WO2021008170A1 - Flavone derivative, preparation method therefor, application thereof, and skin whitening product comprising same - Google Patents

Flavone derivative, preparation method therefor, application thereof, and skin whitening product comprising same Download PDF

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WO2021008170A1
WO2021008170A1 PCT/CN2020/082047 CN2020082047W WO2021008170A1 WO 2021008170 A1 WO2021008170 A1 WO 2021008170A1 CN 2020082047 W CN2020082047 W CN 2020082047W WO 2021008170 A1 WO2021008170 A1 WO 2021008170A1
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group
substituted
unsubstituted
hydrogen atom
formula
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French (fr)
Chinese (zh)
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汪君
王子豪
李周芳
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南方科技大学
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This application belongs to the technical field of daily chemical products, and specifically relates to a flavonoid derivative, its preparation method, use, and whitening products containing the same.
  • whitening cosmetics are mainly added with ingredients with whitening and antioxidant effects such as ⁇ -arbutin, vitamin C and its derivatives, but they gradually reveal poor absorption, instability, strong irritation and effects during use. Not obvious and other issues. Therefore, the development of cosmetic raw materials with high safety levels, good absorption effects, strong stability, and mild properties has become a hot spot for cosmetic research and development institutions and manufacturers in recent years.
  • Flavonoids are the general term for compounds with benzopyran as the skeleton and substituents at the C2 position, including flavonoids, dihydroflavonoids, flavans, flavanes and other structures.
  • the large family of natural products based on flavonoids as the skeleton has a wide range of biological activities and is distributed in various plants such as vegetables and fruits.
  • Many flavonoid polyphenols have a wide range of physiological functions and activities, such as antioxidant, anti-tumor, antibacterial, anti-inflammatory, and whitening effects.
  • Natural flavonoid polyphenol compounds such as catechin, naringenin, hesperetin, cyanidin, tocopherol, etc. have always been important active ingredients in skin care products.
  • the purpose of this application is to provide a flavonoid derivative, its preparation method, use, and a whitening product containing it.
  • the flavonoid derivative can inhibit the production of melanin, reduce pigmentation, has anti-oxidation, has a whitening effect, and can be used for preparing whitening products.
  • this application provides a flavone derivative, the flavone derivative having the structure shown in the following formula I or formula II:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 10 are each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a Bpin group, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted One of C6-C18 aryl groups, substituted or unsubstituted C1-C
  • R 6 , R 8 and R 9 are each independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkyne Group, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted C6-C18 Aryl, substituted or unsubstituted C5-C18 heteroaryl, substituted or unsubstituted C7-C21 aralkyl or One of wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently a hydrogen atom or a hydroxyl group, and the dashed line represents the group connection position;
  • X is selected from oxygen atom, sulfur atom,
  • R 16 , R 17 and R 18 are each independently selected from a hydrogen atom, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted One of substituted C6-C18 aryl groups, substituted or unsubstituted C5-C18 heteroaryl groups, substituted or unsubstituted C7-C21 aralkyl groups, and the dashed line represents the group connection position;
  • the substituents are halogen atoms, hydroxyl groups, carboxyl groups, amino groups, mercapto groups or silyl groups;
  • n is an integer of 0-3 (for example, 0, 1, 2 or 3).
  • the inventors found through research that the flavonoids are modified with styryl groups, and the obtained flavonoid derivatives with the above-mentioned structure can significantly inhibit melanin production, reduce pigmentation and anti-oxidation, have whitening effects, and are better than unmodified flavonoids Class compound.
  • the C1-C6 alkyl group may be a C1, C2, C3, C4, C5 or C6 alkyl group;
  • the C1-C6 alkoxy group may be a C1, C2, C3, C4, C5 or C6 alkoxy group;
  • the C1-C6 alkylamino group may be a C1, C2, C3, C4, C5 or C6 alkylamino group;
  • the C2-C6 alkenyl group may be a C2, C3, C4, C5 or C6 alkenyl group;
  • the C2-C6 alkynyl group may be a C2, C3, C4, C5 or C6 alkynyl group;
  • the C3-C6 cycloalkyl group may be a C3, C4, C5 or C6 cycloalkyl group;
  • the C3-C6 cycloalkenyl group may be a C3, C4, C5 or C6 cycloalkenyl group;
  • the C3-C6 cycloalkynyl group may be a C3, C4, C5 or C6 cycloalkynyl group;
  • the C6-C18 aryl group may be a C6, C7, C10, C12, C14 or C18 aryl group;
  • the C5-C18 heteroaryl group may be a C5, C6, C9, C11, C13 or C18 heteroaryl group;
  • the C6-C18 aryloxy group may be a C6, C7, C10, C12, C14 or C18 aryloxy group
  • the C7-C21 aralkyl group may be a C7, C8, C10, C12, C14, C15, C18, C20 or C21 aralkyl group.
  • the silyl group is preferably a tetramethylsilyl group.
  • the flavonoid derivatives having the same structure shown in Formula I or Formula II also have different configurations, including stereoisomers, tautomers, optical isomers and enantiomers. Isomers, the performance of different isomers is different.
  • the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkoxy group or a C6-C18 aromatic group.
  • the R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group or an ethoxy group, and not all are hydrogen atoms.
  • the R 7 is a hydrogen atom.
  • the R 10 is selected from halogen atoms, hydroxyl groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamino groups, C2-C6 alkenyl groups, C3-C6 cycloalkyl, C2-C6 alkynyl or Bpin group ( Wherein the dotted line represents one of the connecting positions of the groups), and n is an integer of 0-3.
  • the R 10 is a halogen atom, a hydroxyl group, an amino group, a methyl group, a methoxy group, an ethylamino group, a vinyl group, a cyclohexyl group, an ethynyl group or a Bpin group, and n is an integer of 0-3.
  • the R 6 , R 8 and R 9 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, a C6-C18 aryl group, a C7-C21 aralkyl group or One of wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently a hydrogen atom or a hydroxyl group.
  • the R 6 , R 8 and R 9 are each independently a hydrogen atom, methyl, ethyl, phenyl, benzyl or
  • the X is an oxygen atom, a sulfur atom or Wherein R 18 is selected from one of a hydrogen atom, a C1-C6 alkyl group or a C7-C21 aralkyl group.
  • the R 18 is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.
  • the flavone derivative has the structure shown in the following formula III, formula IV, formula V, formula VI, formula VII or formula VIII:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group or an ethoxy group, and not all are hydrogen atoms;
  • R 6 , R 8 and R 9 are each independently a hydrogen atom, methyl, ethyl, phenyl, benzyl or
  • R 10 is a halogen atom, a hydroxyl group, an amino group, a methyl group, a methoxy group, an ethylamino group, a vinyl group, a cyclohexyl group, an ethynyl group or a Bpin group, and n is an integer of 0-3;
  • X is oxygen atom, sulfur atom or Wherein R 18 is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.
  • the flavone derivative is selected from any one of the following compounds C1-C21 or any one of the following compounds D1-D21:
  • Bn in the said compound is benzyl (benzyl).
  • this application provides a method for preparing the above-mentioned flavonoid derivative, and the preparation method is:
  • Flavonoids And phenylacetaldehyde compounds As a raw material, react in an organic solvent under an acidic environment to obtain the flavonoid derivative;
  • R 1 -R 10 , X and n have the same meanings as R 1 -R 10 , X and n in the structural formula of the flavone derivative provided in the first aspect of this application, and will not be repeated here.
  • the molar ratio of the flavonoid compound to the phenylacetaldehyde compound is 1:(1.1-5); for example, it may be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1: 4.2, 1:4.5, 1:4.8 or 1:5, etc.
  • the acid in the acidic environment is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or nitric acid, more preferably hydrochloric acid.
  • the organic solvent is diethylene glycol.
  • the reaction temperature is 80-140°C, for example 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C or 140°C, etc.; time is 0.5-12h, such as 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h.
  • the preparation method further includes purifying the reaction product after the reaction is completed, and the purification method is: removing the organic solvent, adding ethyl acetate to dissolve, washing with water, separating the organic phase, and vacuuming the organic phase Concentrate to dryness, and separate the flavonoid derivatives by column chromatography, thin layer chromatography or recrystallization.
  • the eluent used in the column chromatography is a mixture of dichloromethane and methanol.
  • the volume ratio of dichloromethane and methanol is 5:1 to 80:1, for example, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1 , 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1 or 80:1, etc.
  • the present application provides a use of the flavonoid derivative described in the first aspect, which is used for inhibiting melanin production or antioxidant.
  • this application provides a whitening product containing at least one flavonoid derivative provided in the first aspect of the application.
  • the whitening product is a skin care product, cosmetics, medicine or food with anti-oxidation, light spot, anti-aging or anti-ultraviolet effects.
  • This application uses styryl-modified flavonoids, and the obtained flavonoid derivatives can significantly inhibit the production of melanin and anti-oxidation, and its effect is better than unmodified flavonoids and alpha-arbutin commonly used in the market; and the application provides Because the flavonoid derivatives are modified with pure natural molecules, they are safe and reduce the risk of harm to the user's skin. They can be used to prepare skin care products, cosmetics, medicines, health products or foods for whitening.
  • Figure 1 is a bar graph of the inhibition rate of different compounds on ROS generation at different concentrations.
  • the organic phase is concentrated to dryness in vacuum, and separated by column chromatography (select 200-300 mesh silica gel, eluent is a mixture of dichloromethane and methanol, volume ratio 10:1), then the colorless oily target product can be obtained.
  • the rate is 82%.
  • the specific synthesis step differs from that in Example 1 in that phenylacetaldehyde is replaced with p-tolueneacetaldehyde with a yield of 69%.
  • N-catechin (540mg, 1eq) to dichloromethane (20mL), slowly add sodium hydride (1g), then add ethanol (5mL), and react at room temperature for 12 After the reaction is completed, remove the solvent in vacuo to obtain N-ethylcatechin;
  • N-catechin (540mg, 1eq) to dichloromethane (20mL), slowly add sodium hydride (1g), and then add benzyl bromide (5mL), at room temperature React for 12 hours. After the reaction is complete, remove the solvent in vacuo to obtain N-benzylcatechin;
  • Example 1 the compound C1 (5-styryl catechin) provided in Example 1 and the compound C1 (5-styryl epicatechin) provided in Example 22 are two different configurations of compound C1. Type, the two are isomers of each other, so they are distinguished. The configuration of the compound is not described in other examples, and the specific configuration can be judged by those skilled in the art based on the configuration of the raw material used to prepare it.
  • the active hydrogen (-OH) in the compounds provided in the examples of the application may not be characterized in the 1 H NMR test. Therefore, the number of hydrogen atoms obtained by the 1 H NMR integration of some compounds is less than the theoretical number of hydrogen atoms.
  • B16-F10 cells (mouse melanoma cells) were seeded on a 96-well plate at a density of 20,000 cells per well, and the medium was 1640 medium with 10 wt% FBS (serum) and 1 wt% double antibody.
  • Five concentration gradients were set for each compound, and the final concentrations were 6.25 ⁇ M, 12.5 ⁇ M, 25 ⁇ M, 50 ⁇ M, and 100 ⁇ M, respectively, and then cultured in a 37°C incubator for 2 days.
  • Inhibition rate [1-(OD plus drug- OD background )/(OD blank- OD background )] ⁇ 100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.
  • B16-F10 cells (mouse melanoma cells) were seeded on a 96-well plate at a density of 20,000 cells per well, and the medium was 1640 medium with 10wt% FBS (serum) and 1wt% double antibody.
  • Inhibition rate [1-(OD plus drug- OD background )/(OD blank- OD background )] ⁇ 100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.
  • Melan-a cells (mouse melanocytes) were seeded on a 96-well plate at a density of 20,000 cells per well, and the medium was 1640 medium with 10 wt% FBS (serum) and 1 wt% double antibody.
  • Inhibition rate [1-(OD plus drug- OD background )/(OD blank- OD background )] ⁇ 100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.
  • Human primary epidermal keratinocytes were seeded on a 96-well plate at a density of 15,000 per well.
  • the medium was 1640 medium with 10wt% FBS and 1wt% double antibody.
  • Inhibition rate [1-(OD plus drug- OD background )/(OD blank- OD background )] ⁇ 100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.

Abstract

The present application provides a flavone derivative, a preparation method therefor, an application thereof, and a skin whitening product comprising same. The flavone derivative is a compound having a structure represented by formula I or a formula II. The flavone derivative is prepared by taking flavonoid compounds and phenylacetaldehyde compounds as raw materials for reaction in an organic solvent under an acid environment. According to the present application, by modifying the flavonoid compounds with styryl, the obtained flavone derivatives can significantly inhibit melanogenesis and resist oxidation, have a better effect than unmodified flavonoid compounds and α-arbutin commonly available on the market, and thus can be used for preparing products such as skin care products, cosmetics, drugs, health care products or foods for skin whitening.

Description

一种黄酮衍生物、其制备方法、用途和包含其的美白产品A flavonoid derivative, its preparation method, application and whitening product containing it 技术领域Technical field
本申请属于日化产品技术领域，具体涉及一种黄酮衍生物、其制备方法、用途和包含其的美白产品。This application belongs to the technical field of daily chemical products, and specifically relates to a flavonoid derivative, its preparation method, use, and whitening products containing the same.
背景技术Background technique
随着社会发展和现代生活节奏加快，由于紫外线、阳光、人体自身等原因使得人体肌肤出现各种问题，较多表现为皮肤细胞损伤，造成皮肤色斑、色素沉积以及干燥等。健康白皙的肌肤是多数人们所追求的，因此具有美白功能的化妆品越来越受到人们的青睐。研究具有美白抗氧化和减少色素沉积等功效的化合物就成了护肤基础研究的重点之一。With the development of society and the accelerated pace of modern life, human skin has various problems due to ultraviolet rays, sunlight, and the human body. Most of the problems are caused by skin cell damage, causing skin spots, pigmentation and dryness. Healthy and fair skin is what most people pursue, so cosmetics with whitening function are more and more popular. The research on compounds with whitening, anti-oxidation and reducing pigment deposition has become one of the focuses of basic skin care research.
目前，美白类化妆品以添加α-熊果苷、维生素C及其衍生物等具有美白、抗氧化功效的成分为主，但在使用过程中逐渐暴露出吸收差、不稳定、刺激强以及作用效果不明显等问题。所以，开发安全级别高、吸收效果好、稳定性强、性质温和的化妆品原料，成为近年来化妆品研发机构和生产企业关注的热点。At present, whitening cosmetics are mainly added with ingredients with whitening and antioxidant effects such as α-arbutin, vitamin C and its derivatives, but they gradually reveal poor absorption, instability, strong irritation and effects during use. Not obvious and other issues. Therefore, the development of cosmetic raw materials with high safety levels, good absorption effects, strong stability, and mild properties has become a hot spot for cosmetic research and development institutions and manufacturers in recent years.
黄酮类化合物是以苯并吡喃为骨架，并且在C2位置有取代基的化合物的总称，包括黄酮、二氢黄酮、黄烷、黄烯等多种结构。基于黄酮类化合物为骨架的天然产物大家庭，具有广泛的生物活性，分布于蔬菜、水果等多种植物中。许多黄酮多酚都具有广泛的生理功能和活性，如抗氧化、抗肿瘤、抗菌、抗炎、美白等的作用等。儿茶素、柚皮素、橙皮素、青花素、生育酚等天然黄酮多酚化合物一直是护肤品中的重要活性成分。Flavonoids are the general term for compounds with benzopyran as the skeleton and substituents at the C2 position, including flavonoids, dihydroflavonoids, flavans, flavanes and other structures. The large family of natural products based on flavonoids as the skeleton has a wide range of biological activities and is distributed in various plants such as vegetables and fruits. Many flavonoid polyphenols have a wide range of physiological functions and activities, such as antioxidant, anti-tumor, antibacterial, anti-inflammatory, and whitening effects. Natural flavonoid polyphenol compounds such as catechin, naringenin, hesperetin, cyanidin, tocopherol, etc. have always been important active ingredients in skin care products.
但是，这些天然黄酮类化合物的美白功效较低，越来越难以满足市场需求，因此具有更强美白功效的产品亟待研发。However, these natural flavonoids have low whitening effects and are increasingly difficult to meet market demand. Therefore, products with stronger whitening effects need to be developed urgently.
发明内容Summary of the invention
针对现有技术存在的不足，本申请的目的在于提供一种黄酮衍生物、其制备方法、用途和包含其的美白产品。该黄酮衍生物能够抑制黑色素生成，减少色素沉积，抗氧化，具有美白效果，可用于制备美白产品。In view of the deficiencies in the prior art, the purpose of this application is to provide a flavonoid derivative, its preparation method, use, and a whitening product containing it. The flavonoid derivative can inhibit the production of melanin, reduce pigmentation, has anti-oxidation, has a whitening effect, and can be used for preparing whitening products.
为达此目的，本申请采用以下技术方案：To achieve this goal, this application adopts the following technical solutions:
第一方面，本申请提供一种黄酮衍生物，所述黄酮衍生物具有如下式I或式II所示结构：In the first aspect, this application provides a flavone derivative, the flavone derivative having the structure shown in the following formula I or formula II:
Figure PCTCN2020082047-appb-000001
Figure PCTCN2020082047-appb-000001
在式I和式II中，R 1、R 2、R 3、R 4、R 5、R 7和R 10各自独立地选自氢原子、卤素原子、羟基、氨基、Bpin基、取代或未取代的C1-C6的烷基、取代或未取代的C1-C6的烷氧基、取代或未取代的C1-C6的烷氨基、取代或未取代的C2-C6的烯基、取代或未取代的C2-C6的炔基、取代或未取代的C3-C6的环烷基、取代或未取代的C3-C6的环烯基、取代或未取代的C3-C6的环炔基、取代或未取代的C6-C18的芳基、取代或未取代的C5-C18的杂芳基、取代或未取代的C6-C18的芳氧基、取代或未取代的C7-C21的芳烷基中的一种； In Formula I and Formula II, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 10 are each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a Bpin group, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted One of C6-C18 aryl groups, substituted or unsubstituted C5-C18 heteroaryl groups, substituted or unsubstituted C6-C18 aryloxy groups, and substituted or unsubstituted C7-C21 aralkyl groups ；
R 6、R 8和R 9各自独立地选自氢原子、取代或未取代的C1-C6的烷基、取代 或未取代的C2-C6的烯基、取代或未取代的C2-C6的炔基、取代或未取代的C3-C6的环烷基、取代或未取代的C3-C6的环烯基、取代或未取代的C3-C6的环炔基、取代或未取代的C6-C18的芳基、取代或未取代的C5-C18的杂芳基、取代或未取代的C7-C21的芳烷基或
Figure PCTCN2020082047-appb-000002
中的一种，其中R 11、R 12、R 13、R 14和R 15各自独立地为氢原子或羟基，并且虚线代表基团连接位置； R 6 , R 8 and R 9 are each independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkyne Group, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted C6-C18 Aryl, substituted or unsubstituted C5-C18 heteroaryl, substituted or unsubstituted C7-C21 aralkyl or
Figure PCTCN2020082047-appb-000002
One of wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently a hydrogen atom or a hydroxyl group, and the dashed line represents the group connection position;
X选自氧原子、硫原子、
Figure PCTCN2020082047-appb-000003
中的一种，其中R 16、R 17和R 18各自独立地选自氢原子、取代或未取代的C1-C6的烷基、取代或未取代的C2-C6的烯基、取代或未取代的C2-C6的炔基、取代或未取代的C3-C6的环烷基、取代或未取代的C3-C6的环烯基、取代或未取代的C3-C6的环炔基、取代或未取代的C6-C18的芳基、取代或未取代的C5-C18的杂芳基、取代或未取代的C7-C21的芳烷基中的一种，并且虚线代表基团连接位置； X is selected from oxygen atom, sulfur atom,
Figure PCTCN2020082047-appb-000003
One of wherein R 16 , R 17 and R 18 are each independently selected from a hydrogen atom, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted One of substituted C6-C18 aryl groups, substituted or unsubstituted C5-C18 heteroaryl groups, substituted or unsubstituted C7-C21 aralkyl groups, and the dashed line represents the group connection position;
如上所述基团中含有取代基时，所述取代基为卤素原子、羟基、羧基、氨基、巯基或硅烷基；When the above group contains substituents, the substituents are halogen atoms, hydroxyl groups, carboxyl groups, amino groups, mercapto groups or silyl groups;
Figure PCTCN2020082047-appb-000004
代表单键或双键，在式I和式II中，2、3和4位的碳原子之间的两个化学键均为单键，或一个为单键，另一个为双键；
Figure PCTCN2020082047-appb-000004
Represents a single bond or a double bond. In Formula I and Formula II, the two chemical bonds between the carbon atoms at positions 2, 3 and 4 are both single bonds, or one is a single bond and the other is a double bond;
n为0-3的整数(例如0、1、2或3)。n is an integer of 0-3 (for example, 0, 1, 2 or 3).
发明人通过研究发现，采用苯乙烯基对黄酮类化合物进行修饰，得到的具有上述结构黄酮衍生物能够显著抑制黑色素生成，减少色素沉积以及抗氧化，具有美白效果，且效果优于未修饰的黄酮类化合物。The inventors found through research that the flavonoids are modified with styryl groups, and the obtained flavonoid derivatives with the above-mentioned structure can significantly inhibit melanin production, reduce pigmentation and anti-oxidation, have whitening effects, and are better than unmodified flavonoids Class compound.
本申请中，所述C1-C6的烷基可以是C1、C2、C3、C4、C5或C6的烷基；In this application, the C1-C6 alkyl group may be a C1, C2, C3, C4, C5 or C6 alkyl group;
所述C1-C6的烷氧基可以是C1、C2、C3、C4、C5或C6的烷氧基；The C1-C6 alkoxy group may be a C1, C2, C3, C4, C5 or C6 alkoxy group;
所述C1-C6的烷氨基可以是C1、C2、C3、C4、C5或C6的烷氨基；The C1-C6 alkylamino group may be a C1, C2, C3, C4, C5 or C6 alkylamino group;
所述C2-C6的烯基可以是C2、C3、C4、C5或C6的烯基；The C2-C6 alkenyl group may be a C2, C3, C4, C5 or C6 alkenyl group;
所述C2-C6的炔基可以是C2、C3、C4、C5或C6的炔基；The C2-C6 alkynyl group may be a C2, C3, C4, C5 or C6 alkynyl group;
所述C3-C6的环烷基可以是C3、C4、C5或C6的环烷基；The C3-C6 cycloalkyl group may be a C3, C4, C5 or C6 cycloalkyl group;
所述C3-C6的环烯基可以是C3、C4、C5或C6的环烯基；The C3-C6 cycloalkenyl group may be a C3, C4, C5 or C6 cycloalkenyl group;
所述C3-C6的环炔基可以是C3、C4、C5或C6的环炔基；The C3-C6 cycloalkynyl group may be a C3, C4, C5 or C6 cycloalkynyl group;
所述C6-C18的芳基可以是C6、C7、C10、C12、C14或C18等的芳基；The C6-C18 aryl group may be a C6, C7, C10, C12, C14 or C18 aryl group;
所述C5-C18的杂芳基可以是C5、C6、C9、C11、C13或C18等的杂芳基；The C5-C18 heteroaryl group may be a C5, C6, C9, C11, C13 or C18 heteroaryl group;
所述C6-C18的芳氧基可以是C6、C7、C10、C12、C14或C18等的芳氧基；The C6-C18 aryloxy group may be a C6, C7, C10, C12, C14 or C18 aryloxy group;
所述C7-C21的芳烷基可以是C7、C8、C10、C12、C14、C15、C18、C20或C21等的芳烷基。The C7-C21 aralkyl group may be a C7, C8, C10, C12, C14, C15, C18, C20 or C21 aralkyl group.
所述硅烷基优选为四甲基硅基。The silyl group is preferably a tetramethylsilyl group.
需要说明的是，本申请中，具有同一种式I或式II所示结构的黄酮衍生物还具有不同的构型，包括立体异构体、互变异构体、光学异构体以及对映异构体，不同的异构体之间的性能有所差异。It should be noted that, in this application, the flavonoid derivatives having the same structure shown in Formula I or Formula II also have different configurations, including stereoisomers, tautomers, optical isomers and enantiomers. Isomers, the performance of different isomers is different.
作为本申请的优选技术方案，所述R 1、R 2、R 3、R 4和R 5各自独立地选自氢原子、卤素原子、羟基、C1-C6的烷氧基或C6-C18的芳氧基中的一种，且不全为氢原子。 As a preferred technical solution of the present application, the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkoxy group or a C6-C18 aromatic group. One of the oxygen groups, and not all hydrogen atoms.
优选地，所述R 1、R 2、R 3、R 4和R 5各自独立地为氢原子、卤素原子、羟基、甲氧基或乙氧基，且不全为氢原子。 Preferably, the R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group or an ethoxy group, and not all are hydrogen atoms.
作为本申请的优选技术方案，所述R 7为氢原子。 As a preferred technical solution of the present application, the R 7 is a hydrogen atom.
作为本申请的优选技术方案，所述R 10选自卤素原子、羟基、氨基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的烷氨基、C2-C6的烯基、C3-C6的环烷基、 C2-C6的炔基或Bpin基(
Figure PCTCN2020082047-appb-000005
其中虚线代表基团的连接位置)中的一种，n为0-3的整数。 As a preferred technical solution of the present application, the R 10 is selected from halogen atoms, hydroxyl groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamino groups, C2-C6 alkenyl groups, C3-C6 cycloalkyl, C2-C6 alkynyl or Bpin group (
Figure PCTCN2020082047-appb-000005
Wherein the dotted line represents one of the connecting positions of the groups), and n is an integer of 0-3.
优选地，所述R 10为卤素原子、羟基、氨基、甲基、甲氧基、乙氨基、乙烯基、环己基、乙炔基或Bpin基，n为0-3的整数。 Preferably, the R 10 is a halogen atom, a hydroxyl group, an amino group, a methyl group, a methoxy group, an ethylamino group, a vinyl group, a cyclohexyl group, an ethynyl group or a Bpin group, and n is an integer of 0-3.
作为本申请的优选技术方案，所述R 6、R 8和R 9各自独立地选自氢原子、C1-C6的烷基、C6-C18的芳基、C7-C21的芳烷基或
Figure PCTCN2020082047-appb-000006
中的一种，其中R 11、R 12、R 13、R 14和R 15各自独立地为氢原子或羟基。 As a preferred technical solution of the present application, the R 6 , R 8 and R 9 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, a C6-C18 aryl group, a C7-C21 aralkyl group or
Figure PCTCN2020082047-appb-000006
One of wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently a hydrogen atom or a hydroxyl group.
优选地，所述R 6、R 8和R 9各自独立地为氢原子、甲基、乙基、苯基、苯甲基或
Figure PCTCN2020082047-appb-000007
Preferably, the R 6 , R 8 and R 9 are each independently a hydrogen atom, methyl, ethyl, phenyl, benzyl or
Figure PCTCN2020082047-appb-000007
作为本申请的优选技术方案，所述X为氧原子、硫原子或
Figure PCTCN2020082047-appb-000008
其中R 18选自氢原子、C1-C6的烷基或C7-C21的芳烷基中的一种。 As a preferred technical solution of this application, the X is an oxygen atom, a sulfur atom or
Figure PCTCN2020082047-appb-000008
Wherein R 18 is selected from one of a hydrogen atom, a C1-C6 alkyl group or a C7-C21 aralkyl group.
优选地，所述R 18为氢原子、甲基、乙基或苯甲基。 Preferably, the R 18 is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.
作为本申请的优选技术方案，所述黄酮衍生物具有如下式III、式IV、式V、式VI、式VII或式VIII所示结构：As a preferred technical solution of the present application, the flavone derivative has the structure shown in the following formula III, formula IV, formula V, formula VI, formula VII or formula VIII:
Figure PCTCN2020082047-appb-000009
Figure PCTCN2020082047-appb-000009
Figure PCTCN2020082047-appb-000010
Figure PCTCN2020082047-appb-000010
式III-式VIII中，R 1、R 2、R 3、R 4和R 5各自独立地为氢原子、卤素原子、羟基、甲氧基或乙氧基，且不全为氢原子； In Formula III-Formula VIII, R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group or an ethoxy group, and not all are hydrogen atoms;
R 6、R 8和R 9各自独立地为氢原子、甲基、乙基、苯基、苯甲基或
Figure PCTCN2020082047-appb-000011
R 6 , R 8 and R 9 are each independently a hydrogen atom, methyl, ethyl, phenyl, benzyl or
Figure PCTCN2020082047-appb-000011
R 10为卤素原子、羟基、氨基、甲基、甲氧基、乙氨基、乙烯基、环己基、乙炔基或Bpin基，n为0-3的整数； R 10 is a halogen atom, a hydroxyl group, an amino group, a methyl group, a methoxy group, an ethylamino group, a vinyl group, a cyclohexyl group, an ethynyl group or a Bpin group, and n is an integer of 0-3;
X为氧原子、硫原子或
Figure PCTCN2020082047-appb-000012
其中R 18为氢原子、甲基、乙基或苯甲基。 X is oxygen atom, sulfur atom or
Figure PCTCN2020082047-appb-000012
Wherein R 18 is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.
作为本申请的优选技术方案，所述黄酮衍生物选自如下化合物C1-C21中的任意一种或化合物D1-D21中的任意一种：As a preferred technical solution of the present application, the flavone derivative is selected from any one of the following compounds C1-C21 or any one of the following compounds D1-D21:
Figure PCTCN2020082047-appb-000013
Figure PCTCN2020082047-appb-000013
Figure PCTCN2020082047-appb-000014
Figure PCTCN2020082047-appb-000014
Figure PCTCN2020082047-appb-000015
Figure PCTCN2020082047-appb-000015
Figure PCTCN2020082047-appb-000016
Figure PCTCN2020082047-appb-000016
需要说明的是，上述化合物中的Bn为苯甲基(苄基)。In addition, Bn in the said compound is benzyl (benzyl).
第二方面，本申请提供一种上述黄酮衍生物的制备方法，所述制备方法为：In the second aspect, this application provides a method for preparing the above-mentioned flavonoid derivative, and the preparation method is:
以黄酮类化合物
Figure PCTCN2020082047-appb-000017
和苯乙醛类化合物
Figure PCTCN2020082047-appb-000018
为原料，在酸性环境下，在有机溶剂中进行反应，得到所述黄酮衍生物； Flavonoids
Figure PCTCN2020082047-appb-000017
And phenylacetaldehyde compounds
Figure PCTCN2020082047-appb-000018
As a raw material, react in an organic solvent under an acidic environment to obtain the flavonoid derivative;
其中，R 1-R 10、X和n具有与本申请第一方面提供的黄酮衍生物的结构式中的R 1-R 10、X和n相同的含义，在此不再赘述。 Wherein, R 1 -R 10 , X and n have the same meanings as R 1 -R 10 , X and n in the structural formula of the flavone derivative provided in the first aspect of this application, and will not be repeated here.
作为本申请的优选技术方案，所述黄酮类化合物与苯乙醛类化合物的摩尔比为1:(1.1-5)；例如可以是1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.8、1:2、1:2.2、1:2.5、1:2.8、1:3、1:3.2、1:3.5、1:3.8、1:4、1:4.2、1:4.5、1:4.8或1:5等。As a preferred technical solution of the present application, the molar ratio of the flavonoid compound to the phenylacetaldehyde compound is 1:(1.1-5); for example, it may be 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1: 4.2, 1:4.5, 1:4.8 or 1:5, etc.
优选地，所述酸性环境中的酸为盐酸、硫酸、磷酸、醋酸或硝酸，更优选为盐酸。Preferably, the acid in the acidic environment is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or nitric acid, more preferably hydrochloric acid.
优选地，所述有机溶剂为二乙二醇。Preferably, the organic solvent is diethylene glycol.
优选地，所述反应的温度为80-140℃，例如可以是80℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃、125℃、130℃、135℃或140℃等；时间为0.5-12h，例如可以是0.5h、1h、1.5h、2h、2.5h、3h、4h、5h、6h、7h、 8h、9h、10h、11h或12h等。Preferably, the reaction temperature is 80-140°C, for example 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C or 140°C, etc.; time is 0.5-12h, such as 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h.
优选地，所述制备方法还包括在反应结束后对反应产物进行提纯，所述提纯的方法为：去除所述有机溶剂，加入乙酸乙酯溶解，水洗，分离有机相，将所述有机相真空浓缩至干，采用柱层析、薄层层析或重结晶的方法分离得到所述黄酮衍生物。Preferably, the preparation method further includes purifying the reaction product after the reaction is completed, and the purification method is: removing the organic solvent, adding ethyl acetate to dissolve, washing with water, separating the organic phase, and vacuuming the organic phase Concentrate to dryness, and separate the flavonoid derivatives by column chromatography, thin layer chromatography or recrystallization.
优选地，所述柱层析使用的洗脱液为二氯甲烷和甲醇的混合液。Preferably, the eluent used in the column chromatography is a mixture of dichloromethane and methanol.
优选的，二氯甲烷和甲醇的体积比为5:1～80:1，例如可以是5:1、8:1、10:1、12:1、15:1、18:1、20:1、25:1、30:1、35:1、40:1、45:1、50:1、55:1、60:1、65:1、70:1、75:1或80:1等。Preferably, the volume ratio of dichloromethane and methanol is 5:1 to 80:1, for example, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1 , 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1 or 80:1, etc.
第三方面，本申请提供一种第一方面所述的黄酮衍生物的用途，所述黄酮衍生物用于抑制黑色素生成或抗氧化。In the third aspect, the present application provides a use of the flavonoid derivative described in the first aspect, which is used for inhibiting melanin production or antioxidant.
第四方面，本申请提供一种美白产品，所述美白产品含有至少一种本申请第一方面提供的黄酮衍生物。In a fourth aspect, this application provides a whitening product containing at least one flavonoid derivative provided in the first aspect of the application.
作为本申请的优选技术方案，所述美白产品为具有抗氧化、淡斑、抗皮肤衰老或抗紫外线功效的护肤品、化妆品、药品或食品。As a preferred technical solution of the present application, the whitening product is a skin care product, cosmetics, medicine or food with anti-oxidation, light spot, anti-aging or anti-ultraviolet effects.
与现有技术相比，本申请具有以下有益效果：Compared with the prior art, this application has the following beneficial effects:
本申请采用苯乙烯基修饰黄酮类化合物，得到的黄酮衍生物能显著抑制黑色素的生成和抗氧化，其效果优于未修饰的黄酮类化合物及市场常用的α-熊果苷；且本申请提供的黄酮衍生物由于采用纯天然分子进行结构修饰，其安全性好，减低了伤害使用者皮肤的风险，可以用于制备美白用的护肤品、化妆品、药品、保健品或食品等产品。This application uses styryl-modified flavonoids, and the obtained flavonoid derivatives can significantly inhibit the production of melanin and anti-oxidation, and its effect is better than unmodified flavonoids and alpha-arbutin commonly used in the market; and the application provides Because the flavonoid derivatives are modified with pure natural molecules, they are safe and reduce the risk of harm to the user's skin. They can be used to prepare skin care products, cosmetics, medicines, health products or foods for whitening.
附图说明Description of the drawings
图1为不同化合物在不同浓度下对ROS生成的抑制率的柱状图。Figure 1 is a bar graph of the inhibition rate of different compounds on ROS generation at different concentrations.
具体实施方式Detailed ways
下面结合附图并通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述具体实施方式仅仅是帮助理解本申请，不应视为对本申请的具体限制。The technical solutions of the present application will be further described below in conjunction with the drawings and specific implementations. Those skilled in the art should understand that the specific implementation manners are only to help understand the application, and should not be regarded as specific limitations to the application.
实施例1Example 1
化合物C1(5-苯乙烯基儿茶素)和化合物D1(7-苯乙烯基儿茶素)的制备，具体合成步骤如下：For the preparation of compound C1 (5-styrylcatechin) and compound D1 (7-styrylcatechin), the specific synthesis steps are as follows:
在100mL圆底烧瓶中，将原料儿茶素(580mg,2mmol,1eq)或表儿茶素(580mg,2mmol,1eq)，和苯乙醛(600μL,2.5eq)加入到二乙二醇(40mL)中，滴加5.3％的盐酸(14mL)，在120℃下加热反应2小时，反应完毕后，真空除去溶剂，加入乙酸乙酯(50mL)溶解，水洗(20mL×3)，分出有机相，有机相真空浓缩至干，使用柱层析分离(选用200-300目的硅胶，洗脱剂为二氯甲烷和甲醇的混合液，体积比20:1)，即可得到无色油状目标产物，根据柱层析结果，首先得到C1(5-苯乙烯基儿茶素)，收率75％，随后分离得到D1(7-苯乙烯基儿茶素)，收率21％。In a 100mL round-bottom flask, add the raw materials catechin (580mg, 2mmol, 1eq) or epicatechin (580mg, 2mmol, 1eq), and phenylacetaldehyde (600μL, 2.5eq) to diethylene glycol (40mL ), add 5.3% hydrochloric acid (14mL) dropwise, heat the reaction at 120°C for 2 hours, after the reaction is complete, remove the solvent in vacuo, add ethyl acetate (50mL) to dissolve, wash with water (20mL×3), separate the organic phase , The organic phase is concentrated to dryness in vacuo, and separated by column chromatography (select 200-300 mesh silica gel, eluent is a mixture of dichloromethane and methanol, volume ratio 20:1), you can get the colorless oily target product. According to the results of column chromatography, C1 (5-styrylcatechin) was first obtained with a yield of 75%, and then D1 (7-styrylcatechin) was separated and obtained with a yield of 21%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.27(s,1H),9.48(s,2H),7.72(d,2H),7.44(m,2H),7.30-7.22(m,2H),6.78-6.64(m,4H),5.98(s,1H),5.84(s,1H),5.02(s,1H),4.88-4.86(m,2H),2.81-2.56(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.27 (s, 1H), 9.48 (s, 2H), 7.72 (d, 2H), 7.44 (m, 2H), 7.30-7.22 (m, 2H), 6.78 -6.64 (m, 4H), 5.98 (s, 1H), 5.84 (s, 1H), 5.02 (s, 1H), 4.88-4.86 (m, 2H), 2.81-2.56 (m, 2H).
13C NMR(100MHz,CDCl 3)，δ＝166.8,165.7,165.4,156.3,152.1,150.2,136.0,133.1,129.8,129.8,129.8,126.7,125.2,121.1,119.3,66.7,44.5,28.5。 13 C NMR (100MHz, CDCl 3 ), δ=166.8, 165.7, 165.4, 156.3, 152.1, 150.2, 136.0, 133.1, 129.8, 129.8, 129.8, 126.7, 125.2, 121.1, 119.3, 66.7, 44.5, 28.5.
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 20O 6，329.1360，测定值329.1362。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 20 O 6 , 329.1360, measured value 329.1362.
实施例2Example 2
化合物C2的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为3',4'-二甲氧基儿茶素，收率52％。For the preparation of compound C2, the specific synthesis procedure is different from that in Example 1 in that the catechin is replaced with 3',4'-dimethoxycatechin, and the yield is 52%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝7.72(m,2H),7.44(m,2H),7.30-7.21(m,2H),6.97-6.96(m,2H),6.87-6.77(m,2H),5.98(s,1H),6.52(d,1H),5.82(s,1H),5.02(s,1H),4.89-4.88(m,2H),3.83(s,3H),3.75(s,3H),2.86-2.81(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 7.72 (m, 2H), 7.44 (m, 2H), 7.30-7.21 (m, 2H), 6.97-6.96 (m, 2H), 6.87-6.77 (m, 2H), 5.98(s, 1H), 6.52(d, 1H), 5.82(s, 1H), 5.02(s, 1H), 4.89-4.88(m, 2H), 3.83(s, 3H), 3.75(s , 3H), 2.86-2.81 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 25H 24O 6420.1573，测定值420.1572。 HRMS (ESI-ion trap) m/z: [M+H] + calculated value C 25 H 24 O 6 420.1573, measured value 420.1572.
实施例3Example 3
化合物C3的制备，具体合成步骤如下：For the preparation of compound C3, the specific synthesis steps are as follows:
(1)在100mL圆底烧瓶中，将原料阿夫儿茶素(540mg,2mmol,1eq)和氯化亚砜(600μL,2.5eq)加入到1,4-二氧六环(20mL)中，滴加1mL二甲基甲酰胺，室温下反应12小时，反应完毕后，真空除去溶剂，得到4'-氯代阿夫儿茶素；(1) In a 100mL round-bottom flask, add the raw materials avcatechin (540mg, 2mmol, 1eq) and thionyl chloride (600μL, 2.5eq) to 1,4-dioxane (20mL), 1mL of dimethylformamide was added dropwise and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was removed in vacuo to obtain 4'-chloroavcatechin;
(2)在100mL圆底烧瓶中，将原料4’-氯代阿夫儿茶素(600mg,1eq)和苯乙醛(600μL,2.5eq)加入到二乙二醇(40mL)中，滴加5.3％的盐酸(14mL)，在140℃下加热反应2小时，反应完毕后，真空除去溶剂，加入乙酸乙酯(50mL)溶解，水洗(20mL×3)，分出有机相，有机相真空浓缩至干，使用柱层析分离(选用200-300目的硅胶，洗脱剂为二氯甲烷和甲醇的混合液，体积比10:1)，即可得到无色油状目标产物，收率78％。(2) In a 100mL round-bottom flask, add the raw materials 4'-chloroafcatechin (600mg, 1eq) and phenylacetaldehyde (600μL, 2.5eq) to diethylene glycol (40mL), and add dropwise 5.3% hydrochloric acid (14mL), heated at 140℃ for 2 hours, after the reaction, the solvent was removed in vacuo, ethyl acetate (50mL) was added to dissolve, washed with water (20mL×3), the organic phase was separated, and the organic phase was concentrated in vacuo To dryness, use column chromatography to separate (select 200-300 mesh silica gel, eluent is a mixture of dichloromethane and methanol, volume ratio 10:1) to obtain the colorless oily target product with a yield of 78%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.27(s,1H),7.68(m,2H),7.44-7.40(m,2H), 7.38-7.14(m,2H),6.79-6.62(m,4H),6.42(dd,1H),5.99(s,1H),5.87(s,1H),5.04(s,1H),4.96-4.88(m,2H),2.96-2.83(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.27 (s, 1H), 7.68 (m, 2H), 7.44-7.40 (m, 2H), 7.38-7.14 (m, 2H), 6.79-6.62 (m, 4H), 6.42 (dd, 1H), 5.99 (s, 1H), 5.87 (s, 1H), 5.04 (s, 1H), 4.96-4.88 (m, 2H), 2.96-2.83 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C23H17ClO6，394.0972，测定值394.0975。HRMS (ESI-ion trap) m/z: [M+H]+calculated value C23H17ClO6, 394.0972, measured value 394.0975.
实施例4Example 4
化合物C4的制备，具体合成步骤如下：For the preparation of compound C4, the specific synthesis steps are as follows:
(1)在100mL圆底烧瓶中，将原料阿夫儿茶素(540mg,2mmol,1eq)加入到草酸(20mL)中，滴加5mL甲醇，100℃反应12小时，反应完毕后，真空除去溶剂，得到2,4,6-三甲氧基阿夫儿茶素；(1) In a 100mL round-bottom flask, add the raw material avcatechin (540mg, 2mmol, 1eq) to oxalic acid (20mL), add 5mL methanol dropwise, and react at 100℃ for 12 hours. After the reaction is complete, remove the solvent in vacuo , Get 2,4,6-trimethoxy avcatechin;
(2)在100mL圆底烧瓶中，将原料2,4,6-三甲氧基阿夫儿茶素(600mg,1eq)和苯乙醛(600μL,2.5eq)加入到二乙二醇(40mL)中，滴加5.3％的盐酸(14mL)，在140℃下加热反应2小时，反应完毕后，真空除去溶剂，加入乙酸乙酯(50mL)溶解，水洗(20mL×3)，分出有机相，有机相真空浓缩至干，使用柱层析分离(选用200-300目的硅胶，洗脱剂为二氯甲烷和甲醇的混合液，体积比10:1)，即可得到无色油状目标产物，收率82％。(2) In a 100mL round-bottom flask, add the raw materials 2,4,6-trimethoxy afcatechin (600mg, 1eq) and phenylacetaldehyde (600μL, 2.5eq) to diethylene glycol (40mL) 5.3% hydrochloric acid (14mL) was added dropwise, and the reaction was heated at 140°C for 2 hours. After the reaction was completed, the solvent was removed in vacuo, ethyl acetate (50mL) was added to dissolve, washed with water (20mL×3), and the organic phase was separated. The organic phase is concentrated to dryness in vacuum, and separated by column chromatography (select 200-300 mesh silica gel, eluent is a mixture of dichloromethane and methanol, volume ratio 10:1), then the colorless oily target product can be obtained. The rate is 82%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.06(s,1H),7.82-7.81(d,2H),7.65-7.42(m,3H),7.30-7.20(m,2H),6.98-6.54(m,4H),6.20(s,1H),5.08(d,1H),4.56(m,1H),3.78(s,3H),3.72(s,3H),3.41(s,3H),2.84-2.79(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.06 (s, 1H), 7.82-7.81 (d, 2H), 7.65-7.42 (m, 3H), 7.30-7.20 (m, 2H), 6.98-6.54 ( m, 4H), 6.20 (s, 1H), 5.08 (d, 1H), 4.56 (m, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.41 (s, 3H), 2.84-2.79 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 26H 26O 5，418.1780，测定值418.1778。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 26 H 26 O 5 , 418.1780, measured value 418.1778.
实施例5Example 5
化合物C5的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为 3'-甲氧基-2,4,6三苄氧基儿茶素，收率72％。For the preparation of compound C5, the specific synthesis procedure is different from that in Example 1 in that the catechin is replaced with 3'-methoxy-2,4,6 tribenzyloxycatechin, and the yield is 72%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.96(s,1H),7.92-7.88(m,4H),7.46-7.39(m,5H),7.35-7.24(m,6H),7.15-7.06(m,6H),6.98-6.84(m,4H),6.78-6.64(m,2H),5.76-5.45(m,4H),5.36-5.11(m,3H),3.37(s,3H),2.79-2.54(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.96 (s, 1H), 7.92-7.88 (m, 4H), 7.46-7.39 (m, 5H), 7.35-7.24 (m, 6H), 7.15-7.06 ( m, 6H), 6.98-6.84 (m, 4H), 6.78-6.64 (m, 2H), 5.76-5.45 (m, 4H), 5.36-5.11 (m, 3H), 3.37 (s, 3H), 2.79- 2.54 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 45H 40O 6,676.2825,测定值676.2822。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 45 H 40 O 6 , 676.2825, measured value 676.2822.
实施例6Example 6
化合物C6的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为3,5-二羟基苯乙醛，收率61％。For the preparation of compound C6, the specific synthesis steps are different from those in Example 1 in that phenylacetaldehyde is replaced with 3,5-dihydroxyphenylacetaldehyde with a yield of 61%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.65-9.48(m,3H),7.65-7.42(m,3H),7.30-7.20(m,2H),6.98-6.54(m,4H),4.88-4.78(m,2H),2.86-2.61(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ=9.65-9.48 (m, 3H), 7.65-7.42 (m, 3H), 7.30-7.20 (m, 2H), 6.98-6.54 (m, 4H), 4.88- 4.78 (m, 2H), 2.86-2.61 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 20O 8,424.1158,测定值424.1159。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 20 O 8 , 424.1158, measured value 424.1159.
实施例7Example 7
化合物C7的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对氨基苯乙醛，收率68％。For the preparation of compound C7, the specific synthesis steps are different from those in Example 1 in that phenylacetaldehyde is replaced with p-aminophenylacetaldehyde, and the yield is 68%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.27(s,1H),9.41(s,1H),7.92-7.77(d,2H),7.55-7.41(m,2H),7.30-7.20(m,3H),6.68-6.39(m,3H),4.76-4.66(m,2H),2.97-2.56(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.27 (s, 1H), 9.41 (s, 1H), 7.92-7.77 (d, 2H), 7.55-7.41 (m, 2H), 7.30-7.20 (m, 3H), 6.68-6.39 (m, 3H), 4.76-4.66 (m, 2H), 2.97-2.56 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 21NO 6，407.1369，测定值 407.1365。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 21 NO 6 , 407.1369, measured value 407.1365.
实施例8Example 8
化合物C8的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对乙胺基苯乙醛，收率74％。For the preparation of compound C8, the specific synthesis steps are different from those in Example 1 in that phenylacetaldehyde is replaced with p-ethylaminophenylacetaldehyde with a yield of 74%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝7.92-7.71(d,2H),7.65-7.52(m,3H),7.38-7.21(m,2H),6.98-6.56(m,3H),4.88-4.85(m,2H),3.45(t,2H),2.81-2.56(m,2H),1.28(t,3H)。 1 H NMR (400MHz, CDCl 3 ), δ=7.92-7.71(d,2H), 7.65-7.52(m,3H), 7.38-7.21(m,2H), 6.98-6.56(m,3H), 4.88- 4.85 (m, 2H), 3.45 (t, 2H), 2.81-2.56 (m, 2H), 1.28 (t, 3H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 25H 25NO 6,435.1682,测定值435.1688。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 25 H 25 NO 6 , 435.1682, measured value 435.1688.
实施例9Example 9
化合物C9的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对溴苯乙醛，收率78％。For the preparation of compound C9, the specific synthesis steps are different from those in Example 1 in that phenylacetaldehyde is replaced with p-bromophenylacetaldehyde, and the yield is 78%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.98(s,1H),7.95-7.83(d,2H),7.75-7.52(m,2H),7.33-7.22(m,2H),6.98-6.54(m,4H),4.48-4.20(m,2H),2.81-2.56(m,2H). 1 H NMR (400MHz, CDCl 3 ), δ = 9.98 (s, 1H), 7.95-7.83 (d, 2H), 7.75-7.52 (m, 2H), 7.33-7.22 (m, 2H), 6.98-6.54 ( m, 4H), 4.48-4.20 (m, 2H), 2.81-2.56 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 19BrO 6,470.0365,测定值470.0362。 HRMS (ESI-ion trap) m/z: [M+H] + calculated value C 23 H 19 BrO 6 , 470.0365, measured value 470.0362.
实施例10Example 10
化合物C10的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对甲基苯乙醛，收率69％。For the preparation of compound C10, the specific synthesis step differs from that in Example 1 in that phenylacetaldehyde is replaced with p-tolueneacetaldehyde with a yield of 69%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.48(s,1H),7.98-7.88(d,2H),7.77-7.32(m, 2H),7.28-7.21(m,3H),6.98-6.64(m,3H),4.90-4.86(m,2H),2.81-2.56(m,2H),2.41(s,3H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.48 (s, 1H), 7.98-7.88 (d, 2H), 7.77-7.32 (m, 2H), 7.28-7.21 (m, 3H), 6.98-6.64 ( m, 3H), 4.90-4.86 (m, 2H), 2.81-2.56 (m, 2H), 2.41 (s, 3H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 24H 22O 6,406.1416,测定值406.1418。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 24 H 22 O 6 , 406.1416, measured value 406.1418.
实施例11Example 11
化合物C11的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对甲氧基苯乙醛，收率55％。For the preparation of compound C11, the specific synthesis steps are different from those in Example 1 in that phenylacetaldehyde is replaced with p-methoxyphenylacetaldehyde, and the yield is 55%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.28(s,1H),7.91-7.83(d,2H),7.77-7.52(m,2H),7.33-7.25(m,2H),6.68-6.54(m,4H),4.90-4.86(m,2H),3.81(s,3H),2.81-2.56(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.28 (s, 1H), 7.91-7.83 (d, 2H), 7.77-7.52 (m, 2H), 7.33-7.25 (m, 2H), 6.68-6.54 ( m, 4H), 4.90-4.86 (m, 2H), 3.81 (s, 3H), 2.81-2.56 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 24H 22O 7,422.1366,测定值422.1371。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 24 H 22 O 7 , 422.1366, measured value 422.1371.
实施例12Example 12
化合物C12的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对乙炔基苯乙醛，收率63％。For the preparation of compound C12, the difference between the specific synthesis steps and Example 1 is that phenylacetaldehyde was replaced with p-ethynylphenylacetaldehyde, and the yield was 63%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.15(s,1H),9.77(s,1H),7.75-7.73(d,2H),7.65-7.42(m,3H),7.38-7.22(m,2H),6.98-6.54(m,3H),4.88-4.66(m,2H),3.04(s,1H),2.81-2.46(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.15 (s, 1H), 9.77 (s, 1H), 7.75-7.73 (d, 2H), 7.65-7.42 (m, 3H), 7.38-7.22 (m, 2H), 6.98-6.54 (m, 3H), 4.88-4.66 (m, 2H), 3.04 (s, 1H), 2.81-2.46 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 25H 20O 6,416.1260,测定值416.1266。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 25 H 20 O 6 , 416.1260, measured value 416.1266.
实施例13Example 13
化合物C13的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对乙烯基苯乙醛，收率75％。For the preparation of compound C13, the specific synthesis steps are different from those in Example 1 in that phenylacetaldehyde is replaced with p-vinylbenzeneacetaldehyde with a yield of 75%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.56(s,1H),7.95-7.83(d,2H),7.79-7.50(m,2H),7.37-7.25(m,3H),6.98-6.54(m,4H),5.76-5.52(m,2H),4.90-4.88(m,2H),2.81-2.56(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.56 (s, 1H), 7.95-7.83 (d, 2H), 7.79-7.50 (m, 2H), 7.37-7.25 (m, 3H), 6.98-6.54 ( m, 4H), 5.76-5.52 (m, 2H), 4.90-4.88 (m, 2H), 2.81-2.56 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 22O 6,418.1416,测定值418.1414。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 22 O 6 , 418.1416, measured value 418.1414.
实施例14Example 14
化合物C14的制备，具体合成步骤与实施例1的区别在于，将苯乙醛替换为对环己基苯乙醛，收率52％。For the preparation of compound C14, the difference between the specific synthesis steps and Example 1 is that phenylacetaldehyde was replaced with p-cyclohexylphenylacetaldehyde, and the yield was 52%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝7.99-7.79(m,2H),7.71-7.52(m,3H),7.34-7.22(m,2H),6.78-6.54(m,2H),5.84(s,1H),4.66-4.62(m,2H),2.80-2.66(m,2H),2.72-2.43(m,3H),2.36-2.31(m,2H),2.11-2.01(m,3H),1.95-1.79(m,3H)。 1 H NMR (400MHz, CDCl 3 ), δ = 7.99-7.79 (m, 2H), 7.71-7.52 (m, 3H), 7.34-7.22 (m, 2H), 6.78-6.54 (m, 2H), 5.84 ( s,1H),4.66-4.62(m,2H),2.80-2.66(m,2H),2.72-2.43(m,3H),2.36-2.31(m,2H),2.11-2.01(m,3H), 1.95-1.79 (m, 3H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 29H 30O 6,474.2042,测定值474.2043。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 29 H 30 O 6 , 474.2042, measured value 474.2043.
实施例15Example 15
化合物C15的制备，具体合成步骤如下：The specific synthesis steps for the preparation of compound C15 are as follows:
在100mL圆底烧瓶中，将原料EGCG(920mg,2mmol,1eq)和苯乙醛(600μL,2.5eq)加入到二乙二醇(40mL)中，滴加5.3％的盐酸(14mL)，在140℃下加热反应2小时，反应完毕后，真空除去溶剂，加入乙酸乙酯(50mL)溶解，水洗(20mL×3)，分出有机相，有机相真空浓缩至干，使用柱层析分离(选用 200-300目的硅胶，洗脱剂为二氯甲烷和甲醇的混合液，体积比10:1)，即可得到无色油状目标产物，收率70％。In a 100mL round-bottomed flask, the raw materials EGCG (920mg, 2mmol, 1eq) and phenylacetaldehyde (600μL, 2.5eq) were added to diethylene glycol (40mL), and 5.3% hydrochloric acid (14mL) was added dropwise. Heat the reaction at ℃ for 2 hours. After the reaction is complete, remove the solvent in vacuo, add ethyl acetate (50mL) to dissolve, wash with water (20mL×3), separate the organic phase, concentrate the organic phase to dryness in vacuo, and separate by column chromatography (optional 200-300 mesh silica gel, the eluent is a mixture of dichloromethane and methanol, the volume ratio is 10:1), the colorless oily target product can be obtained with a yield of 70%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.42(s,1H),9.31(s,2H),8.73(s,1H),7.78(d,2H),7.45(m,2H),7.20-7.30(m,2H),6.62-6.80(m,4H),5.84-5.98(m,3H),5.02(s,1H),4.86-4.88(m,2H),2.56-2.81(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.42 (s, 1H), 9.31 (s, 2H), 8.73 (s, 1H), 7.78 (d, 2H), 7.45 (m, 2H), 7.20-7.30 (m, 2H), 6.62-6.80 (m, 4H), 5.84-5.98 (m, 3H), 5.02 (s, 1H), 4.86-4.88 (m, 2H), 2.56-2.81 (m, 2H).
13C NMR(100MHz,CDCl 3)，δ＝176.8,168.7,165.6,164.2,156.3,152.8,150.2,136.2,133.2,129.6,129.5,129.6,128.7,123.1,119.3,63.7,41.5,29.5。 13 C NMR (100MHz, CDCl 3 ), δ=176.8, 168.7, 165.6, 164.2, 156.3, 152.8, 150.2, 136.2, 133.2, 129.6, 129.5, 129.6, 128.7, 123.1, 119.3, 63.7, 41.5, 29.5.
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 30H 24O 11，560.1319，测定值560.1321。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 30 H 24 O 11 , 560.1319, measured value 560.1321.
实施例16Example 16
化合物C16的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为1-(3',4'-二羟基苯酚)-3H-色烯-2,4,6-三醇，收率52％。For the preparation of compound C16, the difference between the specific synthesis steps and Example 1 is that the catechins were replaced with 1-(3',4'-dihydroxyphenol)-3H-chromene-2,4,6-triol, The yield was 52%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.27(s,1H),7.95-7.83(m,2H),7.71-7.62(m,2H),7.33-7.22(m,3H),6.98-6.74(m,2H),6.64-6,62(m,1H),5.88(m,1H),3.22(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.27 (s, 1H), 7.95-7.83 (m, 2H), 7.71-7.62 (m, 2H), 7.33-7.22 (m, 3H), 6.98-6.74 ( m, 2H), 6.64-6, 62 (m, 1H), 5.88 (m, 1H), 3.22 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 18O 6,390.1103,测定值390.1105。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 18 O 6 , 390.1103, measured value 390.1105.
实施例17Example 17
化合物C17的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为1-(3',4'-二羟基苯酚)-1H-色烯-2,4,6-三醇，收率46％。For the preparation of compound C17, the difference between the specific synthesis steps and Example 1 is that the catechin is replaced with 1-(3',4'-dihydroxyphenol)-1H-chromene-2,4,6-triol, The yield was 46%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.77(s,1H),7.75-7.63(m,2H),7.45-7.32(m,2H),7.33-7.22(m,3H),6.98-6.54(m,4H),5.66(s,1H),5.12(s,1H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.77 (s, 1H), 7.75-7.63 (m, 2H), 7.45-7.32 (m, 2H), 7.33-7.22 (m, 3H), 6.98-6.54 ( m, 4H), 5.66 (s, 1H), 5.12 (s, 1H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 18O 6,390.1103,测定值390.1107。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 18 O 6 , 390.1103, measured value 390.1107.
实施例18Example 18
化合物C18的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为S-儿茶素，收率72％。For the preparation of compound C18, the specific synthesis steps are different from those in Example 1 in that catechins are replaced with S-catechins, and the yield is 72%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.27(s,1H),7.92-7.71(d,2H),7.65-7.42(m,3H),7.28-7.21(m,3H),6.78-6.56(m,3H),4.26-4.07(m,2H),2.81-2.56(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.27 (s, 1H), 7.92-7.71 (d, 2H), 7.65-7.42 (m, 3H), 7.28-7.21 (m, 3H), 6.78-6.56 ( m, 3H), 4.26-4.07 (m, 2H), 2.81-2.56 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 20O 5S,408.1031,测定值408.1034。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 20 O 5 S, 408.1103, measured value 408.1034.
实施例19Example 19
化合物C19的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为N-儿茶素，收率48％。For the preparation of compound C19, the specific synthesis procedure is different from that in Example 1 in that catechin is replaced with N-catechin, and the yield is 48%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.48(s,2H),8.29(s,1H),7.72-7.42(m,3H),7.28-7.21(m,3H),6.78-6.61(m,5H),4.31-3.81(m,2H),2.81-2.56(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 9.48 (s, 2H), 8.29 (s, 1H), 7.72-7.42 (m, 3H), 7.28-7.21 (m, 3H), 6.78-6.61 (m, 5H), 4.31-3.81 (m, 2H), 2.81-2.56 (m, 2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 21NO 5,391.1420,测定值391.1422。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 21 NO 5 , 391.1420, measured value 391.1422.
实施例20Example 20
化合物C20的制备，具体合成步骤如下：For the preparation of compound C20, the specific synthesis steps are as follows:
(1)在100mL圆底烧瓶中，将原料N-儿茶素(540mg,1eq)加入到二氯 甲烷(20mL)中，缓慢加入氢化钠(1g)，随后加入乙醇(5mL),室温反应12小时，反应完毕后，真空除去溶剂，得到N-乙基儿茶素；(1) In a 100mL round bottom flask, add the raw material N-catechin (540mg, 1eq) to dichloromethane (20mL), slowly add sodium hydride (1g), then add ethanol (5mL), and react at room temperature for 12 After the reaction is completed, remove the solvent in vacuo to obtain N-ethylcatechin;
(2)在100mL圆底烧瓶中，将原料N-乙基儿茶素(600mg,1eq)和苯乙醛(600μL,2.5eq)加入到二乙二醇(40mL)中，滴加5.3％的盐酸(14mL)，在140℃下加热反应2小时，反应完毕后，真空除去溶剂，加入乙酸乙酯(50mL)溶解，水洗(20mL×3)，分出有机相，有机相真空浓缩至干，使用柱层析分离(选用200-300目的硅胶，洗脱剂为二氯甲烷和甲醇的混合液，体积比10:1)，即可得到无色油状目标产物，收率56％。(2) In a 100mL round-bottom flask, add the raw materials N-ethylcatechin (600mg, 1eq) and phenylacetaldehyde (600μL, 2.5eq) into diethylene glycol (40mL), and add 5.3% of Hydrochloric acid (14mL), heated at 140°C for 2 hours. After the reaction is complete, remove the solvent in vacuo, add ethyl acetate (50mL) to dissolve, wash with water (20mL×3), separate the organic phase, and concentrate the organic phase to dryness in vacuo. Use column chromatography to separate (select 200-300 mesh silica gel, eluent is a mixture of dichloromethane and methanol, volume ratio 10:1) to obtain the colorless oily target product with a yield of 56%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝9.27(s,1H),7.64-7.42(m,3H),7.29-7.12(m,3H),6.78-6.64(m,2H),6.35-6.24(m,3H),4.31(m,1H),3.81(m,1H),3.39(t,2H),2.81-2.56(s,2H),1.12(t,3H). 1 H NMR (400MHz, CDCl 3 ), δ = 9.27 (s, 1H), 7.64-7.42 (m, 3H), 7.29-7.12 (m, 3H), 6.78-6.64 (m, 2H), 6.35-6.24 ( m, 3H), 4.31 (m, 1H), 3.81 (m, 1H), 3.39 (t, 2H), 2.81-2.56 (s, 2H), 1.12 (t, 3H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 25H 25NO 5，329.1360，测定值329.1362。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 25 H 25 NO 5 , 329.1360, measured value 329.1362.
实施例21Example 21
化合物C21的制备，具体合成步骤如下：For the preparation of compound C21, the specific synthesis steps are as follows:
(1)在100mL圆底烧瓶中，将原料N-儿茶素(540mg,1eq)加入到二氯甲烷(20mL)中，缓慢加入氢化钠(1g)，随后加入溴化苄(5mL),室温反应12小时，反应完毕后，真空除去溶剂，得到N-苄基儿茶素；(1) In a 100mL round bottom flask, add the raw material N-catechin (540mg, 1eq) to dichloromethane (20mL), slowly add sodium hydride (1g), and then add benzyl bromide (5mL), at room temperature React for 12 hours. After the reaction is complete, remove the solvent in vacuo to obtain N-benzylcatechin;
(2)在100mL圆底烧瓶中，将原料N-苄基儿茶素(600mg,1eq)和苯乙醛(600μL,2.5eq)加入到二乙二醇(40mL)中，滴加5.3％的盐酸(14mL)，在140℃下加热反应2小时，反应完毕后，真空除去溶剂，加入乙酸乙酯(50mL)溶解，水洗(20mL×3)，分出有机相，有机相真空浓缩至干，使用柱层析分离 (选用200-300目的硅胶，洗脱剂为二氯甲烷和甲醇的混合液，体积比10:1)，即可得到无色油状目标产物，收率69％。(2) In a 100mL round-bottom flask, add the raw materials N-benzylcatechin (600mg, 1eq) and phenylacetaldehyde (600μL, 2.5eq) to diethylene glycol (40mL), and add 5.3% Hydrochloric acid (14mL), heated at 140°C for 2 hours. After the reaction is complete, remove the solvent in vacuo, add ethyl acetate (50mL) to dissolve, wash with water (20mL×3), separate the organic phase, and concentrate the organic phase to dryness in vacuo. Use column chromatography to separate (select 200-300 mesh silica gel, eluent is a mixture of dichloromethane and methanol, volume ratio 10:1) to obtain the colorless oily target product with a yield of 69%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝7.92-7.71(d,3H),7.65-7.52(m,3H),7.44(s,1H),7.38-7.21(m,2H),6.98-6.56(m,3H),6.49-6.41(m,3H),6.22(s,1H),5.37(s,1H),4.61.4-45(m,2H),3.81(s,1H),2.81-2.55(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ=7.92-7.71 (d, 3H), 7.65-7.52 (m, 3H), 7.44 (s, 1H), 7.38-7.21 (m, 2H), 6.98-6.56 ( m,3H),6.49-6.41(m,3H),6.22(s,1H),5.37(s,1H),4.61.4-45(m,2H),3.81(s,1H),2.81-2.55( m,2H).
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 30H 27NO 5,481.1889,测定值481.1888。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 30 H 27 NO 5 , 481.1889, measured value 481.1888.
实施例22Example 22
化合物C1(5-苯乙烯基表儿茶素)的制备，具体合成步骤与实施例1的区别在于，将儿茶素替换为表儿茶素，收率55％。For the preparation of compound C1 (5-styryl epicatechin), the specific synthesis step differs from that in Example 1 in that catechin is replaced with epicatechin, and the yield is 55%.
结构表征：Structure Characterization:
1H NMR(400MHz,CDCl 3)，δ＝10.27(s,1H),9.48(s,1H),7.85(d,2H),7.54-7.45(m,2H),7.30-7.22(m,2H),6.88-6.74(m,4H),5.86(s,1H),5.57(s,1H),5.02(s,1H),4.88-4.77(m,2H),2.95-2.85(m,2H)。 1 H NMR (400MHz, CDCl 3 ), δ = 10.27 (s, 1H), 9.48 (s, 1H), 7.85 (d, 2H), 7.54-7.45 (m, 2H), 7.30-7.22 (m, 2H) , 6.88-6.74 (m, 4H), 5.86 (s, 1H), 5.57 (s, 1H), 5.02 (s, 1H), 4.88-4.77 (m, 2H), 2.95-2.85 (m, 2H).
13C NMR(100MHz,CDCl 3)，δ＝166.8,165.7,165.4,156.3,152.1,150.2,136.0,133.1,129.8,129.8,129.8,126.7,125.2,121.1,119.3,66.7,44.5,28.5。 13 C NMR (100MHz, CDCl 3 ), δ=166.8, 165.7, 165.4, 156.3, 152.1, 150.2, 136.0, 133.1, 129.8, 129.8, 129.8, 126.7, 125.2, 121.1, 119.3, 66.7, 44.5, 28.5.
HRMS(ESI-ion trap)m/z:[M+H]+计算值C 23H 20O 6，329.1360，测定值329.1362。 HRMS (ESI-ion trap) m/z: [M+H]+calculated value C 23 H 20 O 6 , 329.1360, measured value 329.1362.
需要说明的是，实施例1提供的化合物C1(5-苯乙烯基儿茶素)和实施例22提供的化合物C1(5-苯乙烯基表儿茶素)为化合物C1的两种不同的构型，二者互为异构体，因此加以区分。其他实施例中未对化合物的构型进行说明，其具体的构型本领域技术人员可根据制备其的原料的构型进行判断。It should be noted that the compound C1 (5-styryl catechin) provided in Example 1 and the compound C1 (5-styryl epicatechin) provided in Example 22 are two different configurations of compound C1. Type, the two are isomers of each other, so they are distinguished. The configuration of the compound is not described in other examples, and the specific configuration can be judged by those skilled in the art based on the configuration of the raw material used to prepare it.
本申请实施例提供的化合物中的活性氢(-OH)在 1H NMR测试中可能表征不出，因此部分化合物通过 1H NMR积分得到的氢原子数量小于其理论氢原子数量。 The active hydrogen (-OH) in the compounds provided in the examples of the application may not be characterized in the 1 H NMR test. Therefore, the number of hydrogen atoms obtained by the 1 H NMR integration of some compounds is less than the theoretical number of hydrogen atoms.
本申请实施例中采用的化合物的结构式如下：The structural formulas of the compounds used in the examples of this application are as follows:
Figure PCTCN2020082047-appb-000019
Figure PCTCN2020082047-appb-000019
对上述实施例提供的化合物进行如下性能测试：The following performance tests were performed on the compounds provided in the above examples:
1、细胞毒性实验1. Cytotoxicity test
将上述实施例制备得到的化合物，以及儿茶素、EGCG、α-熊果苷分别用DMSO配制成不同浓度的水溶性试剂，备用。The compounds prepared in the foregoing examples, as well as catechin, EGCG, and α-arbutin were respectively formulated into water-soluble reagents of different concentrations with DMSO, and were used for later use.
把B16-F10细胞(小鼠黑色素瘤细胞)按每孔20000枚的密度接种在96孔 板上，培养基为加入10wt％FBS(血清)和1wt％双抗的1640培养基。在接种B16-F10细胞的96孔板上每孔加入90μL培养基，然后在每孔中分别加入10μL上述不同浓度的水溶性试剂(以DMSO作为空白对照，α-熊果苷作为阳性对照)，每一种化合物均设置5个浓度梯度，终浓度分别为6.25μM、12.5μM、25μM、50μM、100μM，然后在37℃培养箱中培养2天。B16-F10 cells (mouse melanoma cells) were seeded on a 96-well plate at a density of 20,000 cells per well, and the medium was 1640 medium with 10 wt% FBS (serum) and 1 wt% double antibody. Add 90μL of medium to each well of the 96-well plate inoculated with B16-F10 cells, and then add 10μL of the above-mentioned water-soluble reagents (with DMSO as a blank control and α-arbutin as a positive control) in each well. Five concentration gradients were set for each compound, and the final concentrations were 6.25 μM, 12.5 μM, 25 μM, 50 μM, and 100 μM, respectively, and then cultured in a 37°C incubator for 2 days.
之后向每孔加入10μL CCK-8溶液，将96孔板在37℃培养箱中培养4小时。用酶标仪测定在450nm处的吸光度，并计算对B16-F10细胞的抑制率。抑制率＝[1-(OD 加药-OD 本底)/(OD 空白-OD 本底)]×100％，其中OD 加药为实验组的吸光度，OD 空白为空白组的吸光度，OD 本底为本底的吸光度。绘制抑制率-浓度标准曲线，根据曲线公式计算出各化合物的IC50值(抑制率为50％时的药物浓度)。 Then add 10 μL of CCK-8 solution to each well, and incubate the 96-well plate in a 37°C incubator for 4 hours. Measure the absorbance at 450nm with a microplate reader, and calculate the inhibition rate on B16-F10 cells. Inhibition rate=[1-(OD plus drug- OD background )/(OD blank- OD background )]×100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background. Draw the inhibition rate-concentration standard curve, and calculate the IC50 value of each compound (the drug concentration when the inhibition rate is 50%) according to the curve formula.
IC50值如下表1所示：The IC50 value is shown in Table 1:
表1Table 1
Figure PCTCN2020082047-appb-000020
Figure PCTCN2020082047-appb-000020
Figure PCTCN2020082047-appb-000021
Figure PCTCN2020082047-appb-000021
表1中，“∞”表示该化合物的毒性极低，无法根据前述公式计算出IC50值。In Table 1, "∞" indicates that the toxicity of the compound is extremely low, and the IC50 value cannot be calculated according to the aforementioned formula.
从表1结果可以看出，儿茶素、表儿茶素、EGCG以及α-熊果苷对于B16-F10(小鼠黑色素瘤细胞)的毒性都非常小，本申请提供的黄酮类衍生物也具有较低的毒性。It can be seen from the results in Table 1 that catechin, epicatechin, EGCG and α-arbutin are very toxic to B16-F10 (mouse melanoma cells), and the flavonoid derivatives provided in this application are also Has low toxicity.
2、黑色素生成抑制实验：2. Melanin production inhibition experiment:
将上述实施例制备得到的化合物，以及儿茶素、EGCG、α-熊果苷分别用DMSO配制成不同浓度的水溶性试剂，备用。The compounds prepared in the foregoing examples, as well as catechin, EGCG, and α-arbutin were respectively formulated into water-soluble reagents of different concentrations with DMSO, and were used for later use.
(1)把B16-F10细胞(小鼠黑色素瘤细胞)按每孔20000枚的密度接种在96孔板上，培养基为加入10wt％FBS(血清)和1wt％双抗的1640培养基。在接种B16-F10细胞的96孔板上每孔加入90μL培养基和10μL α-MSH(粗黑色素细胞激素)，然后在每孔中分别加入10μL上述不同浓度的水溶性试剂(以DMSO作为空白对照，α-熊果苷作为阳性对照)，每一种化合物均设置5个浓度梯度，终浓度分别为6.25μM、12.5μM、25μM、50μM、100μM；以不添加α-MSH且水溶性试剂为DMSO的组作为本底；然后在37℃培养箱中培养2天。(1) B16-F10 cells (mouse melanoma cells) were seeded on a 96-well plate at a density of 20,000 cells per well, and the medium was 1640 medium with 10wt% FBS (serum) and 1wt% double antibody. Add 90μL of medium and 10μL of α-MSH (crude melanocyte hormone) to each well of 96-well plate inoculated with B16-F10 cells, and then add 10μL of the above-mentioned water-soluble reagents of different concentrations (with DMSO as blank control) , Α-Arbutin as a positive control), each compound is set with 5 concentration gradients, the final concentration is 6.25μM, 12.5μM, 25μM, 50μM, 100μM; the water-soluble reagent without α-MSH is DMSO The group was used as background; then cultured in a 37°C incubator for 2 days.
培养结束后，利用酶标仪在405nm的波长下测量培养液的吸光度，并计算对黑色素生成的抑制率。抑制率＝[1-(OD 加药-OD 本底)/(OD 空白-OD 本底)]×100％，其中OD 加药为实验组的吸光度，OD 空白为空白组的吸光度，OD 本底为本底的吸光度。 After the cultivation, the absorbance of the culture solution was measured at a wavelength of 405nm using a microplate reader, and the inhibition rate of melanin production was calculated. Inhibition rate=[1-(OD plus drug- OD background )/(OD blank- OD background )]×100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.
抑制率数据如下表2所示：The inhibition rate data is shown in Table 2 below:
表2Table 2
Figure PCTCN2020082047-appb-000022
Figure PCTCN2020082047-appb-000022
(2)把Melan-a细胞(小鼠黑色素细胞)按每孔20000枚的密度接种在96 孔板上，培养基为加入10wt％FBS(血清)和1wt％双抗的1640培养基。在接种Melan-a细胞的96孔板上每孔加入90μL的培养基和10μL α-MSH(粗黑色素细胞激素)，在每孔中分别加入10μL上述不同浓度的水溶性试剂(以DMSO作为空白对照，α-熊果苷作为阳性对照)，每一种化合物均设置5个浓度梯度，终浓度分别为6.25μM、12.5μM、25μM、50μM、100μM；以不添加α-MSH且水溶性试剂为DMSO的组作为本底；然后在37℃培养箱中培养2天。(2) Melan-a cells (mouse melanocytes) were seeded on a 96-well plate at a density of 20,000 cells per well, and the medium was 1640 medium with 10 wt% FBS (serum) and 1 wt% double antibody. Add 90 μL of medium and 10 μL of α-MSH (crude melanocyte hormone) to each well of a 96-well plate seeded with Melan-a cells, and add 10 μL of the above-mentioned water-soluble reagents of different concentrations to each well (with DMSO as a blank control) , Α-Arbutin as a positive control), each compound is set with 5 concentration gradients, the final concentration is 6.25μM, 12.5μM, 25μM, 50μM, 100μM; the water-soluble reagent without α-MSH is DMSO The group was used as background; then cultured in a 37°C incubator for 2 days.
培养结束后，利用酶标仪在405nm的波长下测量培养液的吸光度，并计算对黑色素生成的抑制率。抑制率＝[1-(OD 加药-OD 本底)/(OD 空白-OD 本底)]×100％，其中OD 加药为实验组的吸光度，OD 空白为空白组的吸光度，OD 本底为本底的吸光度。 After the cultivation, the absorbance of the culture solution was measured at a wavelength of 405nm using a microplate reader, and the inhibition rate of melanin production was calculated. Inhibition rate=[1-(OD plus drug- OD background )/(OD blank- OD background )]×100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.
抑制率数据如下表3所示：The inhibition rate data is shown in Table 3 below:
表3table 3
Figure PCTCN2020082047-appb-000023
Figure PCTCN2020082047-appb-000023
Figure PCTCN2020082047-appb-000024
Figure PCTCN2020082047-appb-000024
由表2和表3的数据可以看出，相较于未经苯乙烯基修饰的黄酮类化合物，本申请提供的黄酮衍生物对黑色素生成的抑制率得到了显著提升。It can be seen from the data in Table 2 and Table 3 that, compared with flavonoids that are not modified by styryl groups, the inhibition rate of melanin production by the flavonoid derivatives provided in the present application has been significantly improved.
3、细胞氧化应激能力抑制实验3. Cell oxidative stress inhibition experiment
把人原发性表皮角质细胞按每孔15000枚的密度接种在96孔板上，培养基为加入10wt％FBS和1wt％双抗的1640培养基。在接种Melan-a细胞的96孔板上每孔加入90μL的培养基，在37℃培养箱中培养24小时。在每孔分别加入10μL上述不同浓度的水溶性试剂(以DMSO作为空白对照，α-熊果苷作为阳性对照)，每一种化合物均设置5个浓度梯度，终浓度分别为6.25μM、12.5μM、25μM、50μM、100μM。随后每孔加入20μL,200μM的H 2O 2溶液(以不添加H 2O 2溶液的空白对照组作为本底)，在37℃培养箱中培养2小时，随后向每孔加入100μL含有25μM DCFA(2,7-二氢二氯荧光黄)的PBS(磷酸盐缓冲液)，在37℃培养箱中培养0.5小时。 Human primary epidermal keratinocytes were seeded on a 96-well plate at a density of 15,000 per well. The medium was 1640 medium with 10wt% FBS and 1wt% double antibody. Add 90 μL of medium to each well of a 96-well plate inoculated with Melan-a cells, and culture in a 37°C incubator for 24 hours. Add 10μL of the above water-soluble reagents (with DMSO as a blank control and α-arbutin as a positive control) into each well. 5 concentration gradients are set for each compound, and the final concentrations are 6.25μM and 12.5μM respectively. , 25μM, 50μM, 100μM. Then add 20μL, 200μM H 2 O 2 solution to each well (using the blank control group without H 2 O 2 solution as background), incubate for 2 hours in a 37°C incubator, and then add 100μL to each well containing 25μM DCFA (2,7-Dihydrodichlorofluorescein) in PBS (phosphate buffered saline), incubate in a 37°C incubator for 0.5 hours.
培养结束后，利用酶标仪在485nm波长和535nm波长下测量培养液的吸光度，并计算对ROS(活性氧簇)生成的抑制率。抑制率＝[1-(OD 加药-OD 本底)/(OD 空白-OD 本底)]×100％，其中OD 加药为实验组的吸光度，OD 空白为空白组的吸光度，OD 本底为本底的吸光度。 After the cultivation, the absorbance of the culture solution was measured at the wavelength of 485nm and 535nm with a microplate reader, and the inhibition rate of ROS (reactive oxygen species) generation was calculated. Inhibition rate=[1-(OD plus drug- OD background )/(OD blank- OD background )]×100%, where OD plus drug is the absorbance of the experimental group, OD blank is the absorbance of the blank group, and OD background The absorbance of the background.
抑制率数据如下表4所示：The inhibition rate data is shown in Table 4 below:
表4Table 4
Figure PCTCN2020082047-appb-000025
Figure PCTCN2020082047-appb-000025
Figure PCTCN2020082047-appb-000026
Figure PCTCN2020082047-appb-000026
其中，化合物C1(5-苯乙烯基儿茶素)、C15、6-CEPN、儿茶素、EGCG和α-熊果苷在不同浓度下对ROS生成的抑制率的柱状图如图1所示。Among them, compound C1 (5-styryl catechin), C15, 6-CEPN, catechin, EGCG and α-arbutin at different concentrations of the inhibition rate of ROS generation is shown in Figure 1 .
由图1和表4的结果可以看出，相较于未经苯乙烯基修饰的黄酮类化合物，本申请提供的黄酮衍生物抗氧化功能得到了显著提升。It can be seen from the results in Fig. 1 and Table 4 that compared with the flavonoids without styryl modification, the antioxidant function of the flavonoid derivatives provided in the present application has been significantly improved.
申请人声明，以上所述仅为本申请的具体实施方式，但本申请的保护范围并不局限于此，所属技术领域的技术人员应该明了，任何属于本技术领域的技术人员在本申请揭露的技术范围内，可轻易想到的变化或替换，均落在本申请的保护范围和公开范围之内。The applicant declares that the above are only specific implementations of this application, but the scope of protection of this application is not limited to this, and those skilled in the art should understand that any person skilled in the art disclosed in this application Within the technical scope, easily conceivable changes or substitutions fall within the scope of protection and disclosure of this application.

Claims (15)

  1. 一种黄酮衍生物，其具有如下式I或式II所示结构：A flavonoid derivative having the structure shown in Formula I or Formula II as follows:
    Figure PCTCN2020082047-appb-100001
    Figure PCTCN2020082047-appb-100001
    在式I和式II中，R 1、R 2、R 3、R 4、R 5、R 7和R 10各自独立地选自氢原子、卤素原子、羟基、氨基、Bpin基、取代或未取代的C1-C6的烷基、取代或未取代的C1-C6的烷氧基、取代或未取代的C1-C6的烷氨基、取代或未取代的C2-C6的烯基、取代或未取代的C2-C6的炔基、取代或未取代的C3-C6的环烷基、取代或未取代的C3-C6的环烯基、取代或未取代的C3-C6的环炔基、取代或未取代的C6-C18的芳基、取代或未取代的C5-C18的杂芳基、取代或未取代的C6-C18的芳氧基、取代或未取代的C7-C21的芳烷基中的一种； In Formula I and Formula II, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 10 are each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a Bpin group, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted One of C6-C18 aryl groups, substituted or unsubstituted C5-C18 heteroaryl groups, substituted or unsubstituted C6-C18 aryloxy groups, and substituted or unsubstituted C7-C21 aralkyl groups ；
    R 6、R 8和R 9各自独立地选自氢原子、取代或未取代的C1-C6的烷基、取代或未取代的C2-C6的烯基、取代或未取代的C2-C6的炔基、取代或未取代的C3-C6的环烷基、取代或未取代的C3-C6的环烯基、取代或未取代的C3-C6的环炔基、取代或未取代的C6-C18的芳基、取代或未取代的C5-C18的杂芳基、 取代或未取代的C7-C21的芳烷基或
    Figure PCTCN2020082047-appb-100002
    中的一种，其中R 11、R 12、R 13、R 14和R 15各自独立地为氢原子或羟基，并且虚线代表基团连接位置；     R 6 , R 8 and R 9 are each independently selected from a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkyne Group, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted C6-C18 Aryl, substituted or unsubstituted C5-C18 heteroaryl, substituted or unsubstituted C7-C21 aralkyl or
    Figure PCTCN2020082047-appb-100002
    One of wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently a hydrogen atom or a hydroxyl group, and the dashed line represents the group connection position;
    X选自氧原子、硫原子、
    Figure PCTCN2020082047-appb-100003
    中的一种，其中R 16、R 17和R 18各自独立地选自氢原子、取代或未取代的C1-C6的烷基、取代或未取代的C2-C6的烯基、取代或未取代的C2-C6的炔基、取代或未取代的C3-C6的环烷基、取代或未取代的C3-C6的环烯基、取代或未取代的C3-C6的环炔基、取代或未取代的C6-C18的芳基、取代或未取代的C5-C18的杂芳基、取代或未取代的C7-C21的芳烷基中的一种，并且虚线代表基团连接位置；     X is selected from oxygen atom, sulfur atom,
    Figure PCTCN2020082047-appb-100003
    One of wherein R 16 , R 17 and R 18 are each independently selected from a hydrogen atom, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted One of substituted C6-C18 aryl groups, substituted or unsubstituted C5-C18 heteroaryl groups, substituted or unsubstituted C7-C21 aralkyl groups, and the dashed line represents the group connection position;
    如上所述基团中含有取代基时，所述取代基为卤素原子、羟基、羧基、氨基、巯基或硅烷基；When the above group contains substituents, the substituents are halogen atoms, hydroxyl groups, carboxyl groups, amino groups, mercapto groups or silyl groups;
    Figure PCTCN2020082047-appb-100004
    代表单键或双键，在式I和式II中，2、3和4位的碳原子之间的两个化学键均为单键，或一个为单键，另一个为双键；
    Figure PCTCN2020082047-appb-100004
    Represents a single bond or a double bond. In Formula I and Formula II, the two chemical bonds between the carbon atoms at positions 2, 3 and 4 are both single bonds, or one is a single bond and the other is a double bond;
    n为0-3的整数。n is an integer of 0-3.
  2. 根据权利要求1所述的黄酮衍生物，其中，所述R 1、R 2、R 3、R 4和R 5各自独立地选自氢原子、卤素原子、羟基、C1-C6的烷氧基或C6-C18的芳氧基中的一种，且不全为氢原子； The flavone derivative according to claim 1, wherein the R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkoxy group or One of the C6-C18 aryloxy groups, and not all hydrogen atoms;
    优选地，所述R 1、R 2、R 3、R 4和R 5各自独立地为氢原子、卤素原子、羟基、甲氧基或乙氧基，且不全为氢原子。 Preferably, the R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group or an ethoxy group, and not all are hydrogen atoms.
  3. 根据权利要求1或2所述的黄酮衍生物，其中，所述R 7为氢原子。 The flavone derivative according to claim 1 or 2, wherein the R 7 is a hydrogen atom.
  4. 根据权利要求1-3中任一项所述的黄酮衍生物，其中，所述R 10选自卤素原子、羟基、氨基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的烷氨基、C2-C6 的烯基、C3-C6的环烷基、C2-C6的炔基或Bpin基中的一种，n为0-3的整数； The flavone derivative according to any one of claims 1 to 3, wherein the R 10 is selected from the group consisting of halogen atom, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 One of the alkylamino group, C2-C6 alkenyl group, C3-C6 cycloalkyl group, C2-C6 alkynyl group or Bpin group, n is an integer of 0-3;
    优选地，所述R 10为卤素原子、羟基、氨基、甲基、甲氧基、乙氨基、乙烯基、环己基、乙炔基或Bpin基，n为0-3的整数。 Preferably, the R 10 is a halogen atom, a hydroxyl group, an amino group, a methyl group, a methoxy group, an ethylamino group, a vinyl group, a cyclohexyl group, an ethynyl group or a Bpin group, and n is an integer of 0-3.
  5. 根据权利要求1-4中任一项所述的黄酮衍生物，其中，所述R 6、R 8和R 9各自独立地选自氢原子、C1-C6的烷基、C6-C18的芳基、C7-C21的芳烷基或
    Figure PCTCN2020082047-appb-100005
    中的一种，其中R 11、R 12、R 13、R 14和R 15各自独立地为氢原子或羟基。     The flavone derivative according to any one of claims 1 to 4, wherein the R 6 , R 8 and R 9 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, and a C6-C18 aryl group , C7-C21 aralkyl group or
    Figure PCTCN2020082047-appb-100005
    One of wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently a hydrogen atom or a hydroxyl group.
  6. 根据权利要求1-5中任一项所述的黄酮衍生物，其中，所述R 6、R 8和R 9各自独立地为氢原子、甲基、乙基、苯基、苯甲基或
    Figure PCTCN2020082047-appb-100006
    The flavone derivative according to any one of claims 1 to 5, wherein the R 6 , R 8 and R 9 are each independently a hydrogen atom, methyl, ethyl, phenyl, benzyl or
    Figure PCTCN2020082047-appb-100006
  7. 根据权利要求1-6中任一项所述的黄酮衍生物，其中，所述X为氧原子、硫原子或
    Figure PCTCN2020082047-appb-100007
    其中R 18选自氢原子、C1-C6的烷基或C7-C21的芳烷基中的一种；     The flavone derivative according to any one of claims 1-6, wherein the X is an oxygen atom, a sulfur atom or
    Figure PCTCN2020082047-appb-100007
    Wherein R 18 is selected from one of hydrogen atom, C1-C6 alkyl group or C7-C21 aralkyl group;
    优选地，所述R 18为氢原子、甲基、乙基或苯甲基。 Preferably, the R 18 is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.
  8. 根据权利要求1-7中任一项所述的黄酮衍生物，其中，所述黄酮衍生物具有如下式III、式IV、式V、式VI、式VII或式VIII所示结构：The flavone derivative according to any one of claims 1-7, wherein the flavone derivative has a structure represented by the following formula III, formula IV, formula V, formula VI, formula VII or formula VIII:
    Figure PCTCN2020082047-appb-100008
    Figure PCTCN2020082047-appb-100008
    Figure PCTCN2020082047-appb-100009
    Figure PCTCN2020082047-appb-100009
    其中，R 1、R 2、R 3、R 4和R 5各自独立地为氢原子、卤素原子、羟基、甲氧基或乙氧基，且不全为氢原子； Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group or an ethoxy group, and not all are hydrogen atoms;
    R 6、R 8和R 9各自独立地为氢原子、甲基、乙基、苯基、苯甲基或
    Figure PCTCN2020082047-appb-100010
    R 10为卤素原子、羟基、氨基、甲基、甲氧基、乙氨基、乙烯基、环己基、乙炔基或Bpin基，n为0-3的整数；     R 6 , R 8 and R 9 are each independently a hydrogen atom, methyl, ethyl, phenyl, benzyl or
    Figure PCTCN2020082047-appb-100010
    R 10 is a halogen atom, a hydroxyl group, an amino group, a methyl group, a methoxy group, an ethylamino group, a vinyl group, a cyclohexyl group, an ethynyl group or a Bpin group, and n is an integer of 0-3;
    X为氧原子、硫原子或
    Figure PCTCN2020082047-appb-100011
    其中R 18为氢原子、甲基、乙基或苯甲基。     X is oxygen atom, sulfur atom or
    Figure PCTCN2020082047-appb-100011
    Wherein R 18 is a hydrogen atom, a methyl group, an ethyl group or a benzyl group.
  9. 根据权利要求1-8中任一项所述的黄酮衍生物，其中，所述黄酮衍生物选自如下化合物C1-C21中的任意一种或化合物D1-D21中的任意一种：The flavone derivative according to any one of claims 1-8, wherein the flavone derivative is selected from any one of the following compounds C1-C21 or any one of the following compounds D1-D21:
    Figure PCTCN2020082047-appb-100012
    Figure PCTCN2020082047-appb-100012
    Figure PCTCN2020082047-appb-100013
    Figure PCTCN2020082047-appb-100013
    Figure PCTCN2020082047-appb-100014
    Figure PCTCN2020082047-appb-100014
    Figure PCTCN2020082047-appb-100015
    Figure PCTCN2020082047-appb-100015
  10. 一种如权利要求1-9中任一项所述的黄酮衍生物的制备方法，其包括：A method for preparing a flavonoid derivative according to any one of claims 1-9, which comprises:
    以黄酮类化合物
    Figure PCTCN2020082047-appb-100016
    和苯乙醛类化合物
    Figure PCTCN2020082047-appb-100017
    为原料，在酸性环境下，在有机溶剂中进行反应，得到所述黄酮衍生物。     Flavonoids
    Figure PCTCN2020082047-appb-100016
    And phenylacetaldehyde compounds
    Figure PCTCN2020082047-appb-100017
    As a raw material, it is reacted in an organic solvent under an acidic environment to obtain the flavonoid derivative.
  11. 根据权利要求10所述的制备方法，其中，所述黄酮类化合物与苯乙醛类化合物的摩尔比为1:(1.1-5)。The preparation method according to claim 10, wherein the molar ratio of the flavonoid compound to the phenylacetaldehyde compound is 1:(1.1-5).
  12. 根据权利要求10或11所述的制备方法，其中，所述酸性环境中的酸为盐酸、硫酸、磷酸、醋酸或硝酸，更优选为盐酸；The preparation method according to claim 10 or 11, wherein the acid in the acidic environment is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or nitric acid, more preferably hydrochloric acid;
    优选地，所述有机溶剂为二乙二醇；Preferably, the organic solvent is diethylene glycol;
    优选地，所述反应的温度为80-140℃，时间为0.5-12h；Preferably, the temperature of the reaction is 80-140°C, and the time is 0.5-12h;
    优选地，所述制备方法还包括在反应结束后对反应产物进行提纯，所述提纯的方法为：去除所述有机溶剂，加入乙酸乙酯溶解，水洗，分离有机相，将所述有机相真空浓缩至干，采用柱层析、薄层层析或重结晶的方法分离得到所述黄酮衍生物。Preferably, the preparation method further includes purifying the reaction product after the reaction is completed, and the purification method is: removing the organic solvent, adding ethyl acetate to dissolve, washing with water, separating the organic phase, and vacuuming the organic phase Concentrate to dryness, and separate the flavonoid derivatives by column chromatography, thin layer chromatography or recrystallization.
  13. 如权利要求1-9中任一项所述的黄酮衍生物用于抑制黑色素生成或抗氧化的用途。The use of the flavonoid derivative according to any one of claims 1-9 for inhibiting melanin production or anti-oxidation.
  14. 一种美白产品，其含有至少一种如权利要求1-9中任一项所述的黄酮衍 生物。A whitening product containing at least one flavonoid derivative according to any one of claims 1-9.
  15. 根据权利要14所述的美白产品，其中，所述美白产品为具有抗氧化、淡斑、抗皮肤衰老或抗紫外线功效的护肤品、化妆品、药品或食品。The whitening product according to claim 14, wherein the whitening product is a skin care product, cosmetics, medicine or food with anti-oxidation, light spot, anti-aging or anti-ultraviolet effects.
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