CN106397669A - Cyanoacrylate material capable of producing fluorescence - Google Patents

Cyanoacrylate material capable of producing fluorescence Download PDF

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Publication number
CN106397669A
CN106397669A CN201610789001.8A CN201610789001A CN106397669A CN 106397669 A CN106397669 A CN 106397669A CN 201610789001 A CN201610789001 A CN 201610789001A CN 106397669 A CN106397669 A CN 106397669A
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alkyl
thiazolinyl
alkynyl
group
octyl
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CN106397669B (en
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刘克良
徐亮
张涛
汤永嘉
高琴
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F222/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof
    • C08F222/30—Nitriles
    • C08F222/32—Alpha-cyano-acrylic acid; Esters thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
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    • C08F8/00—Chemical modification by after-treatment
    • C08F8/34—Introducing sulfur atoms or sulfur-containing groups
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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F222/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof
    • C08F222/30—Nitriles
    • C08F222/32—Alpha-cyano-acrylic acid; Esters thereof
    • C08F222/324—Alpha-cyano-acrylic acid butyl ester
    • C—CHEMISTRY; METALLURGY
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    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2800/00—Copolymer characterised by the proportions of the comonomers expressed
    • C08F2800/20—Copolymer characterised by the proportions of the comonomers expressed as weight or mass percentages
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2810/00—Chemical modification of a polymer
    • C08F2810/50—Chemical modification of a polymer wherein the polymer is a copolymer and the modification is taking place only on one or more of the monomers present in minority
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/14—Macromolecular compounds
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    • C09K2211/145—Heterocyclic containing oxygen as the only heteroatom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a cyanoacrylate material capable of producing fluorescence, in particular to a method for preparing a cyanoacrylate polymer containing fluorophores. The method is implemented according to a route shown in the specifications. The invention further relates to a monomer 1, a polymer 1, a polymer 2, a polymer 1', a polymer 2', an adhesive containing the compounds or the polymers, a dressing containing the compounds, the polymers or the adhesive as well as an application of the compounds or the polymers in preparation of the cyanoacrylate polymer containing the fluorophores.

Description

The alpha-cyanoacrylate ester material of fluorescence can be produced
Technical field
The present invention relates to biomedical sector and Material Field are and in particular to a kind of cyano group third prepared with fluorophor The method of olefine acid ester polymer, compound and polymer that methods described is related to, comprise the gluing of described compound or polymer Agent, comprises the dressing of described compound, polymer or adhesive, and described compound or polymer are used for preparation and carry fluorescence The purposes of the cyanoacrylate polymer of group.
Background technology
Cyanoacrylate compound was synthesized by Germany scientist first in 1949.Such compound is at normal temperatures Colourless transparent liquid, in nucleopilic reagent (such as NH2 -、OH-) in the presence of, it is susceptible to anionic polymerisation, generate water white Solid polymer.Cyanoacrylate compound is to materials such as plastics, pottery, timber, glass, and skin, blood vessel, flesh The human bodies such as meat, mucosa or animal body tissue, all show good cementability, for example, 502 common glue in daily life Main component be exactly ethyl α-cyanoacrylate.Medically, cyanoacrylate compound can be used for preparing medical adhesive, Adhesion process is carried out to wound, compares traditional suture means, there is quick acting, the advantage such as easy to use.FDA approved cyanogen Base acrylate material is in the use of skin surface.
Due to the water white feature of cyanoacrylate polymer, this kind of material after a procedure, is only seen with naked eyes Examine and distinguish and can have difficulties.In addition although current FDA only have approved this kind of material in body surface use, but in research In, the use in animal body of alpha-cyanoacrylate ester material can be related to, in this case, be difficult to pass through direct visual perception material Situation after a procedure.For example, bonding cyanoacrylate materials application organized in animal intestinal, postoperative needs are opened and are subject to Whether the abdominal cavity of examination animal, otherwise cannot effectively observe material adhesive effect organizationally, and fall off, shift Situation.Therefore, in medical application and research, need a kind of alpha-cyanoacrylate ester material that can produce fluorescence, in order to make User observes to material.
Content of the invention
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology The implication that personnel are generally understood that.And, laboratory operation step involved herein is in corresponding field and widely uses Conventional steps.Meanwhile, for a better understanding of the present invention, definition and the explanation of relational language are provided below.
As used in this article, term " fluorescent chemicalses " is the thing referring to absorb ultraviolet light and launch visible ray Matter, or can the shorter visible ray of absorbing wavelength, and launch the material of longer wavelengths of visible ray, such as FITC (different sulfur Cyanic acid fluorescein), FAM (CF 5(6)-Carboxyfluorescein), Cy2, Cy3, Cy5, Cy7, TAMRA and Rhodamin (rhodamine).Term " fluorescence Group " refers to the chromophore in fluorescent chemicalses, can produce the group of fluorescence.In the present invention, fluorescent chemicalses carry can The group reacting with amino, such as-N=C=S ,-COOH, alkyl ester group and/or butanimide ester group.
As used in this article, compound FITC (Fluorescein isothiocyanate), FAM (CF 5(6)-Carboxyfluorescein), Cy2, Cy3, Cy5 It is respectively provided with structure shown below (X in structural formula is halogen) with Cy7：
As used in this article, compound TAMRA (carboxyl tetramethylrhodamine) includes 5-TAMRA and 6-TAMRA, both It is respectively provided with structure shown below：
As used in this article, compound R hodamin (rhodamine) include Rhodamin6G, RhodaminB and Rhodamin123, three is respectively provided with structure shown below：
As used in this article, the auxiliary material during term " auxiliary agent " refers to adhesive production process and/or uses. Gluing agent aid includes but is not limited to：Additive synthesis, reactive assistant, function additive, process auxiliaries and stabilization aid.
As used in this article, term " additive synthesis " is mainly included in synthesis and/or the process for preparation of adhesive, institute Emulsifying agent, initiator, polymerization inhibitor, catalyst, solvent, oxidant, dispersant, chain extender, regulator, nertralizer and the end using Only agent etc..
As used in this article, term " reactive assistant " refers to the compound with reactive group, its can and gluing Matrix polymer reaction in agent, forms netted or cross-linked structure, mainly includes toughener, firming agent, cross-linking agent, light-initiated Agent, accelerator and reactive flame retardant etc..
As used in this article, term " function additive " is also referred to as " modified additive ", refers to improve original property of adhesive Can, or give the auxiliary agent of its new function, mainly include plasticizer, coupling agent, viscosifier, foaming agent, coloring agent, reinforcing agent, Filler, fire retardant, softening agent, antistatic additive, mask agent, toughener, accelerator and chelating agen etc..
As used in this article, term " process auxiliaries " refers to for the preparation of adhesive and easy to use, and ensures Its estimated performance and the auxiliary agent that uses, mainly include thickening agent, defoamer, antifreezing agent, antitack agent, diluent, thixotropic agent and anti- Burnt agent etc..
As used in this article, term " stabilization aid " refers to be prevented from adhesive in synthetically prepared, accumulating and use During aged deterioration, increase the service life and/or improve the auxiliary agent of storage stability, mainly include antioxidant, heat stabilizer, Light stabilizer, antibacterial, preservative and metallic ion passivation agent etc..
As used in this article, term " dressing " refers to be used in medical treatment wrapping up or cover the material of other damages such as skin ulcer, wound Material.Described dressing can comprise the base materials such as paper, fabric, non-woven fabrics, membrane material, gel and/or expanded material, for example, comprises this The compound of invention or the binding agent of polymer, can be coated on base material, constitute dressing；Or, described dressing can not wrap Containing base material.
As used in this article, term " room temperature " refers to 25 DEG C ± 5 DEG C.
As used in this article, term " weak acid " refers to the acid that ionization constant is less than 0.0001, including but not limited to acetic acid.
The present inventor passes through cleverly to conceive and performing creative labour, has obtained a kind of alpha-cyanoacrylate that can produce fluorescence The preparation method of ester polymer, thus provides following inventions：
In one aspect, this application provides a kind of side preparing the cyanoacrylate polymer with fluorophor Method, methods described is carried out according to route as follows：
Wherein, R1For hydrogen atom or C1-10(for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- are different pungent for alkyl Base)；
R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl C1-10Alkyl)；Alkylaryl (example As C1-10Alkyl 6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example count equal molecular masses be The Polyethylene Glycol segment of 100-5000)；
Z be amino protection group, for example benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), allyloxycarbonyl (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl Base (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyanogen The acrylate-based C of base1-10Alkyl；
N is the integer more than or equal to 2, such as 2-1000,2-10000 or 2-100000；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is whole more than or equal to 1 Number (such as 1-1000,1-10000 or 1-100000), and m and p sum be more than or equal to 2 (such as 2-1000,2-10000 or 2-100000).
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
The method comprising the steps of：
Step 1：Make compound 1 and compound Z-NH-R2- OH reacts, and obtains compound 2；
Step 2：By the anthracene protection group removing on compound 2, obtain monomer 1；
Step 3：Monomer 1 is polymerized, obtains polymer 1；Or, monomer 1 and monomer 2 are carried out combined polymerization, obtain Polymer 1 ', described monomer 2 is alpha-cyanoacrylate or alpha-cyanoacrylate C1-10Arrcostab (for example, methyl 2-cyanoacrylate, cyano group Ethyl acrylate, alpha-cyanoacrylate n-propyl, BCA, alpha-cyanoacrylate n-octyl or alpha-cyanoacrylate 2- are different Monooctyl ester)；
Step 4：By the Z group removing on polymer 1, obtain polymer 2；Or, the Z group on polymer 1 ' is taken off Remove, obtain polymer 2 '；
Step 5：So that polymer 2 and fluorescent chemicalses is reacted, obtain polymer 3, or, make polymer 2 ' and fluorescence Compound is reacted, and obtains polymer 3 '；Preferably, described fluorescent chemicalses be selected from FITC, FAM, TAMRA, Rhodamin, One or more of Cy2, Cy3, Cy5 and Cy7.
In a preferred embodiment, the reaction of described step 1 is in DMAP (DMAP) and N, N- bis- Diisopropylcarbodiimide (DIC) is carried out under conditions of existing.
In a preferred embodiment, the reaction of described step 1 is carried out at room temperature.
In a preferred embodiment, described step 1 also includes：Compound 2 is carried out separate and/or purification.
In a preferred embodiment, the reaction of described step 2 is carried out under conditions of maleic anhydride presence.
In a preferred embodiment, described step 2 includes：Compound 2 is carried out at room temperature with maleic anhydride Stirring, is stirred afterwards at 40 DEG C -60 DEG C.
In a preferred embodiment, described step 2 includes：Compound 2 and maleic anhydride are stirred at room temperature 3-7 hour, is stirred 1-5 hour afterwards at 40 DEG C -60 DEG C.
In a preferred embodiment, the reaction of described step 2 is carried out in solvent (such as dimethylbenzene).
In a preferred embodiment, described step 2 includes：After reaction, solvent is removed by vacuum distillation.
In a preferred embodiment, the reaction of described step 3 is under conditions of with the presence of aqueous water or vapor Carry out.
In a preferred embodiment, the reaction of described step 4 is carried out in the aqueous solution of weak acid (such as acetic acid).
In a preferred embodiment, described step 5 includes, and polymer 2 and fluorescent chemicalses are entered at room temperature Row stirring, or polymer 2 ' is stirred at room temperature with fluorescent chemicalses.
In a preferred embodiment, in described step 5, fluorescent chemicalses are present in fluorescent labeling reagent box, Described step 5 is operated according to the description of fluorescent labeling reagent box.
In certain embodiments, fluorescent labeling reagent box, in addition to comprising fluorescent chemicalses, also comprises other reagent (examples As buffer solution).
In one aspect, this application provides having the compound of structure as shown in formula (I)：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
Z be amino protection group, for example benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), allyloxycarbonyl (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl Base (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT).
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
In one aspect, this application provides having the polymer of structure as shown in formula (II)：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
Z be amino protection group, for example benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), allyloxycarbonyl (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl Base (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
N is the integer (such as 2-1000,2-10000 or 2-100000) more than or equal to 2.
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
In one aspect, this application provides having the polymer of structure as shown in formula (III)：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
N is the integer more than or equal to 2, such as 2-1000,2-10000 or 2-100000.
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In one aspect, this application provides having the polymer of structure as shown in formula (II ')：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
Z be amino protection group, for example benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), allyloxycarbonyl (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl Base (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyanogen The acrylate-based C of base1-10Alkyl；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is whole more than or equal to 1 Number (such as 1-1000,1-10000 or 1-100000), and m and p sum be more than or equal to 2 (such as 2-1000,2-10000 or 2-100000).
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
In one aspect, this application provides having the polymer of structure as shown in formula (III ')：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyanogen The acrylate-based C of base1-10Alkyl；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is whole more than or equal to 1 Number (such as 1-1000,1-10000 or 1-100000), and m and p sum be more than or equal to 2 (such as 2-1000,2-10000 or 2-100000).
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In one aspect, this application provides a kind of adhesive, it contains the compound of the present invention or polymer.
In a preferred embodiment, described adhesive also contains auxiliary agent, for example additive synthesis, reactive assistant, Function additive, process auxiliaries and/or stabilization aid.
In one aspect, this application provides a kind of dressing, it contains the compound of the present invention, polymer or adhesive.
In a preferred embodiment, described dressing also comprises base material.
In a preferred embodiment, in described dressing, the compound of the present invention, polymer or adhesive are applied On base material.
In a preferred embodiment, described base material is selected from paper, fabric, non-woven fabrics, membrane material, gel and foaming material Material.
The dressing that the application provides, can be by the compound of the present invention, polymer or adhesive, to the position being used Produce gluing effect, thus keeping the relatively stable of dressing position；Or, the dressing that the present invention provides, can produce containing other The material of gluing effect, or by having the article (for example, adhesive tape) of gluing effect, or using other fixing article and mode (for example, using bandaging), to keep the relatively stable of dressing position.
In one aspect, this application provides the compound of the present invention or polymer are used for the cyanogen with fluorophor for the preparation The purposes of base acrylate polymer, structure such as formula (IV) institute of the described cyanoacrylate polymer with fluorophor Show：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
N is the integer (such as 2-1000,2-10000 or 2-100000) more than or equal to 2；
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In a preferred embodiment, fluorophor be selected from FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and One or more of chromophore in Rhodamin.
In one aspect, this application provides the compound of the present invention or polymer are used for the cyanogen with fluorophor for the preparation The purposes of base acrylate polymer, structure such as formula (the IV ') institute of the described cyanoacrylate polymer with fluorophor Show：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, institute State C1-30Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20 Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkyl Aryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts and divides equally Protonatomic mass is the Polyethylene Glycol segment of 100-5000)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyanogen The acrylate-based C of base1-10Alkyl；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is whole more than or equal to 1 Number (such as 1-1000,1-10000 or 1-100000), and m and p sum be more than or equal to 2 (such as 2-1000,2-10000 or 2-100000).
In a preferred embodiment, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, different Octyl group or isohesyl.
In a preferred embodiment, fluorophor be selected from FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and One or more of chromophore in Rhodamin.
In one aspect, the invention provides preparing the method with the compound of structure as shown in formula (I), methods described Carry out according to route as follows：
Wherein, R1For hydrogen atom or C1-10(for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- are different pungent for alkyl Base)；
R2Defined with Z such as formula (I)；
The method comprising the steps of：
Step 1：Make compound 1 and compound Z-NH-R2- OH reacts, and obtains compound 2；With
Step 2：By the anthracene protection group removing on compound 2, obtain the compound with structure as shown in formula (I).
In a preferred embodiment, the reaction of described step 1 is in DMAP (DMAP) and N, N- bis- Diisopropylcarbodiimide (DIC) is carried out under conditions of existing.
In a preferred embodiment, the reaction of described step 1 is carried out at room temperature.
In a preferred embodiment, described step 1 also includes：Compound 2 is carried out separate and/or purification.
In a preferred embodiment, the reaction of described step 2 is carried out under conditions of maleic anhydride presence.
In a preferred embodiment, described step 2 includes：Compound 2 is carried out at room temperature with maleic anhydride Stirring, is stirred afterwards at 40 DEG C -60 DEG C.
In a preferred embodiment, described step 2 includes：Compound 2 and maleic anhydride are stirred at room temperature 3-7 hour, is stirred 1-5 hour afterwards at 40 DEG C -60 DEG C.
In a preferred embodiment, the reaction of described step 2 is carried out in solvent (such as dimethylbenzene).
In a preferred embodiment, described step 2 includes：After reaction, solvent is removed by vacuum distillation.
Beneficial effect
The invention provides a kind of preparation method of the cyanoacrylate polymer that can produce fluorescence.The method of the present invention The cyanoacrylate polymer of preparation, can act as adhesive or dressing, the fluorescence that described polymer produces can be effectively Visually play the effect of auxiliary observation.For example, the adhesive containing described polymer or dressing are applied to intracorporeal site Afterwards, can easily be monitored and observed situations such as it come off, degrades, retaining by the way of fluorescent vital imaging.By institute State polymer and make Nano microsphere, can be entered by the metabolic condition after intuitively fluorescence imaging method enters in animal body to it Row observes detection.
The preparation method of the present invention, the purification and the detached operation that are related to small molecule are less, and significant loss is little, step 3 To after polymer, you can carry out deprotection (step 4) and fluorescent labeling (step 5).In step 4 and step 5, polymer enters After row reaction, unreacted reagent can be removed by polymer is carried out or is centrifuged etc. with simple operationss.The present invention's Method is operationally easy to be flexible, and user can be after obtaining the cyanoacrylate polymer with amino, according to reality Border needs, and selects the fluorescent chemicalses that can react with amino to be marked.
Below in conjunction with embodiment, embodiment of the present invention is described in detail, but, those skilled in the art will Understand, the following example is merely to illustrate the present invention, rather than the restriction to the scope of the present invention.According to preferred embodiment Following detailed description, the various purposes of the present invention and favourable aspect will be apparent to those skilled in the art.
Specific embodiment
Below in conjunction with drawings and Examples, embodiment of the present invention is described in detail, but people in the art Member will be understood that, drawings below and embodiment are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Accompanying drawing and Unreceipted actual conditions person in embodiment, the condition according to normal condition or manufacturer's suggestion is carried out.Agents useful for same or instrument are not Dated production firm person, be can by city available from conventional products.Anhydrous solvent used is commercially available.
Brief description
Fig. 1 is in embodiment 4, and the blob of viscose being marked with FITC is embedded in mice body, the fluorescent vital imaging knot of mice Really.Figure 1A-C be respectively the embedding same day, 7 days after and the imaging results after 14 days.As illustrated, at the embedding position of blob of viscose (as schemed Middle arrow indication) it is observed that obvious fluorescence, other positions of mice no substantially interfere with.After embedding 14 days, embedding position is still Fluorescence can be detected.
Fig. 2 is in embodiment 5, the blob of viscose being marked with Cy2 is embedded in mice body, the fluorescent vital of embedding same day mice Imaging results.As illustrated, being observed that obvious fluorescence, other portions of mice at the embedding position of blob of viscose (as indicated by the arrows in the figure) Position no substantially interferes with.
Preparation example 1. anthracene closes the synthesis of alpha-cyanoacrylate
The method of referenced patent US4012402, makes ethyl α-cyanoacrylate, with anthracene, additive reaction occur, and obtains anthracene and closes cyanogen Base ethyl acrylate, then hydrolyze in alkaline solution, obtain anthracene and close alpha-cyanoacrylate.
The synthesis of preparation example 2.4,4 '-dimethoxytrityl-amino-hexanol (DMT- amino-hexanol)
6- amino-hexanol (5g, 0.043mol) is placed in 250mL there-necked flask, adds 50mL pyridine, stirring and dissolving, in ice Deca trim,ethylchlorosilane (13.9g, 0.128mol) under the conditions of bath, reacts 4h, adds 4,4 '-dimethoxytrityl chlorine (DMT-Cl, 17.3g, 0.051mol), room temperature reaction 12h；Vacuum distillation removes pyridine, adjusts reactant liquor pH to neutral, extraction, Organic faciess are respectively with 100mL saturation NaHCO3Solution, 100mL saturation NaCl solution are washed 2 times, use anhydrous Na2SO4It is dried overnight. With petroleum ether-ethyl acetate mixed liquor (volume ratio 4:1) it is eluent, column chromatography separates to product purification, is removed under reduced pressure molten Agent, obtains faint yellow glutinous thick liquid 9.71g, and as 4,4 '-dimethoxytrityl-amino-hexanol (DMT- amino-hexanol), Yield is 53.9%.
1H NMR(CDCl3,400MHz),δ:1.25～1.62 [m, 8H, (CH2)4],2.72(d,2H,CH2CH2NH),3.80 (s,6H,Ph-OCH3),4.22(s,1H,CH2), OH 6.83～7.48 (m, 13H, Ph-H), 8.29 (s, 1H, CH2NH).MS,m/ z:420[M-H+].
The synthesis of preparation example 3. fluorenylmethyloxycarbonyls-amino-hexanol (Fmoc- amino-hexanol)
By 2.65g Na2CO3It is dissolved in 25ml H2In O, add 2.9g 6- amino-hexanol and 25ml dioxane, ice bath is cold But it is slowly added dropwise Fmoc-Cl/ dioxane (6.5g/25ml) solution afterwards, drip off rear room temperature stirring reaction 2h.Dioxane is revolved Dry, increasing amount dichloromethane dissolves, and solution uses 10% citric acid successively, and saturation NaCl washed once, and merges organic faciess, anhydrous Na2SO4It is dried overnight.With dichloromethane/petroleum ether recrystallization, obtain 5.9g white crystal within second day, as fluorenylmethyloxycarbonyl-ammonia Base hexanol, yield is 72.5%.
1H NMR(CDCl3,400MHz),δ:1.29～1.53 [m, 9H, (CH2)4],3.2(t,2H,CH2NH),3.51(t, 2H,CH2OH),3.89(s,1H,CH2OH),4.5[t,1H,CH2CH(Ph)2],4.73(d,2H,OCH2CH), 7.23～7.78 (m, 8H, Ph-H), 8.02 (s, 1H, CH2NHCOO).MS,m/z:340[M-H+].
The preparation of embodiment 1. alpha-cyanoacrylate (FITC- amino-hexanol) ester-BCA copolymer
According to following route and step, prepare alpha-cyanoacrylate (FITC- amino-hexanol) ester-BCA common Polymers.
Step 1：Anthracene is closed alpha-cyanoacrylate (12.7g, 0.046mol) be added in 50mL dichloromethane, sequentially add DMAP (0.56g, 4.60mmol) and DIC (5.8g, 0.046mol), stirs to being completely dissolved under room temperature, is subsequently adding DMT- ammonia Base hexanol (that is, Z-NH-R2- OH, Z are-DMT, R2For normal hexane base) (19.3g, 0.046mol), react 6h at room temperature；Cross Filter, filtrate is with saturation NaHCO3Solution and saturation NaCl solution are washed 3 times respectively, use anhydrous Na2SO4It is dried；With petroleum ether-second Acetoacetic ester-triethylamine mixed liquor (volume ratio 5:1:0.2) it is eluent, column chromatography carries out purifies and separates to product, decompression is steamed Evaporate removing solvent, obtain yellow oily liquid 21g, as anthracene closes alpha-cyanoacrylate (DMT- amino-hexanol) ester, and yield is 67.5%.
1H NMR(CDCl3,400MHz),δ:1.25～1.62 [m, 8H, (CH2)4],2.20(dd,2H,CCH2CH),2.72 (d,2H,CH2CH2NH),2.77(dd,2H,CCH2CH),3.80(s,6H,Ph-OCH3),4.05(t,2H,COOCH2),4.43 (t, 1H, Ph-CH-Ph), 4.86 (s, 1H, CCH-Ph), 6.83～7.48 (m, 21H, Ph-H), 8.29 (s, 1H, CH2NH).MS, m/z:677.5[M-H+],698.9[M-Na+].
Step 2：Anthracene is closed alpha-cyanoacrylate (DMT- amino-hexanol) ester 0.5g, maleic anhydride 0.2g, dimethylbenzene 10mL throw Enter in reaction bulb, after 5h is stirred at room temperature, be heated to 50 DEG C of reaction 2h, vacuum distillation removes removal xylene.After vacuum distillation, anthracene is multiple Compound and maleic anhydride separate out.Through filtering to obtain thick liquid, there are bonding force, as alpha-cyanoacrylate (DMT- amino-hexanol) Ester.
Step 3：By alpha-cyanoacrylate (DMT- amino-hexanol) ester and BCA with 10:90 mass ratio mixes Close, under normal temperature and pressure, in atmosphere, two kinds of monomers are copolymerized, and obtain the copolymer of both monomers, in block (blob of viscose 1a).
Step 4：Blob of viscose 1a is placed in 5 minutes in 5% aqueous acetic acid, DMT group is removed, afterwards with distillation washing Wash twice, obtain blob of viscose 1b, wherein contain alpha-cyanoacrylate amino-hexanol ester-BCA copolymer.
Step 5：Blob of viscose 1b is placed in the Na of pH=92CO3/NaHCO3In buffer, buffer solution contains FITC, and FITC is dense Spend for 1mg/ml.Blob of viscose 1b is marked, makes FITC and alpha-cyanoacrylate amino-hexanol ester-BCA copolymerization The amino of thing is reacted, and obtains blob of viscose 1c, and ester-alpha-cyanoacrylate is just wherein to contain alpha-cyanoacrylate (FITC- amino-hexanol) Acrylate copolymer.
Using non-intrusion type three-dimensional (3D) imaging quantitative system (IVIS SPECTRUM, Caliper company of the U.S.), to glue Block 1c is detected, under the conditions of exciting light 488nm, launching light 525nm, obvious fluorescence can be detected, illustrate FITC Pass flag has arrived on cyanoacrylate polymer.
The preparation of embodiment 2. alpha-cyanoacrylate (FITC- amino-hexanol) ester-BCA copolymer
In accordance with the following steps, prepare poly- alpha-cyanoacrylate (FITC- amino-hexanol) ester.
Step 1：Make anthracene close alpha-cyanoacrylate and the reaction of Fmoc- amino-hexanol, prepare anthracene and close alpha-cyanoacrylate (Fmoc- ammonia Base hexanol) ester.
7.1g Fmoc- amino-hexanol and 5.76g anthracene are closed alpha-cyanoacrylate be added in 150ml dichloromethane, stirring is molten Xie Hou, sequentially adds DMAP and DIC, after stirring at normal temperature 6h, sucking filtration, and collect filtrate, by filtrate with using saturation NaHCO successively3Molten Liquid, 1N hydrochloric acid, saturation NaCl solution respectively washed once, and merges organic faciess, anhydrous Na2SO4It is dried.Mixed with petroleum ether-ethyl acetate Close liquid (volume ratio 3:1) it is eluent, column chromatography separates to product purification, removal of solvent under reduced pressure obtains faint yellow sticky shape liquid Body 9.5g, as anthracene close alpha-cyanoacrylate (Fmoc- amino-hexanol) ester, and yield is 76.1%.
1H NMR(CDCl3,400MHz),δ:1.26～1.68 [m, 8H, (CH2)4], 2.21～2.8 [dd, 2H, CCH2CH (Ph)2],3.22(t,2H,CH2NH),4.08(t,2H,COOCH2),4.23[t,1H,CH2CH(Ph)2],4.41[d,2H, OCH2CH(Ph)2],4.87[s,1H,CCH(Ph)2], 7.12～7.8 (m, 16H, Ph-H), 8.1 (s, 1H, NH) .MS, m/z:597 [M-H+],619[M-Na+].
Step 2：With reference to the operation in embodiment 1, anthracene is closed the anthryl group on alpha-cyanoacrylate (Fmoc- amino-hexanol) ester Removing, obtains thick liquid, has bonding force, as alpha-cyanoacrylate (Fmoc- amino-hexanol) ester, its structure is as follows：
Step 3：By alpha-cyanoacrylate (Fmoc- amino-hexanol) ester and BCA with 10:90 mass ratio Mixing, under normal temperature and pressure, in atmosphere, two kinds of monomers are copolymerized, and obtain the copolymer of both monomers, in block (blob of viscose 2a).
Step 4：With reference to the operation in embodiment 1, Fmoc group is removed, obtains blob of viscose 2b, wherein contain cyanoacrylate Sour amino-hexanol ester-BCA copolymer.
Step 5：With reference to the operation in embodiment 1, to blob of viscose 2b flag F ITC, obtain blob of viscose 2c, wherein contain cyano group third Olefin(e) acid (FITC- amino-hexanol) ester-BCA copolymer.
Fluoroscopic examination is carried out to blob of viscose 2c, it can detect substantially under the conditions of exciting light 488nm, launching light 525nm Fluorescence, illustrates that pass flag has arrived on cyanoacrylate polymer FITC.
The preparation of embodiment 3. alpha-cyanoacrylate (Cy2- amino-hexanol) ester-BCA copolymer
In reference embodiment 1, the operation of step 1- step 4, prepared blob of viscose 3b, wherein contains alpha-cyanoacrylate amino-hexanol Ester-BCA copolymer.
Na with the pH=9 containing cy22CO3/NaHCO3Buffer, is marked to blob of viscose 3b, obtains blob of viscose 3c, wherein Containing alpha-cyanoacrylate (Cy2- amino-hexanol) ester-BCA copolymer, its structure is as follows：
Blob of viscose 3c, under the conditions of exciting light 492nm, launching light 510nm, can detect obvious fluorescence, illustrates Cy2 Pass flag has arrived on cyanoacrylate polymer.
The Fluirescence observation experiment in animal body of the blob of viscose of embodiment 4.FITC labelling
After SD mouse anesthesia, remove back wool, cut the otch of a 0.5cm length with scalpel, as deep as chamber film layer, take about 0.3cm about size, 1mm about the polymer blob of viscose of FITC labelling that is obtained of thick embodiment 1, be placed on Musclar layer and chamber film Between layer, reuse common 504 glue and wound is bonded.
Observed little using non-intrusion type three-dimensional (3D) imaging quantitative system (IVIS SPECTRUM, Caliper company of the U.S.) The fluorescent vital imaging results of Mus, testing conditions are exciting light 488nm, launching light 525nm.Figure 1A-C be respectively the embedding same day, 7 Fluorescent vital imaging results after it and after 14 days.As illustrated, can see at the embedding position of blob of viscose (as indicated by the arrows in the figure) Observe obvious fluorescence, other positions of mice no substantially interfere with.The fluorescence intensity on the embedding same day is 6.8 ± 3.73 × 109p/sec/ cm2/ sr, after embedding 14 days, embedding position still can detect fluorescence.
The Fluirescence observation experiment in animal body of the blob of viscose of embodiment 5.Cy2 labelling
With reference to the experimentation of embodiment 4, the polymer blob of viscose of the Cy2 labelling that embodiment 3 is obtained is embedded in Mice Body Interior.Observe the fluorescent vital imaging results of mice, testing conditions are exciting light 492nm, launching light 510nm.Fig. 2 is the embedding same day Fluorescent vital imaging results.As illustrated, being observed that obvious fluorescence at the embedding position of blob of viscose (as indicated by the arrows in the figure), Other positions of mice no substantially interfere with.
Although the specific embodiment of the present invention has obtained detailed description, it will be appreciated by those skilled in the art that：Root According to disclosed all teachings, details can be carried out with various modifications and changes, and these change the guarantor all in the present invention Within the scope of shield.The four corner of the present invention is given by claims and its any equivalent.

Claims (11)

1. a kind of method preparing the cyanoacrylate polymer with fluorophor, methods described is according to road as follows Line is carried out：
Wherein, R1For hydrogen atom or C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl)；
R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30Alkyl Replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl (such as C1-6 Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl C1-10Alkyl)；Alkylaryl (example As C1-10Alkyl 6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example count equal molecular masses be The Polyethylene Glycol segment of 100-5000)；
Z is the protection group of amino, such as benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), alkene Propylene carbonyl oxygen (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyano group third Olefin(e) acid ester group C1-10Alkyl；
N is the integer more than or equal to 2, such as 2-1000,2-10000 or 2-100000；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is the integer more than or equal to 1 (such as 1-1000,1-10000 or 1-100000), and m is more than or equal to 2 (such as 2-1000,2-10000 or 2- with p sum 100000)；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl；
Preferably, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT)；
The method comprising the steps of：
Step 1：Make compound 1 and compound Z-NH-R2- OH reacts, and obtains compound 2；
Step 2：By the anthracene protection group removing on compound 2, obtain monomer 1；
Step 3：Monomer 1 is polymerized, obtains polymer 1；Or, monomer 1 and monomer 2 are carried out combined polymerization, are polymerized Thing 1 ', described monomer 2 is alpha-cyanoacrylate or alpha-cyanoacrylate C1-10Arrcostab (for example, methyl 2-cyanoacrylate, cyanoacrylate Acetoacetic ester, alpha-cyanoacrylate n-propyl, BCA, alpha-cyanoacrylate n-octyl or alpha-cyanoacrylate 2- are different pungent Ester)；
Step 4：By the Z group removing on polymer 1, obtain polymer 2；Or, the Z group removing on polymer 1 ' obtains To polymer 2 '；
Step 5：So that polymer 2 and fluorescent chemicalses is reacted, obtain polymer 3, or, make polymer 2 ' and fluorescence chemical combination Thing is reacted, and obtains polymer 3 '；Preferably, described fluorescent chemicalses be selected from FITC, FAM, TAMRA, Rhodamin, Cy2, One or more of Cy3, Cy5 and Cy7；
Preferably, in DMAP (DMAP) and N, N- DIC (DIC) is deposited for the reaction of described step 1 Carry out under the conditions；
Preferably, described step 1 also includes：Compound 2 is carried out separate and/or purification；
Preferably, the reaction of described step 2 is carried out under conditions of maleic anhydride presence；
Preferably, the reaction of described step 3 is carried out under conditions of with the presence of aqueous water or vapor；
Preferably, the reaction of described step 4 is carried out in the aqueous solution of weak acid (such as acetic acid)；
Preferably, described step 5 includes, and polymer 2 and fluorescent chemicalses are stirred at room temperature, or by polymer 2 ' with Fluorescent chemicalses are stirred at room temperature.
2. a kind of compound, it has the structure as shown in formula (I)：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
Z is the protection group of amino, such as benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), alkene Propylene carbonyl oxygen (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl；
Preferably, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
3. a kind of polymer, it has the structure as shown in formula (II)：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
Z is the protection group of amino, such as benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), alkene Propylene carbonyl oxygen (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
N is the integer (such as 2-1000,2-10000 or 2-100000) more than or equal to 2；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl；
Preferably, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
4. a kind of polymer, it has the structure as shown in formula (III)：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
N is the integer more than or equal to 2, such as 2-1000,2-10000 or 2-100000；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl.
5. a kind of polymer, it has the structure as shown in formula (II ')：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
Z is the protection group of amino, such as benzyloxycarbonyl group (- Cbz), tertbutyloxycarbonyl (- Boc), fluorenylmethyloxycarbonyl (- Fmoc), alkene Propylene carbonyl oxygen (- Alloc), trimethylsilyl ethoxycarbonyl (- Teoc), methoxycarbonyl group, carbethoxyl group, phthalyl (- Pht), p-toluenesulfonyl (- Tos), trifluoroacetyl group (- Tfa), trityl (- Trt), 2,4- dimethoxy-benzyl (- Dmb), to methoxy-benzyl (- PMB), benzyl (- Bn) or 4,4 '-dimethoxytrityl (- DMT)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyano group third Olefin(e) acid ester group C1-10Alkyl；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is the integer more than or equal to 1 (such as 1-1000,1-10000 or 1-100000), and m is more than or equal to 2 (such as 2-1000,2-10000 or 2- with p sum 100000)；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl；
Preferably, Z is fluorenylmethyloxycarbonyl (- Fmoc) or 4,4 '-dimethoxytrityl (- DMT).
6. a kind of polymer, it has the structure as shown in formula (III ')：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyano group third Olefin(e) acid ester group C1-10Alkyl；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is the integer more than or equal to 1 (such as 1-1000,1-10000 or 1-100000), and m is more than or equal to 2 (such as 2-1000,2-10000 or 2- with p sum 100000)；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl.
7. a kind of adhesive, it contains the compound of claim 2 or the polymer of any one of claim 3-6；
Preferably, described adhesive also contains auxiliary agent, for example additive synthesis, reactive assistant, function additive, process auxiliaries and/ Or stabilization aid.
8. a kind of dressing, it contains the compound of claim 2, the polymer of any one of claim 3-6 or claim 7 Adhesive；
Preferably, described dressing also comprises base material；
Preferably, in described dressing, the compound of claim 2, the polymer of any one of claim 3-6 or claim 7 Adhesive be applied on base material；
Preferably, described base material is selected from paper, fabric, non-woven fabrics, membrane material, gel and expanded material.
9. the polymer of the compound of claim 2 or any one of claim 3-4 is used for the cyano group with fluorophor for the preparation The purposes of acrylate polymer, shown in the structure such as formula (IV) of the described cyanoacrylate polymer with fluorophor：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
N is the integer (such as 2-1000,2-10000 or 2-100000) more than or equal to 2；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl；
Preferably, fluorophor is selected from one or more in FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and Rhodamin Chromophore.
10. the polymer of the compound of claim 2 or any one of claim 5-6 is used for the cyano group with fluorophor for the preparation The purposes of acrylate polymer, shown in the structure such as formula (IV ') of the described cyanoacrylate polymer with fluorophor：
Wherein, R2For C1-30Alkyl (such as C1-6Alkyl, C1-10Alkyl, C10-20Alkyl or C20-30Alkyl), optionally, described C1-30 Alkyl is replaced by one or more of acyloxy, haloalkyl, alkoxyl, halogen atom and cyano group；C1-30Thiazolinyl is (for example C1-6Thiazolinyl, C1-10Thiazolinyl, C10-20Thiazolinyl or C20-30Thiazolinyl)；C1-30Alkynyl (such as C1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl)；Cycloalkyl (such as 5-10 unit cycloalkyl)；Aralkyl (such as 6-14 unit aryl-C1-10Alkyl)；Alkylaryl (such as C1-10Alkyl -6-14 unit aryl)；Aryl (such as 6-14 unit aryl)；Or Polyethylene Glycol segment (for example counts equal molecule matter Measure the Polyethylene Glycol segment for 100-5000)；
R3For hydrogen atom, C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl) or cyano group third Olefin(e) acid ester group C1-10Alkyl；
M is the integer (such as 1-1000,1-10000 or 1-100000) more than or equal to 1, and p is the integer more than or equal to 1 (such as 1-1000,1-10000 or 1-100000), and m is more than or equal to 2 (such as 2-1000,2-10000 or 2- with p sum 100000)；
Preferably, R2For C1-6Alkyl, such as normal-butyl, n-octyl, n-hexyl, isobutyl group, iso-octyl or isohesyl；
Preferably, fluorophor is selected from one or more in FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and Rhodamin Chromophore.
11. prepare in claim 2, the method with the compound of structure as shown in formula (I), and methods described is according to as follows Route carry out：
Wherein, R1For hydrogen atom or C1-10Alkyl (for example, methyl, ethyl, n-pro-pyl, normal-butyl, n-octyl or 2- iso-octyl)；
R2Define with formula (I) in Z such as claim 2；
The method comprising the steps of：
Step 1：Make compound 1 and compound Z-NH-R2- OH reacts, and obtains compound 2；With
Step 2：By the anthracene protection group removing on compound 2, obtain the compound with structure as shown in formula (I)；
Preferably, in DMAP (DMAP) and N, N- DIC (DIC) is deposited for the reaction of described step 1 Carry out under the conditions；
Preferably, described step 1 also includes：Compound 2 is carried out separate and/or purification；
Preferably, the reaction of described step 2 is carried out under conditions of maleic anhydride presence.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN103083718A (en) * 2011-11-02 2013-05-08 中国人民解放军军事医学科学院毒物药物研究所 Biodegradable medical adhesive, and preparation method and purpose thereof
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CN103083718A (en) * 2011-11-02 2013-05-08 中国人民解放军军事医学科学院毒物药物研究所 Biodegradable medical adhesive, and preparation method and purpose thereof
CN105541664A (en) * 2016-03-09 2016-05-04 潍坊同业化学有限公司 Method for synthesizing cyanoacrylate

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