Esterification and rearrangement reaction method of phenols and acylating agent

Abstract

The invention discloses an esterification and rearrangement reaction method of phenols and an acylating agent, and belongs to the technical field of chemical synthesis.The method comprises the steps that an amido phenol compound and the acylating agent serve as raw materials, trifluoromethanesulfonic acid is added to serve as a catalyst, the pH of reaction liquid is controlled, reaction is conducted at low temperature, and ester is formed; and adding Lewis acid, carrying out rearrangement reaction under acidic heating conditions, and extracting and recrystallizing after the reaction to obtain the phenolic ketone compound. According to the reaction method provided by the invention, trifluoromethanesulfonic acid and lewis acid are combined to control the selectivity of the reaction, the yield of the final product phenolic ketone compound is improved, a one-pot process for esterification and rearrangement of phenols and acylating agents is realized, and the reaction flow is simplified.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to an esterification and rearrangement reaction method of phenols and an acylating agent. Background Art

[0002] Ketone derivatives are a very important class of carbonyl compounds and are extremely important starting materials in organic synthesis reactions. Among them, phenolic ketones are widely used in the fields of pesticides, medicines, dyes, plastics, etc. Therefore, research on the preparation of phenolic ketone compounds has received widespread attention. The commonly used synthesis route is: first, phenolic compounds are reacted with acyl chlorides or acid anhydrides under the catalysis of bases to form esters (acylation reaction), and then the esterification products are heated with Lewis acid or Bronsted acid to cause acyl rearrangement to form a mixture of o-hydroxy or p-hydroxy aromatic ketones (Fries rearrangement).

[0003] The patent application document with publication number CN113527123A discloses a photochemical Fries rearrangement synthesis of a beta-receptor blocker Acebutolol intermediate, which prepares 2-acetyl-4-n-butyrylaminophenol through a two-step reaction. First, p-aminophenol and n-butyric anhydride are used to form a phenol salt under alkaline conditions, acetic anhydride is added dropwise to form an ester, and recrystallization is performed to form the first-step product N-(4-acetoxyphenyl)butyramide. Then, a photochemical Fries liquid phase rearrangement reaction is performed, and the first-step product is subjected to Fries rearrangement under ultraviolet-visible light irradiation to obtain 2-acetyl-4-n-butyrylaminophenol after recrystallization. Although the reagents used in the process of this method are green and environmentally friendly, the maximum yield of 2-acetyl-4-n-butyrylaminophenol is only 78.9%, and the yield is difficult to meet production needs. Summary of the invention

[0004] The object of the present invention is to provide a method for esterification and rearrangement reaction of phenols and acylating agents, which simplifies the reaction process and improves the yield.

[0005] The purpose of the present invention can be achieved through the following technical solutions: The present invention provides a method for esterification and rearrangement of phenols and an acylating agent, comprising the following steps: Step 1, dissolving an amide phenol compound in an organic solvent, adding trifluoromethanesulfonic acid, controlling the pH to 5-6, and mixing uniformly to form a reaction solution; Step 2: adding an acylating agent to an organic solvent to form a mixed solution, controlling the temperature of the reaction solution to 10-30° C. in a water bath, adding the mixed solution dropwise to the reaction solution under constant temperature stirring, and reacting under constant temperature reflux for 2-5 hours after the addition is completed; Step 3: After the reaction is completed, Lewis acid is added according to the molar ratio of amide phenol compound to Lewis acid of 1:2-4, an acidic reagent is added to adjust the pH to 2-3, the temperature is raised to 100-130°C, the reaction is carried out at a constant temperature for 1-3h, the solvent is recovered by vacuum distillation, and the product is naturally cooled to 30°C; Step 4: extract the cooled product to obtain an organic phase, evaporate the extractant, and use petroleum ether to recrystallize to obtain phenolic ketone compounds.

[0006] Furthermore, the structural formula of the amide phenol compound is: , Among them, R 1 It is an alkyl group having 1 to 3 carbon atoms.

[0007] Furthermore, the organic solvent is one of chloroform, ethyl acetate, chlorobenzene and toluene.

[0008] Furthermore, the Lewis acid is one of aluminum trichloride, zinc dichloride and tin tetrachloride.

[0009] Furthermore, in step 2, the mixed solution is added dropwise to the reaction solution at a molar ratio of the acylating agent to the amide phenol compound of 1-1.05:1; The acylating agent is an acid anhydride or an acid chloride, and the structural formula of the acid anhydride is: , The structural formula of acyl chloride is: , Among them, R 2 It is an alkyl group having 1 to 4 carbon atoms.

[0010] Furthermore, the acidic reagent is one of acetic acid, propionic acid and n-butyric acid.

[0011] Furthermore, in step 4, the extraction agent used in the extraction is a mixture of petroleum ether and water, and the volume ratio of petroleum ether to water in the mixture is (1-2): (3-4).

[0012] Furthermore, in step 4, the volume ratio of the product to the extractant in the extraction is (7-9): (1-3).

[0013] Furthermore, the structural formula of the phenolic ketone compound is: , Among them, R 1 is an alkyl group having 1 to 3 carbon atoms, R 2 It is an alkyl group having 1 to 4 carbon atoms.

[0014] Beneficial effects of the present invention: The present invention adjusts the amount of trifluoromethanesulfonic acid added to the reaction solution to ensure that the pH value is in the range of 5-6, and realizes a highly selective O-acylation reaction in amide-phenol compounds under low temperature (i.e., 10-30°C), and the acyl ions react with the hydroxyl groups on the phenol to form ester compounds, and then Lewis acid is added as a rearrangement catalyst. Under high temperature (i.e., 100-130°C), the Lewis acid increases the activity of the carbon ortho position of the hydroxyl group on the aromatic ring, thereby improving the efficiency of the rearrangement reaction. The reaction method provided by the present invention combines trifluoromethanesulfonic acid and Lewis acid to control the selectivity of the reaction, improves the yield of the final product phenolic ketone compounds, realizes the one-pot process of esterification and rearrangement of phenols and acylating agents, and simplifies the reaction process. DETAILED DESCRIPTION

[0015] The following will be combined with 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.

[0016] Example 1

[0017] Preparation of 2-acetyl-4-n-butyramidophenol: Step 1, dissolving p-butyrylaminophenol in chlorobenzene at a concentration of 1 mol / L, adding trifluoromethanesulfonic acid, controlling the pH to 5, and mixing uniformly to form a reaction solution; Step 2: Add acetyl chloride to chlorobenzene at a concentration of 1 mol / L to form a mixed solution; control the temperature of the reaction solution prepared in step 1 to be 15° C. in a water bath; add the mixed solution dropwise at a molar ratio of acetyl chloride to p-butyrylaminophenol of 1:1 under constant temperature stirring conditions; and after the addition is completed, reflux at a constant temperature for 3 hours; Step 3: After the reaction is completed, aluminum chloride is added in a molar ratio of p-butyrylaminophenol to aluminum chloride of 1:2, acetic acid is added to adjust the pH to 3, the temperature is raised to 130°C, the reaction is carried out at a constant temperature for 1 hour, the solvent is recovered by vacuum distillation, and the product is naturally cooled to 30°C; Step 4: Add the cooled product to an extractant (a mixture of petroleum ether and water in a volume ratio of 1:4), let stand to obtain a primary organic phase, add the primary organic phase to an extractant (a mixture of petroleum ether and water in a volume ratio of 2:3), let stand to obtain a secondary organic phase, put the secondary organic phase into a rotary evaporator to evaporate and remove the extractant, and use petroleum ether to recrystallize to obtain 2-acetyl-4-n-butyrylaminophenol, which has an appearance of off-white solid and a yield of 87%. The purity reaches 99.5% as determined by high performance liquid chromatography.

[0018] Example 2

[0019] The difference from Example 1 is that the pH in step 1 is controlled to be 5.5, and the other steps and conditions are the same as in Example 1. The obtained 2-acetyl-4-n-butyramidophenol has an appearance of an off-white solid, a yield of 90%, and a purity of 99.6% as determined by high performance liquid chromatography.

[0020] Example 3

[0021] The difference from Example 1 is that the pH in step 1 is controlled to be 6, and the other steps and conditions are the same as in Example 1. The appearance of 2-acetyl-4-n-butyramidophenol obtained is an off-white solid with a yield of 88%. The purity reaches 99.6% as determined by high performance liquid chromatography.

[0022] Example 4

[0023] The difference from Example 2 is that in step 2, the temperature of the reaction solution prepared in step 1 is controlled by a water bath to be 10° C., the constant temperature reflux reaction time is 5 h, and the other steps and conditions are the same as in Example 2. The appearance of the obtained 2-acetyl-4-n-butyramidophenol is an off-white solid with a yield of 93%. The purity is 99.7% as determined by high performance liquid chromatography.

[0024] Example 5

[0025] The difference from Example 2 is that in step 2, the temperature of the reaction solution prepared in step 1 is controlled by a water bath to be 30° C., the constant temperature reflux reaction time is 2 h, and the other steps and conditions are the same as in Example 2. The obtained 2-acetyl-4-n-butyramidophenol has an appearance of an off-white solid, a yield of 86%, and a purity of 99.6% as determined by high performance liquid chromatography.

[0026] Example 6

[0027] The difference from Example 4 is that the molar ratio of p-butyrylaminophenol and aluminum chloride is adjusted to 1:3, and the other steps and conditions are the same as Example 4. The obtained 2-acetyl-4-n-butyrylaminophenol has an appearance of an off-white solid, a yield of 95%, and a purity of 99.6% as determined by high performance liquid chromatography.

[0028] Example 7

[0029] The difference from Example 4 is that the molar ratio of p-butyrylaminophenol and aluminum chloride is adjusted to 1:4, and the other steps and conditions are the same as Example 4. The obtained 2-acetyl-4-n-butyrylaminophenol has an appearance of an off-white solid, a yield of 94%, and a purity of 99.5% as determined by high performance liquid chromatography.

[0030] Example 8

[0031] The difference from Example 6 is that the heating temperature in step three is controlled to be 100° C., the constant temperature reaction time is 3 h, and the other steps and conditions are the same as Example 6. The obtained 2-acetyl-4-n-butyramidophenol has an appearance of off-white solid and a yield of 92%. The purity reaches 99.7% as determined by high performance liquid chromatography.

[0032] Example 9

[0033] The difference from Example 6 is that the heating temperature in step three is controlled to be 120° C., the constant temperature reaction time is 2 h, and the other steps and conditions are the same as Example 6. The obtained 2-acetyl-4-n-butyramidophenol has an appearance of an off-white solid and a yield of 97%. The purity reaches 99.7% as determined by high performance liquid chromatography.

[0034] Example 10

[0035] Preparation of 2-acetyl-4-acetamidophenol: Step 1, dissolving acetaminophen in ethyl acetate at a concentration of 1 mol / L, adding trifluoromethanesulfonic acid, controlling the pH to 5, and mixing uniformly to form a reaction solution; Step 2: Add acetyl chloride to ethyl acetate at a concentration of 1 mol / L to form a mixed solution; control the temperature of the reaction solution prepared in step 1 to be 15° C. in a water bath; add the mixed solution dropwise at a molar ratio of acetyl chloride to acetaminophen of 1:1 under constant temperature stirring conditions; and after the addition is completed, reflux at a constant temperature for 3 hours; Step 3: After the reaction is completed, zinc dichloride is added according to the molar ratio of acetaminophen to zinc dichloride of 1:2, acetic acid is added to adjust the pH to 3, the temperature is raised to 130°C, the reaction is carried out at a constant temperature for 1h, the solvent is recovered by vacuum distillation, and the product is naturally cooled to 30°C; Step 4: Add the cooled product to an extractant (a mixture of petroleum ether and water in a volume ratio of 1:4), and after standing to obtain a primary organic phase, add the primary organic phase to an extractant (a mixture of petroleum ether and water in a volume ratio of 2:3). After standing to obtain a secondary organic phase, the secondary organic phase is placed in a rotary evaporator for evaporation to remove the extractant, and 2-acetyl-4-acetamidophenol is recrystallized from petroleum ether to obtain 2-acetyl-4-acetamidophenol, which has an appearance of an off-white solid and a yield of 85%. The purity of the obtained 2-acetyl-4-acetamidophenol is 99.7% as determined by high performance liquid chromatography.

[0036] Comparative Example 1 Compared with Example 1, trifluoromethanesulfonic acid was not added in this comparative example to control the pH of the reaction solution, and other conditions and steps were the same as in Example 1. The obtained 2-acetyl-4-n-butyramidophenol had an appearance of an off-white solid and a yield of 74.7%. The purity reached 90.3% as determined by high performance liquid chromatography.

[0037] Comprehensive analysis shows that the reaction steps of the embodiments of the present invention are simplified, and compared with the reaction method of the comparative example, the yield is improved. The embodiments control the concentration of the catalyst and the reaction temperature to reduce side reactions and generate products with high selectivity.

[0038] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0039] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for esterification and rearrangement of phenols and acylating agents, characterized in that: The following steps are involved: Step 1, dissolving an amide phenol compound in an organic solvent, adding trifluoromethanesulfonic acid, controlling the pH to 5-6, and mixing uniformly to form a reaction solution; Step 2, adding an acylating agent to an organic solvent to form a mixed solution; controlling the temperature of the reaction solution to 10-30° C. in a water bath, adding the mixed solution dropwise to the reaction solution under constant temperature stirring, and then refluxing at a constant temperature for 2-5 hours after the addition is completed; Step 3: After the reaction is completed, Lewis acid is added according to the molar ratio of amide phenol compound to Lewis acid of 1:2-4, an acidic reagent is added to adjust the pH to 2-3, the temperature is raised to 100-130°C, the reaction is carried out at a constant temperature for 1-3h, the solvent is recovered by vacuum distillation, and the product is naturally cooled to 30°C; Step 4: extract the cooled product to obtain an organic phase, evaporate the extractant, and use petroleum ether to recrystallize to obtain phenolic ketone compounds.

2. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: The structural formula of the amide phenol compound is: ， Wherein, R1 is an alkyl group having 1 to 3 carbon atoms.

3. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: The organic solvent is one of chloroform, ethyl acetate, chlorobenzene and toluene.

4. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: The Lewis acid is one of aluminum trichloride, zinc dichloride and tin tetrachloride.

5. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: In step 2, the mixed solution is added dropwise to the reaction solution in a molar ratio of acylating agent to amide phenol compound of 1-1.05:1; The acylating agent is an acid anhydride or an acid chloride, and the structural formula of the acid anhydride is: ， The structural formula of acyl chloride is: ， Wherein, R2 is an alkyl group having 1 to 4 carbon atoms.

6. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: The acidic reagent is one of acetic acid, propionic acid and n-butyric acid.

7. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: In step 4, the extraction solvent used in the extraction is a mixture of petroleum ether and water, and the volume ratio of petroleum ether to water in the mixture is (1-2): (3-4).

8. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: In step 4, the volume ratio of the product to the extractant in the extraction is (7-9): (1-3).

9. The method for esterification and rearrangement of phenols and acylating agents according to claim 1, characterized in that: The structural formula of the phenolic ketone compound is: ， Wherein, R1 is an alkyl group having 1 to 3 carbon atoms, and R2 is an alkyl group having 1 to 4 carbon atoms.

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