Synthesis method of tocopherol glucoside

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of tocopherol glucoside. The method comprises the following specific steps: dissolving tocopherol and beta-penta-acetyl glucose in an organic solvent to obtain a mixed solution, adding a catalyst for reaction, washing with water and separating liquid after the reaction is finished, and drying, filtering and concentrating an organic phase to obtain an SN1 intermediate; and mixing the SN1 intermediate with alkali to react, adjusting the pH value to be neutral, filtering and desalting, concentrating into a solid, adding alcohol and recrystallizing to obtain tocopherol glucoside. The synthesis method provided by the invention is simple in preparation process, short in production period, relatively low in content of by-products in each step of reaction, and more suitable for industrial production; high pressure and high temperature do not exist in the whole synthesis process, a catalyst, a solvent and the like adopted in the process are conventional reagents, safety is high, and operability is high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing tocopherol glucoside. Background Art

[0002] Tocopherol is one of the vitamins necessary for normal life activities in the human body. It can promote the activation of human physiological functions, improve human cell metabolism, inhibit fat deposition and the production of lipid peroxides in the body, and is an important physiologically active substance. However, it is very easy to be oxidized and inconvenient to store. Tocopherol glucoside products can make up for the deficiency of tocopherol. They not only increase water solubility, but also have other biological activities, such as antiviral activity, anti-human immunodeficiency disease, anti-aging, etc., which expand the application field of tocopherol. At the same time, tocopherol glucoside products are not as easy to oxidize as tocopherol products. Tocopherol glucoside has good chemical stability and is easy to store and transport.

[0003] As a derivative of tocopherol, tocopherol glucoside often has the physiological and pharmacological effects of both tocopherol and glucose, and can eliminate the possible side effects of tocopherol and glucose. Tocopherol glucoside can not only effectively treat skin diseases, but also can be used for skin moisturizing and anti-aging. It is often added to cosmetics, food and medicine as a wetting agent, antioxidant, etc.

[0004] Tocopherol glucoside products are a type of vitamin E products. Compared with free tocopherol products, they have certain improvements in many functions and ease of use. In the application fields of medicine, cosmetics, food and feed industry, α-tocopherol glycoside has paved the way for the best-selling commercial market of vitamin E preparations. The preparation of tocopherol glycosides through the glycosylation process of natural tocopherol is an important link in the industrialization process of natural vitamin E, which has good economic benefits and social significance.

[0005] There are two main methods for preparing tocopherol glucoside: one is the Helferich method; the other is the method using different Lewis acid catalysis.

[0006] ①Helferich method: B.Helferich and E.Schmitz-Hillebrecht first studied the preparation of tocopherol oligosaccharides in 1933, mainly producing β-type glycosides. By the mid-1980s, KokaiTokkyo Koho et al. in Japan conducted a large number of experiments on the synthesis of tocopherol glycoside compounds. They only obtained a 13% recovery rate using 4-toluenesulfonic acid as a catalyst, but 80% of α-tocopherol-α-D-mannoside was obtained using a mixed catalyst of copper and zinc halides. M.Lahmam and J.Thiem reported that a series of glycoside compounds were successfully synthesized using ether solution of boron trifluoride, but the catalyst was a toxic catalyst and difficult to separate from the product. Subsequently, T.Satoh, H.Miyamataka et al. also conducted some research on the preparation of tocopherol glycosides using the Helferich method, but the yields were not very high. In addition, other chemists and drug synthesis workers have used this method to further study the synthesis, reaction mechanism and pharmacology of tocopherol glycosides. In general, this synthesis method has the following practical problems:

[0007] (1) Low yield; (2) Poor selectivity; (3) Requires an excess of raw materials, even 6 times the amount of tocopherol, resulting in great waste and difficulty in product separation; (4) The protection and deprotection reaction process is long; (5) Produces side reactions, etc.

[0008] ② The use of different proton acids or Lewis acids and other acid catalysts to prepare some monosaccharide or disaccharide tocopherol glycosides using the Helferich method is usually accompanied by the formation of by-products and has many defects. Drug and chemical researchers have begun to seek other methods to synthesize tocopherol glycosides. SK Chatterjee and P. Nuhn also reported the reaction of synthesizing tocopherol glycosides using anhydrous FeCl3 as a catalyst, and obtained a relatively good recovery rate (45-50%). The key to success lies in the anhydrous conditions of the reaction. If water is present during the reaction, some tocopherol will be oxidized by FeCl3. 3+ / Fe 2+ The system is oxidized to tocopherol quinone compounds, which greatly reduces the recovery rate of the generated target product. Even in the presence of active molecular sieves, the recovery rate is not high. This type of reaction requires strict control of reaction conditions and is difficult to operate.

[0009] Therefore, it is of great significance to develop a new synthesis method of tocopherol glucoside. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for synthesizing tocopherol glucoside in view of the deficiencies in the prior art. The specific steps are as follows: tocopherol and β-pentacetyl glucose are dissolved in an organic solvent to obtain a mixed solution, a catalyst is added to react, after the reaction is completed, the solution is washed with water and separated, and the organic phase is dried, filtered and concentrated to obtain an SN1 intermediate; the SN1 intermediate is mixed with a base for reaction, the pH is adjusted to neutral, the solution is filtered and desalted, and then the solution is concentrated into a solid, and alcohol is added for recrystallization to obtain the tocopherol glucoside.

[0011] The molar ratio of tocopherol to β-pentaacetyl glucose is 1:(1-1.5); the amount of the organic solvent used is 3-5 times the mass of tocopherol;

[0012] Preferably, the tocopherol includes one or a combination of α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol.

[0013] Wherein, the organic solvent comprises one or a combination of dichloroethane, dichloromethane, n-hexane and petroleum ether;

[0014] Preferably, the organic solvent is dichloromethane.

[0015] Wherein, the molar ratio of the catalyst to tocopherol is (1-1.5):1.

[0016] Wherein, the catalyst comprises one or a combination of SnCl4, TiCl4, ZnCl2 and SbCl5;

[0017] Preferably, the catalyst is SnCl4.

[0018] The specific reaction conditions of the mixed solution after adding the catalyst are to react at a temperature of 30 to 50° C. for 6 to 8 hours.

[0019] The specific steps of washing are: firstly cooling to room temperature and adding water for washing, standing and separating to obtain a primary washed organic phase, then adding saturated brine to the primary washed organic phase for a secondary washing, standing and separating to obtain an organic phase.

[0020] The specific steps of drying are: adding anhydrous magnesium sulfate to the organic phase for drying; the mass ratio of anhydrous magnesium sulfate to tocopherol is 1:1.

[0021] The specific steps of the concentration are: raising the temperature to 50° C., the pressure to -0.9 MPa, and distilling the organic solvent under reduced pressure.

[0022] The molar ratio of the base to tocopherol is (0.3-1.5):1; the base includes any one or a combination of sodium methoxide, sodium ethoxide, sodium hydroxide and potassium hydroxide;

[0023] Preferably, the base is sodium methoxide, and the sodium methoxide is a methanol solution with a mass fraction of 30%.

[0024] The specific reaction conditions after the SN1 intermediate is mixed with the base are a temperature of 30 to 50° C. and a reaction time of 1 to 3 hours.

[0025] Wherein, the amount of the alcohol used is 2 to 4 times the mass of tocopherol; the alcohol is methanol and / or ethanol;

[0026] Preferably, the alcohol is ethanol.

[0027] Beneficial effects:

[0028] (1) The present invention uses tocopherol and β-pentaacetyl glucose as raw materials, reacts under the action of a catalyst, and then adds alkali for treatment to obtain the product tocopherol glucoside. The entire preparation process is simple, the production cycle is short, the content of by-products in each step of the reaction is low, and it is more suitable for industrial production;

[0029] (2) The process provided by the present invention, by reasonably adjusting the parameters of each step of the synthesis process, the yield and purity of the product obtained are significantly improved compared with the traditional method. The experimental results show that when tocopherol glucoside is prepared by the process of the present invention, the total yield of the product is above 50% and the purity is above 97.0%;

[0030] (3) The synthesis method provided by the present invention can successfully obtain the product tocopherol glucoside when α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol with different structures are used as raw materials, and the total yield of the product is above 50% and the purity is above 97.0%, indicating that the synthesis method of the present invention has greater flexibility and product diversity, and has greater cost advantages in the industrial production process;

[0031] (4) The entire synthesis process of the present invention does not involve high pressure and high temperature. The catalysts, solvents, etc. used in the process are all conventional reagents, which are highly safe and operable, and the reaction can be carried out in a conventional reactor. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0033] Figure 1 The synthetic route diagram of the present invention is:

[0034] Figure 2 This is a high performance liquid chromatogram of the target product after purification by the process in Example 1 of the present invention;

[0035] Figure 3This is a high performance liquid chromatogram of the target product after purification in Example 2 of the present invention;

[0036] Figure 4 is a high performance liquid chromatogram of the SN1 intermediate in Example 1 of the present invention;

[0037] Figure 5 This is the NMR image of the target product after process purification in Example 1 of the present invention.

[0038] Figure 6 1 is the structural formula diagram of the SN1 intermediate in Example 1 of the present invention. DETAILED DESCRIPTION

[0039] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0040] In the following embodiments, the synthetic route of tocopherol glucoside is as follows Figure 1 shown.

[0041] Embodiment 1:

[0042] A chemical synthesis process of tocopherol glucoside comprises the following steps:

[0043] (1) In a 500 mL three-necked flask, 10 g (0.02 mol) of δ-tocopherol, 11.7 g (0.03 mol) of β-pentacetyl glucose, 50 g of dichloromethane, and 7.8 g (0.03 mol) of SnCl4 were added, the temperature was raised to 45°C, and the mixture was stirred for 6 h. The mixture was cooled to room temperature and washed with water. The mixture was allowed to stand for separation. The organic phase was washed twice with saturated saline solution. The mixture was allowed to stand for separation. 10 g of anhydrous magnesium sulfate was added to the organic phase for drying. The organic phase was filtered and concentrated (the temperature was raised to 50°C, the pressure was -0.9 MPa, and the organic solvent was distilled under reduced pressure) to obtain the SN1 intermediate. The SN1 intermediate was purified by liquid chromatography ( Figure 4 ) Determine that the intermediate content is above 95%;

[0044] (2) The SN1 intermediate obtained in (1) was added to a 500 mL three-necked flask, 50 g of ethanol, 5.4 g (0.03 mol) of 30% sodium methoxide solution (solvent: methanol), stirred and heated to 50° C., reacted for 2 h, cooled to room temperature, and hydrochloric acid was added dropwise to adjust the pH to 7. The inorganic salt was filtered off and concentrated to obtain a light yellow solid product. 2 times ethanol was added for recrystallization to obtain the final product, tocopherol glucoside, which was analyzed by liquid chromatography ( Figure 2 ) determined that the product content was 98%, the yield was 55%, and the NMR data of the product were as follows: 1H NMR (500MHz, CDCl3) δ6.62(s,1H,Ph-H,11),6.54(s,1H,Ph-H,7),4.74(d,J=4.4Hz,1H,O-CH-O,4),3.79(d,J=9.9Hz,1 H,CH,1),3.78(d,J=7.9Hz,2H,2CH,2,3),3.72(s,2H,CH2OH,28),3.32(d,J=6.4Hz,1H,CH,6),2.54(s,2H,2OH,29,30) ,2.17(s,3H,Ph-CH3,31),2.01(s,2H,2OH,26,27),1.63(td,J=13.1,6.6Hz,2H,CH2,16),1.56–1.46(m,3H,CH3,18),1 .40–1.01(m,23H,CH2,CH,15,17,19,20,21,22,23,24,25,34,35,36,37),0.85(t,J=8.1Hz,12H,4CH3,32,33,38,39).

[0045] Embodiment 2:

[0046] A chemical synthesis process of tocopherol glucoside comprises the following steps:

[0047] (1) In a 500 mL three-necked flask, 10 g (0.02 mol) of δ-tocopherol, 7.8 g (0.02 mol) of β-pentacetyl glucose, 50 g of dichloromethane, and 7.8 g (0.03 mol) of SnCl4 were added, the temperature was raised to 40°C, and the mixture was stirred for reaction for 8 h. The mixture was cooled to room temperature and washed with water. The mixture was allowed to stand for separation. The organic phase was washed twice with saturated saline solution. The mixture was allowed to stand for separation. 10 g of anhydrous magnesium sulfate was added to the organic phase for drying. The organic phase was filtered and concentrated (the temperature was raised to 50°C, the pressure was -0.9 MPa, and the organic solvent was distilled under reduced pressure) to obtain the SN1 intermediate. The SN1 intermediate was purified by liquid chromatography ( Figure 4 ) Determine that the intermediate content is above 95%;

[0048] (2) The SN1 intermediate obtained in (1) was added to a 500 mL three-necked flask, 50 g of ethanol, 1.08 g (0.006 mol) of 30% sodium methoxide solution (solvent: methanol), stirred and heated to 45°C, reacted for 2.5 h, cooled to room temperature, and hydrochloric acid was added dropwise to adjust the pH to 7. The inorganic salt was filtered off and concentrated to obtain a light yellow solid product. 2 times ethanol was added for recrystallization to obtain the final product. The product was analyzed by liquid chromatography ( Figure 3 ) determined that the product content was 99% and the yield was 52%.

[0049] Embodiment 3:

[0050] A chemical synthesis process of tocopherol glucoside comprises the following steps:

[0051] (1) Add 10 g (0.02 mol) of α-tocopherol, 7.8 g (0.02 mol) of β-pentacetyl glucose, 50 g of dichloromethane, and 7.8 g (0.03 mol) of SnCl4 to a 500 mL three-necked flask, heat to 40°C, stir and react for 8 h, cool to room temperature, add water to wash, stand and separate, add saturated brine to the organic phase for a second wash, stand and separate, add 10 g of anhydrous magnesium sulfate to the organic phase for drying, filter and concentrate (heat to 50°C, pressure -0.9 MPa, and distill the organic solvent under reduced pressure) to obtain SN1 intermediate, the intermediate content is more than 95%;

[0052] (2) The SN1 intermediate obtained in (1) was added to a 500 mL three-necked flask, 50 g of ethanol and 1.08 g (0.006 mol) of a 30% sodium methoxide solution (solvent: methanol) were added, the mixture was stirred and heated to 45° C., reacted for 2.5 h, cooled to room temperature, and hydrochloric acid was added dropwise to adjust the pH to 7. The inorganic salt was filtered off and concentrated to obtain a light yellow solid product. The final product was recrystallized by adding 2 times ethanol. The product content was 98.5% and the yield was 53.4%.

[0053] Embodiment 4:

[0054] A chemical synthesis process of tocopherol glucoside comprises the following steps:

[0055] (1) Add 10 g (0.02 mol) of β-tocopherol, 11.7 g (0.03 mol) of β-pentacetyl glucose, 50 g of dichloromethane, and 7.8 g (0.03 mol) of SnCl4 to a 500 mL three-necked flask, heat to 45°C, stir and react for 6 h, cool to room temperature, add water to wash, stand and separate, add saturated brine to the organic phase for a second wash, stand and separate, add 10 g of anhydrous magnesium sulfate to the organic phase for drying, filter and concentrate (heat to 50°C, pressure -0.9 MPa, and distill the organic solvent under reduced pressure) to obtain SN1 intermediate, the intermediate content is more than 95%;

[0056] (2) The SN1 intermediate obtained in (1) was added to a 500 mL three-necked flask, 50 g of ethanol and 1.08 g (0.006 mol) of a 30% sodium methoxide solution (the solvent is methanol), stirred and heated to 45° C., reacted for 2.5 h, cooled to room temperature, and hydrochloric acid was added dropwise to adjust the pH to 7. The inorganic salt was filtered off and concentrated to obtain a light yellow solid product. The final product was recrystallized by adding 2 times ethanol. The product content was 98.7% and the yield was 52.1%.

[0057] Embodiment 5:

[0058] A chemical synthesis process of tocopherol glucoside comprises the following steps:

[0059] (1) Add 10 g (0.02 mol) of γ-tocopherol, 11.7 g (0.03 mol) of β-pentacetyl glucose, 50 g of dichloromethane, and 7.8 g (0.03 mol) of SnCl4 to a 500 mL three-necked flask, heat to 45°C, stir and react for 6 h, cool to room temperature, add water to wash, stand and separate, add saturated brine to the organic phase for a second wash, stand and separate, add 10 g of anhydrous magnesium sulfate to the organic phase for drying, filter and concentrate (heat to 50°C, pressure -0.9 MPa, and distill the organic solvent under reduced pressure) to obtain SN1 intermediate, the intermediate content is above 95%;

[0060] (2) The SN1 intermediate obtained in (1) was added to a 500 mL three-necked flask, 50 g of ethanol and 1.08 g (0.006 mol) of a 30% sodium methoxide solution (the solvent is methanol), stirred and heated to 45° C., reacted for 2.5 h, cooled to room temperature, and hydrochloric acid was added dropwise to adjust the pH to 7. The inorganic salt was filtered off and concentrated to obtain a light yellow solid product. The final product was recrystallized by adding 2 times ethanol. The product content was 99.1% and the yield was 52.7%.

[0061] The present invention provides a method for synthesizing tocopherol glucoside. There are many methods and approaches to realize the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for synthesizing tocopherol glucoside, characterized in that: The specific steps are: dissolving tocopherol and β-pentacetyl glucose in an organic solvent to obtain a mixed solution, adding a catalyst to react, washing with water and separating the liquids after the reaction is completed, drying, filtering and concentrating the organic phase to obtain the SN1 intermediate; then mixing the SN1 intermediate with a base to react, adjusting the pH to neutral, filtering and desalting, concentrating into a solid, and adding alcohol for recrystallization to obtain tocopherol glucoside.

2. The synthesis method according to claim 1, characterized in that The molar ratio of tocopherol to beta-pentaacetyl glucose is 1:(1-1.5); and the amount of the organic solvent used is 3-5 times the mass of tocopherol.

3. The synthesis method according to claim 1 or 2, characterized in that The organic solvent includes one or a combination of dichloroethane, dichloromethane, n-hexane and petroleum ether.

4. The synthesis method according to claim 1, characterized in that The molar ratio of the catalyst to tocopherol is (1-1.5):

1.

5. The synthesis method according to claim 1 or 4, characterized in that: The catalyst includes one or a combination of SnCl4, TiCl4, ZnCl2 and SbCl5.

6. The synthesis method according to claim 1, characterized in that The specific reaction conditions of the mixed solution after adding the catalyst are: reacting at a temperature of 30 to 50° C. for 6 to 8 hours.

7. The synthesis method according to claim 1, characterized in that The specific steps of drying are: adding anhydrous magnesium sulfate to the organic phase for drying; the mass ratio of anhydrous magnesium sulfate to tocopherol is 1:

1.

8. The synthesis method according to claim 1, characterized in that The molar ratio of the base to tocopherol is (0.3-1.5):1; the base comprises one or a combination of sodium methoxide, sodium ethoxide, sodium hydroxide and potassium hydroxide.

9. The synthesis method according to claim 1, characterized in that The specific reaction conditions of the SN1 intermediate after mixing with the base are: reacting at a temperature of 30 to 50° C. for 1 to 3 hours.

10. The synthesis method according to claim 1, characterized in that The amount of the alcohol used is 2 to 4 times the mass of tocopherol; the alcohol is methanol and / or ethanol.

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