CN105531258A - Reactive antibacterial compound and preparation method thereof - Google Patents

Reactive antibacterial compound and preparation method thereof Download PDF

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CN105531258A
CN105531258A CN201580001140.3A CN201580001140A CN105531258A CN 105531258 A CN105531258 A CN 105531258A CN 201580001140 A CN201580001140 A CN 201580001140A CN 105531258 A CN105531258 A CN 105531258A
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alkyl
antimicrobial
aryl
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replace
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CN105531258B (en
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陈仕国
袁玲君
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Haisi Meiyu (Shenzhen) Technology Co.,Ltd.
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Shenzhen University
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Abstract

The invention discloses a reactive antibacterial compound and a preparation method thereof, wherein the reactive antibacterial compound has a structure as shown in a formula (I) or (II), wherein, R1 is selected from OCN-L-NHCOOR', OCN-L-NHCONHR', OCN-L-NHCOSR', OCN-L-COOR' and OCN-L-COONHR'; G1 is selected from OCN-M-NHCOOG', OCN-M-NHCONHG', OCN-M-NHCOSG', OCN-M-COOG' and OCN-M-COONHG'; L, M, R' and G' are selected from bivalent alkyl and aryl from C1-18 independently, and the optional part can be replaced by at most 18 hetero atoms; R2 and R3 are selected from monovalent Alkyl and aryl from C1-18 independently, and the optional part can be replaced by at most 18 hetero atoms; R4 and G4 are selected from bivalent alkyl and aryl from C1-18 independently, and the optional part can be replaced by at most 18 hetero atoms; G2 and G3 are selected from -H, -F, -Cl, -Br, -I, -OCH3, -OCH2CH3, -OPr, -CN, -SCN, -NO, -NO2 and monovalent unsubstituted or substituted alkyl, cycloalkyl and aryl from C1-7 independently; Z and X are selected from -COO, -SO3 and -OPO2OR5 independently; and R5 is selected from monovalent unsubstituted or substituted alkyl, cycloalkyl and aryl from C1-6 independently.

Description

Reactive antimicrobial compounds and preparation method thereof
cross reference
Being this application claims on February 6th, 2015 at the application number that China national Department of Intellectual Property submits to is the right of priority of the international application of PCT/CN2015/072439, and its content is contained in this by way of reference.
Technical field
The application belongs to antimicrobial technology field, especially, relates to a kind of reactive antimicrobial compounds and preparation method thereof, more particularly, relates to a kind of reactive antimicrobial compounds containing positively charged nitrogen-atoms and preparation method thereof.
Background technology
Bacterium and fungi infestation have become and have threatened human health and the worldwide major issue enjoying global medical health protection to pay close attention to.Giving material or product surface anti-microbial property, to stop bacterium or fungi in its surface growth or breeding, even kill the bacterium or fungi that have been present in surface, is one of important means solving bacterium or fungi infestation.Common solution is the mode by spraying, chemical bonding, will have component or the material attachment of germ resistance or be anchored on product surface, thus realize antibacterial performance.Known anti-biotic material is widely used in the aspects such as pottery, glasswork, plastics, rubber, fiber, paper and coating, as household electrical appliance, household goods, sanitary product, food pack and clothing etc.At present, international anti-biotic material can be divided into four large classes: (1) inorganic antiseptic, such as nano titanium oxide, nanometer silver, Nanometer Copper, and their ion etc.; (2) organic antibacterial agent, such as quaternary ammonium salt, alcohols, halogen amine, biguanides and thiazoles etc.; (3) polymer antibacterial agent, such as high molecular quaternary; (4) natural and modification antiseptic-germicide: as chitosan and Sorbic Acid etc.
In order to give material or product surface anti-microbial property, the most frequently used method is in the coating of its surface coverage one deck containing antiseptic-germicide (as nanometer silver, Nanometer Copper and their ion or other antiseptic-germicides), nanometer silver, Nanometer Copper, silver ions, cupric ion, other heavy metals and heavy metal ion, rely on the slow releasing of its metal ion environment towards periphery, and reach antibacterial or the object of sterilization.But along with the prolongation of duration of service, its anti-microbial activity reduces gradually, until finally completely lose its anti-microbial activity, simultaneously also may inducing microbial variation, increase the probability that microorganism produces resistance.In addition, the hazardness of nano material also gradually be familiar with by the mankind and pay close attention to.
Organic anti-bacterial class, as compounds such as quaternary ammonium salt, alcohols, halogen amine, biguanides and thiazoless, has instant effect, the feature that sterilizing ability is strong, this class antiseptic-germicide, again based on quaternary ammonium salt Yu quaternary alkylphosphonium salt (tetra-Ji phosphonium salt).Usually, the cell walls of bacterium is electronegative, and quaternary ammonium salt is Yu quaternary alkylphosphonium salt plasma is electropositive, and electropositive quaternary ammonium salt is easily by bacterial adsorption, and after close to bacterium, penetration cell wall, is combined with cytolemma, upset cytolemma forms, and causes intracellular organic matter to leak, finally causes bacterial death.But quaternary ammonium salt chemically reactive is lower, substantially exist with free state during application, toxicity is larger, pungency is comparatively strong, it can be used as antiseptic-germicide poor heat resistance, easily moves, easy wash-out, and easily in human body surface enrichment gradually, life-time service easily produces pathology, microorganism is made to produce resistance.Meanwhile, organic antibacterial agent thermotolerance is poor, thus limits its use range.
The shortcomings such as volatile, the difficult processing that high molecular quaternary antiseptic-germicide can overcome small molecules antiseptic-germicide and poor chemical stability, and anti-microbial activity is excellent, not easily permeates, and thus receives the concern of people.But at present, also there is high leachability, lack the problems such as persistence in not immobilized polymer antibacterial agent, causes certain pressure equally also to the environment of surrounding.
Natural antibacterial agent comes from the extract of natural phant, animal or mineral, main Antibacterial Mechanism and organic quaternary ammonium salt similar, but effect is not as organic antibacterial agent, and product is still immature.Another shortcoming of natural antibacterial agent is that it is not suitable for scale operation, and therefore application is not extensive yet at present.
Therefore, exploitation and preparation green, can immobilization, to have long-lasting antiseptic-germicide be trend of the times.
Summary of the invention
According to embodiments of the invention, a kind of reactive antimicrobial compounds is provided, it not only has excellent anti-microbial property and wetting ability, and can be reacted by the functional group of terminal isocyanate group and natural fiber, regenerated fiber and polymer surface and combine, thus realizes long acting antibiotic.Described terminal isocyanate group refers to the isocyanate group being in a molecular chain end.
The antimicrobial compounds that the embodiment of the present invention provides is with terminal isocyanate group, the zwitterionic compound simultaneously containing quaternary ammonium group structure.Quaternary nitrogen atoms with positive charge can destroy microorganisms cytolemma, make protein denaturation and destroy cellularstructure.Mentioned microorganism includes but not limited to, intestinal bacteria, Salmonella typhimurium, Pseudomonas aeruginosa, streptococcus aureus, Candida albicans, sulphate reducing bacteria, gram-positive microorganism, Gram-negative bacteria, staphylococcus epidermidis, Bacillus subtilus, enterococcus faecalis, Corynebacterium xerosis and anthrax bacillus etc.Can be used for stoping infection, killing microorganism as anti-microbial agents or antibacterial reagent, or suppress microbial physiology function, and therefore can effectively treat the infection caused by these microorganisms, or control its pollution caused.
The antimicrobial compounds that the embodiment of the present invention provides, can pass through terminal isocyanate group, realize the combination of chemical bond with material surface.Described antimicrobial compounds can be applied in multiple fields such as textiles, medicine, food and agricultural, but is not limited to above-mentioned field.Such as, isocyanate group can prepare more wash fast antibacterial fabric with the hydroxyl on fiber, cotton textiles, nylon surface or amino combination; With the hydroxyl of medical infusion lines, medical package material surface or amino can to combine, prepare antibacterial pharmaceutical prod, or combine with the hydroxyl of food product pack or food fresh keeping material surface or amino, prepare antibiotic packaging material.
According to an aspect of the embodiment of the present invention, the general structure of this reactive antimicrobial compounds is (I):
Wherein, R 1be selected from OCN-L-NHCOOR ', OCN-L-NHCONHR ', OCN-L-NHCOSR ', OCN-L-COOR ' and OCN-L-COONHR ';
L is selected from the C of divalence 1-18alkyl, cycloalkyl and aryl, it is optionally by 18 hybrid atom MCM-41 at the most;
R ' is selected from the C of divalence 1-18alkyl, cycloalkyl and aryl, it is optionally by 18 hybrid atom MCM-41 at the most;
R 2with R 3be selected from the C of monovalence independently of one another 1-18alkyl, cycloalkyl and aryl, it is optionally by 18 hybrid atom MCM-41 at the most;
R 4independently selected from the C of divalence 1-18alkyl, cycloalkyl and aryl, it is optionally by 18 hybrid atom MCM-41 at the most;
Z is selected from-COO ,-SO 3with-OPO 2oR 5;
Wherein, R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl.
According to embodiments of the invention, in reactive antimicrobial compounds, R 2with R 3identical group or not identical group.
According to embodiments of the invention, wherein, R 2with R 3be selected from-(CH independently of one another 2) ucH 3, wherein u be not less than 0 and be not more than 17 integer, 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; Still more preferably, u is 0,1 or 2.
According to embodiments of the invention, in reactive antimicrobial compounds, Z is-SO 3.
According to embodiments of the invention, in reactive antimicrobial compounds, Z is-CO 2.
According to embodiments of the invention, in reactive antimicrobial compounds, Z is-OPO 2oR 5.
According to embodiments of the invention, R in reactive antimicrobial compounds 5for-(CH 2) wcH 3, wherein w be not less than 0 and be not more than 5 integer.
According to embodiments of the invention, in reactive antimicrobial compounds, R 4-(CH is selected from independently of one another with R ' 2) n-, n be not less than 1 and be not more than 18 integer, wherein 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.
According to embodiments of the invention, in reactive antimicrobial compounds, R 1be selected from OCN-L-NHCOOR ' and OCN-L-NHCONHR '.
According to embodiments of the invention, in reactive antimicrobial compounds, L has the structure be shown below:
Another aspect according to an embodiment of the invention, the general structure of reactive antimicrobial compounds is (II):
Wherein, G 1be selected from OCN-M-NHCOOG ', OCN-M-NHCONHG ', OCN-M-NHCOSG ', OCN-M-COOG ' and OCN-M-COONHG ';
M is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
G ' is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
G 2with G 3be selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH independently of one another 3,-OCH 2cH 3,-OPr (Pr is n-propyl or sec.-propyl) ,-CN ,-SCN ,-NO ,-NO 2the C not replacing with monovalence or replace 1-7alkyl, cycloalkyl, aryl;
G 4be selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
X is selected from-COO ,-SO 3with-OPO 2oR 5;
R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl.
According to embodiments of the invention, in antimicrobial compounds, G 1be selected from OCN-M-NHCOOG ' and OCN-M-NHCONHG '.
According to embodiments of the invention, in antimicrobial compounds, G 2with G 3identical group or not identical group.
According to embodiments of the invention, in antimicrobial compounds, G 2with G 3be selected from-H ,-CH independently of one another 3,-CH 2cH 3,-NO 2,-F ,-Cl ,-Br and-I.
According to embodiments of the invention, in antimicrobial compounds, X is-SO 3.
According to embodiments of the invention, in antimicrobial compounds, X is-CO 2.
According to embodiments of the invention, in antimicrobial compounds, X is-OPO 2oR 5.
According to embodiments of the invention, in antimicrobial compounds, R 5be selected from-(CH 2) wcH 3, wherein w be not less than 0 and be not more than 5 integer, wherein preferably, w is 0,1,2,3 or 4, and further preferably, w is 0,1 or 2.
According to embodiments of the invention, in antimicrobial compounds, G 4-(CH is selected from independently of one another with G ' 2) n-, n be not less than 1 and be not more than 18 integer, wherein 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.
According to embodiments of the invention, in antimicrobial compounds, M has the structure be shown below:
An aspect according to an embodiment of the invention, a kind of preparation method of antimicrobial compounds comprises the following steps:
One is had the tertiary amine of general formula (III) structure, react with the reactant B with general formula (IV) structure, obtain a kind of mixture;
OCN-L-D(IV)
Wherein, Y is selected from-OH ,-NH 2with-SH; R ' is selected from the C of divalence 1-18alkyl, cycloalkyl and aryl, it is optionally by 18 hybrid atom MCM-41 at the most; R 2with R 3be selected from the C that monovalence does not replace or replaces independently of one another 1-18alkyl, cycloalkyl and aryl; L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl; D is selected from-COOH and-NCO.
Described mixture and reactant A are reacted, obtains described antimicrobial compounds;
Wherein, described reactant A is selected from propane sultone, butyl sultone, β-propiolactone, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +with annular phosphate, wherein X is selected from Br, Cl and I, v be not less than 1 integer, Mt +be selected from Li +, Na +, K +, NH 4 +, Ag +, 1/2Mg 2+with 1/2Ca 2+, wherein said annular phosphate has the structure be shown below:
Wherein, R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl; R 6be selected from the C that divalence does not replace or replaces 1-6alkyl.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, it is carry out under the existence of catalyzer C that described tertiary amine and described reactant B are reacted, and described catalyzer C is selected from least one in organic amine compound, phosphines and metallic catalyzer.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described catalyzer C is described metallic catalyzer.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described metallic catalyzer is selected from tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous oleate, stannous tartrate, dibutyl tin laurate, stannous octoate, at least one in metallic naphthenate.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described metallic catalyzer is metallic naphthenate.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described metallic naphthenate is selected from least one in naphthenic acid mantoquita, naphthenic acid zinc salt, naphthenic acid lead salt, naphthenic acid lithium salts, naphthenic acid cobalt salt, naphthenic acid nickel salt, naphthenic acid cadmium salt, naphthenic acid mercury salt, naphthenic acid indium salt, bismuth naphthenate salt.
According to an embodiment of the invention on the other hand, the preparation method of antimicrobial compounds, comprises the following steps:
1) by a kind of pyridine with logical formula V structure, react with the reactant B with general formula (IV) structure, obtain a kind of mixture;
OCN-L-D(IV)
Wherein, Q is selected from-OH ,-NH 2,-SH; G ' is selected from divalence and does not replace or replace C 1-18alkyl, cycloalkyl and aryl; G 2with G 3be selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH independently of one another 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO ,-NO 2the C not replacing with monovalence or replace 1-7alkyl, cycloalkyl, aryl; D is selected from-COOH and-NCO; L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl.
2) described mixture and reactant A are reacted, obtain described antimicrobial compounds;
Wherein, described reactant A is selected from propane sultone, butyl sultone, β-propiolactone, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +with annular phosphate, wherein X is selected from Br, Cl and I, v be not less than 1 integer, Mt +be selected from Li +, Na +, K +, NH 4 +, Ag +, 1/2Mg 2+with 1/2Ca 2+, wherein said annular phosphate has the structure be shown below:
Wherein, R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl; R 6be selected from the C that divalence does not replace or replaces 1-6alkyl.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, it is carry out under the existence of catalyzer C that described tertiary amine and described reactant B are reacted, and described catalyzer C is selected from least one in organic amine compound, phosphines and metallic catalyzer.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described catalyzer C is described metallic catalyzer.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described metallic catalyzer is selected from tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous oleate, stannous tartrate, dibutyl tin laurate, at least one in stannous octoate and metallic naphthenate.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, described metallic catalyzer is metallic naphthenate.
According to embodiments of the invention, in the preparation method of antimicrobial compounds, wherein, described metallic naphthenate is selected from least one in naphthenic acid mantoquita, naphthenic acid zinc salt, naphthenic acid lead salt, naphthenic acid lithium salts, naphthenic acid cobalt salt, naphthenic acid nickel salt, naphthenic acid cadmium salt, naphthenic acid mercury salt, naphthenic acid indium salt and bismuth naphthenate salt.
Embodiment
Be described below in conjunction with specific embodiment, it should be noted that, description given here and embodiment are only used to describe the specific embodiment of the present invention, and the feature of the embodiment of the present invention is more easily understood, and they are not intended to limit the scope of claim.
Except as otherwise noted, term used herein " aliphatics ", " cycloaliphatic ring race " and " aromatic series " include but not limited to the group of straight chain, side chain or ring-type, can be unsubstituted, or by one or more hybrid atom MCM-41, or be replaced containing heteroatomic group by one or more.Wherein, " aliphatics " and " cycloaliphatic ring race " can be saturated, also can be undersaturated, as alkene, cycloolefin, diolefine, cyclodiene, alkynes, cycloalkyne and polynuclear hydrocarbon etc.Aromatic series refers to the system at least containing an aromatic ring, and can be namely not only pure aromatic substance, as benzene, naphthalene and anthracene etc., also can be the aromatic substance containing aliphatic group, as toluene, vinylbenzene and phenylacetylene etc.Pure aromatic substance, comprises monocyclic aromatic compound and fused aromatic compounds, and can be arene, as benzene, naphthalene and anthracene etc., also can be containing heteroatomic aroma system, as pyridine, furans and thiophene etc.
Heteroatoms or include but not limited to containing heteroatomic group, halogen (-F ,-Cl ,-Br ,-I), hydroxyl (-OH), carboxyl (-COOH), acyl group (-CO-), acyloxy (-COO-), amino (-NH 2), alkylamino (-NHR), dialkyl amido (-NR 1r 2), arylamino (-NHAr), amide group (-CONH 2), ester (-COOR), carboxylic acid amides (-CONR 1r 2), carbamate (-NHCOOR), alkoxyl group (-OR), aryloxy (-OAr), alkylthio (-SR), arylthio (-SAr), alkyl sulfonic ester (-OSO 2r), nitroso-group (-NO), nitro (-NO 2), cyano group (-CN), isocyano-(-NC), oxo (=O), azo-group (-N=N-), sulfydryl (-SH), alkylsulfonyl (-SO 2r), phosphono (-PO (OR 1) (OR 2)), phosphinyl thioesters (-SCOR), thio alkoxy (-OCSR), thiocyanic ester (-SCN), lsothiocyanates (-NCS), phosphoric acid ester or salt (-OP (O) (OH) 2), sulfuric ester or salt (-OSO 2(OH)) and combination.
At this, alkyl, cycloalkyl and aryl should take following lexical or textual analysis.As understood by those skilled in the art, alkyl, refers to saturated hydrocarbyl, is the alkyl that alkane molecule removes hydrogen atom, such as methyl, methylene radical, ethyl and sec.-propyl etc.; Cycloalkyl, refers to the stable hydrocarbon containing alicyclic structure, as monocycle alicyclic hydrocarbon and condensed ring alicyclic hydrocarbon, removes the general name of the alkyl that hydrogen atom is formed, such as cyclobutyl and cyclopentyl etc.; Aryl, the general name of the group formed after referring to that the fragrant core carbon of any aromatic hydrocarbon molecule or other carbon atoms remove a hydrogen atom, such as: phenyl, o-tolyl, 1-naphthyl (or Alpha-Naphthyl), 2-naphthyl (or betanaphthyl), phenmethyl (benzyl) and styroyl etc., all belong to this type of.
Monovalent hydrocarbon, refers to the group formed after hydro carbons removes a hydrogen atom, as methyl (-CH 3), ethyl (-CH 2cH 3), phenyl (-C 6h 5) etc.; Bivalent hydrocarbon radical, refers to the group formed after hydro carbons removes two hydrogen atoms, as methylene radical (-CH 2-), ethylidene (-CH 2cH 2-), to phenylene (-p-C 6h 4-) etc.Similarly, the valency of other functional groups also takes implication consistent therewith, if nitro is monovalence (-NO 2), oxo is divalence (=O).
According to the embodiment of the present invention, in the structural framework of antimicrobial compounds, containing positively charged quaternary ammonium group, this group has good antimicrobial property, in order to make whole compound be electric neutrality, in antimicrobial compounds structure, also have a negative charge group to be connected with the main body framework of compound simultaneously.In addition, also have at least one to be in the isocyanate groups of molecular end in compound, reacted by the functional group in isocyanate groups and the material such as macromolecular fibre, natural fiber, this compound can combine with material.
An aspect according to an embodiment of the invention, a kind of preparation method of antimicrobial compounds comprises the following steps:
One is had the tertiary amine of general formula (III) structure, react with the reactant B with general formula (IV) structure, obtain a kind of mixture;
OCN-L-D(IV)
Wherein, Y is selected from-OH ,-NH 2with-SH; R ' is selected from the C of divalence 1-18alkyl, cycloalkyl and aryl, it is optionally by 18 hybrid atom MCM-41 at the most; R 2with R 3be selected from the C that monovalence does not replace or replaces independently of one another 1-18alkyl, cycloalkyl and aryl; L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl; D is selected from-COOH and-NCO.
In this single step reaction, there is functional group Y (-OH ,-SH or the-NH in the tertiary amine of general formula (III) structure 2), can there is typical nucleophilic addition in the isocyanate functional group (-NCO) with having in the reactant B of general formula (IV) structure, generate carbamate, thiocarbamate acid esters or urea formula structure.There is in reactant B an isocyanate functional group, also have another one isocyanate functional group or carboxyl (functional group D) simultaneously.In the first step reaction, having isocyanate functional group in the compound of general formula (III) structure can react with the functional group Y had in the compound of general formula (IV) structure, retains functional group D at an end simultaneously.
Be understandable that, any compound containing at least two isocyanate groups can be obtained by reacting the similar antimicrobial compounds containing terminal isocyanate group by above-mentioned.Owing to there is multiple isocyanate groups in polyisocyanate compound, when nucleophilic reagent is inexcessive, the multiple isocyanate groups in a molecule only react one, and other isocyanate groups is carried in last antimicrobial compounds.The carbon atom number of polyisocyanate compound or molecular weight itself do not affect the carrying out of reaction, if it can with nucleophilic reagent generation nucleophilic addition.Polyisocyanates can be aliphatic polyisocyante, fatty lopps polyisocyanates, the polyisocyanates of heterochain, aromatic polyisocyanate, the aliphatics of replacement or cycloaliphatic ring or heterocyclic polyisocyanate, and wherein substituting group includes but not limited to-F ,-Cl ,-Br ,-I ,-OCH 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO and-NO 2deng group.Be well known to those skilled in the art, polyisocyanate compound usually can exist with the form of dimer, tripolymer or other polymkeric substance, and therefore polyisocyanates herein also comprises the monomer of above species, dimer, tripolymer or other oligomer.
Wherein, aliphatic polyisocyante includes but not limited to, hexamethylene diisocyanate, tetramethylene diisocyanate, 1,8-eight methylene diisocyanate, 1,10-decamethylene vulcabond, 1, the dimer of the derivative of 12-ten dimethylene diisocyanate, 1,14-ten tetramethylene diisocyanate, lysinediisocyanate, trimethylhexane diisocyanate, tetramethylhexane diisocyanate and above species, tripolymer and other oligomer etc.
Cycloaliphatic ring or heterocyclic polyisocyanates include but not limited to, 1, 4-, 1, 3-or 1, 2-vulcabond butylcyclohexane, 4, 4-or 2, 4-bis-(isocyanic ester butylcyclohexyl) methane, 1-isocyanate group-3, 3, 5-trimethylammonium-5-(isocyanatomethyl) hexanaphthene (isophorone diisocyanate), 1, 3-or 1, 4-bis-(isocyanatomethyl) hexanaphthene, 2, 4-or 2, diisocyanate based-1-the methylcyclohexane of 6-, 3 (or 4), 8 (or 9)-two (isocyanatomethyl) three ring [5.2.1.0.2.6] decane isomer mixture, norbornylene vulcabond, 4, 5-bis-(isocyanatomethyl)-1, the dimer of 3-dithiolane and above species, tripolymer and other oligomer etc.
The polyisocyanates of heterochain includes but not limited to, two (isocyanato-methylthio group) methane, two (isocyanato-methylthio group) methylthio group methane, two (2-isocyanato-ethylmercapto group) methane, two (3-isocyanato-rosickyite base) methane, isocyanato-methylthio group (2-isocyanato-ethylmercapto group) methane, 2-isocyanato-ethylmercapto group (3-isocyanato-rosickyite base) methane, two (isocyanato-methylthio group) phenylmethane, two (2-isocyanato-ethylmercapto group) phenylmethane, two (3-isocyanato-rosickyite base) phenylmethane, 1,2-(two isocyanato-ethylmercapto groups) ethane, 1-isocyanato-methylthio group-2-(2-isocyanato-ethylmercapto group) ethane, 1-isocyanato-ethylmercapto group-2-(3-isocyanato-rosickyite base) ethane, two (isocyanato-methylmercaptoethyl) thioether, four (isocyanato-methylthio group)-Isosorbide-5-Nitrae-dithiane, 2,2,5,5-tetra-(isocyanato-methylthio group)-1,3-dithiane, the dimer of three (isocyanato-methylthio group) methane and above species, tripolymer and other oligomer etc.
Aromatic polyisocyanate includes but not limited to, tolylene diisocyanate, diphenylmethanediisocyanate, o-Xylol vulcabond, m xylene diisocyanate, p-Xylol vulcabond, α, α, α ', α '-tetramethyl-p-Xylol vulcabond, 1, 3, 5-tri-(isocyanatomethyl) benzene, 4-methyl m xylene diisocyanate, 4-ethyl m xylene diisocyanate, 1, the dimer of 5-naphthalene diisocyanate and above species, tripolymer and other oligomer, 4-chloro-m-xylene vulcabond, 4, 5-dichloro-m-xylene vulcabond, 2, 3, 5, the dimer of 6-tetrabromo p-Xylol vulcabond and above species, tripolymer and other oligomer etc.
Isocyanate structural for the preparation of the present embodiment can also be the isocyanate terminated organism comprising at least one carboxyl (-COOH), this organism backbone structure can be substituted or unsubstituted aliphatics, cycloaliphatic ring race, heterochain, heterocycle, aromatic structure, and wherein substituting group can include but not limited to-F ,-Cl ,-Br ,-I ,-OCH 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO and-NO 2deng atom or group.
React for dimethylethanolamine and tetramethylene diisocyanate, when two kinds of reactant molar ratios are 1:1, its reaction formula is:
For the amine of the first step reaction, need to be one and contain hydroxyl, sulfydryl, amino (-NH 2) tertiary amine of contour nucleophilic group Y.Wherein the effect of group Y is the lone-pair electron that carry with oxygen, sulphur, nitrogen-atoms on it, and the carbon atom of attack isocyanate groups, coupling occurs.Because aminated compounds also with nitrogen-atoms and isocyanic ester coupling, may may cause competition to the reaction of group Y and isocyanic ester, therefore need the tertiary amine adopting reactive behavior lower here.Nitrogen-atoms on tertiary amine is comparatively large due to steric hindrance, is comparatively difficult to coupling occurs.
The exemplary tertiary amine containing nucleophilic group, includes but not limited to, N, N-dimethylethanolamine, N, N-diethylethanolamine, N, N-dimethyl-ethylenediamine, N, N-diη-propyl thanomin, N, N-diisopropyl ethanolamine, N, N-di-n-butyl thanomin, N, N-bis-n-pentyl thanomin, N, N-dicyclohexyl thanomin, dimethylamino thiomethyl alcohol, dimethylamino sulfur alcohol and 3,3'-imido grpup two (N, N-dimethyl propylamine) etc.
Under having alkaline reagents (as tertiary amine, phosphine class) to exist, the hydrogen atom in Y functional group, also may slough with hydrogen ion form, can strengthen the equiatomic nucleophilicity of O, S, N in Y functional group further, therefore can utilize as catalyzer.And at Lewis acid, as under the existence such as metal ion, organometallic compound, Sauerstoffatom in isocyanic ester can form coordinate bond with Lewis acid, a part electronics by Oxygen atom transfer on atoms metal, thus further increase the electropositivity of isocyanic ester carbon atom, be conducive to the attack accepting nucleophilic reagent, therefore this class Lewis acid also can use as catalyzer.
In the preparation using catalyzer, preferably, catalyzer is one or both and the two or more combination in organic amine compound, phosphines and metallic catalyzer.
Wherein organic amine can be divided into a few class: aliphatics amine, e.g., N, N-dimethylcyclohexylamine, two (2-dimethylaminoethyl) ether, N, N, N ', N '-tetramethyl-Alkylenediamine, triethylamine and N, N-dimethyl benzylamine etc.; Alicyclic amine, has triethylenediamine (Gu amine, DABCO), N-ethylmorpholine, N-methylmorpholine, N, N '-diethyl piperazine and dimethylamino hexanaphthene; Aromatic amine, has DMA, pyridine and DMAP (N, N-lutidine) etc.The general character of these aminated compoundss is, they all have alkalescence, can the carrying out of accelerated reaction.Meanwhile, they all contain three grades of nitrogen-atoms or pyridine nitrogen atom, therefore can not with isocyanate reaction.
Phosphines, similar with aminated compounds, be also the effect playing alkali, accelerated reaction is carried out.Phosphines, can include but not limited to, various tertiary phosphine, and three organic groups wherein replacing three hydrogen atoms can be identical, also can be incomplete same.By the tertiary phosphine that three same organic groups replace, include but not limited to, triphenylphosphine, trimethyl-phosphine, triethyl phosphine, three n-propyl phosphines, tri isopropyl phosphine, tri-n-butyl phosphine and tri-butyl phosphine etc.By the tertiary phosphine that not identical organic group replaces, include but not limited to, dimethylphenylphosphine, methyldiphenyl base phosphine, diethyl Phenylphosphine and ethyldiphenylphosphine etc.
Metallic catalyzer, because metal ion can be combined formation title complex by the Sauerstoffatom in isocyanate groups usually, cause the electronics on Sauerstoffatom to shift to atoms metal, increase the electropositivity being attached thereto the carbon atom connect, make the attack of its more acceptant nucleophilic reagent.Containing metal catalyzer, can include but not limited to, the inorganic salt, carboxylate salt, phenates, metal alkyl compound etc. of metal, and wherein carboxylate salt can be divided into again the alkyl salt of straight or branched and naphthenate circlewise.Contained metallic element mainly contains basic metal (lithium, sodium, potassium, rubidium, caesium etc.), alkaline-earth metal (magnesium, calcium, strontium, barium), transition metal (uranium, cerium, titanium, zirconium, vanadium, chromium, molybdenum, manganese, iron, cobalt, nickel, copper, zinc, cadmium, mercury etc.), aluminium, gallium, indium, thallium, tin, lead, antimony and bismuth etc., but is also not limited thereto.
Conventional metallic catalyzer includes but not limited to, lithium acetate, sad lithium, naphthenic acid lithium, sodium 2,4,5-trichlorophenate, sodium stearate, potassium acetate, potassium octanoate, lime acetate, calcium octoate, naphthenic acid strontium, barium acetate, uranyl nitrate, cerous nitrate, titanium tetrachloride, dichloride dibutyl titanium, tetrabutyl titanium, butoxy titanous chloride, zirconium naphthenate, zirconium caprylate, vanadium trichloride, chromium naphthenate, six carbonylation molybdenums, manganese octoate, iron trichloride, iron octoate, praseodynium iron, ferrocene, cobalt octoate, cobalt naphthenate, sub-oleo-resinous acid cobalt, cobaltous benzoate, nickelocene, nickel octoate, nickel naphthenate, venus crystals, cupric octoate, copper naphthenate, zinc octoate, zinc naphthenate, cadmium nitrate, naphthenic acid cadmium, phenyl mercurial, mercury naphthenate, triphenyl aluminum, aluminum stearate, acetic acid gallium, naphthenic acid indium, sad thallium, tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyl tin laurate, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous octoate, stannous oleate, stannous tartrate, phenylformic acid is sub-plumbous, sad sub-plumbous, oleic acid is sub-plumbous, lead naphthenate, butter of antimony, antimony pentachloride, dichloride antimony triphenyl, antimony triphenyl, bismuth naphthenate and acetic acid diethyl bismuth etc.
Preferably, catalyzer is metallic catalyzer.Further preferably, described metallic catalyzer is selected from: tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous oleate, stannous tartrate, dibutyl tin laurate, at least one in stannous octoate and metallic naphthenate.Again further preferably, metallic catalyzer is metallic naphthenate.Still more preferably, metallic naphthenate is selected from least one in naphthenic acid mantoquita, naphthenic acid zinc salt, naphthenic acid lead salt, naphthenic acid lithium salts, naphthenic acid cobalt salt, naphthenic acid nickel salt, naphthenic acid cadmium salt, naphthenic acid mercury salt, naphthenic acid indium salt and bismuth naphthenate salt.
In some cases, also can not add catalyzer, directly be reacted by reactant B and Amino End Group, terminal hydroxy group or the tertiary amine holding sulfydryl to replace or pyridine.
Described mixture and reactant A are reacted, obtains described antimicrobial compounds;
Wherein, described reactant A is selected from propane sultone, butyl sultone, β-propiolactone, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +with annular phosphate, wherein X is selected from Br, Cl and I, v be not less than 1 integer, Mt +be selected from Li +, Na +, K +, NH 4 +, Ag +, 1/2Mg 2+with 1/2Ca 2+, wherein said annular phosphate has the structure be shown below:
Wherein, R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl; R 6be selected from the C that divalence does not replace or replaces 1-6alkyl.
In reactant A, due to propane sultone and the attack of the acceptant nucleophilic reagent of carbon atom be connected with Sauerstoffatom in butyl sultone, and the first step is reacted in the mixture obtained and be there is the good tertiary amine nitrogen atom of nucleophilicity, therefore ring-opening reaction can be there is between the mixture that reactant A and the first step are obtained by reacting, form C-N key, on tertiary amine, three grades of nitrogen-atoms are because this in turn increases a linking group, define quaternary ammonium group, together form zwitterionic compound with sulfonic acid group.
When reactant A is annular phosphate (such as 2-oxyethyl group-2-oxygen-1,3,2-dioxaphospholane, i.e. EOP) time, the carbon atom that ring is connected with Sauerstoffatom can accept the attack of three grades of nitrogen-atoms, there is ring-opening reaction, thus make three grades of nitrogen-atoms become quaternary ammonium group, constitute zwitterionic compound together with phosphate group.And the ring of the compound such as propiolactone, butyrolactone, because atomicity is less, ring strain is larger, also be easier to open loop, therefore under three grades of nitrogen-atoms that nucleophilicity is strong exist, also ring-opening reaction can occur, form quaternary ammonium group, generate a carboxyl simultaneously, define zwitterionic compound.
Equally similarly, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +deng in compound, because the electronegativity of X (halogen such as Cl, Br, I) atom is large, the key formed with carbon atom is more weak, easily leave away, be attached thereto the carbon atom connect and be therefore also easily subject to nucleophilic reagent attack, therefore under three grades of nitrogen-atoms attacks, C-N key can be formed, form quaternary ammonium group, form zwitterionic compound with carboxyl or sulfonic acid group.Similar; the carboxylic metallic salt that other leavings group replaces; similar nucleophilic substitution reaction can occur, and other leavings groups include but not limited to, p-toluenesulfonyl (-OTs), methylsulfonyl (-OMs) and trifyl (-OTf) etc.
For the preparation of the solvent of antimicrobial compounds, include but not limited to the organic solvents such as ethers, ketone, aromatic compound, nitrile, ester class and amides.Solvent itself can also be the mixture of several solvent composition, such as the mixture etc. of above two or more solvent.Solvent is selected to be subject to reactants dissolved degree, temperature of reaction, the chemically reactive impact of solvent itself.Usually, easily with the solvent of-N=C=O radical reaction, as water, alcohol, amine and carboxylic acid etc. are not suitable as the solvent of this reaction.Therefore, the solvent used in the present embodiment, need to carry out in advance dewater or except the operation such as alcohol.
Further preferably, ether solvent can be THF, Isosorbide-5-Nitrae-epoxy six ring, glycol dimethyl ether and tetrahydropyrans etc.; Ketones solvent can be acetone, butanone, pimelinketone, methyl phenyl ketone and sym.-diisopropylideneacetone etc.; Aromatic compound can be toluene, pyridine and imidazoles etc.; Ester class can be ethyl acetate, n-propyl acetate, n-butyl acetate, methyl-formiate and ethyl formate etc.; Nitrile can be acetonitrile, propionitrile and cyanobenzene etc.; Amides can be N-Methyl pyrrolidone, DMF and N,N-dimethylacetamide etc.Below be only the example to the common solvents that can be used for this reaction, and be not used in the scope of limitation reaction solvent.
In fact, any can the aprotic solvent of solubilizing reaction raw material, all may be used as reaction solvent, such as, ethylene carbonate (ethylenecarbonate), trimethylene carbonate (trimethylenecarbonate) etc.
For the preparation of the alr mode taked in the process of antimicrobial compounds, can be mechanical stirring, also can be that magnetic agitation etc. can the alr mode that fully contacts of realization response thing.
Adding of reactant solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be constant, also constantly can change along with the carrying out of reaction.
The separation of final product, also can adopt different separate modes for different Product Form, if non-precipitating thing, extraction or distillation mode can be adopted to purify; If precipitation, the modes such as centrifugal or filtration can be adopted to purify.
According to an embodiment of the invention on the other hand, the preparation method of antimicrobial compounds, comprises the following steps:
1) by a kind of pyridine with logical formula V structure, react with the reactant B with general formula (IV) structure, obtain a kind of mixture;
OCN-L-D(IV)
Wherein, Q is selected from-OH ,-NH 2,-SH; G ' is selected from divalence and does not replace or replace C 1-18alkyl, cycloalkyl and aryl; G 2with G 3be selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH independently of one another 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO ,-NO 2the C not replacing with monovalence or replace 1-7alkyl, cycloalkyl, aryl; D is selected from-COOH and-NCO; L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl.
In this single step reaction, there is functional group Q (-OH ,-the SH ,-NH in the pyridine of logical formula V structure 2), can there is typical nucleophilic addition in the isocyanate functional group (-NCO) with having in the reactant B of general formula (IV) structure, generate carbamate, thiocarbamate acid esters or urea formula structure.In reaction, the atom (O, S, N) that electronegativity in functional group Q is higher has lone-pair electron, and the carbon atom on isocyanate functional group, due to height electron deficiency, especially easily and nucleophilic reagent generation addition reaction, the structures such as carbamate, thiocarbamide, urea are formed.
Under having alkaline reagents (as tertiary amine, phosphine class) to exist, hydrogen atom in functional group Q, also may slough with hydrogen ion form, the negative ion of formation can strengthen the equiatomic nucleophilicity of O, S, N in functional group Q further, therefore can utilize as catalyzer.And at Lewis acid, as under the existence such as metal ion, organometallic compound, Sauerstoffatom in isocyanate groups can form coordinate bond with Lewis acid, a part electronics by Oxygen atom transfer on atoms metal, thus further increase the electropositivity of isocyanate groups carbon atom, be conducive to the attack accepting nucleophilic reagent, therefore this class Lewis acid also can use as catalyzer.
In the preparation using catalyzer, preferably, catalyzer is one or more in organic amine compound, phosphines and metallic catalyzer.
Wherein organic amine can be divided into a few class: aliphatics amine, e.g., N, N-dimethylcyclohexylamine, two (2-dimethylaminoethyl) ether, N, N, N ', N '-tetramethyl-Alkylenediamine, triethylamine and N, N-dimethyl benzylamine etc.; Alicyclic amine, has triethylenediamine (Gu amine, DABCO), N-ethylmorpholine, N-methylmorpholine, N, N '-diethyl piperazine and dimethylamino hexanaphthene; Aromatic amine, has DMA, pyridine and DMAP (N, N-lutidine) etc.The general character of these aminated compoundss is, they all have alkalescence, can the carrying out of accelerated reaction.Meanwhile, they all contain three grades of nitrogen-atoms or pyridine nitrogen atom, therefore not containing active N-H key or O-H key, can not with isocyanate reaction.
Phosphines, similar with aminated compounds, be also the effect playing alkali, accelerated reaction is carried out.Phosphines, can include but not limited to, various tertiary phosphine, and three organic groups wherein replacing three hydrogen atoms can be identical, also can be incomplete same.By the tertiary phosphine that three same organic groups replace, include but not limited to, triphenylphosphine, trimethyl-phosphine, triethyl phosphine, three n-propyl phosphines, tri isopropyl phosphine, tri-n-butyl phosphine and tri-butyl phosphine etc.By the tertiary phosphine that not identical organic group replaces, include but not limited to, dimethylphenylphosphine, methyldiphenyl base phosphine, diethyl Phenylphosphine and ethyldiphenylphosphine etc.
Metallic catalyzer, because metal ion can be combined formation title complex by the Sauerstoffatom in isocyanate groups usually, cause the electronics on Sauerstoffatom to shift to atoms metal, increase the electropositivity being attached thereto the carbon atom connect, make the attack of its more acceptant nucleophilic reagent.Containing metal catalyzer, can include but not limited to, the inorganic salt, carboxylate salt, phenates, metal alkyl compound etc. of metal, and wherein carboxylate salt can be divided into again the alkyl salt of straight or branched and naphthenate circlewise.Contained metallic element mainly contains basic metal (lithium, sodium, potassium, rubidium, caesium etc.), alkaline-earth metal (magnesium, calcium, strontium, barium), transition metal (uranium, cerium, titanium, zirconium, vanadium, chromium, molybdenum, manganese, iron, cobalt, nickel, copper, zinc, cadmium, mercury etc.), aluminium, gallium, indium, thallium, tin, lead, antimony and bismuth etc., but is also not limited thereto.
Conventional metallic catalyzer includes but not limited to, lithium acetate, sad lithium, naphthenic acid lithium, sodium 2,4,5-trichlorophenate, sodium stearate, potassium acetate, potassium octanoate, lime acetate, calcium octoate, naphthenic acid strontium, barium acetate, uranyl nitrate, cerous nitrate, titanium tetrachloride, dichloride dibutyl titanium, tetrabutyl titanium, butoxy titanous chloride, zirconium naphthenate, zirconium caprylate, vanadium trichloride, chromium naphthenate, six carbonylation molybdenums, manganese octoate, iron trichloride, iron octoate, praseodynium iron, ferrocene, cobalt octoate, cobalt naphthenate, sub-oleo-resinous acid cobalt, cobaltous benzoate, nickelocene, nickel octoate, nickel naphthenate, venus crystals, cupric octoate, copper naphthenate, zinc octoate, zinc naphthenate, cadmium nitrate, naphthenic acid cadmium, phenyl mercurial, mercury naphthenate, triphenyl aluminum, aluminum stearate, acetic acid gallium, naphthenic acid indium, sad thallium, tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyl tin laurate, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous octoate, stannous oleate, stannous tartrate, phenylformic acid is sub-plumbous, sad sub-plumbous, oleic acid is sub-plumbous, lead naphthenate, butter of antimony, antimony pentachloride, dichloride antimony triphenyl, antimony triphenyl, bismuth naphthenate and acetic acid diethyl bismuth etc.
Preferably, catalyzer is metallic catalyzer.Further preferably, described metallic catalyzer is selected from: tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous oleate, stannous tartrate, dibutyl tin laurate, at least one in stannous octoate and metallic naphthenate.Again further preferably, metallic catalyzer is metallic naphthenate.Still more preferably, metallic naphthenate is selected from least one in naphthenic acid mantoquita, naphthenic acid zinc salt, naphthenic acid lead salt, naphthenic acid lithium salts, naphthenic acid cobalt salt, naphthenic acid nickel salt, naphthenic acid cadmium salt, naphthenic acid mercury salt, naphthenic acid indium salt and bismuth naphthenate salt.
In some cases, also can not add catalyzer, directly be reacted by reactant B and Amino End Group, terminal hydroxy group or the tertiary amine holding sulfydryl to replace or pyridine.
In a first step, the nitrogen-atoms in pyridine compounds and their does not participate in reaction.Pyridine compounds and their effect is here, is first to provide the functional group Q of a nucleophilicity, reacts with the reactant B containing isocyanate groups; Secondly, the pyridine nitrogen atom of pyridine compounds and their itself is the parent of the quaternary ammonium salt structure unit of final antimicrobial compounds, and in subsequent synthetic procedures, pyridines nitrogen-atoms becomes level Four nitrogen-atoms, i.e. pyridine quaternary ammonium salt structure because of a new formation C-N key.The amount of carbon atom of pyridine compounds and their itself does not affect the carrying out of reaction, as long as pyridine compounds and their has the group that can react with isocyanate groups, such as hydroxyl, sulfydryl or amino, namely can carry out the first step reaction.
General character for the preparation of the pyridine of antimicrobial compounds is that it all has one or more group containing reactive hydrogen atom, and as hydroxyl, amino, sulfydryl etc., pyridine compounds and their reacts with this and isocyanate groups, together coupled.
Exemplary pyridine can include but not limited to, 4-4-hydroxymethylpiperidine, 4-aminopyridine, 4-mercaptopyridine and 2,6-dimethyl-4-aminopyridine etc.Hydrogen atom on pyridine ring, can by halogen (-F ,-Cl ,-Br ,-I) or pseudohalogen (-CN ,-SCN ,-OCN etc.), alkoxyl group (-OCH 3,-OCH 2cH 3,-OPr etc.) ,-NO and-NO 2deng group or C 1-7the substituting group such as alkyl, aryl replaced, substituent number is at most 7.
2) described mixture and reactant A are reacted, obtain described antimicrobial compounds;
Described reactant A is selected from propane sultone, butyl sultone, β-propiolactone, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +with annular phosphate, wherein X is selected from Br, Cl and I, v be not less than 1 integer, Mt +be selected from Li +, Na +, K +, NH 4 +, Ag +, 1/2Mg 2+with 1/2Ca 2+, wherein said annular phosphate has the structure be shown below:
Wherein, R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl; R 6be selected from the C that divalence does not replace or replaces 1-6alkyl.
In reactant A, due to the attack of the acceptant nucleophilic reagent of the carbon atom be connected with Sauerstoffatom in sultones, and the first step is reacted in the mixture obtained and be there is the good tertiary N atom of nucleophilicity, therefore ring-opening reaction can be there is between the mixture that reactant A and the first step are obtained by reacting, form C-N key, on tertiary amine, three grades of nitrogen-atoms are because this in turn increases a linking group, define quaternary ammonium group, together form zwitterionic compound with sulfonic acid group.Similar to sultones, the carbon atom be connected with Sauerstoffatom in annular phosphate can accept the attack of three grades of nitrogen-atoms, ring-opening reaction occurs, thus makes three grades of nitrogen-atoms become quaternary ammonium group, and constitute zwitterionic compound together with phosphate group.And the ring of the compound such as propiolactone, butyrolactone, because atomicity is less, ring strain is larger, also be easier to open loop, therefore under three grades of nitrogen-atoms that nucleophilicity is strong exist, also ring-opening reaction can occur, form quaternary ammonium group, generate a carboxyl simultaneously, form zwitterionic compound.X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +deng in compound, the halogen atoms such as Cl, Br, I due to electronegativity large, the key formed with carbon atom is more weak, easily leave away, be attached thereto the carbon atom connect and be therefore also easily subject to nucleophilic reagent attack, therefore under three grades of nitrogen-atoms attacks, C-N key can be formed, form quaternary ammonium group, and form zwitterionic compound with carboxyl or sulfonic group.Similar; the carboxylic metallic salt that other leavings group replaces; similar nucleophilic substitution reaction can occur, and other leavings groups include but not limited to, p-toluenesulfonyl (-OTs), methylsulfonyl (-OMs) and trifyl (-OTf) etc.
For the preparation of the solvent of antimicrobial compounds, include but not limited to the organic solvents such as ethers, ketone, aromatic compound, nitrile, ester class and amides.Solvent itself can also be the mixture of several solvent composition, such as the mixture etc. of above two or more solvent.Solvent is selected to be subject to reactants dissolved degree, temperature of reaction, the chemically reactive impact of solvent itself.Usually, easily with the solvent of-N=C=O radical reaction, as water, alcohol, amine and carboxylic acid etc. are not suitable as the solvent of this reaction.Therefore, the solvent used in the present embodiment, need to carry out in advance dewater or except the operation such as alcohol.
Further preferably, ether solvent can be THF, Isosorbide-5-Nitrae-epoxy six ring, glycol dimethyl ether and tetrahydropyrans etc.; Ketones solvent can be acetone, butanone, pimelinketone, methyl phenyl ketone and sym.-diisopropylideneacetone etc.; Aromatic compound can be toluene, pyridine and imidazoles etc.; Ester class can be ethyl acetate, n-propyl acetate, n-butyl acetate, methyl-formiate and ethyl formate etc.; Nitrile can be acetonitrile, propionitrile and cyanobenzene etc.; Amides can be N-Methyl pyrrolidone, DMF and N,N-dimethylacetamide etc.
Below be only the example to the common solvents that can be used for this reaction, and be not used in the scope of limitation reaction solvent.In fact, any can the aprotic solvent of solubilizing reaction raw material, all may be used as reaction solvent, such as, ethylene carbonate (ethylenecarbonate), trimethylene carbonate (trimethylenecarbonate) etc.
For the preparation of the alr mode taked in the process of antimicrobial compounds, can be mechanical stirring, also can be that magnetic agitation etc. can the alr mode that fully contacts of realization response thing.
Adding of reactant solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be constant, also constantly can change along with the carrying out of reaction.
The separation of final product, also can adopt different separate modes for different Product Form, if non-precipitating thing, extraction or distillation mode can be adopted to purify; If precipitation, the modes such as centrifugal or filtration can be adopted to purify.
The raw material that embodiment is used below and other chemical reagent all obtain by commercial sources.Use after adopting means well known in the art to carry out purifying if desired, as oxidation component in the dewatering of tertiary amine, tertiary amine removal, remove primary amine in tertiary amine and secondary amine etc., these purifying can realize by distilling, shunting, extract or add the means such as reaction reagent usually.
Embodiment 1
Take 44.6g (0.2mol) isophorone diisocyanate (IPDI), structure is as follows,
Join with in churned mechanically round-bottomed flask, after adding dibutyl tin dilaurate (DBTDL) catalyzer of 0.2ml, under stirring and 30 DEG C of temperature, slowly drip 17.8g (0.2mol) dimethylethanolamine (HOCH with dropping funnel 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then drip 24.4g (0.2mol) propane sultone (hereinafter referred to as 1,3-PS, under structure is shown in) be dissolved in the anhydrous THF of 400mL,
Dropwise rear continuation reaction 1h, be precipitated, centrifugation is purifying for several times, obtains the antimicrobial compounds containing terminal isocyanate group described in the present embodiment.
Isophorone diisocyanate is have employed as the reactant containing isocyanate groups in the present embodiment, be understandable that, any compound containing at least two isocyanate groups can be obtained by reacting the similar antimicrobial compounds containing terminal isocyanate group by above-mentioned.Owing to there is multiple isocyanate groups in polyisocyanate compound, when nucleophilic reagent is inexcessive, the multiple isocyanate groups in a molecule only have one to react, and other isocyanate groups is carried in last antimicrobial compounds.The carbon atom number of polyisocyanate compound or molecular weight itself do not affect the carrying out of reaction, if it can with nucleophilic reagent generation nucleophilic addition.Isocyanate structural for the preparation of the present embodiment can also be the isocyanate terminated organism comprising at least one carboxyl, this organism backbone structure can be substituted or unsubstituted aliphatics, cycloaliphatic ring race, heterochain, heterocycle, aromatic structure, and wherein substituting group can include but not limited to Cl, Br, I ,-OCH 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO and-NO 2deng atom or group.
In the reaction, the effect that propane sultone plays is the nucleophilic attack by receiving atom of tertiary amine N, opens five-ring and forms sulfonic acid group, forming quaternary ammonium group simultaneously.Due to the attack of the acceptant nucleophilic reagent of the carbon atom be connected with Sauerstoffatom in sultones, and the first step is reacted in the mixture obtained and be there is the good tertiary N atom of nucleophilicity, therefore ring-opening reaction can be there is between the mixture that reactant A and the first step are obtained by reacting, form C-N key, on tertiary amine, three grades of nitrogen-atoms are because this in turn increases a linking group, define quaternary ammonium group, together define zwitterionic compound with sulfonic acid group.Similar, other sultones, as butyl sultone and ethyl sulfonic acid lactone, owing to can there is similar reaction, also can be used in second step reaction.
Although adopt dibutyl tin dilaurate as catalyzer in the present embodiment, catalyzer is not always necessary, active higher organic amine compound, directly can react with the compound containing multiple isocyanate groups, and not need the participation of catalyzer.In the preparation using catalyzer, preferably, catalyzer is one or more in organic amine compound, phosphines and metallic catalyzer.Such as, triethylamine, triphenylphosphine, two sad dibutyl tins etc.
In some cases, also can not add catalyzer, directly be reacted by reactant B and Amino End Group, terminal hydroxy group or the tertiary amine holding sulfydryl to replace or pyridine.
For the preparation of the amine of the present embodiment, outside N, N-dimethylethanolamine, can also be N, N-diethylethanolamine, N, N-dimethyl-ethylenediamine, N, N-diη-propyl thanomin, N, N-diisopropyl ethanolamine, N, N-di-n-butyl thanomin, N, N-bis-n-pentyl thanomin, N, N-dicyclohexyl thanomin or 3,3'-imido grpup two (N, N-dimethyl propylamine) etc.
And, although the present embodiment adopts amine, can also adopt with end alcohol radical or tertiary amines or the pyridines organism of holding sulfydryl, as 4-4-hydroxymethylpiperidine, 2,6-dimethyl-4-aminopyridine.
Embodiment 2
Take 50.1g (0.2mol) '-diphenylmethane diisocyanate (MDI), join with in mechanical stirring round-bottomed flask, after adding the dibutyl tin dilaurate catalyzer of 0.2ml, under stirring and 30 DEG C of temperature, 23.5g (0.2mol) N, N-diethylethanolamine (HOCH is slowly dripped with dropping funnel 2cH 2n (CH 2cH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then drip 24.4g (0.2mol) propane sultone be dissolved in the anhydrous THF of 400mL, dropwise rear continuation reaction 1h, obtain oily matter, adopt polar aprotic solvent DMSO extraction, except desolventizing, purifying, obtains the antimicrobial compounds containing terminal isocyanate group described in the present embodiment.
Embodiment 3
Take 33.6g (0.2mol) hexamethylene diisocyanate (HDI), join with in mechanical stirring round-bottomed flask, add the stannous octoate (Sn (CH of 0.2ml 3(CH 2) 3cH (C 2h 5) CO 2) 2) after catalyzer, under stirring and 30 DEG C of temperature, slowly drip the N of 17.8g (0.2mol) with dropping funnel, N-dimethylethanolamine (HOCH 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, and in filtrate, drip 23.6g (0.2mol) sodium chloroacetate (ClCH be dissolved in the anhydrous THF of 400mL 2cO 2na), react 24h at 20 DEG C of temperature, obtain crude product, centrifugation is purifying for several times, obtains the antimicrobial compounds containing terminal isocyanate group described in the present embodiment.
In the reaction, the effect that sodium chloroacetate plays is the nucleophilic attack by receiving atom of tertiary amine N, chlorine atom of leaving away, and forms quaternary ammonium group.Similar, other halogen (Br, I etc.) or other be easy to the carboxylic acid sodium that leavings group (OTs, OMs, OTf etc.) replaces, as bromoacetic acid sodium, sodium iodoacetate, 2-chloropropionic acid sodium, 3-chloropropionic acid sodium, 2 bromopropionic acid sodium, 3-bromo-propionic acid sodium, 2-iodopropionic acid sodium, 3-iodopropionic acid sodium, or the more halogenated carboxylic acids etc. of Long carbon chain, because halogen is easily left away under atom N nucleophillic attack, similar reaction can be there is, also can be used in second step reaction.
The dropping of sodium chloroacetate solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be constant, also constantly can change along with the carrying out of reaction.
Embodiment 4
Take 34.8g (0.2mol) tolylene diisocyanate (containing 2,4-tolylene diisocyanate and 2, the mixture of 6-tolylene diisocyanate) join with in mechanical stirring round-bottomed flask, after adding the dibutyltin dilaurate catalyst (DBTDL) of 0.2ml, under stirring and 30 DEG C of temperature, slowly drip 17.8g (0.2mol) dimethylethanolamine (HOCH with dropping funnel 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, and in filtrate, drip 14.4g (0.2mol) beta-propiolactone be dissolved in 400mL butanone, structure is as follows,
Continue reaction 6h at 40 DEG C of temperature, obtain product, natural filtration, purifying, obtain the antimicrobial compounds containing terminal isocyanate group described in the present embodiment.
In the reaction, the effect that beta-propiolactone plays is by receiving the nucleophilic attack of atom of tertiary amine N, thus open loop form a carboxyl, form quaternary ammonium group simultaneously.Similar, other lactone, as beta-butyrolactone, gamma-butyrolactone, β-valerolactone and γ-valerolactone etc., owing to can there is similar reaction, also can be used, be generated corresponding zwitterionic compound in second step reaction.
The dropping of beta-propiolactone solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be constant, also constantly can change along with the carrying out of reaction.
Embodiment 5
Taking 52.5g (0.2mol) dicyclohexyl methane diisocyanate (HMDI) joins with in mechanical stirring round-bottomed flask, after adding the dibutyltin dilaurate catalyst of 0.2ml, 17.8g (0.2mol) N, N-dimethyl-ethylenediamine (H is slowly dripped with dropping funnel under stirring and 30 DEG C of temperature 2nCH 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then 24.4g (0.2mol) propane sultone be dissolved in 400mL anhydrous propanone is dripped, dropwise rear continuation reaction 1h, be precipitated, centrifugation is purifying for several times, obtains the antimicrobial compounds containing terminal isocyanate group described in the present embodiment.
Embodiment 6
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in mechanical stirring round-bottomed flask, after adding the dibutyl tin dilaurate catalyzer of 0.2ml, 17.8g (0.2mol) N, N-dimethyl-ethylenediamine (H is slowly dripped with dropping funnel under stirring and 30 DEG C of temperature 2nCH 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, and in filtrate, drip 14.4g (0.2mol) beta-propiolactone be dissolved in the anhydrous butanone of 400mL, reaction 6h is continued at 40 DEG C of temperature, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
Embodiment 7
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in mechanical stirring round-bottomed flask, after adding the dibutyltin dilaurate catalyst of 0.2ml, 37.4g (0.2mol) 3 is slowly dripped with dropping funnel under stirring and 30 DEG C of temperature, two (the N of 3'-imido grpup, N-dimethyl propylamine), skeleton symbol is
Dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then 48.8g (0.4mol) propane sultone be dissolved in 400mL anhydrous ethyl acetate is dripped, dropwise rear continuation reaction 1h, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
For the preparation of the amine of the present embodiment, except the two (N of 3,3'-imido grpup, N-dimethyl propylamine) outside, can also be that other have tertiary amine or the pyridine of reactive hydrogen atom, such as but not limited to, N, N-dimethylethanolamine, N, N-dimethyl-ethylenediamine, N, N-diethylethanolamine, N, N-diisopropyl ethanolamine, N, N-di-n-butyl thanomin, N, N-bis-n-pentyl thanomin, N, N-dicyclohexyl thanomin, 4-4-hydroxymethylpiperidine and 2,6-dimethyl-4-aminopyridine etc.
Embodiment 8
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in mechanical stirring round-bottomed flask, after adding the dibutyltin dilaurate catalyst of 0.2ml, 21.8g (0.16mol) 4-4-hydroxymethylpiperidine is slowly dripped with dropping funnel under stirring and 30 DEG C of temperature, dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then 24.4g (0.2mol) propane sultone be dissolved in the anhydrous THF of 400mL is dripped, dropwise rear continuation reaction 1h, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
For the preparation of the nitrogenous compound of the present embodiment with a functional group containing reactive hydrogen atom, such as hydroxyl, amino and sulfydryl, can be pyridine compounds and their, can also be tertiary amine, and this type organic can be replace or non-substituted aliphatics, cycloaliphatic ring race or aromatic series etc.Except 4-4-hydroxymethylpiperidine, can also be 2,6-dimethyl-4-aminopyridine, N, N-dimethylethanolamine, N, N-dimethyl-ethylenediamine, N, N-diethylethanolamine, DIPEA, N, N-di-n-butyl thanomin, N, two (the N of N-bis-n-pentyl thanomin, N, N-dicyclohexyl thanomin, 3,3'-imido grpups, N-dimethyl propylamine), 4-thiopurine methyltransferase pyridine or 2,6-dimethyl-4-aminopyridine etc.Above as just the example to available amine/pyridine compounds and their, and be not used in the scope of nitrogenous compound in this reaction of limitation, any pyridine containing reactive hydrogen atom or tertiary amine compounds, all may as reaction substrate, such as, 4-pyridone.
Embodiment 9
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in mechanical stirring round-bottomed flask, after adding the stannous octoate catalyst of 0.2ml, 24.4g (0.2mol) 2 is slowly dripped with dropping funnel under stirring and 30 DEG C of temperature, 6-dimethyl-4-aminopyridine, dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then 24.4g (0.2mol) propane sultone be dissolved in the anhydrous THF of 400mL is dripped, dropwise rear continuation reaction 1h, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
Although adopt stannous octoate as catalyzer in the present embodiment, catalyzer is not always necessary, active higher organic amine compound, directly can react with the compound containing multiple isocyanate groups, and not need the participation of catalyzer.In the preparation using catalyzer, the material used as catalyzer can see the description in embodiment 1.
For the preparation of the nitrogenous compound that the present embodiment adopts, in its structure except pyridine nitrogen atom or tertiary amine nitrogen atom, also there is the group with reactive hydrogen atom, as amino, hydroxyl and sulfydryl etc.Exemplarily, nitrogenous compound, except 2, outside 6-dimethyl-4-aminopyridine, can also be N, N-dimethylethanolamine, N, N-dimethyl-ethylenediamine, N, N-diethylethanolamine, N, N-diisopropyl ethanolamine, N, N-di-n-butyl thanomin, N, N-bis-n-pentyl thanomin, N, N-dicyclohexyl thanomin, 3, two (the N of 3'-imido grpup, N-dimethyl propylamine), 4-4-hydroxymethylpiperidine, 4-thiopurine methyltransferase pyridine, 2-dimethylamino sulfur alcohol, 2-diethylamino ethanethiol, 2-dimethylamino propylmercaptan, 2-diethylin propylmercaptan, 2, 6-diethyl-4-aminopyridine or 2 with 6 on by other alkyl, halogen (-F,-Cl,-Br,-I),-NO 2, the 4-aminopyridine etc. that replaces of alkoxyl group.
Embodiment 10
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in mechanical stirring round-bottomed flask, after adding the dibutyl tin dilaurate catalyzer of 0.2ml, under stirring and 30 DEG C of temperature, slowly drip 17.8g (0.2mol) dimethylethanolamine (HOCH with dropping funnel 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then 42.2g (0.2Mol) the 2-bromine ethyl sulfonic acid sodium be dissolved in the anhydrous THF of 400mL is dripped, dropwise rear continuation reaction 1h, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
In the reaction, the effect that 2-bromine ethyl sulfonic acid sodium plays is the nucleophilic attack by receiving atom N, bromine atoms of leaving away, and forms quaternary ammonium group, generates final zwitterionic compound.Similar, other halogen or other be easy to the sodium sulfonate that leavings group replaces, if 2-chloroethene sodium sulfonate, 2-iodine ethyl sulfonic acid sodium, 2-chlorine propanesulfonate, 2-bromine propanesulfonate, 2-iodine propanesulfonate or 2-are to benzene sulfonyl propanesulfonate etc., due to similar reaction can be there is, also can be used in second step reaction.
The dropping of 2-bromine ethyl sulfonic acid sodium solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be take certain constant speed to drip, and also constantly can change rate of addition along with the carrying out of reaction.
Embodiment 11
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in mechanical stirring round-bottomed flask, after adding the dibutyl tin dilaurate catalyzer of 0.2ml, under stirring and 30 DEG C of temperature, slowly drip 17.8g (0.2mol) dimethylethanolamine (HOCH with dropping funnel 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then 37.4g (0.22mol) the 4-bromo-butyric acid sodium be dissolved in the anhydrous THF of 400mL is dripped, dropwise rear continuation reaction 1h, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
In the reaction, the effect that 4-bromo-butyric acid sodium plays is the nucleophilic attack by receiving atom N, bromine atoms of leaving away, and forms quaternary ammonium group.Similar, the carboxylic metallic salt that other halogen or other leavings groups replace.Wherein halogen includes but not limited to, chlorine, bromine and iodine etc.; Other leavings groups include but not limited to, p-toluenesulfonyl (-OTs), methylsulfonyl (-OMs) and trifyl (-OTf) etc.; Metal in carboxylic metallic salt, includes but not limited to, lithium, sodium, potassium, ammonium, silver, magnesium and calcium etc.; Carboxylic acid includes but not limited to, the carboxylic acid of acetic acid, propionic acid, butyric acid, valeric acid and more carbon atoms; Halogen or the position residing for other substituting groups can be the positions such as α, β, γ of closing on carboxylic acid carbon atom.The carboxylic metallic salt of typical halogen substiuted, include but not limited to, sodium chloroacetate, bromoacetic acid sodium, sodium iodoacetate, 2-chloropropionic acid sodium, 3-chloropropionic acid sodium, 2 bromopropionic acid sodium, 3-bromo-propionic acid sodium, 2-iodopropionic acid sodium, 3-iodopropionic acid sodium, 4-chloro-butyric acid sodium and 4-iodine Sodium propanecarboxylate etc.Because above-mentioned substance with tertiary amine, similar reaction can occur, also can be used in second step reaction.
The dropping of 4-bromo-butyric acid sodium solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be constant, also constantly can change along with the carrying out of reaction.
The separation of final product, also can adopt different separate modes for different Product Form, if oily matter or sticky solid, extraction or distillation mode can be adopted to purify; If precipitation can adopt the modes such as centrifugal or filtration.
Embodiment 12
Measure 9.3g (0.2mol) ethanol and 20.2g (0.2mol) triethylamine (TEA) is dissolved in the anhydrous THF of 100ml, and join in the round-bottomed flask with magnetic agitation, at-20 DEG C of cooling 20min, keep-20 DEG C, and in reaction vessel, drip the chloro-2-oxygen-1 of 28.392g (0.2mol) 2-being dissolved in the anhydrous THF of 30ml, 3, 2-dioxaphospholane (COP), after dropwising, leave standstill at-20 DEG C, thing to be precipitated is separated out, throw out is distilled under vacuo and obtains 2-oxyethyl group-2-oxygen-1, 3, 2-dioxaphospholane (EOP).
Taking 44.6g (0.2mol) isophorone diisocyanate (IPDI) joins with in churned mechanically round-bottomed flask, after adding the dibutyl tin dilaurate catalyzer of 0.2ml, under stirring and 30 DEG C of temperature, slowly drip 17.8g (0.2mol) dimethylethanolamine (HOCH with dropping funnel 2cH 2n (CH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then at 75 DEG C, drip 30.4g (0.2mol) EOP be dissolved in the anhydrous THF of 400mL, dropwise rear continuation reaction 24h, obtain crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
In above-mentioned reaction, the P atom of ethanol attack COP, loses HCl between the two further, substitution reaction occurs and obtains product EOP.Similar, can with COP occur substitution reaction except ethanol, can also be other fatty alcohols, alicyclic alcohol or aromatic alcohol etc., as methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, Pentyl alcohol, n-hexyl alcohol, n-Heptyl alcohol, vinyl alcohol, vinylcarbinol, ring propyl alcohol, cyclopentanol, hexalin or phenylcarbinol etc.
Although the present embodiment adopts COP as phosphorus reagent, for phosphorus reagent can also be other 2-halos-1,3,2-dioxy phosphorus heterocycle compounds, wherein ring atom number can be 4,5,6,7,8 or 9, is preferably 5,6 and 7, i.e. 2-halo-1,3,2-dioxaphospholane, 2-halo-1,3,2-dioxaphosphorinane and 2-halo-1,3,2-dioxy phosphorus heterocycle heptane.In this reaction, the phosphorus atom on 2-halo-1,3,2-dioxy phosphorus heterocycle compounds, except being connected with Sauerstoffatom, is also connected with a halogen atom.As US granted patent US2,982, disclosed by 862, the halogen atom in this compounds comprises chlorine, bromine and iodine, owing to having leaving away property preferably, easily replace by the alkoxyl group on alcohol.The hydrogen atom that carbon atom connects ring, can by one or more alkyl, and such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl etc. replaced.
Except COP, this compounds also includes but not limited to, 2-chloro-4, 5-dimethyl-1, 3, 2-dioxaphospholane-2-oxide compound, 2-chloro-1, 3, 2-dioxaphosphorinane-2-oxide compound, 2-chloro-5, 5-dimethyl-4-phenyl-1, 3, 2-dioxaphosphorinane-2-oxide compound, 2-chloro-4, 6-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide compound, 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide compound, 2-chloro-1, 3, 2-dioxy phosphorus heterocycle heptane-2-oxide compound, 2-chloro-1, 3, 2-dioxy phosphorus heterocycle octane-2-oxide compound, 2-bromo-1, 3, 2-dioxaphospholane-2-oxide compound, 2-bromo-1, 3, 2-dioxaphosphorinane-2-oxide compound and 2-bromo-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide compound etc.
Although the present embodiment adopts triethylamine as reaction promoter, but other can also be adopted not contain the tertiary amine of reactive hydrogen, such as, Trimethylamine 99, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine, N-methyldioctylamine, N, N-dimethyl cyclopentamine or N, N-dimethylcyclohexylamine etc.In this alcoholysis reaction, tertiary amine, as alkali, helps sloughing of HCl.
Although the present embodiment adopts THF as organic solvent, acetonitrile, DMF, DMSO, anhydrous butanone, anhydrous propanone, pimelinketone, toluene, ethyl acetate, n-propyl acetate, n-butyl acetate, acetonitrile, 1 can also be adopted, the mixture etc. of 4-epoxy six ring, N-Methyl pyrrolidone, pyridine, DMF or more two or more solvent.
In second step reaction, the effect that EOP plays is the nucleophilic attack of the C atom accepts atom N by being connected with O atom on ring, ring-opening reaction occurs, and forms quaternary ammonium group.
The dropping of EOP solution can be manual drop addition, also can be to adopt the dropping liquid machine of machinery to drip, and rate of addition can be constant, also constantly can change along with the carrying out of reaction.
The separation of final product, also can adopt different separate modes for different Product Form, if oily matter, organic solvent extracting can be adopted to fetch purification, or be purified by the mode of distilling product solution in organic solvent; If precipitation, the modes such as centrifugal or filtration can be adopted.
Embodiment 13
Measure 9.3g (0.2mol) ethanol and 20.2g (0.2mol) triethylamine (TEA) is dissolved in the anhydrous THF of 100ml, and join in the round-bottomed flask with magnetic agitation, at-20 DEG C of cooling 20min, keep-20 DEG C, and in reaction vessel, drip 28.392g (0.2mol) 2-chloro-5 being dissolved in the anhydrous THF of 30ml, 5-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide compound, after dropwising, leave standstill at-20 DEG C, thing to be precipitated is separated out, throw out is distilled under vacuo, removing impurity, obtain 2-oxyethyl group-2-oxygen-1, 3, 2-dioxaphosphorinane.
50.1g (0.2mol) '-diphenylmethane diisocyanate (MDI) is joined with in mechanical stirring round-bottomed flask, after adding the dibutyl tin dilaurate catalyzer of 0.2ml, 23.5g (0.2mol) N, N-diethylethanolamine (HOCH is slowly dripped with dropping funnel under stirring and 30 DEG C of temperature 2cH 2n (CH 2cH 3) 2), dropwise rear continuation reaction 1h, and continue stirring reaction 12h at this temperature, then at 70 DEG C, drip 30.4g (0.2mol) 2-oxyethyl group-2-oxygen-1 be dissolved in the anhydrous THF of 400mL, 3,2-dioxaphosphorinane, dropwises rear continuation reaction 24h, obtains crude product, centrifugation is purifying for several times, must containing the antimicrobial compounds of terminal isocyanate group.
The antimicrobial compounds that the embodiment of the present invention provides is the zwitterionic compound with terminal isocyanate group.Quaternary nitrogen atoms with positive charge can destroy microorganisms cytolemma, make protein denaturation and destroy cellularstructure.Mentioned microorganism includes but not limited to, intestinal bacteria, Salmonella typhimurium, Pseudomonas aeruginosa, streptococcus aureus, Candida albicans, sulphate reducing bacteria, gram-positive microorganism, Gram-negative bacteria, staphylococcus epidermidis, Bacillus subtilus, enterococcus faecalis, Corynebacterium xerosis and anthrax bacillus etc.Can be used for stoping infection, killing microorganism as anti-microbial agents or antibacterial reagent, or suppress microbial physiology function, and therefore can effectively treat the infection caused by these microorganisms, or control its pollution caused.
The antimicrobial compounds that the embodiment of the present invention provides by terminal isocyanate group, can realize the combination of chemical bond with material surface.Described antimicrobial compounds can be applied in multiple fields such as textiles, medicine, food and agricultural, but is not limited to above-mentioned field.Such as, isocyanate group can prepare more wash fast antibacterial fabric with the hydroxyl on fiber, cotton textiles, nylon surface or amino combination; With the hydroxyl of medical infusion lines, medical package material surface or amino can to combine, prepare antibacterial pharmaceutical prod, or combine with the hydroxyl of food product pack or food fresh keeping material surface or amino, prepare antibiotic packaging material.
Carry out intestinal bacteria (E.coli, American Type Culture Collection center ATCC25922) to the product of embodiment of the present invention 1-13 to test with the minimum inhibitory concentration of streptococcus aureus (S.aureas, ATCC6538).Wherein, minimum inhibitory concentration (minimuminhibitoryconcentration is called for short MIC) refers in certain circumstances, after 24h cultivates, the growth of bacterium can be made to be blocked and the Cmin of the antibacterial agent be observed.The method measuring minimum inhibitory concentration can be constant broth dilution method, micro-broth dilution method, agar dilution and E test.The antiseptic-germicide minimum inhibitory concentration test result of embodiment of the present invention 1-13 is as shown in table 1.
The antiseptic-germicide minimum inhibitory concentration (MIC, unit: μm ol/mL) of table 1 embodiment 1-13
The compound obtained in the embodiment of the present invention has very low Mlc for bacterium, is enough to ensure that bacterial population quantity is extremely low, very little to human health damage when using this compound.
With the glass surface of embodiment 1-13 products therefrom process cleaning, and adopt colony counting method to test its anti-microbial activity and sustainable antimicrobial activity, the present embodiment adopts bacterium to be intestinal bacteria and streptococcus aureus, and result is as shown in table 2.
The sustainable antimicrobial activity analysis (colony counting method) on table 2 antiseptic-germicide modified glass surface
According to upper table, the antimicrobial compounds that the embodiment of the present invention provides, for common bacteria as intestinal bacteria and streptococcus aureus, all has very excellent anti-microbial property and persistence.Even if through repeatedly washing, also only having there is weakening very by a small margin in anti-microbial property, but still remains on more than 94%.
The antimicrobial compounds that embodiments of the invention provide, there is reactive functional groups---isocyanic ester, this reactive group can with the functional group that exists on multiple material interface, as cotton fibre, flaxen fiber, trevira (as terylene PET), hydroxyl in poly(lactic acid) (PLA), amino in nylon, and wool, cashmere, silk, amide group etc. in polyamide fibre and aramid fiber, there is chemical bonding effect, on material interface, grappling has the component of germ resistance, thus give by the material of reactive antimicrobial compounds process or the lasting antibacterial didirtresistance of product surface.Meanwhile, preparation method's technique of this compound is simple, and condition easily controls, and is easy to industrialization, provides conveniently for it uses in broad range.The antimicrobial compounds that the embodiment of the present invention provides has wide prospects for commercial application.
Above content is the further description done the embodiment of the present invention in conjunction with concrete embodiment, be convenient to these those skilled in the art and can understand and apply the invention the antimicrobial compounds that embodiment provides, can not assert that embodiments of the present invention are confined to these examples.It should be pointed out that for a person skilled in the art, under the prerequisite of design not departing from the embodiment of the present invention, can also make some other distortion or improvement, these distortion or improvement do not depart from the protection domain that claim defines.

Claims (32)

1. an antimicrobial compounds, has the structure of general formula (I):
Wherein,
R 1be selected from OCN-L-NHCOOR ', OCN-L-NHCONHR ', OCN-L-NHCOSR ', OCN-L-COOR ' and OCN-L-COONHR ';
L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
R ' is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
R 2with R 3be selected from the C that monovalence does not replace or replaces independently of one another 1-18alkyl, cycloalkyl and aryl;
R 4be selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
Z is selected from-COO ,-SO 3with-OPO 2oR 5;
R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl.
2. antimicrobial compounds according to claim 1, wherein, R 2with R 3identical group or not identical group.
3. antimicrobial compounds according to claim 2, wherein, R 2with R 3be selected from-(CH independently of one another 2) ucH 3, wherein, u be not less than 0 and be not more than 17 integer.
4. antimicrobial compounds according to claim 1, wherein, Z is-SO 3.
5. antimicrobial compounds according to claim 1, wherein, Z is-CO 2.
6. antimicrobial compounds according to claim 1, wherein, Z is-OPO 2oR 5.
7. antimicrobial compounds according to claim 6, wherein R 5for-(CH 2) wcH 3, wherein w be not less than 0 and be not more than 5 integer.
8. antimicrobial compounds according to claim 1, wherein, R 4-(CH is selected from independently of one another with R ' 2) n-, n be not less than 1 and be not more than 18 integer.
9. antimicrobial compounds according to claim 1, wherein, R 1be selected from OCN-L-NHCOOR ' and OCN-L-NHCONHR '.
10. antimicrobial compounds according to claim 1, wherein, L has the structure be shown below:
11. 1 kinds of antimicrobial compoundss, have the structure of general formula (II):
Wherein,
G 1be selected from OCN-M-NHCOOG ', OCN-M-NHCONHG ', OCN-M-NHCOSG ', OCN-M-COOG ' and OCN-M-COONHG ';
M is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
G ' is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
G 2with G 3be selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH independently of one another 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO ,-NO 2the C not replacing with monovalence or replace 1-7alkyl, cycloalkyl, aryl;
G 4be selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
X is selected from-COO ,-SO 3with-OPO 2oR 5;
R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl.
12. antimicrobial compoundss according to claim 11, wherein, G 1be selected from OCN-M-NHCOOG ' and OCN-M-NHCONHG '.
13. antimicrobial compoundss according to claim 11, wherein, G 2with G 3identical group or not identical group.
14. antimicrobial compoundss according to claim 13, wherein, G 2with G 3be selected from-H ,-CH independently of one another 3,-CH 2cH 3,-NO 2,-F ,-Cl ,-Br and-I.
15. antimicrobial compoundss according to claim 11, wherein, X is-SO 3.
16. antimicrobial compoundss according to claim 11, wherein, X is-CO 2.
17. antimicrobial compoundss according to claim 11, wherein, X is-OPO 2oR 5.
18. antimicrobial compoundss according to claim 17, wherein, R 5be selected from-(CH 2) wcH 3, wherein w be not less than 0 and be not more than 5 integer.
19. antimicrobial compoundss according to claim 11, wherein, G 4-(CH is selected from independently of one another with G ' 2) n-, n be not less than 0 and be not more than 18 integer.
20. antimicrobial compoundss according to claim 11, wherein, M has the structure be shown below:
The preparation method of 21. 1 kinds of antimicrobial compoundss according to claim 1, comprises the steps:
1) one is had the tertiary amine of general formula (III) structure, react with the reactant B with general formula (IV) structure, obtain a kind of mixture;
OCN-L-D(IV)
Wherein,
Y is selected from-OH ,-NH 2with-SH;
R ' is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
R 2with R 3be selected from the C that monovalence does not replace or replaces independently of one another 1-18alkyl, cycloalkyl and aryl;
L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
D is selected from-COOH and-NCO;
2) described mixture and reactant A are reacted, obtain described antimicrobial compounds;
Wherein, described reactant A is selected from propane sultone, butyl sultone, β-propiolactone, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +with annular phosphate, wherein X is selected from Br, Cl and I, v be not less than 1 integer, Mt +be selected from Li +, Na +, K +, NH 4 +, Ag +, 1/2Mg 2+with 1/2Ca 2+, wherein said annular phosphate has the structure be shown below:
Wherein,
R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl;
R 6be selected from the C that divalence does not replace or replaces 1-6alkyl.
The preparation method of 22. antimicrobial compoundss according to claim 21, wherein, it is carry out under the existence of catalyzer C that described tertiary amine and described reactant B are reacted, and described catalyzer C is selected from least one in organic amine compound, phosphines and metallic catalyzer.
The preparation method of 23. antimicrobial compoundss according to claim 22, wherein, described catalyzer C is described metallic catalyzer.
The preparation method of 24. antimicrobial compoundss according to claim 23, wherein, described metallic catalyzer is selected from tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous oleate, stannous tartrate, dibutyl tin laurate, at least one in stannous octoate and metallic naphthenate.
The preparation method of 25. antimicrobial compoundss according to claim 24, wherein, described metallic catalyzer is metallic naphthenate.
The preparation method of 26. antimicrobial compoundss according to claim 25, wherein, described metallic naphthenate is selected from least one in naphthenic acid mantoquita, naphthenic acid zinc salt, naphthenic acid lead salt, naphthenic acid lithium salts, naphthenic acid cobalt salt, naphthenic acid nickel salt, naphthenic acid cadmium salt, naphthenic acid mercury salt, naphthenic acid indium salt and bismuth naphthenate salt.
The preparation method of 27. 1 kinds of antimicrobial compoundss as claimed in claim 11, comprises the steps:
1) by a kind of pyridine with logical formula V structure, react with the reactant B with general formula (IV) structure, obtain a kind of mixture;
OCN-L-D(IV)
Wherein, Q is selected from-OH ,-NH 2with-SH;
G ' is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
G 2with G 3be selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH independently of one another 3,-OCH 2cH 3,-OPr ,-CN ,-SCN ,-NO ,-NO 2the C not replacing with monovalence or replace 1-7alkyl, cycloalkyl, aryl;
D is selected from-COOH and-NCO;
L is selected from the C that divalence does not replace or replaces 1-18alkyl, cycloalkyl and aryl;
2) described mixture and reactant A are reacted, obtain described antimicrobial compounds;
Wherein, described reactant A is selected from propane sultone, butyl sultone, β-propiolactone, X (CH 2) vcO 2 -mt +, X (CH 2) vsO 3 -mt +with annular phosphate, wherein X is selected from Br, Cl and I, v be not less than 1 integer, Mt +be selected from Li +, Na +, K +, NH 4 +, Ag +, 1/2Mg 2+with 1/2Ca 2+, wherein said annular phosphate has the structure be shown below:
Wherein, R 5be selected from the C that monovalence does not replace or replaces 1-6alkyl, cycloalkyl and aryl; R 6be selected from the C that divalence does not replace or replaces 1-6alkyl.
The preparation method of 28. antimicrobial compoundss according to claim 27, wherein, described pyridine and described reactant B are reacted, and are to carry out under the existence of catalyzer C, and described catalyzer C is selected from least one in organic amine compound, phosphines and metallic catalyzer.
The preparation method of 29. antimicrobial compoundss according to claim 28, wherein, described catalyzer C is described metallic catalyzer.
The preparation method of 30. antimicrobial compoundss according to claim 29, wherein, described metallic catalyzer is selected from tin tetrachloride, tetrabutyl tin, tributyltin chloride, dichloride butyl tin, butyiin trichioride, cyaniding tributyl tin, dibutyltin diacetate, two sad dibutyl tins, sad tributyl tin, two sad tin diphenyls, dibutoxy dibutyl tin, bis-acetylacetonate base dibutyl tin, two (iso-octyl toxilic acid) dibutyl tin, be oxidized two stannous octoates, butyl disulfide tin, stannous oleate, stannous tartrate, dibutyl tin laurate, at least one in stannous octoate and metallic naphthenate.
The preparation method of 31. antimicrobial compoundss according to claim 30, wherein, described metallic catalyzer is metallic naphthenate.
The preparation method of 32. antimicrobial compoundss according to claim 31, wherein, described metallic naphthenate is selected from least one in naphthenic acid mantoquita, naphthenic acid zinc salt, naphthenic acid lead salt, naphthenic acid lithium salts, naphthenic acid cobalt salt, naphthenic acid nickel salt, naphthenic acid cadmium salt, naphthenic acid mercury salt, naphthenic acid indium salt and bismuth naphthenate salt.
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CN113181963A (en) * 2021-05-14 2021-07-30 安庆精益精化工有限公司 Preparation method of solid alkyl sulfonic acid catalyst
CN113181963B (en) * 2021-05-14 2022-10-11 安庆精益精化工有限公司 Preparation method of solid alkyl sulfonic acid catalyst
CN116283667A (en) * 2023-03-06 2023-06-23 江苏海洋大学 Functional isocyanate crosslinking agent and preparation method thereof
CN116283667B (en) * 2023-03-06 2023-12-29 江苏海洋大学 Functional isocyanate crosslinking agent and preparation method thereof

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