WO2021052269A1 - 水溶性组合物及其制备方法与应用 - Google Patents

水溶性组合物及其制备方法与应用 Download PDF

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WO2021052269A1
WO2021052269A1 PCT/CN2020/114939 CN2020114939W WO2021052269A1 WO 2021052269 A1 WO2021052269 A1 WO 2021052269A1 CN 2020114939 W CN2020114939 W CN 2020114939W WO 2021052269 A1 WO2021052269 A1 WO 2021052269A1
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formula
group
compound
substituted
unsubstituted
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PCT/CN2020/114939
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English (en)
French (fr)
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张兵
张炽坚
伍宇飞
何廷刚
胡丽云
艾勇
张文环
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 WO2021052269A1 publication Critical patent/WO2021052269A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • 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
    • 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 invention relates to the field of Magnolia officinalis total phenol derivatives, in particular to a water-soluble composition and a preparation method and application 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 dried 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 the "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.
  • a small amount of alkali can be added to the formulation system to turn the total phenols of magnolia officinalis into a salt and increase its water solubility.
  • the total phenolate of magnolia officinalis formed by this method is extremely unstable and easily turns golden yellow, resulting in electrical conductivity of the system. The rate increases and the antibacterial ability decreases.
  • the above methods have very high requirements on the accuracy of the pH, thickener and emulsifier dosage of the product formulation system, which makes it difficult to process and apply.
  • the purpose of the present invention is to overcome the problems of poor water solubility of Magnolia officinalis total phenol and decreased bacteriostatic ability after being dissolved in an aqueous system, and to provide a water-soluble composition and a preparation method and application thereof.
  • the water-soluble composition magnolia total phenol derivative provided by the present invention has excellent stability and antibacterial ability when used in preservatives.
  • the present invention provides a water-soluble composition, which comprises a compound having a structure of formula (1) and a compound having a structure of formula (2):
  • the content of the compound having the structure of formula (1) in the water-soluble composition is 20-80% by weight.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, A substituted or unsubstituted C 1 -C 12 alkoxy group, a substituted or unsubstituted C 6 -C 10 aryl group.
  • 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 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.
  • the present invention provides a method for preparing a water-soluble composition.
  • the method includes combining a compound having a structure of formula (3) and/or formula (5) with a compound having a structure of formula (4) under Mannich reaction conditions. And/or the compound of the formula (6) structure in the first contact, and then the product obtained in the first contact is in the second contact with the composition consisting of the compound having the structure of the formula (7) and the compound having the structure of the formula (8), The Mannich reaction product is obtained.
  • the content of the compound represented by formula (7) and the compound represented by formula (8) in the water-soluble composition is not zero.
  • the content of the compound having the structure of formula (1) in the water-soluble composition prepared by the method is 20-80% by weight.
  • 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 an unsubstituted C 1 -C 12 alkoxy group, a substituted or unsubstituted C 6 -C 10 aryl group.
  • 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 water-soluble composition described in the aforementioned first aspect or the water-soluble composition prepared by the method described in the aforementioned second aspect in bacteriostasis.
  • the present invention prepares a water-soluble composition that can be used for bacteriostasis by modifying the structure of Magnolia officinalis, which has good water solubility, is colorless and transparent after dissolution, and is resistant to common gram-negative bacteria and gram-negative bacteria. Positive bacteria, fungi, etc. have a significant inhibitory effect, and can be used as a green and natural preservative 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, for example, 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 and the like.
  • 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 water-soluble composition
  • the content of the compound having the structure of formula (1) in the water-soluble composition is 20-80% by weight.
  • 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 an unsubstituted C 1 -C 12 alkoxy group, a substituted or unsubstituted C 6 -C 10 aryl group.
  • 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 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, fluorine, chlorine, bromine, substituted or unsubstituted A substituted C 1 -C 5 alkyl group, a substituted or unsubstituted C 1 -C 6 alkoxy group, a substituted or unsubstituted C 6 -C 8 aryl group.
  • 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.
  • 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.
  • R 9 is a C 1 -C 3 alkylene group.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from methyl,
  • 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;
  • R 5 , R 6 , R 7 and R 8 are all hydrogen.
  • the compound having the structure of formula (1) is selected from at least one of the following compounds:
  • the compound having the structure of formula (2) is selected from at least one of the following compounds:
  • the inventors of the present invention found that the water-soluble composition of the total phenol derivatives of magnolia in the above preferred embodiments has more excellent water solubility and antibacterial ability.
  • the present invention provides a method for preparing a water-soluble composition, the method comprising, under Mannich reaction conditions, combining a compound having a structure of formula (3) and/or formula (5) with a compound having a structure of formula (4) ) And/or the compound of the formula (6) structure in the first contact, and then the product obtained in the first contact is in the second contact with the composition consisting of the compound having the structure of the formula (7) and the compound having the structure of the formula (8) , To obtain the Mannich reaction product.
  • the content of the compound represented by formula (7) and the compound represented by formula (8) in the water-soluble composition is not zero.
  • the content of the compound having the structure of formula (1) in the water-soluble composition is 20-80% by weight.
  • 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 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 an unsubstituted C 1 -C 12 alkoxy group, a substituted or unsubstituted C 6 -C 10 aryl group.
  • 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 preferred ranges of R 1 , R 2 , R 3 and R 4 in formulas (3) and (5), R 1 , R 2 , R
  • the preferred ranges of 3 and R 4 in formula (4) and formula (6), the preferred ranges of R 5 , R 6 , R 7 and R 8 are respectively the same as the preferred ranges of the corresponding groups in the first aspect described above , I won’t repeat it here.
  • the compound having the structure of formula (3) and/or formula (5) is an amine compound.
  • the amine is not particularly limited in the present invention, and may be linear alkyl amine or branched alkyl amine. , Cycloalkylamines, hydroxyalkylamines or various amino acids, 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 dimethylacetal, diethanolamine , At least one of dimethylamine, diethylamine, and di-n-propylamine.
  • the total amount of compounds having the structure of formula (3) and/or formula (5), the total amount of compounds having the structure of formula (4) and/or formula (6) and the total amount of compounds having the structure of formula (7) and formula (7) is 0.5-6:0.5-6:1, preferably 1-4:1-4:1.
  • the compound having the structure of formula (4) and/or formula (6) 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 above-mentioned first contact and second contact of the present invention are carried out in the presence of an acidic substance and a solvent, and the solvent is water and/or an organic solvent.
  • the acidic substance is not particularly limited, and may be at least one of hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid.
  • 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 water-soluble composition includes under Mannich reaction conditions, combining a compound having a structure of formula (3) and/or formula (5) with a compound having a structure of formula (4) And/or the compound of the formula (6) structure is mixed for the first contact, and then the product obtained from the first contact is subjected to the second contact with the composition having the structure of the formula (7) and the compound having the structure of the formula (8).
  • the aldehyde compound is first contacted with the secondary amine compound, and the temperature is controlled to be 20-50°C, preferably 30-40°C, and the time is 5-20 min, preferably 10-15 min.
  • the aldehyde compound may be in the form of a solution, and the solvent of the solution is water. Subsequently, the first contacted system is placed in a low-temperature water bath, an acidic substance or a solution formed by an acidic substance in the organic solvent is added to the system, and the temperature is controlled to be 1-10°C, preferably 2-5°C, continue
  • the contact time is 0.5-2h, preferably 0.6-1.5h.
  • the present invention does not specifically limit the timing of adding the acidic substance.
  • the acid can be added at the same time as the first contact. Preferably, the acid is added to the organic solvent first, and then added together with the organic solvent.
  • the inventors of the present invention have found that, compared with the method of directly adding acid to the reactant, the above-mentioned preferred method can effectively reduce acid mist and avoid violent reaction exotherm and side reactions.
  • the present invention does not particularly limit the low-temperature water bath, which can be a conventional choice in the field, preferably an ice salt bath.
  • the present invention does not specifically limit the salt in the ice salt bath, preferably potassium chloride, chlorinated At least one of sodium, sodium sulfate, and potassium sulfate.
  • the salt is used in an amount of 0.5 to 5% by weight based on the weight of water.
  • the second contact method includes dissolving the compound having the structure of formula (7) and formula (8) in the solvent in the presence of an acidic substance to form a solution, and then performing the second contact with the product obtained from the first contact. Two contacts.
  • the temperature during the second contact is 30-90°C, preferably 70-85°C, and the time is 1-3h, preferably 1.5-2h.
  • the method further includes: successively evaporating and purifying the product of the second contact.
  • the present invention does not specifically limit the evaporation operation, which can be a conventional choice in the field.
  • the present invention uses a rotary evaporator to evaporate most of the organic solvent; the present invention does not specifically limit the purification operation, which can be Conventional operations in the field preferably use column chromatography for purification.
  • the purification filler is 100-200 mesh silica gel.
  • the eluent is not particularly limited and can be conventionally selected in the field.
  • the eluent is acetic acid.
  • the volume ratio of ethyl acetate/acetone, ethyl acetate and acetone is preferably 2-6:1, particularly preferably 4:1.
  • the compound having the structure of formula (7) and the compound having the structure of formula (8) are both derived from plant extracts.
  • the plant described in the present invention is magnolia officinalis.
  • the content of the composition of the compound having the structure of formula (7) and the compound having the structure of formula (8) is ⁇ 80% by weight.
  • the present invention also provides the use of the water-soluble composition described in the first aspect or the water-soluble composition prepared by the method described in the second aspect in antibacterial applications.
  • the water-soluble composition of total phenolic derivatives of magnolia bark provided by the present invention can be used in foods, medicines and cosmetics as preservatives or preservative components.
  • preservatives or preservative components For common Escherichia coli, Staphylococcus aureus, and aeruginosa Pseudomonas, Candida albicans, Aspergillus niger, etc. have inhibitory effects.
  • the dosage of the water-soluble composition is 0.001-0.01 g per gram of the food, medicine or cosmetic.
  • the molecular structure of the prepared Magnolia total phenol 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.
  • 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 Company;
  • plant-derived Magnolia officinalis has three specifications of 70%, 80%, and 90% by weight, purchased from Hunan Jiamu Biotechnology Co., Ltd.; used N-methyl-glycine powder, N-methylaminoethane Dimethyl acetal was purchased from Shanghai Macleans Bioreagent Co., Ltd.;
  • the nutrient broth was purchased from Beijing Merida Technology Co., Ltd., and the main ingredients were peptone, beef extract, sodium chloride and water;
  • Sabouraud medium was purchased from Shandong West Asia Chemical Industry Co., Ltd., the main components are peptone and agar;
  • TTC is the abbreviation of 2,3,5-triphenyltetrazolium chloride, the T
  • 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 : ATCC5478 4th generation, purchased from Guangdong Institute of Microbiology; Sabouraud medium was purchased from Shandong West Asia Chemical Industry Co., Ltd.
  • the yield was 35%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed that it is a total phenol derivative of magnolia with the structure shown in formula (1) and (2) of the present invention.
  • the reaction mechanism is as follows:
  • the structural formula of the compound having the structure represented by formula (2) 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 structural formula of the compound having the structure represented by formula (2) 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 total phenols of magnolia was 6:6:1, and the others were the same as in Example 1.
  • the yield was 27%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and it was confirmed that the prepared product is a total phenolic derivative of magnolia with the structure represented by formula (1) and formula (2) of the present invention, and its structural formula is the same as that of Example 1.
  • Example 1 It was carried out according to the method of Example 1, except that the total phenols of magnolia were not added, and the total phenolic compounds of magnolia with the structure represented by formula (7) and the structure represented by formula (8) were used in the same molar amount, so The molar ratio of the compound having the structure represented by formula (7) to the compound having the structure represented by formula (8) in the total phenolic compounds of magnolia is 1:1, and in formula (7) and formula (8), R 1 , R 2 , R 3 and R 4 are hydrogen, chlorine, methyl, and methoxy in this order, and the others are the same as in Example 1.
  • the yield was 32%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the result of the characterization confirmed that the product prepared in this example is a total phenolic derivative of magnolia with the structure represented by formula (1) and formula (2) of the present invention (wherein, R 1 , R 2 , R 3 and R 4 are hydrogen, chlorine, methyl and methoxy in sequence, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same as in Example 1. ).
  • Example 1 It was carried out according to the method of Example 1, except that the total phenols of magnolia were not added, and the total phenolic compounds of magnolia with the structure represented by formula (7) and the structure represented by formula (8) were used in the same molar amount, so The molar ratio of the compound having the structure represented by formula (7) to the compound having the structure represented by formula (8) in the total phenolic compounds of magnolia is 1:1, and in formula (7) and formula (8), R 1 , R 2 , R 3 and R 4 are hydrogen, chlorine, methyl and tolyl in this order, and the others are the same as in Example 1.
  • the yield was 21%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the result of the characterization confirmed that the product prepared in this example is a total phenolic derivative of magnolia with the structure represented by formula (1) and formula (2) of the present invention (wherein, R 1 , R 2 , R 3 and R 4 are hydrogen, chlorine, methyl and tolyl in turn, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all the same as in Example 1) .
  • 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 total phenols of magnolia and the product obtained from the first contact for reaction; the others are the same as in Example 1.
  • the yield was 32%. It was characterized by flight mass spectrometry and nuclear magnetic resonance, and the result of the characterization confirmed that the product prepared in this example is a total phenolic derivative of magnolia with the structure represented by formula (1) and formula (2) of the present invention. The product of 1 is the same.
  • 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 the total phenols of Magnolia officinalis and the samples in Examples 1-9 to test their solubility. During the test, 0.1 g each time was dissolved in deionized water until it could not be completely dissolved after stirring for 10 minutes, and the maximum dissolved mass was recorded. The results are shown in Table 1.
  • the samples of the total phenolic derivatives of Magnolia Bark prepared in Examples 1-9 were used as the test objects to quantitatively test the MIC value of the minimum inhibitory concentration.
  • a 10% by weight Magnolia total phenolic ethanol solution, traditional chemical preservatives methyl paraben and phenoxyethanol were used as controls.
  • the minimum inhibitory concentration MIC value test method use sterilized nutrient broth (used to cultivate Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa), Sabouraud medium (used to cultivate white pseudo Silk yeast and Aspergillus niger) were used as diluents.
  • the test samples were diluted by the two-fold dilution method, and then the bacteria were inoculated at the concentrations shown in Table 2 respectively. 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 total phenol derivatives of Magnolia Bark prepared in Examples 1-9 were added to the spray formulation in Table 4 below or a similar spray formulation. 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 in accordance with the detection method of the USP32 ⁇ 51> microbial preservative efficacy test in the United States Pharmacopoeia. Among them, the test results of the total magnolia phenol derivatives prepared in Examples 1, 2, 3 and 7 are shown in Table 5 below, and the test results of the total magnolia phenol derivatives prepared in the remaining examples (all use the following table The spray formula of 4) is similar, and all are qualified.
  • Example 1 sample Solvent water (100g) Magnolol - Example 1 >3g Example 2 >1g Example 3 >10g Example 4 >2g Example 5 >3g Example 6 >3g Example 7 >3g Example 8 >0.5
  • 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 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, 2, 3, and 7 of the present invention show Excellent antibacterial ability. After 28 days of spray antiseptic challenge test of water formulation, the total phenolic derivatives of magnolia in Examples 1, 2, 3, and 7 passed the antiseptic challenge test as preservatives, and the effects of the other examples were similar.
  • Magnolia officinalis does not dissolve in water, it is difficult to test the antibacterial effect.
  • the antibacterial effect of the ethanol solution of 10% by weight of total phenols of magnolol is very good, but the national standards have strict restrictions on the amount of ethanol in cosmetics, and it is used in water systems. Magnolol and honokiol will be removed from ethanol. It precipitates out, so it cannot be used in industry.
  • the total magnolia phenol derivative obtained by modifying the total phenol of magnolia by the method of the present invention has good water solubility and effectively improves the solubility of the total magnolia phenol in water; Lan's negative bacteria, gram-positive bacteria, fungi, etc. have a significant inhibitory effect.

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Abstract

一种水溶性组合物及其制备方法与应用，该水溶性组合物由具有式(1)和式(2)结构的化合物组成。所述的水溶性组合物具有良好水溶性，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。

Description

水溶性组合物及其制备方法与应用
相关申请的交叉引用
本申请要求2019年09月20日提交的中国专利申请201910894304.X的权益，该申请的内容通过引用被合并于本文。
技术领域
本发明涉及厚朴总酚衍生物领域，具体涉及水溶性组合物及其制备方法与应用。
背景技术
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。
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。
厚朴(Magnolia officinalis cortex)为木兰科植物厚朴Magnolia officinalis Rehd.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，极大的阻碍了厚朴总酚在食品、药品及化妆品中的应用。通常，可以用常规的表面活性剂、乳化剂增溶厚朴总酚，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，厚朴总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，将厚朴总酚变成盐，增加其水溶性，这种方法形成的厚朴总酚盐极不稳定，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，导致其基本难以工艺应用。
传统提高厚朴总酚溶解度的方法会给原体系引入杂质化合物，而且使厚厚朴总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，对厚朴总酚结构进行改性，提高厚朴总酚在水中的溶解度和抑菌能力，是厚朴总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。
发明内容
本发明的目的是为了克服厚朴总酚水溶性差和溶解在水剂体系后抑菌能力下降的问题，提供了一种水溶性组合物及其制备方法与应用。本发明提供的水溶性组合物厚朴总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。
为了实现上述目的，第一方面，本发明提供一种水溶性组合物，该组合物包括具有式(1)结构的化合物和具有式(2)结构的化合物：
Figure PCTCN2020114939-appb-000001
其中，所述水溶性组合物中具有式(1)结构的化合物的含量为20-80重量％。
根据本发明，在式(1)和式(2)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。
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。
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。
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。
第二方面，本发明提供一种水溶性组合物的制备方法，该方法包括在曼尼希反应条件下，将具有式(3)和/或式(5)结构的化合物与具有式(4)和/或式(6)结构的化合物进行第一接触，然后将第一接触所得产物与由具有式(7)结构的化合物和具有式(8)结构的化合物组成的组合物进行第二接触，得到曼尼希反应产物。
Figure PCTCN2020114939-appb-000002
Figure PCTCN2020114939-appb-000003
其中，其中，所述水溶性组合物中式(7)所示的化合物与式(8)所示的化合物的含量均不为零。
优选地，所述方法制备得到的水溶性组合物中具有式(1)结构的化合物的含量为20-80重量％。
优选地，在式(3)和式(5)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。
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。
优选地，在式(4)和式(6)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。
优选地，在式(7)和式(8)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。
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。
第三方面，本发明提供前述第一方面所述的水溶性组合物或前述第二方面所述的方法制备得到的水溶性组合物在抑菌中的应用。
本发明通过对厚朴总酚结构进行改性，制备出了可以用于抑菌的水溶性组合物，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。
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。
具体实施方式
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。
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。
以下对本方面中涉及的部分术语进行解释：
“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，例如可以为甲基、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 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 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。
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。
第一方面，本发明提供一种水溶性组合物，该组合物包括具有式(1)结构的化合物和具有式(2)结构的化合物：
Figure PCTCN2020114939-appb-000004
其中，所述水溶性组合物中具有式(1)结构的化合物的含量为20-80重量％。
优选地，在式(1)和式(2)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。
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。
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。
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。
根据本发明一种优选实施方式，其中，在式(1)和式(2)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。
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氟、氯、溴、C 1-C 3的烷氧基和C 6-C 8的芳基。
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。
其中，R 9为C 1-C 3的亚烷基。
优选地，R 1、R 2、R 3和R 4各自独立地选自甲基、
Figure PCTCN2020114939-appb-000005
Figure PCTCN2020114939-appb-000006
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；
优选地，在式(1)和式(2)中，R 5、R 6、R 7和R 8均为氢。
根据本发明一种优选实施方式，所述水溶性组合物中，具有式(1)结构的化合物选自以下化合物中的至少一种：
Figure PCTCN2020114939-appb-000007
Figure PCTCN2020114939-appb-000008
其中，具有式(2)结构的化合物选自以下化合物中的至少一种：
Figure PCTCN2020114939-appb-000009
Figure PCTCN2020114939-appb-000010
本发明的发明人发现，上述优选实施方式中的厚朴总酚衍生物的水溶性组合物具有更优异的水溶性和抑菌能力。
第二个方面，本发明提供一种水溶性组合物的制备方法，该方法包括在曼尼希反应条件下，将具有式(3)和/或式(5)结构的化合物与具有式(4)和/或式(6)结构的化合物进行第一接触，然后将第一接触所得产物与由具有式(7)结构的化合物和具有式(8)结构的化合物组成的组合物进行第二接触，得到曼尼希反应产物。
Figure PCTCN2020114939-appb-000011
其中，所述水溶性组合物中式(7)所示的化合物与式(8)所示的化合物的含量均不为零。
优选地，所述水溶性组合物中具有式(1)结构的化合物的含量为20-80重量％。
优选地，在式(3)和式(5)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。
优选地，在式(4)和式(6)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。
优选地，在式(7)和式(8)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。
本发明中，在式(7)和式(8)中，R 1、R 2、R 3和R 4的优选范围，在式(3)和式(5)中，R 1、R 2、R 3和R 4的优选范围，在式(4)和式(6)中，R 5、R 6、R 7和R 8的优选范围，分别与前述第一方面中的对应基团的优选范围相同，在此不再赘述。
根据本发明，具有式(3)和/或式(5)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。
优选地，具有式(3)和/或式(5)结构的化合物的总量、具有式(4)和/或式(6)结构的化合物的总量与由具有式(7)结构和式(8)结构的化合物组成的组合物的摩尔比为0.5-6：0.5-6：1，优选为1-4：1-4：1。
优选地，具有式(4)和/或式(6)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、邻甲基苯甲醛中的至少一种，优选为甲醛。
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在酸性物质以及溶剂的存在下进 行，所述的溶剂为水和/或有机溶剂。对所述酸性物质没有特别地限定，可以为盐酸、硫酸、磷酸或乙酸中的至少一种。
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。
根据本发明的一种优选实施方式，所述水溶性组合物的制备方法包括在曼尼希反应条件下，将具有式(3)和/或式(5)结构的化合物与具有式(4)和/或式(6)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由具有式(7)结构和具有式(8)结构的化合物的组合物进行第二接触。进行第一接触时，首先醛类化合物与二级胺化合物进行接触，控制温度为20-50℃，优选为30-40℃，时间为5-20min，优选为10-15min。所述醛类化合物，可以为溶液的形式，所述溶液的溶剂为水。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所述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。本发明对所述酸性物质的加入时机没有特别的限定，可以在进行第一接触的同时加酸，优选为将所述酸先加入所述有机溶剂，然后随所述有机溶剂一起加入。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。本发明对所述低温水浴没有特别的限定，可以为本领域的常规选择，优选为冰盐浴，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，以水的重量计，所述盐的用量为0.5-5重量％。
优选地，所述第二接触的方式包括将具有式(7)和式(8)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进行所述第二接触。
优选地，进行第二接触时的温度为30-90℃，优选为70-85℃，时间为1-3h，优选为1.5-2h。
根据本发明，优选地，该方法还包括：对第二接触的产物依次进行蒸发和纯化。本发明对所述蒸发操作没有特别地限定，可以为本领域的常规选择，本发明采用的是旋转蒸发仪，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，可以为本领域的常规操作，优选为采用柱层析方法进行纯化，纯化填料为100-200目硅胶，对洗脱剂没有特别地限定，可以为本领域的常规选择，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。
根据本发明，优选地，具有式(7)结构的化合物和具有式(8)结构的化合物均来自于植物提取物，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(7)结构的化合物和具有式(8)结构的化合物的组合物的含量≥80重量％。
第三方面，本发明还提供一种前述第一方面所述的水溶性组合物或前述第二方面所述的方法制备得到的水溶性组合物在抑菌中的应用。
本发明提供的厚朴总酚衍生物的水溶性组合物可以应用于食品、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，所述水溶性组合物的用量为0.001-0.01克。
以下将通过实施例对本发明进行详细描述。以下实施例中，所制备的厚朴总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三重四极杆质谱仪，购买自赛默飞公司；植物来源的厚朴总酚重量含量为70％、80％、90％三个规格，购买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(Aspergillus niger)：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。
实施例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。称取7.6g N-甲基-甘氨酸粉末放入三口烧瓶中，缓慢滴加37重量％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。称取植物来源的厚朴总酚(含量为70％)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85℃，加入厚朴总酚的甲醇酸溶液，冷凝回流，反应12h。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，得到厚朴总酚衍生物(即水溶性组合物)。
以反应原料中的厚朴总酚计，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)和(2)所示结构的厚朴总酚衍生物。反应的机理如下：
Figure PCTCN2020114939-appb-000012
实施例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。称取11.3g 40％浓度的二甲胺溶液放入三口烧瓶中，缓慢滴加37重量％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。称取植物来源的厚朴总酚(含量为80％)13.3g，溶 解在剩余的30ml甲醇酸溶液里。将三口烧瓶放在油浴中控制温度为75℃，加入厚朴总酚的甲醇酸溶液，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，得到厚朴总酚衍生物(即水溶性组合物)。以反应原料中的厚朴总酚计，收率为74％。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)和(2)所示结构的厚朴总酚衍生物。反应的机理如下：
Figure PCTCN2020114939-appb-000013
实施例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。称取13g二乙醇胺放入三口烧瓶中，缓慢滴加37重量％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℃。在冰水浴中，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。称取植物来源的厚朴总酚(含量为90％)10g，溶解剩余的30ml甲醇酸溶液里。将三口烧瓶放在油浴中控制温度为70℃，加入厚朴总酚的甲醇酸溶液，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，得到厚朴总酚衍生物(即水溶性组合物)。以反应原料中的厚朴总酚计，收率为92％。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)和(2)所示结构的厚朴总酚衍生物。反应的机理如下：
Figure PCTCN2020114939-appb-000014
Figure PCTCN2020114939-appb-000015
实施例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。
以反应原料中的厚朴总酚计，收率为46％。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)和(2)所示结构的厚朴总酚衍生物，其中，具有式(1)所示结构的化合物的结构式如下：
Figure PCTCN2020114939-appb-000016
具有式(2)所示结构的化合物的结构式如下：
Figure PCTCN2020114939-appb-000017
实施例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。
以反应原料中的厚朴总酚计，收率为57％。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)和(2)所示结构的厚朴总酚衍生物，其中，具有式(1)所示结构的化合 物的结构式如下：
Figure PCTCN2020114939-appb-000018
具有式(2)所示结构的化合物的结构式如下：
Figure PCTCN2020114939-appb-000019
实施例6
按照实施例1的方法进行，不同的是，所述N-甲基-甘氨酸与所述厚朴总酚的摩尔比为6:6:1，其他与实施例1相同。
以反应原料中的厚朴总酚计，收率为27％。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)和式(2)所示结构的厚朴总酚衍生物，其结构式与实施例1相同。
实施例7
按照实施例1的方法进行，不同的是，不加入厚朴总酚，而采用相同摩尔量的具有式(7)所示结构和式(8)所示结构的厚朴总酚类化合物，所述厚朴总酚类化合物中具有式(7)所示结构的化合物与具有式(8)所示结构的化合物的摩尔比为1:1，且在式(7)和式(8)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。
以反应原料中的厚朴总酚类化合物计，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具有式(1)和式(2)所示结构的厚朴总酚衍生物(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、R 4、R 5、R 6、R 7和R 8均与实施例1相同)。
实施例8
按照实施例1的方法进行，不同的是，不加入厚朴总酚，而采用相同摩尔量的具有式(7)所示结构和式(8)所示结构的厚朴总酚类化合物，所述厚朴总酚类化合物中具有式(7)所示结构的化合物与具有式(8)所示结构的化合物的摩尔比为1:1，且在式(7)和式(8)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。
以反应原料中的厚朴总酚类化合物计，收率为21％。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具有式(1)和式(2)所示结构的厚朴总酚衍生物(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、R 4、R 5、R 6、R 7和R 8均与实施例1相同)。
实施例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厚朴总酚、第一接触所得产物混合进行反应；其他与实施例1相同。
以反应原料中的厚朴总酚计，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具有式(1)和式(2)所示结构的厚朴总酚衍生物，其结构式与实施例1的产物相同。
测试例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。用分析天平称取厚朴总酚、实施例1-9中样品测试其溶解性，测试时每次0.1g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。
测试例2
以实施例1-9中制备得到的厚朴总酚衍生物的样品为测试对象，定量测试其最小抑菌浓度MIC值。以10重量％厚朴总酚乙醇溶液、传统化学防腐剂尼泊金甲酯和苯氧乙醇作为对照。
最小抑菌浓度MIC值的测试方法：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进行稀释，然后分别以表2所示的浓度接种菌。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，则认定为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。
测试例3
将实施例1-9中制备得到的厚朴总酚衍生物，添加到如下表4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、2、3和7制得的厚朴总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厚朴总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。
表1
样品 溶剂水(100g)
厚朴总酚 --
实施例1 ＞3g
实施例2 ＞1g
实施例3 ＞10g
实施例4 ＞2g
实施例5 ＞3g
实施例6 ＞3g
实施例7 ＞3g
实施例8 ＞0.5
实施例9 ＞3g
注：--表示0.1g也不能完全溶解；＞代表样品全部溶解
表2
Figure PCTCN2020114939-appb-000020
表3
Figure PCTCN2020114939-appb-000021
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
表4
原料 含量，重量
丁二醇 2.4％
甜菜碱 0.04％
甘草酸二钾 0.05％
可溶性蛋白多糖 0.05％
蜂王浆提取物(购自片仓工业株式会社) 0.05％
厚朴总酚衍生物(实施例3) 0.4％
水 余量
柠檬酸 调节pH＝6-7
表5
Figure PCTCN2020114939-appb-000022
Figure PCTCN2020114939-appb-000023
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。
通过表1的结果可以看出，在溶解度定性测试中，本发明各实施例制备得到的厚朴总酚衍生物在100g溶剂水中的溶解度均大于1g，即实施例制得的样品已全部溶解，而从植物提取的厚朴总酚是不溶于水的。
从表3的数据可以看出实施例1-9制备得到的厚朴总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。
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、2、3、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、2、3、7中的厚朴总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。
由于厚朴总酚本身不溶解于水，很难测试抑菌效果。10重量％厚朴总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，厚朴酚、和厚朴酚会从乙醇中析出，所以无法工业应用。
采用本发明的方法对厚朴总酚进行改性得到的厚朴总酚衍生物，具有良好的水溶性，有效提高了厚朴总酚在水中的溶解度；厚朴总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。
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。

Claims (14)

  1. 一种水溶性组合物，该水溶性组合物包括具有式(1)结构的化合物和具有式(2)结构的化合物：
    Figure PCTCN2020114939-appb-100001
    其中，所述水溶性组合物中具有式(1)结构的化合物的含量为20-80重量％；
    在式(1)和式(2)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；
    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；
    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。
  2. 根据权利要求1所述的水溶性组合物，其中，在式(1)和式(2)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；
    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；
    其中，R 9为C 1-C 3的亚烷基；
    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；
    优选地，在式(1)和式(2)中，R 5、R 6、R 7和R 8均为氢。
  3. 根据权利要求1或2所述的水溶性组合物，其中，具有式(1)结构的化合物选自以下化合物中的至少一种：
    Figure PCTCN2020114939-appb-100002
    Figure PCTCN2020114939-appb-100003
    其中，具有式(2)结构的化合物选自以下化合物中的至少一种：
    Figure PCTCN2020114939-appb-100004
    Figure PCTCN2020114939-appb-100005
  4. 一种水溶性组合物的制备方法，其特征在于，该方法包括在曼尼希反应条件下，将具有式(3)和/或式(5)结构的化合物与具有式(4)和/或式(6)结构的化合物进行第一接触，然后将第一接触所得产物与由具有式(7)结构的化合物和具有式(8)结构的化合物组成的组合物进行第二接触，得到曼尼希反应产物；
    Figure PCTCN2020114939-appb-100006
    Figure PCTCN2020114939-appb-100007
    其中，所述水溶性组合物中式(7)所示的化合物与式(8)所示的化合物的含量均不为零；
    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；
    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；
    在式(7)和式(8)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。
  5. 根据权利要求4所述的方法，其中，在式(7)和式(8)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；
    在式(3)和式(5)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；
    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；
    其中，R 9为C 1-C 3的亚烷基；
    在式(4)和式(6)中，R 5、R 6、R 7和R 8各自独立地选自氢、C 6-C 8的芳基和C 1-C 3的烷基；
    优选地，在式(4)和式(6)中，R 5、R 6、R 7和R 8均为氢。
  6. 根据权利要求4或5所述的方法，其中，具有式(4)和/或式(6)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。
  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。
  8. 根据权利要求4-7中任意一项所述的方法，其中，具有式(3)和/或式(5)结构的化合物的总量、具有式(4)和/或式(6)结构的化合物的总量与由具有式(7)结构和式(8)结构的化合物组成的组合物的摩尔比为0.5-6：0.5-6：1，优选为1-4：1-4：1。
  9. 根据权利要求4所述的方法，该所述第一接触和第二接触均在酸性物质以及水和/或有机溶剂的存在下进行，所述酸性物质选自盐酸、磷酸、硫酸和乙酸中的至少一种；
    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，优选为甲醇和/或乙醇。
  10. 根据权利要求9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(4)和/或式(6)结构的化合物加入到具有式(3)和/或式(5)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。
  11. 根据权利要求9或10所述的方法，其中，所述第二接触的方式包括将具有式(7)和式(8)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进行所述第二接触。
  12. 权利要求1-3中任意一项所述的水溶性组合物或权利要求4-11中任意一项所述的水溶性组合物在抑菌中的应用。
  13. 根据权利要求12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。
  14. 根据权利要求12或13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，所述水溶性组合物的用量为0.001-0.01克。
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