P1 is arranged on a channel between the material channel A and the first micro-reaction mixer M1, a second flat flow pump P2 is arranged on a channel between the material channel B and the first micro-reaction mixer M1, and a third flat flow pump P3 is arranged on a channel between the material channel C and the second micro-reaction mixer M2.

The invention provides a continuous flow microreactor which is used as follows: respectively pumping the homogeneous phase A solution and the homogeneous phase B solution into a first micro-reaction mixer M1 through a first advection pump P1 and a second advection pump P2, uniformly mixing, transferring to a first reaction module L1 for carrying out Friedel-crafts acylation reaction, and placing the first micro-reaction mixer M1 and the first reaction module L1 at preset temperatures, wherein the reaction temperatures are 0-25 ℃, and the reaction time is 5-15 min; and pumping the solution C into a second reaction mixer M2 by a third advection pump P3, pumping reaction liquid obtained after Friedel-crafts acylation reaction into a second reaction mixer M2, uniformly mixing, transferring to a second reaction module L2 for quenching reaction, placing a second micro reaction mixer M2 and a second reaction module L2 at a preset temperature, reacting at 0-25 ℃ for 1-10 min, after the reaction is finished, feeding the reaction liquid obtained after quenching reaction into a receiving reaction kettle R, uniformly stirring, discharging the reaction liquid from a liquid outlet O, collecting the reaction liquid into a liquid separating device, and extracting, washing, acidifying, extracting, washing, drying, concentrating and drying to obtain ezetimibe intermediate 4- (4-fluorobenzoyl) butyric acid and analogues thereof.

Example 1:

(1) glutaric anhydride (compound 2) and fluorobenzene (compound 1) are mixed uniformly to obtain a homogeneous phase A solution, and the concentration of the glutaric anhydride (compound 2) in the homogeneous phase A solution is 1.5 mol/L.

(2) Anhydrous aluminum trichloride, fluorobenzene (compound 1) and dichloromethane are uniformly mixed to obtain a homogeneous phase B solution, wherein the concentration of the aluminum trichloride in the homogeneous phase B solution is 0.75mol/L, and the molar ratio of the aluminum trichloride to the fluorobenzene (compound 1) is 1: 1.7.

(3) And (3) adding water to dilute the concentrated hydrochloric acid to prepare a solution C, wherein the concentration of the hydrochloric acid in the solution C is 1 mol/L.

(4) The first micro-reaction mixer M1 and the first reaction module L1 are both placed at preset temperatures, the homogeneous phase A solution obtained in the step (1) and the homogeneous phase B solution obtained in the step (2) are respectively pumped into the first micro-reaction mixer M1 by a first flat-flow pump P1 and a second flat-flow pump P2 according to the flow rate ratio (1:2), the homogeneous phase A solution is pumped into the first micro-reaction mixer M1 by a first flat-flow pump P1, the flow rate is 0.2mL/min, the homogeneous phase A solution is uniformly mixed and then transferred into the first reaction module L1 (the inner diameter: 0.1mm and the length: 20M) to carry out Friedel-crafts acylation reaction, the reaction temperature is 0 ℃, and the reaction time is 15 min. The second micro-reaction mixer M2 and the second reaction module L2 are also placed at preset temperatures, after the Friedel-crafts acylation reaction is finished, the obtained reaction liquid (marked as D reaction liquid) is pumped into the second reaction mixer M2 at the flow rate of 0.1mL/min, meanwhile, the solution C is pumped into the second reaction mixer M2 by a third flow pump P3 according to the flow rate ratio (2:1) of the D reaction liquid, and after being uniformly mixed, the solution C is transferred to a second reaction module L2 (inner diameter: 1mm, length: 5M) for quenching reaction, the reaction temperature is 0 ℃, and the reaction time is 10 min.

Pumping the reaction solution obtained after quenching reaction into a receiving reaction kettle R, stirring for 5min, flowing out through a liquid outlet O, collecting the reaction solution into a liquid separating device, standing for liquid separation, extracting the upper aqueous phase by using dichloromethane, combining organic phases, adding an isovolumetric saturated sodium carbonate solution for alkalization, extracting the liquid separation, and acidifying the obtained aqueous phase by using concentrated hydrochloric acid until the pH value is 1. Extracting water phase with dichloromethane, mixing organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, vacuum filtering, concentrating under reduced pressure at 35 deg.CDrying for 12h in the air to obtain white solid 4- (4-fluorobenzoyl) butyric acid with the yield of 95%.¹H NMR(400MHz,CDCl₃):δ8.02-7.98(m,2H),7.18-7.13(m,2H),3.06(t,J＝6.4Hz,2H),2.52(t,J＝7.0Hz,2H),2.20-2.12(m,2H).

Example 2:

(1) succinic anhydride (compound 2) and fluorobenzene (compound 1) are mixed uniformly to obtain a homogeneous phase A solution, and the concentration of the succinic anhydride (compound 2) in the homogeneous phase A solution is 1.5 mol/L.

(2) Anhydrous aluminum trichloride, fluorobenzene (compound 1) and dichloromethane are uniformly mixed to obtain a homogeneous phase B solution, wherein the concentration of the aluminum trichloride in the homogeneous phase B solution is 0.75mol/L, and the molar ratio of the aluminum trichloride to the fluorobenzene (compound 1) is 1: 1.7.

(3) And (3) adding water to dilute the concentrated hydrochloric acid to prepare a solution C, wherein the concentration of the hydrochloric acid in the solution C is 1 mol/L.

(4) The first micro-reaction mixer M1 and the first reaction module L1 are both placed at preset temperatures, the homogeneous phase A solution obtained in the step (1) and the homogeneous phase B solution obtained in the step (2) are pumped into the first micro-reaction mixer M1 through a first advection pump P1 and a second advection pump P2 respectively according to the flow rate ratio (1:6), the homogeneous phase A solution is pumped into the first micro-reaction mixer M1 through a first advection pump P1, the flow rate of the homogeneous phase A solution is 10mL/min, the homogeneous phase A solution is uniformly mixed and then transferred into the first reaction module L1 (the inner diameter is 10mm, the length is 5M) to carry out Friedel-crafts acylation reaction, the reaction temperature is 25 ℃, and the reaction time is 5 min. The second micro-reaction mixer M2 and the second reaction module L2 are also placed at preset temperatures, after the Friedel-crafts acylation reaction is finished, the obtained reaction liquid (marked as D reaction liquid) is pumped into the second reaction mixer M2 at the flow rate of 2mL/min, meanwhile, the solution C is pumped into the second reaction mixer M2 by a third flow pump P3 according to the flow rate ratio (5:1) of the D reaction liquid, and after uniform mixing, the solution C is transferred to a second reaction module L2 (the inner diameter: 2mm, the length: 10M) for quenching reaction, the reaction temperature is 25 ℃, and the reaction time is 1 min.

Pumping the reaction solution obtained after quenching reaction into a receiving reaction kettle R, stirring for 5min, flowing out through a liquid outlet O, collecting into a liquid separating device, standing for liquid separation, extracting the upper aqueous phase with dichloromethane, and mixingAnd adding an equal volume of saturated sodium carbonate solution into the organic phase for alkalization, extracting and separating liquid, and acidifying the obtained water phase by using concentrated hydrochloric acid until the pH value is 1. Extracting the water phase with dichloromethane, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, vacuum-drying at 35 deg.C for 12h after vacuum concentration to obtain white solid 4- (4-fluorobenzoyl) propionic acid with yield of 92%.¹H NMR(400MHz,CDCl₃):δ7.90(d,J＝8.0Hz,2H),7.71(d,J＝8.4Hz,2H),3.29(t,J＝6.4Hz,2H),2.83(t,J＝6.4Hz,2H).

Example 3:

(1) glutaric anhydride (compound 2) and chlorobenzene (compound 1) are uniformly mixed to obtain a homogeneous phase A solution, and the concentration of the glutaric anhydride (compound 2) in the homogeneous phase A solution is 1.5 mol/L.

(2) Anhydrous aluminum trichloride, chlorobenzene (compound 1) and dichloromethane are uniformly mixed to obtain a homogeneous phase B solution, wherein the concentration of the aluminum trichloride in the homogeneous phase B solution is 0.75mol/L, and the molar ratio of the aluminum trichloride to the chlorobenzene (compound 1) is 1: 1.7.

(3) And (3) adding water to dilute the concentrated hydrochloric acid to prepare a solution C, wherein the concentration of the hydrochloric acid in the solution C is 1 mol/L.

(4) The first micro-reaction mixer M1 and the first reaction module L1 are both placed at preset temperatures, the homogeneous phase A solution obtained in the step (1) and the homogeneous phase B solution obtained in the step (2) are pumped into the first micro-reaction mixer M1 through a first advection pump P1 and a second advection pump P2 respectively according to the flow rate ratio (1:4), the homogeneous phase A solution is pumped into the first micro-reaction mixer M1 through a first advection pump P1, the flow rate is 2mL/min, the homogeneous phase A solution is uniformly mixed and then transferred into the first reaction module L1 (the inner diameter: 5mm, the length: 15M) to carry out Friedel-crafts acylation reaction, the reaction temperature is 10 ℃, and the reaction time is 12 min. The second micro-reaction mixer M2 and the second reaction module L2 are also placed at preset temperatures, after the Friedel-crafts acylation reaction is finished, the obtained reaction liquid (marked as D reaction liquid) is pumped into the second reaction mixer M2 at the flow rate of 1mL/min, meanwhile, the solution C is pumped into the second reaction mixer M2 by a third flow pump P3 according to the flow rate ratio (2:1) of the D reaction liquid, and after uniform mixing, the solution C is transferred to a second reaction module L2 (inner diameter: 0.5mm, length: 10M) for quenching reaction, the reaction temperature is 15 ℃, and the reaction time is 5 min.

Pumping the reaction solution obtained after quenching reaction into a receiving reaction kettle R, stirring for 5min, flowing out through a liquid outlet O, collecting the reaction solution into a liquid separating device, standing for liquid separation, extracting the upper aqueous phase by using dichloromethane, combining organic phases, adding an isovolumetric saturated sodium carbonate solution for alkalization, extracting the liquid separation, and acidifying the obtained aqueous phase by using concentrated hydrochloric acid until the pH value is 1. Extracting the water phase with dichloromethane, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, vacuum-drying at 35 deg.C for 12h after vacuum concentration to obtain white solid 4- (4-chlorobenzoyl) butyric acid with yield of 97%.¹H NMR(400MHz,CDCl₃):δ11.20(br,1H),7.90(d,J＝7.6Hz,2H),7.44(d,J＝7.6Hz,2H),3.06(t,J＝6.4Hz,2H),2.55(t,J＝6.4Hz,2H),2.15-2.09(m,2H).

Example 4:

(1) glutaric anhydride (compound 2) and bromobenzene (compound 1) are mixed uniformly to obtain homogeneous phase A solution, and the concentration of glutaric anhydride (compound 2) in the homogeneous phase A solution is 1.5 mol/L.

(2) Anhydrous aluminum trichloride, bromobenzene (compound 1) and dichloromethane are uniformly mixed to obtain a homogeneous phase B solution, the concentration of the aluminum trichloride in the homogeneous phase B solution is 0.75mol/L, and the molar ratio of the aluminum trichloride to the bromobenzene (compound 1) is 1: 1.7.

(3) And (3) adding water to dilute the concentrated hydrochloric acid to prepare a solution C, wherein the concentration of the hydrochloric acid in the solution C is 1 mol/L.

(4) The first micro-reaction mixer M1 and the first reaction module L1 are both placed at preset temperatures, the homogeneous phase A solution obtained in the step (1) and the homogeneous phase B solution obtained in the step (2) are pumped into the first micro-reaction mixer M1 through a first advection pump P1 and a second advection pump P2 respectively according to the flow rate ratio (1:5), the homogeneous phase A solution is pumped into the first micro-reaction mixer M1 through a first advection pump P1, the flow rate is 5mL/min, the homogeneous phase A solution is uniformly mixed and then transferred into the first reaction module L1 (the inner diameter: 6mm, the length: 13M) to carry out Friedel-crafts acylation reaction, the reaction temperature is 15 ℃, and the reaction time is 10 min. The second micro-reaction mixer M2 and the second reaction module L2 are also placed at preset temperatures, after the Friedel-crafts acylation reaction is finished, the obtained reaction liquid (marked as D reaction liquid) is pumped into the second reaction mixer M2 at the flow rate of 0.5mL/min, meanwhile, the solution C is pumped into the second reaction mixer M2 by a third flow pump P3 according to the flow rate ratio (3:1) of the D reaction liquid, and after being uniformly mixed, the solution C is transferred to a second reaction module L2 (inner diameter: 2mm, length: 8M) for quenching reaction, the reaction temperature is 10 ℃, and the reaction time is 8 min.

Pumping the reaction solution obtained after quenching reaction into a receiving reaction kettle R, stirring for 5min, flowing out through a liquid outlet O, collecting the reaction solution into a liquid separating device, standing for liquid separation, extracting the upper aqueous phase by using dichloromethane, combining organic phases, adding an isovolumetric saturated sodium carbonate solution for alkalization, extracting the liquid separation, and acidifying the obtained aqueous phase by using concentrated hydrochloric acid until the pH value is 1. Extracting the water phase by using dichloromethane, then combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, decompressing, concentrating, and drying for 12 hours in vacuum at the temperature of 35 ℃ to obtain white solid 4- (4-bromobenzoyl) butyric acid with the yield of 94 percent.¹H NMR(400MHz,CDCl₃):δ10.50(br,1H),7.89(d,J＝6.4Hz,2H),7.71(d,J＝8.4Hz,2H),3.05(t,J＝7.0Hz,2H),2.51(t,J＝7.0Hz,2H),2.23-2.15(m,2H).

Example 5:

(1) glutaric anhydride (compound 2) and toluene (compound 1) are mixed uniformly to obtain homogeneous phase A solution, and the concentration of the glutaric anhydride (compound 2) in the homogeneous phase A solution is 1.5 mol/L.

(2) Anhydrous aluminum trichloride, toluene (compound 1) and dichloromethane are uniformly mixed to obtain a homogeneous phase B solution, wherein the concentration of the aluminum trichloride in the homogeneous phase B solution is 0.75mol/L, and the molar ratio of the aluminum trichloride to the toluene (compound 1) is 1: 1.7.

(3) And (3) adding water to dilute the concentrated hydrochloric acid to prepare a solution C, wherein the concentration of the hydrochloric acid in the solution C is 1 mol/L.

(4) The first micro-reaction mixer M1 and the first reaction module L1 are both placed at preset temperatures, the homogeneous phase A solution obtained in the step (1) and the homogeneous phase B solution obtained in the step (2) are pumped into the first micro-reaction mixer M1 through a first advection pump P1 and a second advection pump P2 respectively according to the flow rate ratio (1:3), the homogeneous phase A solution is pumped into the first micro-reaction mixer M1 through a first advection pump P1, the flow rate is 4mL/min, the homogeneous phase A solution is uniformly mixed and then transferred into the first reaction module L1 (the inner diameter: 1mm, the length: 10M) to carry out Friedel-crafts acylation reaction, the reaction temperature is 5 ℃, and the reaction time is 12 min. The second micro-reaction mixer M2 and the second reaction module L2 are also placed at preset temperatures, after the Friedel-crafts acylation reaction is finished, the obtained reaction liquid (marked as D reaction liquid) is pumped into the second reaction mixer M2 at the flow rate of 1.5mL/min, meanwhile, the solution C is pumped into the second reaction mixer M2 by a third flow pump P3 according to the flow rate ratio (3:1) of the D reaction liquid, and after being uniformly mixed, the solution C is transferred to a second reaction module L2 (inner diameter: 1mm, length: 5.5M) for quenching reaction, the reaction temperature is 5 ℃, and the reaction time is 5 min.

Pumping the reaction solution obtained after quenching reaction into a receiving reaction kettle R, stirring for 5min, flowing out through a liquid outlet O, collecting the reaction solution into a liquid separating device, standing for liquid separation, extracting the upper aqueous phase by using dichloromethane, combining organic phases, adding an isovolumetric saturated sodium carbonate solution for alkalization, extracting the liquid separation, and acidifying the obtained aqueous phase by using concentrated hydrochloric acid until the pH value is 1. Extracting the water phase with dichloromethane, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, vacuum-drying at 35 deg.C for 12h after vacuum concentration to obtain white solid 4- (4-methylbenzoyl) butyric acid with yield of 95%.¹H NMR(400MHz,CDCl₃):δ11.12(br,1H),7.86(d,J＝7.2Hz,2H),7.30(d,J＝7.6Hz,2H),3.06(t,J＝6.6Hz,2H),2.50(t,J＝6.8Hz,2H),2.30(s,3H),2.15-2.09(m,2H).

Example 6:

(1) glutaric anhydride (compound 2) and anisole (compound 1) are mixed uniformly to obtain homogeneous phase A solution, and the concentration of the glutaric anhydride (compound 2) in the homogeneous phase A solution is 1.5 mol/L.

(2) Anhydrous aluminum trichloride, anisole (compound 1) and dichloromethane are uniformly mixed to obtain a homogeneous phase B solution, wherein the concentration of the aluminum trichloride in the homogeneous phase B solution is 0.75mol/L, and the molar ratio of the aluminum trichloride to the anisole (compound 1) is 1: 1.7.

(3) And (3) adding water to dilute the concentrated hydrochloric acid to prepare a solution C, wherein the concentration of the hydrochloric acid in the solution C is 1 mol/L.

(4) The first micro-reaction mixer M1 and the first reaction module L1 are both placed at preset temperatures, the homogeneous phase A solution obtained in the step (1) and the homogeneous phase B solution obtained in the step (2) are pumped into the first micro-reaction mixer M1 through a first advection pump P1 and a second advection pump P2 respectively according to the flow rate ratio (1:4), the homogeneous phase A solution is pumped into the first micro-reaction mixer M1 through a first advection pump P1, the flow rate is 6mL/min, the homogeneous phase A solution is uniformly mixed and then transferred into the first reaction module L1 (the inner diameter: 3mm, the length: 9M) to carry out Friedel-crafts acylation reaction, the reaction temperature is 10 ℃, and the reaction time is 12 min. The second micro-reaction mixer M2 and the second reaction module L2 are also placed at preset temperatures, after the Friedel-crafts acylation reaction is finished, the obtained reaction liquid (marked as D reaction liquid) is pumped into the second reaction mixer M2 at the flow rate of 0.8mL/min, meanwhile, the solution C is pumped into the second reaction mixer M2 by a third flow pump P3 according to the flow rate ratio (2:1) of the D reaction liquid, and after being uniformly mixed, the solution C is transferred to a second reaction module L2 (the inner diameter: 3mm, the length: 12.5M) for quenching reaction, the reaction temperature is 20 ℃, and the reaction time is 5 min.

Pumping the reaction solution obtained after quenching reaction into a receiving reaction kettle R, stirring for 5min, flowing out through a liquid outlet O, collecting the reaction solution into a liquid separating device, standing for liquid separation, extracting the upper aqueous phase by using dichloromethane, combining organic phases, adding an isovolumetric saturated sodium carbonate solution for alkalization, extracting the liquid separation, and acidifying the obtained aqueous phase by using concentrated hydrochloric acid until the pH value is 1. Extracting the water phase with dichloromethane, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, vacuum-drying at 35 deg.C for 12h after vacuum concentration to obtain white solid 4- (4-methoxybenzoyl) butyric acid with a yield of 96%.¹H NMR(400MHz,CDCl₃):δ11.01(br,1H),7.78(d,J＝7.2Hz,2H),7.25(d,J＝7.6Hz,2H),3.89(s,3H),3.07(t,J＝7.2Hz,2H),2.51(t,J＝7.2Hz,2H),2.12-2.07(m,2H).

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.