Preparation method of vitamin E acetate

Abstract

The invention discloses a preparation method of vitamin E acetate, which comprises the following steps: taking 2, 3, 5-trimethylhydroquinone diester and isophytol as raw materials, and carrying out catalytic reaction in Lewis acid and a catalytic promoter to synthesize the vitamin E acetate. According to the preparation method, aqueous hydrochloric acid is avoided from being used by adding a catalyst aid, the vitamin E acetate can be prepared in one step through reaction, meanwhile, the content of key impurities A and B can be obviously reduced, and the content of product impurities A + B is low.

Description

Technical Field

[0001] This invention belongs to the field of vitamin preparation, and specifically relates to a method for preparing vitamin E acetate. Background Technology

[0002] Vitamin E acetate is a form of vitamin E, a fat-soluble vitamin. Its hydrolysis product is tocopherol (vitamin E), which is commonly used as a nutrient and antioxidant with many important functions. Numerous studies have shown that vitamin E and its esterified derivatives have equivalent biological activities. Vitamin E has effects such as treating infertility, anti-oxidation, tumor prevention, wound healing, enhancing immune function, and preventing cardiovascular and cerebrovascular diseases. It can also enhance the body's anti-fatigue ability and oxygen transport capacity during exercise. Due to its unique stability and ester solubility, vitamin E acetate has broad application prospects and significant market value in many fields, including medicine, food, cosmetics, and animal feed.

[0003] German patent DE2000111402 discloses a method for producing vitamin E acetate. This method uses zinc halide (Lewis acid) and an aqueous protic acid as catalysts, and involves a condensation reaction between trimethylhydroquinone and isophytol in a polar solvent and water mixture. Its advantage lies in using a polar solvent to dissolve the catalyst, facilitating subsequent recovery and reuse. However, this method has drawbacks: the use of the aqueous protic acid easily causes some vitamin E acetate to decompose into vitamin E and other impurities; further esterification is required to synthesize vitamin E acetate, making the synthesis process cumbersome.

[0004] European patent EP603695 discloses a process for synthesizing vitamin E in a liquid or supercritical carbon dioxide system. It uses hydrochloric acid, zinc chloride, and an ion exchanger as acidic catalysts to induce a condensation reaction between trimethylhydroquinone and isophytol to produce vitamin E. However, it does not avoid the use of aqueous hydrochloric acid, resulting in complex process operation and difficult catalyst recovery.

[0005] Most current mainstream technologies for preparing vitamin E acetate use a combination of Lewis acids and hydrochloric acid as catalytic catalysts. The use of hydrochloric acid leads to partial hydrolysis of vitamin E acetate during synthesis, generating tocopherol, which requires further esterification with acetic anhydride to finally obtain vitamin E acetate, making the process cumbersome. Furthermore, the hydrochloric acid process involves high levels of key impurities A and B, which are similar to vitamin E acetate impurities and are difficult to separate.

[0006]

[0007] Existing production methods struggle to avoid the formation of key impurities A and B. These impurities are isomers of vitamin E acetate, making separation difficult. Currently, the European Pharmacopoeia EP11 requires impurity A to be ≤0.5% and impurity B to be ≤1.5%. The levels of impurities A and B directly impact a company's ability to produce high-content vitamin E and are crucial for achieving high-standard pharmaceutical-grade vitamin E. Therefore, a new method for synthesizing vitamin E acetate is needed to address these technical challenges. Summary of the Invention

[0008] To address the aforementioned problems, the present invention aims to provide a method for preparing vitamin E acetate, using 2,3,5-trimethylhydroquinone diester and isophytol as raw materials, and synthesizing vitamin E acetate through a reaction under the synergistic catalysis of Lewis acid and a catalyst. This preparation method avoids the use of aqueous hydrochloric acid by adding a catalyst, and the reaction can produce vitamin E acetate in one step. Simultaneously, it significantly reduces the content of key impurities A and B, resulting in a product with a low content of impurities A+B (≤1000 ppm).

[0009] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0010] A method for preparing vitamin E acetate includes the following steps: using 2,3,5-trimethylhydroquinone diester and isophytol as raw materials, and reacting them under the catalysis of Lewis acid and a catalyst to synthesize vitamin E acetate;

[0011] The reaction equation is as follows:

[0012]

[0013] In this invention, the Lewis acid is a substance capable of accepting electron pairs, such as a compound containing simple Lewis acids (BF3, AlCl3, ZnCl2) or an octet (PCl5, SF6).

[0014] Preferably, the Lewis acid is a substance containing a simple cation, such as AlCl3 or ZnCl2.

[0015] Preferably, hydrochloric acid is not added during the reaction.

[0016] Preferably, the amount of Lewis acid added is 0.1-0.5 times the molar amount of 2,3,5-trimethylhydroquinone diester, and more preferably 0.2-0.4 times.

[0017] In this invention, the catalyst is a silane compound, such as one or more of trimethylchlorosilane, triethylchlorosilane, tripropylchlorosilane, and tert-butyldimethylchlorosilane. More preferably, trimethylchlorosilane is used.

[0018] Preferably, the amount of the catalyst added is 0.1-0.3 times the molar amount of 2,3,5-trimethylhydroquinone diester, and more preferably 0.15-0.2 times.

[0019] In this invention, the reaction is carried out in the presence of a solvent, which is selected from petroleum ether, n-hexane, n-heptane, n-octane, cyclohexane, and toluene. Petroleum ether, n-hexane, n-heptane, n-octane, and cyclohexane are preferred; n-heptane is more preferred.

[0020] The mass ratio of 2,3,5-trimethylhydroquinone diester to solvent is 1:1-5, preferably 1:2-4.

[0021] In this invention, the mass ratio of 2,3,5-trimethylhydroquinone diester to isophytol is 1:1-3, preferably 1:1.1-1.5.

[0022] The reaction is carried out by first laying the solvent and trimethylhydroquinone diester at the bottom, then adding Lewis acid and catalyst after reaching the reaction temperature, and finally adding isophytol to the reaction system to carry out the reaction.

[0023] Preferably, the reaction temperature is 50-100℃, and more preferably 65-75℃.

[0024] Preferably, the isophytol is added over a period of 2-5 hours, and more preferably over a period of 3-4 hours.

[0025] The beneficial effects of this invention are as follows:

[0026] Vitamin E acetate can be synthesized in one step using 2,3,5-trimethylhydroquinone diester and isophytol as basic raw materials under the synergistic catalysis of Lewis acid and chlorosilane catalyst (Route 2). This avoids the hydrolysis of vitamin E acetate into tocopherol caused by the use of hydrochloric acid as a catalyst, which requires further esterification with acetic anhydride to finally obtain vitamin E acetate (Route 1).

[0027]

[0028] This preparation method involves adding a chlorosilane catalyst to react with isophytol to form a sterically hindered intermediate, which then reacts with trimethylhydroquinone diester to reduce the formation of impurities A and B. The hydrochloric acid catalytic mechanism involves the reaction of hydrochloric acid with isophytol to form a carbocation intermediate, which then undergoes a Friedel-Crafts reaction with trimethylhydroquinone diester. The double bond in isophytol, when combined with hydrogen ions to form a carbocation, is more stable at the α-terminus. However, due to steric hindrance, the main reaction product is the β-terminal product, vitamin E acetate, while the α-terminal products, i.e., impurities A and B, are less abundant. The chlorosilane mechanism, by introducing a chlorosilane catalyst, further increases the steric hindrance of isophytol, directing the reaction towards the product vitamin E acetate, significantly reducing the formation of impurities A and B. Simultaneously, the self-generated hydrogen chloride participates in the catalytic reaction, avoiding the use of aqueous hydrochloric acid as a catalyst, which would otherwise lead to the hydrolysis of vitamin E acetate into tocopherol, thus simplifying the production process and reducing production costs.

[0029] The structure of impurity A is as follows:

[0030]

[0031] The structure of impurity B is as follows:

[0032] The catalytic mechanism is as follows:

[0033] Detailed Implementation

[0034] The following embodiments will further illustrate the method provided by the present invention, but the present invention is not limited to the listed embodiments, and should also include any other known modifications within the scope of the claims of the present invention.

[0035] Gas chromatography characterization: Agilent 8890, flame ionization detector (FID), with squalane as an internal standard for qualitative and quantitative analysis of the product composition. Chromatographic conditions were as follows:

[0036]

[0037]

[0038] The main raw materials used in the following examples and comparative examples are as follows:

[0039] Isophytol: Zhejiang Medicine Co., Ltd.;

[0040] Ferric chloride, zinc chloride, aluminum chloride, trimethylchlorosilane, triethylchlorosilane, tripropylchlorosilane, etc.: Sigma (Shanghai) Trading Co., Ltd.;

[0041] Alkanes (n-pentane, n-hexane, n-heptane, n-octane): Bailingwei;

[0042] Hydrochloric acid: Beijing Innocare Technology Co., Ltd.;

[0043] 2,3,5-Trimethylhydroquinone diester: prepared using the same method as in Example 1 as described in patent CN102180793B.

[0044] Comparative Example 1:

[0045] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 4.17 g of zinc chloride, 1.82 g of 36% hydrochloric acid, and 47.51 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.28 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas chromatographic analysis was performed to detect the conversion rate and selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.51%, the selectivity of vitamin E acetate was 71.48%, the yield of vitamin E acetate was 71.12%, the yield of tocopherol was 26.46%, and the mass content of impurities A+B was 0.56%.

[0046] In Comparative Example 1, the tocopherol needs to be further esterified to produce vitamin E acetate, which increases the number of reaction steps and production costs, and reduces the overall yield of vitamin E acetate.

[0047] Example 1:

[0048] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 4.17 g of zinc chloride, 1.97 g of trimethylchlorosilane, and 47.49 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.28 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.5%, the selectivity of vitamin E acetate was 99.10%, the reaction yield was 98.60%, and the content of impurities A+B was 800 ppm.

[0049] Example 2

[0050] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 4.17 g of zinc chloride, 3.29 g of trimethylchlorosilane, and 71.25 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.27 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.48%, the selectivity of vitamin E acetate was 98.99%, the reaction yield was 98.48%, and the content of impurities A+B was 866 ppm.

[0051] Example 3

[0052] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 4.17 g of zinc chloride, 1.1 g of trimethylchlorosilane, and 47.51 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.27 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.58%, the selectivity of vitamin E acetate was 98.87%, the reaction yield was 98.45%, and the content of impurities A+B was 873 ppm.

[0053] Example 4

[0054] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 1.39 g of zinc chloride, 1.97 g of trimethylchlorosilane, and 47.48 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.28 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.68%, the selectivity of vitamin E acetate was 98.85%, the reaction yield was 98.45%, and the content of impurities A+B was 851 ppm.

[0055] Example 5

[0056] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 6.85 g of zinc chloride, 1.97 g of trimethylchlorosilane, and 47.52 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.29 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.59%, the selectivity of vitamin E acetate was 98.83%, the reaction yield was 98.42%, and the content of impurities A+B was 843 ppm.

[0057] Example 6

[0058] Under a nitrogen atmosphere, 23.75 g of 2,3,5-trimethylhydroquinone diester, 4.08 g of aluminum chloride, 1.97 g of trimethylchlorosilane, and 47.50 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.29 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.42%, the selectivity of vitamin E acetate was 98.96%, the reaction yield was 98.39%, and the content of impurities A+B was 845 ppm.

[0059] Example 7

[0060] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 4.17 g of zinc chloride, 3.51 g of tripropylchlorosilane, and 47.49 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.28 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.13%, the selectivity of vitamin E acetate was 99.35%, the reaction yield was 98.49%, and the content of impurities A+B was 856 ppm.

[0061] Example 8

[0062] Under a nitrogen atmosphere, 23.74 g of 2,3,5-trimethylhydroquinone diester, 4.08 g of aluminum chloride, 2.74 g of triethylchlorosilane, and 47.49 g of n-heptane were added to a 250 mL three-necked reaction flask. The oil bath was turned on to raise the temperature of the system to 70 °C. Then, 33.28 g of isophytol was added dropwise over 3 hours. After the addition was complete, the reaction was continued for 2 hours. A gas phase analysis was performed to detect the conversion rate and product selectivity of 2,3,5-trimethylhydroquinone diester. The conversion rate was 99.05%, the selectivity of vitamin E acetate was 99.26%, the reaction yield was 98.32%, and the content of impurities A+B was 872 ppm.

Claims

1. A method for preparing vitamin E acetate, characterized in that, The process includes the following steps: using 2,3,5-trimethylhydroquinone diester and isophytol as raw materials, vitamin E acetate is synthesized by reacting under Lewis acid and catalytic agent.

2. The preparation method according to claim 1, characterized in that, The Lewis acid includes one or more of BF3, AlCl3, ZnCl2PCl5, and SF6; Preferably, the Lewis acid is AlCl3 or ZnCl2; Preferably, hydrochloric acid is not added during the reaction.

3. The preparation method according to claim 1 or 2, characterized in that, The amount of Lewis acid added is 0.1-0.5 times the molar amount of 2,3,5-trimethylhydroquinone diester, preferably 0.2-0.4 times.

4. The preparation method according to any one of claims 1-3, characterized in that, The catalyst is a silane compound, preferably one or more of trimethylchlorosilane, triethylchlorosilane, tripropylchlorosilane, and tert-butyldimethylchlorosilane; more preferably trimethylchlorosilane. Preferably, the amount of the catalyst added is 0.1-0.3 times the molar amount of 2,3,5-trimethylhydroquinone diester, and more preferably 0.15-0.2 times.

5. The preparation method according to any one of claims 1-4, characterized in that, The reaction is carried out in the presence of a solvent, which is selected from petroleum ether, n-hexane, n-heptane, n-octane, cyclohexane, and toluene; preferably petroleum ether, n-hexane, n-heptane, n-octane, and cyclohexane; more preferably n-heptane. Preferably, the mass ratio of 2,3,5-trimethylhydroquinone diester to solvent is 1:1-5, and more preferably 1:2-4. Preferably, the mass ratio of 2,3,5-trimethylhydroquinone diester to isophytol is 1:1-3, and more preferably, the mass ratio is 1:1.1-1.

5.

6. The preparation method according to any one of claims 1-5, characterized in that, The reaction is carried out by first laying the solvent and trimethylhydroquinone diester at the bottom, then adding Lewis acid and catalyst after reaching the reaction temperature, and finally adding isophytol to the reaction system to carry out the reaction.

7. The preparation method according to any one of claims 1-6, characterized in that, The reaction temperature is 50-100℃, with a preferred temperature of 65-75℃; Preferably, the isophytol is added over a period of 2-5 hours, and more preferably over a period of 3-4 hours.

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