Method for synthesizing 2-phenylpropionic acid through reaction of styrene and carbon dioxide under catalysis of nickel

Abstract

The invention discloses a method for synthesizing 2-phenylpropionic acid through reaction of styrene and carbon dioxide under the catalysis of nickel, which comprises the following steps: adding styrene, a nickel compound, an organic ligand and manganese into a reactor, reacting with carbon dioxide in an organic solvent medium at a certain temperature and pressure, then adding diluted hydrochloric acid, and stirring at normal temperature to complete the reaction, and extracting the reaction mixed solution with an organic extractant to separate out an organic phase, and carrying out reduced pressure distillation on the organic solvent on the organic phase to obtain 2-phenylpropionic acid. According to the invention, styrene is taken as a raw material, under the action of the nickel compound catalyst, direct carboxylation reaction of styrene and carbon dioxide is effectively realized, and compared with the traditional oxidation, hydrolysis and other multi-step carboxylic acid preparation methods, the method provided by the invention has the advantages of high atom utilization rate, simple technical process and other industrial application sustainable development characteristics; particularly, the atom economy of the synthetic reaction is highlighted by recycling the carbon dioxide.

Description

Technical Field

[0001] The invention relates to the field of petroleum styrene and carbon dioxide fixation and conversion, and in particular to a method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel. Background Art

[0002] Phenylpropionic acid compounds are an important class of phenylpropanoid compounds, which were originally derived from C3-C6 natural organic acids. Among them, phenylpropionic acid compounds have biological activities such as antioxidant, antibacterial, immune enhancement, anticancer, antiviral, anti-inflammatory, lipid-lowering, and cardiovascular disease treatment, and are widely used in the fields of medicine, food, fragrance, cosmetics, agricultural chemicals, organic intermediates, etc. In particular, 2-phenylpropionic acid is the most basic and simplest arylpropionic acid compound, and is the basic intermediate for the synthesis of arylpropionic acid drugs.

[0003] 2-Phenylpropionic acid compounds are a class of non-steroidal anti-inflammatory drugs with good effects that came out in the 1960s. This type of drug not only has obvious anti-inflammatory, antipyretic and analgesic effects, but also has the characteristics of small dosage, fast action, good efficacy and weak side effects during the treatment process. Since the successful development of ibuprofen by the British Boots Company in the 1970s, the research and development of 2-arylpropionic acid drugs has made great progress. A large number of similar drugs such as naproxen, ibuprofen, ketoprofen, flurbiprofen and etodolac have been launched on the market. These drugs have good clinical effects on acute and chronic arthritis, frozen shoulder, soft tissue rheumatic pain, neuritis, respiratory inflammation, etc., and are also used for pain relief in cancer and other aspects. Due to its own high efficiency and low toxicity, it is gradually replacing aspirin. At present, the demand for 2-phenylpropionic acid compounds is increasing. 3-Phenylpropionic acid can be polymerized into dimers or trimers. It is the active ingredient of Salvia miltiorrhiza for treating coronary heart disease. It is used to synthesize 3-(4-hydroxyphenyl)propionamide drugs, which exhibits anti-aging, anti-slackening and skin-maintaining activities. It is a component of anti-aging drugs / health products.

[0004] In addition to being used as a functional material for medicine, 2-phenylpropionic acid has a significant inhibitory effect on the activity of mushroom tyrosinase. Tyrosinase is a key enzyme in the formation of biological melanin. This enzyme inhibitor has important applications in the preservation of fruits and vegetables to prevent browning. It has a good preservation effect on mushrooms to prevent browning and is used as a food preservative. 2-phenylpropionic acid is used to synthesize the universal hapten of dimethoxyphosphate pesticides. After coupling with proteins, this substance can be used as a coating antigen in the enzyme-linked immunosorbent assay of such pesticides. The difference in the structure of the coating antigen and the immunogen is used to further improve the detection sensitivity and reduce the detection limit. Therefore, 2-phenylpropionic acid plays an important role in the application of medicine, fragrances, cosmetics, pesticides, etc.

[0005] At present, the preparation method of 2-phenylpropionic acid is to use styrene to react with hydrogen chloride under the action of a catalyst to form 1-phenylethyl chloride, and then react with sodium cyanide in an N,N-dimethylformamide solvent medium to obtain 2-phenylpropionitrile. The cyano substitution product is further refluxed and hydrolyzed in a 30% sodium hydroxide aqueous solution to prepare sodium 2-phenylpropionate, and the 2-phenylpropionic acid product is obtained after hydrochloric acid acidification, solvent extraction, and distillation. This method uses styrene as a raw material to synthesize phenylpropionic acid through a four-step unit reaction aromatic method of addition, substitution, hydrolysis, and acidification. It requires the use of highly toxic sodium cyanide and corrosive substances such as hydrochloric acid to form a large amount of sodium chloride brine. The process has poor safety and environmental performance, low reaction atom utilization, and does not have the characteristics of sustainable development of industrial preparation. In order to avoid CN in toxic cyanide - and Cl in hydrochloric acid - Influence on the quality of medicine, etc., acetophenone is also used as raw material abroad, and phenylethanol is prepared by Raney nickel catalytic hydrogenation, and then further synthesized by precious metal palladium catalyzed carbon monoxide reaction 2-phenylpropionic acid. This method has the characteristics of high raw material cost, harsh process control, and high process safety requirements. Some newly developed synthesis methods use basic raw materials such as benzaldehyde, ethylbenzene and acetophenone, which need to react with sodium cyanide reaction reagents with one carbon added. These methods involve highly toxic sodium cyanide substances in the process of reaction, and do not have the characteristics of industrial application environment economy and greenness. Summary of the invention

[0006] The object of the present invention is to provide a method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, which has the characteristics of suitable reaction conditions, high conversion rate and atom economy.

[0007] In one aspect of the present invention, the present invention provides a method for synthesizing 2-phenylpropionic acid by the reaction of styrene and carbon dioxide catalyzed by nickel. According to an embodiment of the present invention, the method comprises the following steps: adding styrene, a nickel compound, an organic ligand and manganese in an organic solvent medium to a reactor to react with carbon dioxide at a certain temperature and pressure, then adding dilute hydrochloric acid to complete the reaction by stirring at room temperature, extracting the reaction mixture with an organic extractant to separate an organic phase, and further subjecting the organic phase to reduced pressure distillation of the organic extractant and the organic solvent to obtain 2-phenylpropionic acid.

[0008] The reaction equation for the synthesis of 2-phenylpropionic acid by the nickel-catalyzed reaction of styrene and carbon dioxide is as follows:

[0009]

[0010] In addition, the method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to the above embodiment of the present invention may also have the following additional technical features:

[0011] In some embodiments of the present invention, the nickel compound is one of nickel chloride, nickel bromide, nickel iodide, nickel nitrate, nickel sulfate, nickel acetate, and nickel acetylacetonate, preferably nickel halide.

[0012] In some embodiments of the present invention, the organic ligand is one of alkyl zinc, 2,2'-bipyridine, 4,4'-bipyridine, 2-methyl-4,4'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, and 4,7-dihydroxy-1,10-phenanthroline, preferably phenanthroline.

[0013] In some embodiments of the present invention, the molar ratio of the nickel compound to styrene is 0.01-1.1:1, and preferably the molar ratio of the nickel compound to styrene is 0.05-0.20:1.

[0014] In some embodiments of the present invention, the molar ratio of the organic ligand to styrene is 0.01 to 0.30:1, and preferably the molar ratio of the organic ligand to styrene is 0.05 to 0.30:1.

[0015] In some embodiments of the present invention, the molar ratio of manganese to styrene is 0.1 to 3:1, and preferably the molar ratio of manganese to styrene is 1 to 3:1.

[0016] In some embodiments of the present invention, the molar ratio of the nickel compound to the organic ligand is 0.5 to 2:1, and preferably the molar ratio of the nickel compound to the organic ligand is 0.5 to 1:1.

[0017] In some embodiments of the present invention, the organic solvent is a polar aprotic solvent such as N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, or a polar protic solvent such as ethanol, propanol, butanol and water, or a combination thereof, and the organic extractant is one of dichloromethane, ethyl acetate, dichloroethane, and petroleum ether. A solution pH regulator is selectively added to the reaction system, and the pH regulator is sodium carbonate, potassium carbonate, cesium carbonate, or ammonium acetate.

[0018] In some embodiments of the present invention, the reaction temperature is room temperature to 100° C., the reaction pressure is normal pressure to 2.0 MPa, and the reaction time is 8 to 30 h.

[0019] In some embodiments of the present invention, the vacuum distillation is specifically performed as follows: placing the organic phase into a distillation reactor, starting a vacuum pump and slowly heating to boiling, and the organic extractant and the organic solvent are passed through a condenser into a corresponding solvent receiver.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1) The present invention uses styrene as a raw material, and uses a nickel compound and an organic ligand to form a complex to in-situ catalyze the direct carboxylation reaction of styrene and carbon dioxide, thereby achieving high atomic utilization rate of the synthesis reaction.

[0022] 2) The present invention adopts a one-pot method to synthesize the product, avoids the use of sensitive and active catalysts such as Gringnard reagent, has mild reaction conditions, simple and easy process operation, and can quickly and efficiently synthesize 2-phenylpropionic acid.

[0023] 3) The method of the present invention has the characteristics of high atom economy, and can utilize carbon dioxide as a resource to synthesize high value-added organic functional materials, and has the sustainability of industrial application development of the synthetic technology method. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The product 2-phenylpropionic acid obtained in Example 1 of the present invention 1 HNMR spectra;

[0025] Figure 2 The product 2-phenylpropionic acid obtained in Example 1 of the present invention 13 CNMR image. DETAILED DESCRIPTION

[0026] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only 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.

[0027] Example 1

[0028] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0029] Styrene (0.25 mmol), nickel chloride (0.025 mmol), 2,2'-bipyridine (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and dissolved in N,N-dimethylformamide (2 mL) while maintaining a CO pressure of 0.10 MPa. 2 The mixture was stirred at 40°C for 28 hours, and then diluted hydrochloric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction. The reaction mixture was extracted with ethyl acetate (3.0 mL × 4 times). The organic phase was subjected to reduced pressure distillation to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 11.0%. The product NMR spectrum analysis showed that Figure 1 and Figure 2 shown.

[0030] Example 2

[0031] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0032] Styrene (0.25 mmol), nickel chloride (0.025 mmol), 1,10-phenanthroline (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and dissolved in N,N-dimethylformamide (2 mL) and propanol (0.17 mL) while maintaining a CO pressure of 0.10 MPa. 2 The mixture was stirred at 40°C for 28 hours, and then diluted hydrochloric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction. The reaction mixture was extracted with ethyl acetate (3.0 mL × 4 times). The organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 25.0%.

[0033] Example 3

[0034] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0035] Styrene (0.25 mmol), nickel bromide (0.025 mmol), 2,9-dimethyl-1,10-phenanthroline (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and stirred in N,N-dimethylformamide (2 mL) while maintaining a CO pressure of 0.10 MPa. 2 atmosphere, stirred and reacted for 28 hours at 40°C, then diluted nitric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction, and the reaction mixture was extracted with dichloromethane (3.0 mL × 4 times), and the organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 15.9%.

[0036] Example 4

[0037] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0038] Styrene (0.25 mmol), nickel acetylacetonate (0.025 mmol), ethyl zinc (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and stirred in tetrahydrofuran (2 mL) under a CO pressure of 1.0 MPa. 2atmosphere, the reaction was continued under stirring at 60°C for 10 hours, and then diluted hydrochloric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction. The reaction mixture was extracted with dichloromethane (3.0 mL × 4 times), and the organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 30.8%.

[0039] Example 5

[0040] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0041] Styrene (0.25 mmol), nickel acetylacetonate (0.025 mmol), ethyl zinc (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and stirred in N,N-dimethylformamide (2 mL) while maintaining a CO pressure of 3.0 MPa. 2 atmosphere, and the reaction was continued under stirring at 60°C for 10 hours, after which 1 mol / L dilute hydrochloric acid (4.0 mL) was added and the reaction was stirred for 1 hour to complete, and the reaction mixture was extracted with ethyl acetate (3.0 mL × 4 times), and the organic phase was subjected to reduced pressure distillation to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 26.8%.

[0042] Example 6

[0043] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0044] Styrene (0.25 mmol), nickel acetylacetonate (0.025 mmol), ethyl zinc (0.625 mmol), manganese powder (0.50 mmol), and cesium carbonate (0.025 mmol) were added to a 10 mL Schlenk reaction tube and dissolved in tetrahydrofuran (2 mL) and n-butanol (0.17 mL) while maintaining a CO pressure of 1.0 MPa. 2 The mixture was stirred at 23°C for 12 hours, and then hydrochloric acid (4.0 mL) was added and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate (3.0 mL × 4 times). The organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 56.0%.

[0045] Example 7

[0046] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0047] Styrene (0.25 mmol), nickel chloride (0.025 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.050 mmol), manganese powder (0.50 mmol), and ammonium acetate (0.75 mmol) were added to a 10 mL Schlenk reaction tube in N,N-dimethylformamide (2 mL). The CO pressure was maintained at 0.10 MPa. 2 atmosphere, the reaction was continued under stirring at 40°C for 28 hours, and then diluted hydrochloric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction. The reaction mixture was extracted with ethyl acetate (3.0 mL × 4 times), and the organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 24.0%.

[0048] Example 8

[0049] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0050] Styrene (0.25 mmol), nickel chloride (0.025 mmol), 2,9-dimethyl-1,10-phenanthroline (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and stirred in N,N-dimethylformamide (2 mL) while maintaining a CO pressure of 0.10 MPa. 2 The mixture was stirred at 40°C for 24 hours, and then diluted hydrochloric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction. The reaction mixture was extracted with ethyl acetate (3.0 mL × 4 times). The organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 73.8%.

[0051] Example 9

[0052] A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, comprising the following steps:

[0053] Styrene (0.25 mmol), nickel chloride (0.025 mmol), 4,7-dihydroxy-1,10-phenanthroline (0.050 mmol), and manganese powder (0.50 mmol) were added to a 10 mL Schlenk reaction tube and stirred in N-methylpyrrolidone (2 mL) while maintaining a CO pressure of 0.10 MPa. 2 The mixture was stirred at 40°C for 24 hours, and then diluted hydrochloric acid (4.0 mL) was added and stirred for 1 hour to complete the reaction. The reaction mixture was extracted with dichloroethane (3.0 mL × 4 times). The organic phase was distilled under reduced pressure to recover the organic solvent to obtain a 2-phenylpropionic acid liquid product. GC analysis with naphthalene as the internal standard showed that the yield of 2-phenylpropionic acid was 43.8%.

[0054] The above contents are merely examples and explanations of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the structure of the present invention or exceed the scope defined by the claims, they shall all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel, characterized in that: The method comprises the following steps: adding styrene, a nickel compound, an organic ligand and manganese into a reactor, reacting them with carbon dioxide in an organic solvent medium at a certain temperature and pressure, then adding dilute hydrochloric acid and stirring at room temperature to complete the reaction, extracting the reaction mixture with an organic extractant to separate an organic phase, and distilling the organic solvent of the organic phase under reduced pressure to obtain 2-phenylpropionic acid.

2. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The nickel compound is one of nickel chloride, nickel bromide, nickel iodide, nickel nitrate, nickel sulfate, nickel acetate and nickel acetylacetonate.

3. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The organic ligand is one of alkyl zinc, 2,2'-bipyridine, 4,4'-bipyridine, 2-methyl-4,4'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, and 4,7-dihydroxy-1,10-phenanthroline.

4. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The molar ratio of the nickel compound to styrene is 0.01-1.1:

1.

5. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The molar ratio of the organic ligand to styrene is 0.01-0.30:

1.

6. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The molar ratio of manganese to styrene is 0.1 to 3:

1.

7. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The molar ratio of the nickel compound to the organic ligand is 0.5-2:

1.

8. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The organic solvent is one or more of N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, ethanol, propanol, butanol and water; the organic extractant is dichloromethane or ethyl acetate; and a solution pH regulator is added to the reaction system.

9. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The reaction temperature is from room temperature to 100° C., the reaction pressure is from normal pressure to 2.0 MPa, and the reaction time is 8 to 30 hours.

10. The method for synthesizing 2-phenylpropionic acid by reacting styrene and carbon dioxide catalyzed by nickel according to claim 1, characterized in that: The specific operation of the reduced pressure distillation is to place the organic phase into a distillation reactor, start the vacuum pump and slowly heat and boil, and the organic extractant and the organic solvent are passed through a condenser into a corresponding solvent receiver.

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