Method for preparing vitamin E acetate without acylation reagent

Abstract

The invention provides a preparation method of a hydrolysis inhibitor cyclohexane-1, 2-dicarboxaldehyde, which comprises the following steps: adding cyclohexane-1, 2-dicarboxaldehyde as a hydrolysis inhibitor into a lewis acid and protonic acid catalytic system to avoid hydrolysis of trimethylhydroquinone diester, so that in a reaction for preparing vitamin E acetate by using trimethylhydroquinone diester as a raw material, the yield of vitamin E acetate is increased, and the yield of vitamin E acetate is increased. No vitamin E intermediate is generated, and the vitamin E acetate can be obtained through high-yield conversion without further addition of an acylation reagent. According to the method, low-concentration cyclohexane-1, 2-dicarboxaldehyde is added as a hydrolysis inhibitor, the hydrolysis inhibition efficiency reaches 99% or above, meanwhile, a reaction system for generating vitamin E acetate by catalyzing trimethylhydroquinone diester through lewis acid and protonic acid is not affected, vitamin E acetate can be generated in one step, introduction of an acylation reagent is avoided, and the method is suitable for industrial production. And the preparation process flow of the vitamin E acetate is simplified.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to application of cyclohexane-1,2-dicarbaldehyde, a hydrolysis inhibitor, in the preparation of vitamin E acetate. Background Art

[0002] Vitamin E is a fat-soluble vitamin. Due to its strong antioxidant properties, it has good therapeutic effects in food nutrition supplementation, beauty and skin care, cardiovascular and cerebrovascular protection, improving self-immunity, protecting cells from damage, and delaying aging.

[0003] Vitamin E acetate can be divided into two preparation processes according to the source of raw materials.

[0004] 1. Trimethylhydroquinone is used as a raw material, which undergoes a condensation reaction with isophytol to produce D,L-α-tocopherol. D,L-α-tocopherol is further esterified with acetic anhydride to produce vitamin E acetate. This process primarily uses a Lewis acid and a strong acid mixture as a catalyst, and the conversion rate of isophytol is as high as over 85%. However, the raw material trimethylhydroquinone is difficult to source, making large-scale industrial application difficult. The resulting D,L-α-tocopherol is also unstable, making it difficult to use in downstream applications.

[0005] 2. Using trimethylhydroquinone diester as raw material, a condensation reaction occurs with isophytol to produce vitamin E acetate. Lewis acid catalysts are also used in traditional reaction systems. Since the catalyst in this system will hydrolyze part of the trimethylhydroquinone diester to produce trimethylhydroquinone, it is necessary to add an acylating agent after the condensation reaction for further esterification to convert D,L-α-tocopherol into vitamin E acetate. This process requires the continued addition of an acylating agent after the condensation reaction for the esterification reaction to occur and completely convert it into vitamin E acetate. The process flow is complicated, and a small amount of D,L-α-tocopherol is present in the prepared product, which also leads to poor product stability in downstream applications.

[0006] CN1315325A reports a condensation reaction using trimethylhydroquinone acetate as a raw material, catalyzed by zinc halide and protic acid, with acetic acid as a solvent, to produce a mixture of vitamin E and vitamin E acetate, with vitamin E comprising 30%. This process requires the addition of 30% mol (based on trimethylhydroquinone acetate) of acetic anhydride as an acylating agent, and the separation of the catalyst phase, making the process complex. Summary of the Invention

[0007] The present invention provides a method for using cyclohexane-1,2-dicarboxaldehyde as a hydrolysis inhibitor in the preparation of vitamin E acetate. Cyclohexane-1,2-dicarboxaldehyde is added as a hydrolysis inhibitor to a Lewis acid and protic acid catalytic system to avoid the hydrolysis of trimethylhydroquinone diester. Thus, in the preparation of vitamin E acetate using trimethylhydroquinone diester as a raw material, no vitamin E intermediates are generated, and vitamin E acetate can be converted into vitamin E acetate in a high yield without the need for further addition of an acylating agent.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0009] In one aspect, the present invention provides the use of cyclohexane-1,2-dicarbaldehyde as a hydrolysis inhibitor in the preparation of vitamin E acetate. The preparation process of cyclohexane-1,2-dicarbaldehyde comprises: using 1,2-cyclohexyl dimethanol as a raw material and performing a one-step oxidation to prepare cyclohexane-1,2-dicarbaldehyde.

[0010]

[0011] Preferably, the method for preparing cyclohexane-1,2-dicarbaldehyde of the present invention comprises the following steps:

[0012] Weigh 1,2-cyclohexyl dimethanol into a reaction kettle, add the reaction solvent, and then add the metal catalyst. The temperature is raised to allow the reaction to proceed. The conversion of the raw material 1,2-cyclohexyl dimethanol is monitored during the reaction. The reaction is completed when the conversion rate is ≥99%. After the reaction is complete, the crude cyclohexane-1,2-dicarbaldehyde solution is washed and extracted with water. The solvent is then removed by distillation under reduced pressure to obtain high-purity cyclohexane-1,2-dicarbaldehyde.

[0013] In the method for preparing cyclohexane-1,2-dicarbaldehyde, the reaction solvent is one or more of propyl acetate, n-butyl acetate and chloroform, preferably chloroform.

[0014] In the method for preparing cyclohexane-1,2-dicarbaldehyde, the metal catalyst is a composite catalyst of palladium acetate and manganese dioxide, and the composite ratio is 1:2-10, preferably 1:4-6.

[0015] In the method for preparing cyclohexane-1,2-dicarbaldehyde, the reaction temperature is 40-100°C, preferably 50-70°C.

[0016] In the method for preparing cyclohexane-1,2-dicarbaldehyde, the mass ratio of the reaction solvent to 1,2-cyclohexyl dimethanol is 1:0.05-0.6, preferably 1:0.2-0.4; the mass ratio of the metal catalyst to 1,2-cyclohexyl dimethanol is 1:50-200, preferably 1:80-150; and the mass ratio of water to 1,2-cyclohexyl dimethanol during water washing is 1:50-150, preferably 1:80-120.

[0017] In the present invention, cyclohexane-1,2-dicarbaldehyde is added to a reaction solution in which vitamin E acetate is prepared using trimethylhydroquinone diester as a raw material, and vitamin E acetate is directly produced in a high yield without adding an acylating agent.

[0018] In another aspect, the present invention provides a method for preparing vitamin E acetate, comprising the following steps:

[0019] Trimethylhydroquinone diester and a solvent are added to a reactor, and then a Lewis acid catalyst, a protonic acid and cyclohexane-1,2-dicarbaldehyde are added. After the temperature is raised to the reaction temperature, isophytol is added. After the isophytol is added dropwise, the temperature is maintained and the reaction is continued to obtain vitamin E acetate.

[0020] In the present invention, the solvent is selected from one or more of n-heptane, petroleum ether, and acetic acid, preferably n-heptane.

[0021] The Lewis acid catalyst is selected from one or more of zinc chloride, copper chloride, zinc bromide and copper bromide, preferably zinc bromide; the protonic acid is one or more of sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid, preferably hydrochloric acid.

[0022] The reaction temperature is 25-100° C., preferably 40-70° C.; the heat preservation reaction time is 2-10 h, preferably 4-8 h.

[0023] The isophytol is added for 0.5-5 hours, preferably 1-3 hours.

[0024] The mass ratio of the solvent to trimethylhydroquinone diester is 1:0.1-1, preferably 1:0.4-0.6.

[0025] The mass ratio of the Lewis acid catalyst to trimethylhydroquinone diester is 1:10-100, preferably 1:40-80; the mass ratio of the protonic acid to trimethylhydroquinone diester is 1:10-100, preferably 1:50-80; the mass ratio of the cyclohexane-1,2-dicarbaldehyde to trimethylhydroquinone diester is 1:20-80, preferably 1:30-50; the mass ratio of the isophytol to trimethylhydroquinone diester is 1:0.5-0.8, preferably 1:0.55-0.65.

[0026] The beneficial effects of the present invention are:

[0027] Adding cyclohexane-1,2-dicarboxaldehyde as a hydrolysis inhibitor to the Lewis acid and protonic acid catalytic system can avoid the hydrolysis of trimethylhydroquinone diester. As a result, in the preparation of vitamin E acetate using trimethylhydroquinone diester as a raw material, no vitamin E intermediate is generated, and vitamin E acetate can be converted into vitamin E acetate in high yield without the need for further addition of an acylating agent. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described below with reference to specific embodiments, but is not limited thereto.

[0029] Raw materials and sources:

[0030]

[0031] Test method:

[0032] Test method reference GB 14756—2010

[0033] Example 1

[0034] Weigh 100g of 1,2-cyclohexyl dimethanol into a reactor, add 500g of propyl acetate, and then weigh 1g of a palladium acetate and manganese dioxide catalyst mixture in a 1:4 ratio. The reaction was heated to 50°C and allowed to react for 5 hours. During the reaction, the conversion of the starting material 1,2-cyclohexyl dimethanol was monitored to be 99%, indicating the end of the reaction. 1.5g of pure water was added, and after extraction and washing, the upper oil phase was separated. The propyl acetate was removed by distillation under reduced pressure to obtain cyclohexane-1,2-dicarbaldehyde with a purity of 98.2%.

[0035] Add 100g trimethylhydroquinone diester and 450g n-heptane solvent to the reactor, then add 2g zinc chloride, 2g hydrochloric acid and 2.5g cyclohexane-1,2-dicarbaldehyde, heat to 60℃ to dissolve it, and then start adding 182g

[0036] Isophytol was added dropwise for 2 hours, and the reaction was continued for 3 hours after the addition was completed. The reaction was completed. The conversion rate of isophytol was 99.8%, the yield of vitamin E acetate in the reaction solution was 98%, and the vitamin E content accounted for only 0.02% of the vitamin E acetate content.

[0037] Example 2

[0038] Weigh 100g of 1,2-cyclohexyl dimethanol into a reactor, add 300g of chloroform, and then weigh 0.68g of a catalyst mixture of palladium acetate and manganese dioxide in a ratio of 1:7. The reaction was heated to 100°C and allowed to react for 3.5 hours. During the reaction, the conversion of the starting material 1,2-cyclohexyl dimethanol was monitored to be 99%, indicating the end of the reaction. Add 2g of pure water, extract and wash, separate the lower oil phase, and remove the chloroform by vacuum distillation to obtain cyclohexane-1,2-dicarbaldehyde with a purity of 98.6%.

[0039] Add 100g trimethylhydroquinone diester and 1000g petroleum ether solvent to the reactor, then add 8g zinc bromide, 5g sulfuric acid and 3g cyclohexane-1,2-dicarbaldehyde, heat to 70℃ to dissolve, and then add 200g

[0040] Isophytol was added dropwise for 3 hours, and the reaction was continued for 4 hours after the addition was completed. The reaction was terminated. The conversion rate of isophytol was 99.6%, the yield of vitamin E acetate in the reaction solution was 98.1%, and the vitamin E content accounted for only 0.01% of the vitamin E acetate content.

[0041] Example 3

[0042] Weigh 100g of 1,2-cyclohexyl dimethanol into a reactor, add 2000g of n-butyl acetate, and then weigh 2g of a mixed catalyst of palladium acetate and manganese dioxide in a 1:2 ratio. The reaction was heated to 40°C and allowed to react for 6 hours. During the reaction, the conversion of the starting material 1,2-cyclohexyl dimethanol was monitored to be 99%, indicating the end of the reaction. 0.67g of pure water was added, and after extraction and washing, the upper oil phase was separated. The propyl acetate was removed by distillation under reduced pressure to obtain cyclohexane-1,2-dicarbaldehyde with a purity of 98.4%.

[0043] Add 100g trimethylhydroquinone diester and 100g acetic acid solvent to the reactor, then add 1g copper chloride, 1g phosphoric acid and 5g cyclohexane-1,2-dicarbaldehyde, heat to 25℃ to dissolve, and then add 125g

[0044] Isophytol was added dropwise for 5 hours, and the reaction was continued for 10 hours after the addition was completed. The reaction was completed. The conversion rate of isophytol was 99.9%, the yield of vitamin E acetate in the reaction solution was 98.6%, and the vitamin E content accounted for only 0.01% of the vitamin E acetate content.

[0045] Example 4

[0046] Weigh 100g of 1,2-cyclohexyl dimethanol into a reactor, add 167g of chloroform, and then weigh 0.5g of a mixed catalyst of palladium acetate and manganese dioxide in a ratio of 1:10. The reaction was heated to 60°C and allowed to react for 6 hours. During the reaction, the conversion of the starting material 1,2-cyclohexyl dimethanol was monitored to be 99%, indicating the end of the reaction. 1.25g of pure water was added, and after extraction and washing, the upper oil phase was separated. Propyl acetate was removed by distillation under reduced pressure to obtain cyclohexane-1,2-dicarbaldehyde with a purity of 98.1%.

[0047] A reactor was charged with 100g of trimethylhydroquinone diester and 250g of n-heptane solvent, followed by 1g of copper bromide, 10g of hydrobromic acid, and 1.25g of cyclohexane-1,2-dicarbaldehyde. The temperature was raised to 100°C to dissolve the solution, and 154g of isophytol was added dropwise. The isophytol was added dropwise for 0.5h. After the addition was complete, the reaction was continued at this temperature for 8h, and the reaction was completed. Testing showed that the isophytol conversion rate was 99.9%, and the yield of vitamin E acetate in the reaction solution was 98.8%. The vitamin E content accounted for only 0.02% of the vitamin E acetate content.

[0048] Comparative Example 1

[0049] A reactor was added with 100g of trimethylhydroquinone diester and 1000g of petroleum ether solvent, followed by 8g of zinc bromide and 5g of sulfuric acid. The temperature was raised to 70°C to dissolve the solution, and then 200g of isophytol was added dropwise. The isophytol was added dropwise for 3 hours. After the addition was complete, the reaction was continued at this temperature for 4 hours, and the reaction was completed. Testing showed that the isophytol conversion rate was 99.5%, the vitamin E acetate yield in the reaction solution was 70.1%, and the vitamin E content accounted for 34% of the vitamin E acetate content.

[0050] Comparative Example 2

[0051] A reactor was charged with 100g of trimethylhydroquinone diester and 450g of n-heptane solvent, followed by 2g of zinc chloride, 2g of hydrochloric acid, and 2.5g of benzaldehyde. The temperature was raised to 60°C to dissolve the mixture, and then 182g of isophytol was added dropwise. The isophytol was added dropwise for 2 hours. After the addition was complete, the reaction was continued at this temperature for 3 hours, and the reaction was terminated. Testing showed that the isophytol conversion rate was 89.1%, the vitamin E acetate yield in the reaction solution was 65.0%, and the vitamin E content accounted for 39% of the vitamin E acetate content.

Claims

1. Use of cyclohexane-1,2-dicarboxaldehyde as a hydrolysis inhibitor in the preparation of vitamin E acetate, wherein the cyclohexane-1,2-dicarboxaldehyde has the following structure:

2. A method for preparing vitamin E acetate, comprising the following steps: Trimethylhydroquinone diester and a solvent are added to a reactor, and then a Lewis acid catalyst, a protonic acid and cyclohexane-1,2-dicarbaldehyde are added. After the temperature is raised to the reaction temperature, isophytol is added. After the isophytol is added dropwise, the temperature is maintained and the reaction is continued to obtain vitamin E acetate.

3. The preparation method according to claim 2, wherein The solvent is selected from one or more of n-heptane, petroleum ether, and acetic acid, preferably n-heptane.

4. The preparation method according to claim 2 or 3, wherein The Lewis acid catalyst is selected from one or more of zinc chloride, copper chloride, zinc bromide and copper bromide, preferably zinc bromide; the protonic acid is one or more of sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid, preferably hydrochloric acid.

5. The preparation method according to any one of claims 2 to 4, wherein The reaction temperature is 25-100° C., preferably 40-70° C.; the heat preservation reaction time is 2-10 h, preferably 4-8 h.

6. The preparation method according to any one of claims 2 to 5, characterized in that: The isophytol is added for 0.5-5 hours, preferably 1-3 hours.

7. The preparation method according to any one of claims 2 to 6, wherein: The mass ratio of the solvent to trimethylhydroquinone diester is 1:0.1-1, preferably 1:0.4-0.6; and / or the mass ratio of the Lewis acid catalyst to trimethylhydroquinone diester is 1:10-100, preferably 1:40-80; and / or the mass ratio of the protonic acid to trimethylhydroquinone diester is 1:10-100, preferably 1:50-80; and / or the mass ratio of the cyclohexane-1,2-dicarbaldehyde to trimethylhydroquinone diester is 1:20-80, preferably 1:30-50; and / or the mass ratio of the isophytol to trimethylhydroquinone diester is 1:0.5-0.8, preferably 1:0.55-0.65.

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