CN110668981B - Magnolol derivative and preparation method and application thereof - Google Patents
Magnolol derivative and preparation method and application thereof Download PDFInfo
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- CN110668981B CN110668981B CN201910894284.6A CN201910894284A CN110668981B CN 110668981 B CN110668981 B CN 110668981B CN 201910894284 A CN201910894284 A CN 201910894284A CN 110668981 B CN110668981 B CN 110668981B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/24—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- 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
Abstract
The invention belongs to the field of magnolol derivatives, and particularly relates to magnolol and a preparation method and application thereof. Disclosed is a magnolol derivative having a structure represented by formula (1). The magnolol derivative provided by the invention has good water solubility, is colorless and transparent after being dissolved, has a remarkable inhibiting effect on common Escherichia coli, golden yellow staphylococcus and the like, and can be used as a green and natural preservative to be applied to the fields of foods, medicines, cosmetics and the like.
Description
Technical Field
The invention relates to the field of magnolol derivatives, and particularly relates to magnolol and a preparation method and application thereof.
Background
The food, the medicine and the cosmetics are rich in a large amount of water and various nutritional ingredients, a good growth environment is provided for microorganisms, and the microorganisms are difficult to invade in the production and use processes of the cosmetics, so that the cosmetics are extremely easy to decay, the quality of the products is reduced, and the health of users is threatened. The addition of the preservative into the cosmetics is an important means for protecting the products from microbial contamination, prolonging the shelf life of the products and ensuring the safety of the products.
Currently, many kinds of preservatives are used in foods, medicines and cosmetics, most of them are chemical preservatives, and dozens of them are commonly used, including acidic preservatives (benzoic acid), ester-type preservatives (parabens) and the like. However, with the development of science and the increasing awareness of safety of consumers, it is gradually found that although chemical preservatives have a good antiseptic effect, some chemical preservatives can produce adverse effects on human bodies, cause skin allergy, decrease physical functions and pollute the environment. Therefore, natural preservatives are urgently needed by various industries, and a natural preservative with low toxicity, low irritation and high performance has great significance in the fields of food, medicines, cosmetics and the like.
Cortex magnoliae officinalis (Magnolia officinalis cortex cortitex) is dried bark, root bark and branch of Magnolia officinalis mah. Cortex Magnolia officinalis is bitter and pungent, warm in nature, and has effects in promoting qi circulation, eliminating dampness, warming middle warmer, relieving pain, lowering adverse qi, and relieving asthma. The main chemical active ingredients of the magnolia officinalis are lignans, magnolol, honokiol and the like. The phenols in cortex Magnolia officinalis have antibacterial, antitumor, analgesic, and antiinflammatory effects. But because the water solubility is poor, the magnolol is easy to oxidize and deteriorate, and the application of the magnolol in foods, health-care products, medicines and cosmetics is greatly hindered. In general, conventional surfactants and emulsifiers can be used for solubilizing magnolol, so that the dosage of the required surfactants and emulsifiers is very large, and the magnolol can be separated out from a water system formula even if the magnolol is applied to a water aqua formula, so that the whole system becomes white and turbid, and the use is seriously influenced. In addition, a small amount of alkali can be added into a formula system to convert magnolol into salt and increase the water solubility of magnolol, however, the magnolol salt formed by the method is extremely unstable and easily turns into golden yellow, so that the conductivity of the system is increased and the bacteriostatic ability is reduced, and the requirements on the pH value of the product formula system and the dosage accuracy of a thickening agent and an emulsifier are very high, so that the magnolol is basically difficult to apply industrially.
The traditional method for improving the solubility of magnolol introduces impurity compounds into a protogen system, and makes magnolol unstable after being dissolved in an aqueous agent system, so that the system is easy to deteriorate, and the bacteriostatic ability is reduced. Therefore, the modification of the structure of magnolol to improve the solubility and the bacteriostatic ability of magnolol in water is an urgent problem to be solved when magnolol is used as a natural preservative in foods, medicines and cosmetics.
Disclosure of Invention
The invention aims to solve the problems of poor water solubility of magnolol and reduced antibacterial ability after being dissolved in an aqueous solution system, and provides a magnolol derivative and a preparation method and application thereof. The water-soluble magnolol derivative provided by the invention has excellent stability and bacteriostatic ability when being applied to a preservative.
In order to achieve the above object, in a first aspect, the present invention provides a magnolol derivative having a structure represented by formula (1):
wherein, in the formula (1), R1、R2、R3、R4、R5And R6Each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C12Alkoxy, substituted or unsubstituted C6-C10Aryl group of (1).
Preferably, R1、R2、R3、R4、R5And R6Each of the substituents optionally present on (A) is independently selected from halogen, C1-C6Alkoxy and C6-C10Aryl group of (1).
Preferably, R1、R2、R3And R4Each independently selected from hydrogen, halogen, SO3 -And C1-C3Alkyl group of (1).
In a second aspect, the present invention provides a process for the preparation of a magnolol derivative, the process comprising the steps of: in the presence of quaternary ammonium salt compound, the compound with the structure of formula (2) is contacted and reacted with bisulfite and/or sulfite,
wherein, in the formula (2), R1、R2、R3、R4、R5And R6Each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C12Alkoxy, substituted or unsubstituted C6-C10Aryl group of (1).
Preferably, R1、R2、R3、R4、R5And R6Each of the substituents optionally present on (A) is independently selected from halogen, C1-C6Alkoxy and C6-C10Aryl group of (1).
In a third aspect, the invention also provides an application of the magnolol derivative prepared by the method in bacteriostasis.
The modified magnolol derivative which can be used for bacteriostasis is prepared by modifying the magnolol structure, has good water solubility, is colorless and transparent after being dissolved, has obvious inhibition effect on common gram-negative bacteria, gram-positive bacteria, fungi and the like, and can be used as a green and natural preservative to be applied to the fields of foods, medicines, cosmetics and the like.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Detailed Description
The following is a detailed description of specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Some of the terms referred to in this aspect are explained below:
“C1-C10the "alkyl group" of (a) represents an alkyl group having 1 to 10 carbon atoms in total, and includes a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group, and may be, for example, a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group having 1, 2,3, 4, 5, 6, 7, 8, 9, 10 carbon atoms in total, and may be, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopentyl group, a methyl-pentyl group, an isopentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, a cyclopropyl group, a methylcyclopropyl group, a cyclopentyl group,Methylcyclopentyl, cyclohexyl, and the like.
“C1-C12The "alkoxy group" of (b) represents an alkoxy group having 1 to 12 carbon atoms in total, and includes a linear alkoxy group, a branched alkoxy group and a cycloalkoxy group, and specifically may be a linear alkoxy group, a branched alkoxy group or a cycloalkoxy group having 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms in total, and may be, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a t-butoxy group, a n-pentoxy group, an isopentoxy group, a n-hexoxy group, a n-heptoxy group, a n-octoxy group, a n-nonoxy group, a n-decoxy group, a cyclopropoxy group, a methyl cyclopropoxy group, an ethyl cyclopropoxy group, a cyclopentoxy group, a methyl cyclopentoxy group, a cyclohexyloxy group and the like.
“C6-C10The "aryl group" of (a) represents an aryl group having 6 to 10 carbon atoms in total, at least one H group being substituted by C on the benzene ring of the aryl group1-C4And alkyl group of (a) is substituted, for example, tolyl, ethylphenyl, n-propylphenyl, isopropylphenyl, n-butylphenyl, orthoxylyl, m-xylyl, p-xylyl, etc.
Other similar groups are defined herein with reference to the foregoing definitions, only with respect to the number of carbon atoms or the manner of isomerisation.
In a first aspect, the present invention provides a magnolol derivative having a structure represented by formula (1):
wherein, in the formula (1), R1、R2、R3、R4、R5And R6Each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C12Alkoxy, substituted or unsubstituted C6-C10Aryl group of (1).
Preferably, R1、R2、R3、R4、R5And R6Each of the substituents optionally present on the above is independently selectedFrom halogen, C1-C6Alkoxy and C6-C10Aryl group of (1).
Preferably, R1、R2、R3And R4Each independently selected from hydrogen, halogen, SO3 -And C1-C3Alkyl group of (1).
According to a preferred embodiment of the present invention, in formula (1), R1、R2、R3、R4、R5And R6Each independently selected from hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C6-C8Aryl group of (1).
Preferably, R1、R2、R3、R4、R5And R6Each of the substituents optionally present on (A) is independently selected from fluorine, chlorine, bromine, C1-C3Alkoxy group of (C)6-C8Aryl group of (1).
Preferably, R1、R2、R3And R4Each independently selected from hydrogen, fluorine, chlorine, bromine, SO3 -Methyl, ethyl and n-propyl.
Preferably, R1、R2、R3、R4、R5And R6Are all hydrogen.
Preferably, R1、R2、R3And R4Each independently selected from hydrogen and SO3 -。
According to a preferred embodiment of the present invention, the compound having a structure represented by formula (1) is selected from at least one of the following compounds:
compound 1:
compound 2:
compound 3:
compound 4:
compound 5:
the inventor of the present invention found that the magnolol derivative related in this embodiment has more excellent water solubility and bacteriostatic ability.
In a second aspect, the present invention provides a process for the preparation of a magnolol derivative, the process comprising the steps of: in the presence of a phase transfer catalyst, a compound with the structure of formula (2) is in contact reaction with bisulfite and/or sulfite,
wherein, in the formula (2), R1、R2、R3、R4、R5And R6Each independently selected from hydrogen, halogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C12Alkoxy, substituted or unsubstituted C6-C10Aryl group of (1).
Preferably, R1、R2、R3、R4、R5And R6Each of the substituents optionally present on (A) is independently selected from halogen, C1-C6Alkoxy and C6-C10Aryl group of (1).
According to the present invention, the type of the bisulfite and/or sulfite is not particularly limited, and may be conventionally selected in the art, and is preferably NaHSO3、KHSO3、Na2SO3、K2SO3、NH4HSO3、(NH4)2SO3﹒H2At least one of O.
The molar ratio of the bisulfite and/or sulfite to the compound having the structure of formula (2) is (0.5-4): 1, preferably (1-2.5): 1.
the phase transfer catalyst of the present invention is not particularly limited, and may be conventionally selected in the art, and for example, it is a quaternary ammonium salt compound, a quaternary phosphonium salt compound, a crown ether compound, and preferably a quaternary ammonium salt compound. The quaternary ammonium salt compound is not particularly limited in the present invention and may be conventionally selected in the art, and preferably, the quaternary ammonium salt compound is selected from at least one of tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium sulfate, trioctylmethylammonium chloride, trioctylmethylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, dodecyltrimethylammonium hydrogen sulfate, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, and tetradecyltrimethylammonium hydrogen sulfate.
In the present invention, the weight ratio of the quaternary ammonium salt compound to the compound having the structure of formula (2) is (0.05-0.5): 100, preferably (0.1-0.3): 100.
in the present invention, the conditions of the contact reaction include: the temperature is 40-100 ℃, preferably 60-80 ℃; the contact time is 4-12h, preferably 5-8 h.
According to the present invention, the contact reaction is carried out in the presence of water and an organic solvent, and the organic solvent is not particularly limited, and may be an alkane, an alcohol, an ester, or an ether, and is preferably at least one selected from methanol, dichloromethane, chloroform, N-dimethylformamide, and diethyl ether, and is more preferably methanol.
In the whole reaction system, the volume ratio of the water to the organic solvent is 1: (1-6), preferably 1: (3-5).
And (3) evaporating, crystallizing, filtering and freeze-drying the reacted substances in sequence to obtain the magnolol derivative to be prepared. The evaporation operation is not particularly limited in the present invention, and may be selected conventionally in the art, and it is preferable to remove most of the organic solvent using a rotary evaporator. The crystallization operation is not particularly limited in the present invention, and may be a conventional operation in the art, and the crystallization solvent is at least one selected from acetone, ethanol, isopropanol, and ethyl acetate, and preferably ethanol and/or isopropanol. The operation of filtration and lyophilization is not particularly limited in the present invention, and may be selected conventionally in the art.
In the invention, the compound shown in the formula (2) is derived from a plant extract, the plant is magnolia officinalis of magnolia, and the content of the compound with the structure shown in the formula (2) in the extract is more than or equal to 80%.
In a third aspect, the invention provides an application of the magnolol derivative prepared by the method in bacteriostasis.
The magnolol derivative provided by the invention can be applied to food, medicines and cosmetics, can be used as a preservative or a preservative component, and has an inhibiting effect on common escherichia coli, staphylococcus aureus, pseudomonas aeruginosa, candida albicans, aspergillus niger and the like. The magnolol derivative is used in an amount of 0.001-0.01 g per gram of the food, pharmaceutical or cosmetic.
The present invention will be described in detail below by way of examples.
In the following examples, the molecular structure of the prepared magnolol derivative was measured by a time-of-flight mass spectrometer, model HR EI-TOFMS, purchased from Kore corporation, uk, and a nuclear magnetic resonance spectrometer; the model of the nmr spectrometer was semer femospin 80, purchased from semer femtole corporation; the method comprises the following steps of (1) purchasing a triple quadrupole mass spectrometer (TSQ Altis) by a liquid chromatography-mass spectrometer (LC/MS) model, from Sammer Fei company; the magnolol content of the plant source is 90%; the dodecyl trimethyl ammonium chloride and benzyl triethyl ammonium chloride used were purchased from Shanghai Meclin Biochemical Co., Ltd; the nutrient broth is purchased from Beijing Meiruida science and technology Limited and mainly comprises peptone, beef extract, sodium chloride and water; TTC is short for 2,3, 5-triphenyltetrazolium chloride, and the used TTC reagent is purchased from Shanghai leaf Biotech limited; nipagin methyl ester is analytically pure and purchased from Shanghai Michelin Biochemical technology, Inc.; phenoxyethanol was analytically pure and purchased from Shanghai Aladdin Biotechnology GmbH.
Example 1
Weighing 10g of magnolol (content of 90%) from plant, and ultrasonically dissolving in 40ml of methanol to obtain methanol phase; 3.9g of sodium bisulfite were weighed out and dissolved in 14ml of deionized water, and 0.01g of dodecyltrimethylammonium chloride was added as an aqueous phase. The water phase and the methanol phase are slowly put into a 250ml three-neck flask to be mixed, the adding speed is controlled to be 4ml/min, and the mixture is magnetically stirred at the rotating speed of 450 rmp/min. The reaction temperature is about 60 ℃, and the reaction time is 8 h. Removing excessive methanol by using a rotary evaporator, recrystallizing in isopropanol at low temperature, filtering, and freeze-drying to obtain magnolol derivatives with yield of 40% based on magnolol in the reaction raw materials. The magnolol derivative with the structure shown in the formula (1) is proved by using a flight mass spectrometer and a nuclear magnetic resonance spectrometer for characterization. The mechanism of the reaction is as follows:
example 2
Weighing 10g of magnolol (content of 90%) from plant, and ultrasonically dissolving in 40ml of methanol to obtain methanol phase; 5.1g of ammonium sulfite monohydrate was weighed out and dissolved in 8ml of deionized water, and 0.02g of benzyltriethylammonium chloride was additionally added as an aqueous phase. The water phase and the methanol phase are slowly put into a 250ml three-neck flask to be mixed, the adding speed is controlled to be 4ml/min, and the mixture is magnetically stirred at the rotating speed of 450 rmp/min. The reaction temperature is about 80 ℃, and the reaction time is 5 h. Removing excessive methanol by using a rotary evaporator, recrystallizing in isopropanol at low temperature, filtering, and freeze-drying to obtain magnolol derivatives with yield of 28% based on magnolol in the reaction raw materials. The magnolol derivative with the structure shown in the formula (1) is proved by using a flight mass spectrometer and a nuclear magnetic resonance spectrometer for characterization. The mechanism of the reaction is as follows:
the above embodiments are illustrative of the present invention, and are not intended to limit the present invention, and any simple modifications of the present invention are within the scope of the present invention.
Test example 1
Solubility test method: a measuring cylinder is used to measure 25 +/-1 ℃ and 100g of deionized water, and the deionized water is put into a 250ml beaker. Put into a magnetic stirrer, and the rotating speed is adjusted to be 200 rmp/min. The samples from examples 1 and 2 were weighed on an analytical balance and dissolved in deionized water at 0.1g each time until complete dissolution was not achieved after 10 minutes of stirring and the maximum mass dissolved was recorded. The results are shown in Table 1.
Test example 2
Samples of magnolol derivatives prepared in examples 1 and 2 were used as test samples, and the MIC values of the minimum inhibitory concentrations were quantitatively measured. A10% magnolol ethanol solution, methyl paraben, a traditional chemical preservative, and phenoxyethanol were used as comparative examples.
The test method of the MIC value of the minimum inhibitory concentration comprises the following steps: the test samples were diluted with sterilized nutrient broths (used for culturing Escherichia coli, Staphylococcus aureus as a diluent, and the test samples were diluted by a two-fold dilution method, and then inoculated with bacteria at concentrations shown in Table 2, respectively, and the bacteria were cultured at 35 ℃ for 36 hours, 3 hours before the end of the culture, TTC reagent was added, and the culture was continued, and if the culture turned red, it was determined that the concentration was not able to inhibit the growth of the microorganism, and if the culture did not turn red, it was determined that the minimum concentration of the drug in the culture that did not turn red was the minimum inhibitory concentration of the bacteriostatic agent against the microorganism, and specific results are shown in Table 3.
Test example 3
Samples of magnolol derivatives prepared in example 2 were added to the spray formulation as in table 4 below. Inoculating a certain amount of bacteria, and detecting the change of microbial quantity according to the detection method of the microbial preservative efficacy test of United states Pharmacopeia USP32<51> at intervals of 0 day, 7 days, 14 days, 21 days and 28 days. The specific results are shown in Table 5.
TABLE 1
| Quality of dissolution | Magnolol | Example 1 | Example 2 |
| Solvent water (100g) | -- | ＞0.42g | ＞1.2g |
Note: - -means that 0.1g is not completely dissolved; indicates that the sample is totally dissolved
TABLE 2
| Bacterial strain | Escherichia coli | Staphylococcus aureus |
| Bacterial liquid concentration (cfu/mL) | 1×107 | 1×108 |
TABLE 3
TABLE 4
| Raw materials | Content (wt.) |
| Butanediol | 2.4％ |
| Betaine | 0.04％ |
| Glycyrrhizic acid dipotassium salt | 0.05％ |
| Soluble proteoglycans | 0.05％ |
| Royal jelly extract | 0.05％ |
| Modified magnolol (example 2) | 2.5％ |
| Water (W) | Balance of |
| Citric acid | Adjusting pH to 6-7 |
TABLE 5
As can be seen from the data in table 1, in the qualitative test of solubility, the magnolol derivative prepared according to the present invention showed excellent water solubility, in 100g of solvent water, the solubility of the sample in example 1 was greater than 0.42g, and the solubility of the sample in example 2 was greater than 1.2g, i.e., the samples measured in examples 1 and 2 were completely dissolved, while the magnolol extracted from the plant was insoluble in water; the data in table 3 show that the magnolol derivative prepared in example 2 has excellent bacteriostatic action on escherichia coli and staphylococcus aureus, and the bacteriostatic effect is equivalent to that of the traditional chemical preservatives, namely methyl paraben and phenoxyethanol; the spray formulation of table 4 provides a very suitable environment for the survival of bacteria and fungi, and the sample of example 2 of the present invention exhibits excellent bacteriostatic ability under such harsh conditions, and as can be seen from the data in table 5, the preservative challenge test of the 28 day spray of the aqueous formulation passed, and the preservative challenge test of the modified magnolol of example 2 as a preservative.
Because magnolol is not dissolved in water, the bacteriostatic effect is difficult to test. The 10% magnolol ethanol solution has a good bacteriostatic effect, but the national standard strictly limits the dosage of ethanol in cosmetics, so that the magnolol ethanol solution cannot be industrially applied.
The magnolol derivative obtained in the embodiment has excellent water solubility, and the solubility of magnolol in water is effectively improved; the magnolol derivative has obvious inhibition effect on common Escherichia coli, golden yellow staphylococcus and the like.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (31)
1. A magnolol derivative selected from the group consisting of:
compound 5:
。
2. a process for the preparation of magnolol derivatives according to claim 1, wherein the process comprises: in the presence of a phase transfer catalyst, a compound with the structure of formula (2) is in contact reaction with bisulfite and/or sulfite,
Wherein, in the formula (2), R1、R2、R3、R4、R5And R6Is hydrogen.
3. The method of claim 2, wherein the bisulfite and/or sulfite is NaHSO3、KHSO3、Na2SO3、K2SO3、NH4HSO3、(NH4)2SO3﹒H2At least one of O;
the molar ratio of the bisulfite and/or sulfite to the compound having the structure of formula (2) is (0.5-4): 1.
4. the method of claim 3, wherein the molar ratio of the bisulfite and/or sulfite to the compound having the structure of formula (2) is (1-2.5): 1.
5. the method of any of claims 2-4, wherein the phase transfer catalyst is a quaternary ammonium salt compound, a quaternary phosphonium salt compound, or a crown ether compound.
6. The process of claim 5, wherein the phase transfer catalyst is a quaternary ammonium compound.
7. The method according to claim 6, wherein the quaternary ammonium salt compound is selected from at least one of tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium sulfate, trioctylmethylammonium chloride, trioctylmethylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, dodecyltrimethylammonium hydrogen sulfate, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium hydrogen sulfate.
8. The method of claim 6 or 7, wherein the weight ratio of the quaternary ammonium salt compound to the compound having the structure of formula (2) is 0.05-0.5: 100.
9. the method of claim 8, wherein the weight ratio of the quaternary ammonium salt compound to the compound having the structure of formula (2) is 0.1-0.3: 100.
10. the method of any one of claims 2-4, 6-7, and 9, wherein the conditions of the contact reaction comprise: the temperature is 40-100 ℃; the time is 4-12 h.
11. The method of claim 10, wherein the conditions of the contact reaction comprise: the temperature is 60-80 ℃; the time is 5-8 h.
12. The method of claim 5, wherein the conditions of the contact reaction comprise: the temperature is 40-100 ℃; the time is 4-12 h.
13. The method of claim 8, wherein the conditions of the contact reaction comprise: the temperature is 40-100 ℃; the time is 4-12 h.
14. The method of claim 12 or 13, wherein the conditions of the contact reaction comprise: the temperature is 60-80 ℃; the time is 5-8 h.
15. The method according to any one of claims 2 to 4, 6 to 7, 9, 11 to 13, wherein the contact reaction is further carried out in the presence of water and an organic solvent selected from at least one of methanol, dichloromethane, chloroform, N-dimethylformamide, diethyl ether;
wherein the volume ratio of water to the organic solvent is 1: (1-6).
16. The method of claim 15, wherein the organic solvent is methanol;
wherein the volume ratio of water to the organic solvent is 1: (3-5).
17. The method according to claim 5, wherein the contact reaction is further carried out in the presence of water and an organic solvent selected from at least one of methanol, dichloromethane, chloroform, N-dimethylformamide, diethyl ether;
wherein the volume ratio of water to the organic solvent is 1: (1-6).
18. The method according to claim 8, wherein the contact reaction is further carried out in the presence of water and an organic solvent selected from at least one of methanol, dichloromethane, chloroform, N-dimethylformamide, diethyl ether;
wherein the volume ratio of water to the organic solvent is 1: (1-6).
19. The method according to claim 10, wherein the contact reaction is further carried out in the presence of water and an organic solvent selected from at least one of methanol, dichloromethane, chloroform, N-dimethylformamide, diethyl ether;
wherein the volume ratio of water to the organic solvent is 1: (1-6).
20. The method according to claim 14, wherein the contact reaction is further carried out in the presence of water and an organic solvent selected from at least one of methanol, dichloromethane, chloroform, N-dimethylformamide, diethyl ether;
wherein the volume ratio of water to the organic solvent is 1: (1-6).
21. The method of any one of claims 17-20, wherein the organic solvent is methanol;
the volume ratio of water to the organic solvent is 1: (3-5).
22. The method according to any one of claims 2 to 4, 6 to 7, 9, 11 to 13 and 16 to 20, wherein the method further comprises sequentially crystallizing, filtering and lyophilizing the product obtained by the contact reaction.
23. The method of claim 5, further comprising sequentially crystallizing, filtering and lyophilizing the product obtained from the contacting reaction.
24. The method of claim 8, further comprising sequentially crystallizing, filtering and lyophilizing the product obtained from the contacting reaction.
25. The method of claim 10, further comprising sequentially crystallizing, filtering and lyophilizing the product of the contact reaction.
26. The method of claim 14, further comprising sequentially crystallizing, filtering and lyophilizing the product of the contact reaction.
27. The method of claim 15, further comprising sequentially crystallizing, filtering and lyophilizing the product of the contact reaction.
28. The method of claim 21, further comprising sequentially crystallizing, filtering, and lyophilizing the product of the contact reaction.
29. Use of magnolol derivatives according to claim 1 for bacteriostasis in non-disease diagnosis or treatment.
30. The use according to claim 29, wherein the bacteria are selected from at least one of escherichia coli, staphylococcus aureus, pseudomonas aeruginosa, candida albicans, aspergillus niger.
31. Use according to claim 29, wherein the bacterium is present in a food, pharmaceutical or cosmetic product in an amount of 0.001 to 0.01 gram per gram of food, pharmaceutical or cosmetic product.
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| PCT/CN2020/114942 WO2021052272A1 (en) | 2019-09-20 | 2020-09-14 | Magnolol derivative, preparation method therefor, and use thereof |
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| CN113024404A (en) * | 2021-03-10 | 2021-06-25 | 郑州大学 | Quaternary ammonium salt type honokiol/magnolol derivative and preparation method and application thereof |
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