Polymerizable compound containing phosphorylcholine group or its analogous group, method for producing the compound, polymer, and resin composition using the compound

Abstract

To provide a polymerizable compound that has excellent biocompatibility, high polymerizability and curability to heat and active energy rays, and has a phosphorylcholine group or analog group, and to provide a method for producing the same and a polymer and curable resin composition or the like using the same.SOLUTION: The compound of the present invention is a polymerizable compound that has two or more unsaturated groups and one or more phosphorylcholine group and / or phosphorylcholine analog group in the molecule, and a polymerizable compound that has one unsaturated group and two or more phosphorylcholine groups and / or phosphorylcholine analog groups in the molecule.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a polymerizable compound containing a phosphorylcholine group or a group analogous thereto, a method for producing the compound, a polymer, and a resin composition using the polymerizable compound and / or the polymer. [Background technology]

[0002] The phosphorylcholine group has the same structure as the phospholipids that make up biological membranes, and materials containing this group or similar groups (phosphorylcholine-like groups) have excellent biocompatibility, such as blood compatibility, complement inactivation, and non-adsorption to biological substances. They also have high moisture retention, antifouling, and antibacterial properties. Therefore, research and development of these materials is being actively conducted as biocompatible materials for medical materials such as artificial blood vessels, artificial organs, artificial joints, and artificial cartilage tissue, medical devices such as medical equipment, medical instruments, and biocompatible materials for cultured drugs, topical medications, cosmetics, and contact lenses.

[0003] Such widely used materials require sufficient strength, hydrolysis resistance, and biocompatibility. In recent years, polymerizable compounds (monomers) containing phosphorylcholine groups or similar groups have been synthesized, and the resulting monomers have been used to produce polymeric materials, such as polymer films and hydrogels, according to the intended purpose. For example, Patent Document 1 discloses a material suitable for ophthalmic soft contact lenses, which is prepared by synthesizing a phosphorylcholine group-containing (meth)acrylate as a polymerizable compound and copolymerizing it with an ophthalmic silicone monomer. Patent Document 2 discloses an ophthalmic lens material with a hydrophilic surface that exhibits high oxygen permeability, surface water wettability, surface lubricity, water retention, contamination resistance, and biocompatibility. This is achieved by contacting the surface of an ophthalmic lens material pretreated by irradiation with high-frequency plasma or excimer light with a compound containing a zwitterionic group, such as a phosphorylcholine group or a similar group, as a hydrophilic monomer, and then irradiating the surface with ultraviolet light having a wavelength of 250 to 500 nm to effect graft polymerization onto the surface of the ophthalmic lens material. Patent Document 3 discloses a method for producing a biocompatible hydrogel by radical polymerization of a monomer containing a phosphorylcholine group and N,N'-methylenebisacrylamide as a crosslinking agent. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-246666 [Patent Document 2] Japanese Patent Application Laid-Open No. 2011-081394 [Patent Document 3] Japanese Patent Publication No. 2020-180240 Summary of the Invention [Problem to be solved by the invention]

[0005] However, the unsaturated groups in the polymerizable compounds containing phosphorylcholine groups or analogous groups described in Patent Documents 1 to 3 are all (meth)acrylate groups. Polymers obtained from such monomers contain easily hydrolyzed ester structures, resulting in poor hydrolysis resistance as biomaterials. Furthermore, because the (meth)acrylate groups are not sufficiently curable with active energy rays, when using highly safe visible light or LED light sources, problems such as high levels of residual monomer in the resulting polymer or cured product and low grafting rates of phosphorylcholine groups or analogous groups to the material surface frequently occur, making it difficult to obtain materials with satisfactory strength and biocompatibility. While the polymerization and curing problems of monofunctional monomers containing phosphorylcholine groups or analogous groups could be improved by copolymerizing them with general-purpose (meth)acrylate or (meth)acrylamide monomers, the use of copolymerizable monomers reduces the content of phosphorylcholine groups or analogous groups in the resulting polymer or cured product, raising concerns about insufficient biocompatibility and other functions. Furthermore, in Patent Document 3, N,N'-methylenebisacrylamide is used as a crosslinking agent having two unsaturated groups to obtain a hydrogel having a crosslinked structure. However, since N,N'-methylenebisacrylamide is a compound that has been confirmed to be positive for mutagenicity, there are concerns about the safety of the obtained hydrogel for the human body, etc.

[0006] As mentioned above, there have been no reports of polyfunctional monomers having phosphorylcholine groups or similar groups that are highly polymerizable and curable and can easily form crosslinked structures, or monofunctional monomers having a high concentration of phosphorylcholine groups or similar groups.

[0007] Therefore, an object of the present invention is to provide a polymerizable compound having two or more unsaturated groups and one or more phosphorylcholine groups and / or phosphorylcholine-like groups in the molecule (hereinafter referred to as a polyfunctional monomer having a phosphorylcholine group or its analogous group, or abbreviated as a polyfunctional-type monomer), and a polymerizable compound having one unsaturated group and two or more phosphorylcholine groups and / or phosphorylcholine-like groups in the molecule (hereinafter referred to as a monofunctional monomer having a phosphorylcholine group or its analogous group, or abbreviated as a monofunctional-type monomer). A second object of the present invention is to provide a method for producing the various polymerizable compounds having a phosphorylcholine group and / or a phosphorylcholine-like group (polyfunctional-type monomer and monofunctional-type monomer). A third object of the present invention is to provide polymers and hydrogels obtained by polymerization using the various polymerizable compounds having a phosphorylcholine group and / or a phosphorylcholine-like group, as well as polymerizable or curable resin compositions containing the polymerizable compounds and / or their polymers. [Means for solving the problem]

[0008] As a result of intensive research conducted by the present inventors to solve these problems, they discovered a polyfunctional monomer (polyfunctional type monomer) having two or more unsaturated groups of any one type selected from (meth)acrylate groups, (meth)acrylamide groups, allyl groups, vinyl groups, and maleimide groups as unsaturated groups in the molecule, and having a phosphorylcholine group or an analogous group thereof having one or more phosphorylcholine groups and / or phosphorylcholine-like groups as biocompatible functional groups, and a monofunctional monomer (monofunctional type monomer) having one unsaturated group of any one type selected from (meth)acrylate groups, (meth)acrylamide groups, allyl groups, vinyl groups, and maleimide groups as unsaturated groups in the molecule, and having a phosphorylcholine group or an analogous group thereof having two or more phosphorylcholine groups and / or phosphorylcholine-like groups as biocompatible functional groups, thereby completing the present invention.

[0009] That is, the present invention provides: (1) A polymerizable compound having two or more unsaturated groups and one or more phosphorylcholine groups and / or phosphorylcholine-like groups in the molecule; (2) a polymerizable compound having one unsaturated group and two or more phosphorylcholine groups and / or phosphorylcholine-like groups in the molecule; (3) The polymerizable compound according to (1) above, represented by general formula (1), [ka] (wherein R1, R2 and R3 each independently represent a linear alkylene group or hydroxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group or alkyleneoxyalkylene group having 2 to 24 carbon atoms; a branched alkylene group or hydroxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon group which may be substituted with a hydroxyl group having 3 to 36 carbon atoms.) represents a cyclic or alicyclic ether group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (however, R3 may not be present). R4 and R5 each independently represent a vinyl group; an allyl group; a maleimide group; a linear alkyl group having 1 to 6 carbon atoms; or an alkenyl group having 2 to 6 carbon atoms. A is any one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. m is an integer of 1 to 10, and Y represents a linking group having a valence of m. (4) The polymerizable compound according to (1) above, represented by general formula (2), [ka] (In the formula, R6, R7, and R8 each independently represent a linear alkylene group or hydroxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 2 to 24 carbon atoms; a branched alkylene group or hydroxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (however, R8 may be absent). 10each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. B is any one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. n is an integer of 1 to 100, and Z represents an n-valent linking group. (5) The polymerizable compound according to (1) above, represented by general formula (3), [ka] (In the formula, R 11 , R 12 and R 13 each independently represents a linear alkylene group or hydroxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 2 to 24 carbon atoms; a branched alkylene group or hydroxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (provided that R 11 and / or R 13 may not be present). 14 and R 15 each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. D and E each independently represent one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. (6) The polymerizable compound according to (2) above, represented by general formula (4), [ka] (In the formula, R 16 and R 17R each independently represents a linear alkylene group or hydroxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 2 to 24 carbon atoms; a branched alkylene group or hydroxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group. 18 , R 19 and R 20 each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or an aromatic hydrocarbon which may be substituted with a hydroxyl group having 6 to 24 carbon atoms. F represents any one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. i represents an integer of 2 to 10. (7) a first step of reacting a compound having a hydroxyl group with 2-chloro-2-oxo-1,3,2-dioxophosphorane to synthesize a compound having a dioxaphosphorane group; a second step in which the compound having a dioxaphospholane group obtained in the first step is ring-opened using an amine compound having a tertiary amino group; A method for producing the polymerizable compound according to any one of (1) to (6), (8) A polymer having a structural unit derived from the polymerizable compound according to any one of (1) to (5). (9) A thermally polymerizable and / or active energy ray-curable resin composition containing the polymerizable compound according to any one of (1) to (5) above and / or the polymer according to (8) above. (10) A hydrogel having a structural unit derived from the polymerizable compound according to any one of (1) to (5). (11) A contact lens having a structural unit derived from the polymerizable compound according to any one of (1) to (5). to provide. [Effects of the Invention]

[0010] The polymerizable compounds of the present invention are polyfunctional monomers having two or more polymerizable unsaturated groups and one or more biocompatible phosphorylcholine groups or analogous groups within the molecule, and monofunctional monomers having one polymerizable unsaturated group and two or more biocompatible phosphorylcholine groups or analogous groups within the molecule. These monomers are characterized by their high polymerizability and curability against heat and / or active energy rays, and their excellent biocompatibility. Furthermore, polyfunctional monomers can also be used as crosslinking agents, allowing for the easy preparation of polymers and hydrogels having crosslinked structures. The polyfunctional monomers are expected to be hydrophilic and biocompatible. Polymerizable and curable resin compositions containing them, as well as polymers and hydrogels polymerized and cured using them, are also expected to be hydrophilic and biocompatible, making them suitable for use as raw materials and materials in a wide range of fields, including cosmetics, daily necessities, medical care, and pharmaceuticals. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described in further detail below. The polymerizable compound (1) of the present invention is a polyfunctional monomer (1) having a phosphorylcholine group or a group analogous thereto, represented by the following general formula (5).

[0012] [ka]

[0013] In general formula (5), A is any one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. A is linked to a zwitterion (betaine structure) composed of a phosphate ester anion and an ammonium cation, thereby forming a zwitterion structure having an unsaturated group. m such zwitterion structures having an unsaturated group are linked via a linking group Y. m is an integer of 1 to 10.

[0014] When m is 1, one unsaturated group A is present in the molecule of polymerizable compound (1). R1, R2, and R3 each independently represent a linear alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 2 to 24 carbon atoms; a branched alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (provided that R3 is optional). R4 and R5 each independently represent a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. Any of R1 to R5 has one or more allyl groups, vinyl groups, or maleimide groups.

[0015] m is preferably an integer of 2 to 10. In this case, 2 to 10 unsaturated groups A of the same or different types are present in the molecule of the polymerizable compound (1). R1, R2, and R3 each independently represent a linear alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 2 to 24 carbon atoms; a branched alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group. R4 and R5 each independently represent a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms.

[0016] The unsaturated group A in the polymerizable compound (1) is preferably any one of a methacrylate group, an acrylate group, a methacrylamide group, and an acrylamide group. When A is one of these unsaturated groups, radical polymerization by heat or irradiation with active energy rays can proceed easily under mild conditions, and further, it can be copolymerized with a wide variety of radically polymerizable monomers to obtain various polymers and crosslinkable cured products (including hydrogels) according to the purpose.

[0017] Furthermore, it is more preferable that at least one of the unsaturated groups A in the polymerizable compound (1) is a methacrylamide group or an acrylamide group, and it is most preferable that at least one of the unsaturated groups A is an acrylamide group. Methacrylamide and acrylamide groups are highly hydrophilic and hydrolysis-resistant, and are expected to have excellent biocompatibility. Furthermore, acrylamide groups have the highest sensitivity (curability) to active energy rays such as ultraviolet (UV) light among the unsaturated groups A. Even when using highly safe visible light or LED light sources, polymerization can proceed rapidly, and almost no unpolymerized or uncured monomers remain. Therefore, acrylamide groups are suitable for use as biomaterials and are suitable for applications in the medical and pharmaceutical fields.

[0018] The polymerizable compound (2) of the present invention is a polyfunctional monomer (2) having a phosphorylcholine group or a group analogous thereto, represented by the following general formula (6).

[0019] [ka]

[0020] In general formula (6), B is any one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. B is linked to a zwitterion (betaine structure) composed of an ammonium cation and a phosphate ester anion, thereby forming a zwitterion structure having an unsaturated group. n such zwitterion structures having an unsaturated group are linked via a linking group Z. n is an integer of 1 to 100.

[0021] When n is 1, one unsaturated group B is present in the molecule of polymerizable compound (2). R6, R7, and R8 each independently represent a linear alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 2 to 24 carbon atoms; a branched alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (however, R8 may be absent). R9 and R 10 R6 to R7 each independently represent a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. 10 Either one of the above has one or more vinyl groups, allyl groups, or maleimide groups.

[0022] n is preferably an integer of 2 to 100. In this case, 2 to 100 of the same or different types of unsaturated groups B are present in the molecule of the polymerizable compound (2). R6, R7, and R8 each independently represent a linear alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 2 to 24 carbon atoms; a branched alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group. R9 and R 10 each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms.

[0023] The unsaturated group B in the polymerizable compound (2) is preferably any one of a methacrylate group, an acrylate group, a methacrylamide group, and an acrylamide group. When B is one of these unsaturated groups, radical polymerization by heat or active energy ray irradiation can proceed easily under mild conditions, and B can be copolymerized with a wide variety of radically polymerizable monomers to obtain various polymers and crosslinkable cured products (including hydrogels) according to the purpose.

[0024] It is more preferable that at least one of the unsaturated groups B in the polymerizable compound (2) is a methacrylamide group or an acrylamide group, and it is most preferable that at least one of the unsaturated groups B is an acrylamide group. Methacrylamide and acrylamide groups are highly polymerizable and hydrophilic, and have excellent hydrolysis resistance, which makes them more biocompatible. Furthermore, acrylamide groups have the highest sensitivity (curability) to actinic energy rays such as ultraviolet (UV) among the unsaturated groups B, and can be polymerized rapidly even using highly safe visible light or LED light sources, with almost no unpolymerized or uncured monomer remaining. Therefore, they are suitable for use as biomaterials and are suitable for applications in the medical and pharmaceutical fields.

[0025] The polymerizable compound (3) of the present invention is a polyfunctional monomer (3) having a phosphorylcholine group or a group analogous thereto, represented by the following general formula (7).

[0026] [ka]

[0027] In the general formula (7), D and E each independently represent one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. 11 , R 12 and R 13 each independently represents a linear alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 2 to 24 carbon atoms; a branched alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (provided that R 11 and / or R 13may not be present). 14 and R 15 each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms.

[0028] The unsaturated groups D and E of the polymerizable compound (3) are preferably each independently any one of unsaturated groups selected from a methacrylate group, an acrylate group, a methacrylamide group, and an acrylamide group. When the unsaturated groups D and E are such unsaturated groups, radical polymerization by heat or active energy ray irradiation can proceed easily under mild conditions, and further, they can be copolymerized with a wide variety of radically polymerizable monomers, allowing various polymers and crosslinkable cured products (including hydrogels) to be obtained according to the purpose.

[0029] Furthermore, it is more preferable that at least one of the unsaturated groups D and E of the polymerizable compound (3) is a methacrylamide group or an acrylamide group, and it is most preferable that at least one is an acrylamide group. Methacrylamide and acrylamide groups are highly polymerizable and hydrophilic, and have excellent hydrolysis resistance, making them more biocompatible. Furthermore, among the unsaturated groups D and E, acrylamide groups have the highest sensitivity (curability) to actinic energy rays such as ultraviolet (UV) light. Even when using highly safe visible light or an LED light source, polymerization can proceed rapidly, leaving almost no unreacted or uncured monomers. Therefore, acrylamide groups are suitable for use as biomaterials and are suitable for applications in the medical and pharmaceutical fields.

[0030] The polymerizable compound (4) of the present invention is a polyfunctional type monomer (4) or a monofunctional type monomer (5) having a phosphorylcholine-like group represented by the following general formula (8).

[0031] [ka]

[0032] In general formula (8), F is an i-valent organic group having one unsaturated group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group. F is linked to i amphoteric ions (betaine structures) composed of phosphate ester anions and ammonium cations, forming a structure having one or more unsaturated groups and two or more amphoteric ions in the molecule. In addition, R 16 may be shared by i betaine structures, where i is an integer of 2 to 10. 16 and R 17 R each independently represents a linear alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 2 to 24 carbon atoms; a branched alkylene group, hydroxyalkylene group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkenyl group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon or alicyclic ether group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon having 6 to 24 carbon atoms which may be substituted with a hydroxyl group. 18 , R 19 and R 20 each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or an aromatic hydrocarbon which may be substituted with a hydroxyl group having 6 to 24 carbon atoms. 18 , R 19 and R 20 When R is at least one unsaturated group selected from a vinyl group, an allyl group, and a maleimide group, the polymerizable compound (4) is a multifunctional type monomer (4). 18 , R 19 and R 20 When none of the above has an unsaturated group, the polymerizable compound (4) is a monofunctional type monomer (5).

[0033] The unsaturated group F in the polymerizable compound (4) is preferably any one of unsaturated groups selected from a methacrylate group, an acrylate group, a methacrylamide group, and an acrylamide group. When the polymerizable compound (4) has such an unsaturated group, radical polymerization by heat or active energy ray irradiation can easily proceed under mild conditions, and further, it can be copolymerized with a wide variety of radically polymerizable monomers, allowing various polymers and crosslinkable cured products (including hydrogels) to be obtained according to the purpose.

[0034] Furthermore, the unsaturated group F of the polymerizable compound (4) is more preferably a methacrylamide group or an acrylamide group, and most preferably an acrylamide group. Methacrylamide and acrylamide groups are highly polymerizable and hydrophilic, and have excellent hydrolysis resistance, making them more biocompatible. Furthermore, among the unsaturated groups F, the acrylamide group has the highest sensitivity (curability) to actinic energy rays such as ultraviolet (UV) light. Even when using highly safe visible light or an LED light source, the acrylamide group can rapidly undergo polymerization, leaving almost no unreacted or uncured monomer. Therefore, the acrylamide group can be suitably used as a biomaterial and is suitable for applications in the medical and pharmaceutical fields.

[0035] The method for producing the polymerizable compounds (1) to (4) of the present invention includes the following two steps. The first step is a step of synthesizing a compound having a dioxaphospholane group by reacting a compound having a hydroxyl group with 2-chloro-2-oxo-1,3,2-dioxophosphorane. The second step is a step of synthesizing the target polymerizable compounds (1) to (4) by ring-opening the compound having a dioxaphospholane group obtained in the first step using an amine compound having a tertiary amino group.

[0036] When the compound having a hydroxyl group, which is the raw material for the first step, is an alcohol having an unsaturated group, and the amine compound having a tertiary amino group, which is the raw material for the second step, is an amine compound having one or more tertiary amine groups (m, where m is an integer from 1 to 10) in the molecule, a polymerizable compound (1) (multifunctional type monomer (1)) can be produced by the reaction of the first step and the second step. The alcohol having an unsaturated group is not particularly limited, but a compound having one or more unsaturated groups and one or more hydroxyl groups in the molecule is preferred. Furthermore, the amine compound having one or more tertiary amino groups in the molecule may or may not have an unsaturated group in the molecule.

[0037] When the compound having a hydroxyl group, which is the raw material of the first step, is an alcohol compound having one or more hydroxyl groups (n hydroxyl groups, n is an integer from 1 to 100) in the molecule, and the amine compound having a tertiary amino group, which is the raw material of the second step, is an amine compound having an unsaturated group, a polymerizable compound (2) (multifunctional type monomer (2)) can be produced by the reaction of the first step and the second step. The amine compound having an unsaturated group is not particularly limited, but a compound having one or more unsaturated groups and one or more tertiary amino groups in the molecule is preferred. Furthermore, the alcohol compound having one or more hydroxyl groups in the molecule may or may not have an unsaturated group in the molecule.

[0038] When the compound having a hydroxyl group, which is the raw material in the first step, is an alcohol having one unsaturated group and one hydroxyl group in the molecule, and the amine compound having a tertiary amino group, which is the raw material in the second step, is an amine compound having one tertiary amino group and one or more unsaturated groups in the molecule, a polymerizable compound (3) (multifunctional type monomer (3)) can be produced by the reaction of the first step and the second step. The unsaturated group in the compound having a hydroxyl group in the first step and the unsaturated group in the amine compound in the second step may be the same or different. In addition, the substituent (R 13 ~R 15 When R 2 has one or more unsaturated groups, a polyfunctional monomer (3-1) having three or more unsaturated groups can be produced. 13 ~R15 When the monomer (3-1) does not have an unsaturated group, a polyfunctional monomer (3-2) having two unsaturated groups can be produced.

[0039] When the compound having a hydroxyl group, which is the raw material of the first step, is an alcohol having one unsaturated group and two or more hydroxyl groups in the molecule, and the amine compound having a tertiary amino group, which is the raw material of the second step, is an amine compound having one tertiary amino group and one or more unsaturated groups in the molecule, a polymerizable compound (4) (multifunctional type monomer (4)) can be produced by the reaction of the first step and the second step. Note that the substituent (R 18 ~R 20 ) has one or more unsaturated groups which may be the same or different.

[0040] When the compound having a hydroxyl group, which is the raw material in the first step, is an alcohol having one unsaturated group and two hydroxyl groups in the molecule, and the amine compound having a tertiary amino group, which is the raw material in the second step, is an amine compound having one or more tertiary amino groups in the molecule and no unsaturated groups, a polymerizable compound (4) (monofunctional type monomer (5)) can be produced by the reaction in the first step and the second step.

[0041] The first step is a step of synthesizing a compound having a dioxaphospholane group by reacting a compound having a hydroxyl group with 2-chloro-2-oxo-1,3,2-dioxophosphorane. The alcohol having an unsaturated group used in the first step is characterized by having one or more hydroxyl groups and one or more unsaturated groups selected from (meth)acrylate groups, (meth)acrylamide groups, allyl groups, vinyl groups, and maleimide groups in the molecule. Specifically, when the unsaturated group of the alcohol having an unsaturated group is a (meth)acrylate group, examples of the alcohol having an unsaturated group include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, [4-(hydroxymethyl)cyclohexyl]methyl (meth)acrylate, 2-hydroxy-3-phenoxypropyl (meth)acrylate, 2-hydroxy-3-(meth)acrylpropyl acrylate, 2,3-dihydroxypropyl (meth)acrylate, glycerin mono(meth)acrylate, glycerin di(meth)acrylate, pentaerythritol tri(meth)acrylate, monopentaerythritol (meth)acrylate, dipentaerythritol penta(meth)acrylate, and 1,4-cyclohexanedimethanol mono(meth)acrylate.

[0042] Furthermore, when the unsaturated group of the alcohol having an unsaturated group is a (meth)acrylamide group, examples of the alcohol having an unsaturated group include hydroxymethyl(meth)acrylamide, hydroxyethyl(meth)acrylamide, hydroxypropyl(meth)acrylamide, hydroxyisopropyl(meth)acrylamide, hydroxybutyl(meth)acrylamide, hydroxyisobutyl(meth)acrylamide, hydroxyhexyl(meth)acrylamide, hydroxycyclohexyl(meth)acrylamide, dihydroxyethyl(meth)acrylamide, dihydroxypropyl(meth)acrylamide, dihydroxyisopropyl(meth)acrylamide, di(2,3-dihydroxypropyl)(meth)acrylamide, dihydroxybutyl(meth)acrylamide, and N-methyl-N-hydroxyethyl(meth)acrylamide.

[0043] Furthermore, when the unsaturated group of the alcohol having an unsaturated group is an allyl group, a vinyl group, or a maleimide group, examples of the alcohol having an unsaturated group include ethylene glycol monoallyl ether, glycerin diallyl ether, neopentyl glycol monoallyl ether, sorbitol triallyl ether, 2-(1-hydroxyallyl)phenol, 4-allyl-1,2-dihydroxybenzene, 4-allyl-1,3-dihydroxybenzene, 1,5-dihydroxy-2-propyl-6-allylanthraquinone, allyl alcohol, p-allylphenol, 4-vinylphenol, 2-hydroxyethyl vinyl ether, ethylene glycol monovinyl ether, diethylene glycol monovinyl ether, 4-hydroxybutyl vinyl ether, N-(2-hydroxyethyl)maleimide, 3-hydroxyphenylmaleimide, and 4-hydroxyphenylmaleimide.

[0044] The above-mentioned alcohols having various unsaturated groups may be used alone or in combination of two or more. Furthermore, from the viewpoints of easy procurement of inexpensive industrial products and high polymerizability and curability, it is preferable that the unsaturated group contains one or more of a methacrylate group, an acrylate group, a methacrylamide group, or an acrylamide group. From the viewpoints of excellent hydrolysis resistance, low skin irritation, and low odor, it is more preferable that the unsaturated group contains a methacrylamide group and / or an acrylamide group. Among these alcohols having unsaturated groups, N-hydroxyethyl acrylamide and N-hydroxyethyl methacrylamide are particularly preferred because they are highly safe, with representative skin irritation values ​​(PII values) of 0.0 and oral toxicity of >2000 mg / kg (rat).

[0045] The alcohol compound having one or more hydroxyl groups in the molecule used in the first step is a compound having one or more primary or secondary hydroxyl groups in the molecule, and more specifically, preferably has 1 to 100 hydroxyl groups (n is an integer of 1 to 100) in the molecule. For example, monofunctional alcohol compounds having one primary or secondary hydroxyl group in the molecule such as methyl alcohol, ethyl alcohol, isopropanol, t-butyl alcohol, 9-decen-1-ol, 1-octacosanol, diethylene glycol monomethyl ether, propylene glycol-1-monomethyl ether, 4-dimethylamino-1-butanol, cyclohexanol, benzyl alcohol, ethylene glycol, 1,3-propanediol, 1,2-propanediol (propylene glycol), 1,4-butanediol, 1,3-butanediol, 1,3-butylene glycol, 1,2-hexanediol, octanediol, 1,3-adamantanedimethanol, 2-hydroxybenzyl alcohol, 2-(2-hydroxyethyl)phenol, stearyldiethanolamine, neopentyl glycol, diethylene glycol, triethylene glycol, isosorbide, cyclohexanedimethanol, norbornanedimethanol, norbornane Diol, norbornene dimethanol, norbornene diol, tricyclodecane dimethanol, pentacyclopentadecanedimethanol, 2,2,4,4-tetramethyl-1,3-cyclobutanediol, spiroglycol, dioxane glycol, 1,4:3,6-dianhydrosorbitol, 1,4:3,6-dianhydroannitol, 1,4:3,6-dianhydroiditol, hydrogenated bisphenol A, hydrogenated bisphenol F, hydrogenated terpene diphenols and their EO, ​​PO, Bifunctional alcohol compounds having two primary or secondary hydroxyl groups in the molecule, such as diols having an alicyclic skeleton, such as modified caprolactone, glycerin, butanetriol, 1,3,5-cyclohexanetriol, 1,3,5-adamantanetriol, trimethylolethane, trimethylolpropane, 1,2,4-butanetriol, 1,2,5-pentanetriol, 1,2,9-nonanetriol, 1,2,7-heptanetriol, pentaerythritol, erythritol, 1,1,3,Examples of polyfunctional alcohol compounds having three or more primary or secondary hydroxyl groups in the molecule include 3-propanetetraol, sorbitan, xylitol, mannitol, sorbitol, inositol, sucrose, estriol, peimin, calcitriol, and polyglycerin. These alcohol compounds may be used alone or in combination.

[0046] The alcohol compound having one or more hydroxyl groups in the molecule may be a polyol compound having a repeating unit (skeleton) with two or more primary or secondary hydroxyl groups in the molecule. Specific examples include polyether polyols having an ether skeleton such as polyethylene polyol, polypropylene polyol, and polytetramethylene ether glycol; polyolefin polyols having an olefin skeleton such as poly1,2-butadiene polyol, hydrogenated 1,2-polybutadiene polyol, poly1,4-butadiene polyol, hydrogenated 1,4-polybutadiene polyol, polyisoprene polyol, and hydrogenated polyisoprene polyol; polycarbonate polyols having a carbonate skeleton composed of a polyol having a linear, branched, or cyclic aliphatic hydrocarbon or an aromatic ring skeleton or a heterocyclic skeleton having 1 to 12 carbon atoms and a carbonate diester; polyester polyols having an ester skeleton of a linear, branched, or cyclic aliphatic hydrocarbon or an aromatic ring or a heterocyclic ring having 1 to 12 carbon atoms composed of an aliphatic or aromatic carboxylic acid and various glycols; polysilicone polyols having a hydroxyl group introduced into a silicone skeleton; and polyacrylic polyols having an acrylic skeleton obtained by homopolymerizing a hydroxyl group-containing (meth)acryloyl monomer and copolymerizing it with other copolymerizable monomers. The molecular weight of each of the polyols is preferably 300 to 10000. One or more of these polyol compounds may be contained.

[0047] The compound having a hydroxyl group used in the first step can be one or a combination of two or more selected from the alcohol having an unsaturated group, monofunctional alcohol compound, difunctional alcohol compound, polyfunctional alcohol compound, and polyol compound.

[0048] In the first step, the reaction between the hydroxyl group-containing compound and 2-chloro-2-oxo-1,3,2-dioxophosphorane proceeds stoichiometrically between the hydroxyl groups of the hydroxyl group-containing compound and the 2-chloro-2-oxo-1,3,2-dioxophosphorane. Therefore, the hydroxyl groups and 2-chloro-2-oxo-1,3,2-dioxophosphorane can be used in a 1.0:1.0 molar ratio. Using an excess of either compound is preferred because it accelerates the completion of the reaction. Generally, 2-chloro-2-oxo-1,3,2-dioxophosphorane is used in a range of 0.8 to 3.0 moles per mole of hydroxyl group of the hydroxyl group-containing compound. The range is preferably 1.0 to 2.0 moles, and particularly preferably 1.05 to 1.5 moles.

[0049] In the first step, in order to promote the progress of the reaction, it is preferable to actively remove hydrogen chloride generated during the reaction from the reaction system. For example, the reaction can be carried out while blowing an inert gas such as dry nitrogen or helium into the reaction system, or an inorganic or organic alkali can be added to the reaction system as a neutralizing agent. The neutralizing agent used in the first step can be a single agent or a combination of two or more agents. Examples of inorganic alkalis that can be used include potassium carbonate, sodium bicarbonate, and sodium hydroxide. When an organic alkali is used, it is preferably a tertiary amine that does not have active hydrogen, such as trimethylamine, triethylamine, tripropylamine, triisopropylamine, methyldiethylamine, dimethylethylamine, methyldiisopropylamine, N,N,N',N'-tetramethylethylenediamine, and N,N-diethylallylamine. The amount of neutralizing agent used is 1.0 to 10.0 times the molar amount of 2-chloro-2-oxo-1,3,2-dioxophosphorane used, preferably 1.2 to 5.0 times the molar amount, and more preferably 1.5 to 3.0 times the molar amount. If the amount of neutralizing agent used is less than 1.0 times the molar amount, it will be impossible to neutralize all of the hydrogen chloride generated upon completion of the reaction. On the other hand, if the amount of neutralizing agent used is more than 10 times the molar amount, the unused neutralizing agent will be contained in large amounts as impurities, which requires recovery or separation, which is not preferable. Furthermore, from the viewpoint of ease of recovery and separation, it is particularly preferable to use low-boiling tertiary amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine, methyldiethylamine, dimethylethylamine, and methyldiisopropylamine as the neutralizing agent.

[0050] In the first step, an aprotic solvent can be used if necessary. Examples include diethyl ether, diisopropyl ether, tetrahydrofuran, acetone, ethyl acetate, toluene, acetonitrile, and N,N-dimethylformamide. Furthermore, from the viewpoint of being able to precipitate a neutralized salt obtained by neutralizing hydrogen chloride generated in the reaction with a neutralizing agent from the reaction solution and easily remove it from the reaction system by filtration or the like, the reaction solvent is preferably a nonpolar one such as diethyl ether, tetrahydrofuran, or toluene. The solvent used in the reaction of the first step may be one type, or two or more types may be used in combination. Furthermore, the amount of the reaction solvent used is not particularly limited, but from the viewpoints of the solubility of the raw materials, the reaction rate, the ease of solvent recovery, and the like, it is 10 to 500%, preferably 20 to 300%, and more preferably 50 to 200% of the total mass of the reaction raw materials (including the neutralizing agent).

[0051] In the first step, the raw materials are charged (mixed) and reacted at a temperature of −30°C to 80°C, preferably −20°C to 60°C, and more preferably −10°C to 40°C. Temperatures below −30°C are undesirable because, depending on the type of raw material, the raw materials may precipitate from the reaction solution or the reaction rate may be significantly reduced, resulting in an extremely long time required to complete the reaction. Temperatures above 80°C are also undesirable because the reaction rate is rapid, and the heat of reaction generated further increases the temperature of the reaction solution, making it difficult to control the reaction rate, resulting in frequent side reactions, and making it impossible to obtain a high-purity target product in high yield. The reaction time varies depending on the temperature, but is generally 0.1 to 48 hours, preferably 0.2 to 24 hours, and more preferably 0.5 to 12 hours.

[0052] In the first step, the method for mixing the raw materials, neutralizing agent, and solvent is not particularly limited. However, due to the generation of reaction heat, the raw materials are preferably mixed by continuously adding 2-chloro-2-oxo-1,3,2-dioxophosphorane dropwise or intermittently to a hydroxyl-containing alcohol or to a mixture of a hydroxyl-containing alcohol and a neutralizing agent and / or solvent. The mixing temperature varies depending on the type of raw materials used, but to appropriately control the reaction rate and suppress side reactions, it is preferably -30°C to 30°C, more preferably -20°C to 10°C, and most preferably -10°C to 0°C. Since the reaction in the first step proceeds simultaneously with the mixing of the raw materials, depending on the type of raw materials, the reaction solution can be treated by immediately filtering the neutralized salt, recovering the reaction solvent, or otherwise processing the reaction solution after mixing. To complete the reaction, it is preferable to raise the temperature of the reaction solution after mixing and continue the remaining reaction. The reaction temperature is -20°C to 80°C, preferably 0°C to 60°C, and more preferably 10°C to 40°C. The required reaction time varies depending on the temperature of the remaining reaction, but is preferably 0.1 to 40 hours, more preferably 0.2 to 20 hours, and most preferably 0.5 to 10 hours.

[0053] The second step is a step of synthesizing polymerizable compounds (1) to (4) having a phosphorylcholine group-like group by reacting the compound having a dioxaphospholane group produced in the first step with an amine compound having one or more tertiary amino groups in the molecule. The reaction solution containing the compound having a dioxaphospholane group obtained in the first step can be used directly in the second step without purification after the reaction in the first step. However, it is preferable to remove the neutralized salt by filtration or the like, recover the solvent by distillation, and then purify the reaction solution by separation or the like. By purifying the reaction solution obtained in the first step, a compound having a dioxaphospholane group with a purity of 80% or more can be obtained. The highly pure compound having a dioxaphospholane group can be used in the second step and reacted with a tertiary amine compound to produce highly pure polyfunctional monomers (1) to (4) and monofunctional monomer (5) having a phosphorylcholine group or a group analogous thereto. In addition, when the neutralizing agent used in the first step is the same as the tertiary amine compound used as the raw material in the second step, the unreacted tertiary amine remaining in the first step can be used in the second step together with the compound having a dioxaphospholane group without being removed.

[0054] The amine compound used in the second step is an amine compound having one or more tertiary amino groups in the molecule. Specifically, it preferably has m tertiary amino groups (m is an integer of 1 to 10) in the molecule. Furthermore, the substituents in the m tertiary amino groups in the amine compound may be independently the same or different, and the amine compound may or may not have an unsaturated group in the molecule.

[0055] The amine compound having an unsaturated group used in the second step is characterized by having one or more unsaturated groups of any one type selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group, and one or more tertiary amino groups in the molecule. Specifically, N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, N,N-dimethylaminobutyl (meth)acrylate, N,N-dimethylaminooctyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-diethylaminopropyl (meth)acrylate, N,N-diethylaminobutyl (meth)acrylate, N,N-diethylaminooctyl (meth)acrylate, N,N-methylethylaminoethyl (meth)acrylate, N,N-diethylaminobutyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylamide, N,N-dimethylaminopropyl (meth)acrylamide, N,N-dimethylaminobutyl (meth)acrylamide, N,N-dimethylaminooctyl (meth)acrylamide, N,N-diethylaminoethyl (meth)acrylamide, N,N-diethylaminopropyl (meth)acrylamide, (meth)acrylamide, N,N-diethylaminobutyl(meth)acrylamide, N,N-diethylaminooctyl(meth)acrylamide, N,N-methylethylaminoethyl(meth)acrylamide, N,N-diethylaminobutyl(meth)acrylamide, dimethyl(meth)allylamine, diethyl(meth)allylamine, dibutyl(meth)allylamine, di(meth)allylmethylamine, di(meth)allylethylamine, di(meth)allylbutylamine, tri(meth)allylamine, N,N-dimethylvinylamine, N,N-diethylvinylamine, N,N-dibutylvinylamine, N,N-dimethylvinylamine, N,N-diethylvinylamine, N,N-dibutylvinylamine, N,N-dimethyl-4-vinylaniline, N-[4-methyl-7-(dimethylamino)coumarin-3-yl]maleimide, 7-diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin, and the like. These amine compounds having an unsaturated group can be used alone or in combination of two or more.

[0056] The amine compound having an unsaturated group preferably has one or more unsaturated groups selected from methacrylate, acrylate, methacrylamide, and acrylamide groups, from the viewpoints of easy procurement of inexpensive industrial products and high polymerizability and curability, and more preferably has methacrylamide and / or acrylamide groups, from the viewpoint of excellent hydrolysis resistance. Among these, N,N-dimethylaminoethyl (meth)acrylate and N,N-dimethylaminopropyl (meth)acrylamide are particularly preferred.

[0057] The amine compound having one or more tertiary amino groups in the molecule used in the second step is a monofunctional amine compound having one tertiary amino group in the molecule and a polyfunctional amine compound having two or more tertiary amino groups in the molecule. Specific examples of the monofunctional amine compound include trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, dimethylethylamine, methyldiethylamine, methylethylpropylamine, N,N-dimethylhexylamine, N,N-dimethyllaurylamine, trihexylamine, tri-n-octylamine, trinonylamine, N,N-dimethylcyclohexylamine, N,N-dioctadecylmethylamine, N,N-dimethylbenzylamine, N,N-dimethyl-1-naphthylamine, N,N-diethyl-1-naphthylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, and 2-[2-(dimethylamino)ethoxy]ethanol. These monofunctional amine compounds may be contained alone or in combination.

[0058] Specific examples of polyfunctional amine compounds having two or more tertiary amino groups in the molecule include N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetraethylethylenediamine, N,N,N',N'-tetramethyl-1,3-diaminopropane, N,N,N',N'-tetramethyl-1,4-diaminobutane, N,N,N',N'-tetramethylhexamethylenediamine, 1,4-dimethylpiperazine, triethylenediamine, bis[2-(N,N-dimethylamino)ethyl]ether, N ,N,N',N'',N''-pentamethyldiethylenetriamine, N,N,N',N'',N''-pentamethyldipropylenetriamine, N-methyl-N,N-bis[3-(dimethylamino)propyl]amine, tris[2-(dimethylamino)ethyl]amine, 1,1,4,7,10,10-hexamethyltriethylenetetramine, N,N,N',N'',N''-pentakis(2-hydroxypropyl)diethylenetriamine, 2,4,6-tris(dimethylaminomethyl)phenol, etc. These polyfunctional amine compounds may be used alone or in combination.

[0059] The amine compound having one or more tertiary amino groups in the molecule may be a polyamine compound having a repeating unit (skeleton) with two or more tertiary amino groups. Specific examples include polyether polyamines, polyolefin polyamines, polycarbonate polyamines, polyester polyamines, polysilicone polyamines, and polyacrylic polyamines obtained by capping conventional polyether polyols, polyolefin polyols, polycarbonate polyamines, polyester polyamines, polysilicone polyamines, and polyacrylic polyamines with N,N-dialkyl glycidyl amines such as N,N-diethyl glycidyl amine or N,N-dibenzyl glycidyl amine. Other examples include polyamines obtained by homopolymerizing or copolymerizing the above-mentioned amine compounds having unsaturated groups with other compounds having copolymerizable unsaturated groups. The molecular weight of the above-mentioned polyamines is preferably 300 to 10,000. These polyamine compounds may be used alone or in combination.

[0060] The compound having a tertiary amino group used in the second step can be one or a combination of two or more selected from the amine compounds having an unsaturated group, monofunctional amine compounds, polyfunctional amine compounds, and polyamine compounds.

[0061] In the second step, the reaction between the compound having a dioxaphospholane group obtained in the first step and an amine compound is characterized in that the tertiary amino group of the amine compound ring-opens the cyclic structure (-1,3,2-dioxophospholane) of the compound having a dioxaphospholane group, forming a zwitterion (phosphorylcholine-like group) composed of a phosphate anion and an ammonium cation. This reaction proceeds stoichiometrically between the tertiary amino group of the amine compound and the cyclic structure of the compound having a dioxaphospholane group. The total number of moles of the tertiary amino groups of the amine compound and the total number of moles of the cyclic structure of the compound having a dioxaphospholane group can be used in a 1:1 molar ratio. Using an excess of either compound is preferred because it accelerates the completion of the reaction. Generally, the tertiary amino groups of the amine compound are used in a range of 0.8 to 20.0 moles per mole of the cyclic structure of the compound having a dioxaphospholane group. The range is preferably 1.0 to 10.0 times by mole, and particularly preferably 1.1 to 5.0 times by mole.

[0062] In the second step, an aprotic solvent can be used if necessary. Examples of suitable solvents include, as in the first step, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, toluene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide. Furthermore, because many of the starting materials, such as amine compounds, are highly polar, polar solvents such as acetone, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide are preferred as the reaction solvent for the second step. The reaction solvent for the second step may be a single solvent, or two or more solvents may be used in combination. The amount of the reaction solvent used is not particularly limited, but is 10 to 5,000 mass%, preferably 100 to 3,000 mass%, and more preferably 200 to 1,000 mass%, based on the total amount of the reaction starting materials, from the viewpoints of the solubility of the starting materials, the reaction rate, and ease of solvent recovery. When the solvent used in the first step and the second step is the same, the solvent can be used in the second step together with the product from the first step without recovery or separation after the completion of the reaction in the first step.

[0063] In the second step, the reaction can be carried out at a temperature of 40 to 150°C. The reaction temperature is preferably within the range of 50 to 120°C, and more preferably within the range of 60 to 100°C. A reaction temperature below 40°C is undesirable because, depending on the type of raw materials, the concentration of the reaction solution, and the like, the reaction rate may be extremely slow and the reaction may not be completed. A reaction temperature above 150°C is undesirable because it increases the likelihood of side reactions and polymerization problems with the target compounds, i.e., polymerizable compounds (1) to (4) having a phosphorylcholine group or a group analogous thereto. The reaction time varies depending on the reaction temperature, but is generally 1 to 168 hours, preferably 4 to 120 hours, and more preferably 8 to 72 hours.

[0064] In the second step, the method for charging the raw materials and solvent is not particularly limited, but since the reaction rate is somewhat slow, it is common to add all the raw materials and the solvent (if necessary) to a reaction vessel and heat them. When low-boiling raw materials or solvents are used, the reaction can be carried out under pressure using a pressurizable device such as a reaction autoclave to promote the reaction.

[0065] After the reaction in the second step is completed, the solvent and unreacted raw materials in the reaction solution are recovered and separated by distillation, and further purified by washing with a poor solvent, precipitation, crystallization, etc., to obtain the target polymerizable compounds (1) to (4) as a pale yellow liquid or a white solid.

[0066] The reactions in the first and second steps are preferably carried out in the presence of a radical polymerization inhibitor. Known polymerization inhibitors can be used, including, for example, phenolic compounds such as hydroquinone, methylhydroquinone, tert-butylhydroquinone, 2,6-di-tert-butylparahydroquinone, 2,5-di-tert-butylhydroquinone, 2,4-dimethyl-6-tert-butylphenol, and hydroquinone monomethyl ether; N-isopropyl-N'-phenyl-para-phenylenediamine; N-(1,3-dimethylbutyl)-N'-phenyl-para-phenylenediamine; and N-(1-methylbutyl)-N'-phenyl-para-phenylenediamine. Examples of polymerization inhibitors include paraphenylenediamines such as N,N'-butyl)-N'-phenyl-para-phenylenediamine, N,N'-diphenyl-para-phenylenediamine, and N,N'-di-2-naphthyl-para-phenylenediamine; amine compounds such as thiodiphenylamine; and piperidine-1-oxyl free radical compounds such as 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and acetamidotetramethylpiperidine-1-oxyl. These polymerization inhibitors may be used alone or in combination. The amount of polymerization inhibitor added is 1 to 10,000 ppm, preferably 5 to 5,000 ppm, and more preferably 10 to 3,000 ppm, based on the total mass of the alcohol having an unsaturated group, the amine compound having an unsaturated group, and the intermediate having an unsaturated group contained in the reaction solution of the first step and / or the second step.

[0067] Specific examples of the polymerizable compounds (1) to (4) of the present invention are shown below, but the present invention is not limited to these.

[0068] Polymerizable Compound (1) (Multifunctional Monomers (1-1) to (1-24)) [ka] Multifunctional Monomer (1-1) JPEG0007778342000010.jpg23102 Multifunctional Monomer (1-2) JPEG0007778342000011.jpg11102 Multifunctional Monomer (1-3) JPEG0007778342000012.jpg13102 Multifunctional Monomer (1-4) JPEG0007778342000013.jpg14102 Multifunctional Monomer (1-5) JPEG0007778342000014.jpg12102 Multifunctional Monomer (1-6) JPEG0007778342000015.jpg13102 Multifunctional Monomer (1-7) JPEG0007778342000016.jpg12102 Multifunctional Monomer (1-8) JPEG0007778342000017.jpg50102 Multifunctional Monomer (1-9) JPEG0007778342000018.jpg30102 Multifunctional Monomer (1-10) JPEG0007778342000019.jpg21102 Multifunctional Monomer (1-11) JPEG0007778342000020.jpg14102 Multifunctional Monomer (1-12) JPEG0007778342000021.jpg23102 Multifunctional Monomer (1-13) JPEG0007778342000022.jpg13102 Multifunctional Monomer (1-14) JPEG0007778342000023.jpg38102 Multifunctional Monomer (1-15) JPEG0007778342000024.jpg5064 Multifunctional Monomer (1-16) JPEG0007778342000025.jpg5064 Multifunctional Monomer (1-17) JPEG0007778342000026.jpg5264 Multifunctional Monomer (1-18) JPEG0007778342000027.jpg5264 Multifunctional Monomer (1-19) JPEG0007778342000028.jpg7777 Multifunctional Monomer (1-20) JPEG0007778342000029.jpg8664 Multifunctional Monomer (1-21) JPEG0007778342000030.jpg53102 Multifunctional Monomer (1-22) JPEG0007778342000031.jpg6489 Multifunctional Monomer (1-23) JPEG0007778342000032.jpg6164 Multifunctional Monomer (1-24)

[0069] Polymerizable Compound (2) (Multifunctional Monomers (2-1) to (2-14)) [ka] Multifunctional Monomer (2-1) JPEG0007778342000034.jpg3864 Multifunctional Monomer (2-2) JPEG0007778342000035.jpg33102 Multifunctional Monomer (2-3) JPEG0007778342000036.jpg22102 Multifunctional Monomer (2-4) JPEG0007778342000037.jpg5689 Multifunctional Monomer (2-5) JPEG0007778342000038.jpg39102 Multifunctional Monomer (2-6) JPEG0007778342000039.jpg12102 Multifunctional Monomer (2-7) JPEG0007778342000040.jpg3064 Multifunctional Monomer (2-8) JPEG0007778342000041.jpg8289 Multifunctional Monomer (2-9) JPEG0007778342000042.jpg8764 Multifunctional Monomer (2-10) JPEG0007778342000043.jpg7689 Multifunctional Monomer (2-11) JPEG0007778342000044.jpg76102 Multifunctional Monomer (2-12) JPEG0007778342000045.jpg10196 Multifunctional Monomer (2-13) JPEG0007778342000046.jpg7064 Multifunctional Monomer (2-14)

[0070] Polymerizable Compound (3) (Multifunctional Monomers (3-1) to (3-10)) [ka] Multifunctional Monomer (3-1) JPEG0007778342000048.jpg5277 Multifunctional Monomer (3-2) JPEG0007778342000049.jpg5864 Multifunctional Monomer (3-3) JPEG0007778342000050.jpg4677 Multifunctional Monomer (3-4) JPEG0007778342000051.jpg4077 Multifunctional Monomer (3-5) JPEG0007778342000052.jpg4064 Multifunctional Monomer (3-6) ) JPEG0007778342000053.jpg4764 Multifunctional type monomer (3-7 JPEG0007778342000054.jpg3164 Multifunctional Monomer (3-8) JPEG0007778342000055.jpg5464 Multifunctional Monomer (3-9) JPEG0007778342000056.jpg4164 Multifunctional Monomer (3-10)

[0071] Polymerizable Compounds (4) (Multifunctional Monomers 4-1 to 4-7) [ka] Multifunctional Monomer (4-1) JPEG0007778342000058.jpg6164 Multifunctional Monomer (4-2) JPEG0007778342000059.jpg5864 Multifunctional Monomer (4-3) JPEG0007778342000060.jpg5564 Multifunctional Monomer (4-4) JPEG0007778342000061.jpg11764 Multifunctional Monomer (4-5) JPEG0007778342000062.jpg7089 Multifunctional Monomer (4-6) JPEG0007778342000063.jpg8064 Multifunctional Monomer (4-7)

[0072] Polymerizable Compounds (4) (Monofunctional Types (5-1) to (5-5)) [ka] Monofunctional Monomer (5-1) JPEG0007778342000065.jpg4964 Monofunctional Monomer (5-2) JPEG0007778342000066.jpg5777 Monofunctional Monomer (5-3) JPEG0007778342000067.jpg5567 Monofunctional Monomer (5-4) JPEG0007778342000068.jpg7564 Monofunctional Monomer (5-5) [Example]

[0073] The present invention will be described in more detail below with reference to synthesis examples and evaluation examples, but the present invention is not limited to these examples. Unless otherwise specified, "parts" and "%" are by mass.

[0074] <Analyzer> ESI-MS: Triple quadrupole LC-MS (TSQ QUANTUM ACCESS MAX, manufactured by Thermo Fisher Scientific Co., Ltd.) FI-IR spectrophotometer: Nicolet iS50 (Thermo Fisher Scientific) GPC: Prominence-I LC-2030C (Shimadzu Corporation)

[0075] The compounds having a hydroxyl group (a), COPs, neutralizing agents (b), amine compounds having a tertiary amino group (c), solvents (d), and polymerization inhibitors (e) used in the examples, reference examples, and comparative examples are as follows:

[0076] (1) Compound (a) having a hydroxyl group (a-1) Alcohol compound having an unsaturated group a-1-1: N-hydroxyethyl acrylamide (registered trademarks of KJ Chemicals Co., Ltd.: "HEAA" and "Kohshylmer") a-1-2: 2-hydroxyethyl acrylate a-1-3: 4-hydroxybutyl acrylate a-1-4: 2-hydroxyethyl methacrylate a-1-5: N-hydroxyisopropyl methacrylamide a-1-6: N-hydroxyethyl methacrylamide a-1-7: 1,4-cyclohexanedimethanol monoacrylate a-1-8: 2-hydroxy-3-phenoxypropyl acrylate a-1-9: Ethylene glycol monoallyl ether a-1-10: N-(2-hydroxyethyl)maleimide a-1-11: Pentaerythritol tetraacrylate a-1-12: N-methyl-N-hydroxyethyl acrylamide a-1-13: Glycerin diacrylate a-1-14: Monopentaerythritol acrylate a-1-15: Ethylene glycol monovinyl ether a-1-16: Allyl alcohol a-1-17: p-Allylphenol a-1-18: Dihydroxyethyl acrylamide a-1-19: Dihydroxyisopropylacrylamide a-1-20: Dihydroxyisopropyl methacrylamide a-1-21: 2,3-dihydroxypropyl acrylate a-1-22: 2,3-dihydroxypropyl methacrylate a-1-23: Di(2,3-dihydroxypropyl)acrylamide a-1-24: Di(2,3-dihydroxypropyl)methacrylamide a-1-25: 4-Allyl-1,2-dihydroxybenzene a-1-26: 4-Allyl-1,3-dihydroxybenzene a-1-27: Glycerin monomethacrylate (a-2) Alcohol compounds without unsaturated groups a-2-1: Isopropyl alcohol a-2-2: Diethylene glycol monomethyl ether a-2-3: 1,3-butylene glycol a-2-4: Triethylene glycol a-2-5: 2-(2-hydroxyethyl)phenol a-2-6: 1,4-cyclohexanedimethanol a-2-7: Diethylene glycol a-2-8: Isosorbide a-2-9: Dioxane glycol a-2-10: Glycerin a-2-11: Pentaerythritol a-2-12: 1,3,5-cyclohexanetriol a-2-13: 1,1,3,3-propanetetraol a-2-14: Trimethylolethane

[0077] (2) COP: 2-chloro-2-oxo-1,3,2-dioxaphosphorane

[0078] (3) Neutralizer (b) b-1: Potassium carbonate b-2: Sodium bicarbonate b-3: Sodium hydroxide b-4: Triethylamine b-5: N,N,N',N'-tetramethylethylenediamine b-6: N,N-diethylallylamine

[0079] (4) Amine compounds having a tertiary amino group (c) (c-1) Amine compounds having an unsaturated group and a tertiary amino group c-1-1: N,N-diethylallylamine c-1-2: N,N-diallylmethylamine c-1-3: N,N-diallylethylamine c-1-4: N,N-diallylbutylamine c-1-5: N,N-dimethylallylamine c-1-6: triallylamine c-1-7: N,N-dimethylvinylamine c-1-8: N,N-dimethyl-4-vinylaniline c-1-9: Dimethylaminoethyl acrylate (registered trademarks of KJ Chemicals Co., Ltd.: "DMAEA" and "Kohshylmer") c-1-10: dimethylaminoethyl methacrylate c-1-11: Dimethylaminopropylacrylamide (registered trademarks of KJ Chemicals Co., Ltd.: "DMAPAA" and "Kohshylmer") C-1-12: Dimethylaminopropyl methacrylamide c-1-13: N-[4-methyl-7-(dimethylamino)coumarin-3-yl]maleimide (c-2) Amine compounds having no unsaturated groups and having a tertiary amino group c-2-1: Trimethylamine c-2-2: Triethylamine c-2-3: N,N-dimethylhexylamine c-2-4: N,N,N',N'-tetramethylethylenediamine c-2-5: N,N,N',N'-tetraethylethylenediamine c-2-6: N,N,N',N'-tetramethyl-1,3-diaminopropane c-2-7: N,N,N',N'-tetramethyl-1,4-diaminobutane c-2-8: N,N,N',N'-tetramethylhexamethylenediamine C-2-9: Triethylenediamine C-2-10: 1,4-dimethylpiperazine C-2-11: N,N,N',N'',N''-Pentamethyldiethylenetriamine C-2-12: 2,4,6-tris(dimethylaminomethyl)phenol C-2-13: Tris[2-(dimethylamino)ethyl]amine C-2-14: 1,1,4,7,10,10-hexamethyltriethylenetetramine

[0080] (5) Solvent (d) d-1: Tetrahydrofuran d-2: Diisopropyl ether d-3: Acetone d-4: Methyl ethyl ketone d-5: Ethyl acetate d-6: Chloroform d-7: Acetonitrile d-8: N,N-dimethylformamide d-9: Dimethylacetamide d-10: Methylformamide d-11: N-methyl-2-pyrrolidone d-12: 3-Methoxy-N,N-dimethylpropanamide (registered trademark of KJ Chemicals Co., Ltd., "KJCMPA")

[0081] (6) Polymerization inhibitor (e) e-1: Thiodiphenylamine e-2: Hydroquinone e-3: Hydroquinone monomethyl ether e-4: 2,2,6,6-tetramethylpiperidine-1-oxyl e-5: 4-tert-butylcatechol e-6: Dibutylhydroxytoluene e-7: Styrylated N-aminobiphenyl e-8: 4,4'-butylidenebis(6-tert-butyl-m-cresol)

[0082] Example 1 Synthesis of polyfunctional monomer (1-1) (First step) Into a 500 mL four-neck flask equipped with a stirrer, a thermometer, a dropping funnel, and a nitrogen inlet tube, 34.5 g (300 mmol) of hydroxyethyl acrylamide (a-1-1), 33.4 g (330 mmol) of triethylamine (b-4), 34 mg of hydroquinone monomethyl ether (e-3) as a polymerization inhibitor, and 170 g of tetrahydrofuran (d-1) as a solvent were added, and the mixture was stirred while blowing in dry nitrogen and cooled to -20 °C. 41.1 g (330 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphosphorane (COP) and the solvent (d-1) were added from the dropping funnel. 60 g of the mixture was slowly added dropwise to the flask, and the reaction was carried out. During the addition, the temperature of the reaction solution in the flask was maintained at -20°C, and the reaction solution was continuously stirred. As the reaction progressed, triethylamine hydrochloride precipitated as a white precipitate. After the addition was completed, the temperature of the reaction solution was gradually raised to 20°C, and stirring was continued at 20°C for another 4 hours. After the reaction was completed, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to recover the solvent (d-1), yielding 66.4 g of a colorless liquid compound having a dioxaphospholane group (intermediate 1). Gas chromatography (GC) analysis revealed that the purity of the intermediate was 98%, and the yield was calculated to be 96%.

[0083] (Step 2) 65.0 g (287 mmol) of intermediate 1 obtained in Step 1, 15.9 g (137 mmol) of N,N,N',N'-tetramethylethylenediamine (c-2-4), 405 g of acetonitrile (d-7) as a solvent, and 32 mg of thiodiphenylamine (e-1) as a polymerization inhibitor were added to a 1000 mL four-neck flask equipped with a stirrer, thermometer, and condenser. The reaction mixture was refluxed at 82 °C and stirred for 120 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the solvent (d-7) was recovered. 500 mL of a mixture of acetone and diisopropylene ether (1 / 1 mass ratio) was added to the remaining reaction mixture, which was washed by stirring for 30 minutes. The mixture was then allowed to stand, and the supernatant liquid separated into two layers was removed by decantation. After two more washing operations, the temperature was raised to 40°C, and volatile components were removed under reduced pressure. The temperature was returned to room temperature, and the pressure was returned to atmospheric pressure, yielding 65 g of a pale yellow liquid product. Liquid chromatography (LC) analysis revealed that the product had a purity of 96% and a yield of 80%. Furthermore, as described below, electrospray ionization mass spectrometry (ESI-MS) and infrared absorption spectroscopy (IR) analyses confirmed that the product was the desired multifunctional monomer (1-1). ESI-MS: m / z = 560 [M+H] + , 582[M+Na] + ; IR:1658cm -1 (CONH C=O), 1625 cm -1 (CH2=CH-C=C), 1230cm -1 (O - -P=O (PO), 1050-1080 cm (POC (CO))

[0084] <Examples 2 to 27> Synthesis of multifunctional monomers (1-2) to (1-27) In Example 1, the hydroxyl-containing compound used as the raw material in the first step was replaced with the alcohol shown in Table 1, and the tertiary amino-containing amine compound used as the raw material in the second step was replaced with the amine compound shown in Table 2. The solvents, polymerization inhibitors, etc. used in the first and second steps, as well as the reaction conditions for each step, were changed as shown in Tables 1 and 2. The reactions in the first and second steps were carried out in the same manner as in Example 1, and the products were identified by ESI-MS and IR analysis. The reaction yields for each step are shown in Tables 1 and 2. The reactions in the second step in Examples 16 and 17 were carried out using a pressure-resistant vessel. After all raw materials and intermediates were added, the vessel was sealed and stirred at a predetermined temperature for a predetermined time using a magnetic stirrer. The intermediates produced after the first step reaction could be used in the second step without purification. Furthermore, the solvent used in the reaction could be recovered by distillation after completion of the reaction and reused. Furthermore, depending on the state and physical properties of the target compound, such as solubility, purification could be carried out by known methods such as neutralization, washing, extraction, recrystallization, ion exchange resin treatment, and chromatography.

[0085] [Table 1]

[0086] [Table 2]

[0087] Example 28: Synthesis of polyfunctional monomer (2-1) (Step 1) 18.0 g (300 mmol) of isopropanol (a-2-1), 30.3 g (300 mmol) of triethylamine (b-4), and 220 g of methyl ethyl ketone (d-4) as a solvent were added to a 500 mL four-neck flask equipped with a stirrer, thermometer, dropping funnel, and nitrogen inlet tube. The mixture was stirred and cooled to -30 °C while blowing in dry nitrogen. A mixture of 30.1 g (240 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphosphorane (COP) and 35 g of solvent (d-4) was slowly added dropwise from the dropping funnel to the flask, and the reaction was carried out. During the dropwise addition, the temperature of the reaction solution in the flask was maintained at -30 °C, and the reaction solution was continuously stirred. As the reaction progressed, triethylamine hydrochloride precipitated as a white precipitate. After the dropwise addition was completed, the temperature of the reaction solution was gradually raised to 10°C, and stirring was continued for an additional 5 hours at 10°C. After the reaction was completed, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to recover the solvent (d-4) and the remaining raw material (a-2-1), yielding 41.6 g of a colorless liquid compound having a dioxaphospholane group (intermediate 28). GC analysis showed that the purity of the intermediate was 98%, and the yield was calculated to be 94%.

[0088] (Step 2) 41.6 g (255 mmol) of intermediate 28 obtained in Step 1, 85.2 g (766 mmol) of N,N-diallylmethylamine (c-1-2), 254 g of acetonitrile (d-7) as a solvent, and 85 mg of hydroquinone monomethyl ether (e-3) as a polymerization inhibitor were added to a 1000 mL four-neck flask equipped with a stirrer, thermometer, and condenser. The reaction mixture was refluxed at 82 °C and stirred for 36 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the solvent (d-7) was recovered. 500 mL of a mixture of acetone and diisopropylene ether (1 / 1 mass ratio) was added to the remaining reaction mixture, which was washed by stirring for 30 minutes. The mixture was then allowed to stand, and the supernatant liquid separated into two layers was removed by decantation. After two more washing operations, the temperature was raised to 40°C, volatile components were removed under reduced pressure, the temperature was returned to room temperature, and the pressure was returned to atmospheric pressure, yielding 57.6 g of a pale yellow liquid product. LC analysis revealed that the product had a purity of 96% and a yield of 86%. Furthermore, as shown below, electrospray ionization mass spectrometry (ESI-MS) and infrared absorption spectroscopy (IR) analyses confirmed that the product was the desired multifunctional monomer (2-1). ESI-MS: m / z=236 [M+H] + , 258[M+Na] + ; IR:2955cm -1 (CH3-CH), 1635 cm -1 (CH2=CH-CH-C=C), 1230cm -1 (O - -P=O (PO), 1050-1080 cm (POC (CO))

[0089] <Examples 29 to 45> Synthesis of multifunctional monomers (2-2) to (2-18) In Example 28, the hydroxyl-containing compound used as the raw material in the first step was replaced with the alcohol shown in Table 3, and the tertiary amino-containing amine compound used as the raw material in the second step was replaced with the amine compound shown in Table 4. The solvents, polymerization inhibitors, etc. used in the first and second steps, as well as the reaction conditions for each step, were changed as shown in Tables 3 and 4. The reactions in the first and second steps were carried out in the same manner as in Example 28, and the products were identified by ESI-MS and IR analysis. The reaction yields for each step are shown in Tables 3 and 4. The reactions in the second step in Examples 35 and 43 were carried out using a pressure-resistant vessel. After adding all raw materials and intermediates, the vessel was sealed and stirred at a predetermined temperature for a predetermined time using a magnetic stirrer. The intermediates produced after the first step reaction could be used in the second step without purification. Furthermore, the solvent used in the reaction could be recovered by distillation after completion of the reaction and reused. Furthermore, depending on the state and physical properties of the target compound, such as solubility, purification could be carried out by known methods such as neutralization, washing, extraction, recrystallization, ion exchange resin treatment, and chromatography.

[0090] [Table 3]

[0091] [Table 4]

[0092] Example 46: Synthesis of polyfunctional monomer (3-1) (Step 1) 34.8 g (300 mmol) of 2-hydroxyethylacrylamide (a-1-1), 33.3 g (330 mmol) of triethylamine (b-4), 200 g of tetrahydrofuran (d-1) as a solvent, and 70 mg of hydroquinone (e-2) as a polymerization inhibitor were added to a 500 mL four-neck flask equipped with a stirrer, thermometer, dropping funnel, and nitrogen inlet tube. The mixture was stirred and cooled to -20 °C while blowing in dry nitrogen. A mixture of 39.5 g (315 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphosphorane (COP) and 47 g of solvent (d-1) was slowly added dropwise from the dropping funnel to the flask, and the reaction was carried out. During the dropwise addition, the temperature of the reaction solution in the flask was maintained at -20 °C, and the reaction solution was continuously stirred. As the reaction progressed, triethylamine hydrochloride precipitated as a white precipitate. After the dropwise addition was completed, the temperature of the reaction solution was gradually raised to 40°C, and stirring was continued for another 2 hours at 40°C. After the reaction was completed, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to recover the solvent (d-1), yielding 65.3 g of a colorless liquid compound having a dioxaphospholane group (intermediate 46). GC analysis showed that the purity of the intermediate was 98%, and the calculated yield was 96%.

[0093] (Step 2) 60 g (275 mmol) of intermediate 46 obtained in Step 1, 78.8 g (550 mmol) of dimethylaminoethyl acrylate (c-1-9), and 278 g of acetonitrile (d-7) as a solvent were added to a 1000 mL four-neck flask equipped with a stirrer, thermometer, and condenser, and the reaction mixture was stirred at reflux at 82 °C for 80 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the solvent (d-7) was recovered. To the remaining reaction mixture, 500 mL of a mixture of acetone and diisopropylene ether (1 / 1 mass ratio) was added and washed by stirring for 30 minutes. The mixture was then allowed to stand, and the supernatant liquid separated into two layers was removed by decantation. After two more washing steps, the temperature was raised to 40 °C, and volatile components were removed under reduced pressure. The temperature was then returned to room temperature, and the pressure was returned to atmospheric pressure, yielding 89.1 g of a pale yellow liquid product. LC analysis revealed that the purity of the product was 97% and the yield was 86%. Furthermore, as described below, electrospray ionization mass spectrometry (ESI-MS) and infrared absorption spectroscopy (IR) confirmed that the product was the desired multifunctional monomer (3-1). ESI-MS: m / z = 365 [M+H] + , 387[M+Na] + ; IR:1750cm -1 (COO C=O), 1655 cm -1 (CONH C=O), 1625 cm -1 (CH2=CH-CH-C=C), 1230cm -1 (O - -P=O (PO), 1050-1080 cm (POC (CO))

[0094] <Examples 47 to 67> Synthesis of multifunctional monomers (3-2) to (3-22) In Example 46, the hydroxyl-containing compound used as the raw material in the first step was replaced with the alcohol shown in Table 5, and the tertiary amino-containing amine compound used as the raw material in the second step was replaced with the amine compound shown in Table 6. The solvents, polymerization inhibitors, etc. used in Steps 1 and 2, as well as the reaction conditions for each step, were changed as shown in Tables 5 and 6. The reactions in Steps 1 and 2 were carried out in the same manner as in Example 46, and the products were identified by ESI-MS and IR analysis. The reaction yields for each step are shown in Tables 5 and 6. The reactions in Step 2 in Examples 55 and 63 were carried out using a pressure-resistant vessel. After adding all raw materials and intermediates, the vessel was sealed and stirred at a predetermined temperature for a predetermined time using a magnetic stirrer. The intermediates produced after the reaction in Step 1 could be used in Step 2 without purification. Furthermore, the solvent used in the reaction could be recovered by distillation after completion of the reaction and reused. Furthermore, depending on the state and physical properties of the target compound, such as solubility, purification could be carried out by known methods such as neutralization, washing, extraction, recrystallization, ion exchange resin treatment, and chromatography.

[0095] [Table 5]

[0096] [Table 6]

[0097] Example 68: Synthesis of multifunctional monomer (4-1) (First step) 14.6 g (100 mmol) of 2,3-dihydroxypropyl acrylate (a-1-21), 25.6 g (220 mmol) of N,N,N',N'-tetramethylethylenediamine (b-5), 150 g of tetrahydrofuran (d-1) as a solvent, and 14.6 mg of hydroquinone monomethyl ether (e-3) as a polymerization inhibitor were added to a 500 mL four-neck flask equipped with a stirrer, thermometer, dropping funnel, and air inlet tube. The mixture was stirred while blowing in dry air and cooled to -25 ° C. A mixture of 31.4 g (220 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphosphorane (COP) and 29 g of solvent (d-1) was slowly added dropwise from the dropping funnel to the flask, and the reaction was carried out. During the dropwise addition, the temperature of the reaction solution in the flask was maintained at -25°C, and the reaction solution was continuously stirred. As the reaction progressed, N,N,N',N'-tetramethylethylenediamine hydrochloride precipitated as a white precipitate. After the dropwise addition was completed, the temperature of the reaction solution was gradually raised to 35°C, and stirring was continued at 35°C for an additional 8 hours. After the reaction was completed, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to recover the solvent (d-1), yielding 35.2 g of a colorless liquid compound having a dioxaphospholane group (intermediate 68). GC analysis revealed that the purity of the intermediate was 96%, and the yield was calculated to be 94%.

[0098] (Step 2) 35 g (95.6 mmol) of intermediate 68 obtained in Step 1, 43.4 g (390 mmol) of N,N-diallylmethylamine (c-1-2), and 392 g of acetonitrile (d-7) were added to a 1000 mL four-neck flask equipped with a stirrer, thermometer, and condenser, and the reaction mixture was stirred at reflux at 82 °C for 160 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the solvent (d-7) was recovered. 500 mL of a mixture of acetone and diisopropylene ether (1 / 1 mass ratio) was added to the remaining reaction mixture, which was washed by stirring for 30 minutes. The mixture was then allowed to stand, and the supernatant liquid separated into two layers was removed by decantation. After two more washes, the temperature was raised to 40 °C, and the volatile components were removed under reduced pressure. The temperature was then returned to room temperature, and the pressure was returned to atmospheric pressure, yielding 50.6 g of a pale yellow liquid product. LC analysis revealed that the purity of the product was 94% and the yield was 84%. Furthermore, as described below, electrospray ionization mass spectrometry (ESI-MS) and infrared absorption spectroscopy (IR) confirmed that the product was the desired multifunctional monomer (4-1). ESI-MS: m / z=582 [M+H] + , 604[M+Na] + ; IR:1750cm -1 (COO C=O), 1635 cm -1 (CH2=CH-CH-C=C), 1620cm -1 (CH2=CH-CH-C=C), 1230cm -1 (O - -P=O (PO), 1050-1080 cm (POC (CO))

[0099] <Examples 69 to 81> Synthesis of multifunctional monomers (4-2) to (4-13) In Example 68, the hydroxyl-containing compound used as the raw material in the first step was replaced with the alcohol shown in Table 7, and the tertiary amino-containing amine compound used as the raw material in the second step was replaced with the amine compound shown in Table 8. The solvents, polymerization inhibitors, etc. used in steps 1 and 2, and the reaction conditions for each step were changed as shown in Tables 7 and 8. The reactions in steps 1 and 2 were carried out in the same manner as in Example 68, and the products were identified by ESI-MS and IR analysis. The reaction yields for each step are shown in Tables 7 and 8. The reactions in steps 2 and 3 in Examples 69 and 70 were carried out using a pressure-resistant vessel. After adding all raw materials and intermediates, the vessel was sealed and stirred at a predetermined temperature for a predetermined time using a magnetic stirrer. The intermediates produced after the reaction in step 1 could be used in step 2 without purification. Furthermore, the solvent used in the reaction could be recovered by distillation and reused after completion of the reaction. Furthermore, depending on the state and physical properties of the target compound, such as solubility, purification could be carried out by known methods such as neutralization, washing, extraction, recrystallization, ion exchange resin treatment, and chromatography.

[0100] [Table 7]

[0101] [Table 8]

[0102] Example 82: Synthesis of monofunctional monomer (5-1) (Step 1) A 1000 mL four-neck flask equipped with a stirrer, thermometer, dropping funnel, and nitrogen inlet tube was charged with 32.0 g (200 mmol) of glycerin monomethacrylate (a-1-27), 60.7 g (600 mmol) of triethylamine (b-4), 250 g of tetrahydrofuran (d-1) as a solvent, and 32 mg of dibutylhydroxytoluene (e-6) as a polymerization inhibitor. The mixture was stirred and cooled to -20 °C while blowing in dry nitrogen. A mixture of 68.6 g (480 mmol) of 2-chloro-2-oxo-1,3,2-dioxaphosphorane (COP) and 73 g of solvent (d-1) was slowly added dropwise to the flask through the dropping funnel, and the reaction was carried out. During the dropwise addition, the temperature of the reaction solution in the flask was maintained at -20 °C, and the reaction solution was continuously stirred. As the reaction progressed, triethylamine hydrochloride precipitated as a white precipitate. After the dropwise addition was completed, the temperature of the reaction solution was gradually raised to 35°C, and stirring was continued at 35°C for an additional 12 hours. After the reaction was completed, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to recover the solvent (d-1), yielding 72.2 g of a colorless liquid compound having a dioxaphospholane group (intermediate 82). GC analysis showed that the purity of the intermediate was 95%, and the calculated yield was 92%.

[0103] (Step 2) 72 g (193 mmol) of intermediate 82 obtained in Step 1, 228 g (3860 mmol) of liquid trimethylamine (c-2-1), and 300 g of acetonitrile (d-7) as a solvent were added to a 1000 mL glass pressure-resistant vessel (autoclave) equipped with a stirrer and temperature sensor. The vessel was sealed and heated in a 90 °C oil bath. The reaction mixture was stirred for 24 hours. After completion of the reaction, the pressure was returned to normal, the reaction mixture was concentrated under reduced pressure, and the solvent (d-7) was recovered. 500 mL of acetone was added to the remaining reaction mixture, stirred for 30 minutes, and then placed in a -20 °C refrigerator for 10 hours. The precipitation of a white precipitate was confirmed. The precipitate was separated by suction filtration, washed twice with -20 °C acetone, transferred to another vessel, and vacuum dried at room temperature to obtain 79.3 g of a highly hygroscopic white powder. LC analysis revealed a purity of 98% and a yield of 82%. Furthermore, as described below, the product was confirmed to be the desired monofunctional monomer (5-1) by electrospray ionization mass spectrometry (ESI-MS) and infrared absorption spectroscopy (IR). ESI-MS: m / z = 492 [M+H] + , 514[M+Na] + ; IR:1750cm -1 (COO C=O), 1620 cm -1 (CH2=CH-CH-C=C), 1230cm -1 (O - -P=O (PO), 1050-1080 cm (POC (CO))

[0104] <Examples 82 to 96> Synthesis of monofunctional monomers (5-2) to (5-15) In Example 82, the hydroxyl-containing compound used as the raw material in the first step was replaced with the alcohol shown in Table 9, and the tertiary amino-containing amine compound used as the raw material in the second step was replaced with the amine compound shown in Table 10. The solvents, polymerization inhibitors, etc. used in steps 1 and 2, as well as the reaction conditions for each step, were changed as shown in Tables 9 and 10. The reactions in steps 1 and 2 were carried out in the same manner as in Example 82, and the products were identified by ESI-MS and IR analysis. The reaction yields for each step are shown in Tables 9 and 10. The intermediates produced after the first step reaction can be used in step 2 without purification. Furthermore, the solvent used in the reaction can be recovered and reused by distillation after the reaction. Furthermore, depending on the state and physical properties of the target compound, such as solubility, purification can be performed by known methods such as neutralization, washing, extraction, recrystallization, ion exchange resin treatment, and chromatography.

[0105] [Table 9]

[0106] [Table 10] [Industrial Applicability]

[0107] As described above, the compounds of the present invention are polymerizable compounds having an unsaturated group and a phosphorylcholine group and / or a phosphorylcholine-like group in the molecule. They are characterized by excellent biocompatibility and high polymerizability and curability against heat and active energy rays. Furthermore, multifunctional monomers having two or more unsaturated groups in the molecule can also be used as crosslinkers, while monofunctional monomers having one unsaturated group and two or more phosphorylcholine groups and / or phosphorylcholine-like groups in the molecule can provide high biocompatibility. These compounds have excellent biocompatibility, such as blood compatibility, complement inactivation, and non-adsorption to biological substances. They also have high moisture retention, antifouling, and antibacterial properties, making them suitable for use in a wide variety of fields, including medical materials such as artificial blood vessels, artificial organs, artificial joints, and artificial cartilage tissues, medical devices such as medical instruments and medical equipment, and as raw materials for biocompatible materials for cultured drugs, topical medications, cosmetics, and contact lenses.

Claims

1. having two or more unsaturated groups and two or more phosphorylcholine groups and / or phosphorylcholine-like groups in the molecule, The polymerizable compound represented by general formula (1) or general formula (2), wherein the unsaturated group is any one group selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group, and at least one of the unsaturated groups is a (meth)acrylamide group. (In the formula, R １ , R ２ and R ３ each independently represents a linear alkylene group or hydroxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 2 to 24 carbon atoms; a branched alkylene group or hydroxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon group having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (provided that R ３ may not be present.) R ４ and R ５ each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. A is an unsaturated group. m is an integer of 2 to 3, and Y is selected from the group consisting of N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetraethylethylenediamine, N,N,N',N'-tetramethyl-1,3-diaminopropane, N,N,N',N'-tetramethyl-1,4-diaminobutane, N,N,N',N'-tetramethylhexamethylenediamine, bis[2-(N,N-dimethylamino)ethyl]ether, N,N,N',N'',N''-pentamethyldiethylenetriamine, N,N,N',N'',N''-pentamethyldipropylenetriamine, N-methyl-N,N-bis[3-(dimethylamino)propyl]amine, tris[2-( (dimethylamino)ethyl]amine, 1,1,4,7,10,10-hexamethyltriethylenetetramine, N,N,N',N'',N''-pentakis(2-hydroxypropyl)diethylenetriamine, or 2,4,6-tris(dimethylaminomethyl)phenol, or a linking group obtained by removing an ammonium cation from the phosphorylcholine-like group represented by general formula (1), which is obtained from one polyfunctional amine compound selected from polyether polyamine, polyolefin polyamine, polycarbonate polyamine, polyester polyamine, polysilicone polyamine, or polyacrylic polyamine. (In the formula, R ６ , R ７ and R ８ each independently represents a linear alkylene group or hydroxyalkylene group having 1 to 24 carbon atoms; a linear alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 2 to 24 carbon atoms; a branched alkylene group or hydroxyalkylene group having 3 to 36 carbon atoms; a branched alkenyl group, hydroxyalkenyl group, or alkyleneoxyalkylene group having 3 to 36 carbon atoms; a saturated or unsaturated alicyclic hydrocarbon group having 3 to 36 carbon atoms which may be substituted with a hydroxyl group; or an aromatic hydrocarbon group having 6 to 24 carbon atoms which may be substituted with a hydroxyl group (provided that R ８ may not be present). ９ and R １０ each independently represents a vinyl group, an allyl group, a maleimide group, a linear alkyl group having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6 carbon atoms. B is an unsaturated group. n is an integer of 2 to 8, and Z is selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,4-butanediol, 1,3-butanediol, 1,3-butylene glycol, 1,2-hexanediol, octanediol, 1,3-adamantanedimethanol, 2-hydroxybenzyl alcohol, 2-(2-hydroxyethyl)phenol, stearyldiethanolamine, neopentyl glycol, diethylene glycol, triethylene glycol, isosorbide, cyclohexanedimethanol, norbornanedimethanol, norbornanediol, norbornene dimethanol, norbornene diol, tricyclodecane dimethanol, pentacyclopentadecanedimethanol, 2,2,4,4-tetramethyl-1,3-cyclobutanediol, spiroglycol, dioxane glycol, 1,4:3,6-dianhydrosorbitol, 1,4:3,6-dianhydrosorbitol, 1,4 : represents a linking group obtained by removing a phosphate ester anion from a phosphorylcholine-like group represented by general formula (2), which is obtained from one polyfunctional alcohol compound selected from 3,6-dianhydroiditol, hydrogenated bisphenol A, hydrogenated bisphenol F, glycerin, butanetriol, 1,3,5-cyclohexanetriol, 1,3,5-adamantanetriol, trimethylolethane, trimethylolpropane, 1,2,4-butanetriol, 1,2,5-pentanetriol, 1,2,9-nonanetriol, 1,2,7-heptanetriol, pentaerythritol, erythritol, 1,1,3,3-propanetetraol, sorbitan, xylitol, mannitol, sorbitol, inositol, sucrose, estriol, peimine, calcitriol, polyether polyol, polyolefin polyol, polycarbonate polyol, polyester polyol, polysilicone polyol, and polyacrylic polyol.

2. R １ is a linear alkylene group having 1 to 6 carbon atoms, R ２ is an ethylene group, R ４ and R ５ The polymerizable compound according to claim 1 , wherein each of the groups independently represents a methyl group or an ethyl group.

3. R ６ is a linear alkylene group having 1 to 6 carbon atoms, R ７ is an ethylene group, R ９ and １０ and each independently represent an allyl group or an alkyl group having 1 to 4 carbon atoms.

4. a first step of synthesizing a compound having a dioxaphospholane group by reacting a compound having a hydroxyl group with 2-chloro-2-oxo-1,3,2-dioxophosphorane; a second step in which the compound having a dioxaphospholane group obtained in the first step is ring-opened using an amine compound having a tertiary amino group; The method for producing the polymerizable compound according to any one of claims 1 to 3, comprising:

5. 5. The method for producing a polymerizable compound according to claim 4, wherein the compound having a hydroxyl group has, in the molecule, one or more unsaturated groups selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group, and one or more hydroxyl groups.

6. 6. The method for producing a polymerizable compound according to claim 4 or 5, wherein the amine compound having a tertiary amino group has, in the molecule, one or more unsaturated groups selected from a (meth)acrylate group, a (meth)acrylamide group, an allyl group, a vinyl group, and a maleimide group, and one or more tertiary amino groups.

7. A polymer having a structural unit derived from the polymerizable compound according to any one of claims 1 to 3.

8. A thermally polymerizable and / or active energy ray-curable resin composition comprising the polymerizable compound according to any one of claims 1 to 3 and / or the polymer according to claim 7.

9. A cured product having a structural unit derived from the polymerizable compound according to any one of claims 1 to 3.

10. A hydrogel having structural units derived from the polymerizable compound according to any one of claims 1 to 3.

11. A contact lens having a structural unit derived from the polymerizable compound according to any one of claims 1 to 3.

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