Carboxylic acid amidation method and gas-liquid mixed flow photochemical device

Abstract

The invention provides a method for carrying out carboxylic acid amidation by adopting a gas-liquid mixed flowing photochemical device. The gas-liquid mixed flowing photochemical device comprises a liquid and gas injection part and a four-way mixer which are connected in sequence, the method comprises the following steps: placing an amine compound, a carboxylic acid compound, an organic solvent, a photocatalyst and alkali in a liquid injection part to obtain a liquid raw material, placing sulfur hexafluoride gas in a gas injection part, injecting the liquid raw material and the gas into a four-way mixer, fully mixing, and carrying out a photochemical reaction in a photoreactor, the amide compound is obtained. According to the method, the sulfur hexafluoride SF6 gas can be turned into wealth, and the simple, convenient, safe, green and efficient carboxylic acid amidation reaction can be carried out.

Description

Technical Field

[0001] The invention relates to the technical field of organic intermediate synthesis, and in particular to a method for carrying out carboxylic acid amidation by using a gas-liquid mixed flow photochemical device. Background Art

[0002] Amidation reaction is the most commonly used organic synthesis reaction. A study on drug synthesis shows that 65% of drug synthesis processes use amidation reactions. In addition, amidation products play an important role in the biomedical, pharmaceutical and food industries, and are also widely used in industrial products. For example, sulfamide can modify peptide units and proteins, and sulfamide modification can significantly improve the stability and activity of peptide drugs; tyramine-derived hydroxycinnamamide in plant-based foods can be used as a food preservative due to its natural antioxidant effect; amide greases are often used in nuclear power and aerospace fields due to their excellent properties such as strong thermal stability, radiation resistance and mechanical stability. At present, the synthesis of amide compounds includes:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid to catalyze the amidation reaction between carboxylic acid and amine.

[0004]

[0005] This method is not only applicable to the reaction of primary and tertiary amines with carboxylic acids, but is also applicable to some special substrates with large steric hindrance and olefin groups. However, it requires high temperature (>100°C) and anhydrous conditions, and has the problem of low atom economy.

[0006] Method 2: Using two zirconium catalysts (ZrCp2Cl2 / ZrCl4) in toluene solvent and heating reflux at 110°C, the amidation reaction of carboxylic acid and amine can be efficiently catalyzed.

[0007]

[0008] This method has a high yield and can achieve the synthesis of two drug molecules, acetaminophen and moclobemide, with a relatively high yield, but this method introduces metal compounds and requires high temperature conditions.

[0009] Method 3: Using active ester as acyl source and zinc powder as catalyst, the synthesis of secondary amide was achieved under the conditions of microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] The reaction has the following characteristics: simple, efficient, environmentally friendly and the catalyst can be reused. However, the substrate has a narrow scope of application and alcohol is also generated, which makes it very difficult to separate the subsequent products.

[0012] According to the above analysis, there is still a need to develop a carboxylic acid amidation method that has simple and readily available raw materials, simple operation, high reaction yield, good functional group tolerance, environmental friendliness, and is easy to promote in industrial production.

[0013] SF6 gas is a colorless, odorless, non-toxic, non-combustible, non-corrosive gas at room temperature and pressure. It is an inert gas with high stability. It does not decompose at high temperatures of 500-600°C and does not react with acids, alkalis, water, etc. It is also an insulating gas with excellent insulation properties and can be used to extinguish high-voltage arcs. Therefore, SF6 is widely used in the power industry. However, SF6 has a strong greenhouse effect, and its climate warming power is 23,900 times that of CO2. Secondly, because SF6 is an artificially synthesized gas and has quite stable chemical properties, SF6 is extremely difficult to decompose and its natural life in the atmosphere can be as long as more than 3,000 years. With its continuous accumulation in the atmosphere, the greenhouse effect it brings is also continuously increasing. The emission of SF6 is strictly restricted, and the large amount of SF6 stored in the power industry faces huge pressure in treatment. Therefore, the method of using SF6 to participate in the carboxylic acid amidation reaction has positive practical significance.

[0014] At the same time, in recent years, photochemical reactions have been favored by domestic and foreign universities, research institutes and industries. This is because compared with traditional chemical reactions, photochemical reactions use light energy to excite molecules to participate in chemical reactions, which has the advantages of high efficiency, energy saving and environmental protection. Photochemical reactions mainly involve excited molecules, which can produce a variety of active substances, and can achieve highly selective and efficient reactions through photosensitizers, catalysts and other means, often allowing the reaction to occur under mild conditions.

[0015] At present, photochemical reactions have broad application prospects in the fields of organic synthesis, drug synthesis, energy conversion, etc. On the other hand, continuous flow reactions have higher production efficiency and better heat and mass transfer performance than batch reactions. The reaction materials held in a continuous flow reactor are significantly less than those in a batch reaction, so the danger of some flammable and highly toxic reactions can be reduced, thereby reducing the safety hazards of the reaction. Continuous flow reactions generally have a smaller amplification effect and are easier to achieve expanded production. Summary of the invention

[0016] The technical problem to be solved by the present invention is how to use a gas-liquid mixed flow photochemical device to perform simple, safe, green and efficient carboxylic acid amidation.

[0017] The present invention solves the above technical problems through the following technical means:

[0018] The present invention provides a method for carboxylic acid amidation, which is carried out in a gas-liquid mixed flow photochemical device, wherein the gas-liquid mixed flow photochemical device comprises a liquid and gas injection part and a four-way mixer connected in sequence;

[0019] The method specifically comprises placing an amine compound, a carboxylic acid compound, an organic solvent, a photocatalyst and a base in a liquid injection part to obtain a liquid raw material, placing sulfur hexafluoride gas in a gas injection part, injecting the liquid raw material and the gas into the four-way mixer for full mixing, and then entering the photoreactor for photochemical reaction to obtain an amide compound. The organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane; and the amine compound is a secondary amine.

[0020] Furthermore, the four-way mixer comprises: a gas input port, a liquid input port and a mixture output port; the gas input port is connected to the gas push injection part and the circulation part; the liquid input port is connected to the liquid push injection part; the mixture output port is connected to the photoreactor; the interior of the four-way mixer is a hollow sphere, the outer wall of the sphere is evenly distributed with millimeter-level small holes, and the outer wall is tightly connected to the input and output ports;

[0021] The liquid raw material and the gas are pushed into the four-way mixer for full mixing as follows: the gaseous sulfur hexafluoride enters through the gas input port of the four-way mixer through the millimeter-level small holes evenly distributed on the outer wall of the inner sphere, filling the entire sphere; the liquid raw material expands along the outer wall of the inner sphere through the liquid input port of the four-way mixer, enters the sphere through the millimeter-level small holes evenly distributed on the outer wall, and is evenly divided into fine liquid flows, which are in full contact with the gas filling the inside of the sphere; and when leaving the four-way mixer, it is squeezed and divided into fine liquid flows again through the millimeter-level small holes evenly distributed on the outer wall of the sphere.

[0022] Preferably, the structural formula of the secondary amine is Wherein, R1 and R2 are both alkyl and substituted alkyl.

[0023] Preferably, the secondary amine is one of morpholine, diethylamine, piperidine, and L-proline methyl ester.

[0024] Preferably, the structural formula of the carboxylic acid compound is Wherein, R is one of aryl, substituted aryl, alkyl, substituted alkyl, and substituted alkenyl.

[0025] Preferably, the reaction formula of the present invention is as follows:

[0026]

[0027] Preferably, the substituents in the substituted alkyl, substituted aryl and substituted alkenyl are all selected from C1-C20 Alkyl, C2-C 20 Alkenyl, C6-C 20 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms of one or more of O, N, S, C2-C 30 Ester group, C3-C 20 and containing 1 to 5 cycloalkyl, trifluoromethyl, halogen, methoxy, dimethylamino, biphenyl, A mixture of one or more of.

[0028] Preferably, the carboxylic acid compound is one of 4-phenylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid, 4-trifluoromethylbenzoic acid, benzoic acid, 4-(N,N-dimethylamino)benzoic acid, 4-vinylbenzoic acid, 1-benzofuran-5-carboxylic acid, p-methoxyphenylacetic acid, 4-biphenylacetic acid, 2-phenylacrylic acid, trans-2-phenylcyclopropane-carboxylic acid, BOC-glycine, probenecid, and (tert-butyloxycarbonyl)glycine.

[0029] Preferably, the organic solvent is acetonitrile.

[0030] The present invention is carried out in a system with a single organic solvent; if necessary, other organic solvents may also be present in the system, but from the perspective of reaction yield and simplicity of operation, it is preferred not to add other organic solvents, that is, to use a single organic solvent as the reaction solvent.

[0031] Preferably, the photocatalyst is an organic photocatalyst or a mixture of one or more transition metal photocatalysts.

[0032] Preferably, the organic photocatalyst is 4CZIPN, Mes-Acr + ClO4 — One or a mixture of two.

[0033] Preferably, the transition metal photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(dtbbpy)ppy2PF6 or a mixture of the two.

[0034] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0035] Preferably, the base is an organic base.

[0036] Preferably, the organic base is a tertiary amine.

[0037] Preferably, the organic base is N,N-diisopropylethylamine. When the base is N,N-diisopropylethylamine, the yield of amide compounds is the highest.

[0038] Preferably, the molar ratio of the amine compound to the carboxylic acid compound is 1:1 to 20:1.

[0039] Preferably, the molar ratio of the amine compound to the carboxylic acid compound is 10:1.

[0040] Preferably, the molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.2-1.

[0041] Preferably, the molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.5.

[0042] Preferably, the molar ratio of the carboxylic acid compound to the base is 1:1-1:10.

[0043] Preferably, the molar ratio of the carboxylic acid compound to the base is 1:5.

[0044] Preferably, during the light irradiation reaction process, blue light with a wavelength of 450-480 nm is used as the light source.

[0045] Preferably, blue light with a wavelength of 465 nm is used as the light source.

[0046] Preferably, during the light irradiation reaction, the SF6 gas pressure is 1 atm. When the pressure is 1 atm, the yield of the amide compound is the highest.

[0047] Preferably, during the light irradiation reaction, the reaction temperature is 0 to 50° C. and the reaction time is 5 to 48 hours.

[0048] Preferably, during the light irradiation reaction, the reaction temperature is room temperature and the reaction time is 20 hours.

[0049] The reaction temperature and reaction time of the present invention can also be determined by technicians according to different amine compounds and carboxylic acid compounds and actual needs.

[0050] Preferably, the usage ratio of the carboxylic acid compound to the solvent is 0.5-0.1 mmol:1 mL.

[0051] Preferably, the ratio of the carboxylic acid compound to the solvent is 0.17 mmol: 1 mL. When the ratio is 0.17 mmol: 1 mL, the yield of the amide compound is the highest.

[0052] Preferably, during the reaction, the decomposition products of SF6 serve as condensation agents.

[0053] The present invention is a carboxylic acid amidation method with a wide range of applications. The present method is applicable to the synthesis of various amide compounds and their derivatives, and has good tolerance for aromatic carboxylic acids, alkyl carboxylic acids, substituted alkyl carboxylic acids, and heteroaryl carboxylic acids. Therefore, there is actually no particularly strict restriction on the types of carboxylic acid compounds.

[0054] The present invention also provides a gas-liquid mixed flow photochemical device using the above-mentioned carboxylic acid amidation method, the device comprising a liquid and gas injection part, a four-way mixer, a photoreactor, a gas-liquid separator, a collection part and a circulation part connected in sequence;

[0055] The four-way mixer comprises: a gas input port, a liquid input port and a mixture output port; the gas input port is connected to the gas push injection part and the circulation part; the liquid input port is connected to the liquid push injection part; the mixture output port is connected to the photoreactor;

[0056] The interior of the four-way mixer is a hollow sphere, and millimeter-level small holes are evenly distributed on the outer wall of the sphere, and the outer wall is tightly connected with the input and output ports.

[0057] The advantages of the present invention are:

[0058] (1) In the present invention, amide compounds are synthesized simply and efficiently under SF6 gas using easily available amine and carboxylic acid compounds as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like as photocatalysts, and cheap and easily available N,N-diisopropylethylamine and the like as bases. Compared with other methods for synthesizing amide compounds, the present invention has mild reaction conditions, and the reaction raw materials used (including amine compounds and carboxylic acid compounds, N,N-diisopropylethylamine) are cheap and easily available, and are cost-saving, environmentally friendly, and can be promoted industrially. The method effectively activates and utilizes SF6, a greenhouse gas, and fully utilizes the decomposition products of SF6 to realize the amidation reaction of carboxylic acids, turning SF6 into treasure. The required raw materials are simple and easily available, the reaction conditions are simple, and the method is green and energy-saving, and has a high application value.

[0059] (2) The present invention is applicable to a variety of carboxyl-containing compounds and has successfully synthesized a variety of amide drug molecules. It can be widely used in drug synthesis and total synthesis of natural products in industry and academia, and has high application value.

[0060] (3) The present invention increases the gas-liquid mixing area and the mixing pressure inside the mixer by setting a uniquely structured four-way mixer in the gas-liquid mixed flow photoreaction device using the carboxylic acid amidation reaction method; the mixing efficiency of liquid and gas is improved for the chemically stable and non-polar gas such as sulfur hexafluoride SF6 used in the method. At the same time, by constructing a cyclic reaction path for continuous flow photochemical reaction, the gas raw material is fully utilized, achieving the purpose of zero emission of SF6 gas, which has a serious impact on the greenhouse effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 [1,1'-biphenyl]-4-yl (morpholinyl) ketone described in Example 1 of the present invention 1 H NMR nuclear magnetic spectrum;

[0062] Figure 2 [1,1'-biphenyl]-4-yl (morpholinyl) ketone described in Example 1 of the present invention 13 C NMR nuclear magnetic spectrum;

[0063] Figure 3 The benzofuran-5-yl (morpholinyl) ketone described in Example 2 of the present invention 1 H NMR nuclear magnetic spectrum;

[0064] Figure 4 The benzofuran-5-yl (morpholinyl) ketone described in Example 2 of the present invention 13 C NMR nuclear magnetic spectrum;

[0065] Figure 5 2-(4-methoxyphenyl)-1-morpholinoethane-1-one as described in Example 3 of the present invention 1 H NMR nuclear magnetic spectrum;

[0066] Figure 6 2-(4-methoxyphenyl)-1-morpholinoethane-1-one as described in Example 3 of the present invention 13 C NMR nuclear magnetic spectrum;

[0067] Figure 7 This is a schematic structural diagram of a gas-liquid mixed flow photochemical device for performing a carboxylic acid amidation reaction according to Example 4 of the present invention;

[0068] Figure 8 This is a schematic diagram of a four-way mixer of a gas-liquid mixed flow photochemical device for performing a carboxylic acid amidation reaction in Example 4 of the present invention.

[0069] in:

[0070] 1-gas supply bottle; 2-gas pipe; 3-liquid pipe; 4-liquid storage bottle; 5-liquid injection pump; 6-pressure reducing valve; 7-gas flow meter; 8-check valve I; 9-four-way mixer; 10-mixing tube; 11-photoreactor; 12-gas-liquid separator; 13-gas outlet pipe; 14-gas collecting bottle; 15-gas injection pump; 16-gas flow meter; 17-check valve II; 18-liquid outlet pipe; 19-circulating material bottle. DETAILED DESCRIPTION

[0071] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0072] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0073] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0074] In the present invention, "amide compounds" have the meaning commonly understood by those skilled in the art, that is, organic compounds in which the hydroxyl group in the carboxylic acid is replaced by an amino group or an amine group.

[0075] The raw materials used in the following specific examples are all commercially available, and each reagent is purified by means known in the art before use when necessary.

[0076] Example 1

[0077] This embodiment provides a method for synthesizing [1,1'-biphenyl]-4-yl (morpholinyl) ketone using a gas-liquid mixed flow photochemical device. The method is specifically as follows:

[0078] The raw material 4-phenylbenzoic acid (99.0 mg), the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg), morpholine (437.3 μL), N,N-diisopropylethylamine (434.6 μL), and 3.0 mL of anhydrous acetonitrile were added to the liquid storage bottle 4 (25.0 mL) equipped with a perforated rubber stopper and a magnetic stirring bar, and added to the liquid storage bottle 4 through a syringe, and the solution was stirred until clear by the magnetic stirring bar. The pipette of the injection pump 5 was placed in the hole of the rubber stopper. After preparation, the gas supply bottle 1 and the pressure reducing valve 6 were opened, and the SF6 gas entered the four-way mixer 9 through the one-way valve I8. At the same time, the injection pump 5 is started. The solution expands along the outer wall of the inner sphere through the liquid input port of the four-way mixer 9 under the thrust of the liquid injection pump 5, and enters the sphere through the millimeter-level holes evenly distributed on the outer wall. The solution is evenly divided into fine liquid flows, which are fully in contact with the SF6 gas filling the inside of the sphere, thereby increasing the contact area between the solution and the gas. At the same time, when the solution leaves the mixing output port of the four-way mixer 9, it is squeezed and divided into fine liquid flows again through the millimeter-level holes evenly distributed on the outer wall of the sphere, thereby increasing the mixing pressure inside the mixer. Thus, the mixing efficiency of the solution and the gas is improved.

[0079] The raw material solution and SF6 gas are fully mixed in a four-way mixer and then enter the photoreactor. The photoreactor 11 is turned on, and the gas-liquid mixture undergoes a continuous flow reaction in the photoreactor 11. The gas-liquid mixture after the reaction is separated into gas and liquid in the gas-liquid separator 12. After the reaction is completed, the organic solvent is removed under vacuum, and [1,1'-biphenyl]-4-yl (morpholinyl) ketone is obtained by silica gel column chromatography separation (petroleum ether: ethyl acetate volume ratio = 3:1).

[0080] The NMR spectrum of the product [1,1'-biphenyl]-4-yl(morpholinyl)methanone is as follows Figure 1 and 2 As shown, the NMR data are as follows: 1 HNMR (400MHz, CDCl3) δ7.64–7.57(m,4H),7.49–7.43(m,4H),7.39–7.35(m,1H),3.75–3.52(m,8H)ppm. 13 C NMR (101MHz, CDCl3) δ170.1,142.7,140.0,133.9,128.8,127.7,127.6,127.1,127.0,66.8ppm.

[0081] Example 2

[0082] This embodiment provides a method for synthesizing benzofuran-5-yl (morpholinyl) ketone using a gas-liquid mixed flow photochemical device.

[0083] This example uses the same apparatus and process as Example 1, and the reaction raw materials are 1-benzofuran-5-carboxylic acid (81.7 mg, 1 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg), morpholine (437.3 μL, 10 equiv.), N,N-diisopropylethylamine (434.6 μL, 5 equiv.), 3.0 mL of anhydrous acetonitrile, and SF6 gas. Benzofuran-5-yl (morpholinyl) ketone is obtained.

[0084] The NMR spectrum of the product benzofuran-5-yl (morpholinyl) ketone is as follows Figure 3 and 4 As shown, the NMR data are as follows: 1 HNMR (400MHz, CDCl3) δ7.68(s,2H),7.53–7.51(m,1H),7.36–7.33(m,1H),6.80–6.79(m,1H),3.76–3.38(m,8H)ppm. 13 C NMR (101MHz, CDCl3) δ170.7,155.4,146.1,130.0,127.4,123.5,120.6,111.5,106.7,66.9ppm.

[0085] Example 3

[0086] This embodiment provides a method for synthesizing 2-(4-methoxyphenyl)-1-morpholineethane-1-one using a gas-liquid mixed flow photochemical device.

[0087] This example uses the same apparatus and process as Example 1, and the reaction raw materials use p-methoxyphenylacetic acid (83.1 mg, 1 equiv.), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg), morpholine (437.3 μL, 10 equiv.), N,N-diisopropylethylamine (434.6 μL, 5 equiv.), 3.0 mL of anhydrous acetonitrile, and SF6 gas. 2-(4-methoxyphenyl)-1-morpholinoethane-1-one was obtained.

[0088] The NMR spectrum of the product 2-(4-methoxyphenyl)-1-morpholinoethane-1-one is as follows Figure 5 and 6 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.14–7.12(m,2H),6.85–6.83(m,2H),3.77(s,3H),3.64–3.61(m,6H),3.48–3.40(m,4H)ppm.13 C NMR (101MHz, CDCl3) δ169.9,158.4,129.5,126.6,114.1,66.7,66.4,55.1,46.4,42.0,39.8ppm.

[0089] As can be seen from Examples 1-3, the present invention uses easily available carboxylic acids and amine compounds as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, cheap and readily available N,N-diisopropylethylamine as a base, and the gas-liquid mixed flow photochemical device for reaction, thereby synthesizing amide compounds simply and efficiently. This method has good reactivity to different amine compounds, and has no particularly strict restrictions on the number and type of substituents in carboxylic acids and amine compounds. Therefore, it is a general method for synthesizing amide compounds with mild conditions, simple operation, and easy industrial promotion. In addition, this method effectively activates and utilizes SF6, a greenhouse gas, and makes full use of SF6 decomposition products to realize the amidation reaction of carboxylic acids, turning SF6 into treasure.

[0090] Example 4

[0091] This embodiment discloses a gas-liquid mixed flow photochemical device used in the carboxylic acid amidation reaction in the above embodiments 1-3, such as Figure 7 As shown, the gas-liquid mixed flow photochemical device includes: a liquid and gas push injection unit, a four-way mixer, a photoreactor, a gas-liquid separator, a collection unit and a circulation unit connected in sequence. The liquid push injection unit includes a liquid storage bottle 4, a liquid injection pump 5 and a liquid pipe 3 connected in sequence. The gas push injection unit includes a gas supply bottle 1, a gas pipe 2, a pressure reducing valve 6, a gas flow meter 7, and a one-way valve Ⅰ8 connected in sequence;

[0092] The four-way mixer 9 is as follows Figure 8 As shown, it includes: two gas input ports, a liquid input port and a mixture output port; the gas input port is connected to the gas push injection part and the circulation part; the liquid input port is connected to the liquid push injection part; the mixture output port is connected to the photoreactor 11;

[0093] The interior of the four-way mixer 9 is a hollow sphere, and the outer wall of the sphere is evenly distributed with millimeter-level holes, and the outer wall is tightly connected to the input and output ports;

[0094] Furthermore, the reaction solid raw materials and liquid solvent are prepared into a solution and placed in a liquid storage bottle 4. By stirring, the solution is ensured to be clear and will not cause clogging of the pipeline; the solution flows in the liquid pipe 3 through the liquid injection pump 5 and is transported to the liquid input port of the four-way mixer 9.

[0095] The gas raw material in the gas supply bottle 1 is transported to the gas input port of the four-way mixer 9 through the gas pipe 2, the pressure reducing valve 6, the gas flow meter 7, and the one-way valve I8.

[0096] The gas enters through the gas input port of the four-way mixer 9 through the evenly distributed millimeter-sized holes on the outer wall of the inner sphere, filling the entire sphere;

[0097] The solution expands along the outer wall of the inner sphere through the liquid input port of the four-way mixer 9 under the thrust of the liquid injection pump 5, and enters the sphere through the millimeter-level small holes evenly distributed on the outer wall. The solution is evenly divided into fine liquid flows, which are fully in contact with the gas filling the inside of the sphere, thereby increasing the contact area between the solution and the gas. At the same time, when the solution leaves the mixing output port of the four-way mixer 9, it is squeezed and divided into fine liquid flows again through the millimeter-level small holes evenly distributed on the outer wall of the sphere, thereby increasing the mixing pressure inside the mixer. Thus, the mixing efficiency of liquid and gas is improved.

[0098] The solution and gas are uniformly and fully mixed in the four-way mixer 9 and then transported to the photoreactor 11 through the mixing tube 10 for chemical reaction. The photoreactor includes: a reaction hose, a light source module, and a temperature control module; the reaction hose is connected to the mixing tube 10, and is wound into a column and placed inside the photoreactor 11; the photoreactor 11 chemically reacts the system in the reaction hose. The separation part adopts a gas-liquid separator; the input port of the gas-liquid separator 12 is connected to the above-mentioned reaction hose, and the output port is connected to the circulation part. The collection part includes a gas collection bottle 14 and a circulation material bottle 19; the gas collection bottle 14 collects the remaining gas; the circulation material bottle 19 collects the solution after the reaction. The circulation part includes: an outlet path 13 and a liquid outlet path 18; the outlet path 13 passes through the gas collection bottle 14, the gas injection pump 15, the gas flowmeter 16 and the one-way valve II 17, and is connected to the input port of the four-way mixer 9; the liquid outlet path 18 passes through the circulation material bottle 19 and the liquid injection pump 5 and is connected to the input port of the four-way mixer 9.

[0099] Furthermore, in actual operation, Figure 7 As shown, the reaction solid raw materials and liquid raw materials are prepared into a solution and placed in a liquid storage bottle 4. By stirring, the solution is ensured to be clear and will not cause the pipeline to be blocked. Preferably, a suction filter head can also be installed at the inlet of the hose. The solution is transported in the liquid pipe 3 by the liquid injection pump 5 and enters the four-way mixer 9; the liquid injection pump 5 can set the liquid flow rate, which can make the liquid flow evenly in the pipeline, which is simple, convenient and easy to operate. The gas raw material in the gas supply bottle 1 passes through the pressure reducing valve 6, the gas pipe 2 and the gas flow meter 7, and the one-way valve I8, and enters the four-way mixer 9; the gas flow meter 7 can control the gas flow rate to match the liquid flow rate; the one-way valve I8 can prevent the liquid from flowing back into the gas path.

[0100] Furthermore, the four-way mixer 9 connects the gas pipe 2 and the liquid pipe 3, where the gas and liquid are evenly and fully mixed. The gas raw material is evenly mixed with the solution through the four-way mixer 9 and then transported to the photoreactor 11 through the mixing tube 10 for chemical reaction; the photoreactor 11 includes a reaction hose, a light source module, and a temperature control module. The reaction hose is wound into a ring in the photoreactor so that the light source can evenly illuminate the gas-liquid mixed system therein, increase the illumination area, and improve the reaction efficiency; the light source module provides light energy to make the reactants enter an excited state. The temperature control module can heat or cool the reaction system to reach the optimal temperature required for the chemical reaction. By setting the temperature by yourself, it is simple and easy to operate.

[0101] Further, the outlet of the photoreactor is connected to the gas-liquid separator 12. An outlet pipe 13 is arranged at the upper end of the gas-liquid separator 12, a liquid outlet pipe 18 is arranged at the bottom of the gas-liquid separator 12, and a TLC spot plate is arranged at the input port of the gas-liquid separator 12. Through the TLC spot plate observation, the solution raw material is detected. If the raw material in the solution is completely converted, the reaction solution is transported to the circulating material bottle 19 for collection, and the gas is transported to the gas collecting bottle 14 for collection; if the raw material in the solution is not completely converted, the reaction system is separated into gas and liquid at the gas-liquid separator 12 and transported to the circulation part, that is, the gas returns to the four-way mixer 9 after passing through the outlet pipe 13, the gas collecting bottle 14, the gas injection pump 15, the gas flow meter 16, and the one-way valve II 17, and the end of the outlet pipe 13 is connected to the four-way mixer 9; the gas injection pump 15 can well control the flow rate of the unreacted gas, better participate in the subsequent reaction, and also achieve the purpose of zero gas emission. The gas flow meter 16 can more intuitively observe the cumulative flow and instantaneous flow. At the same time, the unreacted solution, raw materials and target products are returned to the circulating material bottle 19 for storage after passing through the liquid outlet pipe 18; when the liquid injection pump 5 has delivered the original material, the solution stored in the circulating material bottle 19 is re-injected into the four-way mixer 9 to be fully mixed with the gas, and then delivered to the photoreactor for reaction again. This cycle is repeated until the raw materials in the solution are completely converted through TLC spot plate observation, and the product is collected through the circulating material bottle 19.

[0102] Preferably, in this embodiment, the raw material solution is limited, while the supply of gas can be unlimited. The gas raw material always circulates in the device until the solution raw material is completely converted, the chemical reaction stops, and the solution product is collected for subsequent operations. Therefore, zero emission of reaction gas can be achieved.

[0103] Preferably, in the above-mentioned cyclic reaction, the flow rate can be set, the liquid flow rate is controlled by the liquid injection pump 5, and the gas flow rate is controlled by the gas injection pump 15, so as to achieve the material ratio designed in the experiment.

[0104] Preferably, when all the solution raw materials in this experiment have reacted completely, the gas supply is stopped, and the remaining gas in the system is transported to the gas collecting bottle 14 for collection, thereby further achieving the purpose of zero gas emission.

[0105] Preferably, the gas-liquid separator 12 described in the embodiment of the present invention can accurately control the collection amount or circulation amount of the solution when the solution product is collected or the solution is circulated again through the liquid outlet path, thereby ensuring that a certain volume of solution is always maintained in the gas-liquid separator to avoid gas leakage when the solution product is collected.

[0106] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for carboxylic acid amidation, characterized in that: The method is carried out by using a gas-liquid mixed flow photochemical device, which comprises a liquid and gas injection part and a four-way mixer connected in sequence; the method specifically comprises placing an amine compound, a carboxylic acid compound, an organic solvent, a photocatalyst and a base in the liquid injection part to obtain a liquid raw material, placing sulfur hexafluoride gas in the gas injection part, injecting the liquid raw material and the gas into the four-way mixer for full mixing, and then performing a photochemical reaction to obtain an amide compound, wherein the organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane; and the amine compound is a secondary amine.

2. The method for carboxylic acid amidation according to claim 1, characterized in that: The four-way mixer comprises: a gas input port, a liquid input port and a mixture output port; the gas input port is connected to the gas push injection part and the circulation part; the liquid input port is connected to the liquid push injection part; the mixture output port is connected to the photoreactor; the interior of the four-way mixer is a hollow sphere, the outer wall of the sphere is evenly distributed with millimeter-level small holes, and the outer wall is tightly connected to the input and output ports; The liquid raw material and the gas are pushed into the four-way mixer for full mixing as follows: the gaseous sulfur hexafluoride enters through the gas input port of the four-way mixer through the millimeter-level small holes evenly distributed on the outer wall of the inner sphere, filling the entire sphere; the liquid raw material expands along the outer wall of the inner sphere through the liquid input port of the four-way mixer, enters the sphere through the millimeter-level small holes evenly distributed on the outer wall, and is evenly divided into fine liquid flows, which are in full contact with the gas filling the inside of the sphere; and when leaving the four-way mixer, it is squeezed and divided into fine liquid flows again through the millimeter-level small holes evenly distributed on the outer wall of the sphere.

3. The method for carboxylic acid amidation according to claim 1, characterized in that: The secondary amine structural formula is Wherein, R1 and R2 are both alkyl and substituted alkyl.

4. The method for carboxylic acid amidation according to claim 1, characterized in that: The structural formula of the carboxylic acid compound is Wherein, R is one of aryl, substituted aryl, alkyl, substituted alkyl, and substituted alkenyl.

5. The method for carboxylic acid amidation according to claim 1, characterized in that: The carboxylic acid compound is one of 4-phenylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid, 4-trifluoromethylbenzoic acid, benzoic acid, 4-(N,N-dimethylamino)benzoic acid, 4-vinylbenzoic acid, 1-benzofuran-5-carboxylic acid, p-methoxyphenylacetic acid, 4-biphenylacetic acid, 2-phenylacrylic acid, trans-2-phenylcyclopropane-carboxylic acid, BOC-glycine, probenecid, and (tert-butyloxycarbonyl)glycine.

6. The method for carboxylic acid amidation according to claim 1, characterized in that: The organic solvent is acetonitrile.

7. The method for carboxylic acid amidation according to claim 1, characterized in that: The photocatalyst is a mixture of one or more organic photocatalysts or transition metal photocatalysts.

8. The method for carboxylic acid amidation according to claim 1, characterized in that: The base is an organic base.

9. The method for carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the amine compound to the carboxylic acid compound is 1:1 to 20:

1.

10. The method for carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.2-1.

11. The method for carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the carboxylic acid compound to the base is 1:1-1:

10.

12. The method for carboxylic acid amidation according to claim 1, characterized in that: During the light reaction process, blue light with a wavelength of 450-480nm is used as the light source.

13. The method for carboxylic acid amidation according to claim 1, characterized in that: During the photoreaction process, the SF6 gas pressure is 1 to 3 atm.

14. A method for carboxylic acid amidation according to claims 1-13, characterized in that: The usage ratio of the carboxylic acid compound and the solvent is 0.5-0.1 mmol:1 mL.

15. A gas-liquid mixed flow photochemical device using the method for carboxylic acid amidation according to claims 1 to 14, characterized in that: The device comprises a liquid and gas injection part, a four-way mixer, a photoreactor, a gas-liquid separator, a collection part and a circulation part which are connected in sequence; The four-way mixer comprises: a gas input port, a liquid input port and a mixture output port; the gas input port is connected to the gas push injection part and the circulation part; the liquid input port is connected to the liquid push injection part; the mixture output port is connected to the photoreactor; The interior of the four-way mixer is a hollow sphere, and millimeter-level small holes are evenly distributed on the outer wall of the sphere, and the outer wall is tightly connected with the input and output ports.

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