Continuous reaction method of 2, 3, 4-trifluorobenzoic acid

Abstract

The invention discloses a 2, 3, 4-trifluorobenzoic acid continuous reaction method which is characterized by comprising the following reaction processes: 1, 2, 3-trifluorobenzene and an organic lithium solution react in a continuous reactor to generate a lithium salt intermediate, the lithium salt intermediate and CO2 are subjected to an addition reaction in the continuous reactor, and 2, 3, 4-trifluorobenzoic acid is obtained after post-treatment. According to the method, a continuous feeding mode is adopted, the operation process is simplified, the working intensity and the labor cost are reduced, the process safety is improved, and the product prepared by the method is high in purity, few in side reaction, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a continuous reaction method of 2,3,4-trifluorobenzoic acid. Background Art

[0002] Fluorinated compounds often exhibit special activities in pharmaceuticals, pesticides, and bioactive molecules, and therefore have a wide range of applications in pharmaceutical molecules and pesticide chemicals. 2,3,4-Trifluorobenzoic acid (CAS 61079-72-9) can be used as an intermediate for pharmaceuticals, pesticides, and liquid crystal materials. Its structural formula is:

[0003]

[0004] The reported method for synthesizing 2,3,4-trifluorobenzoic acid is as follows:

[0005] It is prepared by fluorination with fluorine gas using 4-fluorobenzoic acid or 2,4-difluorobenzoic acid as substrate (J. Chem. Soc., Perkin Trans, 1, 1996, 605).

[0006]

[0007] The reaction has a low conversion rate, produces many by-products, has a low yield, and is difficult to separate and purify. Furthermore, because it uses very dangerous fluorine gas and requires a reactor made of special materials, it cannot be industrialized.

[0008] Prepared from 1,2,3-trifluorobenzene as the starting material (Eur. J. Org. Chem. 2003, 447).

[0009]

[0010] This reaction uses butyl lithium to extract hydrogen at -75°C to form a lithium salt intermediate, which is then poured into dry ice. This process, performed in anhydrous, ultra-low-temperature conditions, is limited to experimental use and produces excessive impurities, making it difficult to scale up to industrial production.

[0011] Patent CN01142637 discloses a method for preparing 2,3,4-trifluoroaniline starting from 2,3,4-trifluoroaniline. 2,3,4-trifluoroaniline is used as the starting material, and the amino group is diazotized and nitrilated to produce 2,3,4-trifluorobenzonitrile, which is then hydrolyzed to produce 2,3,4-trifluorobenzoic acid. This route involves multiple steps, high costs, and involves a dangerous diazotization reaction, making it unsuitable for industrial production.

[0012]

[0013] Patent CN01142637 also discloses that 2,3,4-trifluoroaniline is diazotized with the amino group and then brominated to obtain 1-bromo-2,3,4-trifluorobenzene, which is then reacted with metallic magnesium to obtain a Grignard reagent, which is then reacted with carbon dioxide and then acidified and hydrolyzed to obtain 2,3,4-trifluorobenzoic acid.

[0014]

[0015] This route has many synthetic steps, high cost, and involves dangerous diazotization and Grignard reactions, which is not conducive to industrial production. Summary of the Invention

[0016] In order to solve the above problems, the present invention discloses a continuous reaction method for 2,3,4-trifluorobenzoic acid. This method uses a continuous feeding method, simplifies the operation process, reduces work intensity and labor costs, and improves process safety. The product prepared by this method has high purity, few side reactions, and high yield, and is suitable for industrial production.

[0017] The first object of the present invention is to disclose a continuous reaction method for 2,3,4-trifluorobenzoic acid, which includes the following reaction process: 1,2,3-trifluorobenzene and an organic lithium solution react in a continuous reactor to generate a lithium salt intermediate, the lithium salt intermediate reacts with CO2 in a continuous reactor, and post-processing is performed to obtain 2,3,4-trifluorobenzoic acid.

[0018] Furthermore, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.5, and the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:0.8-10.

[0019] Furthermore, the temperature for the reaction of 1,2,3-trifluorobenzene with organic lithium is -30 to -110°C, and the temperature for the reaction of the lithium salt intermediate with CO2 is -10 to -110°C.

[0020] Furthermore, the organic lithium solution includes one or more combinations of n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, n-pentyl lithium, n-hexyl lithium, bistrimethylsilyl lithium, and lithium diisopropylamide.

[0021] Furthermore, the 1,2,3-trifluorobenzene is a solution, the solvent is one or more combinations of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene, the amount of the solvent is 5-30V, and the 1,2,3-trifluorobenzene solution and the organic lithium solution are pre-reacted before the reaction, including mixing and / or pre-cooling, and the pre-cooling temperature is -10 to -110°C.

[0022] Furthermore, CO2 is dissolved using a solvent, and the solvent is one or more combinations of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

[0023] Furthermore, the CO2-dissolving solvent is pre-cooled and then mixed with CO2, and the pre-cooling temperature is -10 to -110°C.

[0024] Furthermore, the residence time of the 1,2,3-trifluorobenzene solution and the organic lithium solution in the continuous reactor is 5s to 20.0min; the residence time of the lithium salt intermediate and CO2 in the continuous reactor is 1s to 10.0min.

[0025] Furthermore, the continuous reactor is one or a combination of a tubular reactor, a microchannel reactor, and a tubular mixer.

[0026] Furthermore, the lithium salt intermediate generated by the reaction of 1,2,3-trifluorobenzene with organic lithium also includes tetramethylethylenediamine.

[0027] Furthermore, the molar ratio of the 1,2,3-trifluorobenzene to tetramethylethylenediamine is 1:0.1-6.0.

[0028] Compared with the prior art, the present application uses a continuous reaction to prepare 2,3,4-trifluorobenzoic acid. The reaction time is easy to control, the heat exchange efficiency is improved, the concentration of each reagent and the reaction equivalent are accurate, the amplification effect can be avoided to the greatest extent, thereby better controlling the generation of by-products and impurities, and the product has high purity, high yield, and few impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The accompanying drawings, which constitute part of the present application, are intended to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are intended to explain the present invention and do not constitute an improper limitation of the present invention.

[0030] In the picture:

[0031] Figure 1 , an embodiment of the present invention in which CO2 is not dissolved in a solvent.

[0032] P1 is a metering pump for delivering 1,2,3-trifluorobenzene solution, and P2 is a metering pump for delivering n-BuLi solution. After decompression, the CO2 gas flow rate is controlled by a flow controller in real time, and all flow rates are automatically controlled. After pre-cooling, the 1,2,3-trifluorobenzene solution and n-BuLi solution undergo a hydrogen extraction reaction in continuous reactor 1. They then enter continuous reactor 2, where they undergo an addition reaction with the metered CO2 delivered there. The reaction liquid is then heated and collected in a collection vessel.

[0033] Figure 2 , a connection diagram of the best embodiment of the present invention.

[0034] Among them, P1 is the metering pump for delivering 1,2,3-trifluorobenzene solution, P2 is the metering pump for delivering n-BuLi solution, and P3 is the metering pump for delivering THF. After the CO2 gas is depressurized, the real-time flow rate is controlled by a flow controller, and all flow rates are controlled automatically. After pre-cooling, the 1,2,3-trifluorobenzene solution and n-BuLi solution undergo a hydrogenation reaction in continuous reactor 1, and then enter continuous reactor 2. The pre-cooled THF is mixed and dissolved with the quantitatively delivered CO2, and then the CO2-THF solution is transported to continuous reactor 2, where it undergoes an addition reaction with the reaction liquid after the hydrogenation reaction in continuous reactor 2. The reaction liquid is heated and collected in a collection container. Example

[0035] It should be noted that, in the absence of conflict, the embodiments and features of the embodiments in this application can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0036] The reaction formula for preparing 2,3,4-trifluorobenzoic acid using 1,2,3-trifluorobenzene in the present invention is as follows:

[0037]

[0038] Disclosed is a continuous reaction method for 2,3,4-trifluorobenzoic acid, comprising the following reaction process: 1,2,3-trifluorobenzene and an organic lithium solution react in a continuous reactor to generate a lithium salt intermediate, the lithium salt intermediate reacts with CO2 in the continuous reactor for addition reaction, and post-processing to obtain 2,3,4-trifluorobenzoic acid.

[0039] The molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.5, and the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:0.8-10. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.2, preferably, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:1-5, preferably, 1:1, 1:2, 1:3, 1:4, or 1:5.

[0040] The temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and the temperature for the reaction of the lithium salt intermediate with CO2 is -10 to -110°C. Further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C. Further, the temperature for the reaction of the lithium salt intermediate with CO2 is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C.

[0041] The organic lithium solution includes one or more combinations of n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, n-pentyl lithium, n-hexyl lithium, bistrimethylsilyl lithium, and lithium diisopropylamide. Further, it includes n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, preferably n-butyl lithium. The solution is one or more combinations of n-hexane, heptane, octane, toluene, ethylbenzene, isopropyl benzene, and xylene, and the preferred solvent is n-hexane. The concentration of the organic lithium solution is 1.5 to 2.8 M, further 1.8 to 2.8 M, preferably 1.8 M, 1.9 M, 2.0 M, 2.1 M, 2.2 M, 2.3 M, 2.4 M, 2.5 M, 2.6 M, 2.7 M, and 2.8 M.

[0042] 1,2,3-Trifluorobenzene is a solution, and the solvent is one or more combinations of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene. The amount of the solvent used is 5-30V.

[0043] The 1,2,3-trifluorobenzene solution and the organic lithium solution are pre-reacted before the reaction, including mixing and / or pre-cooling. Further, mixing, pre-cooling, mixing and pre-cooling are performed. In some embodiments, the pre-reaction includes pre-cooling, and the pre-cooling temperature is -10 to -110°C.

[0044] CO2 is dissolved in a solvent, and the solvent is one or more combinations of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

[0045] The CO2-dissolving solvent is pre-cooled and then mixed with CO2, wherein the pre-cooling temperature is -10 to -110°C.

[0046] The residence time of 1,2,3-trifluorobenzene solution and organic lithium solution in the continuous reactor is 5s to 20.0min. Furthermore, the residence time of 1,2,3-trifluorobenzene solution and organic lithium solution in the continuous reactor is 5s to 10.0min; the residence time of lithium salt intermediate and CO2 in the continuous reactor is 1s to 10.0min.

[0047] The continuous reactor is one or a combination of a tubular reactor, a microchannel reactor, and a tubular mixer.

[0048] The lithium salt intermediate generated by the reaction of 1,2,3-trifluorobenzene with organic lithium also includes tetramethylethylenediamine.

[0049] The molar ratio of 1,2,3-trifluorobenzene to tetramethylethylenediamine is 1:0.1-6.0.

[0050] In some embodiments, the continuous reaction method of 2,3,4-trifluorobenzoic acid comprises the following reaction process:

[0051] (1) Lithiation reaction: 1,2,3-Trifluorobenzene and organic lithium solution react in a continuous reactor to generate a lithium salt intermediate;

[0052] (2) Addition reaction: The lithium salt intermediate reacts with CO2 in a continuous reactor;

[0053] (3) Post-treatment: The reaction mixture of step (2) is post-treated to obtain 2,3,4-trifluorobenzoic acid.

[0054] In some embodiments, 1,2,3-trifluorobenzene is dissolved in a solvent such as Figure 1 shown

[0055] (1) Lithiation reaction: The solvent solution of 1,2,3-trifluorobenzene is transported to the continuous reactor 1 through the metering pump P1 and the organic lithium solution is transported through the metering pump P2 to carry out the lithiation reaction at -30 to -110°C to generate a lithium salt intermediate mixed reaction solution;

[0056] (2) Addition reaction: CO2 is transported to the continuous reactor 2 through a flow controller, mixed with the lithium salt intermediate mixed reaction liquid of step (1), and an addition reaction occurs at -30 to -110°C to generate a lithium 2,3,4-trifluorobenzoate mixed reaction liquid;

[0057] (3) collecting the mixed reaction liquid of lithium 2,3,4-trifluorobenzoate and performing post-treatment to obtain 2,3,4-trifluorobenzoic acid.

[0058] The molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.5, and the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:0.8-10. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.2, preferably, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:1-5, preferably, 1:1, 1:2, 1:3, 1:4, or 1:5.

[0059] The organic lithium solution includes one or more combinations of n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, n-pentyl lithium, n-hexyl lithium, bistrimethylsilyl lithium, and lithium diisopropylamide. Further, it includes n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, preferably n-butyl lithium. The solution is one or more combinations of n-hexane, heptane, octane, toluene, ethylbenzene, isopropyl benzene, and xylene, and the preferred solvent is n-hexane. The concentration of the organic lithium solution is 1.5 to 2.8 M, further 1.8 to 2.8 M, preferably 1.8 M, 1.9 M, 2.0 M, 2.1 M, 2.2 M, 2.3 M, 2.4 M, 2.5 M, 2.6 M, 2.7 M, and 2.8 M.

[0060] The temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and the temperature for the reaction of the lithium salt intermediate with CO2 is -10 to -110°C. Further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C. Further, the temperature for the reaction of the lithium salt intermediate with CO2 is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C.

[0061] The 1,2,3-trifluorobenzene solvent solution comprises a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and toluene, wherein the solvent is used in an amount of 5-30V.

[0062] In some embodiments, CO2 is dissolved in a solvent and then undergoes an addition reaction.

[0063] (1) Lithiation reaction: The solvent solution of 1,2,3-trifluorobenzene and the organic lithium solution are transported to a precooler via metering pump P1 and metering pump P2 for precooling at a temperature of -10 to -110°C, and then enter the continuous reactor 1 for lithiation reaction at a temperature of -30 to -110°C to generate a lithium salt intermediate mixed reaction solution;

[0064] (2) Addition reaction: The solvent is delivered to the mixer via metering pump P3, and the pre-cooling temperature is -10 to -110°C. CO2 is delivered to the mixer via a flow controller, mixed with the solvent, and then enters the continuous reactor 2, where it is mixed with the lithium salt mixed reaction liquid of step (1) to allow the lithium salt intermediate and CO2 to undergo an addition reaction to generate a lithium 2,3,4-trifluorobenzoate mixed reaction liquid;

[0065] Alternatively, the solvent is transported to a precooler via a metering pump P3 for precooling at a temperature of -10 to -110°C, and CO2 is transported to a mixer via a flow controller, mixed with the precooled solvent, and then enters a continuous reactor 2 to mix with the lithium salt mixed reaction liquid of step (1) so that the lithium salt intermediate and CO2 undergo an addition reaction to generate a lithium 2,3,4-trifluorobenzoate mixed reaction liquid;

[0066] (3) collecting the mixed reaction liquid of lithium 2,3,4-trifluorobenzoate and performing post-treatment to obtain 2,3,4-trifluorobenzoic acid.

[0067] The molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.5, and the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:0.8-10. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.2, preferably, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:1-5, preferably, 1:1, 1:2, 1:3, 1:4, or 1:5.

[0068] The organic lithium solution includes one or more combinations of n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, n-pentyl lithium, n-hexyl lithium, bistrimethylsilyl lithium, and lithium diisopropylamide. Further, it includes n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, preferably n-butyl lithium. The solution is one or more combinations of n-hexane, heptane, octane, toluene, ethylbenzene, isopropyl benzene, and xylene, and the preferred solvent is n-hexane. The concentration of the organic lithium solution is 1.5 to 2.8 M, further 1.8 to 2.8 M, preferably 1.8 M, 1.9 M, 2.0 M, 2.1 M, 2.2 M, 2.3 M, 2.4 M, 2.5 M, 2.6 M, 2.7 M, and 2.8 M.

[0069] The temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and the temperature for the reaction of the lithium salt intermediate with CO2 is -10 to -110°C. Further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C. Further, the temperature for the reaction of the lithium salt intermediate with CO2 is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C.

[0070] The 1,2,3-trifluorobenzene solvent solution comprises a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and toluene, wherein the solvent is used in an amount of 5-30V.

[0071] The 1,2,3-trifluorobenzene solvent solution and the organic lithium solution are pre-reacted before the reaction, including mixing and / or pre-cooling. Further, mixing, pre-cooling, mixing and pre-cooling are performed. In some embodiments, the pre-reaction includes pre-cooling, and the pre-cooling temperature is -10 to -110°C.

[0072] CO2 is dissolved in a solvent, which is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene, and the amount of solvent used to dissolve CO2 is 0-30V. The solvent is pre-cooled and then mixed with CO2, and the pre-cooling temperature is -10 to -110°C.

[0073] In some embodiments, the solvent solution of 1,2,3-trifluorobenzene further comprises tetramethylethylenediamine,

[0074] (1) Lithiation reaction: The solvent solution of 1,2,3-trifluorobenzene and tetramethylethylenediamine is transported to a precooler via metering pump P1 and the organic lithium solution is transported via metering pump P2 for precooling at a temperature of -10 to -110°C. The solution is then fed into the continuous reactor 1 for lithiation reaction at a temperature of -30 to -110°C to generate a mixed reaction solution of a lithium salt intermediate.

[0075] (2) Addition reaction: The solvent is transported to a precooler via a metering pump P3 for precooling at a temperature of -10 to -110°C. CO2 is transported to a mixer via a flow controller, mixed with the precooled solvent, and then enters a continuous reactor 2 to mix with the lithium salt mixed reaction liquid of step (1) so that the lithium salt intermediate and CO2 undergo an addition reaction to generate a lithium 2,3,4-trifluorobenzoate mixed reaction liquid;

[0076] (3) collecting the mixed reaction liquid of lithium 2,3,4-trifluorobenzoate and performing post-treatment to obtain 2,3,4-trifluorobenzoic acid.

[0077] The molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.5, and the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:0.8-10. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.2, preferably, the molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. Furthermore, the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:1-5, preferably, 1:1, 1:2, 1:3, 1:4, or 1:5.

[0078] The organic lithium solution includes one or more combinations of n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, n-pentyl lithium, n-hexyl lithium, bistrimethylsilyl lithium, and lithium diisopropylamide. Further, it includes n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, preferably n-butyl lithium. The solution is one or more combinations of n-hexane, heptane, octane, toluene, ethylbenzene, isopropyl benzene, and xylene, and the preferred solvent is n-hexane. The concentration of the organic lithium solution is 1.5 to 2.8 M, further 1.8 to 2.8 M, preferably 1.8 M, 1.9 M, 2.0 M, 2.1 M, 2.2 M, 2.3 M, 2.4 M, 2.5 M, 2.6 M, 2.7 M, and 2.8 M.

[0079] The temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and the temperature for the reaction of the lithium salt intermediate with CO2 is -10 to -110°C. Further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -30 to -110°C, and further, the temperature for the reaction of 1,2,3-trifluorobenzene with the organolithium is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C. Further, the temperature for the reaction of the lithium salt intermediate with CO2 is -40 to -80°C, preferably, -40°C, -45°C, -50°C, -55°C, -60°C, -65°C, -70°C, -75°C, or -80°C.

[0080] The 1,2,3-trifluorobenzene solvent solution comprises a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and toluene, wherein the solvent is used in an amount of 5 to 30 V.

[0081] The 1,2,3-trifluorobenzene solvent solution and the organic lithium solution are pre-reacted before the reaction, including mixing and / or pre-cooling. Further, mixing, pre-cooling, mixing and pre-cooling are performed. In some embodiments, the pre-reaction includes pre-cooling, and the pre-cooling temperature is -10 to -110°C.

[0082] CO2 is dissolved in a solvent, which is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene, and the amount of solvent used to dissolve CO2 is 0-30V. The solvent is pre-cooled and then mixed with CO2, and the pre-cooling temperature is -10 to -110°C.

[0083] The molar ratio of 1,2,3-trifluorobenzene to tetramethylethylenediamine is 1:0.1-6.0. Further, the molar ratio of 1,2,3-trifluorobenzene to tetramethylethylenediamine is 1:0.1-3.0; further, the molar ratio of 1,2,3-trifluorobenzene to tetramethylethylenediamine is 1:0.5-5; further, 1:0.5-2.0; further, 1:0.5-1.5; further, 1:0.8-1.2, preferably, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:0.10 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20.

[0084] In some embodiments, as Figure 1 In the connection mode shown, the 1,2,3-trifluorobenzene solution includes tetramethylethylenediamine and 1,2,3-trifluorobenzene.

[0085] The pump flow rates of the present invention are: metering pump P1 has a flow rate of 1 to 20 mL / min, metering pump P2 has a flow rate of 0.1 to 5 mL / min, and CO2 has a flow rate of 200 to 400 mL / min. In certain embodiments, metering pump P1 has a flow rate of 1 to 20 mL / min, metering pump P2 has a flow rate of 0.1 to 5 mL / min, metering pump P3 has a flow rate of 0.5 to 10 mL / min, and CO2 has a flow rate of 200 to 400 mL / min. As long as 2, 3, and 4 are prepared according to the technical solution of the present invention, other flow rates besides those disclosed in the present invention are considered to fall within the scope of protection of the present invention.

[0086] In all examples, the residence time of the continuous reactor 1 is 5 s to 10 min, and the residence time of the continuous reactor 2 is 1 s to 10 min.

[0087] Furthermore, the residence time of the continuous reactor 1 is 1 min to 10 min, preferably, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, or 10 min.

[0088] Furthermore, the residence time of the continuous reactor 2 is 1s to 1min, preferably, 1s, 5s, 10s, 15s, 20s, 25s, 30s, 35s, 40s, 45s, 50s, 55s, or 1min.

[0089] In the embodiment, the continuous reactor is one or a combination of a tubular reactor, a microchannel reactor, and a tubular mixer.

[0090] Post-treatment: After the reaction is completed, the qualified reaction solution is further purified: water is added to the above reaction solution to quench, the liquid is separated, and the aqueous phase is collected; the aqueous phase is extracted twice with MTBE and the aqueous phase is collected; the aqueous phase is distilled under reduced pressure to remove residual organic solvent; 2M HCl solution is added dropwise to the aqueous phase to adjust the pH to 1-2, filtered, the filter cake is rinsed with water, and the filter cake is dried under vacuum to obtain the target product as a white powder.

[0091] Example 1

[0092] (1) Preparation of Solution 1: Prepare 1,2,3-trifluorobenzene solution: To a 500 ml round-bottom flask at 15-30°C, add THF (178.0 g, 10 V), 1,2,3-trifluorobenzene (20.0 g, 1.0 eq), and TMEDA (17.9 g, 1.02 eq, tetramethylethylenediamine) in sequence, stir well, and fill with nitrogen for later use;

[0093] (2) Preparation of Solution 2: Prepare a 2.5 M n-BuLi (37.2 g, 0.9 eq) n-hexane solution for later use;

[0094] (3) Prepare solution 3: Take tetrahydrofuran (124.6 g, 7V) and set aside;

[0095] (4) Press Figure 2 Set up the equipment, fill all pipes with tetrahydrofuran, check for leaks; calibrate the pump flow rate;

[0096] (5) Adjust the pre-cooling and cold bath temperature of the reaction equipment to -40 to -50°C;

[0097] (6) Set the material flow rate: P1: 11.62 mL / min, P2: 2.65 mL / min, P3: 6.78 mL / min, and the CO2 flow rate to 329 mL / min;

[0098] (7) Turn on P1, P2, P3 and CO2 gas, and after 10 minutes, switch the reaction liquid at the coil outlet to the product collection container. The reaction liquid enters the collection container after heating, and the temperature of the collection container is controlled below 30°C;

[0099] (8) Take samples for testing and conduct continuous reaction control;

[0100] (9) After the reaction is completed, the qualified reaction solution is further purified: 10V water is added to the above reaction solution to quench it, the liquid is separated, and the aqueous phase is collected; the aqueous phase is extracted twice with 5V MTBE and the aqueous phase is collected; the aqueous phase is distilled under reduced pressure at 40°C to remove the residual organic solvent; 2M HCl solution is added dropwise to the aqueous phase to adjust the pH to 1-2, and the reaction mixture is filtered at low temperature at 0-5°C, the filter cake is rinsed with 2V water, and the filter cake is vacuum-dried at 50°C to obtain the target product as a white powder.

[0101] (10) Target product nuclear magnetic resonance data: 1H NMR (400 MHz, DMSO-d6): δ 13.65 (brs, 1H), 7.79-7.73 (m, 1H), 7.46-7.39 (m, 1H) ppm.

[0102] Example 2

[0103] (1) Preparation of Solution 1: Prepare 1,2,3-trifluorobenzene solution: Add THF (178.0 g, 10 V), 1,2,3-trifluorobenzene (20.0 g, 1.0 eq), and TMEDA (17.9 g, 1.02 eq) to a 500 ml round-bottom flask at 15-30°C, stir well, and fill with nitrogen for later use;

[0104] (2) Preparation of Solution 2: Prepare a 2.5 M n-BuLi (41.3 g, 1.0 eq) n-hexane solution for later use;

[0105] (3) Prepare solution 3: Take tetrahydrofuran (89.0 g, 5V) and set aside

[0106] (4) Press Figure 2 Set up the equipment, fill all pipes with tetrahydrofuran, check for leaks; calibrate the pump flow rate;

[0107] (5) Adjust the temperature of the cold bath where the reaction pipe is located to -60 to -80°C;

[0108] (6) Set the material flow rate to: P1: 6.83 mL / min, P2: 1.73 mL / min, P3: 2.85 mL / min, CO2 flow rate to 290 mL / min;

[0109] (7) Turn on P1, P2, P3 and CO2 gas, and after 12 minutes, switch the reaction liquid at the coil outlet to the product collection container, and control the temperature of the collection container below 30°C;

[0110] (8) Take samples for testing and conduct continuous reaction control;

[0111] (9) After the reaction is completed, the qualified reaction solution is further purified: 10V water is added to the above reaction solution to quench it, the liquid is separated, and the aqueous phase is collected; the aqueous phase is extracted twice with 5V MTBE and the aqueous phase is collected; the aqueous phase is distilled under reduced pressure at 40°C to remove the residual organic solvent; 2M HCl solution is added dropwise to the aqueous phase to adjust the pH to 1-2, and the filter is filtered at low temperature at 0-5°C, and the filter cake is rinsed with 2V water. The filter cake is vacuum dried at 50°C to obtain the target product.

[0112] Example 3

[0113] (1) Preparation of Solution 1: Prepare 1,2,3-trifluorobenzene solution: Add THF (267.0 g, 15V), 1,2,3-trifluorobenzene (20.0 g, 1.0 eq), and TMEDA (17.9 g, 1.02 eq) to a 500 ml round-bottom flask at 15-30°C, stir well, and fill with nitrogen for later use;

[0114] (2) Preparation of Solution 2: Prepare a 2.5 M n-BuLi (45.4 g, 1.1 eq) n-hexane solution for later use;

[0115] (3) Prepare solution 3: Take tetrahydrofuran (178.0 g, 10 V) and set aside

[0116] (4) Press Figure 2 Set up the equipment, fill all pipes with tetrahydrofuran, check for leaks; calibrate the pump flow rate;

[0117] (5) Adjust the temperature of the cold bath where the reaction pipe is located to -50 to -60°C;

[0118] (6) Set the material flow rate to: P1: 5.11 mL / min, P2: 1.01 mL / min, P3: 3.02 mL / min, CO2 flow rate to 256 mL / min;

[0119] (7) Turn on P1, P2, P3 and CO2 gas, and after 16 minutes, switch the reaction liquid at the coil outlet to the product collection kettle, and control the temperature of the collection kettle below 30°C;

[0120] (8) Take samples for testing and conduct continuous reaction control;

[0121] (9) After the reaction is completed, the qualified reaction solution is further purified: 10V water is added to the above reaction solution to quench it, the liquid is separated, and the aqueous phase is collected; the aqueous phase is extracted twice with 5V MTBE and the aqueous phase is collected; the aqueous phase is distilled under reduced pressure at 40°C to remove the residual organic solvent; 2M HCl solution is added dropwise to the aqueous phase to adjust the pH to 1-2, and the filter is filtered at low temperature at 0-5°C, and the filter cake is rinsed with 2V water. The filter cake is vacuum dried at 50°C to obtain the target product.

[0122] Example 4

[0123] (1) Preparation of Solution 1: Prepare 1,2,3-trifluorobenzene solution: Add THF (178.0 g, 10 V), 1,2,3-trifluorobenzene (20.0 g, 1.0 eq), and TMEDA (17.9 g, 1.02 eq) to a 500 ml round-bottom flask at 15-30°C, stir well, and fill with nitrogen for later use;

[0124] (2) Prepare solution 2: Prepare a 2.5 M n-BuLi (49.5 g, 1.2 eq) n-hexane solution for later use;

[0125] (3) Prepare solution 3: Take tetrahydrofuran (231.4 g, 7V) and set aside

[0126] (4) Press Figure 2 Set up the equipment, fill all pipes with tetrahydrofuran, check for leaks; calibrate the pump flow rate;

[0127] (5) Adjust the temperature of the cold bath where the reaction pipe is located to -60 to -80°C;

[0128] (6) Set the material flow rate to: P1: 6.56 mL / min, P2: 1.99 mL / min, P3: 7.12 mL / min, and the CO2 flow rate to 279 mL / min;

[0129] (7) Turn on P1, P2, P3 and CO2 gas, and after 12 minutes, switch the reaction liquid at the coil outlet to the product collection kettle, and control the temperature of the collection kettle below 30°C;

[0130] (8) Take samples for testing and conduct continuous reaction control;

[0131] (9) After the reaction is completed, the qualified reaction solution is further purified: 10V water is added to the above reaction solution to quench it, the liquid is separated, and the aqueous phase is collected; the aqueous phase is extracted twice with 5V MTBE and the aqueous phase is collected; the aqueous phase is distilled under reduced pressure at 40°C to remove the residual organic solvent; 2M HCl solution is added dropwise to the aqueous phase to adjust the pH to 1-2, and the reaction mixture is filtered at low temperature at 0-5°C, the filter cake is rinsed with 2V water, and the filter cake is vacuum dried at 50°C to obtain the target product.

[0132] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A continuous reaction method for 2,3,4-trifluorobenzoic acid, characterized in that: The method includes the following reaction process: 1,2,3-trifluorobenzene and an organic lithium solution react in a continuous reactor to generate a lithium salt intermediate, the lithium salt intermediate and CO2 undergo an addition reaction in the continuous reactor, and post-processing is performed to obtain 2,3,4-trifluorobenzoic acid.

2. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 1, characterized in that: The molar ratio of 1,2,3-trifluorobenzene to organic lithium is 1:0.8-1.5, and the molar ratio of 1,2,3-trifluorobenzene to CO2 is 1:0.8-10.

3. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 2, characterized in that: The temperature for the reaction of 1,2,3-trifluorobenzene with organic lithium is -30 to -110°C, and the temperature for the reaction of the lithium salt intermediate with CO2 is -10 to -110°C.

4. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 3, characterized in that: The organic lithium solution includes one or more combinations of n-butyl lithium, tert-butyl lithium, isobutyl lithium, isopropyl lithium, n-pentyl lithium, n-hexyl lithium, bistrimethylsilyl lithium, and lithium diisopropylamide.

5. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 4, characterized in that: The 1,2,3-trifluorobenzene is a solution, and the solvent is one or more combinations of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene. The amount of the solvent is 5-30V. The 1,2,3-trifluorobenzene solution and the organic lithium solution are pre-reacted before the reaction, including mixing and / or pre-cooling. The pre-cooling temperature is -10 to -110°C.

6. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 5, characterized in that: CO2 is dissolved in a solvent, and the solvent is one or more combinations of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

7. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 6, characterized in that: The solvent dissolving CO2 is pre-cooled and then mixed with CO2, and the pre-cooling temperature is -10 to -110°C.

8. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 7, characterized in that: The residence time of the 1,2,3-trifluorobenzene solution and the organic lithium solution in the continuous reactor is 5 seconds to 20.0 minutes; The residence time of the lithium salt intermediate and CO2 in the continuous reactor is 1s to 10.0min.

9. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 8, characterized in that: The continuous reactor is one or a combination of a tubular reactor, a microchannel reactor, and a tubular mixer.

10. A continuous reaction method of 2,3,4-trifluorobenzoic acid according to any one of claims 1 to 9, characterized in that: The lithium salt intermediate generated by the reaction of 1,2,3-trifluorobenzene with organic lithium also includes tetramethylethylenediamine.

11. A 2,3,4-trifluorobenzoic acid continuous reaction method according to claim 10, characterized in that: The molar ratio of the 1,2,3-trifluorobenzene to tetramethylethylenediamine is 1:0.1-6.0.

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