Preparation method of p-hydroxyacetophenone

Abstract

The invention is applied to the technical field of compound preparation, and discloses a preparation method of p-hydroxyacetophenone, which comprises the following steps: S1, Friedel-Crafts acylation: chlorobenzene and acetic anhydride are subjected to Friedel-Crafts acylation reaction under the catalysis of Lewis acid AlCl3 to generate p-chloroacetophenone; s2, substitution: carrying out substitution reaction on p-chloroacetophenone in an alkaline aqueous solution environment under the catalysis of a catalyst, cooling and crystallizing to obtain a p-hydroxyacetophenone crude product, and recrystallizing the crude product through a water system to obtain a final finished product. The method is environment-friendly in reaction, high in product yield, few in by-products, simple in process and easy to industrialize.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of compound preparation, in particular to a preparation method of p-hydroxyacetophenone. BACKGROUND

[0002] p-Hydroxyacetophenone (p-HAP) is an important chemical raw material, which can be used for the preparation of synephrine and other pharmaceutical intermediates, and has the effect of lowering blood lipids in medicine. There are several methods for preparing p-hydroxyacetophenone: Method one: phenol or anisole is used as raw material, acetic anhydride or acetyl chloride is used for acylation reaction to generate phenyl acetate, and then Fries rearrangement reaction is carried out under the catalysis of anhydrous aluminum chloride to obtain hydroxyacetophenone. The disadvantage is that acetyl chloride is prone to hydrolysis, which is difficult to handle and pollutes the environment. The yield of p-hydroxyacetophenone is not high (referring to prior art DE3108076).

[0003] Method two: on the basis of method one, concentrated sulfuric acid is used as esterification catalyst, and a composite catalyst NaCl-AlCl3 is used for rearrangement to obtain hydroxyacetophenone. This method has mild reaction and short time, but the overall yield is not high (referring to Journal of Zhengzhou University, 2000, 32(2): 89-90).

[0004] Method three: chlorobenzene and acetic anhydride are used as raw materials, and p-chloroacetophenone is prepared under the catalysis of Lewis acid. Substitution occurs in strong alkaline solution under high temperature and high pressure to obtain p-hydroxyacetophenone. This method has excessive chlorobenzene, which needs to be recovered and reused. High-pressure substitution is prone to side reactions, and the process has high risk and is difficult to industrialize (referring to prior art CN109384657A).

[0005] Method four: phenol and acetic anhydride are used as raw materials, and AlCl3 is used as catalyst to prepare p-hydroxyacetophenone and o-hydroxyacetophenone. The total yield is 90.2%, and the proportion of o-hydroxyacetophenone is 80.5%. This method uses chlorobenzene or 1,2-dichloroethane as solvent, the reaction temperature is 60-90℃, and AlCl3 is excessive. The post-treatment is complex (referring to prior art CN1119639A). SUMMARY

[0006] In order to solve the above technical problems, the purpose of the present application is to provide a preparation method of p-hydroxyacetophenone, which is environmentally friendly, has high product yield, less by-products, and simple process and is easy to industrialize.

[0007] In order to achieve the above purpose, the present application provides the following technical scheme: the preparation method comprises the following steps: S1. Friedel-Crafts acylation: Friedel-Crafts acylation reaction of chlorobenzene and acetic anhydride under the catalysis of Lewis acid AlCl3, to generate p-chloroacetophenone; the solvent used in the Friedel-Crafts acylation reaction is polyethylene glycol 400; S2. Substitution: substitution reaction of p-chloroacetophenone in an alkaline aqueous solution environment under the catalysis of a catalyst, to obtain p-hydroxyacetophenone crude product by cooling and crystallization, and the crude product is recrystallized in a water system to obtain the final product; the catalyst is CuCl or Cu2O.

[0008] Preferably, the amount of chlorobenzene in S1 is 1.1-1.5 eq, with reference to acetic anhydride.

[0009] Preferably, the amount of polyethylene glycol 400 in S1 is 3-5 times that of acetic anhydride.

[0010] Preferably, the molar ratio of AlCl3 to acetic anhydride in S1 is 1.1.

[0011] Preferably, the temperature of the Friedel-Crafts acylation reaction in S1 is 50-80℃.

[0012] Preferably, the molar ratio of the catalyst to acetic anhydride in S2 is 0.011.

[0013] Preferably, the temperature of the substitution reaction in S2 is 150-180℃.

[0014] Compared with the prior art, the present application has the following beneficial effects: first, the Friedel-Crafts acylation reaction of chlorobenzene and acetic anhydride under the catalysis of Lewis acid AlCl3 generates p-chloroacetophenone, and then the substitution reaction of p-chloroacetophenone in an alkaline aqueous solution environment under the catalysis of a catalyst generates p-hydroxyacetophenone crude product by cooling and crystallization, and the crude product is recrystallized in a water system to obtain the final product. In the present application, green solvent polyethylene glycol 400 is added during the Friedel-Crafts acylation reaction, which greatly reduces the use amount of traditional solvent chlorobenzene and is environmentally friendly. In addition, the substitution reaction catalyst uses CuCl or Cu2O, which converts the high-pressure reaction into a normal-pressure reaction, thereby reducing the equipment requirements and risk coefficient of the reaction. The present application has the advantages of environmentally friendly reaction, high product yield, few by-products, and simple process that is easy to industrialize. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 The synthesis route of the present application is shown in the figure.

[0016] Figure 2 The HPLC spectrum of p-hydroxyacetophenone of the present application is shown in the figure. DETAILED DESCRIPTION

[0017] With reference to the accompanying drawings, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application.

[0018] Comparative Example 1: In a 1L four-necked flask, chlorobenzene 337g (3eq) was added, and aluminum trichloride 147g (1.1eq) was slowly added under stirring. Acetic anhydride 102g (1eq, 1.0mol) was added dropwise at 25℃, and the temperature during the dropwise addition was ≤40℃, and the dropwise addition was completed in about 2 hours. After being warmed to 80℃, the system was kept for 3.5 hours. The content of chlorobenzene was 2.6% (HPLC). The holding time was prolonged, and the content of chlorobenzene was ≥2.5% (HPLC). After the reaction was completed, p-chloroacetophenone 122.0g was obtained with a yield of 78.9%, and o-chloroacetophenone 7.4g was obtained with a yield of 4.8%.

[0019] Comparative Example 2: In a 1L four-necked flask, chlorobenzene 123.8g (1.1eq) was added, and aluminum trichloride 147g (1.1eq) was slowly added under stirring. Polyethylene glycol 800: 500g was added. Acetic anhydride 102g (1eq, 1.0mol) was added dropwise at 25℃, and the temperature during the dropwise addition was ≤40℃, and the dropwise addition was completed in about 2 hours. After being warmed to 80℃, the system was kept for 2.5 hours. The content of chlorobenzene was ≤0.8% (HPLC). After the reaction was completed, p-chloroacetophenone 132.8g was obtained with a yield of 85.9%, and o-chloroacetophenone 9.3g was obtained with a yield of 6.0%.

[0020] Example 1: In a 1L four-necked flask, chlorobenzene 123.8g (1.1eq) was added, and aluminum trichloride 147g (1.1eq) was slowly added under stirring. Polyethylene glycol 400: 500g (5 times the mass of acetic anhydride) was added. Acetic anhydride 102g (1eq, 1.0mol) was added dropwise at 25℃, and the temperature during the dropwise addition was ≤40℃, and the dropwise addition was completed in about 2 hours. After being warmed to 80℃, the system was kept for 1.5 hours. The content of chlorobenzene was ≤0.5% (HPLC). After the reaction was completed, p-chloroacetophenone 134.3g was obtained with a yield of 86.9%, and o-chloroacetophenone 9.4g was obtained with a yield of 6.1%.

[0021] The temperature was lowered to 50℃, 32% liquid alkali 80g was added, CuCl: 1.1g was added, the temperature was raised to 160℃ under an oil bath, and stirring was performed for 1 hour, and the substitution was completed. The temperature was lowered to 60℃, 150g of water was added, the pH of the system was adjusted to 4 with 31% hydrochloric acid, and the product was crystallized at 0-5℃, stirring was performed for 0.5 hours, and the filter cake was washed with ice water 50g, and p-hydroxyacetophenone crude product was obtained. The crude product was dissolved in 250g of water, and the temperature was raised to dissolve, and the product was crystallized to obtain finished p-hydroxyacetophenone 131.2g with a yield of 96.4% and a purity of 99.68%.

[0022] Example 2: In a 1L four-necked flask, add chlorobenzene 123.8g (1.1eq), slowly add aluminum trichloride 147g (1.1eq) under stirring, polyethylene glycol 400: 500g (5 times the mass of acetic anhydride). At 25°C, add acetic anhydride 102g (1eq, 1.0mol) dropwise, the temperature during dropwise addition should be ≤40°C, about 2 hours for dropwise addition. Increase the temperature to 50°C, increase by 10°C every 0.5 hours, after the system temperature reaches 80°C, keep for 1 hour. Control the chlorobenzene ≤0.5% (HPLC), the reaction is completed, get p-chloroacetophenone 135.0g, yield 87.3%; o-chloroacetophenone 9.5g, yield 6.1%.

[0023] Cool to 50°C, add 32% liquid alkali 80g, CuCl: 1.1g, increase the temperature to 160°C under oil bath, stir for 1 hour, substitution is completed. Cool to 60°C, add water 150g, adjust the system pH to 4 with 31% hydrochloric acid, crystallize at 0-5°C, stir for 0.5 hours, suction filtration, rinse the filter cake with ice water 50g, get the crude p-hydroxyacetophenone. Add water 250g to the crude product, increase the temperature to dissolve, cool to crystallize to get the finished product p-hydroxyacetophenone 134.2g, yield 98.6%, purity 99.7%.

[0024] Example 3: In a 1L four-necked flask, add chlorobenzene 123.8g (1.1eq), slowly add aluminum trichloride 147g (1.1eq) under stirring, polyethylene glycol 400: 500g (5 times the mass of acetic anhydride). At 25°C, add acetic anhydride 102g (1eq, 1.0mol) dropwise, the temperature during dropwise addition should be ≤40°C, about 2 hours for dropwise addition. Increase the temperature to 50°C, increase by 10°C every 0.5 hours, after the system temperature reaches 80°C, keep for 1 hour. Control the chlorobenzene ≤0.5% (HPLC), the reaction is completed, get p-chloroacetophenone 135.3g, yield 87.5%; o-chloroacetophenone 9.5g, yield 6.1%.

[0025] Cool to 50°C, add 32% liquid alkali 80g, Cu2O: 1.6g, increase the temperature to 160°C under oil bath, stir for 1 hour, substitution is completed. Cool to 60°C, add water 150g, adjust the system pH to 4 with 31% hydrochloric acid, crystallize at 0-5°C, stir for 0.5 hours, suction filtration, rinse the filter cake with ice water 50g, get the crude p-hydroxyacetophenone. Add water 250g to the crude product, increase the temperature to dissolve, cool to crystallize to get the finished product p-hydroxyacetophenone 135.0g, yield 99.1%, purity 99.7%.

[0026] Although embodiments of the present application have been shown and described, it is to be understood that various modifications, substitutions, alternatives and variations can be made to these embodiments without departing from the principles and spirit of the present application, 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 comprises the following steps: S1. Friedel-Crafts acylation: chlorobenzene and acetic anhydride undergo 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 in the presence of a catalyst, which is cooled and crystallized to obtain a crude p-hydroxyacetophenone. The crude product is then recrystallized from an aqueous system to obtain the final product; the catalyst is CuCl or Cu2O.

2. The method for preparing parahydroxyacetophenone according to claim 1, wherein: The amount of chlorobenzene added 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, wherein: The feeding amount of polyethylene glycol 400 in S1 is 3-5 times that of acetic anhydride.

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

1.

5. The method for preparing p-hydroxyacetophenone according to claim 1, wherein: The Friedel-Crafts acylation reaction described in S1 was subjected to a temperature program of 50-80°C.

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

011.

7. The method for preparing p-hydroxyacetophenone according to claim 1, wherein: The substitution reaction temperature in S2 is 150-180°C.

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