A method for preparing p-hydroxyacetophenone

Abstract

The application discloses a preparation method of p-hydroxyacetophenone, and belongs to the technical field of compound preparation, and discloses the preparation method of p-hydroxyacetophenone, which comprises the following steps: S1, Friedel-Crafts acylation: Friedel-Crafts acylation reaction of chlorobenzene and acetic anhydride is catalyzed by Lewis acid AlCl3, and p-chloroacetophenone is generated in the reaction; S2, substitution: substitution reaction of p-chloroacetophenone occurs in an alkaline aqueous solution environment and under the catalysis of a catalyst, and p-hydroxyacetophenone crude product is obtained by cooling and crystallization, and the crude product is subjected to water system recrystallization to obtain final product. The application has the advantages of friendly reaction environment, high product yield, few by-products and simple process and is easy to be industrialized.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, specifically to a method for preparing p-hydroxyacetophenone. Background Technology

[0002] p-Hydroxyacetophenone (p-HAP) is an important chemical raw material used in the preparation of pharmaceutical intermediates such as synephrine, and it has lipid-lowering effects in medicine. There are several methods for preparing p-hydroxyacetophenone:

[0003] Method 1: Using phenol or anisole as raw materials, phenyl acetate is generated through acetic anhydride or acetyl chloride acylation, followed by a Fries rearrangement reaction catalyzed by anhydrous aluminum trichloride to obtain hydroxyacetophenone. Its disadvantages are that acetyl chloride is easily hydrolyzed, making it difficult to handle and prone to environmental pollution. The yield of p-hydroxyacetophenone is also low (refer to existing technology DE3108076).

[0004] Method 2: Based on Method 1, concentrated sulfuric acid is used as the esterification catalyst, and the rearrangement is catalyzed by the composite catalyst NaCl-AlCl3 to obtain hydroxyacetophenone. This method has a mild reaction and short reaction time, but the overall yield is not high (refer to Journal of Zhengzhou University, 2000, 32(2):89-90).

[0005] Method 3: Using chlorobenzene and acetic anhydride as raw materials, p-chloroacetophenone is prepared under Lewis acid catalysis. Substitution occurs in a strongly alkaline aqueous solution under high temperature and pressure to obtain p-hydroxyacetophenone. This method involves a large excess of chlorobenzene, which needs to be recovered and reused. High-pressure substitution easily leads to side reactions, making the process highly hazardous and difficult to industrialize (refer to existing technology CN109384657A).

[0006] Method 4: Using phenol and acetic anhydride as raw materials and AlCl3 as a catalyst, p-hydroxyacetophenone and o-hydroxyacetophenone are prepared with an overall yield of 90.2% and an o-hydroxyacetophenone content of 80.5%. This method uses chlorobenzene or 1,2-dichloroethane as solvent, reacts at 60–90°C, requires a large excess of AlCl3, and involves complex post-processing (refer to existing technology CN 1119639A). Summary of the Invention

[0007] In order to solve the above-mentioned technical problems, the purpose of this invention is to provide an environmentally friendly method for preparing p-hydroxyacetophenone with high product yield, few by-products, and simple and easily industrialized process.

[0008] To achieve the above objectives, the present invention provides the following technical solution: the preparation method includes the following steps:

[0009] S1. Friedel-Crafts acylation: Chlorobenzene and acetic anhydride undergo a Friedel-Crafts acylation reaction catalyzed by Lewis acid AlCl3 to produce p-chloroacetophenone; the solvent used in the Friedel-Crafts acylation reaction is polyethylene glycol 400;

[0010] S2. Substitution: p-Chloroacetophenone undergoes a substitution reaction in an alkaline aqueous solution environment under the catalysis of a catalyst. After cooling and crystallization, crude p-hydroxyacetophenone is obtained. The crude product is recrystallized in an aqueous system to obtain the final product. The catalyst is CuCl or Cu2O.

[0011] Preferably, the amount of chlorobenzene fed in S1 is 1.1-1.5 eq, with acetic anhydride as a reference.

[0012] Preferably, the amount of polyethylene glycol 400 in S1 is 3-5 times that of acetic anhydride.

[0013] Preferably, the molar ratio of AlCl3 to acetic anhydride in S1 is 1.1.

[0014] Preferably, the Friedel-Crafts acylation reaction in S1 is programmed to be heated to 50-80°C.

[0015] Preferably, the molar ratio of the catalyst to acetic anhydride in S2 is 0.011.

[0016] Preferably, the substitution reaction temperature in S2 is 150-180°C.

[0017] Compared with existing technologies, the advantages of this invention are as follows: This invention first involves a Friedel-Crafts acylation reaction. Chlorobenzene and acetic anhydride undergo Friedel-Crafts acylation under the catalysis of Lewis acid AlCl3, producing p-chloroacetophenone. Then, p-chloroacetophenone undergoes a substitution reaction in an alkaline aqueous solution environment under the catalysis of a catalyst. Cooling and crystallization yield crude p-hydroxyacetophenone, which is then recrystallized in an aqueous system to obtain the final product. In this invention, the addition of the green solvent polyethylene glycol 400 during the Friedel-Crafts acylation reaction significantly reduces the amount of traditional solvent chlorobenzene used, making it environmentally friendly. Furthermore, the substitution reaction catalyst uses CuCl or Cu2O, converting the high-pressure reaction to an atmospheric-pressure reaction, reducing equipment requirements and the risk factor. This invention is environmentally friendly, has a high product yield, few byproducts, and a simple process that is easily industrialized. Attached Figure Description

[0018] Figure 1 This is a synthetic route diagram for the present invention.

[0019] Figure 2 This is the HPLC chromatogram of p-hydroxyacetophenone of the present invention. Detailed Implementation

[0020] 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, and 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.

[0021] Comparative Example 1: 337 g (3 eq) of chlorobenzene was added to a 1 L four-necked flask. While stirring, 147 g (1.1 eq) of aluminum trichloride was slowly added. At 25 °C, 102 g (1 eq, 1.0 mol) of acetic anhydride was added dropwise, with the temperature ≤40 °C, and the addition was completed in approximately 2 hours. The temperature was then raised to 80 °C and maintained for 3.5 hours. The chlorobenzene concentration was maintained at 2.6% (HPLC). With extended holding time, the chlorobenzene concentration was maintained at ≥2.5% (HPLC). After the reaction was complete, 122.0 g of p-chloroacetophenone (78.9% yield) and 7.4 g of o-chloroacetophenone (4.8% yield) were obtained.

[0022] Comparative Example 2: 123.8 g (1.1 eq) of chlorobenzene was added to a 1 L four-necked flask. While stirring, 147 g (1.1 eq) of aluminum trichloride and 500 g of polyethylene glycol 800 were slowly added. At 25 °C, 102 g (1 eq, 1.0 mol) of acetic anhydride was added dropwise, with the temperature ≤40 °C, over approximately 2 hours. The temperature was then raised to 80 °C and maintained for 2.5 hours. The chlorobenzene content was controlled to be ≤0.8% (HPLC). After the reaction was complete, 132.8 g of p-chloroacetophenone (85.9% yield) and 9.3 g of o-chloroacetophenone (6.0% yield) were obtained.

[0023] Example 1: 123.8 g (1.1 eq) of chlorobenzene was added to a 1 L four-necked flask. While stirring, 147 g (1.1 eq) of aluminum trichloride and 500 g of polyethylene glycol 400:acetic anhydride (5 times the mass of acetic anhydride) were slowly added. At 25°C, 102 g (1 eq, 1.0 mol) of acetic anhydride was added dropwise, with the temperature ≤40°C, over approximately 2 hours. The temperature was then raised to 80°C and maintained for 1.5 hours. The chlorobenzene concentration was controlled to be ≤0.5% (HPLC). The reaction was then complete, yielding 134.3 g of p-chloroacetophenone (86.9% yield) and 9.4 g of o-chloroacetophenone (6.1% yield).

[0024] The mixture was cooled to 50℃, and 80g of 32% liquid alkali and 1.1g of CuCl were added. The mixture was then heated to 160℃ in an oil bath and stirred for 1 hour until substitution was complete. The mixture was cooled to 60℃, and 150g of water was added. The pH of the system was adjusted to 4 with 31% hydrochloric acid. Crystallization was carried out at 0-5℃, and the mixture was stirred for 0.5 hours before filtration. The filter cake was washed with 50g of ice water to obtain crude p-hydroxyacetophenone. 250g of water was added to the crude product, and the mixture was heated until dissolved. After cooling, crystallization was observed to obtain 131.2g of the final product, p-hydroxyacetophenone, with a yield of 96.4% and a purity of 99.68%.

[0025] Example 2: 123.8 g (1.1 eq) of chlorobenzene was added to a 1 L four-necked flask. While stirring, 147 g (1.1 eq) of aluminum trichloride and 500 g of polyethylene glycol 400 (5 times the mass of acetic anhydride) were slowly added. At 25°C, 102 g (1 eq, 1.0 mol) of acetic anhydride was added dropwise, with the temperature ≤40°C during the addition, which was completed in approximately 2 hours. The temperature was then raised to 50°C, increasing by 10°C every 0.5 hours. Once the system temperature reached 80°C, it was maintained at this temperature for 1 hour. The chlorobenzene content was controlled to be ≤0.5% (HPLC). The reaction was then complete, yielding 135.0 g of p-chloroacetophenone (87.3% yield) and 9.5 g of o-chloroacetophenone (6.1% yield).

[0026] The mixture was cooled to 50°C, and 80g of 32% liquid alkali and 1.1g of CuCl were added. The mixture was then heated to 160°C in an oil bath and stirred for 1 hour until substitution was complete. The mixture was cooled to 60°C, and 150g of water was added. The pH of the system was adjusted to 4 with 31% hydrochloric acid. Crystallization was carried out at 0-5°C, and the mixture was stirred for 0.5 hours before filtration. The filter cake was washed with 50g of ice water to obtain crude p-hydroxyacetophenone. 250g of water was added to the crude product, and the mixture was heated until dissolved. After cooling, crystallization was observed to obtain 134.2g of the final product, p-hydroxyacetophenone, with a yield of 98.6% and a purity of 99.7%.

[0027] Example 3: 123.8 g (1.1 eq) of chlorobenzene was added to a 1 L four-necked flask. While stirring, 147 g (1.1 eq) of aluminum trichloride and 500 g of polyethylene glycol 400:acetic anhydride (5 times the mass of acetic anhydride) were slowly added. At 25°C, 102 g (1 eq, 1.0 mol) of acetic anhydride was added dropwise, with the temperature ≤40°C during the addition, which was completed in approximately 2 hours. The temperature was then raised to 50°C, increasing by 10°C every 0.5 hours. Once the system temperature reached 80°C, it was maintained at this temperature for 1 hour. The chlorobenzene content was controlled to be ≤0.5% (HPLC). The reaction was then complete, yielding 135.3 g of p-chloroacetophenone (87.5% yield) and 9.5 g of o-chloroacetophenone (6.1% yield).

[0028] The mixture was cooled to 50°C, and 80g of 32% liquid alkali and 1.6g of Cu₂O were added. The mixture was then heated to 160°C in an oil bath and stirred for 1 hour until substitution was complete. The mixture was cooled to 60°C, and 150g of water was added. The pH of the system was adjusted to 4 with 31% hydrochloric acid. Crystallization was carried out at 0-5°C, and the mixture was stirred for 0.5 hours before filtration. The filter cake was washed with 50g of ice water to obtain crude p-hydroxyacetophenone. 250g of water was added to the crude product, and the mixture was heated until dissolved. After cooling, crystallization was observed to obtain 135.0g of the final product, p-hydroxyacetophenone, with a yield of 99.1% and a purity of 99.7%.

[0029] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing p-hydroxyacetophenone, characterized in that: The preparation method includes the following steps: S1. Friedel-Crafts acylation: Chlorobenzene and acetic anhydride undergo a Friedel-Crafts acylation reaction catalyzed by Lewis acid AlCl3 to produce p-chloroacetophenone; the solvent used in the Friedel-Crafts acylation reaction is polyethylene glycol 400; S2. Substitution: p-Chloroacetophenone undergoes a substitution reaction in an alkaline aqueous solution environment under the catalysis of a catalyst. After cooling and crystallization, crude p-hydroxyacetophenone is obtained. The crude product is recrystallized in an aqueous system to obtain the final product. The catalyst is CuCl or Cu2O.

2. The method for preparing p-hydroxyacetophenone according to claim 1, characterized in that: The amount of chlorobenzene fed in S1 is 1.1-1.5 eq, with acetic anhydride as a reference.

3. The method for preparing p-hydroxyacetophenone according to claim 1, characterized in that: The amount of polyethylene glycol 400 added in S1 is 3-5 times that of acetic anhydride.

4. The method for preparing p-hydroxyacetophenone according to claim 1, characterized in that: The molar ratio of AlCl3 to acetic anhydride in S1 is 1.

1.

5. The method for preparing p-hydroxyacetophenone according to claim 1, characterized in that: The Friedel-Crafts acylation reaction described in S1 is programmed to be heated to 50-80°C.

6. The method for preparing p-hydroxyacetophenone according to claim 1, characterized in that: The molar ratio of the catalyst to acetic anhydride in S2 is 0.

011.

7. The method for preparing p-hydroxyacetophenone according to claim 1, characterized in that: The substitution reaction temperature described in S2 is 150-180℃.

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