Preparation method of methyl p-cyanobenzoate

Abstract

The invention relates to a preparation method of methyl p-cyanobenzoate. The preparation method is mainly characterized by comprising the following steps: dissolving p-cyanobenzoic acid, N-methyl-N-nitrosourea and inorganic base in a certain molar ratio in a mixed solvent, uniformly stirring, and reacting for several hours at a certain temperature; and after the reaction is completed, adding hydrochloric acid with a certain concentration to quench a reaction solution, extracting with an organic solvent, washing an organic phase with an alkali solution, concentrating, drying, and recrystallizing (or column chromatography) to obtain methyl p-cyanobenzoate. The method is easy to treat three wastes and is green and environment-friendly; the process is simple and the reaction temperature is low; the product purity is high, the yield is remarkably improved, and the method is suitable for expanded production.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of methyl p-cyanobenzoate, and in particular to a method for preparing green and low-carbon methyl p-cyanobenzoate. Background Art

[0002] Methyl p-cyanobenzoate is a white crystal, soluble in common organic solvents such as ethanol, ether, and chloroform. This product has a wide range of applications in the fields of drug synthesis, pesticides, and materials: in the synthesis of anticancer drugs and anti-epileptic drugs, molecular structures with specific pharmacological activities can be constructed through the transformation of functional groups such as cyano and ester groups; pesticide compounds with high selectivity and high activity against pests or pathogens can be synthesized through combination and modification with other active groups; it can be used to prepare high-performance polymer materials to improve the heat resistance, mechanical strength, and corrosion resistance of polymers.

[0003] At present, the preparation methods of methyl p-cyanobenzoate mainly include the following: Method 1: Using p-cyanobenzoic acid as raw material, it is synthesized by esterification reaction under the catalysis of strong acid such as concentrated sulfuric acid. This method has harsh reaction conditions, concentrated sulfuric acid is highly corrosive and pollutes the environment, and complex post-processing steps such as neutralization and separation are required after the reaction, which is not suitable for industrial production.

[0004] Method 2: Using methyl p-aminobenzoate as raw material, diazotizing the amino group, and then converting the diazo group into a cyano group. This method involves toxic cyanating agents, causing environmental pollution, and requires strict safety protection measures during operation, which brings great difficulties to industrial production.

[0005] Method 3: Using methyl p-bromobenzoate and sodium cyanide as raw materials, methyl p-cyanobenzoate is produced through cyanation coupling reaction under the action of transition metal catalyst. The catalyst of this method is expensive, and the reaction system has strict requirements on reaction temperature, ligand, etc.

[0006] In summary, the current synthesis method of methyl p-cyanobenzoate has the problems of using highly corrosive or toxic reagents and expensive catalysts, and is not suitable for industrial production.

[0007] The invention provides a green and environment-friendly preparation method of methyl p-cyanobenzoate: p-cyanobenzoic acid and N-methyl-N-nitrosourea are used as raw materials to synthesize methyl p-cyanobenzoate, the process has few side reactions, is environmentally friendly, has high product purity, and has a very high yield, which can reach up to 98.6%. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing methyl p-cyanobenzoate. The method is green and low-carbon, and the product has high purity and high yield.

[0009] The technical solution adopted by the present invention is: The methyl p-cyanobenzoate of the present invention is obtained by esterification reaction of p-cyanobenzoic acid and N-methyl-N-nitrosourea as raw materials, and the specific steps are as follows: (1) Dissolve a certain molar ratio of p-cyanobenzoic acid, N-methyl-N-nitrosourea and inorganic base in a mixed solvent and stir evenly; (2) reacting the solution in step (1) at a certain temperature for several hours; (3) After the reaction in step (2) is completed, a hydrochloric acid solution of a certain concentration is added to quench the reaction solution; (4) extracting the solution from step (3) with an organic solvent; (5) washing the organic phase from step (4) with an alkaline solution; (6) The organic phase from step (5) is dried and concentrated, and then recrystallized (or column chromatographed) to obtain methyl p-cyanobenzoate.

[0010] Preferably, in step (1), the molar ratio of p-cyanobenzoic acid and N-methyl-N-nitrosourea is 1:1 to 1:2; Preferably, in step (1), the inorganic base is one of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; Preferably, in step (1), the molar ratio of p-cyanobenzoic acid to the inorganic base is 1:1 to 1:5; Preferably, in step (1), the mixed solvent is one of 1,4-dioxane+water, tetrahydrofuran+water, and acetonitrile+water; wherein the volume ratio of 1,4-dioxane to water is 5:1-1:1; the volume ratio of tetrahydrofuran to water is 5:1-1:1; the volume ratio of acetonitrile to water is 5:1-1:1; Preferably, in step (2), the reaction temperature is between 10°C and 28°C; Preferably, in step (2), the reaction time is 3 hours to 6 hours; Preferably, in step (3), the concentration of the hydrochloric acid solution is 0.05M~0.3M; Preferably, in step (4), the organic solvent is one of ethyl acetate, dichloromethane and diethyl ether; Preferably, in step (5), the alkaline solution is one of saturated sodium carbonate solution, saturated sodium bicarbonate solution, and 8% sodium hydroxide solution.

[0011] The main advantages of the present invention are: (1) Methyl p-cyanobenzoate is synthesized using p-cyanobenzoic acid and N-methyl-N-nitrosourea as raw materials, wherein N-methyl-N-nitrosourea is used as a diazomethane precursor, and diazomethane is generated in situ through a "one-pot method" to participate in the reaction, thereby avoiding the preparation and separation of highly toxic and explosive diazomethane, making the three wastes easy to treat and being green and environmentally friendly; (2) The process is simple and does not require high temperature, high pressure or other reaction conditions; (3) Suitable for large-scale production. After concentration and drying, no further purification is required. High-purity products can be obtained by recrystallization, with the highest purity reaching 97.8%; (4) The product yield is greatly improved, reaching up to 98.6%. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The methyl p-cyanobenzoate prepared in Example 1 of the present invention 1 H NMR spectra; Figure 2 The methyl p-cyanobenzoate prepared in Example 1 of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0013] In order to illustrate the features of the present invention in more detail, the present invention is further described below through specific implementation examples, but the scope of the present invention is not limited.

[0014] Embodiment 1: To a 10ml reaction tube, add p-cyanobenzoic acid (73.6mg; 0.5mmol), N-methyl-N-nitrosourea (0.103g; 1.0mmol), sodium carbonate (0.106g; 1.0mmol) and a mixed solvent (2ml of 1,4-dioxane + 0.5ml of water), and stir the reaction mixture at 28°C for 3 hours. After the reaction is completed, add 3ml of 0.1M hydrochloric acid to quench the reaction solution, extract with 20ml of ethyl acetate, wash the organic phase with saturated sodium bicarbonate solution, dry and concentrate the organic phase, and obtain 79.5mg of high-purity target product by column chromatography, with a purity of 97.2% and a yield of 98.6%. The NMR data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ8.18 – 8.08 (m, 2H), 7.79 – 7.69 (m, 2H), 3.96 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 165.4, 133.9, 132.2, 130.0, 117.9, 116.3, 52.7 ppm.

[0015] Embodiment 2: To a 10 ml reaction tube, p-cyanobenzoic acid (73.6 mg; 0.5 mmol), N-methyl-N-nitrosourea (51.5 mg; 0.5 mmol), potassium phosphate (0.318 g; 1.5 mmol) and a mixed solvent (1.5 ml of acetonitrile + 1.0 ml of water) were added in sequence, and the reaction mixture was stirred at 22°C for 3 hours. After the reaction was completed, 3 ml of 0.2 M hydrochloric acid was added to quench the reaction solution, and 20 ml of ethyl acetate was used for extraction. The organic phase was washed with a saturated sodium carbonate solution, dried and concentrated, and column chromatography was performed to obtain 79.1 mg of a high-purity target product with a purity of 97.8% and a yield of 92.3%.

[0016] Embodiment 3: To a 100 ml round-bottom flask, p-cyanobenzoic acid (0.736 g; 5 mmol), N-methyl-N-nitrosourea (0.618 g; 6 mmol), potassium phosphate (2.55 g; 12 mmol) and a mixed solvent (15 ml of tetrahydrofuran + 5 ml of water) were added in sequence, and the reaction mixture was stirred at 12°C for 6 hours. After the reaction was completed, 30 ml of 0.05 M hydrochloric acid was added to quench the reaction solution, and 50 ml of ethyl acetate was used for extraction. The organic phase was washed with a saturated sodium bicarbonate solution, and the organic phase was concentrated and dried without further purification. Recrystallization can obtain 0.786 g of high-purity target product with a purity of 96.9% and a yield of 95.1%.

[0017] Embodiment 4: To a 500ml round-bottom flask, p-cyanobenzoic acid (3.68g; 25mmol), N-methyl-N-nitrosourea (3.09g; 30mmol), sodium carbonate (6.36g; 60mmol) and a mixed solvent (1,4-dioxane 90ml + water 60ml) were added in sequence, and the reaction mixture was stirred at 18°C ​​for 4 hours. After the reaction was completed, 120ml of 0.1M hydrochloric acid was added to quench the reaction solution, and 200ml of ethyl acetate was used for extraction. The organic phase was washed with a saturated sodium bicarbonate solution, and the organic phase was concentrated and dried without further purification. Recrystallization can obtain 3.96g of high-purity target product with a purity of 97.5% and a yield of 98.3%.

Claims

1. A method for preparing methyl p-cyanobenzoate. It is characterized by: (1) dissolving a certain molar ratio of p-cyanobenzoic acid, N-methyl-N-nitrosourea and inorganic base in a mixed solvent and stirring evenly; (2) reacting the solution in step (1) at a certain temperature for several hours; (3) After the reaction in step (2) is completed, a hydrochloric acid solution of a certain concentration is added to quench the reaction solution; (4) extracting the solution from step (3) with an organic solvent; (5) washing the organic phase from step (4) with an alkaline solution; (6) The organic phase from step (5) is concentrated and dried, and then recrystallized (or column chromatographed) to obtain methyl p-cyanobenzoate.

2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of p-cyanobenzoic acid to N-methyl-N-nitrosourea is 1:1 to 1:

2.

3. The preparation method according to claim 1, characterized in that: In step (1), the inorganic base is one of sodium carbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

4. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of p-cyanobenzoic acid to the inorganic base is 1:1 to 1:

5.

5. The preparation method according to claim 1, characterized in that: In step (1), the mixed solvent is one of 1,4-dioxane+water, tetrahydrofuran+water, and acetonitrile+water; wherein the volume ratio of 1,4-dioxane to water is 5:1-1:1; the volume ratio of tetrahydrofuran to water is 5:1-1:1; and the volume ratio of acetonitrile to water is 5:1-1:

1.

6. The preparation method according to claim 1, characterized in that: In step (2), the reaction temperature is between 10°C and 28°C.

7. The preparation method according to claim 1, characterized in that: In step (2), the reaction time is 3 hours to 6 hours.

8. The preparation method according to claim 1, characterized in that: In step (3), the concentration of the hydrochloric acid solution is 0.05M~0.3M.

9. The preparation method according to claim 1, characterized in that: In step (4), the organic solvent is one of ethyl acetate, dichloromethane and diethyl ether.

10. The preparation method according to claim 1, characterized in that: In step (5), the alkaline solution is one of saturated sodium carbonate solution, saturated sodium bicarbonate solution, and 8% sodium hydroxide solution.

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