A two-step method for synthesizing 2,3,5-trimethylhydroquinone diester

Abstract

The application belongs to the technical field of organic synthesis and relates to a two-step method for synthesizing 2,3,5-trimethyl hydroquinone diester, and the specific steps are as follows: S1: raw materials KIP, solid acid catalyst and liquid strong acid catalyst are mixed in a reaction kettle, after being warmed, acylation reagent A is added dropwise for reaction, an intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is prepared by reaction, the reaction is stopped when the content of the raw material is lower than 0.5%, after the reaction is completed, unreacted acylation reagent and solid acid catalyst are recovered, and the oil phase containing the intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is separated and enters the next step; S2: liquid strong acid catalyst is added to the oil phase, acylation reagent B is added dropwise for reaction, when the content of the intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is lower than 0.5%, unreacted acylation reagent is recovered to obtain a crude product, then petroleum ether is added to the crude product for washing, and 2,3,5-trimethyl hydroquinone diester is obtained.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to the synthesis of the organic intermediate 2,3,5-trimethylhydroquinone diester, specifically to a two-step method for synthesizing 2,3,5-trimethylhydroquinone diester. Background Technology

[0002] 2,3,5-Trimethylhydroquinone diester (TMHQ-DA) is an important intermediate in the preparation of vitamin E. It can react directly with isophytol to form vitamin acetate, or it can be hydrolyzed to trimethylhydroquinone, making it a crucial intermediate in the synthesis of vitamin E. Furthermore, 2,3,5-Trimethylhydroquinone diester is widely used as an antioxidant. Therefore, the industrial production of 2,3,5-Trimethylhydroquinone diester has significant application and economic value.

[0003] Currently, several methods have been reported for synthesizing 2,3,5-trimethylhydroquinone diester. For example, CN1420859A and US5955628 describe a method that uses protic acids or Lewis acids as catalysts (such as sulfuric acid, nitric acid, and hydrochloric acid) to catalyze the reaction of KIP and acetic anhydride to prepare TMHQ-DA. This method not only uses a large amount of acid, causing significant corrosion to equipment, but also has a low yield (66%). The main byproduct is the formation of 3,4,5-trimethylpyrocatechol diester.

[0004]

[0005] Patents CN1102138C and CN1420859 use trifluoromethanesulfonic acid and polyphosphoric acid as catalysts to catalyze the reaction of KIP and acetic anhydride to prepare TMHQ-DA. This method easily forms acid mist, requires highly sophisticated equipment, and still results in low yields. The byproduct remains 3,4,5-trimethylpyrocatechol diester.

[0006] Patent CN111392390A describes the rearrangement of 2,3,5-trimethylhydroquinone diester via a modified cyclodextrin-supported solid acid catalysis. However, the catalyst used in this method is expensive and can only be reused a limited number of times, resulting in a yield of only about 85%. Therefore, the cost is high, making it unsuitable for industrial production. The main byproduct is 3,4,5-trimethylpyrocatechin diester.

[0007] Patent CN1886361A uses trivalent indium salt as a catalyst to catalyze the reaction of KIP and acetic anhydride to prepare TMHQ-DA, which can increase the yield to 90%. However, the catalyst used in this method is expensive and easily pollutes the environment. Its main byproduct is still 3,4,5-trimethylpyrocatechol diester.

[0008] Patent CN100374408C uses trifluoromethanesulfonyl salts with NH and CH groups as catalysts to catalyze the preparation of TMHQ-DA from KIP and acetic anhydride. The yield of this method is 85%, and the byproduct is still 3,4,5-trimethylpyrocatechol diester. Moreover, the catalyst trifluoromethanesulfonate is expensive, which is not conducive to industrial production.

[0009] As described in the aforementioned patents, the yield of TMHQ-DA prepared by the reaction of KIP and acetic anhydride is between 65% and 90%, often accompanied by side reactions. The generated 3,4,5-trimethylpyrocatechol diester (TMBC-DA) affects the reaction yield, increases the reaction residue ratio, and leads to significant economic losses. Because TMBC-DA has similar properties to the product, its purification is difficult. As a byproduct, it cannot be separated by distillation and is generally separated by recrystallization, which significantly reduces the yield. Therefore, reducing the amount of the byproduct 3,4,5-trimethylpyrocatechol diester (TMBC-DA) has become a key research focus for various companies. Summary of the Invention

[0010] To address the shortcomings of existing technologies, the present invention aims to provide a two-step method for synthesizing 2,3,5-trimethylhydroquinone diester. The starting material KIP undergoes a two-step reaction to synthesize TMHQ-DA. In the first step, an esterification reaction is performed to generate an acylated 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate, which then undergoes an acylation-rearrangement reaction to generate the product TMHQ-DA. This invention can significantly reduce the amount of the byproduct TMBC-DA and significantly improve the selectivity and yield of TMHQ-DA.

[0011] This invention is achieved through the following technical solution:

[0012] A two-step method for synthesizing 2,3,5-trimethylhydroquinone diester includes the following steps:

[0013] S1: Raw material KIP, solid acid catalyst and liquid strong acid catalyst are mixed in a reactor. After heating, acylation reagent A is added dropwise to carry out the reaction. The reaction prepares intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate. The reaction is stopped when the raw material content is less than 0.5%. After the reaction is completed, the unreacted acylation reagent and solid acid catalyst are recovered. The oil phase containing intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is separated and proceeded to the next step.

[0014] S2: Add a liquid strong acid catalyst to the oil phase, and add acylation reagent B dropwise to carry out the reaction. When the content of intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is less than 0.5%, recover the unreacted acylation reagent to obtain the crude product. Then, add petroleum ether to the crude product for washing to obtain 2,3,5-trimethylhydroquinone diester.

[0015]

[0016] A further improvement to the present invention is as follows:

[0017] The solid acid catalyst is one or a mixture of two or more of oxalic acid, boric acid, phenylboronic acid or adipic acid.

[0018] Furthermore, the liquid strong acid catalyst is one or a mixture of two or more of sulfuric acid, perchloric acid, nitric acid, fluoroboric acid, hydrochloric acid, or methanesulfonic acid.

[0019] Furthermore, the acylation reagent A is vinyl acetate, isopropyl acetate, or a mixture of both.

[0020] Furthermore, the acylation reagent B is acetic anhydride.

[0021] Furthermore, the amount of solid acid catalyst used in S1 is 0.01% to 5% of the raw material mass, the amount of liquid strong acid catalyst used is 0.001% to 0.05% of the raw material mass, and the amount of liquid strong acid catalyst used in S2 is 0.01% to 0.5% of the raw material mass.

[0022] Furthermore, the molar ratio of the raw material KIP, acylation reagent A, and acylation reagent B is 1:1.0~2.0:1.0~2.0.

[0023] Furthermore, the reaction temperature in S1 is 50~100℃, and the reaction temperature in S2 is -10~30℃.

[0024] The beneficial effects of this invention are as follows:

[0025] This invention divides the reaction into two steps, which can significantly improve the selectivity and yield of TMHQ-DA. After the two-step reaction, the KIP conversion rate is 100%, the TMHQ-DA selectivity is 99%, the final separation yield is 96%, and the content of the byproduct TMBC-DA is as low as 0.2%.

[0026] The present invention has convenient post-processing. After the reaction, the product can be obtained by washing with petroleum ether directly, with a purity of 99%, without recrystallization, which greatly improves production efficiency.

[0027] This invention innovatively uses mixed acids as catalysts, wherein the solid acid catalyst used in the first step of the reaction can be washed out with water and reused, thereby reducing the catalytic cost. Detailed Implementation

[0028] The present invention will now be described in detail with reference to specific embodiments.

[0029] Example 1

[0030] 500g of raw material was added to a reactor, along with 0.1g of boric acid and 0.1g of sulfuric acid. The temperature was raised to 70°C, and 340g of vinyl acetate was added dropwise over 4 hours, maintaining the reactor temperature at approximately 70°C throughout the process. After the addition was complete, the mixture was kept at this temperature for 1-3 hours until the GC content of the raw material was less than 0.5%, at which point the reaction was stopped. After the reaction, excess vinyl acetate was recovered under normal pressure, followed by washing with 100g of water. The water was separated, and the boric acid catalyst was recovered by evaporation of the aqueous phase. 1g of sulfuric acid was added to the oil phase, and the temperature was maintained at 10°C. 400g of acetic anhydride was added dropwise, and the reaction was stopped until the GC content of 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate was less than 0.5%. Acetic anhydride was then recovered under low vacuum, and the oil phase was washed three times with 400g of petroleum ether to obtain 745g of the final product, 2,3,5-trimethylhydroquinone ethyl ester, with a GC content of 99.1% and a yield of 96%. Example 2

[0031] 500g of raw material was added to a reactor, along with 0.1g of oxalic acid and 0.1g of perchloric acid. The temperature was raised to 100°C, and 400g of isopropyl acetate was added dropwise over 4 hours, maintaining the reactor temperature at approximately 100°C throughout the process. After the addition was complete, the mixture was kept at this temperature for 1-3 hours until the GC content of the raw material was less than 0.5%, at which point the reaction was stopped. After the reaction, excess isopropyl acetate was recovered under normal pressure. Then, 100g of water was added for washing, and the water was separated. The oxalic acid catalyst was recovered by evaporation of the aqueous phase. 1g of perchloric acid was added to the oil phase, and the temperature was maintained at -10°C. 450g of acetic anhydride was added dropwise, and the reaction was stopped until the GC content of 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate was less than 0.5%. Acetic anhydride was then recovered under low vacuum. The oil phase was washed three times with 400g of petroleum ether to obtain 714g of the final product, 2,3,5-trimethylhydroquinone ethyl ester, with a GC content of 99.5% and a yield of 92%. Example 3

[0032] 500g of raw material was added to a reactor, along with 0.25g of phenylboronic acid and 0.05g of fluoroboronic acid. The temperature was raised to 80°C, and 360g of isopropyl acetate was added dropwise over 4 hours, maintaining the reactor temperature at approximately 100°C throughout the process. After the addition was complete, the mixture was kept at this temperature for 1-3 hours until the GC content of the raw material was less than 0.5%, at which point the reaction was stopped. After the reaction, excess isopropyl acetate was recovered under normal pressure, followed by washing with 100g of water. The water was separated, and the phenylboronic acid catalyst was recovered by evaporation of the aqueous phase. 0.6g of fluoroboronic acid was added to the oil phase, and the temperature was maintained at 5°C. 470g of acetic anhydride was added dropwise, and the reaction was stopped until the GC content of 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate was less than 0.5%. Acetic anhydride was then recovered under low vacuum, and the oil phase was washed three times with 400g of petroleum ether to obtain 683g of the final product, 2,3,5-trimethylhydroquinone ethyl ester, with a GC content of 99.0% and a yield of 88%. Example 4

[0033] 500g of raw material was added to a reaction vessel, along with 0.2g of adipic acid and 0.05g of methanesulfonic acid. The temperature was raised to 60°C, and 390g of vinyl acetate was added dropwise over 4 hours, maintaining the vessel temperature at approximately 60°C throughout the process. After the addition was complete, the mixture was kept at this temperature for 1-3 hours until the GC content of the raw material was less than 0.5%, at which point the reaction was stopped. After the reaction, excess vinyl acetate was recovered under normal pressure, followed by washing with 100g of water. The water was separated, and the adipic acid catalyst was recovered by evaporation of the aqueous phase. 0.02g of methanesulfonic acid was added to the oil phase, and the temperature was maintained at 15°C. 420g of acetic anhydride was added dropwise, and the reaction was stopped until the GC content of 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate was less than 0.5%. Acetic anhydride was then recovered under low vacuum, and the oil phase was washed three times with 400g of petroleum ether to obtain 720g of the final product, 2,3,5-trimethylhydroquinone ethyl ester, with a GC content of 99.3% and a yield of 92.7%.

[0034] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A two-step method for synthesizing 2,3,5-trimethylhydroquinone diester, characterized in that, Includes the following steps: S1: Raw material KIP, solid acid catalyst and liquid strong acid catalyst are mixed in a reactor. After heating, acylation reagent A is added dropwise to carry out the reaction. The reaction prepares intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate. The reaction is stopped when the raw material content is less than 0.5%. After the reaction is completed, the unreacted acylation reagent and solid acid catalyst are recovered. The oil phase containing intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is separated and proceeded to the next step. S2: Add a liquid strong acid catalyst to the oil phase, and add acylation reagent B dropwise to carry out the reaction. When the content of intermediate 2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl acetate is less than 0.5%, the unreacted acylation reagent is recovered to obtain the crude product. Then, petroleum ether is added to the crude product for washing to obtain 2,3,5-trimethylhydroquinone diester. The solid acid catalyst is one or a mixture of two or more of oxalic acid, phenylboronic acid, or adipic acid. The liquid strong acid catalyst is one or a mixture of two or more of sulfuric acid, perchloric acid, nitric acid, fluoroboric acid, hydrochloric acid, or methanesulfonic acid. The acylation reagent A is vinyl acetate, isopropyl acetate, or a mixture of the two; The acylation reagent B is acetic anhydride; The amount of solid acid catalyst in S1 is 0.01% to 5% of the raw material mass, and the amount of liquid strong acid catalyst is 0.001% to 0.05% of the raw material mass. The amount of liquid strong acid catalyst in S2 is 0.01% to 0.5% of the raw material mass.

2. The method for synthesizing 2,3,5-trimethylhydroquinone diester in two steps according to claim 1, characterized in that: The molar ratio of the raw material KIP, acylation reagent A, and acylation reagent B is 1:1.0~2.0:1.0~2.

0.

3. The method for synthesizing 2,3,5-trimethylhydroquinone diester in two steps according to claim 1, characterized in that: The reaction temperature in S1 is 50~100℃, and the reaction temperature in S2 is -10~30℃.

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