High-purity tocopherol glucoside and synthesis method thereof

Abstract

The invention relates to high-purity tocopherol glucoside and a synthesis method thereof, and belongs to the technical field of organic synthesis. The technical problems that an existing synthesis method of tocopherol glucoside is low in yield and poor in stereoselectivity, oxidation by-products are generated, tocopherol is excessively used, and toxic metal reagents are used are solved. The synthesis method comprises the following steps: dissolving a tocopherol monomer and alpha-D-fluoroglucopyranose in a water-containing mixed reagent, carrying out a glycosylation reaction under the action of an alkaline reagent, after the reaction is finished, extracting a reaction product by using an organic solvent, washing, drying and concentrating an organic phase to obtain a crude product, recrystallizing the crude product by using an alcohol solvent, filtering, and drying to obtain the tocopherol-alpha-D-fluoroglucopyranose. The tocopherol glucoside is obtained. According to the synthesis method, only one-step reaction is needed, a protecting group removal step is omitted, the utilization rate of the tocopherol monomer is high, reaction conditions are mild, anhydrous glycosylation reaction conditions are not needed, post-treatment is convenient, the product yield is high, the purity is high, and the synthesis method is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a high-purity tocopherol glucoside and its synthesis method. Background Technology

[0002] Tocopherol is one of the essential fat-soluble vitamins for maintaining normal human life activities. It possesses a wide range of biological activities, including antioxidant, immune-enhancing, anti-infertility, and inhibition of lipid peroxide production. It is widely used in pharmaceuticals, food, cosmetics, and feed industries. Natural tocopherol is in the d-configuration, including four analogs: α, β, γ, and δ. However, the inherent physicochemical properties of tocopherol also limit its applications. First, the phenolic hydroxyl group on the benzodihydropyran ring in the tocopherol structure is crucial for its antioxidant effect, but its susceptibility to oxidation causes inconvenience in the production, storage, and use of tocopherol. Second, tocopherol is a fat-soluble substance with low water solubility, which limits its absorption in the body, resulting in low bioavailability. Therefore, how to simultaneously enhance the stability and water solubility of tocopherol has received continuous attention from pharmaceutical and chemical researchers.

[0003] Tocopherol glucosides are a class of compounds formed by the hydroxyl groups of tocopherol linked to glucose via glycosidic bonds. These compounds are similar to tocopherol in physicochemical properties and biological activities, while effectively compensating for the shortcomings of tocopherol itself, including its poor water solubility and stability. After entering the human body, tocopherol glucosides are gently broken down into tocopherol precursors by enzymes, thereby exerting their effects. Furthermore, tocopherol glucosides possess biological activities not found in tocopherol, such as anti-allergic and anti-inflammatory properties, and show improvements in surface activity, moisturizing properties, and skin affinity, thus finding widespread application in the cosmetics industry.

[0004] Currently, the preparation of tocopherol glucoside typically involves a two-step reaction. First, tocopherol monomers undergo glycosylation coupling with pentaacetyl glucose under the action of an activator to prepare a protected tocopherol glycoside intermediate. Subsequently, the acyl protecting group is removed, and the product is purified. The first step is the key step in the synthesis, and many types of activators are used, mainly including protic acids and Lewis acids, such as copper chloride, ferric chloride, zinc chloride, aluminum chloride, titanium tetrachloride, tin tetrachloride, boron trifluoride, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. However, the above methods for preparing tocopherol glucoside usually face some problems, such as low yield, poor stereoselectivity, generation of oxidation byproducts, use of excess tocopherol, and the use and separation of toxic metal reagents. These factors hinder the large-scale industrial production of high-purity tocopherol glucoside. Summary of the Invention

[0005] This invention addresses the shortcomings of existing technologies by providing a high-purity tocopherol glucoside and its synthesis method.

[0006] The method for synthesizing high-purity tocopherol glucoside of the present invention includes the following steps: Tocopherol monomers and α-D-fluoropyranose were dissolved in an aqueous mixed reagent and glycosylated under alkaline conditions. After the reaction was completed, the reaction product was extracted with an organic solvent. The organic phase was washed, dried and concentrated, and the crude product was recrystallized with an alcohol solvent, filtered and dried to obtain high-purity tocopherol glucoside.

[0007] Preferably, the tocopherol monomer is one or a combination of α-tocopherol, δ-tocopherol, β-tocopherol, and γ-tocopherol.

[0008] Preferably, the molar ratio of the tocopherol monomer to α-D-fluoropyranose is 1:(2-4).

[0009] Preferably, the mass ratio of the tocopherol monomer to the volume ratio of the aqueous mixed reagent is 20g:(150-160)ml.

[0010] Preferably, the molar ratio of the α-D-fluoropyranose to the alkaline reagent is 1:(1-1.5).

[0011] Preferably, the aqueous mixed reagent is one or more of a mixture of water and an organic solvent, or an aqueous solution of trimethylamine, wherein the organic solvent includes one or more combinations of acetonitrile, acetone, tetrahydrofuran, and ethanol; The alkaline reagent includes one or a combination of two of calcium hydroxide and calcium trifluoromethanesulfonate.

[0012] More preferably, the aqueous mixed reagent is a mixture of water and an organic solvent, wherein the organic solvent includes one or more combinations of acetonitrile, acetone, tetrahydrofuran, and ethanol, and the alkaline reagent is calcium hydroxide.

[0013] Particularly preferred is that the volume ratio of water to organic solvent is (1-4):1.

[0014] More preferably, the aqueous mixed reagent is a trimethylamine aqueous solution, and the alkaline reagent is calcium trifluoromethanesulfonate; Particularly preferred is that the concentration of the trimethylamine aqueous solution is 35wt%-45wt%.

[0015] Preferably, an alkaline reagent is added at 0℃-40℃.

[0016] Preferably, the glycosylation reaction is carried out at a temperature of 0°C to 40°C and for a reaction time of 6 to 12 hours.

[0017] Preferably, the organic solvent used in the extraction is dichloromethane.

[0018] Preferably, the organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.

[0019] Preferably, the alcohol solvent is one or a combination of ethanol, methanol, and isopropanol.

[0020] Preferably, the volume ratio of the alcohol solvent to the mass ratio of the tocopherol monomer is (2-5) ml:1g.

[0021] The present invention also provides tocopherol glucoside synthesized by the above-mentioned method for synthesizing high-purity tocopherol glucoside.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows: The method for synthesizing tocopherol glucoside of the present invention requires only one reaction step, has no protecting group removal step, has high utilization of tocopherol monomer, mild reaction conditions and does not require anhydrous glycosylation reaction conditions, convenient post-processing, high product yield (above 78%), high purity (greater than 98%), and is suitable for large-scale industrial production. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the synthetic route for the synthesis of tocopherol glucoside according to the present invention.

[0024] Figure 2 The 1H NMR spectrum (600M, CDCl3) of α-tocopherol glucoside prepared in Example 1 of this invention.

[0025] Figure 3 The 1H NMR spectrum (600M, CDCl3) of δ-tocopherol glucoside prepared in Example 2 of this invention. Detailed Implementation

[0026] To further understand the present invention, preferred embodiments of the present invention are described below. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0027] like Figure 1 As shown, the method for synthesizing high-purity tocopherol glucoside of the present invention includes the following steps: Tocopherol monomers and α-D-fluoropyranose were dissolved in an aqueous mixed reagent and subjected to a (aqueous) glycosylation reaction under the action of an alkaline reagent. After the reaction was completed, the reaction product was extracted with an organic solvent. The organic phase was washed, dried and concentrated, and the crude product was recrystallized with an alcohol solvent, filtered and dried to obtain high-purity tocopherol glucoside.

[0028] In this invention, the tocopherol monomer is one or a combination of α-tocopherol, δ-tocopherol, β-tocopherol, and γ-tocopherol.

[0029] In this invention, the preferred molar ratio of tocopherol monomer to α-D-fluoropyranose is 1:(2-4). In some embodiments, molar ratios of 1:2, 1:3, 1:4, etc., are used.

[0030] In this invention, there are no special restrictions on the amount of aqueous mixed reagent used, as long as it can achieve the dissolution effect. Preferably, the mass ratio of tocopherol monomer to the volume ratio of aqueous mixed reagent is 20g:(150-160)ml. For example, in some embodiments, 20g:150ml, 20g:151ml, 20g:152ml, 20g:153ml, 20g:154ml, 20g:155ml, 20g:156ml, 20g:157ml, 20g:158ml, 20g:159ml, and 20g:160ml are used.

[0031] In this invention, the molar ratio of α-D-fluoropyranose to the alkaline reagent is 1:(1-1.5). For example, in some embodiments, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, and 1:1.5 are used.

[0032] In this invention, the aqueous mixed reagent is one or more of a mixture of water and an organic solvent, or an aqueous solution of trimethylamine, wherein the organic solvent includes one or more combinations of acetonitrile, acetone, tetrahydrofuran, and ethanol; the alkaline reagent includes one or a combination of calcium hydroxide and calcium trifluoromethanesulfonate. Preferably, the aqueous mixed reagent is a mixture of water and an organic solvent, and the alkaline reagent is calcium hydroxide. Preferably, the aqueous mixed reagent is a 35wt%-45wt% aqueous solution of trimethylamine, and the alkaline reagent is calcium trifluoromethanesulfonate. Preferably, the alkaline reagent is added at 0℃-40℃.

[0033] In this invention, the glycosylation reaction is carried out at a temperature of 0°C-40°C for 6 hours to 12 hours. In some embodiments, the reaction temperature is 25°C-30°C, and the reaction time is 6 hours, 8 hours, 10 hours, or 12 hours.

[0034] In this invention, the organic solvent used for extraction is dichloromethane.

[0035] In this invention, the organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.

[0036] In this invention, the alcohol solvent is one or a combination of ethanol, methanol, and isopropanol. The volume ratio of the alcohol solvent to the mass ratio of the tocopherol monomer is (2-5) ml:1g. For example, in some embodiments, 2 ml:1g, 3 ml:1g, 4 ml:1g, and 5 ml:1g are used.

[0037] In this invention, the crude product is preferably recrystallized in an alcohol solvent, and the resulting solid is dried under reduced pressure to obtain high-purity tocopherol glucoside.

[0038] This invention also provides high-purity tocopherol glucoside synthesized using the above-mentioned method. Testing shows that the purity can reach 78%-82%.

[0039] The present invention will be described in more detail below through examples, but the present invention is not limited to the following examples. Unless otherwise specified, the experimental methods described in the following experiments are conventional methods, and the reagents, consumables and instruments used are commercially available unless otherwise specified.

[0040] Example 1 α-D-fluoropyranose (25 g, 140 mmol) and α-tocopherol (20 g, 47.0 mmol) were placed in a round-bottom flask, and a water-acetone mixture (v / v = 1:1, 156 mL) was added and stirred to dissolve. Calcium hydroxide (10 g, 140 mmol) was added under ice bath conditions, and the reaction was continued at room temperature with stirring for 12 hours until the α-tocopherol reaction was complete. The reaction product was then extracted with dichloromethane. The extracted organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ethanol (80 mL), and the solid was filtered and dried under reduced pressure to obtain α-tocopherol glucoside (23 g, yield 82%, purity >98%).

[0041] The α-tocopherol glucoside prepared in Example 1 was analyzed by NMR. 1 The H NMR spectrum is shown in Figure 2 NMR data: 1 HNMR (600 MHz, CDCl3) δ : 5.37 (br d, 1H), 4.87 (br d, 1H), 4.78 (br d, 1H), 4.56 (d, J = 7.2 Hz, 1H), 3.79 – 3.68 (m, 5H), 3.17 (d, J= 9.6 Hz, 1H), 2.86 (brd, 1H), 2.51 – 2.45 (m, 2H), 2.12 (s, 3H), 2.09 (s, 3H), 2.00 (s, 3H), 1.76 – 1.68 (m, 2H), 1.55 – 1.03 (m, 24H), 0.86 – 0.83 (m, 12H). This confirms that the present invention synthesizes α-tocopherol glucoside.

[0042] Example 2 α-D-fluoropyranose (36 g, 200 mmol) and δ-tocopherol (20 g, 50.0 mmol) were placed in a round-bottom flask, and a water-acetonitrile mixture (v / v = 1:1, 150 mL) was added and stirred to dissolve. Calcium hydroxide (15 g, 200 mmol) was added under ice bath conditions, and stirring continued for 6 hours at room temperature until the δ-tocopherol reaction was complete. The reaction product was then extracted with dichloromethane. The extracted organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ethanol (60 mL), and the solid was filtered and dried under reduced pressure to obtain δ-tocopherol glucoside (22 g, yield 78%, purity >98%).

[0043] The δ-tocopherol glucoside prepared in Example 2 was subjected to NMR detection. 1 The H NMR spectrum is shown in Figure 3 NMR data: 1 HNMR (600 MHz, CDCl3) δ 6.64 (d, J = 3.0 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 4.76(d, J = 7.2 Hz, 1H), 4.38 (br d, 4H), 3.85 – 3.64 (m, 5H), 3.34 (d, J = 9.6 Hz, 1H), 2.59 – 2.53 (m, 2H), 2.02 (s, 3H), 1.68 – 1.03 (m, 26H), 0.86 – 0.83 (m, 12H). This confirms that the present invention synthesizes δ-tocopherol glucoside.

[0044] Example 3 α-D-fluoropyranose (26 g, 144 mmol) and β-tocopherol (20 g, 48.0 mmol) were placed in a round-bottom flask, and 45 wt% trimethylamine aqueous solution (160 mL) was added and stirred to dissolve. Calcium trifluoromethanesulfonate (49 g, 144 mmol) was added at room temperature, and the reaction was continued with stirring for 8 hours until the β-tocopherol reaction was complete. The reaction product was then extracted with dichloromethane. The extracted organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from methanol (100 mL), and the solid was filtered and dried under reduced pressure to obtain β-tocopherol glucoside (22 g, yield 80%, purity >98%).

[0045] Example 4 α-D-fluoropyranose (17 g, 96 mmol) and γ-tocopherol (20 g, 48.0 mmol) were placed in a round-bottom flask, and a water-tetrahydrofuran mixed solvent (v / v = 4:1, 160 mL) was added and stirred to dissolve. Calcium hydroxide (10.7 g, 144 mmol) was added under ice bath conditions, and the reaction was continued at 40 °C with stirring for 10 hours until the γ-tocopherol reaction was complete. Subsequently, dichloromethane was added to extract the reaction product. The extracted organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from isopropanol (40 mL), and the solid was filtered and dried under reduced pressure to obtain γ-tocopherol glucoside (22 g, yield 79%, purity >98%).

[0046] Obviously, the above embodiments are merely examples for clear illustration and are not intended to limit the embodiments. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all embodiments here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing tocopherol glucoside, characterized in that, Includes the following steps: Tocopherol monomer and α-D-fluoropyranose were dissolved in an aqueous mixed reagent and glycosylated under alkaline conditions. After the reaction was completed, the reaction product was extracted with an organic solvent. The organic phase was washed, dried and concentrated. The crude product was recrystallized with an alcohol solvent, filtered and dried to obtain tocopherol glucoside.

2. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, The tocopherol monomers include one or more combinations of α-tocopherol, δ-tocopherol, β-tocopherol, and γ-tocopherol.

3. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, The molar ratio of the tocopherol monomer to α-D-fluoropyranose is 1:(2-4).

4. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, The molar ratio of the α-D-fluoropyranose to the alkaline reagent is 1:(1-1.5).

5. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, It possesses one or more of the following characteristics: The mass ratio of the tocopherol monomer to the volume ratio of the aqueous mixed reagent is 20g:(150-160)ml; The aqueous mixed reagent is one or more of a mixture of water and an organic solvent, or an aqueous solution of trimethylamine, wherein the organic solvent includes one or more of acetonitrile, acetone, tetrahydrofuran, and ethanol. The alkaline reagent includes one or a combination of two of calcium hydroxide and calcium trifluoromethanesulfonate; Add an alkaline reagent at 0℃-40℃.

6. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, The glycosylation reaction is carried out at a temperature of 0℃-40℃ for a time of 6h-12h.

7. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, The organic solvent used in the extraction is dichloromethane.

8. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.

9. The method for synthesizing tocopherol glucoside according to claim 1, characterized in that, It possesses one or more of the following characteristics: The alcohol solvent is one or a combination of ethanol, methanol, and isopropanol; The volume ratio of the alcohol solvent to the mass ratio of the tocopherol monomer is (2-5) ml:1 g.

10. Tocopherol glucoside synthesized by the method for synthesizing tocopherol glucoside according to any one of claims 1-9.

Images