Glucoside derivative as well as synthesis method and application thereof

Abstract

The invention provides a glucoside derivative as well as a synthesis method and application thereof. The structure of the glucoside derivative is as follows: R1 is selected from alpha glucoside, beta glucoside or hydroxyl; r2 is selected from alpha glucoside, beta glucoside or hydroxyl; r3 is alkyl; the synthesis method comprises the following steps: S1, carrying out amination reaction on pentaacetylglucose serving as a raw material to obtain tetraacetylglucose; s2, obtaining a glycosylation donor from the tetraacetylglucose under the action of a glycosylation donor reagent; s3, carrying out glycosylation reaction on the glycosylation donor to obtain a glycosylation intermediate product; and S4, carrying out deprotection on the glycosylation intermediate product to obtain a target product. Research finds that when R3 is an alkyl group with the carbon atom number of 3, a more advantageous whitening characteristic is achieved, and the method has the advantages of being milder and low in cost.

Description

Technical Field

[0001] This invention relates to chemical methods and new cosmetic raw materials, specifically to a synthetic process for a glucoside derivative and several new compounds synthesized based on this process, as well as the application of these new compounds in the cosmetic field. Background Technology

[0002] Compounds containing resorcinol structures, such as 4-butylresorcinol, have good whitening effects in cosmetics. However, these compounds are prone to auto-oxidation, resulting in problems such as strong irritation, reduced whitening activity, easy discoloration, and affecting the overall stability of the formula.

[0003] To address the aforementioned shortcomings, existing patent (CN 120173034 A) discloses a class of skin-whitening compounds in which glycosides are grafted onto the phenolic hydroxyl position of 4-butylresorcinol, including 4-butylresorcinol-1-o-α-glucoside and 4-butylresorcinol-1-o-β-glucoside. These compounds protect the hydroxyl group through the steric hindrance effect of the glycosides, reducing free radical generation and skin irritation. Furthermore, they can restore skin-whitening activity through skin microecological degradation, significantly improving the application defects of 4-butylresorcinol. However, research on the synthesis process of this compound has revealed certain limitations, specifically as follows: The preparation of α-glucosides requires the use of BF3-Et2O catalysis to initiate the glycosylation donor under low temperature conditions of -15 to -20℃, and the reaction must be carried out under argon protection for 18 hours. The reaction conditions are harsh and the energy consumption is high.

[0004] The preparation of β-glucosides requires the first reaction of fully acetylated glucose with 33% HBr / acetic acid solution to prepare a bromoglycoside donor, followed by reaction with activated 4-butylresorcinol at 55°C for 24 hours. The reaction involves highly corrosive HBr / acetic acid solution, which poses a high operational risk and results in a long reaction time and low production efficiency.

[0005] Insufficient optimization of the elution system in column chromatography purification steps leads to a need for further improvement in product yield and purity, which is detrimental to large-scale industrial production.

[0006] The cost of some raw materials in the existing process is extremely high (the lowest cost per kilogram is 500,000), which is not conducive to large-scale industrial production and market promotion. Summary of the Invention

[0007] The present invention aims to overcome the above-mentioned defects and develop a new process for synthesizing whitening compounds with mild reaction conditions, simple operation, high production efficiency and controllable cost, which is of great significance for promoting the large-scale application of such whitening compounds.

[0008] This invention discloses a method for synthesizing a glucoside derivative. The structure of the glucoside derivative is as follows: ; R1 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R2 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R3 is an alkyl group; The synthesis method is as follows: S1. Tetraacetyl glucose is obtained from pentaacetyl glucose via an amination reaction; S2. Tetraacetyl glucose is converted into a glycosylation donor by the action of a glycosylation donor reagent; S3. Glycosylation of the glycosylation donor yields the glycosylation intermediate; S4. The target product is obtained by deprotection of the glycosylation intermediate; The structural formula of tetraacetyl glucose is shown below: ; The structural formula of the glycosylation donor is shown below: ; The structural formula of the glycosylation intermediate is shown below: ; R1' is Or hydroxyl group, R2' is Or hydroxyl group.

[0009] In the above synthesis method, the amination reaction is carried out at room temperature for 25-35 h; The molar ratio of pentaacetyl glucose to the amination reagent is 1:1-1.6.

[0010] In S2, under the protection of a protective gas and at a temperature not exceeding 0°C, the glycosylation donor and the catalytic activator are added sequentially to the reaction product of S1, and the reaction is carried out at room temperature for 2.5-3.5 h. The molar ratio of tetraacetyl glucose, glycosylation donor reagent, and catalytic activator is 1:3.8-4.2:0.18-0.22.

[0011] In S3, under the protection of a protective gas, at a temperature of -15 to -5°C, a catalyst is added to the mixture of the reaction product of S2 and 4-alkylresorcinol, and the reaction is carried out at -8 to -2°C for 8-12 hours. The molar ratio of the glycosylation donor to 4-alkylresorcinol and the catalyst is 1.4-2.8:1:0.4-0.6.

[0012] In S4, after adding the deprotecting agent to the reaction product of S3 at a temperature not exceeding 0°C, the reaction is carried out at room temperature for 6-8 hours. The molar ratio of the glycosylation intermediate to the deprotecting agent is 1:0.9-1.1.

[0013] In S4, after the reaction is complete, the reaction is quenched by the acidic medium; The amount of acidic medium added is 0.6-0.8 times the mass of the glycosylation intermediate.

[0014] In addition, the present invention also provides a new class of glucoside derivatives, the structural formula of which is shown below: ; R1 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R2 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R3 is an alkyl group with 3 carbon atoms.

[0015] The preferred compounds are: 4-Propylresorcinol-1-o-α-glucoside, 4-Propylresorcinol-1-o-β-glucoside, 4-Propylresorcinol-1,3-bis-α-glucoside, 4-Propylresorcinol-1,3-bis-β-glucoside, 4-Isopropylresorcinol-1-o-α-glucoside, 4-Isopropylresorcinol-1-o-β-glucoside, 4-Propylresorcinol-1,3-bis-α-glucoside, 4-Isopropylresorcinol-1,3-bis-β-glucoside.

[0016] This invention also suggests the application of glucoside derivatives in the preparation of cosmetics / skincare products, particularly for the preparation of whitening products.

[0017] Functions and effects of this invention: This invention provides a novel synthetic process for skin-whitening compounds. The process uses pentaacetyl glucose as the starting material and proceeds through four steps: amination, glycosylation donor preparation, glycosylation, and deprotection to obtain the target product. It offers advantages such as mild reaction conditions, safe operation, readily available raw materials, high product yield and purity, and low production cost, making it suitable for industrial production.

[0018] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] This embodiment provides a method for synthesizing a glucoside derivative, the structure of which is shown below: R1 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R2 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group. R3 is an alkyl group.

[0020] The synthesis method includes the following steps: S1. Amination Reaction: Using pentaacetyl glucose as a raw material, tetraacetyl glucose is obtained through an amination reaction. Specifically, pentaacetyl glucose is dissolved in a polar aprotic solvent (such as tetrahydrofuran, dioxane, ethers, acetone, nitrile solvents), and an amination reagent (such as benzylamine, N-methylbenzylamine, dibenzylamine, methylamine, ethylamine, etc.) is added. The reaction is carried out at room temperature for 25-35 hours. After removing the solvent under reduced pressure, the residue is purified by column chromatography to obtain pure tetraacetyl glucose and a mixture of tetraacetyl glucose and acetylbenzylamine.

[0021] The structural formula of tetraacetyl glucose is shown below: .

[0022] In this embodiment, solvents with good solubility, such as tetrahydrofuran, are used to ensure thorough mixing of the reactants.

[0023] Using amines such as benzylamine as amination reagents, the molar ratio of benzylamine to pentaacetyl glucose is controlled between 1.1 and 1.6 equivalents, preferably between 1.4 and 1.6, which can ensure that the reaction proceeds fully and avoid the subsequent separation difficulties caused by excess amine.

[0024] The room temperature reaction conditions are mild, requiring no additional heating or cooling equipment, which reduces energy consumption and operational difficulty.

[0025] In post-processing, the eluent for column chromatography is selected from a mixture of ether and ester, preferably a mixture of petroleum ether and ethyl acetate, with a volume ratio of 5:1 to 2:1. In some experimental examples, alcohol was used as the eluent, but the products could not be effectively separated.

[0026] S2. Preparation of Glycosylation Donor: Tetraacetyl glucose is used to obtain a glycosylation donor under the action of a glycosylation donor reagent. Specifically: Under the protection of nitrogen or other protective atmosphere, the tetraacetyl glucose obtained in S1 (which may contain unseparated acetylbenzylamine, but this does not affect subsequent reactions) is dissolved in a solvent (the solvent can be selected from low-boiling-point, slightly polar solvents that can dissolve a variety of organic compounds, such as anhydrous dichloromethane, chloroform, tetrachloromethane, ethyl acetate, acetone, etc.). After cooling to a temperature not higher than 0°C, a glycosylation donor reagent (such as trichloroacetonitrile) and a catalyst activator (such as DBU, MTBD, DBN, DABCO, TMG, DMAP, etc.) are added sequentially. The reaction is carried out at room temperature for 2.5-3.5 h. After removing the solvent under reduced pressure, the residue is purified by column chromatography to obtain the glycosylation donor.

[0027] The structural formula of the glycosylation donor is shown below: .

[0028] In this embodiment, the protective gas protection can effectively prevent oxygen in the air from interfering with the reaction, ensuring the selectivity and repeatability of the reaction.

[0029] Trichloroacetonitrile and other key reagents, when used as glycosylation donors, are present in a molar ratio of 3.8-4.2 with the reactants, ensuring that tetraacetyl glucose is fully converted into glycosylation donors.

[0030] When DBU and other catalysts are used, a molar ratio of 0.18 to 0.22 with the reactants can efficiently catalyze the reaction, thus reducing the cost of the catalyst.

[0031] Cooling at 0°C can prevent the reaction from becoming too violent and improve the safety of the reaction.

[0032] In the post-processing, the eluent for column chromatography is selected from a mixture of ether and ester, preferably a mixture of petroleum ether and ethyl acetate, with a volume ratio of 10:1 to 3:1.

[0033] S3. Glycosylation reaction: The glycosylation donor of S2 is glycosylated to obtain a glycosylation intermediate. Specifically: Under the protection of a protective gas, the glycosylation donor obtained from S2 is dissolved with 4-alkylresorcinol in a solvent (the solvent can be selected from low-boiling-point, slightly polar solvents that can dissolve a variety of organic compounds, such as anhydrous dichloromethane, chloroform, tetrachloromethane, ethyl acetate, acetone, etc.), cooled to -15~-5℃, and a catalyst (such as boron trifluoride diethyl ether, aluminum trichloride, titanium tetrachloride, etc.) is added. The reaction is carried out at -8~-2℃ for 8-12 hours. The reaction is quenched with an inorganic alkaline solution such as saturated sodium bicarbonate. The aqueous phase is extracted with haloalkanes such as dichloromethane and chloroform. The organic phases are combined, washed, dried, and the solvent is removed under reduced pressure. The residue is purified by column chromatography to obtain the glycosylation intermediate.

[0034] The structural formula of the glycosylation intermediate is shown below: ; R1' is Or hydroxyl group, R2' is Or hydroxyl group.

[0035] In this embodiment, anhydrous dichloromethane and the like are used as solvents with good hydrophobicity and solubility, which is beneficial to the reaction and subsequent separation.

[0036] Adding catalysts such as boron trifluoride diethyl ether under cooling conditions of -15~-5℃ can avoid excessive activation of the reactants by the catalyst, which could lead to side reactions.

[0037] Controlling the reaction temperature between -8 and -2℃ ensures both the reaction rate and the regioselectivity of the reaction, while reducing the formation of byproducts.

[0038] The molar ratio of the glycosylation donor to 4-alkylresorcinol is 2.4-2.8:1.

[0039] Boron trifluoride diethyl ether and other catalysts, used in amounts of 0.4-0.6 equivalents, exhibit high catalytic efficiency and can effectively promote the glycosylation reaction between glycosylation donors and 4-alkylresorcinol.

[0040] Alkaline solutions such as saturated sodium bicarbonate can mildly quench the reaction, effectively neutralize excess catalyst, and prevent product degradation.

[0041] Washing the organic phase with saturated brine and drying it with anhydrous sodium sulfate can effectively remove impurities and moisture, improving the efficiency of subsequent purification.

[0042] In the post-processing, the eluent for column chromatography is selected from a mixture of ether and ester, preferably a mixture of petroleum ether and ethyl acetate, with a volume ratio of 5:1 to 1:1.

[0043] S4. Deprotection reaction: The glycosylation intermediate of S3 is deprotected to obtain the target product. Specifically: The glycosylation intermediate obtained from S3 is dissolved in an alcohol (e.g., anhydrous methanol), cooled to a temperature not exceeding 0°C, and a deprotection reagent (e.g., sodium methoxide, K2CO3 / MeOH, NaOH / H2O, LiOH / H2O, etc.) is added. The reaction is carried out at room temperature for 6-8 hours, and the reaction is quenched by adding an acidic medium (e.g., acidic resin Amberlite IR-120H). After stirring for 0.5-1.5 hours, the acidic medium is removed by filtration, and the solvent is removed from the filtrate under reduced pressure to obtain the target compound.

[0044] In this embodiment, anhydrous methanol and other alcohols have good solubility for the glycosylation intermediates as solvents, and when sodium methoxide is used as the deprotection reagent, it has good solubility in methanol, which can ensure that the deprotection reaction proceeds fully.

[0045] Adding the deprotecting agent at a temperature not exceeding 0°C can prevent the deprotection reaction from being too vigorous and causing the glycosidic bond to break.

[0046] The molar ratio of the deprotecting agent to the glycosylation intermediate is 0.9-1.1 equivalents, which ensures complete removal of the acetyl group while avoiding product contamination caused by excessive deprotecting agent.

[0047] The acidic medium quenches the reaction gently, facilitates filtration and separation, and does not introduce new impurities, effectively ensuring product purity.

[0048] Based on the above method, the following compounds were preferably obtained: 4-propylresorcinol-1-o-α-glucoside, 4-propylresorcinol-1-o-β-glucoside, 4-propylresorcinol-1,3-bis-α-glucoside, 4-propylresorcinol-1,3-bis-β-glucoside, 4-isopropylresorcinol-1-o-α-glucoside, 4-isopropylresorcinol-1-o-β-glucoside, 4-propylresorcinol-1,3-bis-α-glucoside, and 4-isopropylresorcinol-1,3-bis-β-glucoside.

[0049] Example 1. Preferred Solution Perform under the preferred conditions shown in the following equation: .

[0050] Example 1.1 Synthesis of 4-Butylresorcinol-1,3-bis-α-glucoside .

[0051] Perform the synthesis according to steps (1)-(4) above: Step (1): Dissolve 39 g (0.1 mol) of pentaacetyl glucose in 300 mL of tetrahydrofuran, add 25 mL (0.15 mol) of benzylamine, react at room temperature for 30 h, remove solvent under reduced pressure, and purify by column chromatography (PE / EA=5:1~2:1) to obtain 32 g of pure tetraacetyl glucose, with a yield of 85%.

[0052] 1H-NMR(500 MHz) δ 5.51(t, 1H, J = 12 Hz), 5.44(d, 1H, J = 4.5 Hz), 5.06(t, 1H, J= 12 Hz), 4.87(dd, 1H, J = 12 Hz, 4.5 Hz), 4.23(m, 2H), 4.10(m,1H), 2.07(d, 6H, J = 5.5 Hz), 2.00(d, 6H, J = 7.9 Hz). HRMS (M+1) m / z349.11243.

[0053] Step (2): Take 17.4 g (50 mmol) of the above mixture, dissolve it in 100 mL of anhydrous dichloromethane, cool it to 0℃ under nitrogen protection, add 9 mL (50 mmol) of trichloroacetonitrile and 0.38 mL (2 mmol) of DBU, react at room temperature for 3 h, remove the solvent under reduced pressure, and purify by column chromatography (PE / EA=10:1~3:1) to obtain 19.5 g of glycosylation donor, with a yield of 80%.

[0054] 1H-NMR(500 MHz) δ 8.69(s, 1H), 6.56(d, 1H, J = 4.5 Hz), 5.56(t, 1H, J = 12.5 Hz), 5.18(m, 2H), 4.87(dd, 1H, J = 12 Hz, 4.5 Hz), 4.23(m, 2H), 4.10(m, 1H), 2.07(s, 3H), 2.05(s, 3H), 2.03(s, 3H), 2.01(s, 3H). HRMS (M+1) m / z492.02417.

[0055] Step (3): Dissolve 9.81 g (20 mmol) of glycosylation donor and 1.66 g (10 mmol) of 4-butylresorcinol in 12 mL of anhydrous dichloromethane. Cool to -10 °C under nitrogen protection, add 31 μL (0.5 mmol) of boron trifluoride ether, react at -5 °C for 10 h, quench with saturated sodium bicarbonate solution, extract with dichloromethane, wash and dry the organic phase, remove solvent under reduced pressure, and purify by column chromatography (PE / EA=5:1~1:1) to obtain 6.2 g of disaccharide glycosylation intermediate, yield 75%.

[0056] Step (4): Take 2.08 g (2.5 mmol) of the glycosylation intermediate, dissolve it in 20 mL of anhydrous methanol, cool it to 0℃, add 14 g (2.5 mmol) of sodium methoxide, react at room temperature for 7 h, add 1.5 g of acidic resin Amberlite IR-120H to quench the reaction, stir for 1 h, filter, remove the solvent from the filtrate under reduced pressure, and obtain 1.2 g of 4-butylresorcinol-1-o-α-glucoside with a purity of 96.3% and a yield of 98.5%. 1 H-NMR(500 MHz) δ 7.15(d, 1H), 6.89(d, 1H, J = 10.5Hz), 6.67(d, 1H, J = 7.9 Hz), 5.81(d, 2H, J = 7.9 Hz), 4.14(d, 2H, J = 7.9 Hz),3.75-3.57(m, 10H), 2.52(t, 2H, J = 7.9 Hz), 1.52(m, 2H), 1.33(m, 2H), 0.90(t,3H, J = 7.9 Hz). HRMS (M+ Na) m / z 513.19452. Example 1.2 Synthesis of 4-n-propylresorcinol-1,3-bis-α-glucoside

[0057] .

[0058] Steps (1)-(2) are the same as in Example 1, yielding 213 g of glycosylated donor.

[0059] Step (3): Take 128 g (0.26 mol) of glycosylation donor and 15.2 g (0.1 mol) of 4-propylresorcinol, dissolve them in 3 L of anhydrous dichloromethane, cool to -10℃ under nitrogen protection, add 62 mL (10 mmol) of boron trifluoride ether, react at -5℃ for 12 h, quench with saturated sodium bicarbonate solution, extract with dichloromethane, wash and dry the organic phase, remove solvent under reduced pressure, and purify by column chromatography (PE / EA=4:1~1:1) to obtain 62 g of disaccharide glycosylation intermediate.

[0060] Step (4): Take 406 mg (0.5 mmol) of the disaccharide glycosylation intermediate, dissolve it in 3 mL of anhydrous methanol, cool it to 0℃, add 27 mg (0.5 mmol) of sodium methoxide, react at room temperature for 8 h, add 200 mg of acidic resin Amberlite IR-120H to quench the reaction, stir for 1 h, filter, remove the solvent from the filtrate under reduced pressure, and obtain 148 mg of 4-n-propylresorcinol-1,3-bis-α-glucoside with a purity of 95.7% and a yield of 62.3%. 1 H-NMR(500 MHz) δ 7.20(d, 1H), 6.77(d, 1H, J =10.5 Hz), 6.60(d, 1H, J = 7.9 Hz), 5.61(d, 2H, J = 7.9 Hz), 4.20(d, 2H, J = 7.9Hz), 3.81-3.55(m, 10H), 2.47(t, 2H, J = 7.9 Hz), 1.63(m, 2H), 0.91(t, 3H, J =7.9 Hz). HRMS (M+ Na) m / z 499.19145. Example 1.3. Synthesis of 4-isopropylresorcinol-1,3-bis-α-glucoside

[0061] .

[0062] Steps (1)-(2) are the same as in Example 1, yielding 213 g of glycosylated donor.

[0063] Step (3): Take 128 g (0.26 mol) of glycosylation donor and 15.2 g (0.1 mol) of 4-isopropylresorcinol, dissolve them in 3 L of anhydrous dichloromethane, cool to -10℃ under nitrogen protection, add 62 mL (10 mmol) of boron trifluoride ether, react at -5℃ for 12 h, quench with saturated sodium bicarbonate solution, extract with dichloromethane, wash and dry the organic phase, remove solvent under reduced pressure, and purify by column chromatography (PE / EA=4:1~1:1) to obtain 59 g of disaccharide glycosylation intermediate.

[0064] Step (4): Take 406 mg (0.5 mmol) of the disaccharide glycosylation intermediate, dissolve it in 3 mL of anhydrous methanol, cool it to 0 °C, add 27 mg (0.5 mmol) of sodium methoxide, react at room temperature for 8 h, add 200 mg of acidic resin Amberlite IR-120H to quench the reaction, stir for 1 h, filter, remove the solvent from the filtrate under reduced pressure, and obtain 155 mg of 4-isopropylresorcinol-1,3-bis-α-glucoside with a purity of 95.7% and a yield of 67.5%. 1 H-NMR(500 MHz) δ 7.21(d, 1H), 6.87(d, 1H, J =10.5 Hz), 6.70(d, 1H, J = 7.9 Hz), 5.66(d, 2H, J = 7.9 Hz), 4.29(d, 2H, J = 7.9Hz), 3.88-3.65(m, 10H), 3.25(m, 1H), 1.10(t, 6H, J = 7.9 Hz). HRMS (M+ Na) m / z 499.19145. Example 2. Inhibitory effect of compounds 1.1-1.3 from the Staphylococcus epidermidis metabolites on intracellular tyrosinase activity in B16F10 melanoma cells.

[0065] 2.1. Preparation of Staphylococcus epidermidis metabolites of whitening compounds Taking the compound provided in Example 1 as an example, *Staphylococcus epidermidis* stored at -80 °C was revived in LB liquid medium at 37 °C and 200 rpm for approximately 24 h. The activated strain was collected by centrifugation at 4000 rpm for 2 min, washed twice with sterile water, and the medium was removed. The bacterial cells were resuspended in sterile water to achieve an OD600 value of approximately 0.6. 600 μl of the bacterial suspension was added to each sample group (whitening agent, compound of Example 1) or blank control in a 24-well plate, with a final concentration of 100 ppm for each sample group. After continuous incubation at 37 °C and 100 rpm for 8 h, the supernatant was collected and filtered twice through a 0.22 μm filter membrane for sterilization, then lyophilized. The supernatant was then dispersed in 600 μL of DMEM high-glucose medium to obtain *Staphylococcus epidermidis* metabolites of the test sample (whitening agent, whitening compound) or blank control sample with a final concentration of 100 ppm for subsequent experiments.

[0066] 2.2. Test of inhibitory effect B16 melanoma cells in good growth condition were seeded at a concentration of 60,000 cells / well in 24-well plates (using Gibco's DMEM high-glucose medium). After 24 hours, the prepared test samples (whitening agents, whitening compounds) or blank control samples containing Staphylococcus epidermidis metabolites were added to bring the final concentration of the sample group to 100 ppm. The plates were then cultured at 37°C for 48 hours. After washing three times with PBS, 500 μL of PBS solution containing 0.1 mmol / L L-DOPA and 0.1% Triton-X was added to each well. After incubation at 37°C for 30 minutes, the OD value at 475 nm was measured. The inhibitory effect of whitening agents or whitening compounds on tyrosinase activity was calculated according to the following formula. The results are shown in the table below.

[0067] Tyrosinase activity inhibition rate = [1 - (sample group OD475nm) / (blank group OD475nm)] × 100%.

[0068] 2.3. Results of the inhibitory effect The results are shown in Table 1. The three compounds provided in Examples 1.1-1.3 showed that they inhibited the activity of tyrosinase in B16F10 melanoma cells, and the inhibition levels were 4-isopropylresorcinol-1,3-bis-α-glucoside > 4-n-propylresorcinol-1,3-bis-α-glucoside > 4-butylresorcinol-1,3-bis-α-glucoside. They all helped to alleviate or improve skin pigmentation.

[0069] Table 1. Effects of Staphylococcus epidermidis metabolites on intracellular tyrosinase activity in B16F10 melanoma cells: Sample Name Tyrosinase activity inhibitors (%) 4-Butylresorcinol-1,3-bis-α-glucoside 58.01 4-Propylresorcinol-1,3-bis-α-glucoside 67.11 4-Isopropylresorcinol-1,3-bis-α-glucoside 73.57 .

[0070] The function and effect of this embodiment: Compared with the existing technology CN 120173034 A process, this embodiment has the following significant advantages: The reaction conditions are milder: Existing processes for preparing α-glucosides require reaction at -15 to -20°C under argon protection for 18 hours; the reaction temperature of the process of this invention is mainly concentrated between -10°C and room temperature, without the need for extreme low or high temperature conditions, and nitrogen protection is sufficient, making the operation simpler, the energy consumption lower, and the equipment requirements simpler.

[0071] Safer operation: Existing processes require the use of a 33% HBr / acetic acid solution, which is highly corrosive and poses a high operational risk; the process in this embodiment does not use any highly corrosive or toxic reagents, and the reaction process is mild and controllable, resulting in higher safety.

[0072] Shorter reaction time: The key reaction step (glycosylation reaction) of the existing process takes 18-24 hours, while the glycosylation reaction of the process in this embodiment only takes 10 hours and the deprotection reaction takes 7 hours. The overall reaction cycle is shortened and the production efficiency is significantly improved.

[0073] Raw materials are more readily available and the cost is lower: The process in this embodiment uses pentaacetyl glucose as the starting material, and reagents such as benzylamine, trichloroacetonitrile, and DBU are all commercially available common chemicals that are inexpensive and readily available. In existing processes, some reagents (such as specific bromoglycoside donor precursors) are more expensive and the preparation process is more complicated. The process of this invention effectively reduces the cost of raw materials.

[0074] High product yield and purity: The process in this embodiment optimizes the column chromatography elution system and adopts a gradient elution method, which effectively improves the separation and purification efficiency of each step of the product. The final target product purity can reach more than 95%, and the yield is stable, which has significant advantages over the existing process.

[0075] Wider applicability: The process in this embodiment can be applied to the preparation of both monoglucoside and diglucoside whitening compounds. By adjusting the molar ratio of glycosylation donor to 4-butylresorcinol, the targeted synthesis of different target products can be achieved. The process in this embodiment is more versatile.

Claims

1. A method for synthesizing a glucoside derivative, characterized in that: The structure of the glucoside derivative is as follows: ； R1 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R2 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R3 is an alkyl group; The synthesis method is as follows: S1. Tetraacetyl glucose is obtained from pentaacetyl glucose via an amination reaction; S2. The tetraacetyl glucose is subjected to a glycosylation donor reagent to obtain a glycosylation donor; S3. The glycosylation donor is subjected to a glycosylation reaction to obtain a glycosylation intermediate; S4. The glycosylation intermediate is deprotected to obtain the target product; The structural formula of the tetraacetyl glucose is shown below: ； The structural formula of the glycosylation donor is shown below: ； The structural formula of the glycosylation intermediate is shown below: ； R1' is Or hydroxyl group, R2' is Or hydroxyl group.

2. The method for synthesizing a glucoside derivative as described in claim 1, characterized in that: The amination reaction is carried out at room temperature for 25-35 hours; The molar ratio of the pentaacetyl glucose to the amination reagent is 1:1-1.

6.

3. The method for synthesizing a glucoside derivative as described in claim 1, characterized in that: In S2, under the protection of a protective gas and at a temperature not exceeding 0°C, the glycosylation donor and the catalytic activator are added sequentially to the reaction product of S1, and the reaction is carried out at room temperature for 2.5-3.5 h. The molar ratio of tetraacetyl glucose, glycosylation donor reagent and catalytic activator is 1:3.8-4.2:0.18-0.

22.

4. The method for synthesizing a glucoside derivative as described in claim 1, characterized in that: In S3, under the protection of a protective gas, at a temperature of -15 to -5°C, a catalyst is added to the mixture of the reaction product of S2 and 4-alkylresorcinol, and the reaction is carried out at -8 to -2°C for 8-12 hours. The molar ratio of the glycosylation donor to 4-alkylresorcinol and the catalyst is 2.4-2.8:1:0.4-0.

6.

5. The method for synthesizing a glucoside derivative as described in claim 1, characterized in that: In S4, after adding the deprotecting agent to the reaction product of S3 at a temperature not exceeding 0°C, the reaction is carried out at room temperature for 6-8 hours. The molar ratio of the glycosylation intermediate to the deprotecting agent is 1:0.9-1.

1.

6. The method for synthesizing a glucoside derivative as described in claim 1, characterized in that: In S4, after the reaction is complete, the reaction is quenched by the acidic medium; The amount of acidic medium added is 0.6-0.8 times the mass of the glycosylation intermediate.

7. A glucoside derivative, characterized in that, The structural formula is as follows: ； R1 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R2 is selected from α-glucosinolate, β-glucosinolate, or hydroxyl group; R3 is an alkyl group with 3 carbon atoms.

8. A glucoside derivative as described in claim 7, characterized in that: The following glucoside derivatives: 4-Propylresorcinol-1-o-α-glucoside, 4-Propylresorcinol-1-o-β-glucoside, 4-Propylresorcinol-1,3-bis-α-glucoside, 4-Propylresorcinol-1,3-bis-β-glucoside, 4-Isopropylresorcinol-1-o-α-glucoside, 4-Isopropylresorcinol-1-o-β-glucoside, 4-Propylresorcinol-1,3-bis-α-glucoside, 4-Isopropylresorcinol-1,3-bis-β-glucoside.

9. The application of the glucoside derivative as described in claim 7 in the preparation of cosmetics / skincare products.

10. The application of the glucoside derivative as described in claim 7 in the preparation of skin whitening products.

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