Sugar derivative of hydroxycinnamic acid, preparation method of sugar derivative and application of sugar derivative in cosmetics

Abstract

The invention discloses a sugar derivative of hydroxycinnamic acid as well as a preparation method and application thereof in cosmetics. Specifically, the invention provides a sugar derivative of hydroxycinnamic acid. The compound is shown as a formula I in the specification. Compared with original hydroxycinnamic acid, the sugar derivative of hydroxycinnamic acid has better water solubility and stability, and has one or more effects of oxidation resistance, whitening, soothing, moisturizing, ultraviolet absorption and the like; when the composition is applied to cosmetics, light aging damage of skin can be relieved, and skin color can be brightened; .

Description

Technical Field

[0001] The present invention relates to a sugar derivative of hydroxycinnamic acid, a preparation method thereof and application thereof in cosmetics. Background Art

[0002] Hydroxycinnamic acid compounds, such as hydroxycinnamic acid, caffeic acid, and ferulic acid, possess significant antioxidant, whitening, and antibacterial properties in cosmetics. They effectively protect against free radical damage to the skin, slow skin aging, inhibit melanin production, brighten the complexion, 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, cinnamic acid compounds have very low solubility in both aqueous and oil phases, making them difficult to fully mix with other ingredients in the formulation, affecting product uniformity and stability. This not only limits their application in cosmetics but can also lead to problems such as stratification and precipitation during use, impacting the consumer experience. Furthermore, these compounds are susceptible to degradation under light conditions and in aqueous solutions with a pH greater than 5, causing discoloration and odor changes, affecting the formulation's stability and the product's shelf life. Therefore, despite the many potential advantages of cinnamic acid compounds, these issues 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 exceptional properties, often serving multiple roles as moisturizers, skin feel modifiers, and skin conditioners. They effectively absorb moisture from the air, providing long-lasting moisturization and helping maintain skin hydration and elasticity. Furthermore, these ingredients possess excellent lubricity, improving product texture, making them smoother and easier to apply, and enhancing the feel of application. Sugars and sugar derivatives have a variety of positive effects on the skin. They can strengthen the skin's barrier function, reduce water loss, promote skin cell repair and regeneration, and help 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 delay aging. Furthermore, the reactivity and water solubility of sugars and sugar derivatives make them compatible with other ingredients in various cosmetic formulations, facilitating processing and application.

[0004] However, current cinnamic acid derivatives often have defects such as poor stability or poor antioxidant activity. There is a need in the art to develop a compound that can retain the activity of cinnamic acid components and sugar or sugar derivatives while having excellent stability and water solubility. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of poor solubility and poor stability of hydroxycinnamic acid derivatives in the prior art and to provide a sugar derivative of hydroxycinnamic acid having good water solubility, excellent stability and good skin efficacy.

[0006] The present invention solves the above technical problems through the following technical solutions:

[0007] The present invention provides a sugar derivative of hydroxycinnamic acid; the sugar derivative 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 a hydroxyl group, an amino group or a hydrogen atom from -NH- from any of the following sugars or sugar derivatives: 、 、 、 、 、 、 or ;

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

[0013] In some embodiments, in the compound represented by Formula I, the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any embodiment of the present invention (hereinafter referred to as "in some embodiments"), and R1 is H, hydroxyl or methoxy.

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

[0015] In some embodiments, R2 is a group formed by removing a hydroxyl group, an amino group, or a hydrogen atom from -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 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 of the following compounds 、 、 、 、 、 、 、 、 、 、 or .

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

[0022] ;

[0023] In the presence of a solvent, a condensation reaction occurs between the compound represented by formula II and R2H to produce the sugar derivative of the hydroxycinnamic acid;

[0024] Wherein, the definitions of R1 and R2 are as described in any solution of this application.

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

[0026] The esterification reaction can use a conventional catalyst for this type of reaction in this application; the catalyst is 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 use conventional solvents for this type of reaction in the present application; including 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 esterification reaction is one or more of pyridine, dichloromethane and toluene.

[0028] In the esterification reaction, the molar ratio of the compound represented by Formula II and R2H can be a conventional molar ratio for this type of reaction in this application; 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 represented by Formula II to the catalyst can be a conventional molar ratio for this type of reaction in the present application, such as 1:(0.05-2); for example, 1:0.1 or 1:1.

[0030] The reaction temperature of the esterification reaction can be a conventional temperature for this type of reaction in the present application, such as 20-100°C, for example 85°C or 25°C.

[0031] The progress of the esterification reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The reaction endpoint is generally when the compound of formula II disappears or is no longer converted. The reaction time can be 12-72 hours, for example, 12 hours or 16 hours.

[0032] The amidation reaction can utilize conventional condensation reagents for this type of reaction, including DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide), HATU (O-(7-aminobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), and TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), for example, HATU. Auxiliary reagents, such as HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-aminobenzotriazole), NMM (4-methylmorpholine), and DIPEA (diisopropylethylamine), for example, NMM, may also be added.

[0033] The reaction solvent of the amidation reaction is a good solvent for the raw 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 represented by Formula II and R2H is a conventional molar ratio for this type of reaction in the present application; such as 1:(1-7); for example, 1:5.

[0035] In the amidation reaction, the molar ratio of the compound represented by Formula II to the catalyst is a conventional molar ratio for this type of reaction in the present application, such as 1:(2-6); for example, 1:4.

[0036] In the amidation reaction, the molar ratio of the compound represented by Formula II to the auxiliary agent is a conventional molar ratio for this type of reaction in the present application, such as 1:(2-6); for example, 1:4.

[0037] The reaction temperature of the amidation reaction can be a conventional reaction temperature of this type of reaction in the present application, such as 0-40°C, for example 20°C.

[0038] The progress of the amidation reaction can be monitored by conventional detection methods in the art (such as HPLC, TLC or NMR). The reaction endpoint is generally when the compound of formula II disappears or is no longer converted. The reaction time can be 2-24 hours.

[0039] To minimize side reactions, the phenolic hydroxyl group of hydroxycinnamic acid can be protected with an acetyl group before the esterification / amidation reaction, and then deprotected with a base such as LiOH after the reaction. When the starting material corresponding to the R2 group is not highly reactive, the starting material hydroxycinnamic acid can be prepared as an acyl chloride before proceeding to the subsequent reaction.

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

[0041] In some embodiments, the cosmetic 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 is 0.001-20%, where the amount refers to the mass percentage of the compound in the cosmetic.

[0043] The present invention also provides use of the sugar derivative of hydroxycinnamic acid described in any of the aforementioned solutions in cosmetics.

[0044] Unless otherwise indicated, the definitions of groups and terms in the present specification and claims, including definitions provided as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the present specification.

[0045] Those skilled in the art will understand that, according to the conventions used in the art, the “ " means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0046] Unless otherwise indicated, the compounds provided herein may have one or more double bonds that exist as Z or E isomers. Additionally, the present disclosure also encompasses compounds in the form of individual isomers that are substantially free of other isomers, and alternatively, in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

[0047] The term "cosmetics" refers to chemical industrial products or fine chemical products that are applied to any part of the human body surface, such as skin, hair, nails, lips and teeth, by smearing, spraying or other similar methods, for the purpose of cleansing, maintenance, beautification, modification and change of appearance, or correction of human odor and maintenance of good condition.

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

[0049] Figure 1 This is the UV absorption test result of the compound. DETAILED DESCRIPTION

[0050] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0051] Example 1 Synthesis of Sugar Derivatives of Hydroxycinnamic Acid

[0052] The synthesis methods for some compounds are listed below; the synthesis methods for other compounds can be inferred. Purity testing was performed by HPLC, where peaks other than the main peak were counted as impurities and the peak area integral percentage was calculated as purity. The molecular weight of the main peak was determined by LCMS.

[0053] Compound 1:

[0054] .

[0055] 1 mmol of ferulic acid (194.2 mg) was dissolved in 15 mL of toluene, and 2 mmol of xylitol (304.2 mg) and 1 mmol of p-toluenesulfonic acid (172 mg) were added. The mixture was heated to 85°C for 16 hours. After the reaction, heating was stopped and the mixture was cooled to room temperature. Saturated sodium bicarbonate solution was added until bubbles disappeared. The organic phase was washed three times with water and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. The product was separated by liquid chromatography (Waters Xbridge BEH C18 column, 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 the product as a white powder with a yield of 25% and a purity of 95.40%.

[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] To 20 mL of DMSO, 1 mmol of acetylferulic acid (CAS No. 2596-47-6, 236.2 mg) and 4 mmol of NMM (404 mg) were added and stirred until completely dissolved. Then, 4 mmol of HATU (1.5 g) was added and stirred at room temperature for 15 minutes. Then, 5 mmol of glucosamine (CAS No. 488-43-7, 906 mg) was added and the reaction was allowed to proceed at 20°C for 12 hours. The solvent was removed by rotary evaporation, and the product was purified by liquid chromatography (WePure Biotech XP tC18 150×40×7 μm column, mobile phase: H2O (10 mM NH4HCO3)-ACN, gradient elution: 1%-40% B over 8.0 min) to obtain 163.7 mg of the intermediate acetylferulyl glucosamine in a 41% yield. 1 mmol acetylferulyl glucosamine (399.4 mg) was added to 15 mL THF / water solution (volume ratio 4:1), and 2 mmol LiOH·H2O (84 mg) was added. The reaction was carried out at 20°C for 12 hours. The solvent was removed by rotary evaporation and the product was purified by liquid chromatography (chromatographic column model: Waters Xbridge BEH C18 250×50 mm×10 um, mobile phase H2O (10 mM NH4HCO3)-ACN, gradient 1%-25% B over 10.0 min) to obtain 228.7 mg of the product with a yield of 64% and a purity of 96.72% as a 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] The product was synthesized using an esterification method similar to compound 1, except that the starting material was acetylglucosamine (CAS No. 5735-25-1). 70 mg of the product was obtained with a purity of 97.65% as a 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] Add 2 mmol of acetylferulic acid (472.4 mg), 0.2 mmol of DMF (15.4 mg), and 4 mmol of oxalyl chloride (510.1 mg) to 5 mL of dichloromethane in an ice bath and stir at room temperature for 2 hours. Remove the solvent by distillation under reduced pressure to obtain the intermediate product, acetylferulic acid chloride, about 500 mg, as a white powder, which is used directly in subsequent reactions. Bosylamine (CAS No. 439685-79-7, 450 mg) was dissolved in 20 mL of pyridine, followed by the addition of 0.2 mmol of DMAP (24.4 mg). Acetylferuloyl chloride was dissolved in 1 mL of dichloromethane and slowly added dropwise to the pyridine in an ice bath. The mixture was allowed to react at room temperature for 12 hours. The solvent was removed under reduced pressure, and the product was purified by liquid chromatography (Phenomenex Luna C18 column, 100×30mm×5μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to obtain the intermediate, acetylferuloyl bosylamine ester, approximately 300 mg, in a 15% yield, as a white powder. The intermediate was redissolved in 1 mL of tetrahydrofuran, and 2 mL of 3M hydrochloric acid was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed under reduced pressure and purified by liquid chromatography (column model: Phenomenex Luna C18 100×30mm×5um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to obtain a mixture of compounds 5 and 4, approximately 70 mg, with a yield of 25%, as a white powder. Liquid chromatography was then repeated (column model: Phenomenex Luna C18 100×30mm×5um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% B over 40.0 min) to separate compounds 4 and 5, yielding approximately 40 mg of 4 with a purity of 94.33% and approximately 20 mg of 5 with a purity of 95.50%. The structures of 4 and 5 were identified by two-dimensional nuclear magnetic resonance. Chemical formula C 18 H 24 O8, molecular weight 368.38, [M+H] + =369.1.

[0075] Compound 4 1H 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 1H spectrum 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] A similar synthesis method was used as compound 2. The starting material was replaced with glucosamine (CAS No. 579-33-9) to obtain 43 mg of the product with a purity of 95.09% as a 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] Add 2 mmol of acetylferulic acid (472.4 mg), 0.2 mmol of DMF (15.4 mg), and 4 mmol of oxalyl chloride (510.1 mg) to 5 mL of dichloromethane in an ice bath and stir at room temperature for 2 hours. Remove the solvent by distillation under reduced pressure to obtain the intermediate product, acetylferulic acid chloride, about 500 mg, as a white powder, which is used directly in subsequent reactions. N-acetylglucosamine (CAS No. 7512-17-6, 454.5 mg) was dissolved in 20 mL of pyridine, and 0.2 mmol of DMAP (24.4 mg) was added. Acetylferuloyl chloride was dissolved in 1 mL of dichloromethane and slowly added dropwise to the pyridine in an ice bath. The mixture was allowed to react at room temperature for 12 hours. The solvent was removed under reduced pressure, and the product was purified by liquid chromatography (Phenomenex Luna C18 column, 100×30mm×5um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to obtain the intermediate product, acetylferuloyl acetylglucosamine ester, approximately 300 mg, with a yield of 15%, as a white powder. The intermediate was redissolved in 1 mL of tetrahydrofuran, and 2 mL of 3M hydrochloric acid was added. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure and the product was purified by liquid chromatography (chromatographic column model: Phenomenex Luna C18 100×30mm×5um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 5%-35% Bover 8.0 min) to obtain the final product, compound 8, approximately 40 mg, with a yield of 16%, as a white powder.

[0085] Chemical formula C 18 H 23 NO9, 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] A similar method to compound 1 was used to synthesize the product, but caffeic acid and xylitol were used as the starting materials. 65 mg of the final product was obtained as a white powder with a purity of 98.60%.

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

[0091] Compound 9:

[0092] .

[0093] The synthesis method was similar to compound 2, but the starting material was replaced with caffeic acid. The final product (52 mg) with a purity of 97.92% was obtained as a 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] A similar synthesis method to compound 2 was used, except that the starting materials were replaced with p-hydroxycinnamic acid and glucosamine. 80 mg of the final product was obtained with a purity of 99.70% as a light yellow powder.

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

[0100] Compound 11:

[0101] .

[0102] A similar method to compound 1 was used to synthesize the compound, except that the starting materials were replaced with p-hydroxycinnamic acid and xylitol. The final product (77 mg) was obtained with a purity of 99.25% as a white powder.

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

[0104] Compound 12:

[0105] .

[0106] The compound was synthesized using a method similar to compound 2, except that the starting material was replaced with p-hydroxycinnamic acid. 65 mg of the final product was obtained as a light yellow powder with a purity of 95.30%.

[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] Ferulate glyceryl ester (120601-69-6) can be obtained by esterification, transesterification or enzyme-catalyzed reaction using the method reported in the paper "Research Progress of Ferulate Glyceryl ester" [J]. Journal of the Chinese Cereals and Oils Association, 2021, 36(09): 194-202.

[0114] Compound 2-2:

[0115] A similar method to compound 1 can be used to synthesize the product via esterification. 1 mmol of ferulic acid (194.2 mg) was dissolved in 15 mL of toluene, and 2 mmol of erythritol (244.2 mg) and 1 mmol of p-toluenesulfonic acid (172 mg) were added. The mixture was heated to 85°C for 16 hours. After the reaction, heating was stopped and the mixture was cooled to room temperature. Saturated sodium bicarbonate solution was added until bubbles disappeared. The organic phase was washed three times with water and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. The product was separated by liquid chromatography (Waters Xbridge BEHC18 column, 250 × 50 mm × 10 μm, mobile phase: H₂O (10 mM NH₄HCO₃)-ACN, gradient elution: 1%-40% B over 10.0 min) to obtain 83.5 mg of the product as a light yellow powder with a yield of 28% and a purity of 99.70%.

[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 toluene, and 2 mmol 1,4-butanediol (180.2 mg) and 0.1 mmol sulfuric acid (10 mg) were added. The reaction was carried out at 80°C for 16 h. After the reaction was completed, heating was stopped and the mixture was cooled to room temperature. Saturated sodium bicarbonate solution was added until no bubbles were generated. The organic phase was washed three times with water and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. The product (119.8 mg) was separated by liquid chromatography (column model: Waters Xbridge BEH C18 250×50 mm×10 um, mobile phase: H2O (10 mM NH4HCO3)-ACN, gradient 1%-40% B over 10.0 min) with 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] A similar method to compound 2-3 was used to synthesize the compound, with the starting material replaced by 1,6-hexanediol, with 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 similar to compound 1, and the other similar to compounds 4 / 5. In the first route, the starting materials were ferulic acid and rhamnose. After 24 hours of reaction catalyzed by p-toluenesulfonic acid, no product was detected by TLC. In the second route, the yield of the third step reaction was too low. The product was detected by TLC, but the product could not be obtained by conventional HPLC column chromatography. Neither synthetic route produced a suitable product. It is speculated that the α-carbon of the ester bond connected to two oxygens may cause the product to be unstable under the synthetic conditions.

[0128] Example 3 Solubility test of compound

[0129] Hydroxycinnamic acid has good solubility in small alcohols, so the test solutions consisted of water and ethanol-water solutions at varying volume ratios. Testing method: 1 mg of the compound was weighed into an EP tube, 10 μL of ethanol was added, and the solution was observed after sonication for 3 minutes, with the ethanol content calculated as 100%. Subsequently, 10 μL, 30 μL, 50 μL, 100 μL, and 800 μL of deionized water were added to the EP tube in sequence. After each addition, the solution was observed under sonication for 3 minutes, with the ethanol content calculated as 50%, 20%, 10%, 5%, and 1%. The results are shown in Table 2.

[0130] Table 2: Solubility test results of compounds

[0131]

[0132] Results showed that compounds obtained by linking sugars or sugar derivatives exhibited significantly improved water solubility relative to ferulic acid, and water solubility increased significantly with increasing the number of free hydroxyl groups in the sugar. Ferulic acid precipitated at 20% ethanol. Increasing the number of free hydroxyl groups to 2, i.e., glyceryl ferulate, did not significantly improve water solubility (Compound 2-1). Further increasing the number of free hydroxyl groups to 3 (Compound 2-2), reduced the ethanol concentration at which precipitation occurred to 10%. Compound 1 with 4 free hydroxyl groups only precipitated at less than 1% ethanol, while Compound 2 with 5 free hydroxyl groups was completely soluble in aqueous solution. Furthermore, cyclic sugars exhibited improved water solubility compared to linear sugars. Compounds 4 and 5, which also have only three free hydroxyl groups, exhibited superior water solubility compared to 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 tested. 10 mg of the corresponding sample (purity greater than 92%) was weighed into an EP tube, 100 μL of dipropylene glycol was added, and sonication was performed until completely dissolved. 900 μL of deionized water was then added to prepare a 1% alcohol-water solution. The EP tube was sealed and placed in an oven at 48 ± 2°C for 4 weeks. The sample purity was then 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 compound obtained in the present application is significantly higher than that of the hydroxycinnamic acid compounds not connected to sugar derivatives.

[0138] Example 5 Antioxidant efficacy test of compounds

[0139] DPPH, also known as 1,1-diphenyl-2-trinitrophenylhydrazine, is a very stable nitrogen-centered free radical. Its stability primarily stems from the steric hindrance of the three benzene rings due to resonance stabilization, which prevents the unpaired electrons on the nitrogen atom in the center from performing their proper electron pairing function. Anhydrous ethanol solutions of DPPH appear purple, with a maximum absorption at 517 nm. The absorbance is linearly related to concentration. Adding a free radical scavenger to an anhydrous ethanol solution of DPPH can combine with or replace DPPH, reducing the number of free radicals, lowering the absorbance, and lightening the solution color. This can be used to evaluate the free radical scavenging ability of a sample. Specifically, antioxidant capacity is calculated by measuring the DPPH scavenging ability of a sample at 517 nm.

[0140] Test method:

[0141] Accurately weigh 5.0 mg of DPPH standard, dissolve in about 100 ml of anhydrous ethanol solvent, ultrasonicate for 5 min, and fully shake to make sure that the upper and lower parts are uniform. The solution is kept in the dark and used up within 3.5 h. Accurately weigh 0.01 g of vitamin C standard, dissolve it in anhydrous ethanol and settle to 10 ml to obtain a 1000 mg / L vitamin C standard stock solution, which is stored in the dark. Respectively draw 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 vitamin C standard stock solution in a 10 mL volumetric flask and settle to the scale with anhydrous ethanol. The sugar derivative sample of hydroxycinnamic acid obtained in Example 1 is diluted with ethanol and configured to a 1000, 500, 200, 100, 50, 10, 5, and 1 ppm gradient concentration sample.

[0142] Add 3.5 mL of DPPH solution in anhydrous ethanol to a small test tube, add 0.5 mL of anhydrous ethanol, mix thoroughly, and adjust the absorbance to A0 at 517 nm using anhydrous ethanol as a reference. Add 3.5 mL of DPPH solution in anhydrous ethanol to a small test tube, add 0.5 mL of the sample solution, mix thoroughly, and allow to stand in the dark for 30 minutes. Centrifuge at 8000 r / min for 5 minutes. Collect the supernatant and adjust the absorbance to Ai at 517 nm using anhydrous ethanol as a reference. Add 3.5 mL of anhydrous ethanol to a small test tube, add 0.5 mL of the sample solution, mix thoroughly, and allow to stand in the dark for 30 minutes. Centrifuge at 8000 r / min for 5 minutes. Collect the supernatant and adjust the absorbance to Aj at 517 nm using anhydrous ethanol as a reference. Vitamin C was used as a positive control. Three replicates were performed for each experimental group.

[0143] Calculation of results: Clearance rate SR / % = [1-(Ai-Aj) / Ao] × 100%. The concentration corresponding to the clearance rate of 50% is determined by fitting the curve, which is the IC50 value. The corresponding results are shown in Table 4:

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

[0145]

[0146] The results showed that the compound proposed in the present invention has a good scavenging effect on DPPH free radicals and may achieve skin protection by scavenging ROS free radicals.

[0147] Example 6 Tyrosinase Inhibitory Efficacy Test of 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 through the action of other enzymes. Tyrosinase activity directly affects melanin production, and its expression and activity are regulated by multiple factors, including UV exposure, hormone levels, and cellular signaling pathways. In the skin, tyrosinase is primarily present in melanocytes. Increased tyrosinase activity leads to increased melanin synthesis, resulting in darker skin pigmentation such as freckles and melasma. Therefore, tyrosinase is an important target for the development of whitening cosmetics. Inhibiting its activity can reduce melanin production and achieve a whitening effect. The inhibitory effect of cinnamic acid sugar on tyrosinase activity was tested using T / SHRH 015-2018, "Cosmetics - Tyrosinase Activity Inhibition Test Method."

[0149] Test method:

[0150] Dissolve 14.33 g of sodium phosphate dodecahydrate in 200 mL of water and stir with a glass rod until dissolved to obtain solution a. Dissolve 2.1 g of citric acid monohydrate in 100 mL of water and stir with a glass plate until dissolved to obtain solution b. Mix 154.5 mL of solution a with 45.5 mL of solution b to obtain a sodium phosphate-citric acid buffer solution. Dissolve tyrosinase (activity ≥1000 units / mg solid) in the buffer solution to 100 units / mL and prepare it immediately before use. Dissolve levodopa (purity ≥98%) in the buffer solution to 1 mg / mL and store in the dark. Positive control kojic acid and hydroxycinnamic acid derivative samples were prepared in buffer solution at concentrations of 1000, 500, 200, 100, 50, 10, 5, and 1 ppm.

[0151] Set up sample group T, sample background group T0, blank group C, and blank background group C0. Add 1 mL of sample solution and 0.5 mL of tyrosinase solution to the sample group, 1 mL of sample solution and 0.5 mL of buffer solution to the sample background group, 1 mL of buffer solution and 0.5 mL of tyrosinase solution to the blank group, and 1.5 mL of buffer solution to the blank group. After thorough mixing, incubate in a 37°C water bath for 10 minutes. Add 2 mL of levodopa solution to each tube, control the reaction time of each tube to be consistent at 5 minutes, and immediately measure the absorbance at 475 nm. Set up three replicates for each sample. Calculate the tyrosinase activity inhibition rate according to the absorbance value using the following formula: SR / % = [1-(T-T0) / (C-C0)] × 100%. Fit the inhibition rate curve based on the gradient concentration, and calculate the concentration at which the inhibition rate is 50% as the IC. 50 The results are shown in Table 5.

[0152] Table 5: Tyrosinase activity inhibition test results of compounds

[0153]

[0154] The results show that the compound proposed by the present invention has a good inhibitory effect on tyrosinase activity, and may reduce the production of melanin in the skin by inhibiting tyrosinase.

[0155] Example 8: UV absorption efficacy of compounds

[0156] The compound was dissolved in DMSO and diluted with ethanol to prepare a solution with a concentration of 20 ppm. The absorption spectrum between 250 and 400 nm was analyzed by UV-visible spectrometer. The results were as follows: Figure 1 shown.

[0157] The results showed that the test samples had good ultraviolet absorption in both UVA and UVB regions, indicating that the hydroxycinnamic acid derivatives proposed in the present invention can reduce photoaging damage to the skin by absorbing ultraviolet rays.

Claims

1. A sugar derivative of hydroxycinnamic acid, characterized in that It is a compound as shown in formula I; ； Among them, the wavy line directly connected to the double bond indicates that the double bond is in E or Z configuration; R1 is H, hydroxyl or C 1-3 alkoxy; R2 is a group formed by removing a hydroxyl group, an amino group or a hydrogen atom from -NH- from any of the following sugars or sugar derivatives: 、 、 、 、 、 、 or ; When R2 is or When a group is formed by removing one H from a hydroxyl group, an amino group or -NH-, R2 is not or .

2. The sugar derivative of hydroxycinnamic acid according to claim 1, characterized in that It meets one or both of the following conditions: (1) R1 is H, hydroxy or methoxy; and (2) R2 is a group formed by removing a hydroxyl group, an amino group or a hydrogen atom from -NH- from any of the following sugars or sugar derivatives: 、 、 、 、 、 or .

3. The sugar derivative of hydroxycinnamic acid according to claim 1, characterized in that It meets one or both of the following conditions: (1) Structural unit for 、 or ;and (2) R2 is 、 、 、 、 、 or .

4. The sugar derivative of hydroxycinnamic acid according to claim 1, wherein The carbon-carbon double bond in the compound shown in Formula I is in E configuration.

5. The sugar derivative of hydroxycinnamic acid according to claim 1, wherein It is any of the following compounds: 、 、 、 、 、 、 、 、 、 、 or .

6. The sugar derivative of hydroxycinnamic acid according to claim 1, characterized in that It is any of the following compounds: 、 、 、 、 、 、 、 、 、 、 or .

7. A method for preparing a sugar derivative of hydroxycinnamic acid according to any one of claims 1 to 6; characterized in that: It includes the following steps: ； In the presence of a solvent, a condensation reaction occurs between the compound represented by formula II and R2H to produce the sugar derivative of the hydroxycinnamic acid; Wherein, the definitions of R1 and R2 are as described in any one of claims 1-6.

8. A cosmetic, characterized in that: It comprises the sugar derivative of hydroxycinnamic acid as claimed in any one of claims 1 to 6.

9. The cosmetic according to claim 8, wherein In the cosmetic, the added amount of the sugar derivative of hydroxycinnamic acid is 0.001-20%.

10. Use of the sugar derivative of hydroxycinnamic acid according to any one of claims 1 to 6 in cosmetics.

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