WO2020199872A1 - 一种碘络合物及其制备方法和用途 - Google Patents
一种碘络合物及其制备方法和用途 Download PDFInfo
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- C08C—TREATMENT OR CHEMICAL MODIFICATION OF RUBBERS
- C08C19/00—Chemical modification of rubber
- C08C19/12—Incorporating halogen atoms into the molecule
- C08C19/14—Incorporating halogen atoms into the molecule by reaction with halogens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
- A61K31/79—Polymers of vinyl pyrrolidone
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- C08C19/00—Chemical modification of rubber
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- C08C—TREATMENT OR CHEMICAL MODIFICATION OF RUBBERS
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- C08C—TREATMENT OR CHEMICAL MODIFICATION OF RUBBERS
- C08C19/00—Chemical modification of rubber
- C08C19/30—Addition of a reagent which reacts with a hetero atom or a group containing hetero atoms of the macromolecule
- C08C19/34—Addition of a reagent which reacts with a hetero atom or a group containing hetero atoms of the macromolecule reacting with oxygen or oxygen-containing groups
- C08C19/40—Addition of a reagent which reacts with a hetero atom or a group containing hetero atoms of the macromolecule reacting with oxygen or oxygen-containing groups with epoxy radicals
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F136/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds
- C08F136/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds the radical having only two carbon-to-carbon double bonds
- C08F136/04—Homopolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds the radical having only two carbon-to-carbon double bonds conjugated
- C08F136/06—Butadiene
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F236/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds
- C08F236/02—Copolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds the radical having only two carbon-to-carbon double bonds
- C08F236/04—Copolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds the radical having only two carbon-to-carbon double bonds conjugated
- C08F236/10—Copolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds the radical having only two carbon-to-carbon double bonds conjugated with vinyl-aromatic monomers
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- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/12—Chemical modification
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
- G02B1/041—Lenses
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B5/00—Optical elements other than lenses
- G02B5/30—Polarising elements
- G02B5/3025—Polarisers, i.e. arrangements capable of producing a definite output polarisation state from an unpolarised input state
- G02B5/3033—Polarisers, i.e. arrangements capable of producing a definite output polarisation state from an unpolarised input state in the form of a thin sheet or foil, e.g. Polaroid
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- C08J2315/00—Characterised by the use of rubber derivatives
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
Definitions
- the invention belongs to the technical field of iodine complexes, and specifically relates to an iodine complex, a preparation method thereof, and use as a radiation marker, or in an iodine therapeutic agent, or in a polarizing film.
- Iodine is one of the extremely important elements for the life of animals and plants, and it is an essential trace element for the human body. Iodine can be complexed with a variety of substances, such as amino acids and polyvinylpyrrolidone (PVP). The complexes obtained by complexation are soluble in water and are often used as plant nutrients, disinfectants, etc., but because such substances are complexed with iodine The obtained complexes are easily soluble in water and/or alcohol, which limits their application range.
- substances such as amino acids and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- starch In nature, the complex formed by starch and iodine exhibits a maximum absorption at 620-680nm and is dark blue. Therefore, many chemical titrations based on iodine use starch as an indicator. Amylose can swell and dissolve in water, but the helical structure formed by the hydrogen bonding of the hydroxyl group on glucose is destroyed, and the ability of starch in the dissolved state to bind iodine drops sharply.
- Iodine and iodine compounds are the main components of contrast agents due to their radiopacity.
- the radiolabeled compound prepared by introducing radioactive iodine 131 , iodine 125 and iodine 123 into the compound carrier can be applied to the iodinated labeling of proteins.
- the binding capacity of iodine is limited. Therefore, finding a suitable compound carrier has always been one of the research and development focuses in these application fields.
- the polyvinyl alcohol (PVA) film is stretched after being dyed with iodine, and the iodine molecules are arranged in an orderly manner on the PVA film to form a polarizing film with uniform bidirectional absorption.
- PVA is obtained by hydrolysis of vinyl acetate polymer.
- the degree of polymerization, the degree of hydrolysis of ester groups, and the configuration of the polymer affect the binding ability of PVA to iodine; PVA has strong water solubility; PVA has weak binding ability to iodine molecules.
- the heating of the iodine film causes iodine loss. How to improve the durability of PVA iodine film in high temperature and high humidity environment has always been a technical difficulty and research hotspot of polarizers.
- the purpose of the present invention is to provide an iodine complex and its preparation method and application.
- the iodine complex can be used as a radiographic marker (such as a radiopaque marker) or In the preparation of iodine therapeutic agents, it can also be used to prepare polarizers; the iodine complex is formed by complexing a polymer carrier and iodine, and the polymer carrier has good biocompatibility.
- the content of iodine in the iodine complex can be adjusted as required, for example, the mass content of the iodine is adjustable within 0.001-60 wt%.
- the present invention provides a use of a polymer comprising a structural unit represented by formula (I) and optionally at least one of structural units represented by formula (II), formula (III) and formula (IV) as an iodine carrier,
- the uses include:
- the polymer containing the structural unit represented by formula (I) and optionally at least one of the structural units represented by formula (II), formula (III) and formula (IV) is used as a carrier to complex with iodine to obtain iodo complex Compound:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different, and are independently selected from H, C 1-8 alkyl, unsubstituted or optionally substituted by one or two One or more R a substituted C 6-20 aryl groups; each R a is the same or different and is independently selected from C 1-12 alkyl groups;
- a, b, c, d, e, and f are independently integers greater than or equal to 0, and a and e are not 0 at the same time;
- R 19 is selected from H, cyano, C 1-8 alkyl, unsubstituted or optionally substituted with one, two or more of the following R a substituents group: C 3-10 cycloalkyl Group, C 6-20 aryl group; each Ra is the same or different, and is independently selected from C 1-12 alkyl groups;
- g is an integer greater than or equal to 1;
- R 13 , R 16 , R 17 and R 18 are the same or different and are independently selected from H, C 1-8 alkyl, unsubstituted or optionally substituted by one, two or more R a substituted C 6-20 aryl group; each Ra is the same or different, and is independently selected from C 1-12 alkyl groups;
- h, i, j, k and n' are independently integers greater than or equal to 1;
- R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different, and are independently selected from H, C 1-8 alkyl, unsubstituted or optionally substituted by one or two One or more R a substituted C 6-20 aryl groups; each R a is the same or different and is independently selected from C 1-12 alkyl groups;
- a', b', c', d', e', and f' are independently integers greater than or equal to 0, and are not 0 at the same time.
- the present invention also provides an iodine complex, wherein the iodine complex comprises a structural unit represented by formula (I) and optionally formula (II), formula (III) and formula (IV)
- iodine complex obtained by complexing at least one polymer in the structural unit with iodine as a carrier:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different, and are independently selected from H, C 1-8 alkyl, unsubstituted or optionally substituted by one or two One or more R a substituted C 6-20 aryl groups; each R a is the same or different and is independently selected from C 1-12 alkyl groups;
- a, b, c, d, e, and f are independently integers greater than or equal to 0, and a and e are not 0 at the same time;
- R 19 is selected from H, cyano, C 1-8 alkyl, unsubstituted or optionally substituted with one, two or more of the following R a substituents group: C 3-10 cycloalkyl Group, C 6-20 aryl group; each Ra is the same or different, and is independently selected from C 1-12 alkyl groups;
- g is an integer greater than or equal to 1;
- R 13 , R 16 , R 17 and R 18 are the same or different and are independently selected from H, C 1-8 alkyl, unsubstituted or optionally substituted by one, two or more R a substituted C 6-20 aryl group; each Ra is the same or different, and is independently selected from C 1-12 alkyl groups;
- h, i, j, k and n' are independently integers greater than or equal to 1;
- R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different, and are independently selected from H, C 1-8 alkyl, unsubstituted or optionally substituted by one or two one or more of the substituents R a C 6 - 20 aryl group;
- Each Ra is the same or different, and is independently selected from C 1-12 alkyl groups
- a', b', c', d', e', and f' are independently integers greater than or equal to 0, and are not 0 at the same time.
- the complexation refers to the connection between iodine and polymer molecules by including but not limited to coordination bonds and/or van der Waals forces.
- the polymer is coordinated with the empty orbital provided by iodine through the lone pair of electrons provided by the oxygen atoms in the two pairs of adjacent hydroxyl groups to form a complex; for example, the following combination method is adopted:
- the iodine is one of iodine molecules, iodine molecules and polyiodide ions combined with iodine ions, or a mixture thereof.
- the polymer may be a homopolymer, or a random copolymer or a block copolymer.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from H, C 1-4 alkyl, unsubstituted or optionally substituted by one, two or more R a substituted C 6-10 aryl group; R a is as defined above.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different, and are independently selected from H, methyl, phenyl, and tolyl.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different, and are independently selected from H and methyl.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same and are selected from H.
- R 19 is selected from H, cyano, C 1-4 alkyl, unsubstituted or optionally substituted with one, two or more R a substituted C 6-10 aryl group; R a is as defined above .
- R 19 is selected from phenyl, tolyl and cyano.
- R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different and are independently selected from H, C 1-4 alkyl, unsubstituted or optionally substituted by one, two or more R a substituted C 6-10 aryl group; R a is as defined above.
- R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different, and are independently selected from H, methyl, phenyl, and tolyl.
- R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same or different, and are independently selected from H and methyl.
- R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are the same and are selected from H.
- R 13, R 16, R 17 and R 18 the same or different, each independently selected from H, C 1-4 alkyl, unsubstituted or optionally substituted with one, two or more substituents R a a C 6-10 aryl group; R a is as defined above.
- R 13 , R 16 , R 17 and R 18 are the same or different, and are independently selected from H, methyl, phenyl, and tolyl.
- R 13 , R 16 , R 17 and R 18 are the same or different, and are independently selected from H and methyl.
- R 13 , R 16 , R 17 and R 18 are the same and are selected from H.
- a is an integer between 0-20000, for example a is 1, 50, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 15000, 18000 or 20000
- a is an integer between 1-7000; preferably, a is an integer between 50-3000.
- g is an integer between 1 and 10,000, such as 1, 50, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000.
- a' is an integer between 0-20000, such as 1, 50, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 15000, 18000 or 20000 ;
- B' is an integer between 0 and 2000, such as 1, 5, 50, 100, 500, 1000, 1500 or 2000;
- c' is an integer between 0 and 2000, such as 1, 5, 50, 100 , 500, 1000, 1500, or 2000;
- a'and e'are are not 0 at the same time.
- h is an integer between 0 and 2000, such as 1, 5, 50, 100, 500, 1000, 1500 or 2000
- i is an integer between 0 and 2000, such as 1, 5, 50, 100, 500, 1000, 1500 or 2000
- j is an integer between 0-2000, such as 1, 5, 50, 100, 500, 1000, 1500 or 2000
- k is an integer between 0-2000, such as 1, 5, 50, 100, 500, 1000, 1500 or 2000.
- n' is an integer between 1-10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
- n' is 1 or 2.
- the mass ratio of polymer to iodine in the iodine complex is 1:0.00001-1.5, for example, 1:0.00001, 1:0.0001, 1:0.001, 1:0.005, 1:0.01, 1:0.05 , 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.2, or 1:1.5.
- the present invention also provides a method for preparing the above-mentioned iodine complex.
- the method includes the following steps:
- the polymer comprising the structural unit represented by formula (I) and optionally at least one of the structural units represented by formula (II), formula (III) and formula (IV) is reacted with iodine to prepare the iodine complex Thing
- reaction may be a gas-solid reaction, a solid-liquid reaction or a liquid-liquid homogeneous reaction
- the gas-solid reaction is the contact of an iodine-containing gas with a solid polymer comprising a structural unit represented by formula (I) and optionally at least one of structural units represented by formula (II), formula (III) and formula (IV) reaction;
- the solid-liquid reaction is the reaction of an iodine-containing solution with a solid polymer comprising a structural unit represented by formula (I) and optionally at least one of structural units represented by formula (II), formula (III) and formula (IV) ;
- Liquid-liquid homogeneous reaction is a solution containing iodine and a polymer containing at least one of the structural units represented by formula (I) and optionally formula (II), formula (III) and formula (IV)
- the mixed solution reacts homogeneously.
- the temperature of the reaction and the time of the reaction can be reasonably adjusted by those skilled in the art to prepare iodine complexes with different iodine content; for example, the temperature of the reaction is minus 20. °C to 110 °C, the reaction time is 0.5-250h.
- the reaction is carried out under closed conditions.
- the iodine-containing gas may be a gas obtained by sublimation of a solid iodine element;
- the iodine-containing solution may be a solid iodine element or an iodine-containing solution formed by a substance containing polyiodide ions and a solvent;
- the solvent can be, for example, water, dimethyl sulfoxide, acetic acid, ethanol, etc.;
- the iodine-containing solid can be elemental iodine or a substance containing polyiodide ions;
- the iodine-containing solid can be a substance containing the structural unit represented by formula (I) and optionally
- the solution of the polymer of at least one of the structural units represented by formula (II), formula (III) and formula (IV) may contain the structural unit represented by formula (I) and optionally formula (II), formula ( III) and a solution formed by a polymer solid of at least one of the structural units represented by formula (
- the polymer containing the structural unit represented by formula (I) can be prepared by the following method:
- the epoxidized polymer is prepared by oxidation reaction of the polymer containing the structural unit represented by formula (V),
- the polymer containing the structural unit represented by formula (V) may also contain at least one of the structural units represented by formula (II), formula (VI) and formula (VII):
- R 19 and g are as defined above;
- n h+i+j+k
- the polymer containing the structural unit represented by formula (V) may be obtained by polymerization of a conjugated diene monomer, and the conjugated diene monomer may be, for example, 1. ,3-butadiene, 1,3-pentadiene or isoprene.
- step (i) the polymer containing the structural unit represented by formula (V) and at least one structural unit of formula (VII) is obtained by copolymerizing at least two conjugated diene monomers, and the conjugate
- the diene monomer may be 1,3-butadiene, 1,3-pentadiene or isoprene, for example.
- a conjugated diene such as 1,3-butadiene, 1,3-pentadiene or isoprene
- alkanes such as toluene- Heptane mixture
- solvent mixing at 30-65°C
- initiator such as nickel naphthenate-BF 3 -Et 3 Al
- molecular weight regulator such as octanol and other alcohols
- reaction terminator such as ethanol, etc.
- the oxidation reaction includes, but is not limited to, a chlorohydrin method, a peroxide epoxidation method, or an oxygen direct oxidation method.
- the oxidation reaction is an epoxidation reaction, and the oxidation reaction may be a partial epoxidation or a complete epoxidation.
- the peroxide may be a mixture of one or more of hydrogen peroxide, peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, tert-butyl hydroperoxide, etc. .
- the oxidation reaction can be carried out in an organic solvent containing a polymer, or in an emulsion of water/organic solvent.
- the organic solvent includes but is not limited to aliphatic alkanes and halogenated fats. Hydrocarbons, aromatic hydrocarbons, cycloalkanes, mineral spirits, etc., preferably hexane, cyclohexane, heptane, methylene chloride, benzene, toluene, mineral spirits, etc.
- the temperature of the oxidation reaction is 0-120°C, preferably 20-80°C.
- the catalytic hydrogenation in step (ii), can open the epoxy ring of the epoxidized polymer by methods such as catalytic hydrogenation to obtain a polymer containing hydroxyl groups on the CC chain; the hydrolysis can be performed by conventional methods.
- the acidic substance or the basic substance hydrolyzes the epoxidized polymer, opens the epoxy ring, and obtains the polymer containing the o-dihydroxy group on the CC chain.
- the catalytic hydrogenation can be partial or full catalytic hydrogenation, and the hydrolysis can be partial or complete hydrolysis.
- the acidic substance includes inorganic acids such as hydrogen halide aqueous solution, sulfuric acid, and nitric acid; organic acids such as alkyl sulfonic acid; solid acids; heteropoly acids and the like.
- inorganic acids such as hydrogen halide aqueous solution, sulfuric acid, and nitric acid
- organic acids such as alkyl sulfonic acid
- solid acids such as heteropoly acids and the like.
- the alkaline substance includes aqueous solutions of alkali metal hydroxides and carbonates.
- the catalytic hydrogenation is carried out under the catalysis of Raney nickel, triphenylphosphine rhodium chloride, platinum, palladium, or the like.
- the catalytic hydrogenation reaction can be carried out in an organic solvent containing a polymer, or in an emulsion of water/organic solvent.
- the organic solvent includes but is not limited to aliphatic alkanes and halogens. Substitute aliphatic hydrocarbons, cycloalkanes, solvent oils, cyclic ether compounds, alcohols, etc., preferably hexane, cyclohexane, tetrahydrofuran, methanol, ethanol, etc.
- the temperature of the catalytic hydrogenation reaction is 0-120°C, preferably 20-80°C.
- the hydrolysis reaction can be carried out in an organic solvent containing a polymer, or in an emulsion of water/organic solvent.
- the organic solvent includes but is not limited to aliphatic alkanes and halogenated fats. Hydrocarbons, aromatic hydrocarbons, cycloalkanes, mineral spirits, cyclic ether compounds, sulfoxides, sulfones, pyrrolidone, methylpyrrolidone, etc., preferably tetrahydrofuran, dimethylsulfoxide, methylpyrrolidone, etc.
- the temperature of the hydrolysis reaction is -20 to 150°C, preferably -10 to 80°C.
- the present invention also provides the use of the above-mentioned iodine complex as a radiation marker, or in an iodine therapeutic agent, or in a polarizing film.
- the radiopaque marker is a radiopaque marker.
- C 1-12 alkyl should be understood to preferably mean a linear or branched saturated monovalent hydrocarbon group having 1-12 carbon atoms, preferably a C 1-8 alkyl group.
- C 1-8 alkyl should be understood to preferably mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
- the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc.
- the group has 1, 2, 3, 4, 5 or 6 carbon atoms ("C 1-6 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl, Isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl Or isopropyl.
- C 1-3 alkyl such as methyl, ethyl, n-propyl Or isopropyl.
- C 6-20 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring with 6-20 carbon atoms, preferably “C 6-14 aryl” .
- C 6-14 aryl should be understood to preferably mean a monocyclic, bicyclic, or partially aromatic monocyclic or partially aromatic monocyclic ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
- Tricyclic hydrocarbon ring (“C 6-14 aryl”), especially a ring with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or one with 9 carbon atoms
- a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl,
- Either a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
- the invention provides an iodine complex, a preparation method thereof, and use as a radiation marker, or in an iodine therapeutic agent, or in a polarizing film.
- the iodine complex is formed by the complexation of a polymer carrier and iodine.
- the polymer carrier has good biocompatibility.
- the iodine complex has a low iodine dissolution rate and can be used as a radiographic marker It can be used to prepare iodine therapeutic agent or to prepare polarizing film.
- the content of iodine in the iodine complex can be adjusted as needed, and the content of iodine can be adjusted within 0.001-60%.
- the difference in iodine content can affect its transmission clarity as a radiation marker and the amount of iodine therapeutic agent.
- Figure 1 is an industrial CT scan image of the iodine complex film of Example 5.
- FIG. 2 is a TGA chart of the iodine complex of Example 5.
- Tg value test is measured by TA Company Q100 Differential Scanning Calorimeter
- TGA test uses TA company’s Q500 thermogravimetric analyzer
- the molecular weight of the polymer was tested by Agilent PL-GPC50 (with differential refractive index detector and evaporative light scattering detector);
- the degree of polarization was measured by an ultraviolet-visible spectrophotometer UV3600 (Shimadzu Corporation, Japan).
- Polybutadiene Commercially purchased polybutadiene rubber block (purchased from Sichuan Petrochemical Co., Ltd., in the structure shown in formula IV, 1,4-cis content is about 98%, and about 2% 1,4- Trans and 1,2-structures; number average molecular weight ), cut into about 2mm rubber particles.
- Epoxidation Into a 250ml three-necked flask equipped with a stirrer and a thermometer, add 7g of the above polybutadiene rubber particles and 100ml of dichloromethane. Dissolve and stir in a constant temperature water bath. When it is completely dissolved and become viscous, let in nitrogen for a few minutes.
- the temperature of the reaction liquid was lowered to 0°C and the pressure was relieved. Filter out the catalyst.
- the reaction solution of the catalyst was filtered off, and a solution prepared by 5ml water, 1ml perchloric acid and 5ml tetrahydrofuran was added dropwise. After 30min, the dropwise addition was completed.
- the reaction temperature was allowed to rise to 25°C and the temperature was kept and stirred for 12hr.
- 1 HNMR (DMSO) analysis showed that the characteristic chemical shift peak of epoxidized butadiene rubber disappeared. 0.37 g of solid sodium carbonate was added to the reaction solution and stirred for 2 hr.
- Styrene butadiene rubber commercially available styrene butadiene rubber blocks (Qilu Petrochemical Co., Ltd., styrene unit/butadiene unit (S/B): 27/73, weight average molecular weight ) Cut into about 2mm rubber particles.
- Epoxidation In a 1000ml three-necked flask equipped with a stirrer and a thermometer, add 6g of the above styrene butadiene rubber pellets and 550ml of toluene. Dissolve and stir in a constant temperature water bath. When it is completely dissolved and become viscous, let in nitrogen for a few minutes. Heat to 40°C, add 3.0 g of formic acid, add dropwise 8.2 g of 30% hydrogen peroxide aqueous solution while stirring; continue the temperature keeping reaction for about 5 hours, 1 HNMR (CDCl 3 ) analysis, the characteristic chemical shift peak of double bond disappears.
- iodine complex is a black hard mass with a weight of 2.0 g, and the mass percentage of iodine in the iodine complex is 50%.
- Solid products (about 3mm pellets) prepared according to the methods of Preparation Examples 1, 2 and 3, ethylene-vinyl alcohol polymer (EVOH, Japan Kuraray Company F171B, ethylene content 32%, about 3mm pellets), Polyvinyl alcohol (PVA, Shanghai Chenqi Chemical Technology Co., Ltd., polymerization degree 1680, alcoholysis degree 99%, molecular weight 81,000, white powder), analytically pure soluble starch, were baked to constant weight at 120°C before use.
- EVOH Japan Kuraray Company F171B, ethylene content 32%
- Polyvinyl alcohol PVA, Shanghai Chenqi Chemical Technology Co., Ltd., polymerization degree 1680, alcoholysis degree 99%, molecular weight 81,000, white powder
- analytically pure soluble starch were baked to constant weight at 120°C before use.
- Weight gain ratio weight gain/weight of solid matter before iodine absorption ⁇ 100%
- Example 5 The iodine complex film obtained in Example 5 was scanned and imaged by XTH225 series industrial CT equipped with a 225kV microfocus X-ray source. The results are shown in FIG. 1.
- the IR spectrum analysis of the iodine complex obtained in Example 5 shows that compared with the translucent solid prepared in Preparation Example 1, the stretching vibration peak of the hydroxyl group gradually shifts to the high wave number direction, and the so-called blue shift phenomenon appears, indicating polymerization
- the hydrogen bond of the hydroxyl group in the structure becomes weaker.
- the lone pair of electrons provided by the oxygen atoms in the two pairs of adjacent hydroxyl groups enters the empty valence electron orbital provided by iodine to form an iodine complex by way of coordination bonds.
- Example 5 The iodine complex obtained in Example 5 was subjected to weight loss analysis. As shown in Figure 2, as the temperature increased, the iodine continued to dissociate and volatilize, and the iodine was completely volatilized at 350°C.
- Physiological saline is prepared according to the standard method of Chinese Pharmacopoeia.
- Iodine dissolution rate % (Iodine content in the soaking solution wt% ⁇ Soaking solution weight)/Iodine weight before soaking in solids ⁇ 100.
- the iodine-containing film prepared in Example 5 was cut into a 5 cm ⁇ 4 cm piece with a thickness of 0.05-0.07 mm; it was stretched on a stretching machine into a film with a thickness of 0.02 mm. Cut the stretched iodine film into two pieces of 2cm ⁇ 2cm, and load them on a white glass sheet (100% light transmittance).
- the stretched iodine film was tested with reference to Example 6.
- the iodine film immersed in physiological saline did not deform, and the iodine dissolution rate was 0.09wt%.
- the polarized light prepared by the polymer provided by the present invention The film has better moisture resistance than PVA-based polarizing films.
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Abstract
提供了一种碘络合物及其制备方法和用途,所述碘络合物是包含式(I)所示结构单元和碘分子或碘分子和碘离子结合的多碘离子络合而成。作为载体与碘络合,得到碘络合物:(I) 所述碘络合物可作为射线标志物,或在碘治疗剂中的用途,或在偏光片中的用途,所述聚合物载体具有良好的生物相容性。所述碘络合物中碘的含量可以根据需要进行调整,且碘的含量在0.001-60%内可调。碘含量的不同可以影响其作为射线标志物的透射清晰度。
Description
本申请要求2019年4月2日向中国国家知识产权局提交的专利申请号为201910263342.5,发明名称为“一种碘络合物及其制备方法和用途”的在先申请的优先权,该在先申请的全文通过引用的方式结合于本申请中。
本发明属于碘络合物技术领域,具体涉及一种碘络合物及其制备方法和作为射线标志物、或在碘治疗剂中、或在偏光膜中的用途。
碘是对动植物的生命极其重要的元素之一,是人体必须的微量元素。碘可与多种物质络合,比如氨基酸和聚乙烯吡咯烷酮(PVP),络合得到的络合物溶于水,常用作植物营养剂、消毒杀菌剂等,但由于这类物质与碘络合得到的络合物易溶于水和/或醇,限制了他们的应用范围。
自然界中,淀粉与碘形成的络合物在620-680nm处呈现最大吸收,呈深蓝色,因此,许多基于碘的化学滴定,选用淀粉作为指示剂。直链淀粉可在水中发生溶胀、溶解,但因葡萄糖上羟基的氢键作用而形成的螺旋结构被破坏,溶解状态下的淀粉结合碘的能力急剧下降。
碘及碘化合物由于具有不透射性,是造影剂的主要成分。将具有放射性的碘
131、碘
125和碘
123等引入化合物载体中制得的放射性标记化合物,可以应用于蛋白质的碘化标记。但是,现有的化合物载体由于结合能力有限,限制了碘的结合量,因此,寻找合适的化合物载体一直是这些应用领域的研发重点之一。
聚乙烯醇(PVA)膜经碘素染色后拉伸,碘分子在PVA膜上有序排列,可形成具有均匀二向吸收性的偏光膜。PVA是由醋酸乙烯酯聚合物水解得到,生产过程中聚合度、酯基水解度、聚合物的构型影响PVA对碘的结合能力;PVA水溶性强;PVA和碘分子结合能力较弱,PVA碘膜受热即造成碘流失。如何提高PVA碘膜在高温高湿环境 下的耐久性一直是偏光片的技术难点和研究热点。
发明内容
为了改善现有技术的不足,本发明的目的是提供一种碘络合物及其制备方法和用途,所述碘络合物可作为射线标志物(如不透射线标志物),也可以用于制备碘治疗剂,还可以用于制备偏光片;所述碘络合物是聚合物载体和碘络合形成的,所述聚合物载体具有良好的生物相容性。所述碘络合物中碘的含量可以根据需要进行调整,如所述碘的质量含量在0.001-60wt%内可调。
本发明目的是通过如下技术方案实现的:
本发明提供一种包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物作为碘载体的用途,所述用途包括:
将包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物作为载体与碘络合,得到碘络合物:
式(I)中,R
1、R
2、R
3、R
4、R
5和R
6相同或不同,彼此独立地选自H、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-20芳基;每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
a、b、c、d、e和f彼此独立地为大于等于0的整数,且a和e不同时为0;
式(II)中,R
19选自H、氰基、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的下列基团:C
3-10环烷基、C
6-20芳基;每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
g为大于等于1的整数;
式(III)中,R
13、R
16、R
17和R
18相同或不同,彼此独立地选自H、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-20芳基;每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
h、i、j、k和n’彼此独立地为大于等于1的整数;
式(IV)中,R
7、R
8、R
9、R
10、R
11和R
12相同或不同,彼此独立地选自H、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-20芳基;每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
a’、b’、c’、d’、e’和f’彼此独立地为大于等于0的整数,且不同时为0。
本发明还提供一种碘络合物,其中,所述碘络合物是将包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物作为载体与碘络合得到的碘络合物:
式(I)中,R
1、R
2、R
3、R
4、R
5和R
6相同或不同,彼此独立地选自H、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-20芳基;每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
a、b、c、d、e和f彼此独立地为大于等于0的整数,且a和e不同时为0;
式(II)中,R
19选自H、氰基、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的下列基团:C
3-10环烷基、C
6-20芳基;每一个R
a相同或不同,彼此独立地选 自C
1-12烷基;
g为大于等于1的整数;
式(III)中,R
13、R
16、R
17和R
18相同或不同,彼此独立地选自H、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-20芳基;每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
h、i、j、k和n’彼此独立地为大于等于1的整数;
式(IV)中,R
7、R
8、R
9、R
10、R
11和R
12相同或不同,彼此独立地选自H、C
1-8烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-
20芳基;
每一个R
a相同或不同,彼此独立地选自C
1-12烷基;
a’、b’、c’、d’、e’和f’彼此独立地为大于等于0的整数,且不同时为0。
根据本发明,所述络合是指碘和聚合物分子之间通过包括但不限于配位键和/或范德华力等连接。示例性地,所述聚合物通过两对邻羟基中的氧原子提供的孤对电子与碘提供的空轨道配位,形成络合物;例如采用如下结合方式:
根据本发明,所述碘为碘分子、碘分子和碘离子结合的多碘离子中的一种,或它们的混合物。
根据本发明,所述聚合物可以为均聚物,也可以为无规则共聚物或者嵌段共聚物。
根据本发明,R
1、R
2、R
3、R
4、R
5和R
6相同或不同,彼此独立地选自H、C
1-4烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-10芳基;R
a的定义同上。优选地,R
1、R
2、R
3、R
4、R
5和R
6相同或不同,彼此独立地选自H、甲基、苯基、甲苯基。还优选地,R
1、R
2、R
3、R
4、R
5和R
6相同或不同,彼此独立地选自H、甲基。进一步优选地,R
1、R
2、R
3、R
4、R
5和R
6相同,选自H。
根据本发明,R
19选自H、氰基、C
1-4烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-10芳基;R
a的定义同上。优选地,R
19选自苯基、甲苯基、氰基。
根据本发明,R
7、R
8、R
9、R
10、R
11和R
12相同或不同,彼此独立地选自H、C
1-4 烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-10芳基;R
a的定义同上。优选地,R
7、R
8、R
9、R
10、R
11和R
12相同或不同,彼此独立地选自H、甲基、苯基、甲苯基。还优选地,R
7、R
8、R
9、R
10、R
11和R
12相同或不同,彼此独立地选自H、甲基。进一步优选地,R
7、R
8、R
9、R
10、R
11和R
12相同,选自H。
根据本发明,R
13、R
16、R
17和R
18相同或不同,彼此独立地选自H、C
1-4烷基、无取代或任选被一个、两个或更多个R
a取代的C
6-10芳基;R
a的定义同上。优选地,R
13、R
16、R
17和R
18相同或不同,彼此独立地选自H、甲基、苯基、甲苯基。还优选地,R
13、R
16、R
17和R
18相同或不同,彼此独立地选自H、甲基。进一步优选地,R
13、R
16、R
17和R
18相同,选自H。
根据本发明,a为0-20000之间的整数,例如a为1、50、500、1000、2000、3000、4000、5000、6000、7000、8000、9000、10000、12000、15000、18000或20000,例如a为1-7000之间的整数;优选地,a为50-3000之间的整数。
根据本发明,b为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;c为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;d为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;e为0-20000之间的整数,例如为1、50、500、1000、2000、3000、4000、5000、6000、7000、8000、9000、10000、12000、15000、18000或20000;f为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000。
根据本发明,g为1-10000之间的整数,例如为1、50、500、1000、2000、3000、4000、5000、6000、7000、8000、9000或10000。
根据本发明,a’为0-20000之间的整数,例如为1、50、500、1000、2000、3000、4000、5000、6000、7000、8000、9000、10000、12000、15000、18000或20000;b’为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;c’为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;d’为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;e’为0-10000之间的整数,例如为1、50、500、1000、2000、3000、4000、5000、6000、7000、8000、9000或10000;f’为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000。优选地,a’和e’不同时为0。
根据本发明,h为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;i为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;j 为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000;k为0-2000之间的整数,例如为1、5、50、100、500、1000、1500或2000。
根据本发明,n’为1-10之间的整数,例如为1、2、3、4、5、6、7、8、9或10。优选地,n’为1或2。
根据本发明,所述碘络合物中聚合物和碘的质量比为1:0.00001-1.5,例如为1:0.00001、1:0.0001、1:0.001、1:0.005、1:0.01、1:0.05、1:0.1、1:0.2、1:0.3、1:0.4、1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1、1:1.2或1:1.5。
本发明还提供上述碘络合物的制备方法,所述方法包括如下步骤:
包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物与碘反应,制备得到所述碘络合物;
其中,所述反应可以是气固反应、固液反应或液液均相反应;
气固反应是含碘的气体与包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物固体接触反应;
固液反应是含碘的溶液与包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物固体反应;
液液均相反应是含碘的溶液与包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物的溶液混合后均相反应。
根据本发明,所述反应的温度和所述反应的时间,本领域技术人员可以进行合理的调整,制备得到不同碘含量的碘络合物;示例性地,所述反应的温度例如为零下20℃至110℃,反应的时间为0.5-250h。
根据本发明,所述反应在密闭条件下进行。
根据本发明,所述的含碘的气体可以是固体碘单质升华得到气体;所述的含碘的溶液可以是固体碘单质或含有多碘离子的物质和溶剂形成的含碘的溶液;所述溶剂例如可以是水、二甲基亚砜、醋酸、乙醇等;所述含碘的固体可以是碘单质或含有多碘离子的物质;所述包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物的溶液可以是包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物固体和有机溶剂形成的溶液;所述有机溶剂例如可以是二甲基亚砜、醋酸、乙醇等。
根据本发明,包含式(I)所示结构单元的聚合物可以通过如下方法制备得到:
(i)将含式(V)所示结构单元的聚合物通过氧化反应制备得到环氧化聚合物,
式(V)中,x=a+b+c,y=d+e+f;R
1、R
2、R
3、R
4、R
5、R
6、a、b、c、d、e和f的定义如上所述;
(ii)将环氧化聚合物水解,或先水解再催化加氢反应,或先催化加氢再水解,制备得到所述聚合物产物。
根据本发明,含式(V)所示结构单元的聚合物还可以包含式(II)、式(VI)和式(VII)所示结构单元中的至少一种:
式(II)中,R
19和g的定义如上所述;
式(VI)中,n=h+i+j+k,R
13、R
16、R
17、R
18、h、i、j、k和n’的定义如上所述;
式(VII)中,x’=a’+b’+c’,y’=d’+e’+f’;R
7、R
8、R
9、R
10、R
11、R
12、a’、b’、 c’、d’、e’和f’的定义如上所述。
根据本发明,步骤(i)中,含式(V)所示结构单元的聚合物可以是一种共轭二烯烃类单体聚合得到的,所述共轭二烯烃类单体例如可以是1,3-丁二烯,1,3-戊二烯或异戊二烯。
步骤(i)中,含式(V)所示结构单元和至少一种式(II)和/或式(VI)所述结构单元的聚合物是通过一种共轭二烯烃类单体与至少一种R
19-CH=CH
2和/或
所示结构单体共聚得到的,所述共轭二烯烃类单体例如可以是1,3-丁二烯,1,3-戊二烯或异戊二烯,所述R
19、R
13、R
16、R
17、R
18和n’的定义如上所述。
步骤(i)中,含式(V)所示结构单元和至少一种式(VII)所述结构单元的聚合物是通过至少两种共轭二烯烃类单体共聚得到的,所述共轭二烯烃类单体例如可以是1,3-丁二烯,1,3-戊二烯或异戊二烯。
步骤(i)中,含式(V)所示结构单元、至少一种式(VII)所述结构单元和至少一种式(II)和/或式(VI)所述结构单元的聚合物是通过至少两种共轭二烯烃类单体与至少一种R
19-CH=CH
2和/或
所示结构单体共聚得到的,所述共轭二烯烃类单体例如可以是1,3-丁二烯,1,3-戊二烯或异戊二烯,所述R
19、R
13、R
16、R
17、R
18和n’的定义如上所述。
具体的,含式(V)所示结构单元的聚合物的制备方法如下所述:
采用连续式溶液聚合法,将一种共轭二烯烃(如1,3-丁二烯、1,3-戊二烯或异戊二烯),与烷烃、芳烃或二者混合物(比如甲苯-庚烷混合物)溶剂混合,在30-65℃下,加入引发剂(如环烷酸镍-BF
3-Et
3Al)引发反应,任选地加入分子量调节剂(如辛醇等醇类)调节分子量,加入反应终止剂(如乙醇等)终止反应,制备得到含式(V)所示结构单元的聚合物。
根据本发明,步骤(i)中,所述氧化反应包括但不限于氯醇法、过氧化物环氧化法或者氧气直接氧化法。所述的氧化反应为环氧化反应,所述氧化反应可以是部分环氧化,也可以是全部环氧化。
示例性地,所述的过氧化物可以选用双氧水、过氧甲酸、过氧乙酸、过氧苯甲酸、间氯过氧苯甲酸、叔丁基过氧化氢等中的一种或多种的混合物。
示例性地,所述的氧化反应可以是在含有高分子的有机溶剂中进行、还可以是在水/有机溶剂的乳液中进行,所述有机溶剂包含但并不局限于脂肪烷烃、卤代脂肪烃、芳烃、环烷烃、溶剂油等,优先选择己烷、环己烷、庚烷、二氯甲烷、苯、甲苯、溶剂油等。所述的氧化反应的温度为0-120℃,优选20-80℃。
根据本发明,步骤(ii)中,所述催化加氢可以通过催化加氢等方法打开环氧化聚合物的环氧环,得到C-C链上含有羟基的聚合物;所述水解可以用常规的酸性物质或碱性物质将环氧化聚合物进行水解,将环氧环打开,得到C-C链上含有邻双羟基的聚合物。所述的催化加氢可以是部分催化加氢,也可以是全部催化加氢,所述水解可以部分水解,也可以是全部水解。这里所述的催化加氢和水解的具体反应条件和物料配比等均为本领域的常规选择,在此没有特别的限定,只要能制备得到本申请的式(I)所示结构单元的聚合物。
示例性地,所述酸性物质包括卤化氢水溶液、硫酸、硝酸等无机酸;烷基磺酸等有机酸;固体酸;杂多酸等等。
示例性地,所述碱性物质包括碱金属的氢氧化物、碳酸盐的水溶液。
示例性地,所述催化加氢在雷尼镍、三苯基膦氯化铑或铂、钯等催化下进行。
示例性地,所述的催化加氢反应可以是在含有高分子的有机溶剂中进行、还可以是在水/有机溶剂的乳液中进行,所述有机溶剂包含但并不局限于脂肪烷烃、卤代脂肪烃、环烷烃、溶剂油、环醚化合物、醇等,优先选择己烷、环己烷、四氢呋喃、甲醇、乙醇等。所述的催化加氢反应的温度为0~120℃,优选20~80℃。
示例性地,所述的水解反应可以是在含有高分子的有机溶剂中进行、还可以是在水/有机溶剂的乳液中进行,所述有机溶剂包含但并不局限于脂肪烷烃、卤代脂肪烃、芳烃、环烷烃、溶剂油、环醚化合物、亚砜、砜、吡咯烷酮、甲基吡咯烷酮等,优先四氢呋喃、二甲亚砜、甲基吡咯烷酮等。所述的水解反应的温度为-20~150℃,优选-10~80℃。
本发明还提供上述碘络合物作为射线标志物,或在碘治疗剂中,或在偏光膜中的用途。
优选地,所述射线标志物为不透射线标志物。
术语和解释:
术语“C
1-12烷基”应理解为优选表示具有1-12个碳原子的直链或支链饱和一价烃基,优选为C
1-8烷基。“C
1-8烷基”应理解为优选表示具有1、2、3、4、5、6、7或8个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2、3、4、5或6个碳原子(“C
1-6烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更特别地,所述基团具有1、2或3个碳原子(“C
1-3烷基”),例如甲基、乙基、正丙基或异丙基。
术语“C
6-20芳基”应理解为优选表示具有6-20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C
6-14芳基”。术语“C
6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C
6-14芳基”),特别是具有6个碳原子的环(“C
6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C
9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C
10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C
13芳基”),例如芴基,或者是具有14个碳原子的环(“C
14芳基”),例如蒽基。
本发明的有益效果:
本发明提供了一种碘络合物及其制备方法和作为射线标志物,或在碘治疗剂中,或在偏光膜中的用途。所述碘络合物是聚合物载体和碘络合形成的,一方面所述聚合物载体具有良好的生物相容性,另一方面该碘络合物的碘溶出率低,可作为射线标志物,或用于制备碘治疗剂,或用于制备偏光膜。再有,基于本发明提供的制备方法,所述碘络合物中碘的含量可以根据需要进行调整,且碘的含量在0.001-60%内可调。碘含量的不同可以影响其作为射线标志物的透射清晰度以及碘治疗剂的用量。
图1为实施例5的碘络合物膜工业CT扫描图像。
图2为实施例5的碘络合物的TGA图。
下文将结合具体实施例对本发明的方法做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法;下述实施例中所用的试剂、材料等,如无特殊说明,均可从商业途径得到。
仪器和设备
物质结构测试
1HNMR、
13CNMR使用JOEL公司600兆脉冲傅立叶变换核磁共振谱仪;
IR由Thermofisher公司傅里叶红外变换光谱仪nicolet is50测试;
Tg值测试使用TA公司Q100差示扫描量热仪测定;
TGA测试使用TA公司Q500热重分析仪;
聚合物分子量由安捷伦公司PL-GPC50(配示差折光检测器和蒸发光散射检测器)测试;
偏光度由紫外可见光分光光度计UV3600(日本岛津公司)测定。
制备例1
环氧化:在装有搅拌器、温度计的250ml三口烧瓶中,加入7g上述聚顺丁二烯胶粒和100ml二氯甲烷。恒温水浴室温溶解、搅拌,待完全溶解为粘稠状时,通入氮气数分钟。加入9.90g甲酸,边搅拌边滴加21.40g 30%过氧化氢水溶液;继续保温反应约15hr,
1HNMR(CDCl
3)分析,1,4-顺式双键特征化学位移峰消失(环氧基团特征化学位移δ=2.98,1,4-顺式双键特征化学位移δ=5.40)。反应产物用10%碳酸钠溶液中和至pH=7,分去水相,水洗,分液,向分出的胶液中加入无水乙醇,析出沉淀,分离析出的沉淀,用无水乙醇洗涤一次,滤去废液,得到的湿胶,室温晾12hr后在真空干燥箱里40℃干燥约24hr至恒重,得环氧化顺丁橡胶7.3g。
水解:取1g上述制备的环氧化顺丁橡胶溶解在100ml四氢呋喃中,在25℃下边搅拌边滴加由5ml水、1ml高氯酸配置的溶液,30min滴加完毕后继续在25℃下搅拌12hr。
1HNMR(DMSO)分析,环氧化顺丁橡胶特征化学位移峰消失(环氧基团特征化学位移δ=2.98,邻双羟基特征化学位移δ=4.18)。反应液加入碳酸钠中和。向反应液中滴加1000ml水,析出沉淀,分离出沉淀,加400ml水浸泡24hr,滤出水,将所得高分子物质在室温下晾24hr,再在真空烘箱中40℃下干燥到恒重。得半透明状固体物1.12g。产物分子量
邻双羟基C4单元摩尔含量98%,Tg值56℃。
制备例2
取2g上述制备的环氧化顺丁橡胶溶解在200ml新蒸馏的四氢呋喃后加入500ml不锈钢高压反应釜中;加入0.4g雷尼镍(乙醇覆盖,加入反应器前用四氢呋喃冲洗3次);高压釜氮气充压到1MPa,泄到常压,充氮泄压重复3次。在50℃下边搅拌边通入氢气,充压到1MPa。保存氢气压力,搅拌反应12hr。
1HNMR测试,环氧基团开环度约为75%(mol)。
反应液降温到0℃,泄压。滤除催化剂。滤除催化剂的反应液,滴加由5ml水、1ml高氯酸、5ml四氢呋喃配置的溶液,30min滴加完毕,反应温度允许升到25℃,保温搅拌12hr。
1HNMR(DMSO)分析,环氧化顺丁橡胶特征化学位移峰消失。反应液中加0.37g固体碳酸钠,搅拌2hr。向反应液中滴加水,析出沉淀,加水浸泡24hr,滤出水,将所得高分子物质在室温下晾24hr,再在真空烘箱中40℃下干燥到恒重。得乳白色固体物质2.35g。数均分子量133000,邻双羟基C4单元摩尔含量24.7%,Tg值为66℃。
制备例3
环氧化:在装有搅拌器、温度计的1000ml三口烧瓶中,加入6g上述丁苯橡胶胶粒和550ml甲苯。恒温水浴室温溶解、搅拌,待完全溶解为粘稠状时,通入氮气数分钟。加热到40℃,加入3.0g甲酸,边搅拌边滴加8.2g 30%过氧化氢水溶液;继续保温反应约5hr,
1HNMR(CDCl
3)分析,双键特征化学位移峰消失。反应产物用10%碳酸钠溶液中和至pH=7,分去水相,水洗,分液,向分出的胶液中加入无水乙醇,析 出沉淀,分离析出的沉淀,用无水乙醇洗涤一次,滤去废液,得到的湿胶,室温晾12hr后在真空干燥箱里40℃干燥约24hr至恒重,得环氧化丁苯橡胶6.33g。
水解:取1g上述制备的环氧化丁苯橡胶溶解在100ml四氢呋喃中,在25℃下边搅拌边滴加由5ml水、1ml高氯酸配置的溶液,30min滴加完毕后继续在25℃下搅拌12hr。
1HNMR(DMSO)分析,环氧特征化学位移峰消失。反应液加入碳酸钠中和。向反应液中滴加1000ml水,析出沉淀,分离出沉淀,加500ml水浸泡24hr,滤出水,将所得高分子物质在室温下晾24hr,再在真空烘箱中40℃下干燥到恒重。得白色固体物1.1g,邻双羟基C4单元比例62%。
实施例1
将按制备例1的方法制备得到的半透明状固体物1g,碘单质颗粒1.1g,一同加入20ml玻璃烧瓶中,密闭,50℃保存24hr,经气固反应得碘络合物。该碘络合物为黑色硬块状物,重量2.0g,碘络合物中碘的质量百分含量为50%。
实施例2
将按制备例1的方法制备得到的半透明状固体物1g,溶于20ml二甲亚砜成聚合物二甲亚砜溶液,25℃下加入单质碘粒1.1g,搅拌,反应液因碘的溶解慢慢变为棕色。2hr后,停止搅拌,液液均相反应结束,加入200ml甲醇,析出深褐色固体黏团,固体物在30℃真空干燥24hr,得1.48g黑色固体块状物、即本发明的碘络合物,该碘络合物中碘的质量百分含量为32%。
实施例3
将按制备例1的方法制备得到的半透明状固体物1g,加入密闭玻璃瓶中,再加入20ml水,2.0g碘单质,溶于水中的碘单质被固体吸收(即液固反应),经25℃下搅拌8hr,无溶解、无变形的固体物质呈黑色,取出固体物质30℃真空干燥24hr,重量1.21g,即本发明的碘络合物,该碘络合物中碘的质量百分含量为17.4%。
实施例4
吸附碘单质实验:
相关物质:按制备例1、2、3的方法制备得到的固体产物(约3mm颗粒状)、乙 烯-乙烯醇聚合物(EVOH,日本可乐丽公司F171B,乙烯含量32%,约3mm颗粒)、聚乙烯醇(PVA,上海臣启化工科技有限公司,聚合度1680,醇解度99%,分子量81000,白色粉末)、分析纯可溶性淀粉,使用前分别在120℃烘到恒重。
取2g,精确到0.0001g,上述6种固体物分别放入100ml玻璃瓶中,再将盛有4g,精确到0.0001g,单质碘的敞口小瓶放入上述玻璃瓶中,20℃下密闭放置100hr。取出固体物称重,计算增加重量。
a、增重比例=增重/固体物质吸收碘前重×100%
实施例5
将制备例1得到的半透明状固体物1g,溶于20ml二甲亚砜,溶液倒入不锈钢托盘(304材质,27×20×2cm),溶液自然流平。干燥到恒重,得柔软聚合物膜。聚合物膜和碘粒放入密闭玻璃容器中,50℃,12hr后,得黑色络合物膜1.2g。碘络合物中碘的质量百分含量为16.7%。
实施例5得到的碘络合物膜,经装配225kV微焦点X射线源的XTH225系列工业CT扫描,成像,结果如图1所示。
实施例5得到的碘络合物经IR分析图谱分析可知,与制备例1制备得到的半透明状固体物比较,羟基的伸缩振动峰值逐渐向高波数方向移动,出现所谓蓝移现象,显示聚合物结构内羟基氢键变弱,两对邻羟基中的氧原子提供的孤对电子进入碘提供的空的价电子轨道,以配位键的方式形成碘络合物。
实施例5得到的碘络合物进行失重分析,如图2所示,随着温度升高,碘不断解离挥发,350℃碘挥发完全。
实施例6
生理盐水浸泡实验,准备以下物质:
实施例1制备的碘络合物(碘含量50.0%);
实施例4中制备的结合碘后的淀粉(碘含量19.4%);
商品聚维酮碘固体(碘含量11.2%);
生理盐水,按照中国药典标准方法配置。
精确称取上述物质各1g,加入到盛有100ml生理盐水中,浸泡24hr。取出固体物质,用少量生理盐水冲洗,冲洗液并入浸泡液。硫代硫酸钠标准溶液滴定浸泡液,计算碘溶出率。
碘溶出率%=(浸泡液中碘含量wt%×浸泡液重量)/固体物浸泡前含碘重量×100。
实施例7
实施例5制备的含碘膜,裁取5cm×4cm块,厚度0.05-0.07mm;在拉伸机上拉伸成厚度0.02mm的膜。将拉伸后的碘膜截取2cm×2cm大小两块,分别负载在白玻璃片(透光率为100%)上。用紫外可见光分光光度计测量膜的透过率Tsp(单体透过率,理论值为50%),T⊥(两片偏光膜吸收轴方向垂直放置测试的正交透过率),T∥(两片偏光膜吸收轴方向平行放置测试的平行透过率),偏振度PE=(T∥-T⊥)/(T∥+T⊥)×100%,计算膜偏振度。经测试计算,偏振度PE=90%。拉伸后的碘膜参照实施例6测试,浸泡在生理盐水中的碘膜,不变形,碘溶出率为0.09wt%,同水溶性较强的PVA比较,本发明提供的聚合物制备的偏光膜比PVA类的偏光膜具有较好的耐湿性能。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
- 一种碘络合物,其中,所述碘络合物是将包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物作为载体与碘络合得到的碘络合物:式(I)中,R 1、R 2、R 3、R 4、R 5和R 6相同或不同,彼此独立地选自H、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的C 6-20芳基;每一个R a相同或不同,彼此独立地选自 C 1-12烷基;a、b、c、d、e和f彼此独立地为大于等于0的整数,且a和e不同时为0;式(II)中,R 19选自H、氰基、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的下列基团:C 3-10环烷基、C 6-20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;g为大于等于1的整数;式(III)中,R 13、R 16、R 17和R 18相同或不同,彼此独立地选自H、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的C 6-20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;h、i、j、k和n’彼此独立地为大于等于1的整数;式(IV)中,R 7、R 8、R 9、R 10、R 11和R 12相同或不同,彼此独立地选自H、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的C 6- 20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;a’、b’、c’、d’、e’和f’彼此独立地为大于等于0的整数,且不同时为0。
- 一种包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物作为碘载体的用途,其中,所述用途包括:将包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物作为载体与碘络合,得到碘络合物:式(I)中,R 1、R 2、R 3、R 4、R 5和R 6相同或不同,彼此独立地选自H、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的C 6-20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;a、b、c、d、e和f彼此独立地为大于等于0的整数,且a和e不同时为0;式(II)中,R 19选自H、氰基、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的下列基团:C 3-10环烷基、C 6-20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;g为大于等于1的整数;式(III)中,R 13、R 16、R 17和R 18相同或不同,彼此独立地选自H、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的C 6-20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;h、i、j、k和n’彼此独立地为大于等于1的整数;式(IV)中,R 7、R 8、R 9、R 10、R 11和R 12相同或不同,彼此独立地选自H、C 1-8烷基、无取代或任选被一个、两个或更多个R a取代的C 6-20芳基;每一个R a相同或不同,彼此独立地选自C 1-12烷基;a’、b’、c’、d’、e’和f’彼此独立地为大于等于0的整数,且不同时为0。
- 根据权利要求1所述的碘络合物或权利要求2所述的用途,其中,R 1、R 2、R 3、R 4、R 5 和R 6相同或不同,彼此独立地选自H、C 1-4烷基、无取代或任选被一个、两个或更多个R a取代的C 6-10芳基;R a的定义同上。优选地,R 1、R 2、R 3、R 4、R 5和R 6相同或不同,彼此独立地选自H、甲基、苯基、甲苯基;还优选地,R 1、R 2、R 3、R 4、R 5和R 6相同或不同,彼此独立地选自H、甲基;进一步优选地,R 1、R 2、R 3、R 4、R 5和R 6相同,选自H。优选地,a为0-20000之间的整数,优选地,a为50-3000之间的整数。优选地,b为0-2000之间的整数、c为0-2000之间的整数、d为0-2000之间的整数、e为0-20000之间的整数、f为0-2000之间的整数。
- 根据权利要求1或3所述的碘络合物或权利要求2或3所述的用途,R 19选自H、氰基、C 1-4烷基、无取代或任选被一个、两个或更多个R a取代的C 6-10芳基;R a的定义同上;优选地,R 19选自苯基、甲苯基、氰基。优选地,g为1-10000之间的整数。
- 根据权利要求4所述的碘络合物或用途,其中,R 7、R 8、R 9、R 10、R 11和R 12相同或不同,彼此独立地选自H、C 1-4烷基、无取代或任选被一个、两个或更多个R a取代的C 6-10芳基;R a的定义同上;优选地,R 7、R 8、R 9、R 10、R 11和R 12相同或不同,彼此独立地选自H、甲基、苯基、甲苯基;还优选地,R 7、R 8、R 9、R 10、R 11和R 12相同或不同,彼此独立地选自H、甲基;进一步优选地,R 7、R 8、R 9、R 10、R 11和R 12相同,选自H。优选地,a’为0-20000之间的整数、b’为0-2000之间的整数、c’为0-2000之间的整数、d’为0-2000之间的整数、e’为0-10000之间的整数、f’为0-2000之间的整数。优选地,a’和e’不同时为0。优选地,R 13、R 16、R 17和R 18相同或不同,彼此独立地选自H、C 1-4烷基、无取代或任选被一个、两个或更多个R a取代的C 6- 10芳基;R a的定义同上;优选地,R 13、R 16、R 17和R 18相同或不同,彼此独立地选自H、甲基、苯基、甲苯基;还优选地,R 13、R 16、R 17和R 18相同或不同,彼此独立地选自H、甲基;进一步优选地,R 13、R 16、R 17和R 18相同,选自H。优选地,h为0-2000之间的整数、i为0-2000之间的整数、j为0-2000之间的整数、k为0-2000之间的整数。优选地,n’为1-10之间的整数;还优选地,n’为1或2。
- 根据权利要求1、3-5任一项所述的碘络合物或权利要求2-5任一项所述的用途,所述碘为碘分子、碘分子和碘离子结合的多碘离子中的一种,或它们的混合物。优选地,所述聚合物为均聚物,也可以为无规则共聚物或者嵌段共聚物。优选地,所述碘络合物中聚合物和碘的质量比为1:0.00001-1.5。
- 权利要求1、3-6任一项所述的或权利要求2所述用途中的碘络合物的制备方法,所述方法包括如下步骤:包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物与碘反应,制备得到所述碘络合物;其中,所述反应可以是气固反应、固液反应或液液均相反应;气固反应是含碘的气体与包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物固体接触反应;固液反应是含碘的溶液与包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物固体反应;液液均相反应是含碘的溶液与包含式(I)所示结构单元和任选地式(II)、式(III)和式(IV)所示结构单元中的至少一种的聚合物的溶液混合后均相反应。
- 权利要求1、3-6任一项所述的碘络合物在射线标志物中的用途,或在碘治疗剂中的用途,或在偏光片中的用途。优选地,所述射线标志物为不透射线标志物。
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