Sugar derivatives of hydroxycinnamic acid, process for their preparation and use in cosmetics

Abstract

The application discloses a sugar derivative of hydroxycinnamic acid, a preparation method thereof and application of the sugar derivative in cosmetics. Specifically, the application provides a sugar derivative of hydroxycinnamic acid, which is a compound as shown in formula I. The sugar derivative of hydroxycinnamic acid has better water solubility and stability than original hydroxycinnamic acid, and has one or more functions such as antioxidation, whitening, soothing, moisturizing and ultraviolet absorption. The application of the sugar derivative in cosmetics can reduce photoaging damage of skin and brighten skin color.

Description

Technical Field

[0001] This invention relates to sugar derivatives of hydroxycinnamic acid, their preparation methods, and their applications in cosmetics. Background Technology

[0002] Hydroxycinnamic acid compounds, such as hydroxycinnamic acid, caffeic acid, and ferulic acid, possess significant antioxidant, whitening, and antibacterial effects in the cosmetics field. They can effectively resist free radical damage to the skin, delay skin aging, inhibit melanin production, brighten skin tone, and maintain a healthy skin environment. However, the application of these compounds is limited by their structural characteristics, resulting in poor solubility and stability. In cosmetic formulations, the low solubility of cinnamic acid compounds in both aqueous and oil phases makes it difficult to mix them thoroughly with other ingredients, affecting the uniformity and stability of the product. This not only limits their application range in cosmetics but may also lead to problems such as layering and precipitation during product use, affecting the consumer experience. Furthermore, these compounds are easily degraded under light conditions and in aqueous solutions with a pH greater than 5, causing discoloration and altered odors, affecting the application stability of the formulation and the product's shelf life. Therefore, despite the many potential advantages of cinnamic acid compounds, these problems still need to be addressed in practical applications to fully realize their efficacy in cosmetics.

[0003] In the cosmetics industry, sugars and sugar derivatives are widely used due to their superior properties, typically playing multiple roles as humectants, skin feel modifiers, and skin conditioning agents. They effectively absorb moisture from the air, providing long-lasting hydration and helping to maintain skin's moisture and elasticity. Simultaneously, these ingredients possess good lubricity, improving product texture, making it smoother and easier to apply, and enhancing the user experience. For the skin, sugars and sugar derivatives have many positive effects; they can strengthen the skin barrier function, reduce moisture loss, and promote skin cell repair and regeneration, helping to improve dryness and roughness. In some cases, these ingredients also possess antioxidant and anti-inflammatory properties, helping to protect the skin from environmental damage and delaying skin aging. Furthermore, the reactivity and water solubility of sugars and sugar derivatives allow them to be well-compatible with other ingredients in various cosmetic formulations, facilitating processing and application.

[0004] However, current cinnamic acid derivatives often suffer from poor stability or weak antioxidant activity. There is a need in this field to develop a compound that can retain the activity of cinnamic acid components and sugars or sugar derivatives while possessing excellent stability and water solubility. Summary of the Invention

[0005] The present application aims to solve the technical problem of overcoming the defects of poor solubility and poor stability of hydroxycinnamic acid derivatives in the prior art, and provides a sugar derivative of hydroxycinnamic acid with good water solubility, excellent stability, and good skin efficacy.

[0006] The present application solves the above technical problems by the following technical solutions:

[0007] The present application provides a sugar derivative of hydroxycinnamic acid; it is a compound as shown in formula I;

[0008] ;

[0009] Among them, the wavy line directly connected to the double bond indicates that the double bond is in E or Z configuration;

[0010] R1 is H, hydroxyl or C 1-3 alkoxy;

[0011] R2 is a group formed by removing one H on the hydroxyl, amino or -NH- of any of the following sugars or sugar derivatives: 、 、 、 、 、 、 or ;

[0012] When R2 is a group formed by removing one H on the hydroxyl, amino or -NH- of or , R2 is not or .

[0013] In some embodiments, in the compound as shown in formula I, the definition of some groups can be as follows, and the definition of other groups can be as described in any scheme of the present application (hereinafter referred to as in some embodiments), R1 is H, hydroxyl or methoxyl.

[0014] In some embodiments, the structural unit is 、 or .

[0015] In some embodiments, R2 is a group formed by removing one H on the hydroxyl, amino or -NH- of any of the following sugars or sugar derivatives: 、 、 、 、 、 or .

[0016] In some embodiments, R2 is , , , , , or .

[0017] In some embodiments, the carbon-carbon double bond in the compound of Formula I is in the E configuration.

[0018] In some embodiments, the sugar derivative of hydroxycinnamic acid is any one of the following compounds:

[0019] , , , , , , , , , , or .

[0020] In some embodiments, the sugar derivative of hydroxycinnamic acid is any one of the following compounds , , , , , , , , , , or .

[0021] The present application also provides a method for preparing the aforementioned sugar derivative of hydroxycinnamic acid; which comprises the following steps:

[0022] ;

[0023] condensing the compound of Formula II and R2H in the presence of a solvent to form the sugar derivative of hydroxycinnamic acid;

[0024] wherein R1 and R2 are as defined in any one of the schemes herein.

[0025] The condensation reaction can be a conventional esterification reaction or amidation reaction; when the atom to which R2 is attached is O, the condensation reaction is an esterification reaction; when the atom to which R2 is attached is N, the condensation reaction is an amidation reaction.

[0026] The esterification reaction can employ a conventional catalyst for such reaction; the catalyst can be an acid or a base; the acid can be a strong acid; such as sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid; for example, p-toluenesulfonic acid; the base can be sodium hydroxide, potassium hydroxide, potassium carbonate, triethylamine, pyridine or 4-dimethylaminopyridine; for example, 4-dimethylaminopyridine.

[0027] The esterification reaction can employ a conventional solvent for such reaction; including one or more of an aromatic heterocyclic solvent, an aromatic hydrocarbon solvent, an amide solvent, a halogenated hydrocarbon solvent, an ether solvent, an aliphatic hydrocarbon solvent and a sulfoxide solvent; the aromatic heterocyclic solvent can be pyridine; the aromatic hydrocarbon solvent can be toluene; the amide solvent can be N,N-dimethylformamide; the halogenated hydrocarbon solvent can be dichloromethane or chloroform; the ether solvent can be tetrahydrofuran; the aliphatic hydrocarbon solvent can be cyclohexane or n-hexane; the sulfoxide solvent can be dimethyl sulfoxide; preferably, the solvent for the esterification reaction is one or more of pyridine, dichloromethane and toluene.

[0028] In the esterification reaction, the molar ratio of the compound of formula II to R2H can be a conventional molar ratio for such reaction; such as 1 : (1-3); for example, 1 :2, 1 : 1.2 or 1 : 1.

[0029] In the esterification reaction, the molar ratio of the compound of formula II to the catalyst can be a conventional molar ratio for such reaction; such as 1 : (0.05-2); for example, 1 :0.1 or 1 : 1.

[0030] The reaction temperature for the esterification reaction can be a conventional temperature for such reaction; such as 20-100°C, for example, 85°C or 25°C.

[0031] The progress of the esterification reaction can be monitored by a conventional detection method in the art (e.g., HPLC, TLC or NMR), generally when the compound of formula II disappears or no longer converts, the reaction is considered to reach the end point; the reaction time can be 12-72 hours; for example, 12 hours or 16 hours.

[0032] The amidation reaction can employ conventional condensing reagents for such reactions; including DCC (dicyclohexyl carbodiimide), DIC (diisopropyl carbodiimide), EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazol-N,N,N',N'-tetramethyluronium tetrafluoroborate); for example HATU. Auxiliary reagents such as HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole), NMM (4-methylmorpholine), DIPEA (diisopropylethylamine) and the like can also be added; for example NMM.

[0033] The reaction solvent for the amidation reaction is a good solvent for the starting materials, such as one or more of aromatic heterocyclic solvents, aromatic hydrocarbon solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents, aliphatic hydrocarbon solvents and sulfoxide solvents; the aromatic heterocyclic solvent can be pyridine; the aromatic hydrocarbon solvent can be toluene; the amide solvent can be N,N-dimethylformamide; the halogenated hydrocarbon solvent can be dichloromethane or chloroform; the ether solvent can be tetrahydrofuran; the aliphatic hydrocarbon solvent can be cyclohexane or n-hexane; the sulfoxide solvent can be dimethyl sulfoxide; preferably, the solvent for the amidation reaction is dimethyl sulfoxide.

[0034] In the amidation reaction, the molar ratio of the compound of formula II to R2H is a conventional molar ratio for such reactions; such as 1 : (1-7); for example 1 :5.

[0035] In the amidation reaction, the molar ratio of the compound of formula II to the catalyst is a conventional molar ratio for such reactions; such as 1 : (2-6); for example 1 :4.

[0036] In the amidation reaction, the molar ratio of the compound of formula II to the auxiliary reagent is a conventional molar ratio for such reactions; such as 1 : (2-6); for example 1 :4.

[0037] The reaction temperature for the amidation reaction can be a conventional reaction temperature for such reactions; such as 0-40°C, for example 20°C.

[0038] The progress of the amidation reaction can be monitored using conventional detection methods in the art (e.g., HPLC, TLC or NMR), generally until the compound of formula II disappears or no longer converts, the reaction time can be 2-24 hours.

[0039] To reduce side reactions, the phenolic hydroxyl group of hydroxycinnamic acid can be protected with acetyl before the esterification / amidation reaction, and then hydrolyzed with LiOH or other bases to remove the protection after the reaction. When the reactivity of the starting material corresponding to the R2group is not strong, the starting material hydroxycinnamic acid can be prepared into an acyl chloride and then subjected to subsequent reactions.

[0040] The present application also provides a cosmetic product comprising any one of the aforementioned sugar derivatives of hydroxycinnamic acid.

[0041] In some embodiments, the cosmetic product has one or more of the following effects: (1) antioxidant effect, (2) whitening effect, and (3) ultraviolet absorption effect.

[0042] In some embodiments, the amount of the sugar derivative of hydroxycinnamic acid added to the cosmetic product is 0.001-20%. The amount refers to the mass percentage of the compound in the cosmetic product.

[0043] The present application also provides the use of the aforementioned sugar derivative of hydroxycinnamic acid in a cosmetic product.

[0044] Unless otherwise specified, the groups and terms defined in the specification and claims of the present application, including their definitions as examples, exemplary definitions, preferred definitions, definitions in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other in any manner. The group definitions and compound structures after such combination and integration should belong to the scope described in the specification of the present application.

[0045] As understood by those skilled in the art, according to the convention used in the art, “ ” used in the structural formula of the group described in the present application means that the corresponding group R is connected to other fragments, groups in the compound through this site.

[0046] Unless otherwise specified, the compounds provided herein can have one or more double bonds in the form of Z or E isomers. In addition, the present disclosure also encompasses compounds in the form of individual isomers substantially free of other isomers, and alternatively, in the form of a mixture of isomers (e.g., a racemic mixture of enantiomers).

[0047] The term “cosmetic product” refers to any chemical industrial product or fine chemical product that is spread on any part of the human body surface, such as skin, hair, nails, lips, teeth, etc., by smearing, spraying or other similar methods, for the purpose of cleaning, maintaining, beautifying, modifying and changing the appearance, or modifying the body odor, and keeping the body in good condition.

[0048] The positive progress effect of the present application is that the sugar derivative of hydroxycinnamic acid provided by the present application has better water solubility and stability than the original hydroxycinnamic acid, and has one or more functions of antioxidant, whitening, soothing, moisturizing, ultraviolet absorption, etc.; application in cosmetics can reduce the photoaging damage of the skin. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 The test result graph of the ultraviolet absorption of the compound. DETAILED DESCRIPTION

[0050] The present application will be further illustrated below by way of examples, but the present application is not limited in the scope of the described examples.

[0051] Example 1 Synthesis of sugar derivative of hydroxycinnamic acid

[0052] The synthesis methods of some compounds are listed below, and the synthesis methods of other compounds can be inferred. The purity test is completed by HPLC, the peaks other than the main peak are counted as impurities, the peak area integral percentage is calculated, and the purity is calculated. The main peak molecular weight data is detected by LCMS.

[0053] Compound 1:

[0054] .

[0055] 1 mmol of ferulic acid (194.2 mg) was dissolved in 15 mL of toluene, 2 mmol of xylitol (304.2 mg) and 1 mmol of p-toluenesulfonic acid (172 mg) were added, and heated to 85℃ for 16 hours. After the reaction was completed, the heating was stopped and cooled to room temperature, saturated sodium bicarbonate solution was added until no bubbles were generated, the organic phase was washed with water for 3 times, then dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the product was separated by liquid chromatography (chromatography column type: Waters Xbridge BEH C18 250×50 mm×10 um, mobile phase H2O (10 mM NH4HCO3)-ACN, gradient 1%-40% B over 10.0 min) to obtain 82.2 mg of product, yield 25%, purity 95.40%, white powder.

[0056] Molecular formula C 15 H 20 O8, molecular weight 328.3, [M+H] + = 329.4.

[0057] 1H NMR (400 MHz, DMSO-d6) δ = 7.46 (d, 1H), 7.17 (s, 1H), 7.06 (dd, 1H), 6.68 (d, 1H), 6.25 (d, 1H), 4.82 - 4.69 (m, 3H), 4.33 (m, 1H), 4.12-3.96 (m, 2H), 3.81 (s, 3H), 3.30 - 3.20 (m, 3H).

[0058] Compound 2:

[0059] .

[0060] Synthesis method:

[0061] Add 1 mmol acetylferulic acid (CAS No. 2596-47-6, 236.2 mg) and 4 mmol NMM (404 mg) in 20 mL DMSO and stir until completely dissolved, add 4 mmol HATU (1.5 g) and stir at room temperature for 15 minutes, add 5 mmol glucosamine (CAS No. 488-43-7, 906 mg) and react at 20°C for 12 hours. After removing the solvent by rotary evaporation, purify by liquid chromatography (column type: WePure Biotech XP tC18 150×40×7 um, mobile phase H2O (10mM NH4HCO3)-ACN, gradient 1%-40% B over 8.0 min) to obtain the intermediate acetylferulic acid glucosamine 163.7 mg, yield 41%. Add 1 mmol acetylferulic acid glucosamine (399.4 mg) to 15 mL THF / water solution (volume ratio 4:1), add 2 mmol LiOH H2O (84 mg), and react at 20°C for 12 hours. After removing the solvent by rotary evaporation, purify by liquid chromatography (column type: Waters Xbridge BEH C18 250×50 mm×10 um, mobile phase H2O (10mM NH4HCO3)-ACN, gradient 1%-25% B over 10.0 min) to obtain the product 228.7 mg, yield 64%, purity 96.72%, light yellow powder.

[0062] Chemical formula C 16 H 23 NO8, molecular weight 357.36, [M+H] + = 358.1.

[0063] 1H NMR (400 MHz, DMSO-d6) δ = 7.92 - 7.83 (m, 1H), 7.30 (d, 1H), 7.12(d, 1H), 6.98 (dd, 1H), 6.78 (d, 1H), 6.54 (d, 1H), 3.80 (s, 3H), 3.65 (dd,1H), 3.61 - 3.55 (m, 2H), 3.47 (dd, 1H), 3.44 - 3.37 (m, 3H), 3.18 - 3.08 (m,1H)..

[0064] Compound 3:

[0065] .

[0066] Synthesized using similar esterification method as compound 1, with acetyl glucosamine (CAS No. 5735-25-1) as starting material. Obtained product 70 mg, purity 97.65%, light yellow powder.

[0067] Molecular formula C 18 H 25 NO9, molecular weight 399.40, [M+H] + = 400.2.

[0068] 1 H NMR (400 MHz, DMSO-d6) δ = 7.90 - 7.80 (m, 1H), 7.24 (d, 1H), 7.09(d, 1H), 6.90 (dd, 1H), 6.82 (d, 1H), 6.36 (d, 1H), 3.80 (s, 3H), 3.57 (d,1H), 3.49 - 3.40 (m, 2H), 3.33 (d, 1H), 3.39 - 3.27 (m, 3H), 3.15 - 3.05 (m,1H), 1.82 (s, 3H).

[0069] Compounds 4 and 5 were synthesized using the same method, and separated during the purification process:

[0070] Compound 4:

[0071] .

[0072] Compound 5:

[0073] .

[0074] To 2 mmol acetylferulic acid (472.4 mg), 0.2 mmol DMF (15.4 mg), 4 mmol oxalyl chloride (510.1 mg) in 5 mL dichloromethane was added in ice bath, stirred at room temperature for 2 hours, removed the solvent under reduced pressure to get intermediate acetylferulic acid chloride about 500 mg, white powder, which was used directly in the following reaction. To boscalid (CAS No. 439685-79-7, 450 mg) was dissolved in 20 mL pyridine, 0.2 mmol DMAP (24.4 mg) was added, acetylferulic acid chloride was dissolved in 1 mL dichloromethane, which was added slowly into the pyridine in ice bath, then stirred at room temperature for 12 hours, removed the solvent under reduced pressure, the intermediate acetylferulic acid boscalid ester was purified by liquid chromatography (column type: Phenomenex Luna C18 100x30mmx5um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) about 300 mg, yield 15%, white powder. The intermediate was dissolved in 1 mL tetrahydrofuran, 2 mL 3M hydrochloric acid was added, stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, the final product mixture of compound 5 and 4 was purified by liquid chromatography (column type: Phenomenex Luna C18 100x30mmx5um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) about 70 mg, yield 25%, white powder. Compound 4 and 5 were separated by liquid chromatography (column type: Phenomenex Luna C18 100x30mmx5um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% B over 40.0 min) about 40 mg of 4, purity 94.33%, 20 mg of 5, purity 95.50%, the structure of 4 and 5 were identified by 2D NMR. Chemical formula C 18 H 24 O8, molecular weight 368.38, [M+H] + = 369.1.

[0075] Compound 4 Hydrogen spectrum data: 1H NMR (400 MHz, ACETONITRILE-d3) δ = 7.66 (d, 1H), 7.24 (d, 1H), 7.12 (dd, 1H), 6.85 (d, 1H), 6.44 (d, 1H), 4.84 (t, 1H), 4.00 - 3.80 (m, 5H), 3.64 (ddd, 1H), 3.40 - 3.17 (m, 3H), 1.92 - 1.82 (m, 1H), 1.54 (ddd, 1H), 1.11 (d, 3H).

[0076] Compound 5 Hydroscopy data: 1 H NMR (400 MHz, ACETONITRILE-d3) δ = 7.64 (d, 1H), 7.29 - 7.19 (m, 1H), 7.15 - 7.05 (m, 1H), 6.85 (d, 1H), 6.38 (d, 1H), 4.75 (dt, 1H), 4.02 - 3.90 (m, 2H), 3.88 (s, 3H), 3.51 (t, 1H), 3.37 - 3.27 (m, 1H), 3.26 - 3.13 (m, 2H), 1.91 - 1.84 (m, 1H), 1.55 (ddd, 1H), 1.12 (d, 3H).

[0077] Compound 6:

[0078] .

[0079] Synthesis method:

[0080] The similar synthesis method as compound 2 was used. The starting material was changed to glucosamine (CAS No. 579-33-9), and 43 mg of product was obtained with a purity of 95.09%, light yellow powder. Molecular formula C 16 H 21 NO8, molecular weight 355.34, [M+H] + = 356.1.

[0081] Compound 7:

[0082] .

[0083] Synthesis method:

[0084] To 2 mmol acetylferulic acid (472.4 mg), 0.2 mmol DMF (15.4 mg), 4 mmol oxalyl chloride (510.1 mg) in 5 mL dichloromethane was added in ice bath, stirred at room temperature for 2 hours, removed the solvent under reduced pressure to get intermediate acetylferulic acid chloride about 500 mg, white powder, used directly in the following reaction. N-acetylglucosamine (CAS No. 7512-17-6, 454.5 mg) was dissolved in 20 mL pyridine, 0.2 mmol DMAP (24.4 mg) was added, acetylferulic acid chloride was dissolved in 1 mL dichloromethane, added slowly into the pyridine solution in ice bath, then stirred at room temperature for 12 hours, removed the solvent under reduced pressure, purified by liquid chromatography (column type: Phenomenex Luna C18 100x30mmx5um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to get intermediate acetylferulic acid acetylglucosamine ester about 300 mg, yield 15%, white powder. The intermediate was dissolved in 1 mL tetrahydrofuran, 2 mL 3M hydrochloric acid was added, stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, purified by liquid chromatography (column type: Phenomenex Luna C18 100x30mmx5um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to get final product compound 8 about 40 mg, yield 16%, white powder.

[0085] Chemical Formula C 18 H 23 NO 9, molecular weight 397.42, [M+H] + = 398.1.

[0086] 1H NMR (400 MHz, DMSO-d6+D2O) δ 7.59 - 7.48 (m, 1H), 7.25 (d, 1H),7.10 (dd, 1H), 6.79 (d, 1H), 6.48 - 6.38 (m, 1H), 4.94 - 4.44 (m, 1H), 4.41 -4.32 (m, 1H), 4.18 (br dd, 1H), 3.78 (s, 3H), 3.71 - 3.57 (m, 1H), 3.56 -3.47 (m, 1H), 3.43 - 3.25 (m, 1H), 3.25 - 3.14 (m, 1H), 1.88 - 1.77 (m, 3H)。

[0087] Compound 8:

[0088] .

[0089] Synthesized by the similar method of compound 1, starting material was replaced by caffeic acid and xylitol. Obtained end product 65 mg, purity 98.60%, white powder.

[0090] Molecular formula C 14 H 18 O8, molecular weight 314.26, [M+H] + = 315.1.

[0091] Compound 9:

[0092] .

[0093] Synthetic method refers to compound 2, starting material was replaced by caffeic acid. Obtained end product 52 mg, purity 97.92%, light yellow powder.

[0094] Molecular formula C 15 H 21 NO8, molecular weight 343.33, [M+H] + = 344.1.

[0095] 1H NMR (400 MHz, DMSO-d6) δ = 7.92 - 7.80 (m, 1H), 7.32 (d, 1H), 7.10(d, 1H), 6.99 (dd, 1H), 6.79 (d, 1H), 6.55 (d, 1H), 3.65 (dd, 1H), 3.60 -3.50 (m, 2H), 3.50 (dd, 1H), 3.44 - 3.37 (m, 3H), 3.18 - 3.10 (m, 1H).

[0096] Compound 10:

[0097] .

[0098] The similar synthesis method as compound 2 was used. The starting material was replaced by p-hydroxycinnamic acid and glucosamine. The final product was obtained 80 mg, purity 99.70%, light yellow powder.

[0099] Molecular formula C 15 H 19 NO8, molecular weight 341.32, [M+H] + = 342.1.

[0100] Compound 11:

[0101] .

[0102] The similar synthesis method as compound 1 was used. The starting material was replaced by p-hydroxycinnamic acid and xylitol. The final product was obtained 77 mg, purity 99.25%, white powder.

[0103] Molecular formula C 14 H 18 O7, molecular weight 298.27, [M+H] + = 299.1.

[0104] Compound 12:

[0105] .

[0106] The similar synthesis method as compound 2 was used. The starting material was replaced by p-hydroxycinnamic acid. The final product was obtained 65 mg, purity 95.30%, light yellow powder.

[0107] Molecular formula C 15 H 21 NO7, molecular weight 327.3, [M+H] + = 328.1.

[0108] 1H NMR (400 MHz, DMSO-d6) δ = 7.95 - 7.82 (m, 1H), 7.30 (d, 2H), 7.15(d, 1H), 6.98 (dd, 2H), 6.78 (d, 2H), 3.63 (dd, 1H), 3.50 - 3.43 (m, 2H),3.37 (m, 1H), 3.33 - 3.14 (m, 4H)。

[0109] Example 2 Synthesis of comparative compounds

[0110] Table 1 List of comparative compounds

[0111]

[0112] Compound 2-1:

[0113] Glyceryl ferulate (120601-69-6) can be obtained by esterification, transesterification or enzyme catalysis reaction using the method reported in the paper Research Progress of Glyceryl Ferulate[J].Chinese Oil and Food Science,2021,36(09):194-202.

[0114] Compound 2-2:

[0115] It can be synthesized by esterification reaction similar to compound 1. 1 mmol of ferulic acid (194.2 mg) is dissolved in 15 mL of toluene, 2 mmol of erythritol (244.2 mg) and 1 mmol of p-toluenesulfonic acid (172 mg) are added, and heated to 85℃ for 16 hours. After the reaction is completed, stop heating and cool to room temperature, add saturated sodium bicarbonate solution until no bubbles are generated, wash the organic phase with water 3 times, then dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and separate the product by liquid chromatography (chromatography column type: Waters Xbridge BEHC18 250×50 mm×10 um, mobile phase H2O (10mM NH4HCO3)-ACN, gradient 1%-40% B over 10.0 min) to obtain 83.5 mg of product, yield 28%, purity 99.70%, light yellow powder.

[0116] Molecular formula C 14 H 18 O7, molecular weight 298.29.

[0117] 1H NMR (400 MHz, DMSO-d6) δ = 7.46 (d, 1H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.78 (d, 1H), 6.43 (d, 1H), 4.46 - 4.35 (m, 3H), 4.11 (d, 1H), 4.02-3.95 (m, 2H), 3.80 (s, 3H), 3.55 - 3.47 (m, 3H).

[0118] Compound 2-3:

[0119] 1 mmol ferulic acid (194.2 mg) was dissolved in 10 mL of toluene, 2 mmol of 1,4-butanediol (180.2 mg) was added, 0.1 mmol of sulfuric acid (10 mg) was added, and the reaction was carried out at 80°C for 16 hours. After the reaction was completed, the heating was stopped and the solution was cooled to room temperature. Saturated sodium bicarbonate solution was added until no bubbles were generated. The organic phase was washed with water three times, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was separated by liquid chromatography (column type: Waters Xbridge BEH C18 250 x 50 mm x 10 um, mobile phase H2O (10 mM NH4HCO3)-ACN, gradient 1%-40% B over 10.0 min) to give 119.8 mg of product at a yield of 45% and a purity of 95.45%.

[0120] Molecular formula C 14 H 18 O5, molecular weight 266.29.

[0121] 1 H NMR (400 MHz, DMSO-d6) δ = 7.53 (d, 1H), 7.32 (d, 1H), 7.10 (dd, 1H), 6.78 (d, 1H), 6.47 (d, 1H), 4.72 (s, 1H), 4.11 (d, 2H), 3.81 (s, 3H), 3.63 (d, 2H), 1.37 - 1.20 (m, 3H).

[0122] Compound 2-4:

[0123] Synthesized using a similar method to compound 2-3, with the starting material changed to 1,6-hexanediol, at a yield of 38% and a purity of 96.67%.

[0124] Molecular formula C 16 H 22 O5, molecular weight 294.15.

[0125] 1 H NMR (400 MHz, DMSO-d6) δ = 9.55 (s, 1H), 7.48 (d, 1H), 7.29 (d,1H), 7.05 (dd, 1H), 6.82 (d, 1H), 6.31 (d, 1H), 4.68 (s, 1H), 4.05 (d, 2H),3.83 (s, 3H), 3.52 (d, 2H), 1.45 - 1.33 (m, 8H)。

[0126] Compound 2-5:

[0127] Two synthetic routes were used, one was similar to compound 1 and the other was similar to compound 4 / 5. In the first route, the starting material was ferulic acid and rhamnose. The reaction was catalyzed by p-toluenesulfonic acid for 24 hours, but no product was detected by TLC. In the second route, the yield of the third step was too low, and the product was detected by TLC, but it could not be separated by conventional HPLC column chromatography. Both synthetic routes did not obtain suitable products, and it was speculated that the α-carbon connected to two oxygen atoms of the ester bond might cause the product to be unstable under synthesis conditions.

[0128] Solubility test of compound in example 3

[0129] Hydroxycinnamic acid has good solubility in small molecule alcohols, so the test solution is water and different volume ratios of ethanol-water solution. Test method: weigh 1 mg of compound in an EP tube, add 10 μL of ethanol, and observe the solution after ultrasonic treatment for 3 min, which is counted as 100% ethanol content. Then add 10 μL, 30 μL, 50 μL, 100 μL and 800 μL of deionized water to the EP tube in turn, and observe the solution after ultrasonic treatment for 3 min each time, which is counted as 50%, 20%, 10%, 5% and 1% ethanol content. The results are shown in Table 2:

[0130] Table 2: Solubility test results of compounds

[0131]

[0132] The results show that the water solubility of the compounds obtained by connecting sugar or sugar derivatives is significantly improved compared to that of ferulic acid, and the water solubility is significantly increased with the increase of the number of free hydroxyl groups in the sugar. Ferulic acid is precipitated when the ethanol content is 20%, and increasing the number of free hydroxyl groups to 2 (compound 2-1) does not significantly improve the water solubility. Further increasing the number of free hydroxyl groups to 3 (compound 2-2) can reduce the ethanol content to 10% when precipitated, and when the number of free hydroxyl groups is 4 (compound 1), it is only precipitated when the ethanol content is less than 1%, and when the number of free hydroxyl groups is 5 (compound 2), it can be completely dissolved in an aqueous solution. In addition, cyclic sugars have better water solubility than linear sugars, and compounds 4 / 5 also have only 3 free hydroxyl groups, which have better water solubility than compound 2-2. Other polar groups such as amides and ethers also contribute to water solubility.

[0133] Example 4 Stability test of compounds

[0134] The stability of hydroxycinnamic acid and its corresponding sugar derivatives in aqueous solution was detected. 10 mg of the corresponding sample (purity greater than 92%) was weighed in an EP tube, 100 μL of dipropylene glycol was added, and ultrasonic was performed until complete dissolution. 900 μL of deionized water was added to prepare an alcohol aqueous solution with a sample concentration of 1%. The EP tube was sealed and placed in a 48±2℃ oven for 4 weeks, and the sample purity change was checked by HPLC. The test results are shown in Table 3:

[0135] Table 3: Stability test results of compounds

[0136]

[0137] The results show that the high-temperature stability of the compounds obtained by the present application is significantly higher than that of hydroxycinnamic acid compounds not connected with sugar derivatives.

[0138] Example 5 Antioxidant efficacy test of compounds

[0139] DPPH, also known as 1,1-diphenyl-2-trinitrobenzene hydrazine, is a very stable nitrogen-centered free radical. Its stability is mainly due to the spatial barrier of the three benzene rings, which makes the unpaired electrons on the nitrogen atom in the middle unable to play their due role. The DPPH anhydrous ethanol solution is purple, and has a maximum absorption at a wavelength of 517 nm. The absorbance is linearly related to the concentration. When a free radical scavenger is added to the DPPH anhydrous ethanol solution, the number of free radicals decreases, the absorbance decreases, and the solution color becomes lighter. Therefore, the ability to scavenge free radicals can be evaluated. That is, by detecting the effect of the sample on DPPH at a wavelength of 517 nm, the antioxidant capacity can be calculated.

[0140] Test method:

[0141] Accurately weigh 5.0 mg of DPPH standard, dissolve in about 100 ml of anhydrous ethanol solvent, ultrasonic for 5 min, shake thoroughly, and make sure that the upper and lower parts are uniform. The solution is stored in the dark, and is used within 3.5 h. Accurately weigh 0.01 g of vitamin C standard, dissolve in anhydrous ethanol, and dilute to 10 ml to obtain a 1000 mg / L vitamin C standard stock solution, which is stored in the dark. Take 0.05 mL, 0.10 mL, 0.15 mL, 0.20 mL, 0.25 mL, 0.50 mL, 0.75 mL, 1.0 mL, and 2.0 mL of the vitamin C standard stock solution into a 10 mL volumetric flask, and dilute to the mark with anhydrous ethanol. The hydroxycinnamic acid sugar derivative sample obtained from Example 1 is diluted with ethanol to prepare samples with gradient concentrations of 1000, 500, 200, 100, 50, 10, 5, and 1 ppm.

[0142] Take 3.5 mL of the DPPH anhydrous ethanol solution into a small test tube, add 0.5 ml of anhydrous ethanol, mix thoroughly, and zero at 517 nm with anhydrous ethanol as the reference to measure the absorbance value A0. Take 3.5 mL of the DPPH anhydrous ethanol solution into a small test tube, add 0.5 ml of the sample liquid, mix thoroughly, and avoid light for 30 min. After centrifugation at 8000 r / min for 5 min on a high-speed centrifuge, take the supernatant to zero at 517 nm with anhydrous ethanol as the reference to measure the absorbance value Ai. Take 3.5 ml of anhydrous ethanol into a small test tube, add 0.5 ml of the sample liquid, mix thoroughly, avoid light for 30 min, and centrifuge at 8000 r / min for 5 min on a high-speed centrifuge to take the supernatant. Zero at 517 nm with anhydrous ethanol as the reference to measure the absorbance value Aj. At the same time, use vitamin C as a positive control. Three parallel samples are set for each experimental group.

[0143] Result calculation: clearance rate SR / % = [1-(Ai-Aj) / Ao]x100%, and the concentration corresponding to a clearance rate of 50% is determined by fitting the curve to obtain the IC50 value. The corresponding results are shown in Table 4:

[0144] Table 4: DPPH clearance effect test results of the compounds

[0145]

[0146] The results show that the compounds proposed in the application have good DPPH radical scavenging effect, and can achieve skin protection by scavenging ROS free radicals.

[0147] Example 6: Inhibition of tyrosinase efficacy test of the compounds

[0148] Tyrosinase is a copper-containing oxidase that plays a key role in melanin biosynthesis. It catalyzes two key reactions: the hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA), and the oxidation of DOPA to dopaquinone. Dopaquinone is then converted to melanin, either spontaneously or with the help of other enzymes. The activity of tyrosinase directly affects the amount of melanin produced, and its expression and activity are regulated by a variety of factors, including ultraviolet radiation, hormone levels, and cell signaling pathways. In the skin, tyrosinase is mainly present in melanocytes, and its increased activity leads to increased melanin synthesis, causing skin pigmentation to darken, such as freckles, chloasma, etc. Therefore, tyrosinase is an important target for the development of whitening cosmetics, and its activity can be inhibited to reduce melanin production and achieve whitening effects. Refer to T / SHRH 015-2018 "Cosmetics - Tyrosinase Activity Inhibition Test Method" to detect the inhibitory effect of cinnamic acid sugar on the activity of tyrosinase.

[0149] Test method:

[0150] 14.33 g of disodium hydrogen phosphate dodecahydrate was dissolved in 200 mL of water with a glass rod to dissolve, to obtain solution a; 2.1 g of citric acid monohydrate was dissolved in 100 mL of water with a glass plate to dissolve, to obtain solution b; 154.5 mL of solution a and 45.5 mL of solution b were mixed to obtain a disodium hydrogen phosphate-citric acid buffer solution. Tyrosinase (activity ≥1000 unit / mg solid) was dissolved in the buffer solution to 100 u / mL, and prepared immediately before use; L-dopa (purity ≥98%) was dissolved in the buffer solution to 1 mg / mL, and stored in the dark. The positive control kojic acid and hydroxycinnamic acid derivative samples were all prepared into gradient concentration samples of 1000, 500, 200, 100, 50, 10, 5, 1 ppm with the buffer solution.

[0151] Set up sample group T, sample background group T0, blank group C, blank background group C0. Add 1 mL of sample solution and 0.5 mL of tyrosinase solution to the sample group, add 1 mL of sample solution and 0.5 mL of buffer solution to the sample background group, add 1 mL of buffer solution and 0.5 mL of tyrosinase solution to the blank group, and add 1.5 mL of buffer solution to the blank background group. After thoroughly mixing, incubate in a 37°C water bath for 10 minutes. Add 2 mL of L-dopa solution to each tube, control the reaction time of each tube to be consistent at 5 min, and immediately measure the absorbance at 475 nm. Set up 3 parallel samples for each sample. According to the following formula, calculate the tyrosinase activity inhibition rate: SR / % = [1-(T-T0) / (C-C0)]x100%. According to the inhibition rate of the gradient concentration, fit the curve, and calculate the concentration when the inhibition rate is 50%, which is the IC 50 value. The results are shown in Table 5.

[0152] Table 5: Results of tyrosinase activity inhibition test of compounds

[0153]

[0154] The results show that the compounds of the present application have good inhibitory effect on tyrosinase activity. It is possible to reduce the generation of melanin in the skin by inhibiting tyrosinase.

[0155] Example 8: UV absorption efficacy of compounds

[0156] After dissolving the compounds in DMSO and diluting with ethanol, a solution with a concentration of 20 ppm was prepared, and the absorption spectrum between 250-400 nm was analyzed and scanned by a UV-visible spectrometer, and the results are shown in Figure 1

[0157] The results show that the test samples have good UV absorption effect in the UVA and UVB regions. It shows that the hydroxycinnamic acid derivatives of the present application can reduce the photoaging damage of the skin by absorbing ultraviolet rays.​

Claims

1. A sugar derivative of hydroxycinnamic acid, characterized in that, which is any one of the following compounds: , , , , , , , or .

2. The sugar derivative of hydroxycinnamic acid according to claim 1, wherein which is any one of the following compounds: , , , , , , , or .

3. A method for preparing a sugar derivative of hydroxycinnamic acid according to claim 1 or 2, characterized by, which comprises the following steps: ； condensing a compound represented by formula II and R2H in the presence of a solvent to produce the sugar derivative of hydroxycinnamic acid.

4. A cosmetic product, characterized by, which comprises the sugar derivative of hydroxycinnamic acid according to claim 1 or 2.

5. The cosmetic product according to claim 4, wherein The amount of the sugar derivative of hydroxycinnamic acid added in the cosmetic is 0.001-20%.

6. Use of the sugar derivative of hydroxycinnamic acid according to claim 1 or 2 in the preparation of a cosmetic.

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