WO2016123987A1 - 反应性抗菌化合物及其制备方法 - Google Patents

反应性抗菌化合物及其制备方法 Download PDF

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Publication number
WO2016123987A1
WO2016123987A1 PCT/CN2015/090059 CN2015090059W WO2016123987A1 WO 2016123987 A1 WO2016123987 A1 WO 2016123987A1 CN 2015090059 W CN2015090059 W CN 2015090059W WO 2016123987 A1 WO2016123987 A1 WO 2016123987A1
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Prior art keywords
group
antibacterial compound
compound according
substituted
naphthenate
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PCT/CN2015/090059
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English (en)
French (fr)
Inventor
陈仕国
袁玲君
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Shenzhen University
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Shenzhen University
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Priority to US15/549,162 priority Critical patent/US10368544B2/en
Priority to CN201580001140.3A priority patent/CN105531258B/zh
Publication of WO2016123987A1 publication Critical patent/WO2016123987A1/zh
Anticipated expiration legal-status Critical
Priority to US16/232,392 priority patent/US10609927B2/en
Priority to US16/804,100 priority patent/US11044908B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/12—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
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    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
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    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/244—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing sulfur or phosphorus
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    • D06M13/244—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing sulfur or phosphorus
    • D06M13/282—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing sulfur or phosphorus with compounds containing phosphorus
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    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
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Definitions

  • the present application relates to the field of antibacterial technology, and in particular, to a reactive antibacterial compound and a preparation method thereof, and more particularly to a reactive antibacterial compound containing a positively charged nitrogen atom and a preparation method thereof.
  • Bacterial and fungal infections have become a worldwide problem that threatens human health and is of global health concern. It is one of the important means to solve bacterial or fungal infections by imparting antibacterial properties to the surface of the material or product to prevent bacteria or fungi from growing or reproducing on its surface, or even killing bacteria or fungi already present on the surface.
  • a common solution is to attach or anchor an antimicrobial component or material to the surface of the article by spraying or chemical bonding to achieve antibacterial properties.
  • Known antibacterial materials are widely used in ceramics, glass products, plastics, rubber, fibers, paper and coatings, such as household appliances, furniture, sanitary products, food packaging bags and clothing.
  • inorganic antibacterial agents such as nano titanium dioxide, nano silver, nano copper, and their ions
  • organic antibacterial agents For example, quaternary ammonium salts, alcohols, halogen amines, biguanides and thiazoles
  • polymeric antibacterial agents such as high molecular quaternary ammonium salts
  • natural and modified antibacterial agents such as chitosan and sorbus Acid, etc.
  • an antibacterial agent such as nanosilver, nano-copper and their ions or other antibacterial agents
  • nano-silver nano-copper
  • silver a coating containing an antibacterial agent
  • Ions, copper ions, other heavy metals and heavy metal ions rely on the slow release of their metal ions to the surrounding environment to achieve the purpose of inhibition or sterilization.
  • its antibacterial activity gradually decreases until it eventually loses its antibacterial activity, and it may also induce microbial variation and increase the probability of microbial resistance.
  • the harmfulness of nanomaterials has gradually been recognized and paid attention by humans.
  • Organic antibacterials such as quaternary ammonium salts, alcohols, haloamines, biguanides and thiazoles have the characteristics of quick effect and strong bactericidal ability.
  • This type of antibacterial agent uses quaternary ammonium salt and quaternary phosphonium salt (four grades). ⁇ salt) is the main.
  • the cell wall of bacteria is negatively charged, while the quaternary ammonium salt and the quaternary phosphonium salt are positively charged.
  • the positively charged quaternary ammonium salt is easily adsorbed by bacteria, and after approaching the bacteria, penetrates the cell wall and binds to the cell membrane, disturbing The composition of the cell membrane causes leakage of intracellular substances, which eventually leads to the death of bacteria.
  • the quaternary ammonium salt has low chemical activity and is mainly present in a free state when applied. It has high toxicity and strong irritancy. It is used as an antibacterial agent with poor heat resistance, easy migration, easy elution, and easy enrichment on the surface of the human body. Long-term use is prone to pathological changes, making microbes resistant. At the same time, organic antibacterial agents have poor heat resistance, which limits their range of use.
  • the polymer quaternary ammonium salt antibacterial agent can overcome the shortcomings of the small molecule antibacterial agent such as volatilization, difficult processing and poor chemical stability, and has excellent antibacterial activity and is not easy to penetrate, and thus has attracted people's attention.
  • unfixed polymer antibacterial agents also have problems such as high loss and lack of durability, and also exert a certain pressure on the surrounding environment.
  • Natural antibacterial agents are derived from natural plant, animal or mineral extracts. The main antibacterial mechanism is similar to organic quaternary ammonium salts, but the effect is not as good as organic antibacterial agents, and the products are not yet mature. Another disadvantage of natural antibacterial agents is that they are not suitable for large-scale production and are therefore not widely used at present.
  • a reactive antibacterial compound which not only has excellent antibacterial properties and hydrophilicity, but also can be bonded by reacting a terminal isocyanate group with a functional group on the surface of natural fibers, rayon and polymer materials.
  • the terminal isocyanate group means an isocyanate group at one end of the molecular chain.
  • the antibacterial compound provided by the embodiment of the present invention is a zwitterionic compound having a terminal isocyanate group and a quaternary ammonium group structure.
  • the positive charge of the quaternary nitrogen atom can destroy the microbial cell membrane, denature the protein and destroy the cell structure.
  • the above microorganisms include, but are not limited to, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, sulfate-reducing bacteria, Gram-positive bacteria, Gram-negative bacteria, Staphylococcus epidermidis, Bacillus subtilis , Enterococcus faecalis, Dry Corynebacterium and Bacillus anthracis. It can be used as a bactericidal or bacteriostatic agent to prevent infection, kill microorganisms, or inhibit the physiological functions of microorganisms, and thus can effectively treat infections caused by these microorganisms or control the pollution caused by them.
  • the antibacterial compound provided by the embodiment of the present invention can achieve chemical bond bonding with the surface of the material through the terminal isocyanate group.
  • the antibacterial compound can be applied to various fields such as textiles, medicine, food, agriculture, and the like, but is not limited to the above fields.
  • isocyanate groups can be combined with fibers, Cotton textiles, hydroxyl or amino groups on the surface of nylon to prepare washable antibacterial textiles; can be combined with hydroxyl or amino groups on the surface of medical infusion tubes and medical packaging materials to prepare antibacterial pharmaceutical products, or hydroxyl groups on the surface of food packaging or food preservation materials.
  • an amino group to prepare an antibacterial packaging material can be combined with fibers, Cotton textiles, hydroxyl or amino groups on the surface of nylon to prepare washable antibacterial textiles.
  • the reactive antibacterial compound has the structural formula (I):
  • R 1 is selected from the group consisting of OCN-L-NHCOOR', OCN-L-NHCONHR', OCN-L-NHCOSR', OCN-L-COOR' and OCN-L-COONHR';
  • L is selected from the group consisting of divalent C 1-18 alkyl, cycloalkyl and aryl groups, which are optionally substituted with up to 18 heteroatoms;
  • R' is selected from the group consisting of divalent C 1-18 alkyl, cycloalkyl and aryl groups, which are optionally substituted with up to 18 heteroatoms;
  • R 2 and R 3 are each independently selected from monovalent C 1-18 alkyl, cycloalkyl and aryl groups, which are optionally substituted with up to 18 heteroatoms;
  • R 4 is independently selected from the group consisting of divalent C 1-18 alkyl, cycloalkyl and aryl groups, which are optionally substituted with up to 18 heteroatoms;
  • Z is selected from the group consisting of -COO, -SO 3 and -OPO 2 OR 5 ;
  • R 5 is selected from a monovalent unsubstituted or substituted C 1-6 alkyl group, a cycloalkyl group and an aryl group.
  • R 2 and R 3 are the same group or a different group.
  • R 2 and R 3 are each independently selected from -(CH 2 ) u CH 3 , wherein u is an integer not less than 0 and not more than 17, wherein preferably, u is 0, 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17; further preferably, u is 0, 1, 2, 3 or 4; Further preferably, u is 0, 1, or 2.
  • Z is -SO 3 .
  • Z is -CO 2 .
  • Z is -OPO 2 OR 5 .
  • R 5 in the reactive antibacterial compound is -(CH 2 ) w CH 3 , wherein w is an integer of not less than 0 and not more than 5.
  • R 4 and R′ are each independently selected from —(CH 2 ) n —, n is an integer of not less than 1 and not more than 18, and preferably, n is 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; further preferably, n is 1, 2, 3, 4, 5 6, 6, 8, 9, or 10; still more preferably, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • R 1 is selected from the group consisting of OCN-L-NHCOOR' and OCN-L-NHCONHR'.
  • L has a structure represented by the following formula:
  • G 1 is selected from the group consisting of OCN-M-NHCOOG', OCN-M-NHCONHG', OCN-M-NHCOSG', OCN-M-COOG' and OCN-M-COONHG';
  • M is selected from a divalent unsubstituted or substituted C 1-18 alkyl group, a cycloalkyl group and an aryl group;
  • G' is selected from a divalent unsubstituted or substituted C 1-18 alkyl group, a cycloalkyl group and an aryl group;
  • G 2 and G 3 are each independently selected from -H, -F, -Cl, -Br, -I, -OCH 3 , -OCH 2 CH 3 , -OPr (Pr is n-propyl or isopropyl), - CN, -SCN, -NO, -NO 2 and monovalent unsubstituted or substituted C 1-7 alkyl, cycloalkyl, aryl;
  • G 4 is selected from a divalent unsubstituted or substituted C 1-18 alkyl group, a cycloalkyl group and an aryl group;
  • X is selected from -COO, -SO 3 and -OPO 2 OR 5 ;
  • R 5 is selected from a monovalent unsubstituted or substituted C 1-6 alkyl group, a cycloalkyl group and an aryl group.
  • G 1 is selected from the group consisting of OCN-M-NHCOOG' and OCN-M-NHCONHG'.
  • G 2 and G 3 are the same group or a different group.
  • G 2 and G 3 are each independently selected from -H, -CH 3 , -CH 2 CH 3 , -NO 2 , -F, -Cl, -Br and -I.
  • X is -SO 3 .
  • X is -CO 2 .
  • X is -OPO 2 OR 5 .
  • R 5 is selected from -(CH 2 ) w CH 3 , wherein w is an integer of not less than 0 and not more than 5, wherein preferably w is 0, 1, 2, 3 Or 4, further preferably, w is 0, 1, or 2.
  • G 4 and G′ are each independently selected from —(CH 2 ) n —, n is an integer of not less than 1 and not more than 18, and preferably, n is 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; further preferably, n is 1, 2, 3, 4, 5, 6 7, 8, 9, or 10; still more preferably, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • M has a structure represented by the following formula:
  • a method of preparing an antibacterial compound comprises the steps of:
  • a tertiary amine having the structure of the general formula (III) is reacted with a reactant B having the structure of the general formula (IV) to obtain a mixture;
  • Y is selected from the group consisting of -OH, -NH 2 and -SH;
  • R' is selected from the group consisting of divalent C 1-18 alkyl groups, cycloalkyl groups and aryl groups, which are optionally substituted with up to 18 heteroatoms;
  • R 2 And R 3 are each independently selected from monovalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and aryl;
  • L is selected from divalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and Aryl;
  • D is selected from the group consisting of -COOH and -NCO.
  • the mixture is reacted with reactant A to obtain the antibacterial compound
  • the reactant A is selected from the group consisting of propane sultone, butane sultone, ⁇ -propionolactone, X(CH 2 ) v CO 2 - Mt + , X(CH 2 ) v SO 3 - Mt and cyclic phosphate +, wherein X is selected from Br, Cl and I, v is an integer of not less than 1, Mt + is selected from Li +, Na +, K + , NH 4 +, Ag +, 1 / 2Mg 2+ And 1/2Ca 2+ , wherein the cyclic phosphate has a structure represented by the following formula:
  • R 5 is selected from a monovalent unsubstituted or substituted C 1-6 alkyl group, a cycloalkyl group and an aryl group; and R 6 is selected from a divalent unsubstituted or substituted C 1-6 alkyl group.
  • the reaction of the tertiary amine with the reactant B is carried out in the presence of a catalyst C selected from the group consisting of organic amine compounds, phosphine compounds, and At least one of the metal catalysts.
  • the catalyst C is the metal-containing catalyst.
  • the metal-containing catalyst is selected from the group consisting of tin tetrachloride, tetrabutyltin, tributyltin chloride, butyltin dichloride, butyltin trichloride, and tributyltin cyanide.
  • the methamic acid is at least one of dibutyltin, tin dioctoate, dibutyltin sulfide, stannous oleate, stannous tartrate, dibutyltin dilaurate, stannous octoate, and a metal naphthenate.
  • the metal-containing catalyst in the method for producing an antibacterial compound, is a metal naphthenate.
  • the metal naphthenate is selected from the group consisting of copper naphthenate, zinc naphthenate, lead naphthenate, lithium naphthenate, and naphthenic acid. At least one of a cobalt salt, a nickel naphthenate salt, a cadmium naphthenate salt, a mercury salt of a naphthenic acid salt, an indium naphthenate salt, and a phosphonium naphthenate salt.
  • a method of preparing an antibacterial compound comprises the steps of:
  • Q is selected from -OH, -NH 2 , -SH;
  • G' is selected from divalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and aryl;
  • G 2 and G 3 are each independently selected from - H, -F, -Cl, -Br, -I, -OCH 3 , -OCH 2 CH 3 , -OPr, -CN, -SCN, -NO, -NO 2 and monovalent unsubstituted or substituted C 1- 7 alkyl, cycloalkyl, aryl;
  • D is selected from -COOH and -NCO;
  • L is selected from divalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and aryl.
  • the reactant A is selected from the group consisting of propane sultone, butane sultone, ⁇ -propionolactone, X(CH 2 ) v CO 2 - Mt + , X(CH 2 ) v SO 3 - Mt and cyclic phosphate +, wherein X is selected from Br, Cl and I, v is an integer of not less than 1, Mt + is selected from Li +, Na +, K + , NH 4 +, Ag +, 1 / 2Mg 2+ And 1/2Ca 2+ , wherein the cyclic phosphate has a structure represented by the following formula:
  • R 5 is selected from a monovalent unsubstituted or substituted C 1-6 alkyl group, a cycloalkyl group and an aryl group; and R 6 is selected from a divalent unsubstituted or substituted C 1-6 alkyl group.
  • the reaction of the tertiary amine with the reactant B is carried out in the presence of a catalyst C selected from the group consisting of organic amine compounds, phosphine compounds, and At least one of the metal catalysts.
  • the catalyst C is the metal-containing catalyst.
  • the metal-containing catalyst is selected from the group consisting of tin tetrachloride, tetrabutyltin, tributyltin chloride, butyltin dichloride, butyltin trichloride, and tributyltin cyanide.
  • the metal-containing catalyst in the method for producing an antibacterial compound, is a metal naphthenate.
  • the naphthenic The acid metal salt is selected from the group consisting of copper naphthenate, zinc naphthenate, lead naphthenate, lithium naphthenate, cobalt naphthenate, nickel naphthenate, cadmium naphthenate, naphthenic acid At least one of a mercury salt, an indium naphthenate salt and a bismuth naphthenate salt.
  • aliphatic include, but are not limited to, straight-chain, branched or cyclic groups, which may be unsubstituted or may be one or more A hetero atom is substituted or substituted by one or more groups containing a hetero atom.
  • aliphatic and aliphatic may be saturated or unsaturated, such as olefins, cyclic olefins, diolefins, cyclic diolefins, alkynes, cycloalkynes and polycyclic hydrocarbons.
  • Aromatic means a system containing at least one aromatic ring, that is, not only a pure aromatic compound such as benzene, naphthalene and anthracene, but also an aromatic compound containing an aliphatic group such as toluene, styrene and phenylacetylene.
  • the pure aromatic compound including the monocyclic aromatic compound and the fused ring aromatic compound, may be an aromatic hydrocarbon such as benzene, naphthalene or anthracene, or an aromatic system containing a hetero atom such as pyridine, furan and thiophene.
  • an alkyl group means a saturated hydrocarbon group, and is a hydrocarbon group obtained by removing a hydrogen atom from an alkane molecule, such as a methyl group, a methylene group, an ethyl group, an isopropyl group or the like; and a cycloalkyl group means a saturated hydrocarbon containing an alicyclic structure, such as a monocyclic alicyclic hydrocarbon and a fused ring alicyclic hydrocarbon, a general term for a hydrocarbon group formed by removing a hydrogen atom, such as a cyclobutyl group and a cyclopentyl group; and an aryl group, which means any aromatic hydrocarbon molecule.
  • a general term for a group formed by removing a hydrogen atom from a nuclear carbon or other carbon atom such as phenyl, o-tolyl, 1-naphthyl (or ⁇ -naphthyl), 2-naphthyl (or ⁇ -naphthalene) Base, benzyl (benzyl) and phenethyl, etc., belong to this class.
  • a monovalent hydrocarbon group refers to a group formed by removing a hydrogen atom from a hydrocarbon, such as methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), phenyl (-C 6 H 5 ), etc.;
  • Valence hydrocarbon group refers to a group formed by removing two hydrogen atoms from a hydrocarbon, such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), p-phenylene (-pC 6). H 4 -) and so on.
  • the structural skeleton of the antibacterial compound contains a positively charged quaternary ammonium group, and the group has good antibacterial properties.
  • the antibacterial compound structure also has a negatively charged group.
  • the group is linked to the main skeleton of the compound.
  • the compound also has at least one isocyanate group at the end of the molecule, through the isocyanate The group reacts with a functional group in a material such as a polymer fiber or a natural fiber, and the compound can be combined with a material.
  • a method of preparing an antibacterial compound comprises the steps of:
  • a tertiary amine having the structure of the general formula (III) is reacted with a reactant B having the structure of the general formula (IV) to obtain a mixture;
  • Y is selected from the group consisting of -OH, -NH 2 and -SH;
  • R' is selected from the group consisting of divalent C 1-18 alkyl groups, cycloalkyl groups and aryl groups, which are optionally substituted with up to 18 heteroatoms;
  • R 2 And R 3 are each independently selected from monovalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and aryl;
  • L is selected from divalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and Aryl;
  • D is selected from the group consisting of -COOH and -NCO.
  • the functional group Y (-OH, -SH or -NH 2 ) in the tertiary amine having the structure of the general formula (III), and the isocyanate functional group (-NCO) in the reactant B having the structure of the general formula (IV)
  • a typical nucleophilic addition reaction can occur to form a carbamate, thiourethane or urea structure.
  • Reactant B has one isocyanate functional group and another isocyanate functional group or carboxyl group (functional group D).
  • the isocyanate functional group in the compound having the structure of the general formula (III) can react with the functional group Y in the compound having the structure of the general formula (IV) while retaining the functional group D at one terminal.
  • any compound containing at least two isocyanate groups can be subjected to the above reaction to give a similar isocyanate group-containing antibacterial compound.
  • the polyisocyanate compound since a plurality of isocyanate groups are present, in the case where the nucleophilic reagent is not excessive, a plurality of isocyanate groups in one molecule are reacted only, and the other isocyanate groups are retained in the final antibacterial compound.
  • the number of carbon atoms or the molecular weight of the polyisocyanate compound itself does not affect the progress of the reaction as long as it can undergo a nucleophilic addition reaction with the nucleophile.
  • the polyisocyanate may be an aliphatic polyisocyanate, an aliphatic cyclic polyisocyanate, a heterochain polyisocyanate, an aromatic polyisocyanate, a substituted aliphatic or aliphatic ring or a heterocyclic polyisocyanate, wherein the substituents include, but are not limited to, -F, - Cl, -Br, -I, -OCH 3 , -OCH 2 CH 3 , -OPr, -CN, -SCN, -NO and -NO 2 groups.
  • polyisocyanate compounds can often be present in the form of dimers, trimers or other polymers, and the polyisocyanates herein also include monomers, dimers, trimers of the above species. Body or other oligomers.
  • the aliphatic polyisocyanate includes, but is not limited to, hexamethylene diisocyanate, tetramethylene diisocyanate, 1,8-octamethylene diisocyanate, 1,10-decethylene diisocyanate, 1,12 - dodecyl diisocyanate, 1,14-tetramethylene diisocyanate, a derivative of lysine diisocyanate, trimethyl hexane diisocyanate, tetramethyl hexane diisocyanate, and two of the above species Polymers, trimers and other oligomers.
  • Aliphatic or heterocyclic polyisocyanates include, but are not limited to, 1,4-, 1,3- or 1,2-diisocyanate cyclohexane, 4,4- or 2,4-di(isocyanatecyclohexyl) Methane, 1-isocyanate-3,3,5-trimethyl-5-(isocyanatemethyl)cyclohexane (isophorone diisocyanate), 1,3- or 1,4-bis(isocyanate) Methyl)cyclohexane, 2,4- or 2,6-diisocyanate-1-methylcyclohexane, 3 (or 4), 8 (or 9)-di(isocyanatemethyl)tricyclo[ 5.2.1.0.2.6] decane isomer mixture, norbornene diisocyanate, 4,5-di(isocyanatomethyl)-1,3-disulfide Pentames and dimers, trimers and other oligomers of the above species.
  • Heterochain polyisocyanates include, but are not limited to, bis(isocyanatomethylthio)methane, bis(isocyanatomethylthio)methylthiomethane, bis(2-isocyanatoethylthio)methane , bis(3-isocyanatopropylthio)methane, isocyanatomethylthio (2-isocyanatoethylthio)methane, 2-isocyanatoethylthio (3-isocyanato) Dipropylthio)methane, bis(isocyanatomethylthio)phenylmethane, bis(2-isocyanatoethylthio)phenylmethane, bis(3-isocyanatopropylthio)benzene Methane, 1,2-(diisocyanatoethylthio)ethane, 1-isocyanatomethylthio-2-(2-isocyanatoethylthio)e
  • Aromatic polyisocyanates include, but are not limited to, toluene diisocyanate, diphenylmethane diisocyanate, o-xylene diisocyanate, m-xylene diisocyanate, p-xylene diisocyanate, ⁇ , ⁇ , ⁇ ', ⁇ '-tetra P-xylene diisocyanate, 1,3,5-tris(isocyanatomethyl)benzene, 4-methylm-xylene diisocyanate, 4-ethylm-xylene diisocyanate, 1,5-naphthalene Isocyanates and dimers, trimers and other oligomers of the above species, 4-chlorom-xylene diisocyanate, 4,5-dichloro-xylene diisocyanate, 2,3,5,6-tetrabromo Xylene diisocyanate and dimers, trimers and other oligomers of the above species.
  • the isocyanate structure used in the preparation of the present embodiment may also be a terminal isocyanate organic material containing at least one carboxyl group (-COOH), and the organic main chain structure may be a substituted or unsubstituted aliphatic, aliphatic ring, hetero chain, heterocyclic ring,
  • An aromatic structure wherein the substituents may include, but are not limited to, -F, -Cl, -Br, -I, -OCH 3 , -OCH 2 CH 3 , -OPr, -CN, -SCN, -NO, -NO 2 , etc. Atom or group.
  • the amine used in the first step reaction needs to be a tertiary amine having a high nucleophilic group Y such as a hydroxyl group, a thiol group or an amino group (-NH 2 ).
  • the role of the group Y is to carry a lone pair of electrons on the oxygen, sulfur, nitrogen atom, attack the carbon atom of the isocyanate group, and coupling occurs.
  • the amine compound may also be coupled to the isocyanate with a nitrogen atom, it may cause competition for the reaction of the group Y with the isocyanate. Therefore, it is necessary to use a tertiary amine having a lower reactivity.
  • the nitrogen atom on the tertiary amine is more difficult to couple due to its higher steric hindrance.
  • Exemplary tertiary amines containing a nucleophilic group including, but not limited to, N,N-dimethylethanolamine, N,N-diethylethanolamine, N,N-dimethylethylenediamine, N,N -di-n-propylethanolamine, N,N-diisopropylethanolamine, N,N-di-n-butylethanolamine, N,N-di-n-pentylethanolamine, N,N-dicyclohexylethanolamine, dimethylamino Mercaptan, dimethylaminoethanethiol and 3,3'-iminobis(N,N-dimethylpropylamine) and the like.
  • the hydrogen atom in the Y functional group may also be removed as a hydrogen ion, which further enhances the nucleophilicity of atoms such as O, S, and N in the Y functional group. Therefore, it can be utilized as a catalyst.
  • a Lewis acid such as a metal ion or an organometallic compound
  • the oxygen atom in the isocyanate forms a coordinate bond with the Lewis acid, and a part of the electron is transferred from the oxygen atom to the metal atom, thereby further increasing the isocyanate carbon atom. Electropositivity is good for the attack of nucleophiles, so this type of Lewis acid can also be used as a catalyst.
  • the catalyst is one or two or a combination of two or more of an organic amine compound, a phosphine compound, and a metal-containing catalyst.
  • organic amines can be divided into several categories: aliphatic amines, such as N,N-dimethylcyclohexylamine, bis(2-dimethylaminoethyl)ether, N,N,N',N'- Tetramethylalkylene diamine, triethylamine and N,N-dimethylbenzylamine; alicyclic amines, triethylenediamine (fixed amine, DABCO), N-ethylmorpholine, N-methylmorpholine, N,N'-diethylpiperazine and dimethylaminocyclohexane; aromatic amines with N,N-dimethylaniline, pyridine and 4-dimethylaminopyridine (N , N-lutidine) and the like.
  • the commonality of these amine compounds is that they are all basic and can accelerate the progress of the reaction. At the same time, they all contain a tertiary nitrogen atom or a pyridine nitrogen atom and thus do not react
  • the phosphine compound similar to the amine compound, also acts as a base to accelerate the reaction.
  • the phosphine compound may include, but is not limited to, various tertiary phosphines, wherein the three organic groups replacing three hydrogen atoms may be identical or not identical.
  • Tertiary phosphine substituted by three identical organic groups including but not limited to, triphenylphosphine, trimethylphosphine, triethylphosphine, tri-n-propylphosphine, triisopropylphosphine, tri-n-butylphosphine Tri-tert-butylphosphine and the like.
  • Tertiary phosphines substituted with different organic groups include, but are not limited to, dimethylphenylphosphine, methyldiphenylphosphine, diethylphenylphosphine, ethyldiphenylphosphine, and the like.
  • Metal-containing catalysts since metal ions can usually combine with oxygen atoms in isocyanate groups to form complexes, resulting in the transfer of electrons on the oxygen atoms to the metal atoms, increasing the electrical polarity of the carbon atoms to which they are attached, It is easier to accept the attack of nucleophiles.
  • Metal-containing catalysts which may include, but are not limited to, inorganic salts, carboxylates, phenates, metal alkyl compounds, etc. of metals
  • the intermediate carboxylate can be further divided into a linear or branched alkanoate and a cyclic naphthenate.
  • the metal elements contained are mainly alkali metals (lithium, sodium, potassium, rubidium, cesium, etc.), alkaline earth metals (magnesium, calcium, strontium, barium), transition metals (uranium, thorium, titanium, zirconium, vanadium, chromium, molybdenum). , manganese, iron, cobalt, nickel, copper, zinc, cadmium, mercury, etc.), aluminum, gallium, indium, antimony, tin, lead, antimony and antimony, etc., but are not limited thereto.
  • Common metal-containing catalysts include, but are not limited to, lithium acetate, lithium octoate, lithium naphthenate, sodium trichlorophenolate, sodium stearate, potassium acetate, potassium octoate, calcium acetate, calcium octoate, bismuth naphthenate, acetic acid.
  • Bismuth uranyl nitrate, cerium nitrate, titanium tetrachloride, dibutyl titanium dichloride, tetrabutyl titanium, butoxy titanium trichloride, zirconium naphthenate, zirconium octoate, vanadium trichloride, naphthenic Chromium acid, molybdenum hexacarbonyl, manganese octoate, ferric chloride, iron octoate, iron triacetylacetonate, ferrocene, cobalt octoate, cobalt naphthenate, cobalt linoleate, cobalt benzoate, nickel pentoxide, Nickel octoate, nickel naphthenate, copper acetate, copper octoate, copper naphthenate, zinc octoate, zinc naphthenate, cadmium nitrate, cadmium naphthenate, diphenyl
  • the catalyst is a metal containing catalyst.
  • the metal-containing catalyst is selected from the group consisting of: tin tetrachloride, tetrabutyltin, tributyltin chloride, butyltin dichloride, butyltin trichloride, tributyltin cyanide, dibutyltin diacetate, dibutyltin dioctoate , tributyltin octoate, diphenyltin dioctoate, dibutyltin dibutoxide, dibutyltin diacetylacetonate, two (isooctyl maleic acid) at least one of dibutyltin, tin dioctoate, dibutyltin sulfide, stannous oleate, stannous tartrate, dibutyltin dilaurate, stannous octoate and a metal naphthen
  • the metal-containing catalyst is a metal naphthenate.
  • the metal naphthenate is selected from the group consisting of copper naphthenate, zinc naphthenate, lead naphthenate, lithium naphthenate, cobalt naphthenate, nickel naphthenate, naphthenic At least one of a cadmium salt of a acid, a mercury salt of a naphthenate, an indium naphthenate, and a phosphonium naphthenate.
  • the mixture is reacted with reactant A to obtain the antibacterial compound
  • the reactant A is selected from the group consisting of propane sultone, butane sultone, ⁇ -propionolactone, X(CH 2 ) v CO 2 - Mt + , X(CH 2 ) v SO 3 - Mt and cyclic phosphate +, wherein X is selected from Br, Cl and I, v is an integer of not less than 1, Mt + is selected from Li +, Na +, K + , NH 4 +, Ag +, 1 / 2Mg 2+ And 1/2Ca 2+ , wherein the cyclic phosphate has a structure represented by the following formula:
  • R 5 is selected from a monovalent unsubstituted or substituted C 1-6 alkyl group, a cycloalkyl group and an aryl group; and R 6 is selected from a divalent unsubstituted or substituted C 1-6 alkyl group.
  • the mixture obtained in the first step reaction has a better nucleophilicity.
  • a tertiary amine nitrogen atom such that a ring opening reaction can occur between the reactant A and the mixture obtained in the first step to form a CN bond.
  • the tertiary nitrogen atom on the tertiary amine thus adds a linking group to form a quaternary ammonium group. Together with the sulfonic acid group, a zwitterionic compound is formed.
  • the reactant A is a cyclic phosphate (for example, 2-ethoxy-2-oxo-1,3,2-dioxaphospholane, ie, EOP)
  • the carbon atom attached to the oxygen atom on the ring may Upon the attack of the tertiary nitrogen atom, a ring opening reaction occurs, thereby changing the tertiary nitrogen atom into a quaternary ammonium group, and together with the phosphoric acid group, constitutes a zwitterionic compound.
  • the ring of a compound such as propionate or butyrolactone has a small number of atoms and a large ring tension, it is also easy to open the ring, so that it can also be opened in the presence of a nucleophilic tertiary nitrogen atom.
  • the ring reacts to form a quaternary ammonium group and simultaneously forms a carboxyl group to form a zwitterionic compound.
  • nucleophilic substitution reactions can occur with other metal carboxylates substituted by leaving groups.
  • Other leaving groups include, but are not limited to, p-toluenesulfonyl (-OTs), methylsulfonyl (- OMs) and trifluoromethanesulfonyl (-OTf) and the like.
  • Solvents for preparing antibacterial compounds including but not limited to organic solvents such as ethers, ketones, aromatic compounds, nitriles, esters and amides.
  • the solvent itself may also be a mixture of several solvent components, such as a mixture of two or more of the above solvents, and the like. Solvent selection is affected by the solubility of the reactants, the reaction temperature, and the chemical reactivity of the solvent itself.
  • the ether solvent may be THF, 1,4-epoxycyclohexane, ethylene glycol dimethyl ether, tetrahydropyran or the like;
  • the ketone solvent may be acetone, methyl ethyl ketone, cyclohexanone, acetophenone Vulgar Etc.;
  • the aromatic compound may be toluene, pyridine and imidazole;
  • the ester may be ethyl acetate, n-propyl acetate, n-butyl acetate, methyl formate and ethyl formate;
  • the nitrile may be acetonitrile, propionitrile and benzene.
  • the amide may be N-methylpyrrolidone, N,N-dimethylformamide or N,N-dimethylacetamide or the like.
  • the above are merely examples of common solvents that can be used in the present reaction, and are not intended to limit the range of reaction solvents.
  • any aprotic solvent which can dissolve the reaction raw material may be used as a reaction solvent, for example, ethylene carbonate, trimethylene carbonate, or the like.
  • the stirring method adopted in the process for preparing the antibacterial compound may be mechanical stirring or magnetic stirring or the like which can achieve sufficient contact of the reactants.
  • the addition of the reactant solution may be manual dropping or dropping by a mechanical drip machine, and the dropping rate may be constant or may be continuously changed as the reaction progresses.
  • a method of preparing an antibacterial compound comprises the steps of:
  • Q is selected from -OH, -NH 2 , -SH;
  • G' is selected from divalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and aryl;
  • G 2 and G 3 are each independently selected from - H, -F, -Cl, -Br, -I, -OCH 3 , -OCH 2 CH 3 , -OPr, -CN, -SCN, -NO, -NO 2 and monovalent unsubstituted or substituted C 1- 7 alkyl, cycloalkyl, aryl;
  • D is selected from -COOH and -NCO;
  • L is selected from divalent unsubstituted or substituted C 1-18 alkyl, cycloalkyl and aryl.
  • the functional group Q (-OH, -SH, -NH 2 ) in the pyridine having the structure of the general formula (V), and the isocyanate functional group (-NCO) in the reactant B having the structure of the general formula (IV)
  • a typical nucleophilic addition reaction can occur to form a carbamate, thiourethane or urea structure.
  • the electronegative atoms (O, S, N) in the functional group Q have a lone pair of electrons, and the carbon atoms on the isocyanate functional group are particularly susceptible to addition reaction with the nucleophile due to high electron deficiency. And form a structure such as a carbamate, thiourea, or urea.
  • the hydrogen atom in the functional group Q may also be removed as a hydrogen ion, and the formed negative ions further enhance the atoms of the O, S, N, etc. in the functional group Q.
  • Nucleophilic therefore, can be utilized as a catalyst.
  • a Lewis acid such as a metal ion, an organometallic compound, or the like
  • an oxygen atom in the isocyanate group forms a coordinate bond with the Lewis acid, and a part of the electron is transferred from the oxygen atom to the metal atom, thereby further increasing the isocyanate group.
  • the electropositivity of the carbon atoms of the group is favorable for the attack of the nucleophile, so this type of Lewis acid can also be used as a catalyst.
  • the catalyst is one or more of an organic amine compound, a phosphine compound, and a metal-containing catalyst.
  • organic amines can be divided into several categories: aliphatic amines, such as N,N-dimethylcyclohexylamine, bis(2-dimethylaminoethyl)ether, N,N,N',N'- Tetramethylalkylene diamine, triethylamine and N,N-dimethylbenzylamine; alicyclic amines, triethylenediamine (fixed amine, DABCO), N-ethylmorpholine, N-methylmorpholine, N,N'-diethylpiperazine and dimethylaminocyclohexane; aromatic amines with N,N-dimethylaniline, pyridine and 4-dimethylaminopyridine (N , N-lutidine) and the like.
  • aliphatic amines such as N,N-dimethylcyclohexylamine, bis(2-dimethylaminoethyl)ether, N,N,N',N'- Tetramethylalkylene
  • amine compounds are all basic and can accelerate the progress of the reaction. At the same time, they all contain a tertiary nitrogen atom or a pyridine nitrogen atom, and thus do not contain an active N-H bond or an O-H bond, and do not react with an isocyanate.
  • the phosphine compound similar to the amine compound, also acts as a base to accelerate the reaction.
  • the phosphine compound may include, but is not limited to, various tertiary phosphines, wherein the three organic groups replacing three hydrogen atoms may be identical or not identical.
  • Tertiary phosphine substituted by three identical organic groups including but not limited to, triphenylphosphine, trimethylphosphine, triethylphosphine, tri-n-propylphosphine, triisopropylphosphine, tri-n-butylphosphine Tri-tert-butylphosphine and the like.
  • Tertiary phosphines substituted with different organic groups include, but are not limited to, dimethylphenylphosphine, methyldiphenylphosphine, diethylphenylphosphine, ethyldiphenylphosphine, and the like.
  • Metal-containing catalysts since metal ions can usually combine with oxygen atoms in isocyanate groups to form complexes, resulting in the transfer of electrons on the oxygen atoms to the metal atoms, increasing the electrical polarity of the carbon atoms to which they are attached, It is easier to accept the attack of nucleophiles.
  • Metal-containing catalysts which may include, but are not limited to, inorganic salts, carboxylates, phenates, metal alkyl compounds, etc. of metal, wherein the carboxylate may be further divided into linear or branched alkanoates and ring-shaped. Naphthenate.
  • Gold contained The genus elements are mainly alkali metals (lithium, sodium, potassium, rubidium, cesium, etc.), alkaline earth metals (magnesium, calcium, strontium, barium), transition metals (uranium, thorium, titanium, zirconium, vanadium, chromium, molybdenum, manganese, Iron, cobalt, nickel, copper, zinc, cadmium, mercury, etc., aluminum, gallium, indium, antimony, tin, lead, antimony and antimony, but not limited thereto.
  • alkali metals lithium, sodium, potassium, rubidium, cesium, etc.
  • alkaline earth metals magnesium, calcium, strontium, barium
  • transition metals uranium, thorium, titanium, zirconium, vanadium, chromium, molybdenum, manganese, Iron, cobalt, nickel, copper, zinc, cadmium, mercury, etc.
  • Common metal-containing catalysts include, but are not limited to, lithium acetate, lithium octoate, lithium naphthenate, sodium trichlorophenolate, sodium stearate, potassium acetate, potassium octoate, calcium acetate, calcium octoate, bismuth naphthenate, acetic acid.
  • Bismuth uranyl nitrate, cerium nitrate, titanium tetrachloride, dibutyl titanium dichloride, tetrabutyl titanium, butoxy titanium trichloride, zirconium naphthenate, zirconium octoate, vanadium trichloride, naphthenic Chromium acid, molybdenum hexacarbonyl, manganese octoate, ferric chloride, iron octoate, iron triacetylacetonate, ferrocene, cobalt octoate, cobalt naphthenate, cobalt linoleate, cobalt benzoate, nickel pentoxide, Nickel octoate, nickel naphthenate, copper acetate, copper octoate, copper naphthenate, zinc octoate, zinc naphthenate, cadmium nitrate, cadmium naphthenate, diphenyl
  • the catalyst is a metal containing catalyst.
  • the metal-containing catalyst is selected from the group consisting of: tin tetrachloride, tetrabutyltin, tributyltin chloride, butyltin dichloride, butyltin trichloride, tributyltin cyanide, dibutyltin diacetate, dibutyltin dioctoate , tributyltin octoate, diphenyltin dioctoate, dibutyltin dibutoxide, dibutyltin diacetylacetonate, dibutyltin di(isooctylmaleate), tin dioctoate dichloride, dibutyltin sulfide, oleic acid Tin, At least one of stannous tartrate, dibutyltin dilaurate, stannous octoate and a metal naphthen
  • the metal-containing catalyst is a metal naphthenate.
  • the metal naphthenate is selected from the group consisting of copper naphthenate, zinc naphthenate, lead naphthenate, lithium naphthenate, cobalt naphthenate, nickel naphthenate, naphthenic At least one of a cadmium salt of a acid, a mercury salt of a naphthenate, an indium naphthenate, and a phosphonium naphthenate.
  • the nitrogen atom in the pyridine compound does not participate in the reaction.
  • the action of the pyridine compound here is firstly to provide a nucleophilic functional group Q to react with the isocyanate group-containing reactant B.
  • the pyridine nitrogen atom of the pyridine compound itself is the quaternary ammonium salt of the final antibacterial compound.
  • the number of carbon atoms of the pyridine compound itself does not affect the progress of the reaction, and the first step reaction can be carried out as long as the pyridine compound has a group reactive with an isocyanate group such as a hydroxyl group, a mercapto group or an amino group.
  • the pyridine used in the preparation of the antibacterial compound has a common property in that it has one or more groups containing an active hydrogen atom such as a hydroxyl group, an amino group, a thiol group or the like, and the pyridine compound is reacted with the isocyanate group to be coupled together.
  • Exemplary pyridines can include, but are not limited to, 4-hydroxymethylpyridine, 4-aminopyridine, 4-mercaptopyridine, 2,6-dimethyl-4-aminopyridine, and the like.
  • a hydrogen atom on the pyridine ring which may be halogen (-F, -Cl, -Br, -I) or pseudohalogen (-CN, -SCN, -OCN, etc.), alkoxy (-OCH 3 , -OCH 2 CH Substituents such as 3 , -OPr, etc., -NO and -NO 2 or a C 1-7 alkyl group or an aryl group are substituted, and the number of substituents is at most 7.
  • the reactant A is selected from the group consisting of propane sultone, butane sultone, ⁇ -propionolactone, X(CH 2 ) v CO 2 - Mt + , X(CH 2 ) v SO 3 - Mt + and a cyclic phosphate wherein X is selected from the group consisting of Br, Cl and I, and v is an integer of not less than 1, and Mt + is selected from the group consisting of Li + , Na + , K + , NH 4 + , Ag + , 1/2 Mg 2+ and /2Ca 2+ , wherein the cyclic phosphate has a structure represented by the following formula:
  • R 5 is selected from a monovalent unsubstituted or substituted C 1-6 alkyl group, a cycloalkyl group and an aryl group; and R 6 is selected from a divalent unsubstituted or substituted C 1-6 alkyl group.
  • the mixture obtained in the first step has a relatively nucleophilic tertiary nitrogen atom, and thus the reactant A ring-opening reaction can occur between the mixture of A and the first step to form a CN bond.
  • the tertiary nitrogen atom on the tertiary amine thus adds a linking group to form a quaternary ammonium group, which together with the sulfonic acid group constitutes amphoteric Ionic compound.
  • a carbon atom attached to an oxygen atom in a cyclic phosphate can be attacked by a tertiary nitrogen atom, and a ring opening reaction occurs, thereby changing the tertiary nitrogen atom into a quaternary ammonium group, and together with the phosphate group.
  • a zwitterionic compound is formed.
  • the ring of a compound such as propionate or butyrolactone has a small number of atoms and a large ring tension, it is also easy to open the ring, so that it can also be opened in the presence of a nucleophilic tertiary nitrogen atom.
  • the ring reacts to form a quaternary ammonium group and simultaneously forms a carboxyl group to form a zwitterionic compound.
  • halogen atoms such as Cl, Br, and I have a large electronegativity and weak bonds with carbon atoms.
  • a CN bond can be formed under the attack of a tertiary nitrogen atom to form a quaternary ammonium group, and a zwitterionic compound can be formed with a carboxyl group or a sulfonic acid group.
  • similar nucleophilic substitution reactions can occur with other metal carboxylates substituted by leaving groups.
  • Other leaving groups include, but are not limited to, p-toluenesulfonyl (-OTs), methylsulfonyl (- OMs) and trifluoromethanesulfonyl (-OTf) and the like.
  • Solvents for preparing antibacterial compounds including but not limited to organic solvents such as ethers, ketones, aromatic compounds, nitriles, esters and amides.
  • the solvent itself may also be a mixture of several solvent components, such as a mixture of two or more of the above solvents, and the like. Solvent selection is affected by the solubility of the reactants, the reaction temperature, and the chemical reactivity of the solvent itself.
  • the ether solvent may be THF, 1,4-epoxycyclohexane, ethylene glycol dimethyl ether, tetrahydropyran or the like;
  • the ketone solvent may be acetone, methyl ethyl ketone, cyclohexanone, acetophenone And the ketone, etc.;
  • the aromatic compound may be toluene, pyridine and imidazole;
  • the ester may be ethyl acetate, n-propyl acetate, n-butyl acetate, methyl formate and ethyl formate;
  • the nitrile may be acetonitrile, Propionitrile and benzonitrile, etc.;
  • the amides may be N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.
  • reaction solvent any aprotic solvent which can dissolve the reaction raw material may be used as a reaction solvent, for example, ethylene carbonate, trimethylene carbonate, or the like.
  • the stirring method used in the process for preparing the antibacterial compound may be mechanical stirring. It may also be a stirring method such as magnetic stirring which can achieve sufficient contact of the reactants.
  • the addition of the reactant solution may be manual dropping or dropping by a mechanical drip machine, and the dropping rate may be constant or may be continuously changed as the reaction progresses.
  • the starting materials and other chemical reagents used in the following examples are commercially available.
  • purification is carried out by means known in the art, such as removal of water from a tertiary amine, removal of an oxidizing component in a tertiary amine, removal of a primary amine and a secondary amine in a tertiary amine, etc., which can usually be purified by distillation or splitting. It is realized by means of extraction or addition of a reagent.
  • IPDI isophorone diisocyanate
  • isophorone diisocyanate is used as a reactant containing an isocyanate group. It is understood that any compound containing at least two isocyanate groups can be similarly reacted with an isocyanate group-containing antibacterial compound by the above reaction. Compound. In the polyisocyanate compound, since a plurality of isocyanate groups are present, in the case where the nucleophilic reagent is not excessive, only one of the plurality of isocyanate groups in one molecule reacts, and the other isocyanate groups are retained in the final antibacterial compound.
  • the number of carbon atoms or the molecular weight of the polyisocyanate compound itself does not affect the progress of the reaction as long as it can undergo a nucleophilic addition reaction with the nucleophile.
  • the isocyanate structure used in the preparation of the present embodiment may also be a terminal isocyanate organic compound containing at least one carboxyl group, and the organic compound main chain structure may be a substituted or unsubstituted aliphatic, aliphatic ring, heterocyclic, heterocyclic, aromatic structure.
  • substituent may include, but is not limited to, an atom or a group such as Cl, Br, I, -OCH 3 , -OCH 2 CH 3 , -OPr, -CN, -SCN, -NO and -NO 2 .
  • the propane sultone serves to form a sulfonic acid group by forming a quaternary ammonium group by receiving a nucleophilic attack of the tertiary amine N atom. Since the carbon atom attached to the oxygen atom in the sultone is easily subjected to attack by the nucleophilic reagent, and the mixture obtained in the first step has a relatively nucleophilic tertiary nitrogen atom, the reactant A and the first step A ring-opening reaction can occur between the mixtures obtained by the reaction to form a CN bond, and the tertiary nitrogen atom on the tertiary amine is thus increased.
  • a linking group is added to form a quaternary ammonium group, which together with the sulfonic acid group forms a zwitterionic compound.
  • other sultone lactones such as butane sultone and ethane sultone, can also be used in the second step reaction since similar reactions can occur.
  • the catalyst is not always necessary, and the more active organic amine compound can be directly reacted with a compound containing a plurality of isocyanate groups without a catalyst. Participation.
  • the catalyst is one or more of an organic amine compound, a phosphine compound, and a metal-containing catalyst.
  • an organic amine compound e.g., triethylamine, triphenylphosphine, dibutyltin dioctoate, and the like.
  • the amines used in the preparation of the present examples may be, in addition to N,N-dimethylethanolamine, N,N-diethylethanolamine, N,N-dimethylethylenediamine, N,N-di N-propylethanolamine, N,N-diisopropylethanolamine, N,N-di-n-butylethanolamine, N,N-di-n-pentylethanolamine, N,N-dicyclohexylethanolamine or 3,3'-Asia Amino bis(N,N-dimethylpropylamine) and the like.
  • the present embodiment employs an amine
  • a tertiary amine or a pyridine organic substance having a terminal alcohol group or a terminal sulfhydryl group such as 4-hydroxymethylpyridine or 2,6-dimethyl-4-aminopyridine.
  • sodium chloroacetate functions to form a quaternary ammonium group by nucleophilic attack by receiving a tertiary amine N atom, leaving the chlorine atom.
  • other halogens Br, I, etc.
  • other sodium carboxylates that are easily substituted by leaving groups (OTs, OMs, OTf, etc.)
  • OTs, OMs, OTf, etc. such as sodium bromoacetate, sodium iodoacetate, sodium 2-chloropropionate, Sodium 3-chloropropionate, sodium 2-bromopropionate, sodium 3-bromopropionate, sodium 2-iodopropionate, sodium 3-iodopropionate, or a halogenated carboxylic acid of longer carbon chain, etc.
  • a N-atomic attack occurs under nucleophilic attack, a similar reaction can occur, or it can be used in the second step reaction.
  • the dropwise addition of the sodium chloroacetate solution may be a manual dropping or a mechanical drip machine.
  • the dropping rate may be constant or may be continuously changed as the reaction progresses.
  • reaction was continued for 6 h at a temperature of 40 ° C to obtain a product, which was filtered under normal pressure and purified to obtain an antibacterial compound containing a terminal isocyanate group as described in this example.
  • ⁇ -propiolactone functions to open the ring and form a carboxyl group by forming a quaternary ammonium group by receiving a nucleophilic attack of the tertiary amine N atom.
  • other lactones such as ⁇ -butyrolactone, ⁇ -butyrolactone, ⁇ -valerolactone and ⁇ -valerolactone, can also be reacted in the second step because a similar reaction can occur. Use to generate the corresponding zwitterionic compound.
  • the dropwise addition of the ⁇ -propiolactone solution may be manual dropping or dropping by a mechanical dripper, and the dropping rate may be constant or may be continuously changed as the reaction progresses.
  • HMDI dicyclohexylmethane diisocyanate
  • IPDI isophorone diisocyanate
  • IPDI isophorone diisocyanate
  • the amines used in the preparation of the present examples may be other than a 3,3'-iminobis(N,N-dimethylpropylamine), or other tertiary amine or pyridine having an active hydrogen atom, for example, but not Limited to, N,N-dimethylethanolamine, N,N-dimethylethylenediamine, N,N-diethylethanolamine, N,N-diisopropylethanolamine, N,N-di-n-butylethanolamine , N,N-di-n-pentylethanolamine, N,N-dicyclohexylethanolamine, 4-hydroxymethylpyridine and 2,6-dimethyl-4-aminopyridine.
  • IPDI isophorone diisocyanate
  • the nitrogen-containing compound used in the preparation of the present embodiment has a functional group containing an active hydrogen atom, such as a hydroxyl group, an amino group and a mercapto group, and may be a pyridine compound or a tertiary amine, and the organic substance may be substituted or unsubstituted.
  • an active hydrogen atom such as a hydroxyl group, an amino group and a mercapto group
  • the organic substance may be substituted or unsubstituted.
  • 4-hydroxymethylpyridine it may be 2,6-dimethyl-4-aminopyridine, N,N-dimethylethanolamine, N,N-dimethylethylenediamine, N,N- Diethylethanolamine, N,N-diisopropylethanolamine, N,N-di-n-butylethanolamine, N,N-di-n-pentylethanolamine, N,N-dicyclohexylethanolamine, 3,3'-Asia Amino bis(N,N-dimethylpropylamine), 4-indolylmethylpyridine or 2,6-dimethyl-4-aminopyridine or the like.
  • IPDI isophorone diisocyanate
  • stannous octoate is used as the catalyst in the present embodiment, the catalyst is not always necessary, and the more active organic amine compound can be directly reacted with the compound containing a plurality of isocyanate groups without the participation of a catalyst.
  • the substance used as a catalyst can be referred to the description in Example 1.
  • a group having an active hydrogen atom such as an amino group, a hydroxyl group and a thiol group may be present.
  • the nitrogen-containing compound may be, in addition to 2,6-dimethyl-4-aminopyridine, N,N-dimethylethanolamine, N,N-dimethylethylenediamine, N,N- Diethylethanolamine, N,N-diisopropylethanolamine, N,N-di-n-butylethanolamine, N,N-di-n-pentylethanolamine, N,N-dicyclohexylethanolamine, 3,3'-Asia Amino bis(N,N-dimethylpropylamine), 4-hydroxymethylpyridine, 4-indolylmethylpyridine, 2-dimethylaminoethanethiol, 2-diethylaminoethanethiol, 2-dimethyl Aminopropyl mercaptan, 2-diethylaminopropyl mercaptan, 2,6-diethyl-4-aminopyridine or other alkyl, halogen (-F, -Cl,
  • IPDI isophorone diisocyanate
  • sodium 2-bromoethanesulfonate serves to remove the bromine atom by nucleophilic attack of the N atom to form a quaternary ammonium group to form the final zwitterionic compound.
  • other halogen or other sodium sulfonate that is readily substituted by a leaving group such as sodium 2-chloroethanesulfonate, sodium 2-iodoethanesulfonate, sodium 2-chloropropanesulfonate, 2-bromopropanesulfonate
  • sodium, sodium 2-iodopropane sulfonate or sodium 2-p-phenylsulfonylpropane sulfonate can also be used in the second step reaction since a similar reaction can occur.
  • the dropwise addition of the sodium 2-bromoethanesulfonate solution may be manual dropping or dropping by a mechanical drip machine, and the dropping acceleration may be a constant constant dropping or a continuous reaction. Change the drop acceleration.
  • IPDI isophorone diisocyanate
  • sodium 4-bromobutyrate serves to form a quaternary ammonium group by receiving a nucleophilic attack of the N atom and leaving the bromine atom.
  • carboxylic acid metal salts substituted with halogen or other leaving groups.
  • halogen includes, but is not limited to, chlorine, bromine, and iodine; and other leaving groups include, but are not limited to, p-toluenesulfonyl (-OTs), methylsulfonyl (-OMs), and trifluoromethanesulfonyl (-OTf).
  • metals in the metal carboxylate including but not limited to, lithium, sodium, potassium, ammonium, silver, magnesium and calcium
  • carboxylic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, valeric acid and more.
  • the carboxylic acid of a carbon atom; the position at which a halogen or other substituent is located may be an ⁇ , ⁇ , ⁇ or the like adjacent to a carbon atom of a carboxylic acid.
  • Typical halogen-substituted metal carboxylates include, but are not limited to, sodium chloroacetate, sodium bromoacetate, sodium iodoacetate, sodium 2-chloropropionate, sodium 3-chloropropionate, sodium 2-bromopropionate, 3- Sodium bromopropionate, sodium 2-iodopropionate, sodium 3-iodopropionate, sodium 4-chlorobutyrate and sodium 4-iodobutyrate. Since the above substances can react similarly to the tertiary amine, they can also be used in the second step reaction.
  • the dropwise addition of the sodium 4-bromobutyrate solution may be manual addition or a drip with a mechanical drip, and the dropping rate may be constant or may be continuously changed as the reaction progresses.
  • the separation of the final product may also be carried out by different separation methods for different product forms. If it is an oil or a viscous solid, it may be purified by extraction or distillation; if it is precipitated, it may be centrifuged or filtered.
  • ethanol attacks the P atom of COP, and further loses HCl between them, and a substitution reaction occurs to obtain a product EOP.
  • ethanol which may be substituted with COP, it may be other aliphatic alcohols, alicyclic alcohols or aromatic alcohols, such as methanol, n-propanol, isopropanol, n-butanol, isobutanol, and Pentanol, n-hexanol, n-heptanol, vinyl alcohol, propylene alcohol, cyclopropanol, cyclopentanol, cyclohexanol or benzyl alcohol.
  • the phosphorus-containing reagent may be other 2-halo-1,3,2-dioxaphosphine heterocyclic compounds, wherein the number of atoms on the ring may be 4. 5, 6, 7, 8 or 9, preferably 5, 6 and 7, ie 2-halo-1,3,2-dioxaphospholane, 2-halo-1,3,2-di Oxafluorocyclohexane and 2-halo-1,3,2-dioxaphosphane.
  • the phosphorus atom on the 2-halo-1,3,2-dioxaphosphine heterocyclic compound is in addition to the oxygen atom A halogen atom is attached.
  • Halogen atoms in such compounds are readily substituted by alkoxy groups on the alcohol due to their better liberation as disclosed in U.S. Patent No. 2,982,862.
  • a hydrogen atom attached to a carbon atom of the ring may be one or more alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl groups. Replaced.
  • such compounds include, but are not limited to, 2-chloro-4,5-dimethyl-1,3,2-dioxaphospholane-2-oxide, 2-chloro-1 , 3,2-dioxaphosphol-2-oxide, 2-chloro-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphane-2 -oxide, 2-chloro-4,6-dimethyl-1,3,2-dioxaphosphane-2-oxide, 2-chloro-5,5-dimethyl-1,3 ,2-dioxaphosphol-2-oxide, 2-chloro-1,3,2-dioxaphosphan-2-oxide, 2-chloro-1,3,2-di Oxacyclooctane-2-oxide, 2-bromo-1,3,2-dioxaphospholane-2-oxide, 2-bromo-1,3,2-dioxaphosphane Hexane-2-oxide and 2-bromo-5,5-
  • triethylamine is used as a reaction aid in this embodiment
  • other tertiary amines containing no active hydrogen may be used, for example, trimethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, N-methyldioctine.
  • the tertiary amine acts as a base to aid in the removal of HCl.
  • THF is used as the organic solvent in this embodiment, acetonitrile, DMF, DMSO, anhydrous butanone, anhydrous acetone, cyclohexanone, toluene, ethyl acetate, n-propyl acetate, n-butyl acetate, acetonitrile, 1,4-epoxycyclohexane, N-methylpyrrolidone, pyridine, N,N-dimethylformamide or a mixture of two or more of the above solvents.
  • the EOP functions to receive a nucleophilic attack of the N atom through a C atom attached to the O atom on the ring, and a ring opening reaction occurs to form a quaternary ammonium group.
  • the drop of the EOP solution can be a manual drop or a mechanical drip drop Plus, the drop acceleration can be constant or it can be constantly changed as the reaction progresses.
  • the separation of the final product may also be carried out in different separations for different product forms. If it is an oil, it may be purified by extraction with an organic solvent or by distillation of a solution of the product in an organic solvent; It can be centrifuged or filtered.
  • the antibacterial compound provided by the examples of the present invention is a zwitterionic compound having a terminal isocyanate group.
  • the positive charge of the quaternary nitrogen atom can destroy the microbial cell membrane, denature the protein and destroy the cell structure.
  • the above microorganisms include, but are not limited to, Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, sulfate-reducing bacteria, Gram-positive bacteria, Gram-negative bacteria, Staphylococcus epidermidis, Bacillus subtilis , Enterococcus faecalis, Dry Corynebacterium and Bacillus anthracis. It can be used as a bactericidal or bacteriostatic agent to prevent infection, kill microorganisms, or inhibit the physiological functions of microorganisms, and thus can effectively treat infections caused by these microorganisms or control the pollution caused by
  • the antibacterial compound provided by the embodiment of the present invention can achieve a chemical bond bond with the surface of the material through the terminal isocyanate group.
  • the antibacterial compound can be applied to various fields such as textiles, medicine, food, agriculture, and the like, but is not limited to the above fields.
  • an isocyanate group can be combined with a fiber, a cotton textile, a hydroxyl group or an amino group of a nylon surface to prepare a washing resistant antibacterial textile; it can be combined with a hydroxyl or amino group on the surface of a medical infusion tube or a medical packaging material to prepare an antibacterial medical product, or with a food.
  • Preparation of antibacterial packaging materials by combining hydroxyl or amino groups on the surface of packaging or food preservation materials.
  • Examples 1-13 of the present invention were tested for minimum inhibitory concentration of E. coli (American model strain collection center ATCC 25922) and Staphylococcus aureus (S. aureas, ATCC 6538).
  • the minimum inhibitory concentration (MIC) refers to the minimum concentration of antibacterial agents that can block the development of bacteria after 24 hours of culture in a specific environment. Determination of minimum inhibitory concentration The method may be a constant broth dilution method, a micro broth dilution method, an agar dilution method and an E experiment.
  • the test results of the minimum inhibitory concentration of the antibacterial agent of Examples 1-13 of the present invention are shown in Table 1.
  • the compound obtained in the examples of the present invention has a very low inhibitory concentration against bacteria, which is sufficient to ensure that the bacterial population is extremely low in the case of using the compound, and the human health is little harmful.
  • the clean glass surface was treated with the products obtained in Examples 1-13, and its antibacterial activity and long-lasting antibacterial activity were tested by colony counting method.
  • bacteria were used for Escherichia coli and Staphylococcus aureus, and the results are shown in Table 2.
  • the antibacterial compound provided by the embodiment of the present invention has excellent antibacterial properties and durability for common bacteria such as Escherichia coli and Staphylococcus aureus. Even after repeated washings, the antibacterial properties only showed a slight decrease, but remained above 94%.
  • the antibacterial compound provided by the embodiment of the present invention has a reactive functional group, isocyanate, and the reactive group can be functional groups existing at the interface with various materials, such as cotton fiber, hemp fiber, polyester fiber (such as polyester PET). , the hydroxyl group in polylactic acid (PLA), the amino group in nylon, and the amide group in wool, cashmere, silk, nylon and aramid, etc., chemical bonding, anchoring the antibacterial component at the material interface, Thereby, the surface of the material or article treated by the reactive antibacterial compound is imparted with long-lasting antibacterial and antifouling properties.
  • the preparation method of the compound is simple in process, easy to control, easy to industrialize, and convenient for its use in a wide range.
  • the antibacterial compound provided by the embodiments of the present invention has broad industrial application prospects.

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Abstract

在此提供了一种反应性抗菌化合物及其制备方法，该反应性抗菌化合物具有通式(I)或(II)的结构其中，R1选自OCN-L-NHCOOR'、OCN-L-NHCONHR'、OCN-L-NHCOSR'、OCN-L-COOR'与OCN-L-COONHR'；G1选自OCN-M-NHCOOG'、OCN-M-NHCONHG'、OCN-M-NHCOSG'、OCN-M-COOG'与OCN-M-COONHG'；其中，L、M、R'与G'各自独立地选自二价的C1-18的烷基与芳基，其任选被至多18个杂原子取代；R2与R3各自独立地选自一价的C1-18的烷基与芳基，其任选被至多18个杂原子取代；R4与G4各自独立地选自二价的C1-18的烷基与芳基，其任选被至多18个杂原子取代；G2与G3各自独立地选自-H、-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO、-NO2与一价未取代或取代的C1-7烷基、环烷基、芳基；Z与X各自独立地选自-COO、-SO3与-OPO2OR5；R5选自一价未取代或取代的C1-6烷基、环烷基与芳基。

Description

反应性抗菌化合物及其制备方法
交叉引用
本申请要求于2015年2月6日在中国国家知识产权局提交的申请号为PCT/CN2015/072439的国际申请的优先权，其内容通过引用的方式被包含于此。
技术领域
本申请属于抗菌技术领域，特别地，涉及一种反应性抗菌化合物及其制备方法，更特别地，涉及一种含有带正电荷氮原子的反应性抗菌化合物及其制备方法。
背景技术
细菌与真菌感染已成为威胁人类健康并备受全球医疗卫生事业关注的世界性重要问题。赋予材料或制品表面抗菌性能，以阻止细菌或真菌在其表面生长或繁殖，甚至杀死已存在于表面的细菌或真菌，是解决细菌或真菌感染的重要手段之一。通常的解决方法是通过喷涂、化学键合的方式，将具有抗菌性的组分或材料附着或锚定在制品表面，从而实现抗菌的性能。已知的抗菌材料被广泛地应用于陶瓷、玻璃制品、塑料、橡胶、纤维、纸张与涂料等方面，如家用电器、家具用品、清洁卫生用品、食品包装袋与衣物等。目前，国际上的抗菌材料可以分为四大类：(1)无机抗菌剂，比如纳米二氧化钛，纳米银，纳米铜，以及它们的离子等；(2)有机抗菌剂， 例如季铵盐、醇类、卤胺、双胍类与噻唑类等；(3)高分子抗菌剂，例如高分子季铵盐；(4)天然及其改性抗菌剂：如壳聚糖与山梨酸等。
为了赋予材料或制品表面抗菌性能，最常用的方法是在其表面覆盖一层含抗菌剂(如纳米银、纳米铜及它们的离子或者其他抗菌剂)的涂层，纳米银、纳米铜、银离子、铜离子、其他重金属以及重金属离子，依靠其金属离子向周围环境的缓慢释放，而达到抑菌或杀菌的目的。然而随着使用时间的延长，其抗菌活性逐渐降低，直至最终完全丧失其抗菌活性，同时还可能诱导微生物变异，增加微生物产生耐药性的概率。另外，纳米材料的危害性也逐渐被人类所认识和关注。
有机抗菌类如季铵盐、醇类、卤胺、双胍类与噻唑类等化合物，具有见效快，杀菌能力强的特点，这一类抗菌剂，又以季铵盐与季鏻盐(四级鏻盐)为主。通常，细菌的细胞壁带负电荷，而季铵盐与季鏻盐等离子是正电性的，正电性的季铵盐容易被细菌吸附，并在接近细菌后，穿透细胞壁，与细胞膜结合，扰乱细胞膜组成，导致胞内物质泄漏，最终导致细菌死亡。但季铵盐化学活性较低，应用时基本以游离态存在，毒性较大，刺激性较强，将其作为抗菌剂耐热性差、易迁移，易洗脱，而且容易在人体表面逐渐富集，长期使用易产生病变，使微生物产生耐药性。同时，有机抗菌剂耐热性较差，从而限制了其使用范围。
高分子季铵盐抗菌剂可克服小分子抗菌剂的易挥发、难加工与化学稳定性差等缺点，而且抗菌活性优良，不易渗透，因而受到人们的关注。但是，目前，未固定化的高分子抗菌剂也存在高流失性、缺乏持久性等问题，同样也给周围的环境造成了一定的压力。
天然抗菌剂来自于天然植物、动物或矿物的提取物，主要抗菌机理与有机季铵盐类似，但是效果不如有机抗菌剂，且产品尚不成熟。天然抗菌剂的另一个缺点是其不适合大规模生产，因此目前应用也不广泛。
因此，开发和制备绿色的、可固定化、具有长效性的抗菌剂是大势所趋。
发明内容
根据本发明的实施例，提供一种反应性抗菌化合物，其不仅具有优异的抗菌性能和亲水性，而且可以通过端异氰酸酯基与天然纤维、人造纤维及高分子材料表面的官能团发生反应而结合，从而实现长效抗菌。所述端异氰酸酯基是指处于分子链一个末端的异氰酸酯基。
本发明实施例所提供的抗菌化合物是带有端异氰酸酯基，同时含有季铵基团结构的两性离子化合物。季氮原子所带的正电荷可破坏微生物细胞膜，使蛋白质变性以及破坏细胞结构。上述微生物包括但不限于，大肠杆菌、鼠伤寒沙门氏菌、绿脓杆菌、金黄色葡萄球菌、白色念珠菌、硫酸盐还原菌、革兰氏阳性菌、革兰氏阴性菌、表皮葡萄球菌、枯草杆菌、粪肠球菌、干燥棒状杆菌和炭疽杆菌等。可以作为杀菌试剂或者抑菌试剂用来阻止传染、杀死微生物，或者抑制微生物生理功能，并因此可以有效治疗由这些微生物引起的感染，或者控制其造成的污染。
本发明实施例提供的抗菌化合物，可以通过端异氰酸酯基，与材料表面实现化学键的结合。所述抗菌化合物可以应用在纺织品、医药、食品与农业等多个领域，但不限于上述领域。例如，异氰酸酯基可以与纤维、 棉纺织品、尼龙表面的羟基或氨基结合制备较耐洗涤的抗菌纺织品；可以与医用输液管、医用包装材料表面的羟基或者氨基结合，制备抗菌医药产品，或者与食品包装或食品保鲜材料表面的羟基或氨基结合，制备抗菌包装材料。
根据本发明实施例的一个方面，该反应性抗菌化合物的结构通式为(I)：
Figure PCTCN2015090059-appb-000001
其中，R1选自OCN-L-NHCOOR’、OCN-L-NHCONHR’、OCN-L-NHCOSR’、OCN-L-COOR’与OCN-L-COONHR’；
L选自二价的C1-18的烷基、环烷基与芳基，其任选被至多18个杂原子取代；
R’选自二价的C1-18的烷基、环烷基与芳基，其任选被至多18个杂原子取代；
R2与R3各自独立地选自一价的C1-18的烷基、环烷基与芳基，其任选被至多18个杂原子取代；
R4独立地选自二价的C1-18的烷基、环烷基与芳基，其任选被至多18个杂原子取代；
Z选自-COO、-SO3与-OPO2OR5；
其中，R5选自一价未取代或取代的C1-6烷基、环烷基与芳基。
根据本发明的实施例，反应性抗菌化合物中，R2与R3是相同的基团或不相同的基团。
根据本发明的实施例，其中，R2与R3各自独立地选自-(CH2)uCH3，其中u为不小于0且不大于17的整数，其中优选地，u为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16或17；进一步优选地，u为0、1、2、3或4；更进一步优选地，u为0、1或2。
根据本发明的实施例，反应性抗菌化合物中，Z为-SO3。
根据本发明的实施例，反应性抗菌化合物中，Z为-CO2。
根据本发明的实施例，反应性抗菌化合物中，Z为-OPO2OR5。
根据本发明的实施例，反应性抗菌化合物中R5为-(CH2)wCH3，其中w为不小于0且不大于5的整数。
根据本发明的实施例，反应性抗菌化合物中，R4与R’各自独立地选自-(CH2)n-，n为不小于1且不大于18的整数，其中优选地，n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18；进一步优选地，n为1、2、3、4、5、6、7、8、9或10；更进一步优选地，n为0、1、2、3、4、5、6或7。
根据本发明的实施例，反应性抗菌化合物中，R1选自OCN-L-NHCOOR’与OCN-L-NHCONHR’。
根据本发明的实施例，反应性抗菌化合物中，L具有如下式所示的结构：
Figure PCTCN2015090059-appb-000002
根据本发明的实施例的另一个方面，反应性抗菌化合物的结构通式 为(II)：
Figure PCTCN2015090059-appb-000003
其中，G1选自OCN-M-NHCOOG’、OCN-M-NHCONHG’、OCN-M-NHCOSG’、OCN-M-COOG’与OCN-M-COONHG’；
M选自二价未取代或取代的C1-18烷基、环烷基与芳基；
G’选自二价未取代或取代的C1-18烷基、环烷基与芳基；
G2与G3各自独立地选自-H、-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr(Pr为正丙基或异丙基)、-CN、-SCN、-NO、-NO2与一价未取代或取代的C1-7烷基、环烷基、芳基；
G4选自二价未取代或取代的C1-18烷基、环烷基与芳基；
X选自-COO、-SO3与-OPO2OR5；
R5选自一价未取代或取代的C1-6烷基、环烷基与芳基。
根据本发明的实施例，抗菌化合物中，G1选自OCN-M-NHCOOG’与OCN-M-NHCONHG’。
根据本发明的实施例，抗菌化合物中，G2与G3是相同的基团或不相同的基团。
根据本发明的实施例，抗菌化合物中，G2与G3各自独立地选自-H、-CH3、-CH2CH3、-NO2、-F、-Cl、-Br与-I。
根据本发明的实施例，抗菌化合物中，X为-SO3。
根据本发明的实施例，抗菌化合物中，X为-CO2。
根据本发明的实施例，抗菌化合物中，X为-OPO2OR5。
根据本发明的实施例，抗菌化合物中，R5选自-(CH2)wCH3，其中w为不小于0且不大于5的整数，其中优选地，w为0、1、2、3或4，进一步优选地，w为0、1或2。
根据本发明的实施例，抗菌化合物中，G4与G’各自独立地选自-(CH2)n-，n为不小于1且不大于18的整数，其中优选地，n为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18；进一步优选地，n为1、2、3、4、5、6、7、8、9或10；更进一步优选地，n为0、1、2、3、4、5、6或7。
根据本发明的实施例，抗菌化合物中，M具有如下式所示的结构：
Figure PCTCN2015090059-appb-000004
根据本发明的实施例的一个方面，抗菌化合物的一种制备方法包括以下步骤：
将一种具有通式(III)结构的叔胺，与具有通式(IV)结构的反应物B反应，得到一种混合物；
Figure PCTCN2015090059-appb-000005
OCN-L-D   (IV)
其中，Y选自-OH、-NH2与-SH；R’选自二价的C1-18的烷基、环烷基与芳基，其任选被至多18个杂原子取代；R2与R3各自独立地选自一价未取代或取代的C1-18烷基、环烷基与芳基；L选自二价未取代或取代的C1-18烷基、环烷基与芳基；D选自-COOH与-NCO。
将所述混合物与反应物A反应，得到所述抗菌化合物；
其中，所述反应物A选自丙磺酸内酯、丁磺酸内酯、β-丙酸内酯、X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+与环状磷酸酯，其中X选自Br、Cl与I，v为不小于1的整数，Mt+选自Li+、Na+、K+、NH4 +、Ag+、1/2Mg2+与1/2Ca2+，其中所述环状磷酸酯具有如下式所示的结构：
Figure PCTCN2015090059-appb-000006
其中，R5选自一价未取代或取代的C1-6烷基、环烷基与芳基；R6选自二价未取代或取代的C1-6烷基。
根据本发明的实施例，抗菌化合物的制备方法中，所述叔胺与所述反应物B反应是在催化剂C的存在下进行，所述催化剂C选自有机胺类化合物、膦类化合物以及含金属的催化剂中的至少一种。
根据本发明的实施例，抗菌化合物的制备方法中，所述催化剂C为所述含金属的催化剂。
根据本发明的实施例，抗菌化合物的制备方法中，所述含金属的催化剂选自四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛 基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、油酸亚锡、酒石酸亚锡、二月桂酸二丁基锡、辛酸亚锡、环烷酸金属盐中的至少一种。
根据本发明的实施例，抗菌化合物的制备方法中，所述含金属的催化剂是环烷酸金属盐。
根据本发明的实施例，抗菌化合物的制备方法中，所述环烷酸金属盐选自环烷酸铜盐、环烷酸锌盐、环烷酸铅盐、环烷酸锂盐、环烷酸钴盐、环烷酸镍盐、环烷酸镉盐、环烷酸汞盐、环烷酸铟盐、环烷酸铋盐中的至少一种。
根据本发明的实施例的另一方面，抗菌化合物的制备方法，包括以下步骤：
1)将一种具有通式(V)结构的吡啶，与具有通式(IV)结构的反应物B反应，得到一种混合物；
Figure PCTCN2015090059-appb-000007
OCN-L-D   (IV)
其中，Q选自-OH、-NH2、-SH；G’选自二价未取代或取代C1-18烷基、环烷基与芳基；G2与G3各自独立地选自-H、-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO、-NO2与一价未取代或取代的C1-7烷基、环烷基、芳基；D选自-COOH与-NCO；L选自二价未取代或取代的C1-18烷基、环烷基与芳基。
2)将所述混合物与反应物A反应，得到所述抗菌化合物；
其中，所述反应物A选自丙磺酸内酯、丁磺酸内酯、β-丙酸内酯、X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+与环状磷酸酯，其中X选自Br、Cl与I，v为不小于1的整数，Mt+选自Li+、Na+、K+、NH4 +、Ag+、1/2Mg2+与1/2Ca2+，其中所述环状磷酸酯具有如下式所示的结构：
Figure PCTCN2015090059-appb-000008
其中，R5选自一价未取代或取代的C1-6烷基、环烷基与芳基；R6选自二价未取代或取代的C1-6烷基。
根据本发明的实施例，抗菌化合物的制备方法中，所述叔胺与所述反应物B反应是在催化剂C的存在下进行，所述催化剂C选自有机胺类化合物、膦类化合物以及含金属的催化剂中的至少一种。
根据本发明的实施例，抗菌化合物的制备方法中，所述催化剂C为所述含金属的催化剂。
根据本发明的实施例，抗菌化合物的制备方法中，所述含金属的催化剂选自四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、油酸亚锡、酒石酸亚锡、二月桂酸二丁基锡、辛酸亚锡与环烷酸金属盐中的至少一种。
根据本发明的实施例，抗菌化合物的制备方法中，所述含金属的催化剂是环烷酸金属盐。
根据本发明的实施例，抗菌化合物的制备方法中，其中，所述环烷 酸金属盐选自环烷酸铜盐、环烷酸锌盐、环烷酸铅盐、环烷酸锂盐、环烷酸钴盐、环烷酸镍盐、环烷酸镉盐、环烷酸汞盐、环烷酸铟盐与环烷酸铋盐中的至少一种。
具体实施方式
以下结合具体实施例进行说明，应当注意到，这里给出的描述和实施例仅仅是为了描述本发明的具体实施方式，使本发明实施例的特征更容易被理解，它们并非用于限定权利要求的范围。
除非另外指明，本文所用术语“脂肪族”、“脂肪环族”与“芳香族”包括但不限于直链、支链或环状的基团，可以是未取代的，或是被一个或多个杂原子取代，或是被一个或多个含有杂原子的基团取代的。其中，“脂肪族”与“脂肪环族”可以是饱和的，也可以是不饱和的，如烯烃、环烯烃、二烯烃、环二烯烃、炔烃、环炔烃与多环烃等。芳香族指至少含有一个芳环的体系，即不仅可以是纯芳族化合物，如苯、萘与蒽等，也可以是含有脂肪族基团的芳族化合物，如甲苯、苯乙烯与苯乙炔等。纯芳族化合物，包括单环芳香族化合物与稠环芳香族化合物，可以是芳香烃类，如苯、萘与蒽等，也可以是含有杂原子的芳香体系，如吡啶、呋喃与噻吩等。
杂原子或含有杂原子的基团包括但不限于，卤素(-F、-Cl、-Br、-I)、羟基(-OH)、羧基(-COOH)、酰基(-CO-)、酰氧基(-COO-)、氨基(-NH2)、烷基氨基(-NHR)、二烷基氨基(-NR1R2)、芳基氨基(-NHAr)、酰胺基(-CONH2)、酯(-COOR)、羧酰胺(-CONR1R2)、氨基甲酸酯(-NHCOOR)、烷氧基(-OR)、芳氧基(-OAr)、烷硫基(-SR)、芳硫基(-SAr)、烷基磺 酸酯(-OSO2R)、亚硝基(-NO)、硝基(-NO2)、氰基(-CN)、异氰基(-NC)、氧代(＝O)、偶氮基(-N＝N-)、巯基(-SH)、磺酰基(-SO2R)、膦酰基(-PO(OR1)(OR2))、氧膦基
Figure PCTCN2015090059-appb-000009
硫酯(-SCOR)、硫代烷氧基(-OCSR)、硫氰酸酯(-SCN)、异硫氰酸酯(-NCS)、磷酸酯或盐(-OP(O)(OH)2)、硫酸酯或盐(-OSO2(OH))及其组合。
在此，烷基、环烷基与芳基应当采取以下释义。如本领域技术人员所理解的，烷基，是指饱和烃基，是烷烃分子去掉氢原子而成的烃基，例如甲基、亚甲基、乙基与异丙基等；环烷基，是指含有脂环结构的饱和烃，如单环脂环烃和稠环脂环烃，去掉氢原子所形成的烃基的总称，例如环丁基与环戊基等；芳基，指任何芳烃分子的芳核碳或其他碳原子上去掉一个氢原子后所形成的基团的总称，例如：苯基、邻甲苯基、1-萘基(或α-萘基)、2-萘基(或β-萘基)、苯甲基(苄基)与苯乙基等，都属于此类。
一价烃基，是指烃类去除一个氢原子后所形成的基团，如甲基(-CH3)、乙基(-CH2CH3)、苯基(-C6H5)等；二价烃基，是指烃类去除两个氢原子后所形成的基团，如亚甲基(-CH2-)、亚乙基(-CH2CH2-)、对亚苯基(-p-C6H4-)等。类似地，其他官能团的价也采取与此一致的含义，如硝基是一价的(-NO2)，氧代是二价的(＝O)。
根据本发明实施例，抗菌化合物的结构骨架中，含有带正电荷的季铵基团，该基团具有良好的抗菌性能，为了使整个化合物呈电中性，抗菌化合物结构中同时还有一个负电荷基团与化合物的主体骨架相连接。另外，化合物中还有至少一个处于分子末端的异氰酸酯基团，通过异氰酸酯 基团与高分子纤维、天然纤维等材料中的官能团发生反应，该化合物可以与材料相结合。
根据本发明的实施例的一个方面，抗菌化合物的一种制备方法包括以下步骤：
将一种具有通式(III)结构的叔胺，与具有通式(IV)结构的反应物B反应，得到一种混合物；
Figure PCTCN2015090059-appb-000010
OCN-L-D   (IV)
其中，Y选自-OH、-NH2与-SH；R’选自二价的C1-18的烷基、环烷基与芳基，其任选被至多18个杂原子取代；R2与R3各自独立地选自一价未取代或取代的C1-18烷基、环烷基与芳基；L选自二价未取代或取代的C1-18烷基、环烷基与芳基；D选自-COOH与-NCO。
这一步反应中，具有通式(III)结构的叔胺中的官能团Y(-OH、-SH或-NH2)，与具有通式(IV)结构的反应物B中的异氰酸酯官能团(-NCO)，可以发生典型的亲核加成反应，生成氨基甲酸酯、硫代氨基甲酸酸酯或脲式结构。反应物B中具有一个异氰酸酯官能团，同时还有另外一个异氰酸酯官能团或者羧基(官能团D)。第一步反应中，具有通式(III)结构的化合物中异氰酸酯官能团可与具有通式(IV)结构的化合物中的官能团Y发生反应，同时在一个末端保留官能团D。
可以理解的是，任何含有至少两个异氰酸酯基团的化合物都可以通 过上述反应得到类似的含端异氰酸酯基的抗菌化合物。多异氰酸酯化合物中由于存在多个异氰酸酯基团，在亲核试剂不过量的情况下，一个分子中的多个异氰酸酯基团只反应一个，其他的异氰酸酯基团被保留到最后的抗菌化合物中。多异氰酸酯化合物的碳原子个数或分子量本身并不影响反应的进行，只要它可以与亲核试剂发生亲核加成反应即可。多异氰酸酯可以是脂肪族多异氰酸酯、脂肪环类多异氰酸酯、杂链的多异氰酸酯、芳香族多异氰酸酯、取代的脂肪族或脂肪环或杂环多异氰酸酯，其中取代基包括但不限于-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN，-SCN，-NO与-NO2等基团。为本领域技术人员所熟知的，多异氰酸酯化合物常常可以以二聚体、三聚体或其他聚合物的形式存在，此处的多异氰酸酯因此也包括以上物种的单体、二聚体、三聚体或其他寡聚体。
其中，脂肪族多异氰酸酯包括但不限于，六亚甲基二异氰酸酯、四亚甲基二异氰酸酯、1，8-八亚甲基二异氰酸酯、1，10-十亚甲基二异氰酸酯、1，12-十二亚甲基二异氰酸酯、1，14-十四亚甲基二异氰酸酯、赖氨酸二异氰酸酯的衍生物、三甲基己烷二异氰酸酯、四甲基己烷二异氰酸酯以及以上物种的二聚体、三聚体与其他寡聚体等。
脂肪环或杂环类多异氰酸酯包括但不限于，1，4-，1，3-或1，2-二异氰酸酯基环己烷、4，4-或2，4-二(异氰酸酯基环己基)甲烷、1-异氰酸酯基-3，3，5-三甲基-5-(异氰酸酯基甲基)环己烷(异佛尔酮二异氰酸酯)、1，3-或1，4-二(异氰酸酯基甲基)环己烷、2，4-或2，6-二异氰酸酯基-1-甲基环己烷、3(或4)，8(或9)-二(异氰酸酯基甲基)三环[5.2.1.0.2.6]癸烷异构体混合物、降冰片烯二异氰酸酯、4，5-二(异氰酸根合甲基)-1，3-二硫 戊环以及以上物种的二聚体、三聚体与其他寡聚体等。
杂链的多异氰酸酯包括但不限于，二(异氰酸根合甲硫基)甲烷、二(异氰酸根合甲硫基)甲硫基甲烷、二(2-异氰酸根合乙硫基)甲烷、二(3-异氰酸根合丙硫基)甲烷、异氰酸根合甲硫基(2-异氰酸根合乙硫基)甲烷、2-异氰酸根合乙硫基(3-异氰酸根合丙硫基)甲烷、二(异氰酸根合甲硫基)苯基甲烷、二(2-异氰酸根合乙硫基)苯基甲烷、二(3-异氰酸根合丙硫基)苯基甲烷、1，2-(二异氰酸根合乙硫基)乙烷、1-异氰酸根合甲硫基-2-(2-异氰酸根合乙硫基)乙烷、1-异氰酸根合乙硫基-2-(3-异氰酸根合丙硫基)乙烷、二(异氰酸根合甲硫基乙基)硫醚、四(异氰酸根合甲硫基)-1，4-二噻烷、2，2，5，5-四(异氰酸根合甲硫基)-1，3-二噻烷、三(异氰酸根合甲硫基)甲烷以及以上物种的二聚体、三聚体与其他寡聚体等。
芳香族多异氰酸酯包括但不限于，甲苯二异氰酸酯、二苯基甲烷二异氰酸酯、邻二甲苯二异氰酸酯、间二甲苯二异氰酸酯、对二甲苯二异氰酸酯、α，α，α’，α’-四甲基对二甲苯二异氰酸酯、1，3，5-三(异氰酸根合甲基)苯、4-甲基间二甲苯二异氰酸酯、4-乙基间二甲苯二异氰酸酯、1，5-萘二异氰酸酯以及以上物种的二聚体、三聚体与其他寡聚体、4-氯间二甲苯二异氰酸酯、4，5-二氯间二甲苯二异氰酸酯、2，3，5，6-四溴对二甲苯二异氰酸酯以及以上物种的二聚体、三聚体与其他寡聚体等。
用于制备本实施例的异氰酸酯结构还可以是包含至少一个羧基(-COOH)的端异氰酸酯有机物，该有机物主链结构可以是取代或未取代的脂肪族、脂肪环族、杂链、杂环、芳香族结构，其中取代基可以包括但 不限于-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO与-NO2等原子或基团。
以二甲基乙醇胺与四亚甲基二异氰酸酯反应为例，当两种反应物摩尔比为1∶1时，其反应式为：
Figure PCTCN2015090059-appb-000011
用于第一步反应的胺类，需要是一个含有羟基、巯基、氨基(-NH2)等高亲核性基团Y的叔胺。其中基团Y的作用在于以氧、硫、氮原子携带其上的孤对电子，进攻异氰酸酯基团的碳原子，发生偶联。由于胺类化合物也可能会以氮原子与异氰酸酯偶联，可能对基团Y与异氰酸酯的反应造成竞争，因此这里需要采用反应活性较低的叔胺。叔胺上的氮原子由于位阻较大，较难以发生偶联。
示例性的含有亲核性基团的叔胺，包括但不限于，N，N-二甲基乙醇胺、N，N-二乙基乙醇胺、N，N-二甲基乙二胺、N，N-二正丙基乙醇胺、N，N-二异丙基乙醇胺、N，N-二正丁基乙醇胺、N，N-二正戊基乙醇胺、N，N-二环己基乙醇胺、二甲氨基甲硫醇、二甲氨基乙硫醇与3，3′-亚胺基双(N，N-二甲基丙胺)等。
在有碱性试剂(如叔胺、膦类)存在下，Y官能团中的氢原子，还可能以氢离子形式脱去，会进一步增强Y官能团中的O、S、N等原子的亲核性，因此可以利用作为催化剂。而在路易斯酸，如金属离子、有机金属化合物等存在下，异氰酸酯中的氧原子会与路易斯酸形成配位键，一部分电子由氧原子转移至金属原子上，从而进一步增大了异氰酸酯碳原子的 电正性，有利于接受亲核试剂的进攻，因此这一类路易斯酸也可以作为催化剂使用。
在使用催化剂的制备中，优选地，催化剂是有机胺类化合物、膦类化合物以及含金属的催化剂中的一种或两种及两种以上的组合。
其中有机胺类可分为几类：脂肪族胺类，如，N，N-二甲基环己胺、双(2-二甲氨基乙基)醚、N，N，N’，N’-四甲基亚烷基二胺、三乙胺与N，N-二甲基苄胺等；脂环族胺类，有三亚乙基二胺(固胺，DABCO)、N-乙基吗啉、N-甲基吗啉、N，N’-二乙基哌嗪与二甲氨基环己烷；芳香族胺类，有N，N-二甲基苯胺、吡啶与4-二甲氨基吡啶(N，N-二甲基吡啶)等。这些胺类化合物的共性在于，它们都具有碱性，可以加速反应的进行。同时，它们都含有三级氮原子或者吡啶氮原子，因此不会与异氰酸酯反应。
膦类化合物，与胺类化合物相类似，也是起到碱的作用，加速反应进行。膦类化合物，可包括但不限于，各种叔膦，其中取代三个氢原子的三个有机基团可以完全相同，也可以不完全相同。被三个同样有机基团取代的叔膦，包括但不限于，三苯基膦、三甲基膦、三乙基膦、三正丙基膦、三异丙基膦、三正丁基膦与三叔丁基膦等。被不相同的有机基团取代的叔膦，包括但不限于，二甲基苯基膦、甲基二苯基膦、二乙基苯基膦与乙基二苯基膦等。
含金属的催化剂，由于金属离子通常可以与异氰酸酯基团中的氧原子结合形成配合物，导致氧原子上的电子向金属原子转移，增大了与之相连接的碳原子的电正性，使其更容易接受亲核试剂的进攻。含金属催化剂，可包括但不限于，金属的无机盐、羧酸盐、酚盐、金属烷基化合物等，其 中羧酸盐又可以分为直链或支链的烷酸盐与成环状的环烷酸盐。所含的金属元素主要有碱金属(锂、钠、钾、铷、铯等)、碱土金属(镁、钙、锶、钡)、过渡金属(铀、铈、钛、锆、钒、铬、钼、锰、铁、钴、镍、铜、锌、镉、汞等)、铝、镓、铟、铊、锡、铅、锑与铋等，但也不限于此。
常用的含金属的催化剂包括但不限于，乙酸锂、辛酸锂、环烷酸锂、三氯苯酚钠、硬脂酸钠、乙酸钾、辛酸钾、乙酸钙、辛酸钙、环烷酸锶、乙酸钡、硝酸铀酰、硝酸铈、四氯化钛、二氯化二丁基钛、四丁基钛、丁氧基三氯化钛、环烷酸锆、辛酸锆、三氯化钒、环烷酸铬、六羰基化钼、辛酸锰、三氯化铁、辛酸铁、三乙酰丙酮铁、二茂铁、辛酸钴、环烷酸钴、亚油树脂酸钴、苯甲酸钴、二茂镍、辛酸镍、环烷酸镍、乙酸铜、辛酸铜、环烷酸铜、辛酸锌、环烷酸锌、硝酸镉、环烷酸镉、二苯基汞、环烷酸汞、三苯基铝、硬脂酸铝、乙酸镓、环烷酸铟、辛酸铊、四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二月桂酸二丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、辛酸亚锡、油酸亚锡、酒石酸亚锡、苯甲酸亚铅、辛酸亚铅、油酸亚铅、环烷酸铅、三氯化锑、五氯化锑、二氯化三苯基锑、三苯基锑、环烷酸铋与乙酸二乙基铋等。
优选地，催化剂为含金属的催化剂。进一步优选地，所述含金属的催化剂选自：四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二 (异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、油酸亚锡、酒石酸亚锡、二月桂酸二丁基锡、辛酸亚锡与环烷酸金属盐中的至少一种。再进一步优选地，含金属的催化剂是环烷酸金属盐。更进一步优选地，环烷酸金属盐选自环烷酸铜盐、环烷酸锌盐、环烷酸铅盐、环烷酸锂盐、环烷酸钴盐、环烷酸镍盐、环烷酸镉盐、环烷酸汞盐、环烷酸铟盐与环烷酸铋盐中的至少一种。
在某些情况下，也可以不加入催化剂，直接由反应物B与端氨基、端羟基或端巯基取代的叔胺或吡啶反应。
将所述混合物与反应物A反应，得到所述抗菌化合物；
其中，所述反应物A选自丙磺酸内酯、丁磺酸内酯、β-丙酸内酯、X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+与环状磷酸酯，其中X选自Br、Cl与I，v为不小于1的整数，Mt+选自Li+、Na+、K+、NH4 +、Ag+、1/2Mg2+与1/2Ca2+，其中所述环状磷酸酯具有如下式所示的结构：
Figure PCTCN2015090059-appb-000012
其中，R5选自一价未取代或取代的C1-6烷基、环烷基与芳基；R6选自二价未取代或取代的C1-6烷基。
反应物A中，由于丙磺酸内酯与丁磺酸内酯中与氧原子连接的碳原子容易接受亲核试剂的进攻，而第一步反应所得到的混合物中存在亲核性较好的叔胺氮原子，因此反应物A与第一步反应得到的混合物之间可以发生开环反应，形成C-N键，叔胺上三级氮原子因此又增加了一个连接基团，形成了季铵基团，与磺酸基团一同构成两性离子化合物。
当反应物A为环状磷酸酯(例如2-乙氧基-2-氧-1，3，2-二氧磷杂环戊烷，即EOP)时，环上与氧原子连接的碳原子可以接受三级氮原子的进攻，发生开环反应，从而使三级氮原子变成季铵基团，与磷酸基团一道构成了两性离子化合物。而丙酸内酯、丁酸内酯等化合物的环，由于原子数较少，环张力较大，也较容易开环，因此在亲核性强的三级氮原子存在下，也可发生开环反应，形成季铵基团，同时生成了一个羧基，形成了两性离子化合物。
同样类似地，X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+等化合物中，由于X(Cl、Br、I等卤素)原子的电负性大，与碳原子形成的键较弱，容易离去，与之相连接的碳原子因此也容易受到亲核试剂进攻，因此可以在三级氮原子进攻下，形成C-N键，形成季铵基团，与羧基或磺酸基团构成两性离子化合物。类似的，其他的离去基团所取代的羧酸金属盐，可以发生类似的亲核取代反应，其他离去基团包括但不限于，对甲苯磺酰基(-OTs)、甲磺酰基(-OMs)与三氟甲磺酰基(-OTf)等。
用于制备抗菌化合物的溶剂，包括但不限于醚类、酮类、芳香化合物、腈类、酯类与酰胺类等有机溶剂。溶剂本身还可以是几种溶剂组分的混合物，例如以上两种或更多溶剂的混合物等。溶剂选择受到反应物溶解度、反应温度、溶剂本身化学反应性的影响。一般地，易与-N＝C＝O基团反应的溶剂，如水、醇、胺与羧酸等不适合作为本反应的溶剂。因此，在本实施例中使用的溶剂，需要进行预先的除水或除醇等操作。
进一步优选地，醚类溶剂可以是THF、1，4-环氧六环、乙二醇二甲醚与四氢吡喃等；酮类溶剂可以是丙酮、丁酮、环己酮、苯乙酮与佛尔酮 等；芳香化合物可以是甲苯、吡啶与咪唑等；酯类可以是乙酸乙酯、乙酸正丙酯、乙酸正丁酯、甲酸甲酯与甲酸乙酯等；腈类可以是乙腈、丙腈与苯甲腈等；酰胺类可以是N-甲基吡咯烷酮、N，N-二甲基甲酰胺与N，N-二甲基乙酰胺等。以上仅仅是对可用于本反应的常见溶剂的示例，并不用于局限反应溶剂的范围。
事实上，任何可以溶解反应原料的非质子溶剂，都可能作为反应溶剂而被使用，例如，碳酸亚乙酯(ethylene carbonate)、三亚甲基碳酸酯(trimethylene carbonate)等。
用于制备抗菌化合物的过程中采取的搅拌方式，可以是机械搅拌，也可以是磁力搅拌等可以实现反应物充分接触的搅拌方式。
反应物溶液的加入，可以是手动滴加，也可以是采用机械的滴液机滴加，滴加速度可以是恒定的，也可以随着反应的进行而不断的改变。
最终产物的分离，针对不同的产物形式也可以采用不同的分离方式，如果是非沉淀物，可采用萃取或蒸馏方式提纯；如果是沉淀，可采用离心或过滤等方式提纯。
根据本发明的实施例的另一方面，抗菌化合物的制备方法，包括以下步骤：
1)将一种具有通式(V)结构的吡啶，与具有通式(IV)结构的反应物B反应，得到一种混合物；
Figure PCTCN2015090059-appb-000013
OCN-L-D   (IV)
其中，Q选自-OH、-NH2、-SH；G’选自二价未取代或取代C1-18烷基、环烷基与芳基；G2与G3各自独立地选自-H、-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO、-NO2与一价未取代或取代的C1-7烷基、环烷基、芳基；D选自-COOH与-NCO；L选自二价未取代或取代的C1-18烷基、环烷基与芳基。
这一步反应中，具有通式(V)结构的吡啶中的官能团Q(-OH、-SH、-NH2)，与具有通式(IV)结构的反应物B中的异氰酸酯官能团(-NCO)，可以发生典型的亲核加成反应，生成氨基甲酸酯、硫代氨基甲酸酸酯或脲式结构。反应中，官能团Q中的电负性较高的原子(O、S、N)上具有孤对电子，而异氰酸酯官能团上的碳原子，由于高度缺电子，特别容易与亲核试剂发生加成反应，而形成氨基甲酸酯、硫脲、脲等结构。
在有碱性试剂(如叔胺、膦类)存在下，官能团Q中的氢原子，还可能以氢离子形式脱去，形成的负离子会进一步增强官能团Q中的O、S、N等原子的亲核性，因此可以利用作为催化剂。而在路易斯酸，如金属离子、有机金属化合物等存在下，异氰酸酯基团中的氧原子会与路易斯酸形成配位键，一部分电子由氧原子转移至金属原子上，从而进一步增大了异氰酸酯基团碳原子的电正性，有利于接受亲核试剂的进攻，因此这一类路易斯酸也可以作为催化剂使用。
在使用催化剂的制备中，优选地，催化剂是有机胺类化合物、膦类化合物以及含金属的催化剂中的一种或多种。
其中有机胺类可分为几类：脂肪族胺类，如，N，N-二甲基环己胺、双(2-二甲氨基乙基)醚、N，N，N’，N’-四甲基亚烷基二胺、三乙胺与N，N-二甲基苄胺等；脂环族胺类，有三亚乙基二胺(固胺，DABCO)、N-乙基吗啉、N-甲基吗啉、N，N’-二乙基哌嗪与二甲氨基环己烷；芳香族胺类，有N，N-二甲基苯胺、吡啶与4-二甲氨基吡啶(N，N-二甲基吡啶)等。这些胺类化合物的共性在于，它们都具有碱性，可以加速反应的进行。同时，它们都含有三级氮原子或者吡啶氮原子，因此不含有活泼的N-H键或O-H键，不会与异氰酸酯反应。
膦类化合物，与胺类化合物相类似，也是起到碱的作用，加速反应进行。膦类化合物，可包括但不限于，各种叔膦，其中取代三个氢原子的三个有机基团可以完全相同，也可以不完全相同。被三个同样有机基团取代的叔膦，包括但不限于，三苯基膦、三甲基膦、三乙基膦、三正丙基膦、三异丙基膦、三正丁基膦与三叔丁基膦等。被不相同的有机基团取代的叔膦，包括但不限于，二甲基苯基膦、甲基二苯基膦、二乙基苯基膦与乙基二苯基膦等。
含金属的催化剂，由于金属离子通常可以与异氰酸酯基团中的氧原子结合形成配合物，导致氧原子上的电子向金属原子转移，增大了与之相连接的碳原子的电正性，使其更容易接受亲核试剂的进攻。含金属催化剂，可包括但不限于，金属的无机盐、羧酸盐、酚盐、金属烷基化合物等，其中羧酸盐又可以分为直链或支链的烷酸盐与成环状的环烷酸盐。所含的金 属元素主要有碱金属(锂、钠、钾、铷、铯等)、碱土金属(镁、钙、锶、钡)、过渡金属(铀、铈、钛、锆、钒、铬、钼、锰、铁、钴、镍、铜、锌、镉、汞等)、铝、镓、铟、铊、锡、铅、锑与铋等，但也不限于此。
常用的含金属的催化剂包括但不限于，乙酸锂、辛酸锂、环烷酸锂、三氯苯酚钠、硬脂酸钠、乙酸钾、辛酸钾、乙酸钙、辛酸钙、环烷酸锶、乙酸钡、硝酸铀酰、硝酸铈、四氯化钛、二氯化二丁基钛、四丁基钛、丁氧基三氯化钛、环烷酸锆、辛酸锆、三氯化钒、环烷酸铬、六羰基化钼、辛酸锰、三氯化铁、辛酸铁、三乙酰丙酮铁、二茂铁、辛酸钴、环烷酸钴、亚油树脂酸钴、苯甲酸钴、二茂镍、辛酸镍、环烷酸镍、乙酸铜、辛酸铜、环烷酸铜、辛酸锌、环烷酸锌、硝酸镉、环烷酸镉、二苯基汞、环烷酸汞、三苯基铝、硬脂酸铝、乙酸镓、环烷酸铟、辛酸铊、四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二月桂酸二丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、辛酸亚锡、油酸亚锡、酒石酸亚锡、苯甲酸亚铅、辛酸亚铅、油酸亚铅、环烷酸铅、三氯化锑、五氯化锑、二氯化三苯基锑、三苯基锑、环烷酸铋与乙酸二乙基铋等。
优选地，催化剂为含金属的催化剂。进一步优选地，所述含金属的催化剂选自：四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、油酸亚锡、 酒石酸亚锡、二月桂酸二丁基锡、辛酸亚锡与环烷酸金属盐中的至少一种。再进一步优选地，含金属的催化剂是环烷酸金属盐。更进一步优选地，环烷酸金属盐选自环烷酸铜盐、环烷酸锌盐、环烷酸铅盐、环烷酸锂盐、环烷酸钴盐、环烷酸镍盐、环烷酸镉盐、环烷酸汞盐、环烷酸铟盐与环烷酸铋盐中的至少一种。
在某些情况下，也可以不加入催化剂，直接由反应物B与端氨基、端羟基或端巯基取代的叔胺或吡啶反应。
在第一步中，吡啶类化合物中的氮原子并不参与反应。吡啶类化合物在这里的作用在于，首先是提供一个亲核性的官能团Q，与含异氰酸酯基团的反应物B发生反应；其次，吡啶类化合物本身的吡啶氮原子是最终抗菌化合物的季铵盐结构单元的母体，在后续合成步骤中，吡啶类氮原子因为新形成一个C-N键而变为四级氮原子，即吡啶季铵盐结构。吡啶类化合物本身的碳原子数量并不影响反应的进行，只要吡啶类化合物上具有可以与异氰酸酯基团反应的基团，例如羟基、巯基或氨基，即可以进行第一步反应。
用于制备抗菌化合物的吡啶的共性在于其都具有一个或多个含有活泼氢原子的基团，如羟基、氨基、巯基等，吡啶类化合物以此与异氰酸酯基团发生反应，偶连在一起。
示例性的吡啶可以包括但不限于，4-羟甲基吡啶、4-氨基吡啶、4-巯基吡啶与2，6-二甲基-4-氨基吡啶等。吡啶环上的氢原子，可以被卤素(-F、-Cl、-Br、-I)或拟卤素(-CN、-SCN、-OCN等)、烷氧基(-OCH3、-OCH2CH3、-OPr等)、-NO与-NO2等基团或C1-7的烷基、芳基等取代基所取代，取代 基的数目至多为7。
2)将所述混合物与反应物A反应，得到所述抗菌化合物；
所述反应物A选自丙磺酸内酯、丁磺酸内酯、β-丙酸内酯、X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+与环状磷酸酯，其中X选自Br、Cl与I，v为不小于1的整数，Mt+选自Li+、Na+、K+、NH4 +、Ag+、1/2Mg2+与1/2Ca2+，其中所述环状磷酸酯具有如下式所示的结构：
Figure PCTCN2015090059-appb-000014
其中，R5选自一价未取代或取代的C1-6烷基、环烷基与芳基；R6选自二价未取代或取代的C1-6烷基。
反应物A中，由于磺酸内酯中与氧原子连接的碳原子容易接受亲核试剂的进攻，而第一步反应所得到的混合物中存在亲核性较好的叔氮原子，因此反应物A与第一步反应得到的混合物之间可以发生开环反应，形成C-N键，叔胺上三级氮原子因此又增加了一个连接基团，形成了季铵基团，与磺酸基团一同构成两性离子化合物。与磺酸内酯相似，环状磷酸酯中与氧原子连接的碳原子可以接受三级氮原子的进攻，发生开环反应，从而使三级氮原子变成季铵基团，并与磷酸基团一道构成了两性离子化合物。而丙酸内酯、丁酸内酯等化合物的环，由于原子数较少，环张力较大，也较容易开环，因此在亲核性强的三级氮原子存在下，也可发生开环反应，形成季铵基团，同时生成了一个羧基，构成两性离子化合物。X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+等化合物中，Cl、Br、I等卤素原子由于电负性大，与碳原子形成的键较弱，容易离去，与之相连接的碳原子因此 也容易受到亲核试剂进攻，因此可以在三级氮原子进攻下，形成C-N键，形成季铵基团，并与羧基或磺酸基构成两性离子化合物。类似的，其他的离去基团所取代的羧酸金属盐，可以发生类似的亲核取代反应，其他离去基团包括但不限于，对甲苯磺酰基(-OTs)、甲磺酰基(-OMs)与三氟甲磺酰基(-OTf)等。
用于制备抗菌化合物的溶剂，包括但不限于醚类、酮类、芳香化合物、腈类、酯类与酰胺类等有机溶剂。溶剂本身还可以是几种溶剂组分的混合物，例如以上两种或更多溶剂的混合物等。溶剂选择受到反应物溶解度、反应温度、溶剂本身化学反应性的影响。一般地，易与-N＝C＝O基团反应的溶剂，如水、醇、胺与羧酸等不适合作为本反应的溶剂。因此，在本实施例中使用的溶剂，需要进行预先的除水或除醇等操作。
进一步优选地，醚类溶剂可以是THF、1，4-环氧六环、乙二醇二甲醚与四氢吡喃等；酮类溶剂可以是丙酮、丁酮、环己酮、苯乙酮与佛尔酮等；芳香化合物可以是甲苯、吡啶与咪唑等；酯类可以是乙酸乙酯、乙酸正丙酯、乙酸正丁酯、甲酸甲酯与甲酸乙酯等；腈类可以是乙腈、丙腈与苯甲腈等；酰胺类可以是N-甲基吡咯烷酮、N，N-二甲基甲酰胺与N，N-二甲基乙酰胺等。
以上仅仅是对可用于本反应的常见溶剂的示例，并不用于局限反应溶剂的范围。事实上，任何可以溶解反应原料的非质子溶剂，都可能作为反应溶剂而被使用，例如，碳酸亚乙酯(ethylene carbonate)、三亚甲基碳酸酯(trimethylene carbonate)等。
用于制备抗菌化合物的过程中采取的搅拌方式，可以是机械搅拌， 也可以是磁力搅拌等可以实现反应物充分接触的搅拌方式。
反应物溶液的加入，可以是手动滴加，也可以是采用机械的滴液机滴加，滴加速度可以是恒定的，也可以随着反应的进行而不断的改变。
最终产物的分离，针对不同的产物形式也可以采用不同的分离方式，如果是非沉淀物，可采用萃取或蒸馏方式提纯；如果是沉淀，可采用离心或过滤等方式提纯。
下面实施例所用的原料及其它化学试剂均可通过商业途径获得。必要时采用本领域所周知的手段进行纯化后使用，如叔胺的除水、叔胺中氧化组分的去除、去除叔胺中的伯胺与仲胺等，这些纯化通常可以借助蒸馏、分流、萃取或加入反应试剂等手段而实现。
实施例1
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)，结构如下，
Figure PCTCN2015090059-appb-000015
加入到带有机械搅拌的圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡(DBTDL)催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加17.8g(0.2mol)二甲基乙醇胺(HOCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水THF中的24.4g(0.2mol)丙磺酸内酯(以下简称1，3-PS，结构见下)，
Figure PCTCN2015090059-appb-000016
滴加完毕后继续反应1h，得到沉淀，离心分离数次纯化，得本实施例所述含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000017
本实施例中采用了异佛尔酮二异氰酸酯作为含有异氰酸酯基团的反应物，可以理解的是，任何含有至少两个异氰酸酯基团的化合物都可以通过上述反应得到类似的含端异氰酸酯基的抗菌化合物。多异氰酸酯化合物中由于存在多个异氰酸酯基团，在亲核试剂不过量的情况下，一个分子中的多个异氰酸酯基团只有一个发生反应，其他的异氰酸酯基团被保留到最后的抗菌化合物中。多异氰酸酯化合物的碳原子个数或分子量本身并不影响反应的进行，只要它可以与亲核试剂发生亲核加成反应即可。用于制备本实施例的异氰酸酯结构还可以是包含至少一个羧基的端异氰酸酯有机物，该有机物主链结构可以是取代或未取代的脂肪族、脂肪环族、杂链、杂环、芳香族结构，其中取代基可以包括但不限于Cl、Br、I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO与-NO2等原子或基团。
在反应中，丙磺酸内酯起到的作用在于通过接收叔胺N原子的亲核进攻，打开五元环而形成磺酸基团，同时形成季铵基团。由于磺酸内酯中与氧原子连接的碳原子容易接受亲核试剂的进攻，而第一步反应所得到的混合物中存在亲核性较好的叔氮原子，因此反应物A与第一步反应得到的混合物之间可以发生开环反应，形成C-N键，叔胺上三级氮原子因此又增 加了一个连接基团，形成了季铵基团，与磺酸基团一同形成了两性离子化合物。类似的，其他的磺酸内酯，如丁磺酸内酯与乙磺酸内酯，由于可以发生类似的反应，也可以在第二步反应中被使用。
尽管本实施例中采用二丁基二月桂酸锡作为催化剂，但催化剂并非总是必须的，活性较高的有机胺类化合物，可以直接与含多个异氰酸酯基团的化合物反应，而不需要催化剂的参与。在使用催化剂的制备中，优选地，催化剂是有机胺类化合物、膦类化合物以及含金属的催化剂中的一种或多种。例如，三乙胺、三苯基膦、二辛酸二丁基锡等。
在某些情况下，也可以不加入催化剂，直接由反应物B与端氨基、端羟基或端巯基取代的叔胺或吡啶反应。
用于制备本实施例的胺类，除了N，N-二甲基乙醇胺之外，还可以是N，N-二乙基乙醇胺、N，N-二甲基乙二胺、N，N-二正丙基乙醇胺、N，N-二异丙基乙醇胺、N，N-二正丁基乙醇胺、N，N-二正戊基乙醇胺、N，N-二环己基乙醇胺或3，3′-亚胺基双(N，N-二甲基丙胺)等。
而且，尽管本实施例采用胺类，还可以采用带有端醇基或端巯基的叔胺类或吡啶类有机物，如4-羟甲基吡啶、2，6-二甲基-4-氨基吡啶。
实施例2
称取50.1g(0.2mol)二苯甲烷二异氰酸酯(MDI)，加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡催化剂后，在搅拌和30℃温度下，用滴液漏斗缓慢滴加23.5g(0.2mol)N，N-二乙基乙醇胺(HOCH2CH2N(CH2CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水THF中的24.4g(0.2mol)丙 磺酸内酯，滴加完毕后继续反应1h，得到油状物，采用极性非质子溶剂DMSO萃取，除去溶剂，纯化，得本实施例所述含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000018
实施例3
称取33.6g(0.2mol)六亚甲基二异氰酸酯(HDI)，加入到带有机械搅拌圆底烧瓶里，加入0.2ml的辛酸亚锡(Sn(CH3(CH2)3CH(C2H5)CO2)2)催化剂后，在搅拌和30℃温度下，用滴液漏斗缓慢滴加17.8g(0.2mol)的N，N-二甲基乙醇胺(HOCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，并向滤液中滴加溶于400mL无水THF中的23.6g(0.2mol)氯乙酸钠(ClCH2CO2Na)，20℃温度下反应24h，得粗产物，离心分离数次纯化，得本实施例所述含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000019
在反应中，氯乙酸钠起到的作用在于通过接收叔胺N原子的亲核进攻，离去氯原子，而形成季铵基团。类似的，其他的卤素(Br、I等)或其他易于离去基团(OTs、OMs、OTf等)所取代的羧酸钠，如溴乙酸钠、碘乙酸钠、2-氯丙酸钠、3-氯丙酸钠、2-溴丙酸钠、3-溴丙酸钠、2-碘丙酸钠、3-碘丙酸钠，或者更长碳链的卤化羧酸等，由于卤素容易在N原子亲核攻击下发生离去，可以发生类似的反应，也可以在第二步反应中被使用。
氯乙酸钠溶液的滴加可以是手动滴加，也可以是采用机械的滴液机 滴加，滴加速度可以是恒定的，也可以随着反应的进行而不断的改变。
实施例4
称取34.8g(0.2mol)甲苯二异氰酸酯(含2，4-甲苯二异氰酸酯与2，6-甲苯二异氰酸酯的混合物)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二月桂酸二丁基锡催化剂(DBTDL)后，在搅拌和30℃温度下，用滴液漏斗缓慢滴加17.8g(0.2mol)二甲基乙醇胺(HOCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，并向滤液中滴加溶解于400mL丁酮中的14.4g(0.2mol)β-丙内酯，结构如下，
Figure PCTCN2015090059-appb-000020
40℃温度下继续反应6h，得到产物，常压过滤，纯化，得本实施例所述含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000021
在反应中，β-丙内酯起到的作用在于通过接收叔胺N原子的亲核进攻，从而开环并形成一个羧基，同时形成季铵基团。类似的，其他的内酯，如β-丁内酯、γ-丁内酯、β-戊内酯与γ-戊内酯等，由于可以发生类似的反应，也可以在第二步反应中被使用，生成相应的两性离子化合物。
β-丙内酯溶液的滴加可以是手动滴加，也可以是采用机械的滴液机滴加，滴加速度可以是恒定的，也可以随着反应的进行而不断的改变。
实施例5
称取52.5g(0.2mol)二环己基甲烷二异氰酸酯(HMDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二月桂酸二丁基锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加17.8g(0.2mol)N，N-二甲基乙二胺(H2NCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水丙酮中的24.4g(0.2mol)丙磺酸内酯，滴加完毕后继续反应1h，得到沉淀，离心分离数次纯化，得本实施例所述含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000022
实施例6
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加17.8g(0.2mol)N，N-二甲基乙二胺(H2NCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，并向滤液中滴加溶解于400mL无水丁酮中的14.4g(0.2mol)β-丙内酯，40℃温度下继续反应6h，得到粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000023
实施例7
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二月桂酸二丁基锡催化剂后，在搅拌和 30℃温度下用滴液漏斗缓慢滴加37.4g(0.2mol)3，3′-亚胺基双(N，N-二甲基丙胺)，结构简式为
Figure PCTCN2015090059-appb-000024
滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水乙酸乙酯中的48.8g(0.4mol)丙磺酸内酯，滴加完毕后继续反应1h，得到粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000025
用于制备本实施例的胺类，除了3，3′-亚胺基双(N，N-二甲基丙胺)之外，还可以是其他具有活泼氢原子的叔胺或吡啶，例如但不限于，N，N-二甲基乙醇胺、N，N-二甲基乙二胺、N，N-二乙基乙醇胺、N，N-二异丙基乙醇胺、N，N-二正丁基乙醇胺、N，N-二正戊基乙醇胺、N，N-二环己基乙醇胺、4-羟甲基吡啶与2，6-二甲基-4-氨基吡啶等。
实施例8
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二月桂酸二丁基锡催化剂后，在搅拌和 30℃温度下用滴液漏斗缓慢滴加21.8g(0.16mol)4-羟甲基吡啶，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水THF中的24.4g(0.2mol)丙磺酸内酯，滴加完毕后继续反应1h，得到粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000026
用于制备本实施例的含氮化合物带有一个含活泼氢原子的官能团，例如羟基、氨基与巯基，可以是吡啶类化合物，还可以是叔胺，该类有机物可以是取代的或非取代的脂肪族、脂肪环族或芳香族等。除了4-羟甲基吡啶之外，还可以是2，6-二甲基-4-氨基吡啶、N，N-二甲基乙醇胺、N，N-二甲基乙二胺、N，N-二乙基乙醇胺、N，N-二异丙基乙醇胺、N，N-二正丁基乙醇胺、N，N-二正戊基乙醇胺、N，N-二环己基乙醇胺、3，3′-亚胺基双(N，N-二甲基丙胺)、4-巯甲基吡啶或2，6-二甲基-4-氨基吡啶等。以上仅仅作为对可选用的胺类/吡啶类化合物的示例，并不用于局限此反应中含氮化合物的范围，任何含有活泼氢原子的吡啶或叔胺类化合物，都可能作为反应底物，例如，4-羟基吡啶。
实施例9
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的辛酸亚锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加24.4g(0.2mol)2，6-二甲基-4-氨基吡啶，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水THF中的24.4g(0.2mol)丙磺酸内酯，滴加完毕后继续反应1h， 得到粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000027
尽管本实施例中采用辛酸亚锡作为催化剂，但催化剂并非总是必须的，活性较高的有机胺类化合物，可以直接与含多个异氰酸酯基团的化合物反应，而不需要催化剂的参与。在使用催化剂的制备中，作为催化剂使用的物质可参见实施例1中的描述。
用于制备本实施例采用的含氮化合物，其结构上除了吡啶氮原子或叔胺氮原子外，还存在带有活泼氢原子的基团，如氨基、羟基与巯基等。作为示例，含氮化合物，除了2，6-二甲基-4-氨基吡啶之外，还可以是N，N-二甲基乙醇胺、N，N-二甲基乙二胺、N，N-二乙基乙醇胺、N，N-二异丙基乙醇胺、N，N-二正丁基乙醇胺、N，N-二正戊基乙醇胺、N，N-二环己基乙醇胺、3，3′-亚胺基双(N，N-二甲基丙胺)、4-羟甲基吡啶、4-巯甲基吡啶、2-二甲氨基乙硫醇、2-二乙氨基乙硫醇、2-二甲氨基丙硫醇、2-二乙氨基丙硫醇、2，6-二乙基-4-氨基吡啶或者2位与6位上由其他烷基、卤素(-F、-Cl、-Br、-I)、-NO2、烷氧基所取代的4-氨基吡啶等。
实施例10
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加17.8g(0.2mol)二甲基乙醇胺(HOCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水THF中的42.2g(0.2Mol)2-溴乙 磺酸钠，滴加完毕后继续反应1h，得到粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000028
在反应中，2-溴乙磺酸钠起到的作用在于通过接收N原子的亲核进攻，离去溴原子，而形成季铵基团，生成最终的两性离子化合物。类似的，其他的卤素或其他易于离去基团所取代的磺酸钠，如2-氯乙磺酸钠、2-碘乙磺酸钠、2-氯丙磺酸钠、2-溴丙磺酸钠、2-碘丙磺酸钠或2-对苯磺酰丙磺酸钠等，由于可以发生类似的反应，也可以在第二步反应中被使用。
2-溴乙磺酸钠溶液的滴加，可以是手动滴加，也可以是采用机械的滴液机滴加，滴加速度可以是采取一定的恒速滴加，也可以随着反应的进行不断的改变滴加速度。
实施例11
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加17.8g(0.2mol)二甲基乙醇胺(HOCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后滴加溶于400mL无水THF中的37.4g(0.22mol)4-溴丁酸钠，滴加完毕后继续反应1h，得到粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000029
在反应中，4-溴丁酸钠起到的作用在于通过接收N原子的亲核进攻，离去溴原子，而形成季铵基团。类似的，其他的卤素或其他离去基团所取代的羧酸金属盐。其中卤素包括但不限于，氯、溴与碘等；其他离去基团包括但不限于，对甲苯磺酰基(-OTs)、甲磺酰基(-OMs)与三氟甲磺酰基(-OTf)等；羧酸金属盐中的金属，包括但不限于，锂、钠、钾、铵、银、镁与钙等；羧酸包括但不限于，乙酸、丙酸、丁酸、戊酸与更多碳原子的羧酸；卤素或其他取代基所处的位置，可以是临近羧酸碳原子的α、β、γ等位置。典型的卤素取代的羧酸金属盐，包括但不限于，氯乙酸钠、溴乙酸钠、碘乙酸钠、2-氯丙酸钠、3-氯丙酸钠、2-溴丙酸钠、3-溴丙酸钠、2-碘丙酸钠、3-碘丙酸钠、4-氯丁酸钠与4-碘丁酸钠等。由于上述物质都可以与叔胺发生类似的反应，也可以在第二步反应中被使用。
4-溴丁酸钠溶液的滴加可以是手动滴加，也可以是采用机械的滴液机滴加，滴加速度可以是恒定的，也可以随着反应的进行不断的改变。
最终产物的分离，针对不同的产物形式也可以采用不同的分离方式，如果是油状物或粘稠固体，可采用萃取或蒸馏方式提纯；如果是沉淀可采用离心或过滤等方式。
实施例12
量取9.3g(0.2mol)乙醇和20.2g(0.2mol)三乙胺(TEA)溶于100ml的无水THF中，并加入到带有磁力搅拌的圆底烧瓶内，在-20℃冷却20min，保持-20℃，并向反应容器内滴加溶于30ml的无水THF的28.392g(0.2mol)2-氯-2-氧-1，3，2-二氧磷杂环戊烷(COP)，滴加完毕后，于-20℃下静置，待沉淀物析出，将沉淀物在真空下蒸馏获得2-乙氧基-2- 氧-1，3，2-二氧磷杂环戊烷(EOP)。
称取44.6g(0.2mol)异佛尔酮二异氰酸酯(IPDI)加入到带有机械搅拌的圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加17.8g(0.2mol)二甲基乙醇胺(HOCH2CH2N(CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后在75℃下，滴加溶于400mL无水THF中的30.4g(0.2mol)EOP，滴加完毕后继续反应24h，得粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000030
在上述反应中，乙醇进攻COP的P原子，两者间进一步失HCl，发生取代反应得到产物EOP。类似的，可以与COP发生取代反应的除了乙醇，还可以是其他脂肪族醇、脂环族醇或芳香醇等，如甲醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、正己醇、正庚醇、乙烯醇、丙烯醇、环丙醇、环戊醇、环己醇或苯甲醇等。
尽管本实施例采用COP作为含磷试剂，但是用于含磷试剂的还可以是其他2-卤代-1，3，2-二氧磷杂环类化合物，其中环上原子数可以是4、5、6、7、8或9，优选为5、6与7，即2-卤代-1，3，2-二氧磷杂环戊烷、2-卤代-1，3，2-二氧磷杂环己烷与2-卤代-1，3，2-二氧磷杂环庚烷。本反应中，2-卤代-1，3，2-二氧磷杂环类化合物上的磷原子除了与氧原子连接外，还和一 个卤素原子连接。如美国授权专利US 2,982,862所披露的，这类化合物中的卤素原子包括氯、溴与碘，由于具有较好的离去性，容易被醇上的烷氧基所取代。环上碳原子上接的氢原子，可以被一个或者多个烷基，例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基等所取代。
除COP之外，这类化合物还包括但不限于，2-氯-4，5-二甲基-1，3，2-二氧磷杂环戊烷-2-氧化物、2-氯-1，3，2-二氧磷杂环己烷-2-氧化物、2-氯-5，5-二甲基-4-苯基-1，3，2-二氧磷杂环己烷-2-氧化物、2-氯-4，6-二甲基-1，3，2-二氧磷杂环己烷-2-氧化物、2-氯-5，5-二甲基-1，3，2-二氧磷杂环己烷-2-氧化物、2-氯-1，3，2-二氧磷杂环庚烷-2-氧化物、2-氯-1，3，2-二氧磷杂环辛烷-2-氧化物、2-溴-1，3，2-二氧磷杂环戊烷-2-氧化物、2-溴-1，3，2-二氧磷杂环己烷-2-氧化物与2-溴-5，5-二甲基-1，3，2-二氧磷杂环己烷-2-氧化物等。
尽管本实施例采用三乙胺作为反应助剂，但是还可以采用其他不含有活泼氢的叔胺，例如，三甲胺、三正丙胺、三异丙胺、三正丁胺、N-甲基二辛基胺、N，N-二甲基环戊胺或N，N-二甲基环己胺等。在这个醇解反应中，叔胺作为碱，帮助HCl的脱去。
尽管本实施例采用THF作为有机溶剂，还可以采用乙腈、DMF、DMSO、无水丁酮、无水丙酮、环己酮、甲苯、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1，4-环氧六环、N-甲基吡咯烷酮、吡啶、N，N-二甲基甲酰胺或以上两种或更多溶剂的混合物等。
在第二步反应中，EOP起到的作用在于通过与环上O原子连接的C原子接收N原子的亲核进攻，发生开环反应，而形成季铵基团。
EOP溶液的滴加可以是手动滴加，也可以是采用机械的滴液机滴 加，滴加速度可以是恒定的，也可以随着反应的进行不断的改变。
最终产物的分离，针对不同的产物形式也可以采用不同的分离方式，如果是油状物，可采用有机溶剂萃取来提纯，或者通过对产物在有机溶剂中的溶液进行蒸馏的方式提纯；如果是沉淀，可采用离心或过滤等方式。
实施例13
量取9.3g(0.2mol)乙醇和20.2g(0.2mol)三乙胺(TEA)溶于100ml的无水THF中，并加入到带有磁力搅拌的圆底烧瓶内，在-20℃冷却20min，保持-20℃，并向反应容器内滴加溶于30ml的无水THF的28.392g(0.2mol)2-氯-5，5-二甲基-1，3，2-二氧磷杂环己烷-2-氧化物，滴加完毕后，于-20℃下静置，待沉淀物析出，将沉淀物在真空下蒸馏，除去杂质，获得2-乙氧基-2-氧-1，3，2-二氧磷杂环己烷。
将50.1g(0.2mol)二苯甲烷二异氰酸酯(MDI)加入到带有机械搅拌圆底烧瓶里，加入0.2ml的二丁基二月桂酸锡催化剂后，在搅拌和30℃温度下用滴液漏斗缓慢滴加23.5g(0.2mol)N，N-二乙基乙醇胺(HOCH2CH2N(CH2CH3)2)，滴加完毕后继续反应1h，并在此温度下继续搅拌反应12h，然后于70℃下，滴加溶于400mL无水THF中的30.4g(0.2mol)2-乙氧基-2-氧-1，3，2-二氧磷杂环己烷，滴加完毕后继续反应24h，得粗产物，离心分离数次纯化，得含端异氰酸酯基的抗菌化合物。
Figure PCTCN2015090059-appb-000031
Figure PCTCN2015090059-appb-000032
本发明实施例所提供的抗菌化合物是带有端异氰酸酯基的两性离子化合物。季氮原子所带的正电荷可破坏微生物细胞膜，使蛋白质变性以及破坏细胞结构。上述微生物包括但不限于，大肠杆菌、鼠伤寒沙门氏菌、绿脓杆菌、金黄色葡萄球菌、白色念珠菌、硫酸盐还原菌、革兰氏阳性菌、革兰氏阴性菌、表皮葡萄球菌、枯草杆菌、粪肠球菌、干燥棒状杆菌和炭疽杆菌等。可以作为杀菌试剂或者抑菌试剂用来阻止传染、杀死微生物，或者抑制微生物生理功能，并因此可以有效治疗由这些微生物引起的感染，或者控制其造成的污染。
本发明实施例提供的抗菌化合物可以通过端异氰酸酯基，与材料表面实现化学键的结合。所述抗菌化合物可以应用在纺织品、医药、食品与农业等多个领域，但不限于上述领域。例如，异氰酸酯基可以与纤维、棉纺织品、尼龙表面的羟基或氨基结合制备较耐洗涤的抗菌纺织品；可以与医用输液管、医用包装材料表面的羟基或者氨基结合，制备抗菌医药产品，或者与食品包装或食品保鲜材料表面的羟基或氨基结合，制备抗菌包装材料。
对本发明实施例1-13的产品进行了大肠杆菌(E.coli，美国模式菌种收集中心ATCC 25922)与金黄色葡萄球菌(S.aureas，ATCC 6538)的最低抑菌浓度测试。其中，最低抑菌浓度(minimum inhibitory concentration，简称MIC)是指在特定环境下，经过24h培养后，能使细菌的发育受到阻滞并被观察到的抗菌试剂的最小浓度。测定最低抑菌浓度 的方法可以是常量肉汤稀释法、微量肉汤稀释法、琼脂稀释法与E实验。本发明实施例1-13的抗菌剂最低抑菌浓度测试结果如表1所示。
表1实施例1-13的抗菌剂最低抑菌浓度(MIC，单位：μmol/mL)
Figure PCTCN2015090059-appb-000033
本发明实施例中所得到的化合物对于细菌有很低的抑菌浓度，足以保证在使用该化合物的情况下，细菌种群数量极低，对人体健康危害很小。
用实施例1-13所得产物处理洁净的玻璃表面，并采用菌落计数法测试其抗菌活性及持久抗菌活性，本实施方案采用细菌为大肠杆菌与金黄色葡萄球菌，结果如表2所示。
表2抗菌剂改性玻璃表面的持久抗菌活性分析(平板计数法)
Figure PCTCN2015090059-appb-000034
Figure PCTCN2015090059-appb-000035
根据上表，本发明实施例所提供的抗菌化合物，对于常见细菌如大肠杆菌与金黄色葡萄球菌，都具有很优异的抗菌性能与持久性。即使经过多次洗涤，抗菌性能也仅仅出现了很小幅度的减弱，但仍然保持在94％以上。
本发明的实施例所提供的抗菌化合物，具有反应性官能团——异氰酸酯，该反应性基团可以与多种材料界面上存在的官能团，如棉纤维、麻纤维、聚酯纤维(如涤纶PET)、聚乳酸(PLA)中的羟基，尼龙中的氨基，以及羊毛、羊绒、蚕丝、锦纶与芳纶中的酰胺基等，发生化学键合作用，在材料界面上锚定具有抗菌性的组分，从而赋予由反应性抗菌化合物处理的材料或制品表面持久的抗菌防污性。同时，该化合物的制备方法工艺简单，条件容易控制，易于产业化，为它在广泛范围内使用提供了方便。本发明实施例所提供的抗菌化合物具有广阔的工业应用前景。
以上内容是结合具体的实施方式对本发明实施例所做的进一步详 细说明，便于该技术领域的技术人员能理解和应用本发明实施例所提供的抗菌化合物，不能认定本发明的实施方式只局限于这些示例。应当指出，对于本领域的技术人员来说，在不脱离本发明实施例的构思的前提下，还可以做出其他若干变形或改进，这些变形或改进都不脱离权利要求所定义的保护范围。

Claims (32)

  1. 一种抗菌化合物，具有通式(I)的结构：
    Figure PCTCN2015090059-appb-100001
    其中，
    R1选自OCN-L-NHCOOR’、OCN-L-NHCONHR’、OCN-L-NHCOSR’、OCN-L-COOR’与OCN-L-COONHR’；
    L选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    R’选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    R2与R3各自独立地选自一价未取代或取代的C1-18烷基、环烷基与芳基；
    R4选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    Z选自-COO、-SO3与-OPO2OR5；
    R5选自一价未取代或取代的C1-6烷基、环烷基与芳基。
  2. 根据权利要求1所述的抗菌化合物，其中，R2与R3是相同的基团或不相同的基团。
  3. 根据权利要求2所述的抗菌化合物，其中，R2与R3各自独立地选自-(CH2)uCH3，其中，u为不小于0且不大于17的整数。
  4. 根据权利要求1所述的抗菌化合物，其中，Z为-SO3。
  5. 根据权利要求1所述的抗菌化合物，其中，Z为-CO2。
  6. 根据权利要求1所述的抗菌化合物，其中，Z为-OPO2OR5。
  7. 根据权利要求6所述的抗菌化合物，其中R5为-(CH2)wCH3，其中w为不小于0且不大于5的整数。
  8. 根据权利要求1所述的抗菌化合物，其中，R4与R’各自独立地选自-(CH2)n-，n为不小于1且不大于18的整数。
  9. 根据权利要求1所述的抗菌化合物，其中，R1选自OCN-L-NHCOOR’与OCN-L-NHCONHR’。
  10. 根据权利要求1所述的抗菌化合物，其中，L具有如下式所示的结构：
    Figure PCTCN2015090059-appb-100002
  11. 一种抗菌化合物，具有通式(II)的结构：
    Figure PCTCN2015090059-appb-100003
    其中，
    G1选自OCN-M-NHCOOG’、OCN-M-NHCONHG’、OCN-M-NHCOSG’、OCN-M-COOG’与OCN-M-COONHG’；
    M选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    G’选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    G2与G3各自独立地选自-H、-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO、-NO2与一价未取代或取代的C1-7烷基、环烷基、芳基；
    G4选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    X选自-COO、-SO3与-OPO2OR5；
    R5选自一价未取代或取代的C1-6烷基、环烷基与芳基。
  12. 根据权利要求11所述的抗菌化合物，其中，G1选自OCN-M-NHCOOG’与OCN-M-NHCONHG’。
  13. 根据权利要求11所述的抗菌化合物，其中，G2与G3是相同的基团或不相同的基团。
  14. 根据权利要求13所述的抗菌化合物，其中，G2与G3各自独立地选自-H、-CH3、-CH2CH3、-NO2、-F、-Cl、-Br与-I。
  15. 根据权利要求11所述的抗菌化合物，其中，X为-SO3。
  16. 根据权利要求11所述的抗菌化合物，其中，X为-CO2。
  17. 根据权利要求11所述的抗菌化合物，其中，X为-OPO2OR5。
  18. 根据权利要求17所述的抗菌化合物，其中，R5选自-(CH2)wCH3，其中w为不小于0且不大于5的整数。
  19. 根据权利要求11所述的抗菌化合物，其中，G4与G’各自独立地选自-(CH2)n-，n为不小于0且不大于18的整数。
  20. 根据权利要求11所述的抗菌化合物，其中，M具有如下式所示的结构：
    Figure PCTCN2015090059-appb-100004
  21. 一种根据权利要求1所述的抗菌化合物的制备方法，包括如下步骤：
    1)将一种具有通式(III)结构的叔胺，与具有通式(IV)结构的反应物B反应，得到一种混合物；
    Figure PCTCN2015090059-appb-100005
    OCN-L-D     (IV)
    其中，
    Y选自-OH、-NH2与-SH；
    R’选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    R2与R3各自独立地选自一价未取代或取代的C1-18烷基、环烷基与芳基；
    L选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    D选自-COOH与-NCO；
    2)将所述混合物与反应物A反应，得到所述抗菌化合物；
    其中，所述反应物A选自丙磺酸内酯、丁磺酸内酯、β-丙酸内酯、X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+与环状磷酸酯，其中X选自Br、Cl与I，v为不小于1的整数，Mt+选自Li+、Na+、K+、NH4 +、Ag+、1/2Mg2+与1/2Ca2+，其中所述环状磷酸酯具有如下式所示的结构：
    Figure PCTCN2015090059-appb-100006
    其中，
    R5选自一价未取代或取代的C1-6烷基、环烷基与芳基；
    R6选自二价未取代或取代的C1-6烷基。
  22. 根据权利要求21所述的抗菌化合物的制备方法，其中，所述叔胺与所述反应物B反应是在催化剂C的存在下进行，所述催化剂C选自有机胺类化合物、膦类化合物与含金属的催化剂中的至少一种。
  23. 根据权利要求22所述的抗菌化合物的制备方法，其中，所述催化剂C为所述含金属的催化剂。
  24. 根据权利要求23所述的抗菌化合物的制备方法，其中，所述含金属的催化剂选自四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、油酸亚锡、酒石酸亚锡、二月桂酸二丁基锡、辛酸亚锡与环烷酸金属盐中的至少一种。
  25. 根据权利要求24所述的抗菌化合物的制备方法，其中，所述含金属的催化剂是环烷酸金属盐。
  26. 根据权利要求25所述的抗菌化合物的制备方法，其中，所述环烷酸金属盐选自环烷酸铜盐、环烷酸锌盐、环烷酸铅盐、环烷酸锂盐、环烷酸钴盐、环烷酸镍盐、环烷酸镉盐、环烷酸汞盐、环烷酸铟盐与环烷酸铋盐中的至少一种。
  27. 一种如权利要求11所述的抗菌化合物的制备方法，包括如下步骤：
    1)将一种具有通式(V)结构的吡啶，与具有通式(IV)结构的反应物B反应，得到一种混合物；
    Figure PCTCN2015090059-appb-100007
    OCN-L-D      (IV)
    其中，Q选自-OH、-NH2与-SH；
    G’选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    G2与G3各自独立地选自-H、-F、-Cl、-Br、-I、-OCH3、-OCH2CH3、-OPr、-CN、-SCN、-NO、-NO2与一价未取代或取代的C1-7烷基、环烷基、芳基；
    D选自-COOH与-NCO；
    L选自二价未取代或取代的C1-18烷基、环烷基与芳基；
    2)将所述混合物与反应物A反应，得到所述抗菌化合物；
    其中，所述反应物A选自丙磺酸内酯、丁磺酸内酯、β-丙酸内酯、X(CH2)vCO2 -Mt+、X(CH2)vSO3 -Mt+与环状磷酸酯，其中X选自Br、Cl与I，v为不小于1的整数，Mt+选自Li+、Na+、K+、NH4 +、Ag+、1/2Mg2+与1/2Ca2+，其中所述环状磷酸酯具有如下式所示的结构：
    Figure PCTCN2015090059-appb-100008
    其中，R5选自一价未取代或取代的C1-6烷基、环烷基与芳基；R6选自二价未取代或取代的C1-6烷基。
  28. 根据权利要求27所述的抗菌化合物的制备方法，其中，所述吡啶与所述反应物B反应，是在催化剂C的存在下进行，所述催化剂C选自有机胺类化合物、膦类化合物与含金属的催化剂中的至少一种。
  29. 根据权利要求28所述的抗菌化合物的制备方法，其中，所述催化剂C为所述含金属的催化剂。
  30. 根据权利要求29所述的抗菌化合物的制备方法，其中，所述含金属的催化剂选自四氯化锡、四丁基锡、氯化三丁基锡、二氯化丁基锡、三氯化丁基锡、氰化三丁基锡、二乙酸二丁基锡、二辛酸二丁基锡、辛酸三丁基锡、二辛酸二苯基锡、二丁氧基二丁基锡、双乙酰丙酮基二丁基锡、二(异辛基马来酸)二丁基锡、氧化二辛酸锡、硫化二丁基锡、油酸亚锡、酒石酸亚锡、二月桂酸二丁基锡、辛酸亚锡与环烷酸金属盐中的至少一种。
  31. 根据权利要求30所述的抗菌化合物的制备方法，其中，所述含金属的催化剂是环烷酸金属盐。
  32. 根据权利要求31所述的抗菌化合物的制备方法，其中，所述环烷酸金属盐选自环烷酸铜盐、环烷酸锌盐、环烷酸铅盐、环烷酸锂盐、环烷酸钴盐、环烷酸镍盐、环烷酸镉盐、环烷酸汞盐、环烷酸铟盐与环烷酸铋盐中的至少一种。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11286390B2 (en) * 2016-09-07 2022-03-29 Van Wijhe Beheer B.V. Antimicrobial surfactants and water borne coatings comprising the same

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108976153B (zh) 2017-05-31 2022-01-11 海思美域(深圳)科技有限公司 抗菌亲水化合物及应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6828029B1 (en) * 2000-02-07 2004-12-07 Biocompatibles Uk Limited Zwitterionic groups containing compounds from michael-type reactions useful as monomers and macromers
CN103361977A (zh) * 2013-07-09 2013-10-23 淮海工学院 季铵盐和水杨醛功能基团表面修饰的聚酰胺材料及其制备方法
JP2013234157A (ja) * 2012-05-10 2013-11-21 Shin-Etsu Chemical Co Ltd シリコーン変性双性イオン化合物とその製造方法
CN103476779A (zh) * 2011-02-01 2013-12-25 帝斯曼知识产权资产管理有限公司 具有亲水性端基的含硅酮的单体

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2982862A (en) 1959-12-31 1961-05-02 Aluminum Co Of America Bottle cap detector
CN101760963B (zh) * 2010-01-29 2011-11-23 深圳大学 一种抗菌防霉纺织品及其制备方法
JP5690671B2 (ja) * 2010-06-30 2015-03-25 富士フイルム株式会社 新規な重合性組成物及びそれに用いる重合性化合物、並びに新規な重合性組成物を用いた画像形成材料及び平版印刷版原版
JP5740234B2 (ja) * 2010-07-30 2015-06-24 富士フイルム株式会社 平版印刷版原版及びそれに用いる新規なベタイン含有ポリマー
JP5776421B2 (ja) 2011-08-02 2015-09-09 日立工機株式会社 エンジン作業機
US20130273580A1 (en) * 2012-04-17 2013-10-17 Barry C. Starcher Elisa assay kit, elisa for determining desmosine levels from urine samples and diagnostic urine assays for aneurysms

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6828029B1 (en) * 2000-02-07 2004-12-07 Biocompatibles Uk Limited Zwitterionic groups containing compounds from michael-type reactions useful as monomers and macromers
CN103476779A (zh) * 2011-02-01 2013-12-25 帝斯曼知识产权资产管理有限公司 具有亲水性端基的含硅酮的单体
JP2013234157A (ja) * 2012-05-10 2013-11-21 Shin-Etsu Chemical Co Ltd シリコーン変性双性イオン化合物とその製造方法
CN103361977A (zh) * 2013-07-09 2013-10-23 淮海工学院 季铵盐和水杨醛功能基团表面修饰的聚酰胺材料及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YUAN, JIANG ET AL.: "Construction of Sulfoammonium Zwitterionic Structure onto Surface of Polyurethane by Hexamethylene Diisocyanate (HDI) Spacer for Improving Blood Compatibility", CHEMICAL JOURNAL OF CHINESE UNIVERSITIES, vol. 5, no. 24, 31 May 2003 (2003-05-31), pages 916 - 919 *
YUAN, JIANG ET AL.: "Improvement of Blood Compatibility on Cellulose Membrane Surface by Grafting Betaines", COLLOIDS AND SURFACES B: BIOINTERFACES, vol. 30, no. 1-2, 31 December 2003 (2003-12-31), pages 147 - 155 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11286390B2 (en) * 2016-09-07 2022-03-29 Van Wijhe Beheer B.V. Antimicrobial surfactants and water borne coatings comprising the same

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