JP6064766B2 - Zwitterionic ethylenically unsaturated monomer and method for producing the same. - Google Patents

Description

  The present invention includes a zwitterionic ethylenically unsaturated monomer derived from a pyrrolidine-2-carboxylic acid skeleton, a method for producing the same, and radical polymerization of the zwitterionic ethylenically unsaturated monomer as a constituent unit. The present invention relates to a pyrrolidine-2-carboxylic acid residue-containing polymer.

In recent years, rapid development of biotechnology has led to the development of biocompatible polymer materials in which biomolecules such as proteins are not adsorbed and activated at the interface between medical devices and healthcare devices and biological components. Actively studied. Above all, polymer materials produced from zwitterionic monomers are attracting attention as materials with excellent biocompatibility because they do not disturb the hydrogen-bonding network of water despite the electrolyte. .
Patent Document 1 discloses a phosphobetaine-type polymer material (MPC polymer) obtained by polymerizing 2-methacrylolyloxyethylphosphocholine. However, 2-methacrylolyloxyethylphosphocholine constituting the MPC polymer has many synthesis steps and is complicated, so it is difficult to increase the purity, and the produced crystals are deliquescent in a short time. There are drawbacks. Therefore, handling is inconvenient and very expensive.
Patent Document 2 discloses a carboxybetaine-type polymer material obtained by polymerizing N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine. However, the amine derived from the raw material remains during monomer synthesis, which may adversely affect biocompatibility. Moreover, since salt is by-produced at the time of synthesis, if the desalting treatment is insufficient, the skin and mucous membrane are stimulated or the metal material is corroded.
Amino acid molecules having a zwitterionic structure are also attracting attention as materials having excellent biocompatibility, like MPC polymers. Patent Document 3 discloses a zwitterionic monomer (meth) acrylic acid serine ester having an amino acid residue and a polymer material obtained by polymerizing the same. However, since there are many steps to obtain a monomer for this, and it is complicated, it is difficult to obtain a high-purity target with high yield at low cost. Residual components derived from raw materials are biocompatible. May adversely affect

JP 09-3132 A JP 2007-130194 A Japanese Patent Laid-Open No. 06-251209

  The first object of the present invention is to provide a novel zwitterionic ethylenically unsaturated monomer derived from a pyrrolidine-2-carboxylic acid skeleton. The second object of the present invention is to provide a method for producing the zwitterionic ethylenically unsaturated monomer which is simple, high purity and high yield. The third object of the present invention is to provide a polymer excellent in biocompatibility containing the zwitterionic ethylenically unsaturated monomer as a constituent component.

That is, the first invention is
The present invention relates to a zwitterionic ethylenically unsaturated monomer represented by the general formula (1).

General formula (1)

X represents a hydrogen atom or a methyl group.
Y represents an oxygen atom or NH.
R is a nonionic divalent functional group composed of an alkylene group, an alkylene group substituted with an alkyl group or a hydroxyl group, a phenylene group, an ester bond, an ether bond, a urethane bond, an amide bond, or a combination thereof. is there.

In addition, the second invention,
A pyrrolidine-2-carboxylic acid is reacted with an acryloyl group of a bifunctional ethylenically unsaturated monomer having one acryloyl group and one methacryloyl group in one molecule of the general formula (2). It relates to the zwitterionic ethylenically unsaturated monomer described.

General formula (2)

Y represents an oxygen atom or NH.
R is a nonionic divalent functional group composed of an alkylene group, an alkylene group substituted with an alkyl group or a hydroxyl group, a phenylene group, an ester bond, an ether bond, a urethane bond, an amide bond, or a combination thereof. is there.

The third invention also relates to a method for producing a zwitterionic ethylenically unsaturated monomer obtained by Michael addition reaction of pyrrolidine-2-carboxylic acid with an acryloyl group-containing compound in an alcohol solvent.
The fourth invention relates to a pyrrolidine-2-carboxylic acid residue-containing polymer obtained by radical polymerization of a monomer containing the zwitterionic ethylenically unsaturated monomer of the first or second invention.

  The fifth invention relates to a biocompatible material resin composition comprising the pyrrolidine-2-carboxylic acid residue-containing polymer of the fourth invention.

  The present invention is a novel zwitterionic ethylenically unsaturated monomer having an amino acid residue, and can provide a polymer excellent in biocompatibility by radical polymerization. In the production method of the present invention, a pyrrolidine-2-carboxylic acid is subjected to a Michael addition reaction with an acryloyl group-containing compound in an alcohol, whereby the zwitterionic ethylenically unsaturated monomer is simply and highly purified and has a high yield. Can be manufactured at a rate. The copolymer using the zwitterionic ethylenically unsaturated monomer has specific compatibility with biological components and is expected to be used as a biocompatible material for medical applications and healthcare applications. The

  The zwitterionic ethylenically unsaturated monomer of the present invention has one (meth) acryloyl group in one molecule and a zwitterionic pyrrolidine-2-carboxylic acid residue in a hydrophilic group. It is characterized by things. The zwitterionic ethylenically unsaturated monomer of the present invention is efficiently obtained by Michael addition reaction of the amino group of pyrrolidine-2-carboxylic acid to the acryloyl group of a bifunctional ethylenically unsaturated monomer having an acryloyl group. Can be obtained.

  The bifunctional ethylenically unsaturated monomer having an acryloyl group used in the present invention includes an ethylenically unsaturated monomer having two acryloyl groups in one molecule and one acryloyl group in one molecule. And an ethylenically unsaturated monomer having one methacryloyl group.

  Examples of the bifunctional ethylenically unsaturated monomer having two acryloyl groups in one molecule include ethylene glycol diacrylate, neopentyl glycol diacrylate, 1,6-hexanediol diacrylate, and 1,9-nonane. Diol diacrylate, triethylene glycol diacrylate, polyethylene glycol diacrylate (manufactured by Kyoeisha, Light acrylate 4EG-A, 9EG-A, 14EG-A), 3-methyl-1,5-pentanediol diacrylate, polytetramethylene glycol Examples include diacrylate, dimethylol tricyclodecane diacrylate, and 2-butyl-2-ethyl-1,3-propanediol diacrylate.

Examples of the ethylenically unsaturated monomer having one acryloyl group and one methacryloyl group in one molecule include methacryloyl chloride and hydroxyl group-containing acrylate (c-1), or acryloyl chloride and hydroxyl group-containing methacrylate ( a bifunctional ethylenically unsaturated monomer obtained by the esterification reaction of c-2),
Bifunctional obtained by ring-opening reaction of carboxyl group-containing acrylate (d-1) and glycidyl group-containing methacrylate (e-1) or carboxyl group-containing methacrylate (d-2) and glycidyl group-containing acrylate (e-2) Ethylenically unsaturated monomers,
Difunctional ethylene obtained by addition reaction of isocyanate group-containing acrylate (f-1) and hydroxyl group-containing methacrylate (c-2) or isocyanate group-containing methacrylate (f-2) and hydroxyl group-containing acrylate (c-1) Unsaturated unsaturated monomers.
These bifunctional ethylenically unsaturated monomers may be synthesized by reacting with a combination of the above monofunctional ethylenically unsaturated monomers, or commercially available products may be used.

  Examples of the hydroxyl group-containing acrylate (c-1) include 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-acryloyloxyethyl 2-hydroxyethylphthalic acid, polyethylene glycol monoacrylate ( Made by NOF, BLEMMER AE-90, AE-200, AE-400) Polypropylene glycol monoacrylate (NOF, BLEMMER AP-150, AP-400, AP-550, AP-800), polyethylene glycol-polypropylene glycol mono Examples thereof include acrylate (manufactured by NOF Corporation, Blemmer AEP), hydroxylethyl acrylamide and the like.

  Examples of the hydroxyl group-containing methacrylate (c-2) include 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-methacryloyloxyethyl 2-hydroxyethylphthalic acid, polyethylene glycol monomethacrylate (manufactured by NOF Corporation, PE- 90, PE-200, PE-350) Polyethylene glycol monomethacrylate (Blenmer PP-1000, PP-500, PP-800) Polyethylene glycol-polypropylene glycol methacrylate (manufactured by NOF, Bremer 50PEP-300, 70PEP-350B), Examples include hydroxylethyl methacrylamide.

Examples of the carboxyl group-containing acrylate (d-1) include acrylic acid, 2-acryloyloxyethyl succinic acid, 2-acryloyloxyethyl phthalic acid, 2-acryloyloxyethyl hexahydrophthalic acid, and the like.
Examples of the carboxyl group-containing methacrylate (d-2) include methacrylic acid, 2-methacryloyloxyethyl succinic acid, 2-methacryloyloxyethyl hexahydrophthalic acid, and the like.

Examples of the glycidyl group-containing methacrylate (e-1) include glycidyl methacrylate.
Examples of the glycidyl group-containing acrylate (e-2) include glycidyl acrylate and 4-hydroxybutyl acrylate glycidyl ether.

Examples of the isocyanate group-containing acrylate (f-1) include 2-isocyanatoethyl acrylate.
Examples of the isocyanate group-containing methacrylate (f-2) include 2-isocyanatoethyl methacrylate, Showa Denko KK, Karenz MOI-EG, and the like.

  Among the bifunctional ethylenically unsaturated monomers mentioned above, an ethylenically unsaturated monomer having one acryloyl group and one methacryloyl group in one molecule is preferable. In an ethylenically unsaturated monomer having two acryloyl groups, a by-product to which pyrrolidine-2-carboxylic acid is added is generated at the same time. Therefore, the yield of the target product in which pyrrolidine-2-carboxylic acid is added to only one acryloyl group is lowered. On the other hand, in an ethylenically unsaturated monomer having one acryloyl group and one methacryloyl group in one molecule, pyrrolidine-2-carboxylic acid is selectively added to the acryloyl group, so that only the methacryloyl group is present. The remaining target product can be obtained in a higher yield.

  In the Michael addition reaction of a bifunctional ethylenically unsaturated monomer and pyrrolidine-2-carboxylic acid, pyrrolidine-2-carboxylic acid is in the form of a powder, so that it must be dissolved in a solvent in order to react. is there. Amino acids are hardly soluble in organic solvents. Although it dissolves easily in water, it is ionized, so the Michael addition reaction does not proceed. Pyrrolidine-2-carboxylic acid is an amino acid that is soluble in alcohol solvents. Alcohol solvents also have the effect of promoting the Michael addition reaction. Therefore, it is preferable to use an alcohol solvent as the reaction solvent in carrying out the Michael addition reaction of pyrrolidine-2-carboxylic acid to the acryloyl group. Further, among alcohol solvents, it is more preferable to use ethanol in consideration of solubility of pyrrolidine-2-carboxylic acid, solvent toxicity, and ease of removal.

  When obtaining the zwitterionic ethylenically unsaturated monomer, an appropriate amount of a polymerization inhibitor can be used in combination in the reaction in order to prevent inadvertent polymerization of the (meth) acryloyl group of the raw material or the target product. Examples of the polymerization inhibitor include methoxyphenol and hydroquinone.

  Then, the manufacturing method of the zwitterionic ethylenically unsaturated monomer of this invention is demonstrated. A bifunctional ethylenically unsaturated monomer having an acryloyl group and pyrrolidine-2-carboxylic acid are charged in an equimolar amount into a reaction vessel equipped with a refluxer and a stirrer. About the bifunctional ethylenically unsaturated monomer which has an acryloyl group, you may synthesize | combine beforehand by the combination of the monofunctional monomer shown above, and you may use a commercial item. Next, ethanol as a reaction solvent is charged. Considering the shortening of the reaction time and the stability of the ethylenically unsaturated monomer, the concentration of the raw material component is preferably in the range of 30 to 70% by weight. After completion of the preparation, the temperature of the reaction vessel is increased while stirring. Considering the amount of pyrrolidine-2-carboxylic acid dissolved in the solvent and the stability of the ethylenically unsaturated monomer, the reaction temperature is preferably 50 to 90 ° C., and the reaction time is 5 to 15 hours. It is preferable that The pyrrolidine-2-carboxylic acid powder dissolves slowly as the reaction proceeds and is consumed while being supplied. When the bifunctional ethylenically unsaturated monomer has two acryloyl groups in one molecule, a by-product in which both pyrrolidine-2-carboxylic acids are added is formed. By-products can be removed by column chromatography. On the other hand, when the bifunctional ethylenically unsaturated monomer has one acryloyl group and one methacryloyl group, it is selectively added only to the acryloyl group, and the above-mentioned by-product is not generated. After completion of the reaction, the target zwitterionic ethylenically unsaturated monomer can be obtained by removing the reaction solvent by drying under reduced pressure. When the target product has crystallinity, recrystallization is performed with a poor solvent such as acetone.

The zwitterionic ethylenically unsaturated monomer was identified by ¹ H-NMR (nuclear magnetic resonance spectroscopy) and elemental analysis.

  Next, the pyrrolidine-2-carboxylic acid residue-containing polymer obtained by radical polymerization of the zwitterionic ethylenically unsaturated monomer of the present invention will be described. The zwitterionic ethylenically unsaturated monomer obtained in the above process can be polymerized alone by radical polymerization or other ethylenically copolymerizable within a range that does not adversely affect biocompatibility. It can also be copolymerized with an unsaturated monomer (g). As the polymerization method, polymerization can be performed by any method such as solution polymerization, emulsion polymerization, and dispersion polymerization.

Examples of other copolymerizable ethylenically unsaturated monomers (g) include methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, t-butyl methacrylate, pentyl (meth) acrylate, and heptyl (meth). Acrylate, hexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, undecyl (meth) acrylate, dodecyl (meth) acrylate, tridecyl (meth) Linear or branched alkyl group-containing ethylenically unsaturated monomers such as acrylate and tetradecyl (meth) acrylate;
Alicyclic alkyl group-containing ethylenically unsaturated monomers such as cyclohexyl (meth) acrylate and isobornyl (meth) acrylate;
Styrene, α-methyl styrene, o-methyl styrene, p-methyl styrene, m-methyl styrene, vinyl naphthalene, benzyl acrylate, benzyl methacrylate, phenoxyethyl acrylate, phenoxyethyl methacrylate, phenoxydiethylene glycol acrylate, phenoxydiethylene glycol methacrylate, phenoxytetraethylene Aromatic ethylenically unsaturated monomers such as glycol acrylate, phenoxytetraethylene glycol methacrylate, phenoxyhexaethylene glycol acrylate, phenoxyhexaethylene glycol methacrylate, phenyl acrylate, phenyl methacrylate;
Fluorinated alkyl group-containing ethylenically unsaturated monomers such as trifluoroethyl (meth) acrylate and heptadecafluorodecyl (meth) acrylate;
(Meth) acrylamide, N-methoxymethyl- (meth) acrylamide, N-ethoxymethyl- (meth) acrylamide, N-propoxymethyl- (meth) acrylamide, N-butoxymethyl- (meth) acrylamide, N-pentoxymethyl -(Meth) acrylamide, N, N-di (methoxymethyl) acrylamide, N-ethoxymethyl-N-methoxymethylmethacrylamide, N, N-di (ethoxymethyl) acrylamide, N-ethoxymethyl-N-propoxymethylmeta Acrylamide, N, N-di (propoxymethyl) acrylamide, N-butoxymethyl-N- (propoxymethyl) methacrylamide, N, N-di (butoxymethyl) acrylamide, N-butoxymethyl-N- (methoxymethyl) meta Acrylic net N, N-di (pentoxymethyl) acrylamide, N-methoxymethyl-N- (pentoxymethyl) methacrylamide, N, N-dimethylaminopropylacrylamide, N, N-diethylaminopropylacrylamide, N, N-dimethyl Amide group-containing ethylenically unsaturated monomers such as acrylamide and N, N-diethylacrylamide;
Polyethylene glycol mono (meth) acrylate (Nippon Yushi Co., Ltd., Bremer PE-90, 200, 350, 350G, AE-90, 200, 400, etc.) Polyethylene glycol / polypropylene glycol mono (meth) acrylate (Nippon Yushi Co., Ltd., Blemmer 50PEP-300, 70PEP-350, etc.), polyethylene oxide group-containing ethylenically unsaturated monomers such as methoxypolyethylene glycol mono (meth) acrylate (manufactured by NOF Corporation, BLEMMER PME-400, 550, 1000, 4000 etc.)
2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, glycerol mono (meth) acrylate, 4-hydroxyvinylbenzene, 1-ethynyl-1-cyclohexanol, allyl Hydroxyl group-containing ethylenically unsaturated monomers such as alcohol;
Etc.

  The polymerization initiator is not particularly limited as long as it has the ability to initiate radical polymerization, and known oil-soluble polymerization initiators and water-soluble polymerization initiators can be used.

The oil-soluble polymerization initiator is not particularly limited, and examples thereof include benzoyl peroxide, tert-butyl peroxybenzoate, tert-butyl hydroperoxide, tert-butyl peroxy (2-ethylhexanoate), and tert-butyl peroxide. Organic peroxides such as oxy-3,5,5-trimethylhexanoate, di-tert-butyl peroxide;
2,2′-azobisisobutyronitrile, 2,2′-azobis-2,4-dimethylvaleronitrile, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 1,1 Mention may be made of azobis compounds such as' -azobis-cyclohexane-1-carbonitrile. These can be used alone or in combination of two or more.

  The water-soluble polymerization initiator is not particularly limited, and for example, conventionally known ones such as ammonium persulfate, potassium persulfate, hydrogen peroxide, 2,2′-azobis (2-methylpropionamidine) dihydrochloride are preferably used. Can be used.

  As the solvent used in the polymerization, any solvent can be used as long as it can dissolve the zwitterionic ethylenically unsaturated monomer. It is preferable to use it. In addition, the alcohol solvent used to obtain the zwitterionic ethylenically unsaturated monomer can be used as a solvent during polymerization without removing it from the reaction system when proceeding to the polymerization process as it is. is there.

As a method for producing a pyrrolidine-2-carboxylic acid residue-containing polymer, a copolymer of n-butyl acrylate and a zwitterionic ethylenically unsaturated monomer will be described as an example. A reaction vessel equipped with a nitrogen gas inlet tube, a condenser, and a stirrer was charged with n-butyl acrylate, a zwitterionic ethylenically unsaturated monomer, and ethanol, and the temperature was raised to 70 ° C. while purging with nitrogen.
The concentration of the monomer component is preferably in the range of 20 to 50% by weight in consideration of shortening of the reaction time and heat generation during polymerization. After nitrogen substitution, initiator azobisisobutylnitrile was added and reacted under reflux conditions. The reaction time is preferably in the range of 5 to 24 hours in consideration of reduction of residual monomer components. Completion of the reaction and confirmation of the residual monomer can be confirmed by a general analytical method such as gas chromatography. After completion of the reaction, the reaction product was cooled to obtain the target pyrrolidine-2-carboxylic acid residue-containing polymer.

  The obtained pyrrolidine-2-carboxylic acid residue-containing polymer was measured for weight average molecular weight. Here, the weight average molecular weight is a value of a weight average molecular weight measured by gel permeation chromatography (GPC) using polyethylene glycol as a standard sample.

  The resin composition for biocompatible materials of the present invention contains the pyrrolidine-2-carboxylic acid residue-containing polymer, and other resins, additives, and the like, as long as the biocompatibility is not adversely affected. A solvent or the like may be contained.

  The method of forming a film comprising the resin composition for biocompatible materials using the pyrrolidine-2-carboxylic acid residue-containing polymer of the present invention is not particularly limited. For example, a medical film-forming resin composition is used. After applying, spraying, and vapor-depositing on a substrate, a method of forming a film by heat drying, applying a liquid mixed with a monomer composition before polymerization and a polymerization initiator to the substrate, then applying heat or light Examples thereof include a method of polymerizing the monomer composition to form a film.

  Examples of the material constituting the substrate include polyethylene, polypropylene, polystyrene, polyvinyl chloride, nylon, polyurethane, polyurea, polylactic acid, polyglycolic acid, polyvinyl alcohol, polyvinyl acetate, poly (meth) acrylic acid, poly (Meth) acrylic acid derivative, polyacrylonitrile, poly (meth) acrylamide, poly (meth) acrylamide derivative, polysulfone, polycarbonate, cellulose, cellulose derivative, polysilicone, glass, ceramic, metal and the like. These materials can be used alone or in combination of two or more.

  EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the following examples do not limit the scope of rights of the present invention. In the examples, “part” represents “part by weight” and “%” represents “% by weight”.

<Production of zwitterionic ethylenically unsaturated monomer>
[Example 1]
In a reaction vessel equipped with a reflux and a stirrer, 93.0 parts by weight of 2-hydroxy-3-acryloyloxypropyl methacrylate, 50.0 parts by weight of pyrrolidine-2-carboxylic acid, and 178.8 parts by weight of ethanol were charged. After raising the temperature with stirring, the mixture was reacted at 70 ° C. for 8 hours. After completion of the reaction, ethanol was removed by drying under reduced pressure to obtain the desired product. The yield was 93%. The obtained product was subjected to ¹ H-NMR and elemental analysis.
[ ¹ H-NMR]
The NMR spectrum was measured using ECX-400P (400 MHz) manufactured by JEOL. Deuterated chloroform (CDCl ₃ ) was used as a heavy solvent for the measurement.
[Elemental analysis]
Elemental analysis was performed using 2400CHN manufactured by PerkinElmer.
[ ¹ H-NMR spectrum]
(Δ value) 1.90-1.98 (5H), 2.21 (1H), 2.33 (1H), 2.94 (3H), 3.2-3.6 (4H), 3.70 (1H), 4.15-4.40 (5H), 5.61 (1H), 6.14 (1H)
[Elemental analysis]
Theoretical value (%) as C15H23N1: H = 10.67 C = 82.89 N = 6.44
Actual value (%): H = 10.43 C = 82.93 N = 6.64
From the above results, the product was identified as a zwitterionic ethylenically unsaturated monomer represented by the following formula.

[Example 2]
A reaction vessel equipped with a refluxing apparatus and a stirrer was charged with 138.0 parts by weight of 4-hydroxybutyl acrylate and 76.0 parts by weight of pyridine. While cooling with ice, 100.0 parts by weight of methacrylic acid chloride was added dropwise over 1 hour. After reacting for 4 hours, pyridine hydrochloride was removed by filtration to obtain 130.0 parts by weight of 4- (acryloyloxy) butyl methacrylate as a raw material.
A reaction vessel equipped with a reflux and a stirrer was charged with 100.0 parts by weight of 4- (acryloyloxy) butyl methacrylate obtained above, 51.5 parts by weight of pyrrolidine-2-carboxylic acid, and 151.5 parts by weight of ethanol. . After raising the temperature with stirring, the reaction was carried out at 70 ° C. for 5 hours. After completion of the reaction, ethanol was removed by drying under reduced pressure, and recrystallization was performed with acetone to obtain the desired product. The yield was 85%. The obtained product was subjected to ¹ H-NMR and elemental analysis.
[ ¹ H-NMR spectrum]
(Δ value) 1.60 (4H), 1.90-1.98 (5H), 2.31 (2H), 2.89 (3H), 3.29 (1H), 3.52 (3H), 3.73 (1H), 3.81 (1H), 4.12 (4H), 5.61 (1H), 6.14 (1H)
[Elemental analysis]
Theoretical value (%) as C16H25N1: H = 10.89 C = 83.06 N = 6.05
Actual value (%): H = 10.75 C = 83.28 N = 5.97
From the above results, the product was identified as a zwitterionic ethylenically unsaturated monomer represented by the following formula.

[Example 3]
In a reaction vessel equipped with a refluxer and a stirrer, 37.4 parts by weight of 2-hydroxyethyl acrylate was charged and heated to 80 ° C. while stirring. Thereto, 50.0 parts by weight of 2-isocyanatoethyl methacrylate was added dropwise from a dropping tank over 1 hour, and further reacted for 10 hours. After cooling, 37.1 parts by weight of pyrrolidine-2-carboxylic acid and 155.7 parts by weight of ethanol were further added to the reaction vessel. After heating again with stirring, the reaction was carried out at 70 ° C. for 10 hours. After completion of the reaction, ethanol was removed by drying under reduced pressure, and recrystallization was performed with acetone to obtain the desired product. The yield was 94.7%. The obtained product was subjected to ¹ H-NMR, IR analysis, and elemental analysis.
[ ¹ H-NMR spectrum]
(Δ value) 1.90-1.98 (5H), 2.31 (2H), 2.89 (3H), 3.29 (1H), 3.52 (3H), 3.73 (1H), 3.81 (1H), 4.14-4.36 (6H)
5.61 (1H), 6.14 (1H)
[Elemental analysis]
Theoretical value (%) as C17H26N2: H = 10.104 C = 79.02 N = 10.84
Actual value (%): H = 10.20 C = 79.25 N = 10.55
From the above results, the product was identified as a zwitterionic ethylenically unsaturated monomer represented by the following formula.

[Example 4]
A reaction vessel equipped with a refluxing apparatus and a stirrer was charged with 87.4 parts by weight of 1,6-hexanediol diacrylate, 44.5 parts by weight of pyrrolidine-2-carboxylic acid, and 164.9 parts by weight of ethanol. After raising the temperature with stirring, the mixture was reacted at 70 ° C. for 12 hours. After completion of the reaction, by-product in which two pyrrolidine-2-carboxylic acids were added in one molecule was removed by silica gel column chromatography (solvent: chloroform / methanol / water mixed solvent), and one by one in one molecule. The target product to which only pyrrolidine-2-carboxylic acid was added was collected. The mixed solvent was removed by drying under reduced pressure to obtain the desired product. The yield was 67%.
¹ H-NMR and elemental analysis were performed on the obtained product.
[ ¹ H-NMR spectrum]
(Δ value) 1.24 (4H), 1.61 (4H), 1.90-1.98 (5H), 2.31 (2H), 2.89 (3H), 3.29 (1H), 3.52 (3H), 3.73 (1H), 3.81 (1H), 4.14 (4H), 5.92 (1H), 6.16 (1H), 6.45 (1H)
[Elemental analysis]
Theoretical value (%) as C17H27N1: H = 11.09 C = 83.20 N = 5.71
Found (%): H = 11.18 C = 83.18 N = 5.57
From the above results, the product was identified as a zwitterionic ethylenically unsaturated monomer represented by the following formula.

[Production of pyrrolidine-2-carboxylic acid residue-containing polymer]
[Example 5]
A reaction vessel equipped with a reflux and a stirrer was charged with 30.0 parts by weight of the zwitterionic ethylenically unsaturated monomer obtained in Example 1, 70.0 parts by weight of butyl methacrylate, and 150.0 parts by weight of ethanol. . While stirring, the temperature was raised to 70 ° C., and after substitution with nitrogen, 5 parts by weight of azobisisobutylnitrile as an initiator was added and reacted for 10 hours under reflux conditions. After cooling, the desired pyrrolidine-2-carboxylic acid residue-containing polymer was obtained. The weight average molecular weight was 235,000. The obtained polymer was reprecipitated with diethyl ether and vacuum-dried at 30 ° C. for 30 hours to remove the solvent to obtain a polymer powder.

[Weight average molecular weight]
The weight average molecular weight is a value in terms of polyethylene glycol as measured by GPC (gel permeation chromatography).
Equipment: GPC SYSTEM24H (Showa Denko)
Column; SB-803HQ + SB-804HQ (Showa Denko)
Elution solvent; 20 mM phosphate buffer standard; polyethylene glycol (manufactured by Agilent Technologies)
Flow rate: 0.5 mL / min, sample solution usage: 10 μL, column temperature: 40 ° C.

[Examples 6 to 11 and Comparative Examples 1 to 5]
A polymer was prepared in the same manner as in Example 5 with the composition shown in Table 1. The obtained polymer solution was vacuum-dried at 40 ° C. for 24 hours to remove the solvent.
The weight average molecular weights of the resins of Comparative Examples 1 to 4 were calculated by changing the column to the following conditions.
Column: LF-604 x 2 (Showa Denko)
Elution solvent: THF
Standard material: Polystyrene (made by Showa Denko)
Flow rate: 0.5 mL / min, sample solution usage: 10 μL, column temperature: 40 ° C.

<Evaluation of biocompatibility>
Protein adsorption suppression test of polymer coating film Examples 5 to 11 and Comparative Examples 1 to 5 were prepared by dissolving 1.0 g of the polymer in 100.0 g of ethanol to prepare a coating solution. A test tube (12 × 75 mm) made of polystyrene was filled with the coating solution, allowed to stand for 30 minutes, then discarded, and dried at 50 ° C. for 3 hours. Bovine serum albumin (0.5% by weight) phosphate buffer (4.0 mL) was placed in a resin-coated tube, incubated for 24 hours, and then washed again with bovine serum albumin (0.5% by weight) phosphate buffer. . Thereafter, sodium lauryl sulfate was added to elute the protein adsorbed on the inner wall of the test tube, and the concentration of the protein in this PBS was measured with Micro BCA Protein Assay Kit (manufactured by Takara Bio Inc.). The results are shown in Table 2.

From the results of Table 2, the polymers of Examples 5 to 11 polymerized using the zwitterionic ethylenically unsaturated monomers of Examples 1 to 4 are those of Comparative Examples 1 to 3 having no zwitterionic group. It was found that the amount of protein adsorbed was smaller than that of the polymer, and the biocompatibility was excellent. Further, a polymer of Comparative Example 4 having 2-methacrylolyloxyethylphosphocholine (MPC) as a structural unit, N-methacryloyloxyethyl-N, N-dimethylammonium-α-N-methylcarboxybetaine (CMB) It was found that the biocompatibility was excellent even when compared with the polymer of Comparative Example 5 as a structural unit.

Claims (5)

A zwitterionic ethylenically unsaturated monomer represented by the general formula (1).
General formula (1):

X represents a hydrogen atom or a methyl group.
Y represents an oxygen atom or NH.
R is a nonionic divalent functional group composed of an alkylene group, an alkylene group substituted with an alkyl group or a hydroxyl group, a phenylene group, an ester bond, an ether bond, a urethane bond, an amide bond, or a combination thereof. is there. Claim formed by Michael addition reaction of pyrrolidine-2-carboxylic acid to the acryloyl group of a bifunctional ethylenically unsaturated monomer having one acryloyl group and one methacryloyl group in one molecule of the general formula (2) Item 12. The zwitterionic ethylenically unsaturated monomer according to Item 1.

General formula (2):

Y represents an oxygen atom or NH.
R is a nonionic divalent functional group composed of an alkylene group, an alkylene group substituted with an alkyl group or a hydroxyl group, a phenylene group, an ester bond, an ether bond, a urethane bond, an amide bond, or a combination thereof. is there. A zwitterionic ethylenically unsaturated monomer obtained by Michael addition reaction of an amino group of pyrrolidine-2-carboxylic acid with an acryloyl group of a bifunctional ethylenically unsaturated monomer having at least one acryloyl group in an alcohol solvent. A method for producing a polymer.   A pyrrolidine-2-carboxylic acid residue-containing polymer obtained by radical polymerization of a monomer containing the zwitterionic ethylenically unsaturated monomer according to claim 1 or 2. A biocompatible material resin composition comprising the pyrrolidine-2-carboxylic acid residue-containing polymer according to claim 4.