WO2021052270A1 - Honokiol derivative, preparation method therefor and use thereof - Google Patents

Honokiol derivative, preparation method therefor and use thereof Download PDF

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WO2021052270A1
WO2021052270A1 PCT/CN2020/114940 CN2020114940W WO2021052270A1 WO 2021052270 A1 WO2021052270 A1 WO 2021052270A1 CN 2020114940 W CN2020114940 W CN 2020114940W WO 2021052270 A1 WO2021052270 A1 WO 2021052270A1
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formula
group
substituted
unsubstituted
independently selected
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PCT/CN2020/114940
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French (fr)
Chinese (zh)
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张兵
张炽坚
张文环
何廷刚
胡丽云
艾勇
伍宇飞
屈恋
克里斯特勒热夫雷
弗兰克吉隆
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广东省禾基生物科技有限公司
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Publication of WO2021052270A1 publication Critical patent/WO2021052270A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/08—Amines; Quaternary ammonium compounds containing oxygen or sulfur
    • A01N33/10—Amines; Quaternary ammonium compounds containing oxygen or sulfur having at least one oxygen or sulfur atom directly attached to an aromatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/40—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the same carbon atom of the carbon skeleton, e.g. amino-ketals, ortho esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of honokiol derivatives, and specifically relates to honokiol derivatives and preparation methods and applications thereof.
  • preservatives used in food, medicine and cosmetics, most of which are chemical preservatives.
  • chemical preservatives There are dozens of commonly used preservatives, including acidic preservatives (benzoic acid) and ester preservatives (parabens) Wait.
  • acidic preservatives benzoic acid
  • ester preservatives parabens
  • people have gradually discovered that although the antiseptic effect of chemical preservatives is very good, some chemical preservatives have adverse effects on the human body, causing skin allergies and lowering body functions. And cause pollution to the environment. Therefore, natural preservatives are urgently needed by various industries.
  • a natural preservative with low toxicity, low irritation and high performance is of great significance in the fields of food, medicine and cosmetics.
  • Magnolia officinalis cortex (Magnolia officinalis cortex) is the dry bark, root bark and branches of Magnolia officinalis Rehd.et Wils. It is an important Chinese medicinal material and is listed as a medium product in "Shen Nong's Herbal Classic". Magnolia officinalis tastes bitter and pungent, has a warm nature, and has the effects of promoting qi, dissipating dampness, relieving pain, reducing adverse effects and reducing asthma.
  • the main chemical active ingredients of Magnolia officinalis are lignans, magnolol, honokiol and so on.
  • the phenols in Magnolia officinalis have antibacterial, anti-tumor, analgesic and anti-inflammatory effects.
  • the honokiol salt formed by this method is extremely unstable and easily turns golden yellow, resulting in The electrical conductivity of the system increases and the antibacterial ability decreases.
  • the above methods have very high requirements on the accuracy of the pH, the amount of thickeners and emulsifiers in the product formulation system, which makes it difficult to industrially apply.
  • honokiol The traditional method of improving the solubility of honokiol will introduce impurity compounds into the original system, and make the honokiol unstable after being dissolved in the aqueous system, resulting in the system being prone to deterioration and reducing the antibacterial ability. Therefore, modifying the structure of honokiol to improve the solubility and antibacterial ability of honokiol in water is an urgent problem in the application of honokiol as a natural preservative in food, medicine and cosmetics.
  • the purpose of the present invention is to overcome the problems of poor water solubility of honokiol and decreased antibacterial ability after being dissolved in an aqueous system, and to provide a honokiol derivative and a preparation method and application thereof.
  • the water-soluble honokiol derivative provided by the invention has excellent stability and antibacterial ability when used in preservatives.
  • the present invention provides a honokiol derivative, which has a structure represented by formula (1):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl; optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1- C 6 alkoxy and C 6 -C 10 aryl groups.
  • R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group.
  • the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 6 alkoxy group, and a group with the general formula -OR 9 -OH structure.
  • R 9 is a C 1 -C 6 alkylene group.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl.
  • the present invention provides a method for preparing honokiol derivatives.
  • the method includes combining a compound having a structure of formula (2) and/or formula (4) with a compound having a structure of formula (2) and/or formula (4) under Mannich reaction conditions. 3) and/or the compound having the structure of formula (5) is subjected to the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound having the structure of formula (6) to obtain a Mannich reaction product.
  • R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group; R 1 , R 2 , R The optional substituents on 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 6 alkoxy group, and a group with the general formula -OR 9 -OH structure.
  • R 9 is a C 1 -C 6 alkylene group.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl .
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1- C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl; optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy and C 6 -C 10 aryl.
  • the present invention provides the use of the honokiol derivative described in the first aspect or the honokiol derivative prepared by the method described in the second aspect in antibacterial applications.
  • the present invention prepares bacteriostatic modified and magnolol derivatives by modifying the structure of honokiol, which has good water solubility, is colorless and transparent after dissolution, and is resistant to common gram-negative bacteria and leather. Langerhans-positive bacteria, fungi, etc. have significant inhibitory effects, and can be used as green and natural preservatives in the fields of food, medicine and cosmetics.
  • C 1 -C 10 alkyl group means an alkyl group with a total number of carbon atoms of 1-10, including straight-chain alkyl, branched-chain alkyl or cycloalkyl. Specifically, the total number of carbon atoms is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 linear alkyl, branched alkyl or cycloalkyl, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, Cyclopentyl, methylcyclopentyl, cyclohexyl, etc.
  • C 1 -C 12 alkoxy group means an alkoxy group with a total number of carbon atoms of 1-12, including straight-chain alkoxy groups, branched-chain alkoxy groups, and cycloalkoxy groups. Specifically, the total number of carbon atoms is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 linear alkoxy, branched alkoxy or cycloalkoxy, for example, methoxy, ethoxy , N-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, n-heptoxy, n-octyloxy, N-nonyloxy, n-decyloxy, cyclopropoxy, methylcyclopropoxy, ethylcyclopropoxy, cyclopentyloxy, methylcyclopentyloxy, cyclohexyloxy, etc.
  • C 6 -C 10 aryl group means an aryl group with a total number of carbon atoms of 6-10, and at least one H on the benzene ring of the aryl group is substituted with a C 1 -C 4 alkyl group, such as tolyl and ethylphenyl , N-propyl phenyl, cumyl phenyl, n-butyl phenyl, o-xylyl, m-xylyl, p-xylyl, etc.
  • the present invention provides a honokiol derivative, which has a structure represented by formula (1):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl; optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1- C 6 alkoxy and C 6 -C 10 aryl groups.
  • R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group.
  • the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydroxyl, carboxyl, C 1 -C 6 alkoxy, and those with the general formula -OR 9 -OH structure Group.
  • R 9 is a C 1 -C 6 alkylene group.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted C 1- C 5 alkyl group, substituted or unsubstituted C 1 -C 6 alkoxy group, substituted or unsubstituted C 6 -C 8 aryl group.
  • the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from fluorine, chlorine, bromine, C 1 -C 3 alkoxy and C 6 -C 8 aryl groups.
  • R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 5 alkyl group; optional substituents on R 1 , R 2 , R 3 and R 4 Each is independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 3 alkoxy group, and a group having the general formula -OR 9 -OH structure.
  • R 9 is a C 1 -C 3 alkylene group.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen.
  • R 1 , R 2 , R 3 and R 4 are each independently a methyl group
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 8 aryl and C 1 -C 3 alkyl.
  • the C 6 -C 8 aryl group may be, for example, one of phenyl, methyl phenyl, o-dimethyl phenyl, m-dimethyl phenyl, p-dimethyl phenyl, and ethyl phenyl.
  • the C 1 -C 3 alkyl group may be, for example, methyl, ethyl, n-propyl or isopropyl.
  • R 5 , R 6 , R 7 and R 8 are all hydrogen.
  • the honokiol derivative having the structure represented by formula (1) is selected from at least one of the following compounds:
  • the inventors of the present invention found that the honokiol derivative involved in the above preferred embodiment has more excellent water solubility and antibacterial ability.
  • the present invention provides a method for preparing a honokiol derivative, which method comprises combining a compound having a structure of formula (2) and/or formula (4) with a compound having a structure of formula (2) and/or formula (4) under Mannich reaction conditions
  • the compound of the structure (3) and/or the formula (5) is subjected to the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound having the structure of the formula (6) to obtain a Mannich reaction product.
  • R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydroxyl, carboxyl, C 1 -C 6 alkoxy, and those with the general formula -OR 9 -OH structure Group.
  • R 9 is a C 1 -C 6 alkylene group.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl .
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1- C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy and C 6 -C 10 aryl.
  • the compound having the structure of formula (2) and/or formula (4) is an amine compound.
  • the amine is not particularly limited in the present invention, and may be linear alkylamine, Branched chain alkyl amines, cycloalkyl amines, hydroxyalkyl amines or various amino acids are preferably secondary amines among them.
  • the present invention has no particular limitation on the secondary amines, preferably N-methyl-glycine, N-ethyl-glycine, N-methyl-aminoethoxyethanol, N-ethyl-aminoethoxyethanol, methylaminoacetaldehyde dimethylacetal, methylaminoacetaldehyde diethanol, ethylaminoacetaldehyde At least one of dimethanol, diethanolamine, dimethylamine, diethylamine, and di-n-propylamine.
  • the compound having the structure of formula (3) and/or formula (5) is an aldehyde compound, and the present invention does not specifically limit the aldehyde compound.
  • the selected aldehyde may be formaldehyde, acetaldehyde, At least one of propionaldehyde, benzaldehyde, phenylacetaldehyde and o-methylbenzaldehyde is preferably formaldehyde.
  • the compound having the structure of formula (6) is derived from a plant extract.
  • the plant described in the present invention is Magnolia officinalis.
  • the compound having the structure of formula (6) is The content is ⁇ 80wt%.
  • the compound having the structure of formula (3) and/or formula (5), and the compound having the structure of formula (6) the prepared and thick
  • the regulation of the antibacterial properties of naphthol derivatives preferably, the total amount of compounds having the structure of formula (2) and/or formula (4), the total amount of compounds having the structure of formula (3) and/or formula (5)
  • the molar ratio of the total amount to the compound having the structure of formula (6) is 0.5-6:0.5-6:1, preferably 1-4:1-4:1.
  • the above-mentioned first contact and second contact of the present invention are both performed in the presence of an acidic substance and a solvent.
  • the present invention does not limit the amount of the acidic substance and the solvent, and those skilled in the art can freely choose according to requirements, as long as it is beneficial to the Mannich reaction.
  • the compound having the structure of formula (3) and/or formula (5) and the compound having the structure of formula (6) is 0.03--10 mL/g, and the dosage of the solvent is 2-15 mL/g.
  • the acidic substance is selected from at least one of hydrochloric acid, phosphoric acid, sulfuric acid and acetic acid.
  • the present invention does not limit the concentration of the hydrochloric acid, phosphoric acid, sulfuric acid or acetic acid, and those skilled in the art can freely choose according to actual needs.
  • the solvent is water and/or an organic solvent.
  • the first contact and the second contact are performed in the presence of water and/or an organic solvent.
  • the present invention does not specifically limit the organic solvent, which can be conventionally selected in the field.
  • a polar organic solvent more preferably a polar solvent containing a hydroxyl group or a carbonyl group
  • the organic solvent is preferably selected from methanol, ethanol, isopropanol and acetic acid, preferably methanol and/or ethanol.
  • the organic solvent and the acidic substance are both acetic acid
  • the amount of acetic acid is sufficient to meet the amount of acidic substance required for catalysis. If the amount is not sufficient to dissolve magnolol, other solvents can be used. (Such as methanol and/or ethanol) is used; the present invention does not limit this.
  • the preparation method of the honokiol derivative includes formula (2) and/or formula (4) in the presence of Mannich reaction conditions and acidic substances and solvents.
  • the compound of the structure is mixed with the compound of the formula (3) and/or the structure of the formula (5) to conduct the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound of the formula (6).
  • the present invention does not specifically limit the timing of adding the acidic substance.
  • the acidic substance can be directly added to the reactant of the first contact or the second contact, or the acidic substance can be added to the solvent first and mixed. , And then added to the reactants of the first contact or the second contact together, preferably the latter.
  • the mixing in the present invention is preferably carried out under stirring.
  • the first contact method includes: a compound having the structure of formula (3) and/or formula (5) (preferably an aldehyde compound or a solution of the compound, the solution is preferably an aqueous solution) is added to a compound having the formula ( 2) and/or the compound of formula (4) (preferably a secondary amine compound or a solution of the compound, and the solution is preferably an aqueous solution) for the first contact, and the temperature is controlled to be 20-50°C, preferably 30-40 °C, the time is 5-20min, preferably 10-15min; then the first contacted system is placed in a low-temperature water bath, and acidic substance or a solution of acidic substance in a solvent (preferably an organic solvent) is added to the system ,
  • the control temperature is 1-10°C, preferably 2-5°C, and the continuous contact time is 0.5-2h, preferably 0.6-1.5h.
  • the present invention does not specifically limit the form of the low-temperature water bath, as long as the purpose of the low-temperature bath can be achieved; it is preferably an ice-water bath and/or an ice-salt bath, and the present invention does not specifically limit the salt in the ice-salt bath.
  • the amount of the salt is 0.5 to 5% by weight.
  • the second contact method includes: dissolving the compound having the structure of formula (6) in the solvent in the presence of an acidic substance to form a solution, and then performing the first contact with the product obtained in the first contact at 30-90°C. Mentioned second contact.
  • the inventors of the present invention found that, compared with the method of directly adding the acid to the reactant, the above-mentioned preferred method of adding the acidic substance to the solvent for mixing, and then adding the reactant of the first contact or the second contact together
  • the medium method can effectively reduce acid mist and avoid side reactions caused by violent reaction exotherm.
  • the Mannich reaction conditions include: a first contact temperature of 1-50°C, more preferably 2-50°C, and a second contact temperature of 30-90°C, more preferably 70-85 °C.
  • the Mannich reaction conditions further include: the first contact time is 5 min to 2 h, more preferably 10 min to 2 h, and the second contact time is 1-20 h, more preferably 5-10 h.
  • the first contact time refers to the total time of the first contact
  • the second contact time refers to the total time of the second contact.
  • the method further comprises: successively evaporating, purifying and lyophilizing the product of the second contact.
  • the present invention does not specifically limit the evaporation operation, which can be any evaporation equipment in the field, preferably a rotary evaporator, to evaporate most of the organic solvents.
  • the present invention does not specifically limit the purification operation, which can be any purification method in the field, preferably using column chromatography.
  • the purification filler is 100-200 mesh silica gel.
  • the eluent used in the column chromatography of the present invention is It is not particularly limited, and it can be any reagent in the art that can achieve the purpose of elution.
  • the eluent is ethyl acetate/acetone, and the volume ratio of ethyl acetate and acetone is preferably 2-6:1, particularly preferably It is 4:1.
  • the present invention also provides the use of the honokiol derivative described in the aforementioned first aspect or the honokiol derivative prepared by the method described in the aforementioned second aspect in bacteriostasis.
  • the honokiol derivatives provided by the present invention can be used in foods, medicines and cosmetics, as preservatives or preservative components, for common Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger have inhibitory effects.
  • the amount of the magnolol derivative is 0.001-0.01 g per gram of the food, medicine or cosmetic.
  • the molecular structure of the prepared honokiol derivative was measured by a time-of-flight mass spectrometer, a nuclear magnetic resonance spectrometer, and a liquid chromatography mass spectrometer.
  • the model of the flight mass spectrometer is HR EI-TOFMS. Purchase From Kore Company in the UK; the model of the NMR spectrometer is Thermo Fisher picoSpin 80, purchased from Thermo Fisher; the model of the liquid chromatography mass spectrometer is TSQ Altis triple quadrupole mass spectrometer, purchased from Thermo Fisher Flying company.
  • the raw materials involved are all commercially available products unless otherwise specified.
  • the plant-derived honokiol content is 98%, purchased from Hunan Jiamu Biotechnology Co., Ltd.; the N-methyl- Glycine powder and N-methylaminoglyoxal dimethylacetal were purchased from Shanghai Maclean Bioreagent Co., Ltd.; the nutrient broth was purchased from Beijing Merida Technology Co., Ltd.
  • the main ingredients were peptone, beef extract, sodium chloride and water; Sabouraud medium was purchased from Shandong West Asia Chemical Industry Co., Ltd., and its main components are peptone and agar; TTC is the abbreviation for 2,3,5-chlorotriphenyltetrazolium, and the TTC reagent used was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Company; Methylparaben is analytical grade, purchased from Shanghai Macleans Biochemical Technology Co., Ltd.; phenoxyethanol is analytical grade, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.
  • Escherichia coli ATCC 8739 4th generation, purchased from Guangdong Institute of Microbiology; Staphylococcus aureus: ATCC 6538, 4th generation, purchased from Guangdong Institute of Microbiology; Verdigris Pseudomonas aeruginosa: ATCC 9027, 6th generation, purchased from Guangdong Institute of Microbiology; Candida albicans: ATCC8327, 4th generation, purchased from Guangdong Institute of Microbiology; Aspergillus niger: The 4th generation of ATCC5478 was purchased from Guangdong Institute of Microbiology; Sabouraud culture medium was purchased from Shandong West Asia Chemical Industry Co., Ltd.
  • the yield was 35%. It was characterized by a flight mass spectrometer and a nuclear magnetic resonance instrument, and it was confirmed to be a honokiol derivative with the structure represented by formula (1) of the present invention.
  • the reaction mechanism is as follows:
  • the yield was 60%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed to be a honokiol derivative with the structure represented by formula (1) of the present invention.
  • the reaction mechanism is as follows:
  • the yield was 35%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed to be a honokiol derivative with the structure represented by formula (1) of the present invention.
  • the reaction mechanism is as follows:
  • Example 2 It was carried out according to the method of Example 1, except that the same amount of methylaminoacetaldehyde dimethyl acetal was used instead of the N-methyl-glycine, and the others were the same as in Example 1.
  • the yield was 63%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed that the prepared product is a honokiol derivative with the structure shown in formula (1) of the present invention, and its structural formula is as follows:
  • Example 2 It was carried out according to the method of Example 1, except that the molar ratio of the N-methyl-glycine to the honokiol was 6:6:1, and the others were the same as in Example 1.
  • the yield of honokiol derivatives was 32%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product prepared in this example was a honokiol derivative with the structure represented by formula (1) of the present invention (wherein, R 1 , R 2 , R 3 and R 4 is hydrogen, chlorine, methyl and methoxy in order, R 1 , R 2 , R 3 and R 4 are in order methyl, methyl, R 5 , R 6 , R 7 and R 8 are all hydrogen).
  • the yield of honokiol derivatives was 18%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product prepared in this example was a honokiol derivative with the structure represented by formula (1) of the present invention (wherein, R 1 , R 2 , R 3 and R 4 is hydrogen, chlorine, methyl and tolyl in sequence, R 1 , R 2 , R 3 and R 4 are methyl, methyl, R 5 , R 6 , R 7 and R 8 are all hydrogen).
  • Example 1 Carry out according to the method of Example 1, the difference is that instead of preparing hydrochloric acid and methanol in advance, the first part of hydrochloric acid and methanol in the same amount are directly added to the aqueous solution of N-methyl-glycine and formaldehyde and mixed, and the The remaining hydrochloric acid and methanol are directly mixed with the honokiol and the product obtained from the first contact for reaction; the others are the same as in Example 1.
  • the yield of the honokiol derivative was 24%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product prepared in this example was a honokiol derivative with the structure represented by formula (1) of the present invention, and its structural formula was the same as the product of Example 1.
  • the solubility test method is: measure 25 ⁇ 1°C with a graduated cylinder, and place 100g deionized water into a 250ml beaker. Put it into a magnetic stirrer and adjust the speed to 200 rpm/min. Use an analytical balance to weigh honokiol and the samples in Examples 1-9 to test their solubility. During the test, 0.1g of the sample is dissolved in deionized water until it cannot be completely dissolved after stirring for 10 minutes. Record the maximum dissolution quality. The results are shown in Table 1.
  • the honokiol derivative samples in Examples 1-9 were used as test samples to quantitatively test the minimum inhibitory concentration MIC value. 10% by weight honokiol ethanol solution, traditional chemical preservatives methyl paraben and phenoxyethanol were used as controls.
  • the minimum inhibitory concentration MIC value test method is: use sterilized nutrient broth (for culturing Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa), Sabouraud medium (for culturing white Candida and Aspergillus niger) were used as diluents.
  • the test samples were diluted by the two-fold dilution method, and then the corresponding bacteria were respectively inoculated at the concentrations shown in Table 2.
  • Bacteria were cultured at 35°C for 36h; fungi were cultured at 28°C for 48h. 3h before the end of the culture, add TTC reagent and continue the culture.
  • the honokiol derivatives prepared in Examples 1-9 were added to the spray formula or similar spray formula of Table 4 below. Inoculate a certain number of bacteria and fungi at intervals of 0 days, 7 days, 14 days, 21 days, and 28 days to detect changes in the number of microorganisms according to the detection method of the USP32 ⁇ 51> Microbial Preservation Efficacy Test.
  • the test results of the honokiol derivatives prepared in 3, 4 and 7 are shown in Table 5 below, and the test results of the honokiol derivatives prepared in the other examples (all using the spray formula of Table 4 below) are similar. All are qualified.
  • Example 1 sample Solvent water (100g) Honokiol -
  • Example 2 >1g
  • Example 3 >10g
  • Example 4 >5g
  • Example 5 >5g
  • Example 6 >5g
  • Example 7 >3g
  • Example 8 >2g
  • Example 9 >3g
  • the logarithmic decrease value refers to the change of the total amount of microorganisms (ie: the difference between the initial logarithmic value and the logarithmic value after a certain period of time). The larger the number, the stronger the antibacterial ability.
  • the honokiol derivative prepared by the present invention exhibits excellent water solubility.
  • the solubility of the sample in Example 1 is greater than 3 g.
  • the solubility of the sample in Example 2 is greater than 1g
  • the solubility of the sample in Example 3 is greater than 10g
  • the water solubility of the honokiol derivatives in Examples 4-9 are all greater than 2g, that is, the samples prepared in the examples have all been dissolved
  • And honokiol extracted from plants is insoluble in water.
  • the honokiol derivatives prepared in Examples 1-9 of the present invention all have good antibacterial effects.
  • the honokiol derivatives prepared in Example 3 have good antibacterial effects on the large intestine. Escherichia, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger have significant bacteriostatic effects, and the bacteriostatic effect is better than the traditional chemical preservatives methyl paraben, Phenoxyethanol, honokiol derivatives prepared in other examples have good antibacterial effects on five common bacteria in cosmetics.
  • the spray formula in Table 4 provides a very suitable environment for the survival of bacteria and fungi. From the data in Table 5, it can be seen that under such harsh conditions, the samples prepared in Examples 1, 3, 4, and 7 of the present invention show Excellent antibacterial ability. After 28 days of spray antiseptic challenge test of water formulation, honokiol derivatives in Examples 1, 3, 4, and 7 passed the antiseptic challenge test as preservatives. The effects of other examples are similar. All have good antibacterial ability.
  • honokiol itself does not dissolve in water, it is difficult to test the antibacterial effect. Although the antibacterial effect of 10% by weight honokiol ethanol solution is very good, but the national standards have strict restrictions on the amount of ethanol in cosmetics, and it is used in water systems. Honokiol will precipitate out of ethanol, so it cannot Industrial applications.
  • the honokiol derivative obtained by modifying honokiol by the method of the present invention has good water solubility, and effectively improves the solubility of honokiol in water; Gram-negative bacteria, Gram-positive bacteria, fungi, etc. have a significant inhibitory effect.

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Abstract

The present invention relates to the field of honokiol derivatives. Disclosed are a honokiol derivative, a preparation method therefor and the use thereof, wherein the derivative has a structure as shown in formula (I). The honokiol derivative has a good water solubility, is colorless and transparent after dissolution, has a significant inhibitory effect on common gram-negative bacteria, gram-positive bacteria, fungi, etc., and can be used in the fields of food, medicine, cosmetics, etc. as a green and natural preservative.

Description

和厚朴酚衍生物及其制备方法与应用Honokiol derivative and its preparation method and application
相关申请的交叉引用Cross-references to related applications
本申请要求2019年09月20日提交的中国专利申请201910894315.8的权益，该申请的内容通过引用被合并于本文。This application claims the rights and interests of the Chinese patent application 201910894315.8 filed on September 20, 2019, the content of which is incorporated herein by reference.
技术领域Technical field
本发明涉及和厚朴酚衍生物领域，具体涉及和厚朴酚衍生物及其制备方法与应用。The present invention relates to the field of honokiol derivatives, and specifically relates to honokiol derivatives and preparation methods and applications thereof.
背景技术Background technique
食品、药品及化妆品富含大量水分和各类营养成分，为微生物提供了良好的生长环境，而且化妆品生产和使用过程中难免会有微生物的侵入，这就使其极易腐败变质，导致产品质量下降，对使用者的健康构成威胁。在化妆品中添加防腐剂是保护产品免受微生物污染，延长产品货架寿命，确保产品安全性的重要手段。Foods, medicines and cosmetics are rich in water and various nutrients, which provide a good growth environment for microorganisms. In addition, the intrusion of microorganisms is inevitable during the production and use of cosmetics, which makes them extremely prone to spoilage and deterioration, leading to product quality. Decline, posing a threat to the health of users. Adding preservatives to cosmetics is an important means to protect products from microbial contamination, extend product shelf life, and ensure product safety.
目前，食品、药品及化妆品中所用防腐剂种类繁多，绝大多数为化学防腐剂，常用的有几十种，包括酸性防腐剂(苯甲酸)、酯型防腐剂(对羟基苯甲酸酯类)等。但是，随着科学的发展和消费者安全意识的不断提高，人们逐渐发现，虽然化学防腐剂的防腐效果很好，但是有些化学防腐剂会对人体产生不良作用，引起皮肤过敏，身体机能下降，并对环境造成污染。因此，天然的防腐剂受到各个行业的迫切需求，一款低毒、低刺激、高效能的天然防腐剂在食品、药品及化妆品等领域具有重要意义。At present, there are many kinds of preservatives used in food, medicine and cosmetics, most of which are chemical preservatives. There are dozens of commonly used preservatives, including acidic preservatives (benzoic acid) and ester preservatives (parabens) Wait. However, with the development of science and the continuous improvement of consumer safety awareness, people have gradually discovered that although the antiseptic effect of chemical preservatives is very good, some chemical preservatives have adverse effects on the human body, causing skin allergies and lowering body functions. And cause pollution to the environment. Therefore, natural preservatives are urgently needed by various industries. A natural preservative with low toxicity, low irritation and high performance is of great significance in the fields of food, medicine and cosmetics.
厚朴(Magnolia officinalis cortex)为木兰科植物厚朴Magnolia officinalisRehd.et Wils.的干燥树皮、根皮及树枝，属于重要的中药材，在《神农本草经》中被列为中品。厚朴味苦辛、性温，具有行气化湿、温中止痛、降逆平喘的作用。厚朴主要化学活性成分为木脂素类、厚朴酚、和厚朴酚等。厚朴中的酚类，具有抑菌、抗肿瘤、镇痛、抗炎等功效。但是由于其水溶性较差，本身易氧化变质，极大的阻碍了和厚朴酚在食品、药品及化妆品中的应用。通常，可以用常规的表面活性剂、乳化剂增溶和厚朴酚，这种情况下不仅所需表面活性剂、乳化剂的用量非常大，而且即使应用在水剂配方中，和厚朴酚也会从水体系配方中析出来，致使整个体系变白浊，从而严重影响使用。此外，还可以在配方体系中加入少量的碱，将和厚朴酚变成盐，增加其水溶性，然而，这种方法形成的和厚朴酚盐极不稳定，容易变成金黄色，导致体系电导率升高、抑菌能力下降。以上方法对产品配方体系的pH、增稠剂和乳化剂的用量精准度要求非常高，导致其基本难以工业应用。Magnolia officinalis cortex (Magnolia officinalis cortex) is the dry bark, root bark and branches of Magnolia officinalis Rehd.et Wils. It is an important Chinese medicinal material and is listed as a medium product in "Shen Nong's Herbal Classic". Magnolia officinalis tastes bitter and pungent, has a warm nature, and has the effects of promoting qi, dissipating dampness, relieving pain, reducing adverse effects and reducing asthma. The main chemical active ingredients of Magnolia officinalis are lignans, magnolol, honokiol and so on. The phenols in Magnolia officinalis have antibacterial, anti-tumor, analgesic and anti-inflammatory effects. However, due to its poor water solubility, it is easy to oxidize and deteriorate, which greatly hinders the application of honokiol in food, medicine and cosmetics. Generally, conventional surfactants and emulsifiers can be used to solubilize and magnolol. In this case, not only the amount of surfactants and emulsifiers required is very large, but also even if it is used in liquid formulations, honokiol It will also separate out from the water system formula, causing the entire system to become turbid, which will seriously affect the use. In addition, a small amount of alkali can be added to the formulation system to turn honokiol into a salt and increase its water solubility. However, the honokiol salt formed by this method is extremely unstable and easily turns golden yellow, resulting in The electrical conductivity of the system increases and the antibacterial ability decreases. The above methods have very high requirements on the accuracy of the pH, the amount of thickeners and emulsifiers in the product formulation system, which makes it difficult to industrially apply.
传统提高和厚朴酚溶解度的方法会给原体系引入杂质化合物，而且使和厚朴酚溶解在水剂体系后不稳定，导致体系容易变质，抑菌能力下降。因此，对和厚朴酚结构进行改性，提高和厚朴酚在水中的溶解度和抑菌能力，是和厚朴酚作为 天然防腐剂应用在食品、药品及化妆品中急需解决的问题。The traditional method of improving the solubility of honokiol will introduce impurity compounds into the original system, and make the honokiol unstable after being dissolved in the aqueous system, resulting in the system being prone to deterioration and reducing the antibacterial ability. Therefore, modifying the structure of honokiol to improve the solubility and antibacterial ability of honokiol in water is an urgent problem in the application of honokiol as a natural preservative in food, medicine and cosmetics.
发明内容Summary of the invention
本发明的目的是为了克服和厚朴酚水溶性差和溶解在水剂体系后抑菌能力下降的问题，提供了一种和厚朴酚衍生物及其制备方法与应用。本发明提供的水溶性和厚朴酚衍生物应用在防腐剂中时具有优异的稳定性和抑菌能力。The purpose of the present invention is to overcome the problems of poor water solubility of honokiol and decreased antibacterial ability after being dissolved in an aqueous system, and to provide a honokiol derivative and a preparation method and application thereof. The water-soluble honokiol derivative provided by the invention has excellent stability and antibacterial ability when used in preservatives.
为了实现上述目的，第一方面，本发明提供一种和厚朴酚衍生物，该衍生物具有式(1)所示的结构：In order to achieve the above objective, in the first aspect, the present invention provides a honokiol derivative, which has a structure represented by formula (1):
Figure PCTCN2020114940-appb-000001
Figure PCTCN2020114940-appb-000001
其中，在式(1)中，R 1、R 2、R 3和R 4各自独立地选自氢、卤素、取代或未取代的C 1-C 10的烷基、取代或未取代的C 1-C 12的烷氧基、取代或未取代的C 6-C 10的芳基；R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自卤素、C 1-C 6的烷氧基和C 6-C 10的芳基。 Wherein, in formula (1), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl; optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1- C 6 alkoxy and C 6 -C 10 aryl groups.
优选地，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 10的烷基。R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 6的烷氧基、通式为-O-R 9-OH结构的基团。其中，R 9为C 1-C 6的亚烷基。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group. The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 6 alkoxy group, and a group with the general formula -OR 9 -OH structure. Wherein, R 9 is a C 1 -C 6 alkylene group.
优选地，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 10的芳基和C 1-C 6的烷基。 Preferably, R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl.
第二方面，本发明提供一种和厚朴酚衍生物的制备方法，该方法包括在曼尼希反应条件下，将具有式(2)和/或式(4)结构的化合物与具有式(3)和/或式(5)结构的化合物进行第一接触，然后第一接触所得产物与具有式(6)结构的化合物进行第二接触，得到曼尼希反应产物。In the second aspect, the present invention provides a method for preparing honokiol derivatives. The method includes combining a compound having a structure of formula (2) and/or formula (4) with a compound having a structure of formula (2) and/or formula (4) under Mannich reaction conditions. 3) and/or the compound having the structure of formula (5) is subjected to the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound having the structure of formula (6) to obtain a Mannich reaction product.
Figure PCTCN2020114940-appb-000002
Figure PCTCN2020114940-appb-000002
Figure PCTCN2020114940-appb-000003
Figure PCTCN2020114940-appb-000003
其中，在式(2)和式(4)中，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 10的烷基；R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 6的烷氧基、通式为-O-R 9-OH结构的基团。其中，R 9为C 1-C 6的亚烷基。 Wherein, in formula (2) and formula (4), R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group; R 1 , R 2 , R The optional substituents on 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 6 alkoxy group, and a group with the general formula -OR 9 -OH structure. Wherein, R 9 is a C 1 -C 6 alkylene group.
优选地，在式(3)和式(5)中，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 10的芳基和C 1-C 6的烷基。 Preferably, in formula (3) and formula (5), R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl .
优选地，在式(6)中，R 1、R 2、R 3和R 4各自独立地选自氢、卤素、取代或未取代的C 1-C 10的烷基、取代或未取代的C 1-C 12的烷氧基、取代或未取代的C 6-C 10的芳基；R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自卤素、C 1-C 6的烷氧基和C 6-C 10的芳基。 Preferably, in formula (6), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1- C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl; optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy and C 6 -C 10 aryl.
第三方面，本发明提供前述第一方面所述的和厚朴酚衍生物或前述第二方面所述方法制备得到的和厚朴酚衍生物在抑菌中的应用。In the third aspect, the present invention provides the use of the honokiol derivative described in the first aspect or the honokiol derivative prepared by the method described in the second aspect in antibacterial applications.
本发明通过对和厚朴酚结构进行改性，制备出了可以抑菌的改性和厚朴酚衍生物，具有良好水溶性，溶解后无色透明，对常见的革兰氏阴性菌、革兰氏阳性菌、真菌等具有显著的抑制效果，可作为绿色天然的防腐剂应用于食品、药品及化妆品等领域。The present invention prepares bacteriostatic modified and magnolol derivatives by modifying the structure of honokiol, which has good water solubility, is colorless and transparent after dissolution, and is resistant to common gram-negative bacteria and leather. Langerhans-positive bacteria, fungi, etc. have significant inhibitory effects, and can be used as green and natural preservatives in the fields of food, medicine and cosmetics.
本发明的其他特征和优点将在随后的具体实施方式部分予以详细说明。Other features and advantages of the present invention will be described in detail in the following specific embodiments.
具体实施方式detailed description
以下是对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。The following is a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described here are only used to illustrate and explain the present invention, and not to limit the present invention.
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the end values of each range, between the end values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges. These values The scope should be considered as specifically disclosed herein.
以下对本发明中涉及的部分术语进行解释：The following explains some terms involved in the present invention:
“C 1-C 10的烷基”表示碳原子总数为1-10的烷基，包括直链烷基、支链烷基或者环烷基，具体可以为碳原子总数为1、2、3、4、5、6、7、8、9、10的直链烷 基、支链烷基或者环烷基，具体可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、正庚基、正辛基、正壬基、正癸基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基等。 "C 1 -C 10 alkyl group" means an alkyl group with a total number of carbon atoms of 1-10, including straight-chain alkyl, branched-chain alkyl or cycloalkyl. Specifically, the total number of carbon atoms is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 linear alkyl, branched alkyl or cycloalkyl, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, Cyclopentyl, methylcyclopentyl, cyclohexyl, etc.
“C 1-C 12的烷氧基”表示碳原子总数为1-12的烷氧基，包括直链烷氧基、支链烷氧基和环烷氧基，具体可以为碳原子总数为1、2、3、4、5、6、7、8、9、10、11、12的直链烷氧基、支链烷氧基或环烷氧基，例如可以为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、正己氧基、正庚氧基、正辛氧基、正壬氧基、正癸氧基、环丙氧基、甲基环丙氧基、乙基环丙氧基、环戊氧基、甲基环戊氧基、环己氧基等。 "C 1 -C 12 alkoxy group" means an alkoxy group with a total number of carbon atoms of 1-12, including straight-chain alkoxy groups, branched-chain alkoxy groups, and cycloalkoxy groups. Specifically, the total number of carbon atoms is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 linear alkoxy, branched alkoxy or cycloalkoxy, for example, methoxy, ethoxy , N-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, n-heptoxy, n-octyloxy, N-nonyloxy, n-decyloxy, cyclopropoxy, methylcyclopropoxy, ethylcyclopropoxy, cyclopentyloxy, methylcyclopentyloxy, cyclohexyloxy, etc.
“C 6-C 10的芳基”表示碳原子总数为6-10的芳基，该芳基的苯环上至少一个H被C 1-C 4的烷基取代，例如甲苯基、乙苯基、正丙苯基、异丙苯基、正丁苯基、邻二甲苯基、间二甲苯基、对二甲苯基等。 "C 6 -C 10 aryl group" means an aryl group with a total number of carbon atoms of 6-10, and at least one H on the benzene ring of the aryl group is substituted with a C 1 -C 4 alkyl group, such as tolyl and ethylphenyl , N-propyl phenyl, cumyl phenyl, n-butyl phenyl, o-xylyl, m-xylyl, p-xylyl, etc.
本文中其他相似基团的定义参照本文前述定义，仅是碳原子数或异构方式不同而已。The definitions of other similar groups herein refer to the aforementioned definitions herein, and only differ in the number of carbon atoms or the way of isomerization.
第一个方面，本发明提供一种和厚朴酚衍生物，该衍生物具有式(1)所示的结构：In the first aspect, the present invention provides a honokiol derivative, which has a structure represented by formula (1):
Figure PCTCN2020114940-appb-000004
Figure PCTCN2020114940-appb-000004
其中，在式(1)中，R 1、R 2、R 3和R 4各自独立地选自氢、卤素、取代或未取代的C 1-C 10的烷基、取代或未取代的C 1-C 12的烷氧基、取代或未取代的C 6-C 10的芳基；R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自卤素、C 1-C 6的烷氧基和C 6-C 10的芳基。 Wherein, in formula (1), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl; optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1- C 6 alkoxy and C 6 -C 10 aryl groups.
优选地，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 10的烷基。优选地，R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 6的烷氧基、通式为-O-R 9-OH结构的基团。其中，R 9为C 1-C 6的亚烷基。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group. Preferably, the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydroxyl, carboxyl, C 1 -C 6 alkoxy, and those with the general formula -OR 9 -OH structure Group. Wherein, R 9 is a C 1 -C 6 alkylene group.
优选地，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 10的芳基和C 1-C 6的烷基。 Preferably, R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl.
根据本发明的一种优选的实施方式，在式(1)中，R 1、R 2、R 3和R 4各自独立地选自氢、氟、氯、溴、取代或未取代的C 1-C 5的烷基、取代或未取代的C 1-C 6的烷氧基、取代或未取代的C 6-C 8的芳基。R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自氟、氯、溴、C 1-C 3的烷氧基和C 6-C 8的芳基。 According to a preferred embodiment of the present invention, in formula (1), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted C 1- C 5 alkyl group, substituted or unsubstituted C 1 -C 6 alkoxy group, substituted or unsubstituted C 6 -C 8 aryl group. The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from fluorine, chlorine, bromine, C 1 -C 3 alkoxy and C 6 -C 8 aryl groups.
优选地，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 5的烷基；R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 3的烷氧基、通式为-O-R 9-OH结构的基团。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 5 alkyl group; optional substituents on R 1 , R 2 , R 3 and R 4 Each is independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 3 alkoxy group, and a group having the general formula -OR 9 -OH structure.
其中，R 9为C 1-C 3的亚烷基。 Wherein, R 9 is a C 1 -C 3 alkylene group.
优选地，R 1、R 2、R 3和R 4各自独立地均为氢。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently hydrogen.
优选地，R 1、R 2、R 3和R 4各自独立地为甲基、
Figure PCTCN2020114940-appb-000005
Figure PCTCN2020114940-appb-000006
Preferably, R 1 , R 2 , R 3 and R 4 are each independently a methyl group,
Figure PCTCN2020114940-appb-000005
Figure PCTCN2020114940-appb-000006
优选地，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 8的芳基和C 1-C 3的烷基。其中，C 6-C 8的芳基例如可以是苯基、甲基苯基、邻二甲基苯基、间二甲基苯基、对二甲基苯基、乙基苯基中的一种。C 1-C 3的烷基例如可以是甲基、乙基、正丙基或异丙基。 Preferably, R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 8 aryl and C 1 -C 3 alkyl. Among them, the C 6 -C 8 aryl group may be, for example, one of phenyl, methyl phenyl, o-dimethyl phenyl, m-dimethyl phenyl, p-dimethyl phenyl, and ethyl phenyl. . The C 1 -C 3 alkyl group may be, for example, methyl, ethyl, n-propyl or isopropyl.
根据本发明，优选地，在式(1)中，R 5、R 6、R 7和R 8均为氢。 According to the present invention, preferably, in formula (1), R 5 , R 6 , R 7 and R 8 are all hydrogen.
根据本发明的一种优选实施方式，具有式(1)所示结构的和厚朴酚衍生物选自以下化合物中的至少一种：According to a preferred embodiment of the present invention, the honokiol derivative having the structure represented by formula (1) is selected from at least one of the following compounds:
Figure PCTCN2020114940-appb-000007
Figure PCTCN2020114940-appb-000007
Figure PCTCN2020114940-appb-000008
Figure PCTCN2020114940-appb-000008
Figure PCTCN2020114940-appb-000009
Figure PCTCN2020114940-appb-000009
本发明的发明人发现，上述优选实施方式中涉及的和厚朴酚衍生物具有更优异的水溶性和抑菌能力。The inventors of the present invention found that the honokiol derivative involved in the above preferred embodiment has more excellent water solubility and antibacterial ability.
第二个方面，本发明提供一种和厚朴酚衍生物的制备方法，该方法包括在曼尼希反应条件下，将具有式(2)和/或式(4)结构的化合物与具有式(3)和/或式(5)结构的化合物进行第一接触，然后第一接触所得产物与具有式(6)结构的化合物进行第二接触得到曼尼希反应产物。In a second aspect, the present invention provides a method for preparing a honokiol derivative, which method comprises combining a compound having a structure of formula (2) and/or formula (4) with a compound having a structure of formula (2) and/or formula (4) under Mannich reaction conditions The compound of the structure (3) and/or the formula (5) is subjected to the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound having the structure of the formula (6) to obtain a Mannich reaction product.
Figure PCTCN2020114940-appb-000010
Figure PCTCN2020114940-appb-000010
其中，在式(2)和式(4)中，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 10的烷基。 Wherein, in formula (2) and formula (4), R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group.
优选地，R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 6的烷氧基、通式为-O-R 9-OH结构的基团。其中，R 9为C 1-C 6的亚烷基。 Preferably, the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydroxyl, carboxyl, C 1 -C 6 alkoxy, and those with the general formula -OR 9 -OH structure Group. Wherein, R 9 is a C 1 -C 6 alkylene group.
优选地，在式(3)和式(5)中，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 10的芳基和C 1-C 6的烷基。 Preferably, in formula (3) and formula (5), R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl .
优选地，在式(6)中，R 1、R 2、R 3和R 4各自独立地选自氢、卤素、取代或未取代的C 1-C 10的烷基、取代或未取代的C 1-C 12的烷氧基、取代或未取代的C 6-C 10的芳基。 Preferably, in formula (6), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1- C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl.
优选地，R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自卤素、C 1-C 6 的烷氧基和C 6-C 10的芳基。 Preferably, the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy and C 6 -C 10 aryl.
在上述式(2)-式(6)中，所述的R 1、R 2、R 3、R 4、R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8的可选范围与前述第一方面中的R 1、R 2、R 3、R 4、R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8的可选范围相同，在此不再赘述。 In the above formula (2) to formula (6), the R 1 , R 2 , R 3 , R 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R The optional range of 8 is the same as that of R 1 , R 2 , R 3 , R 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 in the foregoing first aspect The scope is the same, so I won't repeat them here.
根据本发明，优选地，所述具有式(2)和/或式(4)结构的化合物为胺类化合物，本发明对所述胺类并没有特别地限定，可以为直链烷基胺、支链烷基胺、环烷基胺、羟烷基胺或各种氨基酸，优选为其中的二级胺，本发明对所述二级胺没有特别的限定，优选为N-甲基-甘氨酸、N-乙基-甘氨酸、N-甲基-氨基乙氧基乙醇、N-乙基-氨基乙氧基乙醇、甲氨基乙醛缩二甲醇、甲氨基乙醛缩二乙醇、乙氨基乙醛缩二甲醇、二乙醇胺、二甲胺、二乙胺、二正丙胺中的至少一种。According to the present invention, preferably, the compound having the structure of formula (2) and/or formula (4) is an amine compound. The amine is not particularly limited in the present invention, and may be linear alkylamine, Branched chain alkyl amines, cycloalkyl amines, hydroxyalkyl amines or various amino acids are preferably secondary amines among them. The present invention has no particular limitation on the secondary amines, preferably N-methyl-glycine, N-ethyl-glycine, N-methyl-aminoethoxyethanol, N-ethyl-aminoethoxyethanol, methylaminoacetaldehyde dimethylacetal, methylaminoacetaldehyde diethanol, ethylaminoacetaldehyde At least one of dimethanol, diethanolamine, dimethylamine, diethylamine, and di-n-propylamine.
优选地，具有式(3)和/或式(5)结构的化合物为醛类化合物，本发明对所述醛类化合物没有特别地限定，例如，所选用的醛类可以为甲醛、乙醛、丙醛、苯甲醛、苯乙醛和邻甲基苯甲醛中的至少一种，优选为甲醛。Preferably, the compound having the structure of formula (3) and/or formula (5) is an aldehyde compound, and the present invention does not specifically limit the aldehyde compound. For example, the selected aldehyde may be formaldehyde, acetaldehyde, At least one of propionaldehyde, benzaldehyde, phenylacetaldehyde and o-methylbenzaldehyde is preferably formaldehyde.
根据本发明，优选地，具有式(6)结构的化合物来自于植物提取物，本发明中所述的植物为木兰科植物厚朴，所述提取物中，具有式(6)结构的化合物的含量≥80wt％。According to the present invention, preferably, the compound having the structure of formula (6) is derived from a plant extract. The plant described in the present invention is Magnolia officinalis. In the extract, the compound having the structure of formula (6) is The content is ≥80wt%.
为了充分发挥具有式(2)和/或式(4)结构的化合物、具有式(3)和/或式(5)结构的化合物与具有式(6)结构的化合物对所制得的和厚朴酚衍生物的抑菌性能的调控作用，优选地，具有式(2)和/或式(4)结构的化合物的总量、具有式(3)和/或式(5)结构的化合物的总量与具有式(6)结构的化合物的摩尔比为0.5-6：0.5-6：1，优选为1-4：1-4：1。In order to give full play to the compound having the structure of formula (2) and/or formula (4), the compound having the structure of formula (3) and/or formula (5), and the compound having the structure of formula (6), the prepared and thick The regulation of the antibacterial properties of naphthol derivatives, preferably, the total amount of compounds having the structure of formula (2) and/or formula (4), the total amount of compounds having the structure of formula (3) and/or formula (5) The molar ratio of the total amount to the compound having the structure of formula (6) is 0.5-6:0.5-6:1, preferably 1-4:1-4:1.
根据本发明一种优选实施方式，本发明上述第一接触和第二接触均在酸性物质以及溶剂的存在下进行。本发明对所述酸性物质和溶剂的用量没有限制，本领域技术人员可以根据需求自由选择，只要利于所述曼尼希反应的进行即可。优选地，相对于所述具有式(2)和/或式(4)结构的化合物、具有式(3)和/或式(5)结构的化合物与具有式(6)结构的化合物的总量，所述酸性物质的用量为0.03--10mL/g，所述溶剂的用量为2-15mL/g。According to a preferred embodiment of the present invention, the above-mentioned first contact and second contact of the present invention are both performed in the presence of an acidic substance and a solvent. The present invention does not limit the amount of the acidic substance and the solvent, and those skilled in the art can freely choose according to requirements, as long as it is beneficial to the Mannich reaction. Preferably, relative to the total amount of the compound having the structure of formula (2) and/or formula (4), the compound having the structure of formula (3) and/or formula (5) and the compound having the structure of formula (6) The dosage of the acidic substance is 0.03--10 mL/g, and the dosage of the solvent is 2-15 mL/g.
根据本发明，优选地，所述酸性物质选自盐酸、磷酸、硫酸和乙酸中的至少一种。本发明对所述盐酸、磷酸、硫酸或乙酸的浓度没有限制，本领域技术人员可以根据实际需求自由选择。According to the present invention, preferably, the acidic substance is selected from at least one of hydrochloric acid, phosphoric acid, sulfuric acid and acetic acid. The present invention does not limit the concentration of the hydrochloric acid, phosphoric acid, sulfuric acid or acetic acid, and those skilled in the art can freely choose according to actual needs.
根据本发明，优选地，所述溶剂为水和/或有机溶剂。According to the present invention, preferably, the solvent is water and/or an organic solvent.
根据本发明的一种优选实施方式，所述第一接触和第二接触在水和/或有机溶剂的存在下进行，本发明对所述有机溶剂没有特别地限定，可以为本领域的常规选择，优选为极性有机溶剂，进一步优选为含有羟基或羰基的极性溶剂，例如，所述有机溶剂优选选自甲醇、乙醇、异丙醇和乙酸，优选为甲醇和/或乙醇。本发明中，当所述有机溶剂和酸性物质均为乙酸时，乙酸的用量以能够满足催化所需的酸性物质的用量即可，若该用量不能满足将厚朴酚溶解，则可以配合其他溶剂(例如甲醇和/或乙醇)使用；本发明对此不做限制。According to a preferred embodiment of the present invention, the first contact and the second contact are performed in the presence of water and/or an organic solvent. The present invention does not specifically limit the organic solvent, which can be conventionally selected in the field. , Preferably a polar organic solvent, more preferably a polar solvent containing a hydroxyl group or a carbonyl group, for example, the organic solvent is preferably selected from methanol, ethanol, isopropanol and acetic acid, preferably methanol and/or ethanol. In the present invention, when the organic solvent and the acidic substance are both acetic acid, the amount of acetic acid is sufficient to meet the amount of acidic substance required for catalysis. If the amount is not sufficient to dissolve magnolol, other solvents can be used. (Such as methanol and/or ethanol) is used; the present invention does not limit this.
根据本发明的一种优选实施方式，所述和厚朴酚衍生物的制备方法包括在曼 尼希反应条件以及酸性物质和溶剂的存在下，将具有式(2)和/或式(4)结构的化合物与具有式(3)和/或式(5)结构的化合物混合进行第一接触，然后第一接触所得产物与具有式(6)结构的化合物进行第二接触。本发明对所述酸性物质的加入时机没有特别的限定，例如，可以直接将酸性物质加入到所述第一接触或第二接触的反应物中，也可以将所述酸性物质先加入溶剂中混合，然后再一起加入所述第一接触或第二接触的反应物中，优选为后者。本发明中所述混合均优选在搅拌下进行。According to a preferred embodiment of the present invention, the preparation method of the honokiol derivative includes formula (2) and/or formula (4) in the presence of Mannich reaction conditions and acidic substances and solvents. The compound of the structure is mixed with the compound of the formula (3) and/or the structure of the formula (5) to conduct the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound of the formula (6). The present invention does not specifically limit the timing of adding the acidic substance. For example, the acidic substance can be directly added to the reactant of the first contact or the second contact, or the acidic substance can be added to the solvent first and mixed. , And then added to the reactants of the first contact or the second contact together, preferably the latter. The mixing in the present invention is preferably carried out under stirring.
优选地，所述第一接触的方式包括：具有式(3)和/或式(5)结构的化合物(优选为醛类化合物或该化合物的溶液，该溶液优选为水溶液)加入到具有式(2)和/或式(4)结构的化合物(优选为二级胺化合物或该化合物的溶液，该溶液优选为水溶液)中进行第一接触，控制温度为20-50℃，优选为30-40℃，时间为5-20min，优选为10-15min；随后将第一接触的体系置于低温水浴中，向所述体系中加入酸性物质或酸性物质在溶剂(优选为有机溶剂)中形成的溶液，控制温度为1-10℃，优选为2-5℃，继续接触时间为0.5-2h，优选为0.6-1.5h。本发明对所述低温水浴的形式没有特别的限定，只要能实现低温浴的目的即可；优选为冰水浴和/或冰盐浴，本发明对所述冰盐浴中的盐没有特别的限定，优选为氯化钾、氯化钠、硫酸钠、硫酸钾中的至少一种。所述冰盐浴中，相对于水的重量，所述盐的用量为0.5-5重量％。Preferably, the first contact method includes: a compound having the structure of formula (3) and/or formula (5) (preferably an aldehyde compound or a solution of the compound, the solution is preferably an aqueous solution) is added to a compound having the formula ( 2) and/or the compound of formula (4) (preferably a secondary amine compound or a solution of the compound, and the solution is preferably an aqueous solution) for the first contact, and the temperature is controlled to be 20-50°C, preferably 30-40 ℃, the time is 5-20min, preferably 10-15min; then the first contacted system is placed in a low-temperature water bath, and acidic substance or a solution of acidic substance in a solvent (preferably an organic solvent) is added to the system , The control temperature is 1-10°C, preferably 2-5°C, and the continuous contact time is 0.5-2h, preferably 0.6-1.5h. The present invention does not specifically limit the form of the low-temperature water bath, as long as the purpose of the low-temperature bath can be achieved; it is preferably an ice-water bath and/or an ice-salt bath, and the present invention does not specifically limit the salt in the ice-salt bath. , Preferably at least one of potassium chloride, sodium chloride, sodium sulfate, and potassium sulfate. In the ice salt bath, relative to the weight of water, the amount of the salt is 0.5 to 5% by weight.
优选地，所述第二接触的方式包括：将具有式(6)结构的化合物在酸性物质存在下溶解在所述溶剂中形成溶液，然后在30-90℃下与第一接触所得产物进行所述第二接触。Preferably, the second contact method includes: dissolving the compound having the structure of formula (6) in the solvent in the presence of an acidic substance to form a solution, and then performing the first contact with the product obtained in the first contact at 30-90°C. Mentioned second contact.
本发明发明人发现，与直接将酸加入到反应物中的方式相比，上述优选的将所述酸性物质先加入溶剂中混合，然后再一起加入所述第一接触或第二接触的反应物中的方式，能够有效减少酸雾和避免反应放热剧烈而产生副反应。The inventors of the present invention found that, compared with the method of directly adding the acid to the reactant, the above-mentioned preferred method of adding the acidic substance to the solvent for mixing, and then adding the reactant of the first contact or the second contact together The medium method can effectively reduce acid mist and avoid side reactions caused by violent reaction exotherm.
根据本发明，优选地，所述曼尼希反应条件包括：第一接触温度为1-50℃、更优选为2-50℃，第二接触温度为30-90℃、更优选为70-85℃。According to the present invention, preferably, the Mannich reaction conditions include: a first contact temperature of 1-50°C, more preferably 2-50°C, and a second contact temperature of 30-90°C, more preferably 70-85 ℃.
优选地，所述曼尼希反应条件还包括：第一接触时间为5min至2h、更优选为10min至2h，第二接触时间为1-20h、更优选为5-10h。本发明中，所述第一接触时间是指第一接触的总时间，所述第二接触时间是指第二接触的总时间。Preferably, the Mannich reaction conditions further include: the first contact time is 5 min to 2 h, more preferably 10 min to 2 h, and the second contact time is 1-20 h, more preferably 5-10 h. In the present invention, the first contact time refers to the total time of the first contact, and the second contact time refers to the total time of the second contact.
根据本发明的一种优选实施方式，该方法还包括：对第二接触的产物依次进行蒸发、纯化和冻干。本发明对所述蒸发操作没有特别地限定，可以为本领域的任何蒸发设备，优选采用旋转蒸发仪，蒸发去掉大部分有机溶剂。本发明对所述纯化操作没有特别地限定，可以为本领域的任何纯化方法，优选采用柱层析的方法，纯化填料为100-200目硅胶，本发明对柱层析中所用的洗脱剂没有特别地限定，可以为本领域的任何能实现洗脱目的的试剂，优选地，洗脱剂为乙酸乙酯/丙酮，乙酸乙酯和丙酮的体积比优选为2-6:1，特别优选为4:1。According to a preferred embodiment of the present invention, the method further comprises: successively evaporating, purifying and lyophilizing the product of the second contact. The present invention does not specifically limit the evaporation operation, which can be any evaporation equipment in the field, preferably a rotary evaporator, to evaporate most of the organic solvents. The present invention does not specifically limit the purification operation, which can be any purification method in the field, preferably using column chromatography. The purification filler is 100-200 mesh silica gel. The eluent used in the column chromatography of the present invention is It is not particularly limited, and it can be any reagent in the art that can achieve the purpose of elution. Preferably, the eluent is ethyl acetate/acetone, and the volume ratio of ethyl acetate and acetone is preferably 2-6:1, particularly preferably It is 4:1.
第三个方面，本发明还提供前述第一方面所述的和厚朴酚衍生物或前述第二方面所述方法制得的和厚朴酚衍生物在抑菌中的应用。In a third aspect, the present invention also provides the use of the honokiol derivative described in the aforementioned first aspect or the honokiol derivative prepared by the method described in the aforementioned second aspect in bacteriostasis.
本发明提供的和厚朴酚衍生物可以应用于食品、药品及化妆品中，作为防腐 剂或防腐剂组分使用，对于常见的大肠埃希氏菌、金黄色葡萄球菌、铜绿假单胞杆菌、白色假丝酵母、黑曲霉等均有抑制作用。相对于每克所述食品、药品或化妆品，所述和厚朴酚衍生物的用量为0.001-0.01克。The honokiol derivatives provided by the present invention can be used in foods, medicines and cosmetics, as preservatives or preservative components, for common Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger have inhibitory effects. The amount of the magnolol derivative is 0.001-0.01 g per gram of the food, medicine or cosmetic.
以下将通过实施例对本发明进行详细描述。以下实施例中，所制备的和厚朴酚衍生物的分子结构由飞行时间质谱仪、核磁共振波谱仪和液相色谱质谱联用仪测得，飞行质谱仪的型号为HR EI-TOFMS，购买自英国Kore公司；核磁共振波谱仪的型号为赛默飞picoSpin80，购买自赛默飞世尔公司；液相色谱质谱联用仪的型号为TSQ Altis的三重四极杆质谱仪，购买自赛默飞公司。Hereinafter, the present invention will be described in detail through examples. In the following examples, the molecular structure of the prepared honokiol derivative was measured by a time-of-flight mass spectrometer, a nuclear magnetic resonance spectrometer, and a liquid chromatography mass spectrometer. The model of the flight mass spectrometer is HR EI-TOFMS. Purchase From Kore Company in the UK; the model of the NMR spectrometer is Thermo Fisher picoSpin 80, purchased from Thermo Fisher; the model of the liquid chromatography mass spectrometer is TSQ Altis triple quadrupole mass spectrometer, purchased from Thermo Fisher Flying company.
以下实施例中，所涉及的原料除另有说明外均为市售品，其中，植物来源的和厚朴酚含量为98％，购自湖南佳沐生物科技有限公司；所用N-甲基-甘氨酸粉末、N-甲基氨基乙二醛缩二甲醇购买自上海麦克林生物试剂有限公司；营养肉汤购买自北京迈瑞达科技有限公司，主要成分为蛋白胨、牛肉膏、氯化钠和水；沙氏培养基购买自山东西亚化学工业有限公司公司，主要成分为蛋白胨和琼脂；TTC为2,3,5-氯化三苯四氮唑的简称，所用TTC试剂购买自上海源叶生物科技有限公司；尼泊金甲酯为分析纯，购买自上海麦克林生化科技有限公司公司；苯氧乙醇为分析纯，购买自上海阿拉丁生化科技股份有限公司。其中，大肠埃希氏菌(Escherichia coli)：ATCC 8739第4代，购自广东省微生物研究所；金黄色葡萄球菌(Staphylococcus aureus)：ATCC 6538第4代，购自广东省微生物研究所；铜绿假单胞杆菌(Pseudomonas aeruginosa)：ATCC 9027第6代，购自广东省微生物研究所；白色念珠菌(Candida albicans)：ATCC8327第4代，购自广东省微生物研究所；黑曲霉(Aspergillusniger)：ATCC5478第4代，购自广东省微生物研究所；沙氏培养基购自山东西亚化学工业有限公司。In the following examples, the raw materials involved are all commercially available products unless otherwise specified. Among them, the plant-derived honokiol content is 98%, purchased from Hunan Jiamu Biotechnology Co., Ltd.; the N-methyl- Glycine powder and N-methylaminoglyoxal dimethylacetal were purchased from Shanghai Maclean Bioreagent Co., Ltd.; the nutrient broth was purchased from Beijing Merida Technology Co., Ltd. The main ingredients were peptone, beef extract, sodium chloride and water; Sabouraud medium was purchased from Shandong West Asia Chemical Industry Co., Ltd., and its main components are peptone and agar; TTC is the abbreviation for 2,3,5-chlorotriphenyltetrazolium, and the TTC reagent used was purchased from Shanghai Yuanye Biotechnology Co., Ltd. Company; Methylparaben is analytical grade, purchased from Shanghai Macleans Biochemical Technology Co., Ltd.; phenoxyethanol is analytical grade, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. Among them, Escherichia coli: ATCC 8739 4th generation, purchased from Guangdong Institute of Microbiology; Staphylococcus aureus: ATCC 6538, 4th generation, purchased from Guangdong Institute of Microbiology; Verdigris Pseudomonas aeruginosa: ATCC 9027, 6th generation, purchased from Guangdong Institute of Microbiology; Candida albicans: ATCC8327, 4th generation, purchased from Guangdong Institute of Microbiology; Aspergillus niger: The 4th generation of ATCC5478 was purchased from Guangdong Institute of Microbiology; Sabouraud culture medium was purchased from Shandong West Asia Chemical Industry Co., Ltd.
实施例1Example 1
将1ml浓度为12mol/L的盐酸加入70ml甲醇中，配制成甲醇酸溶液备用。Add 1ml of hydrochloric acid with a concentration of 12mol/L to 70ml of methanol to prepare a methanolic acid solution for later use.
称取7.6g N-甲基-甘氨酸粉末放入三口烧瓶中，缓慢滴加37质量％甲醛溶液10ml，磁力搅拌，控制滴加速度为1ml/min，控制温度在30-35℃。在冰水浴条件下，在三口烧瓶中加入40ml配制好的甲醇酸溶液，控制滴加速度为4ml/min，温度为2-5℃，继续磁力搅拌1h，得到第一接触所得产物。Weigh 7.6g of N-methyl-glycine powder into a three-necked flask, slowly drop 10ml of 37% by mass formaldehyde solution, magnetically stir, control the dropping rate to 1ml/min, and control the temperature at 30-35°C. Under ice-water bath conditions, add 40ml of the prepared methanolic acid solution to the three-necked flask, control the dropping rate to 4ml/min and the temperature to 2-5°C, continue magnetic stirring for 1h to obtain the product obtained by the first contact.
称取和厚朴酚(含量为98重量％)13.3g，溶解在剩余的30ml甲醇酸溶液里。将上述装有第一接触所得产物的三口烧瓶放在油浴中控制温度为75℃，加入和厚朴酚的甲醇酸溶液，冷凝回流，反应10h。采用旋转蒸发仪除掉多余的甲醇，采用200目硅胶柱进行纯化，洗脱剂为乙酸乙酯/丙酮，乙酸乙酯与丙酮体积比为4:1，将所得洗脱液合并浓缩，然后进行冻干，得到和厚朴酚衍生物。Weigh 13.3 g of honokiol (98% by weight), and dissolve it in the remaining 30 ml of methanolic acid solution. The above three-necked flask containing the product obtained from the first contact was placed in an oil bath to control the temperature to 75° C., and the methanolic acid solution of honokiol was added, condensed and refluxed, and reacted for 10 hours. Use a rotary evaporator to remove the excess methanol, use a 200 mesh silica gel column for purification, the eluent is ethyl acetate/acetone, the volume ratio of ethyl acetate to acetone is 4:1, the obtained eluates are combined and concentrated, and then proceed Lyophilized to obtain honokiol derivatives.
以反应原料中的和厚朴酚计，收率为35％。使用飞行质谱仪和核磁共振仪对其进行表征，证实为本发明式(1)所示结构的和厚朴酚衍生物。反应的机理如下：Based on the honokiol in the reaction raw materials, the yield was 35%. It was characterized by a flight mass spectrometer and a nuclear magnetic resonance instrument, and it was confirmed to be a honokiol derivative with the structure represented by formula (1) of the present invention. The reaction mechanism is as follows:
Figure PCTCN2020114940-appb-000011
Figure PCTCN2020114940-appb-000011
实施例2Example 2
将1ml浓度为12mol/L的盐酸加入70ml甲醇中，配制成甲醇酸溶液备用。Add 1ml of hydrochloric acid with a concentration of 12mol/L to 70ml of methanol to prepare a methanolic acid solution for later use.
称取11.3g 40重量％浓度的二甲胺水溶液放入三口烧瓶中，缓慢滴加37质量％甲醛溶液10ml，磁力搅拌，控制滴加速度为1ml/min，控制温度在30-35℃。在冰水浴条件下，在三口烧瓶中加入40ml配制好的甲醇酸溶液，控制滴加速度为4ml/min，温度为2-5℃，继续磁力搅拌1h，得到第一接触所得产物。Weigh 11.3g of a 40% by weight dimethylamine aqueous solution into a three-necked flask, slowly drop 10ml of 37% by weight formaldehyde solution, magnetically stir, control the dropping rate to 1ml/min, and control the temperature at 30-35°C. Under ice-water bath conditions, add 40ml of the prepared methanolic acid solution to the three-necked flask, control the dropping rate to 4ml/min and the temperature to 2-5°C, continue magnetic stirring for 1h to obtain the product obtained by the first contact.
称取和厚朴酚(含量为98重量％)13.3g，溶解在剩余的30ml甲醇酸溶液里。将上述装有第一接触所得产物的三口烧瓶放在油浴中控制温度为75℃，加入和厚朴酚的甲醇酸溶液，冷凝回流，反应6h。采用旋转蒸发仪除掉多余的甲醇，采用200目硅胶柱进行纯化，洗脱剂为乙酸乙酯/丙酮，乙酸乙酯与丙酮体积比为4:1，将所得洗脱液合并浓缩，然后进行冻干，得到和厚朴酚衍生物。Weigh 13.3 g of honokiol (98% by weight), and dissolve it in the remaining 30 ml of methanolic acid solution. The above three-necked flask containing the product obtained from the first contact was placed in an oil bath to control the temperature to 75° C., and the methanolic acid solution of honokiol was added, condensed and refluxed, and reacted for 6 hours. Use a rotary evaporator to remove the excess methanol, use a 200 mesh silica gel column for purification, the eluent is ethyl acetate/acetone, the volume ratio of ethyl acetate to acetone is 4:1, the obtained eluates are combined and concentrated, and then proceed Lyophilized to obtain honokiol derivatives.
以反应原料中的和厚朴酚计，收率为60％。使用飞行质谱和核磁共振对其进行表征，证实为本发明式(1)所示结构的和厚朴酚衍生物。反应的机理如下：Based on honokiol in the reaction raw materials, the yield was 60%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed to be a honokiol derivative with the structure represented by formula (1) of the present invention. The reaction mechanism is as follows:
Figure PCTCN2020114940-appb-000012
Figure PCTCN2020114940-appb-000012
实施例3Example 3
将1ml浓度为12mol/L的盐酸加入70ml甲醇中，配制成甲醇酸溶液备用。Add 1ml of hydrochloric acid with a concentration of 12mol/L to 70ml of methanol to prepare a methanolic acid solution for later use.
称取13g二乙醇胺放入三口烧瓶中，缓慢滴加37质量％甲醛溶液10ml，磁力搅拌，控制滴加速度为1ml/min，控制温度在30-35℃。在冰水浴条件下，在 三口烧瓶中加入40ml配制好的甲醇酸溶液，控制滴加速度为4ml/min，温度为2-5℃，继续磁力搅拌1h，得到第一接触所得产物。Weigh 13g of diethanolamine into a three-necked flask, slowly drop 10ml of 37% by mass formaldehyde solution, magnetically stir, control the dropping rate to 1ml/min, and control the temperature at 30-35°C. Under ice-water bath conditions, add 40ml of the prepared methanolic acid solution to a three-necked flask, control the dropping rate to 4ml/min and the temperature to 2-5°C, continue magnetic stirring for 1h to obtain the first contact product.
称取和厚朴酚(含量为98重量％)10g，溶解在剩余的30ml甲醇酸溶液里。将上述装有第一接触所得产物的三口烧瓶放在油浴中控制温度为85℃，加入和厚朴酚的甲醇酸溶液，冷凝回流，反应6.5h。采用旋转蒸发仪除掉多余的甲醇，采用200目硅胶柱进行纯化，洗脱剂为乙酸乙酯/丙酮，乙酸乙酯与丙酮体积比为4:1，将所得洗脱液合并浓缩，然后进行冻干，得到和厚朴酚衍生物。Weigh 10 g of honokiol (98% by weight) and dissolve it in the remaining 30 ml of methanolic acid solution. The above three-necked flask containing the product obtained from the first contact was placed in an oil bath to control the temperature to 85° C., and the methanolic acid solution of honokiol was added, condensed and refluxed, and reacted for 6.5 hours. Use a rotary evaporator to remove the excess methanol, use a 200 mesh silica gel column for purification, the eluent is ethyl acetate/acetone, the volume ratio of ethyl acetate to acetone is 4:1, the obtained eluates are combined and concentrated, and then proceed Lyophilized to obtain honokiol derivatives.
以反应原料中的和厚朴酚计，收率为35％。使用飞行质谱和核磁共振对其进行表征，证实为本发明式(1)所示结构的和厚朴酚衍生物。反应的机理如下：Based on the honokiol in the reaction raw materials, the yield was 35%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed to be a honokiol derivative with the structure represented by formula (1) of the present invention. The reaction mechanism is as follows:
Figure PCTCN2020114940-appb-000013
Figure PCTCN2020114940-appb-000013
实施例4Example 4
按照实施例1的方法进行，不同的是，采用相同用量的N-甲基-氨基乙氧基乙醇代替所述N-甲基-甘氨酸，其他与实施例1相同。It was carried out in accordance with the method of Example 1, except that the same amount of N-methyl-aminoethoxyethanol was used instead of the N-methyl-glycine, and the others were the same as in Example 1.
以反应原料中的和厚朴酚计，收率为48％。使用飞行质谱和核磁共振对其进行表征，证实制备得到的产物为本发明式(1)所示结构的和厚朴酚衍生物，其结构式如下：
Figure PCTCN2020114940-appb-000014
Based on honokiol in the reaction raw materials, the yield was 48%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed that the prepared product is a honokiol derivative with the structure shown in formula (1) of the present invention, and its structural formula is as follows:
Figure PCTCN2020114940-appb-000014
实施例5Example 5
按照实施例1的方法进行，不同的是，采用相同用量的甲氨基乙醛缩二甲醇 代替所述N-甲基-甘氨酸，其他与实施例1相同。It was carried out according to the method of Example 1, except that the same amount of methylaminoacetaldehyde dimethyl acetal was used instead of the N-methyl-glycine, and the others were the same as in Example 1.
以反应原料中的和厚朴酚计，收率为63％。使用飞行质谱和核磁共振对其进行表征，证实制备得到的产物为本发明式(1)所示结构的和厚朴酚衍生物，其结构式如下：
Figure PCTCN2020114940-appb-000015
Based on the honokiol in the reaction raw materials, the yield was 63%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed that the prepared product is a honokiol derivative with the structure shown in formula (1) of the present invention, and its structural formula is as follows:
Figure PCTCN2020114940-appb-000015
实施例6Example 6
按照实施例1的方法进行，不同的是，所述N-甲基-甘氨酸与所述和厚朴酚的摩尔比为6:6:1，其他与实施例1相同。It was carried out according to the method of Example 1, except that the molar ratio of the N-methyl-glycine to the honokiol was 6:6:1, and the others were the same as in Example 1.
以反应原料中的和厚朴酚计，收率为26％。使用飞行质谱和核磁共振对其进行表征，证实制备得到的产物为本发明式(1)所示结构的和厚朴酚衍生物，其结构式与实施例1相同。Based on honokiol in the reaction raw materials, the yield was 26%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed that the prepared product was a honokiol derivative with the structure represented by formula (1) of the present invention, and its structural formula was the same as that of Example 1.
实施例7Example 7
按照实施例1的方法进行，不同的是，不加入和厚朴酚，而采用相同摩尔量的式(6)结构的和厚朴酚类化合物，且在式(6)中，R 1、R 2、R 3和R 4依次为氢、氯、甲基和甲氧基，其他与实施例1相同。 It was carried out according to the method of Example 1, except that honokiol was not added, and the honokiol compound of formula (6) was used in the same molar amount, and in formula (6), R 1 , R 2. R 3 and R 4 are hydrogen, chlorine, methyl, and methoxy in that order, and the others are the same as in Example 1.
以反应原料中的和厚朴酚类化合物计，和厚朴酚衍生物的收率为32％。使用飞行质谱和核磁共振对其进行表征，表征结果证实本实施例制得的产物为本发明式(1)所示结构的和厚朴酚衍生物(其中，R 1、R 2、R 3和R 4依次为氢、氯、甲基和甲氧基，R 1、R 2、R 3和R 4依次为甲基、
Figure PCTCN2020114940-appb-000016
甲基、
Figure PCTCN2020114940-appb-000017
R 5、R 6、R 7和R 8均为氢)。 Based on the honokiol compounds in the reaction raw materials, the yield of honokiol derivatives was 32%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product prepared in this example was a honokiol derivative with the structure represented by formula (1) of the present invention (wherein, R 1 , R 2 , R 3 and R 4 is hydrogen, chlorine, methyl and methoxy in order, R 1 , R 2 , R 3 and R 4 are in order methyl,
Figure PCTCN2020114940-appb-000016
methyl,
Figure PCTCN2020114940-appb-000017
R 5 , R 6 , R 7 and R 8 are all hydrogen).
实施例8Example 8
按照实施例1的方法进行，不同的是，不加入和厚朴酚，而采用相同摩尔量的式(6)结构的和厚朴酚类化合物，且在式(6)中，R 1、R 2、R 3和R 4依次为氢、氯、甲基和甲苯基，其他与实施例1相同。 It was carried out according to the method of Example 1, except that honokiol was not added, and the honokiol compound of formula (6) was used in the same molar amount, and in formula (6), R 1 , R 2. R 3 and R 4 are hydrogen, chlorine, methyl and tolyl in sequence, and the others are the same as in Example 1.
以反应原料中的和厚朴酚类化合物计，和厚朴酚衍生物的收率为18％。使用 飞行质谱和核磁共振对其进行表征，表征结果证实本实施例制得的产物为本发明式(1)所示结构的和厚朴酚衍生物(其中，R 1、R 2、R 3和R 4依次为氢、氯、甲基和甲苯基，R 1、R 2、R 3和R 4依次为甲基、
Figure PCTCN2020114940-appb-000018
甲基、
Figure PCTCN2020114940-appb-000019
R 5、R 6、R 7和R 8均为氢)。 Based on the honokiol compounds in the reaction raw materials, the yield of honokiol derivatives was 18%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product prepared in this example was a honokiol derivative with the structure represented by formula (1) of the present invention (wherein, R 1 , R 2 , R 3 and R 4 is hydrogen, chlorine, methyl and tolyl in sequence, R 1 , R 2 , R 3 and R 4 are methyl,
Figure PCTCN2020114940-appb-000018
methyl,
Figure PCTCN2020114940-appb-000019
R 5 , R 6 , R 7 and R 8 are all hydrogen).
实施例9Example 9
按照实施例1的方法进行，不同的是，不事先将盐酸和甲醇配制，而是将同等量的第一部分的盐酸和甲醇分别直接加入N-甲基-甘氨酸和甲醛的水溶液中混合，且将剩余的盐酸和甲醇直接与和厚朴酚、第一接触所得产物混合进行反应；其他与实施例1相同。Carry out according to the method of Example 1, the difference is that instead of preparing hydrochloric acid and methanol in advance, the first part of hydrochloric acid and methanol in the same amount are directly added to the aqueous solution of N-methyl-glycine and formaldehyde and mixed, and the The remaining hydrochloric acid and methanol are directly mixed with the honokiol and the product obtained from the first contact for reaction; the others are the same as in Example 1.
以反应原料中的和厚朴酚计，和厚朴酚衍生物的收率为24％。使用飞行质谱和核磁共振对其进行表征，表征结果证实本实施例制得的产物为本发明式(1)所示结构的和厚朴酚衍生物，其结构式与实施例1的产物相同。Based on the honokiol in the reaction raw material, the yield of the honokiol derivative was 24%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product prepared in this example was a honokiol derivative with the structure represented by formula (1) of the present invention, and its structural formula was the same as the product of Example 1.
测试例1Test case 1
溶解性的测试方法为：用量筒量取25±1℃，100g去离子水，放入250ml烧杯中。放入磁力搅拌器，调节转速为200rmp/min。用分析天平分别称取和厚朴酚、实施例1-9中样品测试其溶解性，测试时每次0.1g样品溶于去离子水中，直到搅拌10分钟后仍无法完全溶解为止，记录最大溶解质量。结果如表1所示。The solubility test method is: measure 25±1℃ with a graduated cylinder, and place 100g deionized water into a 250ml beaker. Put it into a magnetic stirrer and adjust the speed to 200 rpm/min. Use an analytical balance to weigh honokiol and the samples in Examples 1-9 to test their solubility. During the test, 0.1g of the sample is dissolved in deionized water until it cannot be completely dissolved after stirring for 10 minutes. Record the maximum dissolution quality. The results are shown in Table 1.
测试例2Test case 2
以实施例1-9中的和厚朴酚衍生物样品为测试样品，定量测试其最小抑菌浓度MIC值。以10重量％和厚朴酚乙醇溶液、传统化学防腐剂尼泊金甲酯和苯氧乙醇作为对照。The honokiol derivative samples in Examples 1-9 were used as test samples to quantitatively test the minimum inhibitory concentration MIC value. 10% by weight honokiol ethanol solution, traditional chemical preservatives methyl paraben and phenoxyethanol were used as controls.
最小抑菌浓度MIC值的测试方法为：以灭菌后的营养肉汤(用于培养大肠埃希氏菌，金黄色葡萄球菌、铜绿假单胞杆菌)、沙氏培养基(用于培养白色假丝酵母、黑曲霉)为稀释液，利用二倍稀释法对测试样品分别进行稀释，然后分别以表2所示的浓度接种相应的菌。细菌在35℃下培养36h；真菌在28℃下培养48h。在培养终点前3h，加入TTC试剂，继续培养，若培养液变红，则认定此浓度不能抑制微生物生长；若培养液未变红，则认定未变红的培养液中的最小药剂浓度为此抑菌剂对此微生物的最小抑菌浓度。具体结果见表3。The minimum inhibitory concentration MIC value test method is: use sterilized nutrient broth (for culturing Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa), Sabouraud medium (for culturing white Candida and Aspergillus niger) were used as diluents. The test samples were diluted by the two-fold dilution method, and then the corresponding bacteria were respectively inoculated at the concentrations shown in Table 2. Bacteria were cultured at 35°C for 36h; fungi were cultured at 28°C for 48h. 3h before the end of the culture, add TTC reagent and continue the culture. If the culture medium turns red, it is deemed that this concentration cannot inhibit the growth of microorganisms; if the culture medium does not turn red, it is deemed that the minimum concentration of the drug in the culture medium that has not turned red is this The minimum inhibitory concentration of the bacteriostatic agent for this microorganism. The specific results are shown in Table 3.
测试例3Test case 3
将实施例1-9中制备得到的和厚朴酚衍生物，添加到如下表4的喷雾配方或类似喷雾配方中。接种一定数量的细菌和真菌，间隔0天、7天、14天、21天、28天按照美国药典USP32<51>微生物防腐功效测试的检测方法检测微生物数量变化情况，其中，采用实施例1、3、4和7制得的和厚朴酚衍生物的测试结果如 下表5所示，其余实施例制备得到的和厚朴酚衍生物的测试结果(均采用下表4的喷雾配方)类似，均为检测合格。The honokiol derivatives prepared in Examples 1-9 were added to the spray formula or similar spray formula of Table 4 below. Inoculate a certain number of bacteria and fungi at intervals of 0 days, 7 days, 14 days, 21 days, and 28 days to detect changes in the number of microorganisms according to the detection method of the USP32<51> Microbial Preservation Efficacy Test. The test results of the honokiol derivatives prepared in 3, 4 and 7 are shown in Table 5 below, and the test results of the honokiol derivatives prepared in the other examples (all using the spray formula of Table 4 below) are similar. All are qualified.
表1Table 1
样品sample 溶剂水(100g)Solvent water (100g)
和厚朴酚Honokiol ---
实施例1Example 1 ＞3g＞3g
实施例2Example 2 ＞1g＞1g
实施例3Example 3 ＞10g＞10g
实施例4Example 4 ＞5g＞5g
实施例5Example 5 ＞5g＞5g
实施例6Example 6 ＞5g＞5g
实施例7Example 7 ＞3g＞3g
实施例8Example 8 ＞2g＞2g
实施例9Example 9 ＞3g＞3g
注：--表示0.1g也不能完全溶解；＞代表样品全部溶解Note: --- means that 0.1g can not be completely dissolved;> means that the sample is completely dissolved
表2Table 2
Figure PCTCN2020114940-appb-000020
Figure PCTCN2020114940-appb-000020
表3table 3
Figure PCTCN2020114940-appb-000021
Figure PCTCN2020114940-appb-000021
Figure PCTCN2020114940-appb-000022
Figure PCTCN2020114940-appb-000022
注：＞表示添加对应浓度的抑菌剂时具有一定抑菌能力，可以和其他抑菌剂复配使用Note:> indicates that it has a certain antibacterial ability when adding the corresponding concentration of antibacterial agent, and can be used in combination with other antibacterial agents
表4Table 4
Figure PCTCN2020114940-appb-000023
Figure PCTCN2020114940-appb-000023
表5table 5
Figure PCTCN2020114940-appb-000024
Figure PCTCN2020114940-appb-000024
Figure PCTCN2020114940-appb-000025
Figure PCTCN2020114940-appb-000025
注：对数减少值是指微生物总量的变化情况(即：初始对数值与放置一定时间后的对数值的差值)，数字越大，代表抑菌能力越强。Note: The logarithmic decrease value refers to the change of the total amount of microorganisms (ie: the difference between the initial logarithmic value and the logarithmic value after a certain period of time). The larger the number, the stronger the antibacterial ability.
通过表1的结果可以看出，在溶解度定性测试中，本发明制备得到的和厚朴酚衍生物表现出了优异的水溶性，在100g溶剂水中，实施例1中样品的溶解度大于3g，实施例2中样品的溶解度大于1g，实施例3中样品的溶解度大于10g，4-9实施例中和厚朴酚衍生物的水溶性均大于2g，即实施例中所制得的样品已全部溶解，而从植物中提取的和厚朴酚是不溶于水的。It can be seen from the results in Table 1 that in the qualitative solubility test, the honokiol derivative prepared by the present invention exhibits excellent water solubility. In 100 g of solvent water, the solubility of the sample in Example 1 is greater than 3 g. The solubility of the sample in Example 2 is greater than 1g, the solubility of the sample in Example 3 is greater than 10g, and the water solubility of the honokiol derivatives in Examples 4-9 are all greater than 2g, that is, the samples prepared in the examples have all been dissolved , And honokiol extracted from plants is insoluble in water.
从表3的数据可以看出，本发明实施例1-9制备得到的和厚朴酚衍生物均具有较好的抑菌作用，其中，实施例3制备得到的和厚朴酚衍生物对大肠埃希氏菌、金黄色葡萄球菌、铜绿假单胞杆菌、白色假丝酵母、黑曲霉这些菌种均有显著抑菌作用，且抑菌效果优于传统的化学防腐剂尼泊金甲酯、苯氧乙醇，其余实施例制备得到的和厚朴酚衍生物对化妆品中常见的五种菌均有较好的抑菌作用。From the data in Table 3, it can be seen that the honokiol derivatives prepared in Examples 1-9 of the present invention all have good antibacterial effects. Among them, the honokiol derivatives prepared in Example 3 have good antibacterial effects on the large intestine. Escherichia, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger have significant bacteriostatic effects, and the bacteriostatic effect is better than the traditional chemical preservatives methyl paraben, Phenoxyethanol, honokiol derivatives prepared in other examples have good antibacterial effects on five common bacteria in cosmetics.
表4的喷雾配方提供了非常适宜细菌和真菌生存的环境，从表5中数据可以看出，在如此苛刻的条件下，本发明的实施例1、3、4、7制得的样品表现出优异的抑菌能力，经过28天水剂配方的喷雾的防腐挑战测试，实施例1、3、4、7中的和厚朴酚衍生物作为防腐剂通过了防腐挑战测试，其余实施例效果类似，均具有较好的抑菌能力。The spray formula in Table 4 provides a very suitable environment for the survival of bacteria and fungi. From the data in Table 5, it can be seen that under such harsh conditions, the samples prepared in Examples 1, 3, 4, and 7 of the present invention show Excellent antibacterial ability. After 28 days of spray antiseptic challenge test of water formulation, honokiol derivatives in Examples 1, 3, 4, and 7 passed the antiseptic challenge test as preservatives. The effects of other examples are similar. All have good antibacterial ability.
由于和厚朴酚本身不溶解于水，很难测试抑菌效果。10重量％和厚朴酚乙醇溶液的抑菌效果固然很好，但是国家标准中对化妆品中乙醇的用量有严格限制，并且应用在水体系中，和厚朴酚会从乙醇中析出，所以无法工业应用。Since honokiol itself does not dissolve in water, it is difficult to test the antibacterial effect. Although the antibacterial effect of 10% by weight honokiol ethanol solution is very good, but the national standards have strict restrictions on the amount of ethanol in cosmetics, and it is used in water systems. Honokiol will precipitate out of ethanol, so it cannot Industrial applications.
采用本发明的方法对和厚朴酚进行改性得到的和厚朴酚衍生物，具有良好的水溶性，有效提高了和厚朴酚在水中的溶解度；该和厚朴酚衍生物对常见的革兰氏阴性菌、革兰氏阳性菌、真菌等具有显著的抑制效果。The honokiol derivative obtained by modifying honokiol by the method of the present invention has good water solubility, and effectively improves the solubility of honokiol in water; Gram-negative bacteria, Gram-positive bacteria, fungi, etc. have a significant inhibitory effect.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于此。在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，包括各个技术特征以任何其它的合适方式进行组合，这些简单变型和组合同样应当视为本发明所公开的内容，均属于本发明的保护范围。The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, including the combination of various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the disclosed content of the present invention. All belong to the protection scope of the present invention.

Claims (15)

  1. 一种和厚朴酚衍生物，该衍生物具有式(1)所示的结构：A honokiol derivative which has the structure shown in formula (1):
    Figure PCTCN2020114940-appb-100001
    Figure PCTCN2020114940-appb-100001
    其中，在式(1)中，R 1、R 2、R 3和R 4各自独立地选自氢、卤素、取代或未取代的C 1-C 10的烷基、取代或未取代的C 1-C 12的烷氧基、取代或未取代的C 6-C 10的芳基； Wherein, in formula (1), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自卤素、C 1-C 6的烷氧基和C 6-C 10的芳基； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy and C 6 -C 10 aryl;
    R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 10的烷基； R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 6的烷氧基、通式为-O-R 9-OH结构的基团； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 6 alkoxy group, and a group with the general formula -OR 9 -OH structure;
    其中，R 9为C 1-C 6的亚烷基； Wherein, R 9 is a C 1 -C 6 alkylene group;
    R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 10的芳基和C 1-C 6的烷基。 R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, a C 6 -C 10 aryl group, and a C 1 -C 6 alkyl group.
  2. 根据权利要求1所述的和厚朴酚衍生物，其中，在式(1)中，R 1、R 2、R 3和R 4各自独立地选自氢、氟、氯、溴、取代或未取代的C 1-C 5的烷基、取代或未取代的C 1-C 6的烷氧基、取代或未取代的C 6-C 8的芳基； The honokiol derivative according to claim 1, wherein in formula (1), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted Substituted C 1 -C 5 alkyl group, substituted or unsubstituted C 1 -C 6 alkoxy group, substituted or unsubstituted C 6 -C 8 aryl group;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自氟、氯、溴、C 1-C 3的烷氧基和C 6-C 8的芳基； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from fluorine, chlorine, bromine, C 1 -C 3 alkoxy and C 6 -C 8 aryl groups;
    R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 5的烷基； R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 5 alkyl group;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 3的烷氧基、通式为-O-R 9-OH结构的基团； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 3 alkoxy group, and a group with the general formula -OR 9 -OH structure;
    其中，R 9为C 1-C 3的亚烷基； Wherein, R 9 is a C 1 -C 3 alkylene group;
    R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 8的芳基和C 1-C 3的烷基； R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 8 aryl and C 1 -C 3 alkyl;
    优选地，在式(1)中，R 5、R 6、R 7和R 8均为氢。 Preferably, in formula (1), R 5 , R 6 , R 7 and R 8 are all hydrogen.
  3. 根据权利要求1或2所述的和厚朴酚衍生物，其中，具有式(1)所示结构的和厚朴酚衍生物选自以下化合物中的至少一种：The honokiol derivative according to claim 1 or 2, wherein the honokiol derivative having the structure represented by formula (1) is selected from at least one of the following compounds:
    Figure PCTCN2020114940-appb-100002
    Figure PCTCN2020114940-appb-100002
    Figure PCTCN2020114940-appb-100003
    Figure PCTCN2020114940-appb-100003
  4. 一种和厚朴酚衍生物的制备方法，其特征在于，该方法包括在曼尼希反应条件下，将具有式(2)和/或式(4)结构的化合物与具有式(3)和/或式(5)结构的化合物进行第一接触，然后将第一接触所得产物与具有式(6)结构的化合物进行第二接触，得到曼尼希反应产物；A method for preparing honokiol derivatives, which is characterized in that the method comprises, under Mannich reaction conditions, combining a compound having a structure of formula (2) and/or formula (4) with a compound having a structure of formula (3) and / Or the compound of the formula (5) is subjected to the first contact, and then the product obtained from the first contact is subjected to the second contact with the compound of the formula (6) to obtain the Mannich reaction product;
    Figure PCTCN2020114940-appb-100004
    Figure PCTCN2020114940-appb-100004
    其中，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 10的烷基； Wherein, R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 10 alkyl group;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 6的烷氧基、通式为-O-R 9-OH结构的基团； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 6 alkoxy group, and a group with the general formula -OR 9 -OH structure;
    其中，R 9为C 1-C 6的亚烷基； Wherein, R 9 is a C 1 -C 6 alkylene group;
    R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 10的芳基和C 1-C 6的烷基； R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 10 aryl and C 1 -C 6 alkyl;
    在式(6)中，R 1、R 2、R 3和R 4各自独立地选自氢、卤素、取代或未取代的C 1-C 10的烷基、取代或未取代的C 1-C 12的烷氧基、取代或未取代的C 6-C 10的芳基； In formula (6), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 -C 10 aryl;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自卤素、C 1-C 6的烷氧基和C 6-C 10的芳基。 The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy and C 6 -C 10 aryl.
  5. 根据权利要求4所述的方法，其中，在式(2)和式(4)中，R 1、R 2、R 3和R 4各自独立地为取代或未取代的C 1-C 5的烷基； The method according to claim 4, wherein, in formula (2) and formula (4), R 1 , R 2 , R 3 and R 4 are each independently a substituted or unsubstituted C 1 -C 5 alkane base;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自羟基、羧基、C 1-C 3的烷氧基或通式为-O-R 9-OH结构的基团； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from a hydroxyl group, a carboxyl group, a C 1 -C 3 alkoxy group, or a group with the general formula -OR 9 -OH structure;
    其中，R 9为C 1-C 3的亚烷基； Wherein, R 9 is a C 1 -C 3 alkylene group;
    在式(3)和式(5)中，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 8的芳基或C 1-C 3的烷基； In formula (3) and formula (5), R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 8 aryl or C 1 -C 3 alkyl;
    在式(6)中，R 1、R 2、R 3和R 4各自独立地选自氢、氟、氯、溴、取代或未取代的C 1-C 5的烷基、取代或未取代的C 1-C 6的烷氧基、取代或未取代的C 6-C 8的芳基中的一种； In formula (6), R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted One of a C 1 -C 6 alkoxy group and a substituted or unsubstituted C 6 -C 8 aryl group;
    R 1、R 2、R 3和R 4上任选存在的取代基各自独立地选自氟、氯、溴、C 1-C 3的烷氧基或C 6-C 8的芳基； The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from fluorine, chlorine, bromine, C 1 -C 3 alkoxy or C 6 -C 8 aryl;
    优选地，在式(3)和式(5)中，R 5、R 6、R 7和R 8均为氢。 Preferably, in formula (3) and formula (5), R 5 , R 6 , R 7 and R 8 are all hydrogen.
  6. 根据权利要求4所述的方法，其中，具有式(2)和/或式(4)结构的化合物选自N-甲基-甘氨酸、N-乙基-甘氨酸、N-甲基-氨基乙氧基乙醇、N-乙基-氨基乙氧基乙醇、甲氨基乙醛缩二甲醇、甲氨基乙醛缩二乙醇、乙氨基乙醛缩二甲醇、二乙醇胺、二甲胺、二乙胺、二正丙胺中的至少一种。The method according to claim 4, wherein the compound having the structure of formula (2) and/or formula (4) is selected from the group consisting of N-methyl-glycine, N-ethyl-glycine, N-methyl-aminoethoxy Ethyl alcohol, N-ethyl-aminoethoxyethanol, methylaminoacetaldehyde dimethylacetal, methylaminoacetaldehyde dimethylacetal, ethylaminoacetaldehyde dimethylacetal, diethanolamine, dimethylamine, diethylamine, two At least one of n-propylamine.
  7. 根据权利要求4-6中任意一项所述的方法，其中，具有式(3)和/或式(5)结构的化合物选自甲醛、乙醛、丙醛、苯甲醛、苯乙醛、邻甲基苯甲醛中的至少一种，优选为甲醛。The method according to any one of claims 4-6, wherein the compound having the structure of formula (3) and/or formula (5) is selected from the group consisting of formaldehyde, acetaldehyde, propionaldehyde, benzaldehyde, phenylacetaldehyde, ortho At least one of methylbenzaldehyde is preferably formaldehyde.
  8. 根据权利要求4-7中任意一项所述的方法，其中，具有式(2)和/或式(4)结构的化合物的总量、具有式(3)和/或式(5)结构的化合物的总量与具有式(6)结构的化合物的摩尔比为0.5-6：0.5-6：1，更优选为1-4：1-4：1。The method according to any one of claims 4-7, wherein the total amount of compounds having the structure of formula (2) and/or formula (4), those having the structure of formula (3) and/or formula (5) The molar ratio of the total amount of compounds to the compound having the structure of formula (6) is 0.5-6:0.5-6:1, more preferably 1-4:1-4:1.
  9. 根据权利要求4-8中任意一项所述的方法，其中，所述曼尼希反应条件包括：第一接触温度为1-50℃、更优选为2-50℃，第二接触温度为30-90℃、更优选为70-85℃；The method according to any one of claims 4-8, wherein the Mannich reaction conditions include: a first contact temperature of 1-50°C, more preferably 2-50°C, and a second contact temperature of 30 -90°C, more preferably 70-85°C;
    优选地，所述曼尼希反应条件还包括：第一接触时间为5min至2h、更优选为10min至2h，第二接触时间为1-20h、更优选为5-10h。Preferably, the Mannich reaction conditions further include: the first contact time is 5 min to 2 h, more preferably 10 min to 2 h, and the second contact time is 1-20 h, more preferably 5-10 h.
  10. 根据权利要求4-9中任意一项所述的方法，其中，所述第一接触和第二接触均在酸性物质以及溶剂的存在下进行；The method according to any one of claims 4-9, wherein the first contact and the second contact are both performed in the presence of an acidic substance and a solvent;
    优选地，所述酸性物质为盐酸、磷酸、硫酸和乙酸中的至少一种，所述溶剂为水和/或有机溶剂；Preferably, the acidic substance is at least one of hydrochloric acid, phosphoric acid, sulfuric acid and acetic acid, and the solvent is water and/or an organic solvent;
    优选地，所述有机溶剂选自甲醇、乙醇、异丙醇和乙酸中的至少一种，更优选为甲醇和/或乙醇。Preferably, the organic solvent is selected from at least one of methanol, ethanol, isopropanol and acetic acid, more preferably methanol and/or ethanol.
  11. 根据权利要求10所述的方法，其中，所述第一接触的方式包括：在20-50℃下将具有式(3)和/或式(5)结构的化合物加入到具有式(2)和/或式(4)结构的化合物中，然后在1-10℃下再加入酸性物质或酸性物质在所述溶剂中形成的溶液，继续反应0.5-2h。The method according to claim 10, wherein the method of the first contact comprises: adding the compound having the structure of formula (3) and/or formula (5) to the compound having the structure of formula (2) and /Or to the compound of formula (4), then add acidic substance or solution formed by acidic substance in the solvent at 1-10°C, and continue the reaction for 0.5-2h.
  12. 根据权利要求10所述的方法，其中，所述第二接触的方式包括：将具有式(6)结构的化合物在酸性物质存在下溶解在所述溶剂中形成溶液，然后与第一接触所得产物在30-90℃下进行所述第二接触。The method according to claim 10, wherein the second contact method comprises: dissolving the compound having the structure of formula (6) in the solvent in the presence of an acidic substance to form a solution, and then contacting the product obtained by the first contact The second contact is performed at 30-90°C.
  13. 权利要求1-3中任意一项所述的和厚朴酚衍生物或权利要求4-12中任意一项所述方法制备得到的和厚朴酚衍生物在抑菌中的应用。Use of the honokiol derivative according to any one of claims 1-3 or the honokiol derivative prepared by the method according to any one of claims 4-12 in antibacterial.
  14. 根据权利要求13所述的应用，其中，所述菌选自大肠埃希氏菌、金黄色葡萄球菌、铜绿假单胞杆菌、白色假丝酵母、黑曲霉中的至少一种。The application according to claim 13, wherein the bacteria are selected from at least one of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.
  15. 根据权利要求13或14所述的应用，其中，所述菌存在于食品、药品或化妆品中，相对于每克的食品、药品或化妆品，所述和厚朴酚衍生物的用量为0.001-0.01克。The application according to claim 13 or 14, wherein the bacteria are present in food, medicine or cosmetics, and the amount of magnolol derivative is 0.001-0.01 per gram of food, medicine or cosmetics. Grams.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114907228A (en) * 2022-06-27 2022-08-16 深圳市锦泰医药科技合伙企业(有限合伙) Colchicine and magnolol compound, synthetic method thereof and application thereof in resisting new coronavirus

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110615742B (en) * 2019-09-20 2021-11-19 广东省禾基生物科技有限公司 Magnolol derivative and preparation method and application thereof
CN110664795B (en) * 2019-09-20 2022-12-27 广东省禾基生物科技有限公司 Water-soluble composition, preparation method and application thereof
CN110845350B (en) * 2019-09-20 2021-11-19 广东省禾基生物科技有限公司 Honokiol derivative and preparation method and application thereof
CN112438260B (en) * 2020-12-08 2022-06-24 中国农业科学院烟草研究所 Application of honokiol in preparation of natural environment-friendly pesticide
CN115215771B (en) * 2022-08-06 2024-04-02 蚌埠医学院 Honokiol derivative, preparation method and application thereof in preparation of antitumor drugs

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2459338A (en) * 1944-04-22 1949-01-18 Parke Davis & Co Amino methyl phenols
CN1044807A (en) * 1989-02-08 1990-08-22 大塚制药株式会社 Neurocyte sex change reparation or protective material are with composition and the preparation method that is used for the benzene derivative of said composition
CN110615742A (en) * 2019-09-20 2019-12-27 广东省禾基生物科技有限公司 Magnolol derivative and preparation method and application thereof
CN110664795A (en) * 2019-09-20 2020-01-10 广东省禾基生物科技有限公司 Water-soluble composition, preparation method and application thereof
CN110845350A (en) * 2019-09-20 2020-02-28 广东省禾基生物科技有限公司 Honokiol derivative and preparation method and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100892596B1 (en) * 2007-02-12 2009-04-09 바이오스펙트럼 주식회사 Biphenyl Diol Derivatives and Compositions Comprising the Same as an Active Ingredient
CN101279901B (en) * 2007-12-25 2011-08-17 四川大学 Honokiol series derivates, preparation and use thereof
CN102408314B (en) * 2011-12-09 2013-10-30 广西大学 Method for preparing high-purity magnolol and magnolol
CN103113264B (en) * 2013-01-22 2015-01-14 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2459338A (en) * 1944-04-22 1949-01-18 Parke Davis & Co Amino methyl phenols
CN1044807A (en) * 1989-02-08 1990-08-22 大塚制药株式会社 Neurocyte sex change reparation or protective material are with composition and the preparation method that is used for the benzene derivative of said composition
CN110615742A (en) * 2019-09-20 2019-12-27 广东省禾基生物科技有限公司 Magnolol derivative and preparation method and application thereof
CN110664795A (en) * 2019-09-20 2020-01-10 广东省禾基生物科技有限公司 Water-soluble composition, preparation method and application thereof
CN110845350A (en) * 2019-09-20 2020-02-28 广东省禾基生物科技有限公司 Honokiol derivative and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIN DING ET AL.: "Anti-proliferative activity and structure-activity relationship of honokiol derivatives", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 27, 27 June 2019 (2019-06-27), XP085746049, DOI: 20201125144812X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114907228A (en) * 2022-06-27 2022-08-16 深圳市锦泰医药科技合伙企业(有限合伙) Colchicine and magnolol compound, synthetic method thereof and application thereof in resisting new coronavirus
CN114907228B (en) * 2022-06-27 2023-11-28 深圳市锦泰医药科技合伙企业(有限合伙) Colchicine and magnolol compound, synthesis method thereof and application thereof in resisting new coronaviruses

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