Preparation method and application of phenylacetic acid and derivatives thereof

Abstract

The invention discloses a method for preparing phenylacetic acid and a derivative thereof from toluene and a derivative thereof and carbon dioxide, which comprises the following steps: adopting a strategy of combining photo-catalysis and electro-catalysis, performing an anodic reaction to obtain electrons from halogen anions at an anode to generate a halogen simple substance, and performing a free radical substitution reaction with toluene and the derivative thereof under optical excitation to obtain an intermediate I; then, adding a nucleophilic species, and carrying out nucleophilic substitution reaction with the intermediate I to generate an intermediate II; the intermediate II is reduced at the cathode and is combined with the introduced carbon dioxide; and after the reaction is finished, acidifying and purifying the reaction liquid to obtain phenylacetic acid and the derivative thereof. According to the method, the raw materials are low in price and easy to obtain, the strategy of catalyzing benzyl C-H bond carboxylation through light and electricity combination is adopted, the yield and the Faraday efficiency are high, use of anode active metal is avoided, and industrial scale production is facilitated. The method has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemicals, specifically to a method for preparing phenylacetic acid and its derivatives from toluene and its derivatives with carbon dioxide. Background Technology

[0002] Phenylacetic acid (PAA), also known as benzyl acetic acid or benzylformic acid, exhibits typical substitution reaction properties of carboxyl groups, methylene hydrogen, and benzene rings. As an important fine chemical, phenylacetic acid has wide applications in the pharmaceutical, fragrance, and pesticide industries. In pharmaceutical applications, phenylacetic acid is a crucial intermediate in the synthesis of various drugs, including antibiotics and antifungal agents. Industrially, phenylacetic acid is used as a plastic curing agent, fluorescent whitening agent, color developer, and fragrance. With the development of the pharmaceutical industry and the growth of other industrial sectors, the demand for PAA is continuously increasing.

[0003] Currently, several methods for preparing phenylacetic acid have been disclosed. For example:

[0004] The phenylacetonitrile hydrolysis method is currently the main method for large-scale industrial production of phenylacetic acid worldwide. Benzyl chloride and sodium cyanide are first reacted with a catalyst in a specific medium to produce phenylacetonitrile, which is then hydrolyzed using either alkaline or acidic methods to obtain crude phenylacetic acid. This crude product is then purified to obtain the final product. Although this method has mild reaction conditions and a simple process, both the raw material sodium cyanide and the intermediate phenylacetonitrile are highly toxic substances. Furthermore, the synthesis of phenylacetonitrile generates volatile, highly toxic, and foul-smelling benzyl isocyanate, posing significant hazards to operators and the environment. The phenylacetic acid product often contains highly toxic free cyanide, making it unsuitable for the production of some downstream products.

[0005] The carbonyl synthesis method involves the addition of a suitable organic solvent to carbonylate benzyl chloride with carbon monoxide under the action of a catalyst and at relatively low pressure and temperature. Sodium phenylacetate is then acidified to produce crude phenylacetic acid, which is subsequently processed to obtain the final product. Although this method has few side reactions and a high product yield, its limitations include unstable and easily deactivated catalysts, complex preparation and recovery processes, and high equipment costs and requirements for auxiliary facilities.

[0006] Chinese invention patent document CN114956979 A discloses a method for synthesizing phenylacetic acid using toluene, carbon monoxide, and water as raw materials, in the presence of inexpensive transition metal nickel, phosphine ligands, a phase-transfer catalyst, and an oxidant. While this invention utilizes widely available toluene as a raw material, it requires a nickel catalyst and structurally complex ligands, which is not conducive to industrial scale-up.

[0007] Therefore, it is necessary to develop a method for preparing phenylacetic acid and its derivatives that has low reaction requirements, is easy to operate, has good production safety, is environmentally friendly, has low cost, has a wide range of raw material sources, and has a high product yield. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a method for preparing phenylacetic acid and its derivatives by utilizing a strategy of photocatalytic benzylic CH bond carboxylation, which has wide availability of raw materials, low requirements for reaction conditions, convenient operation, good production safety, good environmental friendliness, low cost, and high product yield, thereby overcoming the defects of the prior art.

[0009] To solve the above problems, the present invention adopts the following technical solution:

[0010] This invention provides a method for preparing phenylacetic acid and its derivatives from toluene and its derivatives with carbon dioxide. The method combines photocatalysis and electrocatalysis. In the anodic reaction, a halide anion gains electrons at the anode to generate a halogen element, which undergoes a free radical substitution reaction with toluene and its derivatives under photoexcitation to obtain intermediate I. Subsequently, a nucleophilic species is added, which undergoes nucleophilic substitution with intermediate I to generate intermediate II. Intermediate II is reduced at the cathode and combines with the introduced carbon dioxide to obtain phenylacetic acid and its derivatives.

[0011] Existing electrochemical methods for preparing phenylacetic acid derivatives primarily use benzyl halides and their derivatives as substrates, employing a sacrificial active metal anode as the anolyte. This invention uses halide anions as the halogen source, combined with inert anodic oxidation, to generate elemental halogens in situ. This not only overcomes the need for equivalent halogens but also avoids sacrificial anodes, improving charge utilization. Combined with photoreaction, it allows for the in-situ generation of benzyl halides and their derivatives using cheaper toluene and its derivatives as starting materials. Benzyl halides and their derivatives are highly electrophilic, readily undergoing substitution reactions with the generated carboxylic acid products and easily undergoing electroreduction self-coupling reactions, resulting in low yields. This invention incorporates nucleophiles, which can convert benzyl halides and their derivatives into less electrophilic intermediates, thereby reducing side reactions and improving reaction efficiency. The method described in this invention is reasonable from both a production safety and cost reduction perspective.

[0012] In this invention, the reaction process of the method is shown in the following reaction formula:

[0013]

[0014] in,

[0015] R 1 Selected from H, aryl, alkyl, amino, and hydroxyl groups;

[0016] R 2 Selected from H, aryl, alkyl, amino, and hydroxyl groups;

[0017] R 3 Selected from H, aryl, alkyl, amino, and hydroxyl groups.

[0018] Preferably, R 1 R 2 R 3 Each can be an aromatic group such as H, phenyl, pyridyl, pyrroleyl, furanyl, or a C1-C10 alkyl, amino, or hydroxyl group.

[0019] Specifically, the structures of the phenylacetic acid and its derivatives are partially as follows:

[0020]

[0021] In this invention, the method includes the following specific steps:

[0022] The first step involves introducing carbon dioxide gas into an electrochemical reaction cell, adding toluene and its derivatives as substrates, then adding a halogen-containing electrolyte solution, and continuously introducing carbon dioxide to form a reaction solution.

[0023] The second step involves connecting the cathode and anode, passing an electric current through them, and connecting a light source to irradiate the reaction solution obtained in the first step. Electrolysis is continued at a temperature of -50 to 100°C until the toluene and its derivatives have completely reacted, after which the power supply is disconnected to obtain the electrolyte of intermediate I. Preferably, electrolysis is continued at a temperature of 25°C until the toluene and its derivatives have completely reacted.

[0024] The third step involves adding a nucleophilic species to the electrolyte obtained in the second step to form an electrolyte containing intermediate II.

[0025] Fourth, continue to apply electricity until intermediate II reacts completely, then disconnect the power supply. The reaction ends, and the reaction solution is acidified and purified to obtain phenylacetic acid and its derivatives.

[0026] In the first step, the electrochemical reaction cell includes a single cell, a double cell, etc., preferably a double cell.

[0027] Specifically, when the electrochemical reaction cell is a dual-cell structure, the cathode cell and the anode cell are separated by a cation exchange membrane or a glass frit, wherein the cation exchange membrane is any one of the following models: Nafion 117, Nafion 115, Nafion 211, etc.

[0028] Specifically, when the electrochemical reaction cell is a dual-cell type, the substrate is added to an anolyte solution containing halogens, and carbon dioxide is introduced. The anolyte is irradiated by a light source, and electrolysis is continued at a temperature of -50 to 100°C until toluene and its derivatives react completely. The power supply is then disconnected to obtain an anolyte containing intermediate I. After adding a nucleophilic species to the anolyte solution, an electrolyte containing intermediate II is formed. The current direction is reversed, and electrolysis continues until intermediate II reacts completely. The power supply is then disconnected, and the reaction ends. The reaction solution is acidified and purified to obtain phenylacetic acid and its derivatives.

[0029] In the first step, the halogen-containing electrolyte solution in the electrochemical reaction is composed of an organic solvent and a halogen-containing electrolyte; wherein,

[0030] The organic solvent is selected from any one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, or N,N-dimethylacetamide; preferably, it is N,N-dimethylformamide.

[0031] The halogen-containing electrolyte is selected from any one or more halides such as tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, sodium bromide, potassium bromide, lithium bromide, cesium bromide, tetramethylammonium iodide, tetraethylammonium iodide, tetrapropylammonium iodide, tetrabutylammonium iodide, sodium iodide, potassium iodide, lithium iodide, cesium iodide, tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, sodium chloride, potassium chloride, lithium chloride, and cesium chloride. Preferably, it is sodium bromide.

[0032] In the first step, the carbon dioxide is introduced by either bubbling or sealed high-pressure filling; preferably, it is bubbling.

[0033] In the first step, the concentration of the electrolyte solution is 0.01-5M; the concentration of the substrate in the electrolyte solution is 0.01-5M; the concentration of the halogen in the electrolyte solution is 0.01-5M; preferably, the concentration of the electrolyte solution is 1M; the concentration of the substrate in the electrolyte solution is 1M; and the concentration of the halogen in the electrolyte solution is 1M.

[0034] In the second step, the cathode is any one or more of the following: an inert metal electrode, a platinum mesh electrode, a carbon electrode, a graphite electrode, and a glassy carbon electrode; preferably, it is a platinum mesh electrode; and / or,

[0035] The anode can be any one or more of inert metal, metal oxide electrode, platinum mesh electrode, carbon electrode, graphite electrode, glassy carbon electrode, etc., preferably a platinum mesh electrode.

[0036] Specifically, when the cathode is an inert metal, the inert metal is any one or more of the following: copper, nickel, platinum, tungsten, lead, stainless steel, silver, and titanium, with copper being preferred.

[0037] Specifically, when the anode is an inert metal, the inert metal is any one or more of platinum, tungsten, silver, tantalum, and titanium, preferably platinum.

[0038] Specifically, when the anode is a metal oxide, the metal oxide is any one or more of copper oxide, lead oxide, iron oxide, iron oxide, cobalt oxide, zinc oxide, and nickel oxide, preferably copper oxide.

[0039] In the second step, the wavelength range of the light source is 200-800nm ​​and the power is 1-1000W; preferably, the wavelength range of the light source is 400nm and the power is 100W.

[0040] In the second step, the current is applied in either a constant voltage or constant current mode, preferably a constant current mode.

[0041] Wherein, the constant current of the constant current mode is 1-5000mA, and the constant voltage of the constant voltage mode is 1-300V; preferably, the constant current of the constant current mode is 100mA, and the constant voltage of the constant voltage mode is 10V.

[0042] In the third step, the nucleophilic species is selected from tertiary amines such as trimethylamine, triethylamine, tripropylamine, and tributylamine, or any one or more of tributylphosphine, tricyclohexylphosphine, triphenylphosphine, pyridine, 4-dimethylaminopyridine, and thiazoline. Preferably, it is triethylamine.

[0043] In the third step, the molar ratio of the amount of the nucleophilic species added to the added toluene and its derivatives is (1-10):1; preferably, the molar ratio is 1:1.

[0044] In the fourth step, the acidifying reagent is any one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, etc., preferably hydrochloric acid.

[0045] In the fourth step, the amount of the acidifying reagent added is in a molar ratio of (1-10):1 with the added toluene and its derivatives; preferably, the molar ratio is 1:1.

[0046] In the fourth step, the purification method includes acid-base extraction and recrystallization. Preferably, it is recrystallization.

[0047] The innovative aspects of this invention include: 1) Utilizing a combination of light and electricity, benzyl halides and their derivatives can be generated in situ at the anode using toluene and its derivatives as starting materials; existing electrochemical methods only utilize the cathode and can only use benzyl halides and their derivatives as starting substrates. 2) Adding nucleophilic substances to benzyl halides and their derivatives to generate less electrophilic intermediates can suppress side reactions and improve yield. Existing technologies directly use benzyl halides and their derivatives as starting substrates, and the resulting carboxylic acid product undergoes a substitution reaction with the benzyl halides and their derivatives, generating ester byproducts.

[0048] The beneficial effects of this invention include:

[0049] This invention provides a method for preparing phenylacetic acid and its derivatives from toluene and its derivatives with carbon dioxide. The method combines photocatalysis and electrocatalysis. The anodic reaction involves a halide anion gaining electrons at the anode to generate a halogen element, which undergoes a free radical substitution reaction with toluene and its derivatives under photoexcitation to obtain intermediate I. Subsequently, a nucleophilic species is added, which undergoes a nucleophilic substitution reaction with intermediate I to generate intermediate II. Intermediate II is reduced at the cathode and combines with the introduced carbon dioxide to obtain phenylacetic acid and its derivatives.

[0050] In summary, this invention utilizes a combined photo- and electro-catalytic strategy for the carboxylation of benzylic CH bonds to prepare phenylacetic acid and its derivatives from toluene and its derivatives with carbon dioxide. This method features mild reaction conditions, a simple process, high operability, good production safety, and excellent environmental friendliness. The raw materials are inexpensive and readily available, resulting in low costs. Furthermore, the product yield is high, and the quality is stable, fully meeting the requirements for use as a pharmaceutical intermediate and suitable for industrial production. Attached Figure Description

[0051] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0052] Figure 1 This is a liquid phase diagram of phenylacetic acid used in this invention;

[0053] Figure 2 This is the hydrogen spectrum of phenylacetic acid used in this invention.

[0054] Figure 3 This is the proton NMR spectrum of naproxen in this invention.

[0055] Figure 4 This is the proton NMR spectrum of ibuprofen used in this invention. Detailed Implementation

[0056] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0057] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use.

[0058] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0059] This invention proposes a method for preparing phenylacetic acid and its derivatives from toluene and its derivatives with carbon dioxide. Taking the preparation of phenylacetic acid as an example, the method includes the following steps: A combined photocatalytic and electrocatalytic strategy is employed. At the anodic reaction, a halide anion gains electrons at the anode to generate a halogen element, which undergoes a free radical substitution reaction with toluene and its derivatives under photoexcitation to obtain intermediate I. Subsequently, a nucleophilic species is added, which undergoes a nucleophilic substitution reaction with intermediate I to generate intermediate II. Intermediate II is reduced at the cathode and combines with the introduced carbon dioxide. After the reaction is completed, the reaction solution is acidified and purified to obtain phenylacetic acid and its derivatives. The method of this invention uses inexpensive and readily available raw materials, employs a combined photocatalytic and electrocatalytic strategy for the carboxylation of benzylic CH bonds, achieves high yield and Faradaic efficiency, avoids the use of active metals at the anode, and is beneficial for industrial-scale production. This invention has broad application prospects.

[0060] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.

[0061] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0062] Raw materials used: toluene, 1-ethyl-4-(2-methylpropyl)benzene, p-toluene methyl ether, 6-ethyl-2-methoxynaphthalene, ethylbenzene, tetrabutylammonium iodide, tetrabutylammonium bromide, sodium bromide, sodium chloride, graphite electrode, platinum electrode, N,N-dimethylformamide, acetonitrile, triethylamine, triphenylphosphine, pyridine, and carbon dioxide gas with a purity of 99.99%.

[0063] Equipment used: constant current electrolyzer, magnetic stirrer, wavelength adjustable light source.

[0064] Instrument and analytical conditions for nuclear magnetic resonance (NMR): A Bruker superconducting NMR spectrometer was used; the resonance frequency was 500 MHz; CDCl3 was used as the solvent and TMS as the internal standard. Product purity was determined by liquid chromatography (LC), using a SIL-16 SLC column and an XB-C18-H reversed-phase LC column.

[0065] Example 1

[0066] A 50 mL electrolytic cell was filled with CO2 gas, and 3.69 g (10 mmol) of tetrabutylammonium iodide, 0.92 g (10 mmol) of toluene, and 40 mL of acetonitrile were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The graphite electrode is the cathode, 10cm 2 A graphite electrode was used as the anode, and the electrolyte was irradiated with a light source of 400 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 20 °C for 2 hours and 40 minutes. Triethylamine 1.01 g (10 mmol) was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain phenylacetic acid.

[0067] The analysis revealed that the mass of phenylacetic acid was 1.224 g, with a yield of 90%. A sample of phenylacetic acid was then subjected to liquid chromatography analysis. Figure 1 The retention time of phenylacetic acid was 13.684 min, and the content was 99.7%. Phenylacetic acid was detected by NMR, and the proton NMR spectrum of phenylacetic acid was obtained as shown below. Figure 2 As shown. By Figure 2 It can be known that:

[0068] 1 H-NMR (CDCl3, 500Hz) δppm: 3.66 (s, 2H), 7.28-7.32 (m, 3H), 7.34-7.36 (m, 2H).

[0069] δ = 3.66 ppm: Hydrogen in -CH2, singlet, number 2; 7.28-7.32 ppm and 7.34-7.36: Hydrogen on the benzene ring, number 5.

[0070] Example 2

[0071] A 50 mL electrolytic cell was filled with CO2 gas, and 3.22 g (10 mmol) of tetrabutylammonium bromide, 0.92 g (10 mmol) of toluene, and 40 mL of acetonitrile were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source with a wavelength of 390 nm. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. Triethylamine 1.01 g (10 mmol) was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain phenylacetic acid.

[0072] The test results showed that the mass of phenylacetic acid was 1.15 g, with a yield of 85%.

[0073] Example 3

[0074] A 50 mL electrolytic cell was filled with CO2 gas, and 1.03 g (10 mmol) of sodium bromide, 0.92 g (10 mmol) of toluene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source with a wavelength of 390 nm. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 2.62 g (10 mmol) of triphenylphosphine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain phenylacetic acid.

[0075] The test results showed that the mass of phenylacetic acid was 1.25 g, with a yield of 92%.

[0076] Example 4

[0077] A 50 mL electrolytic cell was filled with CO2 gas, and 0.58 g (10 mmol) of sodium chloride, 0.92 g (10 mmol) of toluene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source of 380 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 0.79 g (10 mmol) of pyridine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain phenylacetic acid.

[0078] The test results showed that the mass of phenylacetic acid was 1.29 g, with a yield of 95%.

[0079] Example 5

[0080] Assemble the dual-cell reaction tank. Use N117 cation exchange membrane. First, fill the 50 mL anode cell with CO2 gas and add 0.58 g (10 mmol) sodium chloride, 0.92 g (10 mmol) toluene, and 40 mL N,N-dimethylformamide. Then, add 3.22 g (10 mmol) tetrabutylammonium bromide and 40 mL N,N-dimethylformamide to the 50 mL anode cell. After stirring until dissolved, continue to purge with CO2 gas. After half an hour, with a surface area of ​​10 cm²... 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the anolyte was irradiated with a light source of 380 nm wavelength. A current of 200 mA was passed through, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. The power was then disconnected, and 0.79 g (10 mmol) of pyridine was added to the anolyte. The current direction was reversed, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, and 100 mL of petroleum ether was added. The mixture was stirred for half an hour, allowed to stand, and the supernatant was discarded. Another 100 mL of petroleum ether was added, and the above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain phenylacetic acid.

[0081] The test results showed that the mass of phenylacetic acid was 1.21 g, with a yield of 89%.

[0082] Example 6

[0083] A 50 mL electrolytic cell was filled with CO2 gas, and 0.58 g (10 mmol) of sodium chloride, 1.86 g (10 mmol) of 6-ethyl-2-methoxynaphthalene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source of 380 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 0.79 g (10 mmol) of pyridine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain naproxen.

[0084] The mass of naproxen was found to be 2.16 g, with a yield of 94%. The obtained naproxen was analyzed by nuclear magnetic resonance (NMR), and the proton NMR spectrum was obtained as follows: Figure 3 As shown. By Figure 3 It can be known that:

[0085] 1 H-NMR (DMSO-d6, 500Hz) δppm: 1.43 (d, 3H), 3.77-3.82 (m, 1H), 3.86 (s, 3H), 7.15 (m, 1H), 7.28-7.29 (d, 1H), 7.40 (m, 1H), 7.71 (s, 1H), 7.78 (m, 2H).

[0086] δ = 1.43 ppm: Hydrogen in the benzyl CH3 group, a singlet with 3 peaks; 3.86 ppm: Hydrogen in the -OCH3 group of the benzene ring, a singlet with 3 peaks; 7.15-7.78 ppm: Hydrogen in the naphthalene ring bonded to carbon atoms, 6 peaks.

[0087] Example 7

[0088] A 50 mL electrolytic cell was filled with CO2 gas, and 0.58 g (10 mmol) of sodium chloride, 1.62 g (10 mmol) of 1-ethyl-4-(2-methylpropyl)benzene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source of 380 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 0.79 g (10 mmol) of pyridine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain ibuprofen.

[0089] The mass of ibuprofen was found to be 1.90 g, with a yield of 92%. The obtained ibuprofen was analyzed by nuclear magnetic resonance (NMR), and the proton NMR spectrum was obtained as shown below. Figure 4 As shown. By Figure 4 It can be known that:

[0090] 1 H-NMR (DMSO-d6, 500Hz) δppm: 0.85 (d, 6H), 1.33 (d, 3H), 1.76-1.85 (m, 1H), 2.40 (d, 2H), 3.62 (m, 1H), 7.09 (2, 2H), 7.18 (d, 2H).

[0091] δ = 0.85 ppm: Hydrogen in -(CH3)2 of isobutyl group, singlet, number 6; 1.33 ppm: Hydrogen in -CH3 at the benzyl position, doublet, number 3; 1.76-1.85 ppm: Hydrogen attached to the tertiary carbon in isobutyl group, number 1; 2.40 ppm: Hydrogen in -CH2- of isobutyl group, doublet, number 2; 3.62 ppm: Hydrogen on the carbon at the benzyl position, number 1; 7.09-7.18 ppm: Hydrogen on the benzene ring, number 4.

[0092] Example 8

[0093] A 50 mL electrolytic cell was filled with CO2 gas, and 0.58 g (10 mmol) of sodium chloride, 1.22 g (10 mmol) of p-toluene methyl ether, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source of 380 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 0.79 g (10 mmol) of pyridine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain p-methoxyphenylacetic acid.

[0094] The test results showed that the mass of p-methoxyphenylacetic acid was 1.50 g, with a yield of 90%.

[0095] Example 9

[0096] A 50 mL electrolytic cell was filled with CO2 gas, and 1.03 g (10 mmol) of sodium bromide, 1.06 g (10 mmol) of ethylbenzene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source of 390 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 2.62 g (10 mmol) of triphenylphosphine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain 2-phenylpropionic acid.

[0097] The mass of 2-phenylpropionic acid was found to be 1.37 g, with a yield of 91%.

[0098] Comparative Example 1

[0099] A 50 mL electrolytic cell was filled with CO2 gas, and 0.58 g (10 mmol) of sodium chloride, 1.62 g (10 mmol) of 1-ethyl-4-(2-methylpropyl)benzene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode. When the electrolyte was not illuminated by a light source, a current of 200 mA was passed through it, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. 0.79 g (10 mmol) of pyridine was added to the electrolyte, and electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. After standing, the supernatant was discarded, and another 100 mL of petroleum ether was added. The above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the above residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain ibuprofen.

[0100] The test results showed that the mass of ibuprofen was 0g, and the yield was 0%.

[0101] Comparative Example 2

[0102] A 50 mL electrolytic cell was filled with CO2 gas, and 0.58 g (10 mmol) of sodium chloride, 1.62 g (10 mmol) of 1-ethyl-4-(2-methylpropyl)benzene, and 40 mL of N,N-dimethylformamide were added. After stirring until dissolved, CO2 gas was continuously introduced. After half an hour, the solution was collected with a surface area of ​​10 cm². 2 The platinum electrode is used as the cathode, 10cm 2 A platinum electrode was used as the anode, and the electrolyte was irradiated with a light source of 380 nm wavelength. A current of 200 mA was passed through the electrolyte, and electrolysis was carried out continuously at 10 °C for 2 hours and 40 minutes. Without adding nucleophilic substances such as pyridine, electrolysis was continued for another 2 hours and 40 minutes. After the reaction was completed, the solvent in the electrolyte was removed under vacuum, 100 mL of petroleum ether was added, and the mixture was stirred for half an hour. The mixture was allowed to stand, and the supernatant was discarded. Another 100 mL of petroleum ether was added, and the above operation was repeated. 50 mL of water and 50 mL of dilute hydrochloric acid (1 M / L) were added to the residue, and the mixture was stirred for half an hour. 50 mL of ethyl acetate was added, and the mixture was separated. The organic layer was collected, and the aqueous phase was extracted twice more with 50 mL of ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain ibuprofen.

[0103] The test results showed that the mass of ibuprofen was 186 mg, with a yield of 9%.

[0104] As can be seen from the above, the reaction conditions of this invention are mild, the process is simple, the operability is strong, the production safety is good, and the environmental friendliness is excellent; the raw materials are inexpensive and readily available, resulting in low cost; and the product has high purity, high yield, and stable quality, fully meeting the requirements for use as a pharmaceutical intermediate and suitable for industrial production.

[0105] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0106] As used in this invention, the term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects.

[0107] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0108] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for the preparation of phenylacetic acid and its derivatives from toluene and its derivatives and carbon dioxide, characterized by, The method comprises: using a method combining light and electrocatalysis, the anode reaction is that halogen anion obtains electrons at the anode to generate halogen element, which, under light excitation, undergoes a free radical substitution reaction with toluene and its derivatives to obtain intermediate I; subsequently, a nucleophilic species is added to undergo a nucleophilic substitution reaction with the intermediate I to generate intermediate II; the intermediate II is reduced at the cathode and reacts with the inhaled carbon dioxide to obtain phenylacetic acid and its derivatives, and the reaction process of the method is shown in the following reaction formula: wherein R 1 is selected from H, aryl, alkyl, amine, hydroxyl; R 2 selected from H, aryl, alkyl, amine, hydroxyl; R 3 selected from H, aryl, alkyl, amine, hydroxyl.

2. The method of claim 1, wherein, R 1 , R 2 , R 3 each independently H, phenyl, pyridyl, pyrrolyl, furanyl, C1-C10 alkyl, amine, hydroxyl.

3. The method of claim 1, wherein, The structure of the phenylacetic acid and its derivatives is as follows:

4. The method of claim 1, wherein, The method comprises the following specific steps: In the first step, carbon dioxide gas is inhaled into an electrochemical reaction cell, toluene and its derivatives are added as substrates, a halogen-containing electrolyte solution is added, and carbon dioxide is continuously inhaled to form a reaction liquid; In the second step, the cathode and the anode are connected, current is inhaled, and the reaction liquid obtained in the first step is irradiated by connecting a light source, and the electrolysis is continuously carried out at a temperature of-50-100 DEG C until toluene and its derivatives are completely reacted, then the power is turned off, and an electrolyte solution of intermediate I is obtained; In the third step, a nucleophilic species is added to the electrolyte solution obtained in the second step to form an electrolyte solution containing intermediate II; In the fourth step, the power is continuously turned on until the intermediate II is completely reacted, then the power is turned off, the reaction is completed, and the reaction liquid is acidified and purified to obtain phenylacetic acid and its derivatives.

5. The method of claim 4, wherein, In the first step, the electrochemical reaction cell comprises a single cell and a double cell; and / or The halogen-containing electrolyte solution is composed of an organic solvent and a halogen-containing electrolyte; wherein the organic solvent is selected from any one or more of acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone and N, N-dimethylacetamide; and the halogen-containing electrolyte is selected from any one or more of tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, sodium bromide, potassium bromide, lithium bromide, cesium bromide, tetramethylammonium iodide, tetraethylammonium iodide, tetrapropylammonium iodide, tetrabutylammonium iodide, sodium iodide, potassium iodide, lithium iodide, cesium iodide, tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, sodium chloride, potassium chloride, lithium chloride and cesium chloride; The inhalation mode of the carbon dioxide comprises bubbling and sealed high-pressure charging; The concentration of the electrolyte solution is 0.01-5M; the concentration of the substrate in the electrolyte solution is 0.01-5M; and the concentration of the halogen in the electrolyte solution is 0.01-5M.

6. The method of claim 5, wherein, When the electrochemical reaction cell is a double cell, the cathode cell and the anode cell are separated by a cation exchange membrane or a glass sand core, wherein the cation exchange membrane is any one of Nafion 117, Nafion 115 and Nafion 211; and / or When the electrochemical reaction cell is a double cell, the substrate is added into an anolyte solution containing halogen, carbon dioxide is introduced, the anolyte solution is irradiated by a light source, and electrolysis is continuously carried out at a temperature of -50-100 ℃ until the reaction of toluene and its derivatives is completed, then the power is turned off to obtain an anolyte solution containing intermediate I, a nucleophilic species is added into the anolyte solution to form an electrolyte solution containing intermediate II, the current direction is changed, and electrolysis is continuously carried out until the reaction of intermediate II is completed, then the power is turned off, and the reaction is completed, and the reaction solution is acidified and purified to obtain phenylacetic acid and its derivatives.

7. The method of claim 4, wherein, In the second step, the cathode is any one or more of an inert metal electrode, a platinum mesh electrode, a carbon electrode, a graphite electrode, and a glassy carbon electrode; and / or, In the second step, the anode is any one or more of an inert metal, a metal oxide electrode, a platinum mesh electrode, a carbon electrode, a graphite electrode, and a glassy carbon electrode; and / or, The wavelength range of the light source is 200-800 nm, and the power is 1-1000 W; and / or, The current introduction mode includes constant voltage or constant current mode, wherein the constant current of the constant current mode is 1-5000 mA, and the constant voltage of the constant voltage mode is 1-300 V.

8. The method of claim 7, wherein, When the cathode is an inert metal, the inert metal is any one or more of copper, nickel, platinum, tungsten, lead, stainless steel, silver, and titanium; and / or, When the anode is an inert metal, the inert metal is any one or more of platinum, tungsten, silver, tantalum, and titanium; and / or, When the anode is a metal oxide, the metal oxide is any one or more of copper oxide, lead oxide, magnetite, iron oxide, cobalt oxide, zinc oxide, and nickel oxide.

9. The method of claim 4, wherein, In the third step, the nucleophilic species is any one or more of trimethylamine, triethylamine, tripropylamine, tributylamine, tributylphosphine, tricyclohexylphosphine, triphenylphosphine, pyridine, 4-dimethylaminopyridine, and thianthrene; and / or, The molar ratio of the amount of the nucleophilic species added to the amount of toluene and its derivatives added is (1-10):

1.

10. The method of claim 4, wherein, In the fourth step, the acidifying agent is any one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid; and / or, The molar ratio of the amount of the acidifying agent added to the amount of toluene and its derivatives added is (1-10):

1. The purification mode includes acid-base extraction and recrystallization.

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