Method for rapidly synthesizing 2-fluoro-3-nitrobenzoic acid based on continuous flow technology

Abstract

The invention belongs to the technical field of organic synthesis, and relates to a method for rapidly synthesizing 2-fluoro-3-nitrobenzoic acid based on a continuous flow technology. The method comprises the following steps: carrying out lithiation reaction on 2-fluoronitrobenzene and a lithium reagent in a lithiation continuous flow reactor to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyl lithium intermediate; the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate and N, N-dimethylformamide are subjected to an aldehyde reaction in an aldehyde continuous flow reactor, a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is obtained, and then the 2-fluoro-3-nitrobenzoic acid is obtained continuously under the action of an oxidizing agent. The continuous flow technology is applied, the reaction condition is mild, the selectivity is good, the yield is high, the problem of amplification of a traditional kettle reaction caused by a metal-containing dangerous reagent is solved, the reaction danger is reduced, and the production efficiency is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for rapidly synthesizing 2-fluoro-3-nitrobenzoic acid based on a continuous flow technology. Background Art

[0002] 2-Fluoro-3-nitrobenzoic acid, molecular formula: C7H4FNO4, is a pale yellow solid. It is an important synthetic intermediate widely used in pharmaceutical molecules and fine chemicals. It can be used to synthesize high-value-added products such as benzenesulfonamide thiazole drugs and quinolone derivatives.

[0003] The traditional method for preparing 2-fluoro-3-nitrobenzoic acid generally uses 2-fluorotoluene as a raw material, prepares 2-fluoro-3-nitrotoluene through a nitration reaction, and then oxidizes the 2-fluoro-3-nitrotoluene to the target product 2-fluoro-3-nitrobenzoic acid using potassium permanganate or chromium trioxide. This method is difficult to separate the ortho- and para-position products after the nitration reaction, resulting in high pollution and low yield, making it unsuitable for large-scale industrial production.

[0004]

[0005] Chinese patent publication number CN114560774A proposes a method for synthesizing 2-fluoro-3-nitrobenzoic acid. The method uses 2-methyl-6-nitroaniline as a raw material, undergoes diazotization and chlorination to produce 2-chloro-3-nitrotoluene. The 2-chloro-3-nitrotoluene is then subjected to a chlorine-fluorine exchange reaction to produce 2-fluoro-3-nitrotoluene, which is then oxidized to obtain the target product. This method uses potassium permanganate or chromium trioxide as an oxidant, which is highly hazardous and polluting, and the wastewater is difficult to treat, making it unsuitable for large-scale production.

[0006]

[0007] Chinese patent publication number CN115322102A proposes a method for synthesizing 2-fluoro-3-nitrobenzoic acid from 2-chloro-3-nitrotoluene. The method involves subjecting 2-chloro-3-nitrotoluene to a chlorine-fluorine exchange reaction to produce 2-fluoro-3-nitrotoluene. The 2-fluoro-3-nitrotoluene is then photochlorinated to produce 2-fluoro-3-nitrobenzotrichloride. Finally, the product is hydrolyzed and acidified to yield the target product. This method uses a high-pressure mercury lamp and chlorine gas for the photochlorination reaction, resulting in high operating costs, high risk, and significant pollution, making it unsuitable for large-scale production.

[0008]

[0009] Publication number CN118271177A Chinese patent proposes a method for producing 2-fluoro-3-nitrobenzoic acid from 2-chloro-3-nitrotoluene. 2-chloro-3-nitrotoluene is first oxidized to 2-chloro-3-nitrobenzaldehyde, which is then prepared by a chlorine-fluorine exchange reaction with a fluorinating agent. 2-fluoro-3-nitrobenzaldehyde is then oxidized to obtain the target product, 2-fluoro-3-nitrobenzoic acid. This method also has the disadvantages of being highly dangerous, difficult to treat halogenated wastewater, and unsuitable for large-scale production. At the same time, 2-chloro-3-nitrotoluene is expensive and has high production costs.

[0010]

[0011] In view of the above technical solutions, the existing synthetic methods for preparing 2-fluoro-3-nitrobenzoic acid have the disadvantages of high risk, high pollution, and difficult operation. It is necessary to develop a safe, green and easy-to-industrial production method. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide a method for rapidly synthesizing 2-fluoro-3-nitrobenzoic acid using a continuous flow reaction technology, thereby enabling efficient and safe synthesis of 2-fluoro-3-nitrobenzoic acid.

[0013] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0014] The present invention discloses a method for rapidly synthesizing 2-fluoro-3-nitrobenzoic acid based on continuous flow technology, comprising the following steps:

[0015]

[0016] (1) Lithiation reaction: dissolving 2-fluoronitrobenzene in a first solvent to obtain a first mixed solution; dissolving a lithium reagent in a second solvent to obtain a second mixed solution; and simultaneously pumping the first mixed solution and the second mixed solution into a lithiation continuous flow reactor of a continuous flow reaction device to perform a lithiation reaction to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyl lithium intermediate;

[0017] (2) Formaldehyde reaction: dissolving N,N-dimethylformamide in a third solvent to obtain a third mixed solution; the third mixed solution and the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate obtained in step (1) are simultaneously pumped into a continuous flow reactor of a continuous flow reactor for formaldehyde reaction to obtain a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde;

[0018] (3) carboxylation reaction: dissolving an oxidant in a fourth solvent to obtain a fourth mixed solution; simultaneously pumping the fourth mixed solution and the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde obtained in step (2) into a carboxylation continuous flow reactor of a continuous flow reaction device for a carboxylation reaction to obtain a reaction effluent containing 2-fluoro-3-nitrobenzoic acid; and post-treating the effluent to obtain 2-fluoro-3-nitrobenzoic acid;

[0019] Wherein, the carboxylation continuous flow reactor is loaded with a catalyst.

[0020] In some embodiments, in step (1), the first solvent is any one of tetrahydrofuran and anhydrous ether or a combination of two; or, the lithium reagent is any one of lithium diisopropylamide, methyl lithium, ethyl lithium, butyl lithium, phenyl lithium and lithium tetramethylpiperidinium or a combination of several; or, the second solvent is any one of tetrahydrofuran, n-hexane and cyclohexane or a combination of several.

[0021] In some embodiments, preferably, in step (1), the first solvent is tetrahydrofuran.

[0022] Wherein, the first solvent is an anhydrous solvent.

[0023] In some embodiments, preferably, in step (1), the lithium reagent is lithium diisopropylamide.

[0024] In some embodiments, preferably, in step (1), the second solvent is tetrahydrofuran.

[0025] Wherein, the second solvent is an anhydrous solvent.

[0026] In some embodiments, in step (1), the concentration of 2-fluoronitrobenzene in the first mixed solution is 1.0 to 2.0 mmol / mL; or, the concentration of the lithium reagent in the second mixed solution is 1.0 to 3.0 mmol / mL; or, the flow rate of the first mixed solution pumped into the lithiation continuous flow reactor of the continuous flow reaction device is 3.3 to 6.7 mL / min; or, the flow rate of the second mixed solution pumped into the lithiation continuous flow reactor of the continuous flow reaction device is 2.1 to 5.6 mL / min; or, during the lithiation reaction, the reaction molar ratio of the 2-fluoronitrobenzene to the lithium reagent is controlled to be 1:(1.0 to 3.0); or, the reaction temperature of the lithiation reaction is -78°C to -50°C; or, the reaction residence time in the lithiation continuous flow reactor is 1 to 30 min.

[0027] In some embodiments, preferably, in step (1), the concentration of 2-fluoronitrobenzene in the first mixed solution is 1.0 to 1.8 mmol / mL, more preferably 1.2 to 1.5 mmol / mL.

[0028] In some embodiments, preferably, in step (1), the concentration of the lithium reagent in the second mixed solution is 1.5 to 3.0 mmol / mL, more preferably 1.5 to 2.5 mmol / mL, and even more preferably 2.0 mmol / mL.

[0029] In some embodiments, preferably, in step (1), the flow rate of the first mixed liquid pumped into the lithiation continuous flow reactor of the continuous flow reaction device is 3.7 to 5.3 mL / min, more preferably 3.8 to 4.5 mL / min, and even more preferably 4.0 mL / min.

[0030] In some embodiments, preferably, in step (1), the flow rate of the second mixed liquid pumped into the lithiation continuous flow reactor of the continuous flow reaction device is 2.5 to 5.0 mL / min, more preferably 2.9 to 4.3 mL / min, and even more preferably 4.0 mL / min.

[0031] In some embodiments, preferably, in step (1), during the lithiation reaction, the reaction molar ratio of the 2-fluoronitrobenzene to the lithium reagent is controlled to be 1:(1.0-2.0), more preferably 1:(1.2-1.8), and even more preferably 1:1.4.

[0032] In some embodiments, preferably, in step (1), the lithiation reaction has a reaction temperature of -78°C to -60°C, more preferably -70°C to -60°C, and even more preferably -70°C.

[0033] In some embodiments, preferably, in step (1), the reaction residence time in the lithiation continuous flow reactor is 10 min to 25 min, more preferably 10 min, 15 min or 25 min, and even more preferably 25 min.

[0034] In some embodiments, in step (2), the third solvent is any one of tetrahydrofuran and anhydrous ether, or a combination of both.

[0035] In some embodiments, preferably, in step (2), the third solvent is tetrahydrofuran.

[0036] Wherein, the third solvent is an anhydrous solvent.

[0037] In some embodiments, in step (2), the concentration of N,N-dimethylformamide in the third mixed solution is 1.0 to 6.0 mmol / mL; or, the flow rate at which the third mixed solution is pumped into the aldehyde continuous flow reactor of the continuous flow reaction device is 1.6 to 9.2 mL / min; or, the flow rate at which the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate is pumped into the aldehyde continuous flow reactor of the continuous flow reaction device is 5.1 to 14.7 mL / min.

[0038] In some embodiments, preferably, in step (2), the concentration of N,N-dimethylformamide in the third mixed solution is 3.0 to 6.0 mmol / mL, more preferably 4.0 to 5.0 mmol / mL, and even more preferably 4.4 to 4.8 mmol / mL.

[0039] In some embodiments, preferably, in step (2), the flow rate of the third mixed liquid pumped into the aldehyde continuous flow reactor of the continuous flow reaction device is 1.8 to 5.0 mL / min, more preferably 1.8 to 4.0 mL / min, and even more preferably 1.8 to 2.4 mL / min.

[0040] In some embodiments, preferably, in step (2), the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate is pumped into the aldehyde continuous flow reactor of the continuous flow reaction device at a flow rate of 7.2 to 9.6 mL / min, more preferably 7.2 to 9.0 mL / min, and even more preferably 8.0 mL / min.

[0041] In some embodiments, in step (2), in the hydroformylation reaction, the reaction molar ratio of 2-fluoronitrobenzene in the lithiation continuous flow reactor to N,N-dimethylformamide in the hydroformylation continuous flow reactor is controlled to be 1:(1.0-3.0) based on the 2-fluoronitrobenzene in step (1); or, the reaction temperature of the hydroformylation reaction is -78°C to -50°C; or, the reaction residence time in the hydroformylation continuous flow reactor is 1-30 min.

[0042] In some embodiments, preferably, in step (2), in the formylation reaction, based on the 2-fluoronitrobenzene in step (1), the reaction molar ratio of 2-fluoronitrobenzene in the lithiation continuous flow reactor to N,N-dimethylformamide in the formylation continuous flow reactor is controlled to be 1:(1.4-1.7), and more preferably 1:(1.5-1.7).

[0043] In some embodiments, preferably, in step (2), the reaction temperature of the hydroformylation reaction is -78°C to -60°C, more preferably -70°C to -60°C, and even more preferably -70°C.

[0044] In some embodiments, preferably, in step (2), the reaction residence time in the hydroformylation continuous flow reactor is 15 to 25 minutes, more preferably 25 minutes.

[0045] In some embodiments, in step (3), the oxidant is any one or a combination of hydrogen peroxide, tert-butyl peroxide, potassium permanganate and chromium trioxide; or, the fourth solvent is any one or a combination of water, tetrahydrofuran, anhydrous ether, acetonitrile and acetone; or, the catalyst is any one or a combination of two of sodium tungstate and cobalt aluminum hydrotalcite.

[0046] In some embodiments, preferably, in step (3), the oxidant is hydrogen peroxide.

[0047] In some embodiments, preferably, in step (3), the fourth solvent is water.

[0048] In some embodiments, preferably, in step (3), the catalyst is sodium tungstate.

[0049] In some embodiments, in step (3), the concentration of the oxidant in the fourth mixed liquid is 10 wt% to 35 wt%; or, the flow rate at which the fourth mixed liquid is pumped into the carboxylation continuous flow reactor of the continuous flow reaction device is 0.3 to 1.5 mL / min; or, the flow rate at which the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is pumped into the carboxylation continuous flow reactor of the continuous flow reaction device is 6.5 to 25.1 mL / min.

[0050] In some embodiments, preferably, in step (3), the concentration of the oxidant in the fourth mixed solution is 20 wt% to 35 wt%, more preferably 26 wt% to 32 wt%, and even more preferably 30 wt%.

[0051] In some embodiments, preferably, in step (3), the flow rate of the fourth mixed liquid pumped into the carboxylation continuous flow reactor of the continuous flow reaction device is 0.8 to 1.5 mL / min, more preferably 1.0 to 1.4 mL / min, and even more preferably 1.2 mL / min.

[0052] In some embodiments, preferably, in step (3), the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is pumped into the carboxylation continuous flow reactor of the continuous flow reaction device at a flow rate of 9.3 to 15.5 mL / min, more preferably 9.3 to 12.0 mL / min, and even more preferably 10.0 mL / min.

[0053] In some embodiments, in step (3), in the carboxylation reaction, the reaction molar ratio of 2-fluoronitrobenzene in the lithiation continuous flow reactor to the oxidant in the carboxylation continuous flow reactor is controlled to be 1:(1.0-3.0) based on the 2-fluoronitrobenzene in step (1); or, the reaction temperature of the carboxylation reaction is 40-60°C; or, the reaction residence time in the carboxylation continuous flow reactor is 1-50 min.

[0054] In some embodiments, preferably, in step (3), in the carboxylation reaction, based on the 2-fluoronitrobenzene in step (1), the reaction molar ratio of 2-fluoronitrobenzene in the lithiation continuous flow reactor to the oxidant in the carboxylation continuous flow reactor is controlled to be 1:(1.5-2.8), more preferably 1:(1.8-2.4), and even more preferably 1:(1.8-2.2).

[0055] In some embodiments, preferably, in step (3), the carboxylation reaction has a reaction temperature of 45 to 55°C, more preferably 50°C.

[0056] In some embodiments, preferably, in step (3), the reaction residence time in the carboxylation continuous flow reactor is 25 to 35 min, more preferably 25 to 30 min, and even more preferably 25 min.

[0057] In some embodiments, in step (3), the carboxylation continuous flow reactor is loaded with a catalyst, the amount of the catalyst used is based on the amount of 2-fluoronitrobenzene used in step (1), and the molar ratio of the 2-fluoronitrobenzene to the catalyst is 1:(0.03-0.07).

[0058] In some embodiments, preferably, in step (3), the carboxylation continuous flow reactor is loaded with a catalyst, the amount of the catalyst is calculated based on the amount of 2-fluoronitrobenzene in step (1), and the molar ratio of the 2-fluoronitrobenzene to the catalyst is 1:(0.03-0.05), more preferably 1:0.04.

[0059] The catalyst loaded in the carboxylation continuous flow reactor can be reused 2 to 3 times. When the yield of 2-fluoro-3-nitrobenzoic acid decreases significantly, the catalyst is replaced. The amount of the catalyst is calculated based on the amount of 2-fluoronitrobenzene in step (1), and the molar ratio of the 2-fluoronitrobenzene to the catalyst is 1: (0.03 to 0.05).

[0060] Wherein, the continuous flow reaction device includes a connecting pipe, a first metering pump, a second metering pump, a third metering pump, a fourth metering pump, a first mixer, a second mixer, a third mixer, a lithiation continuous flow reactor, a formaldehyde continuous flow reactor, a carboxylation continuous flow reactor and a collecting tank; wherein, the first metering pump and the second metering pump are connected to the first mixer in parallel through a connecting pipe, and the first mixer and the lithiation continuous flow reactor are connected in series through a connecting pipe; the lithiation continuous flow reactor and the third metering pump are connected to the second mixer in parallel through a connecting pipe, and the second mixer and the formaldehyde continuous flow reactor are connected in series through a connecting pipe; the formaldehyde continuous flow reactor and the fourth metering pump are connected to the third mixer in parallel through a connecting pipe, and the third mixer, the carboxylation continuous flow reactor and the collecting tank are connected in series through a connecting pipe.

[0061] The remaining connection ports of the first mixer are connected to nitrogen inlet pipes. Before the continuous flow reactor is started, nitrogen is used to exhaust the air in the continuous flow reactor to balance the system pressure.

[0062] Wherein, a flow meter is provided on the pipeline connecting each metering pump and the mixer.

[0063] The collecting tank may be connected to a gas processing device for processing the air and nitrogen in the continuous flow reaction device.

[0064] The continuous flow reaction device further comprises a first temperature control device for controlling the temperature of the lithiation continuous flow reactor and the formaldehyde continuous flow reactor.

[0065] Wherein, the continuous flow reaction device further comprises a second temperature control device for controlling the temperature of the carboxylation continuous flow reactor.

[0066] Wherein, a metering pump may be provided on the pipeline connecting the lithiation continuous flow reactor and the second mixer.

[0067] Wherein, a metering pump may be provided on the pipeline connecting the formaldehyde continuous flow reactor and the third mixer.

[0068] Wherein, the lithiation continuous flow reactor is a tubular reactor, and the inner diameter of the tube is 0.2 to 10.0 mm, preferably 0.2 to 2.0 mm, more preferably 0.5 to 1.5 mm, and even more preferably 1.0 mm.

[0069] Wherein, the retention volume of the lithiation continuous flow reactor is 0.05L to 0.5L, preferably 0.05L to 0.3L.

[0070] Wherein, the formaldehyde continuous flow reactor is a tubular reactor, and the inner diameter of the tube is 0.2 to 10.0 mm, preferably 0.2 to 2.0 mm, more preferably 0.5 to 1.5 mm, and even more preferably 1.0 mm.

[0071] The retention volume of the hydroformylation continuous flow reactor is 0.05L to 0.5L, preferably 0.1L to 0.3L.

[0072] Wherein, the carboxylation continuous flow reactor is a tubular reactor, and the inner diameter of the tube is 0.2 to 10.0 mm, preferably 0.2 to 2.0 mm, more preferably 0.5 to 1.5 mm, and even more preferably 1.0 mm.

[0073] Wherein, the retention volume of the carboxylation continuous flow reactor is 0.05L-1.0L, preferably 0.1L-0.3L.

[0074] Beneficial effects:

[0075] (1) The present invention uses cheaper raw materials and combines the synthesis route with continuous flow reaction technology, thereby reducing the operational risk factor of using organic lithium reagents and oxidants. At the same time, the reaction waste liquid and tail gas are conveniently treated, reducing pollution to the environment, and solving the scale-up problem of traditional kettle reactions. It provides a safe, efficient, green, and low-cost process for the production and synthesis of 2-fluoro-3-nitrobenzoic acid.

[0076] (2) Compared with the prior art, the present invention has low production cost, shorter time consumption, milder reaction, and convenient solvent recovery and catalyst recovery.

[0077] (3) The present invention applies continuous flow technology, which has mild reaction conditions, good selectivity, and high yield, solves the scale-up problem of traditional kettle reactions caused by metal-containing hazardous reagents, reduces the risk of the reaction, and improves production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0079] Figure 1 Schematic diagram of the continuous flow reaction device used in the embodiment of the present invention.

[0080] Figure 2 It is a typical example of the target compound 2-fluoro-3-nitrobenzoic acid. 1 H NMR spectrum.

[0081] Figure 3 It is a typical example of the target compound 2-fluoro-3-nitrobenzoic acid. 13C NMR spectrum. DETAILED DESCRIPTION

[0082] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0083] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0084] Figure 1 Schematic diagram of a continuous flow reaction device used in an embodiment of the present invention. The continuous flow reaction device includes a connecting pipe, a raw material storage tank 1, a raw material storage tank 2, a raw material storage tank 3, a raw material storage tank 4, a first metering pump 5, a second metering pump 6, a third metering pump 7, a fourth metering pump 8, a first mixer 21, a second mixer 22, a third mixer 23, a lithiation continuous flow reactor 13, a formaldehyde continuous flow reactor 14, a carboxylation continuous flow reactor 15, and a collecting tank 16; wherein the first metering pump 5 and the second metering pump 6 are connected in parallel to the first mixer 21 via a connecting pipe, and the first mixer 21 and the lithiation continuous flow reactor 13 are connected in series through a connecting pipe; the lithiation continuous flow reactor 13 and the third metering pump 7 are connected in parallel to the second mixer 22 through a connecting pipe, and the second mixer 22 and the formaldehyde continuous flow reactor 14 are connected in series through a connecting pipe; the formaldehyde continuous flow reactor 14 and the fourth metering pump 8 are connected in parallel to the third mixer 23 through a connecting pipe, and the third mixer 23, the carboxylation continuous flow reactor 15 and the collecting tank 16 are connected in series through a connecting pipe.

[0085] The remaining connection ports of the first mixer 21 are connected to nitrogen inlet pipes 17. Before starting the continuous flow reactor, nitrogen is used to expel air from the reactor to balance the system pressure. After the reaction is complete, nitrogen can continue to be introduced through the nitrogen inlet pipes 17 to expel the liquid from the reactor.

[0086] Wherein, flow meters are provided on the pipelines connecting the metering pumps and the mixer, namely a first flow meter 9, a second flow meter 10, a third flow meter 11, and a fourth flow meter 12.

[0087] The collecting tank 16 may be connected to a gas processing device 18 for processing the air and nitrogen in the continuous flow reaction device.

[0088] The continuous flow reaction device further includes a first temperature control device 19 for controlling the temperature of the lithiation continuous flow reactor 13 and the formaldehyde continuous flow reactor 14 .

[0089] The continuous flow reaction device further includes a second temperature control device 20 for controlling the temperature of the carboxylation continuous flow reactor 15 .

[0090] Wherein, a metering pump may be provided on the pipeline connecting the lithiation continuous flow reactor 13 and the second mixer 22 .

[0091] Wherein, a metering pump may be provided on the pipeline connecting the formaldehyde continuous flow reactor 14 and the third mixer 23 .

[0092] The solvents used in the first mixed solution and the second mixed solution in the embodiment of the present invention are both anhydrous solvents.

[0093] The solvents used in the third mixed solution of the embodiment of the present invention are all anhydrous solvents.

[0094] Example 1:

[0095]

[0096] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran to obtain a first mixed solution, which was placed in raw material storage tank 1; 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF), referred to as the second mixed solution, was placed in raw material storage tank 2.

[0097] The temperature of the lithiation continuous flow reactor 13 was set to -70°C using the first temperature control device 19; the first mixed liquid and the second mixed liquid were then simultaneously pumped into the lithiation continuous flow reactor 13 through the first metering pump 5 and the second metering pump 6 for a lithiation reaction, wherein the injection flow rate of the first mixed liquid was 4.0 mL / min, the injection flow rate of the second mixed liquid was 4.0 mL / min, the retention volume of the lithiation continuous flow reactor 13 was 200 mL, and the retention reaction time of the lithiation reaction in the lithiation continuous flow reactor 13 was 25 min to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyl lithium intermediate.

[0098] (2) 18 mL of N,N-dimethylformamide was dissolved in tetrahydrofuran solution to prepare 50 mL of a mixed solution, which was recorded as the third mixed solution and placed in the raw material storage tank 3.

[0099] The temperature of the hydroformylation continuous flow reactor 14 was set to -70°C using the first temperature control device 19. The third mixed liquid and the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate in step (1) were simultaneously pumped into the hydroformylation continuous flow reactor 14 by the third metering pump 7 for hydroformylation reaction, wherein the injection flow rate of the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate was measured to be approximately 8.0 mL / min, the injection flow rate of the third mixed liquid was 2.0 mL / min, the retention volume of the hydroformylation continuous flow reactor 14 was 250 mL, and the retention reaction time of the hydroformylation reaction in the hydroformylation continuous flow reactor 14 was 25 min, thereby obtaining a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde.

[0100] (3) 30 mL of 30% hydrogen peroxide aqueous solution is recorded as the fourth mixed liquid and placed in the raw material storage tank 4.

[0101] The carboxylation continuous flow reactor 15 is filled with sodium tungstate (1.6 g, 5.6 mmol), and the temperature of the carboxylation continuous flow reactor 15 is preheated to 50° C. in advance using the second temperature control device 20. The fourth mixed solution is pumped into the carboxylation continuous flow reactor 15 by the fourth metering pump 8 and the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde in step (2) at the same time to carry out carboxylation reaction, wherein the injection flow rate of the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is measured to be about 10.0 mL / min, the injection flow rate of the fourth mixed solution is 1.2 mL / min, the retention volume of the carboxylation continuous flow reactor 15 is 280 mL, and the retention reaction time of the carboxylation reaction in the carboxylation continuous flow reactor 15 is 25 min. After the reaction is completed, the reaction effluent containing 2-fluoro-3-nitrobenzoic acid is passed into the quenching collection tank 16. The organic phase of the reaction solution was diluted with acetonitrile and filtered, and then HPLC analysis showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 95.6% (based on the starting material 2-fluoronitrobenzene). The reaction solution was distilled under reduced pressure to remove tetrahydrofuran, and the remaining solid was dissolved with dichloromethane. The organic phase was washed with purified water, dried, and concentrated under reduced pressure. An appropriate amount of dichloromethane was added to the solid residue, washed with saturated brine, and the organic phase was separated. The organic phase was recrystallized in ice water, filtered, and dried to obtain the compound 2-fluoro-3-nitrobenzoic acid with a purity of 98.2%. The structure of the compound was identified by nuclear magnetic resonance (H spectrum and C spectrum). The specific nuclear magnetic resonance data are shown in the figure. Figure 2 、 Figure 3 .

[0102] The NMR data of 2-fluoro-3-nitrobenzoic acid are as follows:

[0103] 1H NMR (400MHz, DMSO-d6) δ13.88(s,1H),8.33(ddd,J=8.4,6.9,1.8Hz,1H),8.21(ddd,J=8.1,6.5,1.8Hz,1H),7.52(td,J=8.1,0.9Hz,1H). 13 C NMR (101MHz, DMSO-d6) δ164.03 (d, J = 2.5Hz), 154.18 (d, J = 273.4Hz), 138.72 (d, J = 8.6Hz), 137.7, 130.3, 125.25 (d, J = 5.3Hz), 122.54 (d, J = 9.9Hz).

[0104] Example 2:

[0105] The specific preparation process is the same as that of Example 1, except that the first temperature control device 19 is used to set the temperature of the lithiation continuous flow reactor 13 and the formaldehyde continuous flow reactor 14 to -50°C.

[0106] After the final reaction was completed, the organic phase of the reaction solution was diluted with acetonitrile, filtered, and then subjected to HPLC analysis, which showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 73.1% and the purity was 92.5%.

[0107] Example 3:

[0108] The specific preparation process is the same as that of Example 1, except that the second temperature control device 20 is used to preheat the temperature of the carboxylation continuous flow reactor 15 to 40° C.

[0109] After the final reaction was completed, the organic phase of the reaction solution was diluted with acetonitrile, filtered, and then subjected to HPLC analysis, which showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 75.9% and the purity was 94.1%.

[0110] Example 4:

[0111] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran to obtain a first mixed solution, which was placed in raw material storage tank 1; 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF), referred to as the second mixed solution, was placed in raw material storage tank 2.

[0112] The temperature of the lithiation continuous flow reactor 13 was set to -70°C using the first temperature control device 19; the first mixed liquid and the second mixed liquid were then simultaneously pumped into the lithiation continuous flow reactor 13 through the first metering pump 5 and the second metering pump 6 for a lithiation reaction, wherein the injection flow rate of the first mixed liquid was 4.0 mL / min, the injection flow rate of the second mixed liquid was 4.0 mL / min, the retention volume of the lithiation continuous flow reactor 13 was 80 mL, and the retention reaction time of the lithiation reaction in the lithiation continuous flow reactor 13 was 10 min to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyllithium intermediate.

[0113] (2) 18 mL of N,N-dimethylformamide was dissolved in tetrahydrofuran solution to prepare 50 mL of a mixed solution, which was recorded as the third mixed solution and placed in the raw material storage tank 3.

[0114] The temperature of the hydroformylation continuous flow reactor 14 was set to -70°C using the first temperature control device 19. The third mixed liquid and the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate in step (1) were simultaneously pumped into the hydroformylation continuous flow reactor 14 by the third metering pump 7 for hydroformylation reaction, wherein the injection flow rate of the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate was measured to be approximately 8.0 mL / min, the injection flow rate of the third mixed liquid was 2.0 mL / min, the retention volume of the hydroformylation continuous flow reactor 14 was 250 mL, and the retention reaction time of the hydroformylation reaction in the hydroformylation continuous flow reactor 14 was 25 min, thereby obtaining a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde.

[0115] (3) 30 mL of 30% hydrogen peroxide aqueous solution is recorded as the fourth mixed liquid and placed in the raw material storage tank 4.

[0116] The carboxylation continuous flow reactor 15 is filled with sodium tungstate (1.6 g, 5.6 mmol), and the temperature of the carboxylation continuous flow reactor 15 is preheated to 50° C. in advance using the second temperature control device 20. The fourth mixed solution is pumped into the carboxylation continuous flow reactor 15 by the fourth metering pump 8 and the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde in step (2) at the same time to carry out carboxylation reaction, wherein the injection flow rate of the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is measured to be about 10.0 mL / min, the injection flow rate of the fourth mixed solution is 1.2 mL / min, the retention volume of the carboxylation continuous flow reactor 15 is 280 mL, and the retention reaction time of the carboxylation reaction in the carboxylation continuous flow reactor 15 is 25 min. After the reaction is completed, the reaction effluent containing 2-fluoro-3-nitrobenzoic acid is passed into the quenching collection tank 16. The organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 48.2% (based on the starting material 2-fluoronitrobenzene). The reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The remaining solid was dissolved with dichloromethane. The organic phase was washed with purified water, dried, and concentrated under reduced pressure. An appropriate amount of dichloromethane was added to the solid residue, and the mixture was washed with saturated brine. The organic phase was separated, recrystallized from ice water, filtered, and dried to obtain the compound 2-fluoro-3-nitrobenzoic acid with a purity of 79.6%.

[0117] Example 5:

[0118] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran to obtain a first mixed solution, which was placed in raw material storage tank 1; 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF), referred to as the second mixed solution, was placed in raw material storage tank 2.

[0119] The temperature of the lithiation continuous flow reactor 13 was set to -70°C using the first temperature control device 19; the first mixed liquid and the second mixed liquid were then simultaneously pumped into the lithiation continuous flow reactor 13 through the first metering pump 5 and the second metering pump 6 for a lithiation reaction, wherein the injection flow rate of the first mixed liquid was 10.0 mL / min, the injection flow rate of the second mixed liquid was 10.0 mL / min, the retention volume of the lithiation continuous flow reactor 13 was 200 mL, and the retention reaction time of the lithiation reaction in the lithiation continuous flow reactor 13 was 10 min to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyl lithium intermediate.

[0120] (2) 18 mL of N,N-dimethylformamide was dissolved in tetrahydrofuran solution to prepare 50 mL of a mixed solution, which was recorded as the third mixed solution and placed in the raw material storage tank 3.

[0121] An effluent collection tank and a fifth metering pump are added to the pipeline from the discharge port of the lithiation continuous flow reactor 13 to the feed port of the formaldehyde continuous flow reactor 14. The reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate flows into the effluent collection tank, and then the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate is pumped into the formaldehyde continuous flow reactor 14 through the fifth metering pump.

[0122] The temperature of the hydroformylation continuous flow reactor 14 was set to -70°C using the first temperature control device 19. The third mixed solution was pumped into the hydroformylation continuous flow reactor 14 simultaneously by the third metering pump 7 and the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate in step (1) was pumped into the hydroformylation continuous flow reactor 14 by the fifth metering pump for hydroformylation reaction. The injection flow rate of the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate was measured to be 8.0 mL / min, the injection flow rate of the third mixed solution was 2.0 mL / min, the retention volume of the hydroformylation continuous flow reactor 14 was 250 mL, and the retention reaction time of the hydroformylation reaction in the hydroformylation continuous flow reactor 14 was 25 min, thereby obtaining a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde.

[0123] (3) 30 mL of 30% hydrogen peroxide aqueous solution is recorded as the fourth mixed liquid and placed in the raw material storage tank 4.

[0124] The carboxylation continuous flow reactor 15 is filled with sodium tungstate (1.6 g, 5.6 mmol), and the temperature of the carboxylation continuous flow reactor 15 is preheated to 50° C. in advance using the second temperature control device 20. The fourth mixed solution is pumped into the carboxylation continuous flow reactor 15 by the fourth metering pump 8 and the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde in step (2) at the same time to carry out carboxylation reaction, wherein the injection flow rate of the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is measured to be about 10.0 mL / min, the injection flow rate of the fourth mixed solution is 1.2 mL / min, the retention volume of the carboxylation continuous flow reactor 15 is 280 mL, and the retention reaction time of the carboxylation reaction in the carboxylation continuous flow reactor 15 is 25 min. After the reaction is completed, the reaction effluent containing 2-fluoro-3-nitrobenzoic acid is passed into the quenching collection tank 16. The organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 59.7% (based on the starting material 2-fluoronitrobenzene). The reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The remaining solid was dissolved with dichloromethane. The organic phase was washed with purified water, dried, and concentrated under reduced pressure. An appropriate amount of dichloromethane was added to the solid residue, and the mixture was washed with saturated brine. The organic phase was separated, recrystallized from ice water, filtered, and dried to obtain the compound 2-fluoro-3-nitrobenzoic acid with a purity of 83.7%.

[0125] Example 6:

[0126] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran to obtain a first mixed solution, which was placed in raw material storage tank 1; 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF), referred to as the second mixed solution, was placed in raw material storage tank 2.

[0127] The temperature of the lithiation continuous flow reactor 13 was set to -70°C using the first temperature control device 19; the first mixed liquid and the second mixed liquid were then simultaneously pumped into the lithiation continuous flow reactor 13 through the first metering pump 5 and the second metering pump 6 for a lithiation reaction, wherein the injection flow rate of the first mixed liquid was 4.0 mL / min, the injection flow rate of the second mixed liquid was 4.0 mL / min, the retention volume of the lithiation continuous flow reactor 13 was 120 mL, and the retention reaction time of the lithiation reaction in the lithiation continuous flow reactor 13 was 15 min to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyllithium intermediate.

[0128] (2) 18 mL of N,N-dimethylformamide was dissolved in tetrahydrofuran solution to prepare 50 mL of a mixed solution, which was recorded as the third mixed solution and placed in the raw material storage tank 3.

[0129] The temperature of the hydroformylation continuous flow reactor 14 was set to -70°C using the first temperature control device 19. The third mixed liquid and the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate in step (1) were simultaneously pumped into the hydroformylation continuous flow reactor 14 by the third metering pump 7 for hydroformylation reaction, wherein the injection flow rate of the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate was measured to be approximately 8.0 mL / min, the injection flow rate of the third mixed liquid was 2.0 mL / min, the retention volume of the hydroformylation continuous flow reactor 14 was 250 mL, and the retention reaction time of the hydroformylation reaction in the hydroformylation continuous flow reactor 14 was 25 min, thereby obtaining a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde.

[0130] (3) 30 mL of 30% hydrogen peroxide aqueous solution is recorded as the fourth mixed liquid and placed in the raw material storage tank 4.

[0131] The carboxylation continuous flow reactor 15 is filled with sodium tungstate (1.6 g, 5.6 mmol), and the temperature of the carboxylation continuous flow reactor 15 is preheated to 50° C. in advance using the second temperature control device 20. The fourth mixed solution is pumped into the carboxylation continuous flow reactor 15 by the fourth metering pump 8 and the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde in step (2) at the same time to carry out carboxylation reaction, wherein the injection flow rate of the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde is measured to be about 10.0 mL / min, the injection flow rate of the fourth mixed solution is 1.2 mL / min, the retention volume of the carboxylation continuous flow reactor 15 is 280 mL, and the retention reaction time of the carboxylation reaction in the carboxylation continuous flow reactor 15 is 25 min. After the reaction is completed, the reaction effluent containing 2-fluoro-3-nitrobenzoic acid is passed into the quenching collection tank 16. The organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 70.8% (based on the starting material 2-fluoronitrobenzene). The reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The remaining solid was dissolved with dichloromethane. The organic phase was washed with purified water, dried, and concentrated under reduced pressure. An appropriate amount of dichloromethane was added to the solid residue, and the mixture was washed with saturated brine. The organic phase was separated, recrystallized from ice water, filtered, and dried to obtain the compound 2-fluoro-3-nitrobenzoic acid with a purity of 90.2%.

[0132] Example 7: Catalyst cycle test experiment

[0133] The experimental method is the same as that of Example 1. After the first batch of experiments, the same amount of materials are prepared for the second and third rounds of circulation experiments. The sodium tungstate catalyst in the carboxylation continuous flow reactor 15 does not need to be replaced.

[0134] After the second cycle, the organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 93.8% (based on the starting material 2-fluoronitrobenzene). The reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The remaining solid was dissolved with dichloromethane. The organic phase was washed with purified water, dried, and concentrated under reduced pressure. An appropriate amount of dichloromethane was added to the solid residue, which was washed with saturated brine. The organic phase was separated, recrystallized from ice water, filtered, and dried to obtain the compound 2-fluoro-3-nitrobenzoic acid with a purity of 96.9%.

[0135] After the third round of experiments, the organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 89.1% (based on the starting material 2-fluoronitrobenzene). The reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The remaining solid was dissolved with dichloromethane. The organic phase was washed with purified water, dried, and concentrated under reduced pressure. An appropriate amount of dichloromethane was added to the solid residue, and the mixture was washed with saturated brine. The organic phase was separated, recrystallized from ice water, filtered, and dried to obtain the compound 2-fluoro-3-nitrobenzoic acid with a purity of 90.4%.

[0136] Comparative Example 1: No catalyst added

[0137] The experimental method was the same as that of Example 1, and the other reaction conditions described in Example 1 were kept unchanged (i.e., the operation process and reaction conditions were the same as those of Example 1). The difference was that the catalyst sodium tungstate used in step (3) was removed, and the yield of the final target product 2-fluoro-3-nitrobenzoic acid was 0%, and a large amount of the intermediate 2-fluoro-3-nitrobenzaldehyde remained.

[0138] Comparative Example 2:

[0139] The experimental method is the same as that of Example 1, and the other reaction conditions described in Example 1 remain unchanged (i.e., the operation process and reaction conditions are the same as those of Example 1). The difference is that only step (1) is changed to a batch reaction.

[0140] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran, and 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF) was added. The mixture was then lithiation-treated under nitrogen at -70°C for 10 h. After completion of the reaction, a reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate was obtained.

[0141] (2) The operation process and reaction conditions are the same as those in step (2) of Example 1, wherein the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate and the third mixed liquid are simultaneously pumped into the hydroformylation continuous flow reactor 14 for hydroformylation reaction, wherein the feed flow rate of the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate is controlled to be 8.0 mL / min, the injection flow rate of the third mixed liquid is controlled to be 2.0 mL / min, the retention volume of the hydroformylation continuous flow reactor 14 is 250 mL, and the retention reaction time of the hydroformylation reaction in the hydroformylation continuous flow reactor 14 is 25 min, thereby obtaining a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde.

[0142] (3) The operation process and reaction conditions were the same as those in step (3) of Example 1. After the final reaction, the organic phase of the reaction solution was diluted with acetonitrile and filtered, and then subjected to HPLC analysis. The results showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 17.2%, the purity was 61.4%, and a large amount of raw material 2-fluoronitrobenzene remained.

[0143] Comparative Example 3:

[0144] The other reaction conditions described in Example 1 remain unchanged (i.e., the operation process and conditions are the same as in Example 1), except that only step (2) is changed to a batch reaction.

[0145] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran to obtain a first mixed solution, which was placed in raw material storage tank 1; 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF), referred to as the second mixed solution, was placed in raw material storage tank 2.

[0146] The temperature of the lithiation continuous flow reactor 13 was set to -70°C using the first temperature control device 19; the first mixed liquid and the second mixed liquid were then simultaneously pumped into the lithiation continuous flow reactor 13 through the first metering pump 5 and the second metering pump 6 for a lithiation reaction, wherein the injection flow rate of the first mixed liquid was 4.0 mL / min, the injection flow rate of the second mixed liquid was 4.0 mL / min, the retention volume of the lithiation continuous flow reactor 13 was 200 mL, and the retention reaction time of the lithiation reaction in the lithiation continuous flow reactor 13 was 25 min to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyl lithium intermediate.

[0147] (2) 18 mL of N,N-dimethylformamide and 32 mL of tetrahydrofuran were added to the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate obtained in step (1), and the aldehyde reaction was carried out at -70°C for 4 hours. After the reaction was completed, a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde was obtained.

[0148] (3) The operation process and reaction conditions were the same as those in step (3) of Example 1. After the final reaction, the organic phase of the reaction solution was diluted with acetonitrile and filtered, and then subjected to HPLC analysis. The results showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 12.4%, the purity was 60.9%, and a large amount of the raw material 2-fluoro-3-nitrophenyl lithium intermediate remained.

[0149] Comparative Example 4:

[0150] The other reaction conditions described in Example 1 remain unchanged (i.e., the operation process and conditions are the same as in Example 1), except that only step (3) is changed to a batch reaction.

[0151] (1) The operation process and reaction conditions are the same as step (1) of Example 1 to obtain a reaction effluent containing 2-fluoro-3-nitrophenyllithium intermediate.

[0152] (2) The operation process and reaction conditions were the same as those in step (2) of Example 1 to obtain a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde.

[0153] (3) 30 mL of 30% hydrogen peroxide solution and a catalyst, sodium tungstate (1.6 g, 5.6 mmol), were added to the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde obtained in step (2), and a carboxylation reaction was carried out at 50° C. for 8 h. After the reaction, the organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The result showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 25.7%, and a large amount of the intermediate 2-fluoro-3-nitrobenzaldehyde remained.

[0154] Comparative Example 5:

[0155] The other reaction conditions described in Example 1 remain unchanged (ie, the operation process and conditions are the same as in Example 1), except that all steps are changed to batch reactions.

[0156] (1) 2-Fluoronitrobenzene (20 g, 141.0 mmol) was dissolved in 100 mL of tetrahydrofuran, and 100 mL of a tetrahydrofuran solution containing lithium diisopropylamide (2.0 M in THF) was added. The mixture was then lithiation-treated under nitrogen at -70°C for 10 h. After completion of the reaction, a reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate was obtained.

[0157] (2) 18 mL of N,N-dimethylformamide and 32 mL of tetrahydrofuran were added to the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate obtained in step (1), and the aldehyde reaction was carried out at -70°C for 4 hours. After the reaction was completed, a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde was obtained.

[0158] (3) 30 mL of 30% hydrogen peroxide solution and a catalyst, sodium tungstate (1.6 g, 5.6 mmol), were added to the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde obtained in step (2), and a carboxylation reaction was carried out at 50° C. for 8 h. After the reaction, the organic phase of the reaction solution was diluted with acetonitrile, filtered, and then analyzed by HPLC. The results showed that the yield of 2-fluoro-3-nitrobenzoic acid in the reaction solution was 3.7%, the purity was 55.2%, and a large amount of the raw material 2-fluoronitrobenzene remained.

[0159] The present invention provides a method and concept for the rapid synthesis of 2-fluoro-3-nitrobenzoic acid based on continuous flow technology. Numerous methods and approaches exist for implementing this technical solution. The foregoing description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of protection of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A method for rapidly synthesizing 2-fluoro-3-nitrobenzoic acid based on continuous flow technology, characterized in that: The steps include: (1) Lithiation reaction: dissolving 2-fluoronitrobenzene in a first solvent to obtain a first mixed solution; dissolving a lithium reagent in a second solvent to obtain a second mixed solution; and simultaneously pumping the first mixed solution and the second mixed solution into a lithiation continuous flow reactor of a continuous flow reaction device to perform a lithiation reaction to obtain a reaction effluent containing a 2-fluoro-3-nitrophenyl lithium intermediate; (2) Formaldehyde reaction: dissolving N,N-dimethylformamide in a third solvent to obtain a third mixed solution; the third mixed solution and the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate obtained in step (1) are simultaneously pumped into a continuous flow reactor of a continuous flow reactor for formaldehyde reaction to obtain a reaction effluent containing 2-fluoro-3-nitrobenzaldehyde; (3) carboxylation reaction: dissolving an oxidant in a fourth solvent to obtain a fourth mixed solution; simultaneously pumping the fourth mixed solution and the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde obtained in step (2) into a carboxylation continuous flow reactor of a continuous flow reaction device for a carboxylation reaction to obtain a reaction effluent containing 2-fluoro-3-nitrobenzoic acid; and post-treating the effluent to obtain 2-fluoro-3-nitrobenzoic acid; Wherein, the carboxylation continuous flow reactor is loaded with a catalyst.

2. The method according to claim 1, characterized in that In step (1), the first solvent is any one of tetrahydrofuran and anhydrous ether or a combination of two; or the lithium reagent is any one of lithium diisopropylamide, methyl lithium, ethyl lithium, butyl lithium, phenyl lithium and lithium tetramethylpiperidinium or a combination of several; or the second solvent is any one of tetrahydrofuran, n-hexane and cyclohexane or a combination of several.

3. The method according to claim 1, characterized in that In step (1), the concentration of 2-fluoronitrobenzene in the first mixed solution is 1.0 to 2.0 mmol / mL; or, the concentration of the lithium reagent in the second mixed solution is 1.0 to 3.0 mmol / mL; or, the flow rate of the first mixed solution pumped into the lithiation continuous flow reactor of the continuous flow reaction device is 3.3 to 6.7 mL / min; or, the flow rate of the second mixed solution pumped into the lithiation continuous flow reactor of the continuous flow reaction device is 2.1 to 5.6 mL / min; or, during the lithiation reaction, the reaction molar ratio of the 2-fluoronitrobenzene to the lithium reagent is controlled to be 1:(1.0 to 3.0); or, the reaction temperature of the lithiation reaction is -78°C to -50°C; or, the reaction residence time in the lithiation continuous flow reactor is 1 to 30 min.

4. The method according to claim 1, wherein In step (2), the third solvent is any one of tetrahydrofuran and anhydrous ether or a combination of two.

5. The method according to claim 1, wherein In step (2), the concentration of N,N-dimethylformamide in the third mixed liquid is 1.0 to 6.0 mmol / mL; or, the flow rate of the third mixed liquid pumped into the aldehyde continuous flow reactor of the continuous flow reaction device is 1.6 to 9.2 mL / min; or, the flow rate of the reaction effluent containing the 2-fluoro-3-nitrophenyl lithium intermediate pumped into the aldehyde continuous flow reactor of the continuous flow reaction device is 5.1 to 14.7 mL / min.

6. The method according to claim 1, wherein In step (2), in the hydroformylation reaction, the reaction molar ratio of 2-fluoronitrobenzene in the lithiation continuous flow reactor to N,N-dimethylformamide in the hydroformylation continuous flow reactor is controlled to be 1:(1.0-3.0) based on the 2-fluoronitrobenzene in step (1); or, the reaction temperature of the hydroformylation reaction is -78°C to -50°C; or, the reaction residence time in the hydroformylation continuous flow reactor is 1-30 min.

7. The method according to claim 1, characterized in that In step (3), the oxidant is any one or a combination of hydrogen peroxide, tert-butyl peroxide, potassium permanganate and chromium trioxide; or, the fourth solvent is any one or a combination of water, tetrahydrofuran, anhydrous ether, acetonitrile and acetone; or, the catalyst is any one or a combination of two of sodium tungstate and cobalt aluminum hydrotalcite.

8. The method according to claim 1, characterized in that In step (3), the concentration of the oxidant in the fourth mixed liquid is 10wt% to 35wt%; or, the flow rate of the fourth mixed liquid pumped into the carboxylation continuous flow reactor of the continuous flow reaction device is 0.3 to 1.5 mL / min; or, the flow rate of the reaction effluent containing 2-fluoro-3-nitrobenzaldehyde pumped into the carboxylation continuous flow reactor of the continuous flow reaction device is 6.5 to 25.1 mL / min.

9. The method according to claim 1, characterized in that In step (3), in the carboxylation reaction, the reaction molar ratio of 2-fluoronitrobenzene in the lithiation continuous flow reactor to the oxidant in the carboxylation continuous flow reactor is controlled to be 1:(1.0-3.0) based on the 2-fluoronitrobenzene in step (1); or, the reaction temperature of the carboxylation reaction is 40-60° C.; or, the reaction residence time in the carboxylation continuous flow reactor is 1-50 min.

10. The method according to claim 1, characterized in that In step (3), the carboxylation continuous flow reactor is loaded with a catalyst, the amount of the catalyst is calculated based on the amount of 2-fluoronitrobenzene in step (1), and the molar ratio of the 2-fluoronitrobenzene to the catalyst is 1:(0.03-0.07).

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