Method for producing organic sulfur compounds, carrier, method for producing said carrier, carrier with immobilized ligand, chromatography column, and method for detecting or isolating target substance

Abstract

To provide a carrier which has excellent pressure resistance, and even when a protein ligand is not immobilized thereon, has a high dynamic binding capacity to a target substance, and has a high performance of separating a target substance from a biological sample.SOLUTION: A method for producing a compound containing a divalent group represented by the following Formula (21), comprises reacting a cyclic ether group-containing compound with a thiocarboxylate in the presence of a hydrous solvent, wherein the hydrous solvent has a water content of 3 to 100 mass%. [In formula (21), R51 and R52 independently represent a divalent group in which a cyclic ether group is ring-opened, X2 represents a thio group, a sulfinyl group, or a sulfonyl group, and * represents a bond.]SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an organic sulfur compound, a support, a method for producing the support, a ligand-immobilized support, a chromatography column, and a method for detecting or isolating a target substance, and more particularly to a method for producing an organic sulfur compound, an organic sulfur compound obtained by the production method, a support, a method for producing the support, a ligand-immobilized support, a chromatography column, and a method for detecting or isolating a target substance. [Background technology]

[0002] There are various types of organic sulfur compounds, such as sulfides, sulfoxides, and sulfones, regardless of whether they are high molecular weight compounds or low molecular weight compounds. Such organic sulfur compounds tend to have properties such as hydrophilicity, antifouling, molecular recognition ability, and stimuli responsiveness, and are used in a wide range of fields such as carriers for antibody purification, surface treatment, and biomaterial production. Among the above organic sulfur compounds, sulfoxides and sulfones are generally produced by oxidation of sulfides (Patent Documents 1, 2, etc.). Also, as a method for producing a sulfide, for example, a method is known in which two cyclic ether groups (e.g., epoxy groups, etc.) are opened using hydrogen sulfide, sodium sulfide, or sodium hydrogen sulfide, and a thio group is introduced between them (Non-Patent Documents 1 to 3). According to this method, a compound having a plurality of hydroxy groups and thio groups derived from a cyclic ether group can be obtained. However, hydrogen sulfide is flammable, combustible, and highly toxic, so its use is greatly restricted.Sodium sulfide and sodium hydrogen sulfide also have safety issues, such as self-heating, causing inflammation and pain in the eyes and skin, and their aqueous solutions are strongly alkaline, which may generate hydrogen sulfide during neutralization treatment.

[0003] Incidentally, in the field of biopharmaceuticals, such as antibody drugs, remarkable progress has been made in expression technology for target substances such as proteins, which has led to a demand for improved productivity in isolation processes using chromatography, etc. One method for improving productivity is to reduce the concentration of impurities present in pharmaceutical raw materials as much as possible in a single isolation, thereby reducing the number of purification steps and steps, and there is an increasing demand for carriers that can achieve this. In order to improve the efficiency of impurity removal in the isolation of a target protein, a technique for hydrophilizing a support has been reported (Patent Document 3). Known examples of such hydrophilized supports include a specific solid support in which the inside of the pores is fixed with a water-soluble polymer (Patent Document 4), a solid support formed by reverse-phase suspension polymerization of hydrophilic monomers such as acrylamide monomers, and a solid support obtained by hydrophobizing a hydrophilic monomer with a protecting group or the like, polymerizing the hydrophilic monomer, and deprotecting the hydrophilic monomer (Patent Documents 5 to 7). However, when the antifouling properties of the carrier are improved by the above-mentioned hydrophilization techniques, there is a problem that the pressure resistance and other properties are reduced. Therefore, a support in which a crosslinked structure is introduced using 3,6-dioxa-1,8-octanedithiol has been proposed as a support with improved pressure resistance (Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2015 / 119255 [Patent Document 2] JP 2016-50897 A [Patent Document 3] International Publication No. 2005 / 010529 [Patent Document 4] Patent No. 5250985 [Patent Document 5] Special Publication No. 2003-511659 [Patent Document 6] Special Publication No. 2009-503203 [Patent Document 7] JP 2006-111717 A [Non-patent literature]

[0005] [Non-Patent Document 1] Journal of the Chemical Society, (1948) p.41 [Non-Patent Document 2] Monatshefte fur Chemie, vol.141, nb.3, (2010) p.323-326 [Non-Patent Document 3] Journal of Organic Chemistry, 1986, 51, p.1128-1130 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention relates to providing a novel means for safely, efficiently, and simply producing an organic sulfur compound, which comprises a step of opening two cyclic ether groups and introducing a thio group between them.

[0007] Incidentally, the carrier described in Patent Document 1 was used for isolating a target protein after immobilizing a protein ligand such as protein A. In general, in order to efficiently capture a target substance, it is necessary to immobilize a protein ligand according to the type of the target substance. In fact, when the present inventors tried to use a carrier cross-linked with 3,6-dioxa-1,8-octanedithiol without immobilizing a protein ligand for isolating an antibody, the antibody was eluted at the stage of washing the carrier, and the antibody could not be successfully separated. On the other hand, when a target substance is separated from a biological sample using a carrier on which a protein ligand is immobilized, the protein ligand may leak from the carrier and become contaminated with the target substance. Such contamination of the protein ligand is particularly problematic when separating substances that require high purity, such as antibody drugs. In addition, there are problems such as high costs and an increase in the number of unit operations. Therefore, the present invention also relates to providing a carrier that has excellent pressure resistance, a large dynamic binding capacity for a target substance even when a protein ligand is not immobilized, and a high performance for separating a target substance from a biological sample. [Means for solving the problem]

[0008] The present inventors attempted to add thiocarboxylic acid to a cyclic ether group-containing compound and react it, but no production of the desired sulfide (a compound in which a thio group is introduced between two divalent groups formed by ring-opening of a cyclic ether group) was observed. However, as a result of extensive research, the present inventors have found that when a cyclic ether group-containing compound is reacted with a thiocarboxylate, a thio group is introduced between two divalent groups formed by ring-opening of the cyclic ether group, and an organic sulfur compound can be produced safely, efficiently, and by a simple operation, thereby completing the present invention.

[0009] That is, the present invention provides the following: <1> ~ <3> This provides:

[0010] <1> A method for producing a compound containing a divalent group represented by the following formula (21), comprising a step of reacting a cyclic ether group-containing compound with a thiocarboxylate (hereinafter also referred to as the "method for producing an organic sulfur compound of the present invention").

[0011] [ka]

[0012] [In formula (21), R 51 and R 52 each independently represents a divalent group formed by ring-opening of a cyclic ether group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, * indicates a bond.

[0013] <2> <1> A compound containing a divalent group represented by formula (21), obtained by the production method described in 2. <3> A compound represented by the following formula (β) (hereinafter also referred to as "compound (β) of the present invention").

[0014] [ka]

[0015] [In formula (β), R 51 and R 52 each independently represents a divalent group formed by ring-opening of a cyclic ether group, R 53 and R 54 each independently represents a hydrogen atom or a methyl group, R 55 and R 56 each independently represents a halogen atom or an organic group, R 57 and R 58 each independently represents a single bond or a divalent linking group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, n1 and n2 each independently represent an integer of 0 to 4.

[0016] Furthermore, as a result of extensive research, the inventors have found that a carrier containing a polymer having a cross-linked structure including a specific divalent group has excellent pressure resistance, and even when a protein ligand is not immobilized, has a large dynamic binding capacity for a target substance and has high performance in separating a target substance from a biological sample, thereby completing the present invention.

[0017] That is, the present invention provides the following: <4> ~ <9> This also provides:

[0018] <4> A support (hereinafter also referred to as "the support of the present invention") comprising a polymer having a crosslinked structure (hereinafter also referred to as "specific crosslinked structure") containing a divalent group represented by the following formula (1).

[0019] [ka]

[0020] [In formula (1), R 1 ~R 4 each independently represents a single bond or a divalent hydrocarbon group, R 5 and R 6 each independently represents a hydrogen atom or a hydrocarbon group, X is a thio group, a sulfinyl group, a sulfonyl group, an oxy group, >N(-R 31 ), >Si(-R 32 )2,>P(-R 33 ),>P(=O)(-R 34 ), >B(-R 35 ), or >C(-R 36 )2 indicates (R 31 ~R 36 each independently represents a hydrogen atom or a hydrocarbon group; * indicates a bond. However, R 1 and R 3 When both are divalent hydrocarbon groups, R 1 and R 3 may be joined together to form a ring with adjacent carbon atoms, R 2 and R 4 When both are divalent hydrocarbon groups, R 2 and R 4 may be joined together with the adjacent carbon atoms to form a ring.

[0021] <5> <4> A ligand-immobilized support (hereinafter also referred to as "ligand-immobilized support of the present invention"), comprising the support and a ligand described above, wherein the ligand is immobilized on the support. <6> <4> or <5> A chromatography column (hereinafter also referred to as "the chromatography column of the present invention"), in which the carrier or ligand-immobilized carrier described in the above is packed in a column container. <7> <4> or <5> A method for detecting or isolating a target substance, comprising using the carrier or ligand-immobilized carrier described in (hereinafter also referred to as "the method for detecting or isolating a target substance of the present invention").

[0022] <8> <4> The method for producing the carrier according to the above-mentioned item 1, which comprises a step of reacting a polymer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by the following formula (α) in the molecule (hereinafter also referred to as "carrier production method PR2-1 of the present invention").

[0023] [ka]

[0024] [In formula (α), R 2 , R 4 , R 6 and * are as defined above.

[0025] <9> <4> The present invention relates to a method for producing a carrier as described above, the method comprising the following steps B-1 and B-2 (hereinafter also referred to as "the carrier production method PR2-2 of the present invention", and the carrier production method PR2-1 of the present invention and the carrier production method PR2-2 of the present invention are collectively referred to as "the carrier production method of the present invention"). (Step B-1) A step of reacting a monomer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by the following formula (α) in the molecule: (Step B-2) A step of preparing a carrier using the crosslinkable monomer obtained in step B-1

[0026] [ka]

[0027] [In formula (α), R 2 , R 4 , R 6 and * are as defined above. Effect of the Invention

[0028] According to the method for producing an organic sulfur compound of the present invention, an organic sulfur compound can be produced safely, efficiently, and through a simple operation. The compound (β) of the present invention is useful as a crosslinking monomer.

[0029] The carrier of the present invention has excellent pressure resistance, and even when a protein ligand is not immobilized, it has a large dynamic binding capacity for a target substance and has a high performance in separating a target substance from a biological sample. Therefore, according to the present invention, a chromatography column can be provided that has excellent pressure resistance, a large dynamic binding capacity for a target substance, and high performance in separating a target substance from a biological sample, even when a protein ligand is not immobilized. Furthermore, according to the carrier production method of the present invention, a carrier that has excellent pressure resistance, and even if a protein ligand is not immobilized, has a large dynamic binding capacity for a target substance and has high performance in separating a target substance from a biological sample can be produced safely, efficiently, and with simple operations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] <Method of producing organic sulfur compounds> The method for producing an organic sulfur compound of the present invention is a method for producing a compound containing a divalent group represented by the following formula (21), and is characterized by including a step of reacting a cyclic ether group-containing compound with a thiocarboxylate.

[0031] [ka]

[0032] [In formula (21), R 51 and R 52 each independently represents a divalent group formed by ring-opening of a cyclic ether group, X 2represents a thio group, a sulfinyl group, or a sulfonyl group, * indicates a bond.

[0033] (Cyclic Ether Group-Containing Compound) The method for producing an organic sulfur compound of the present invention uses a cyclic ether group-containing compound. Here, the "cyclic ether group" in this specification is preferably a cyclic ether group having 3 to 7 atoms constituting the ring. The cyclic ether group may have an alkyl group as a substituent. Specific examples of the cyclic ether group include cyclic ether groups represented by the following formulas (3) to (8), and in order to improve the reaction efficiency, the cyclic ether group represented by formula (3), (7) or (8) is preferred, and the cyclic ether group represented by formula (3) is more preferred.

[0034] [ka]

[0035] [In the formula, R 11 ~R 14 each independently represents a hydrogen atom or an alkyl group, and * represents a bond.

[0036] R 11 ~R 14 The number of carbon atoms in the alkyl group represented by the formula (I) is preferably 1 to 4, and more preferably 1 or 2. The alkyl group may be linear or branched, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group. 11 ~R 14 is preferably a hydrogen atom.

[0037] Cyclic ether group-containing compounds can be roughly divided into low molecular weight compounds and high molecular weight compounds. In addition, cyclic ether group-containing compounds may have polymerizable functional groups other than cyclic ether groups (hereinafter also referred to as "other polymerizable functional groups"), whether they are low molecular weight compounds or high molecular weight compounds. That is, cyclic ether group-containing compounds may be macromonomers. The cyclic ether group-containing compound may be used alone or in combination of two or more kinds for the reaction. The cyclic ether group-containing compound may be a commercially available product or may be prepared by referring to a known method.

[0038] -Low molecular weight compounds containing cyclic ether groups- Here, the cyclic ether group-containing low molecular weight compound will be specifically described. In the present specification, the term "cyclic ether group-containing low molecular weight compound" refers to a cyclic ether group-containing compound other than the "cyclic ether group-containing polymer compound". The molecular weight of the cyclic ether group-containing low molecular weight compound is preferably 40 or more, more preferably 50 or more, particularly preferably 60 or more, and is preferably less than 5000, more preferably less than 2500, even more preferably less than 1000, and particularly preferably less than 750. As a specific range, 40 or more and less than 5000 are preferred, 50 or more and less than 2500 are more preferred, 60 or more and less than 1000 are even more preferred, and 60 or more and less than 750 are particularly preferred. When the cyclic ether group-containing compound is a low molecular weight compound, the number of cyclic ether groups is not particularly limited, but is preferably 1 to 20, more preferably 1 to 6, even more preferably 1 to 4, and particularly preferably 1 to 2 in one molecule. When the number of cyclic ether groups is one, it is easy to obtain a single type of compound. When the number of cyclic ether groups is two or more, for example, a cyclic sulfide compound, a chain sulfide compound, a thio group-containing network polymer, a thio group-containing dendron, a thio group-containing dendrimer, a thio group-containing block copolymer, a thio group-containing star polymer, a thio group-containing ladder polymer, a thio group-containing hyperbranched polymer, etc. can be obtained. The total number of carbon atoms of the cyclic ether group-containing low molecular weight compound is preferably 2 to 80, more preferably 2 to 40, even more preferably 3 to 35, still more preferably 3 to 30, and particularly preferably 4 to 25, in order to improve the solubility and viscosity in the reaction system and thereby improve the reaction efficiency.

[0039] Cyclic ether group-containing low molecular weight compounds can be roughly divided into those having polymerizable functional groups other than cyclic ether groups and those not having such groups. Examples of "other polymerizable functional groups" include polymerizable unsaturated groups. When the cyclic ether group-containing low molecular weight compound has other polymerizable functional groups, the number of the other polymerizable functional groups in one molecule is preferably 1 to 10, more preferably 1 to 6, even more preferably 1 to 3, and particularly preferably 1 to 2.

[0040] Examples of low molecular weight compounds having one cyclic ether group in the molecule but no other polymerizable functional groups include alkylene oxides (preferably alkylene oxides having a total of 2 to 80 carbon atoms) such as ethylene oxide, propylene oxide, 1,2-butylene oxide, 2,3-butylene oxide, 1,2-epoxypentane, 1,2-epoxyhexane, and 1,2-epoxyheptane; haloalkylene oxides (preferably haloalkylene oxides having a total of 2 to 80 carbon atoms) such as epichlorohydrin, epibromohydrin, and 3-perfluorooctyl-1,2-epoxypropane; alkyl glycidyl ethers (preferably alkyl glycidyl ethers having a total of 4 to 80 carbon atoms) such as glycidyl methyl ether and ethyl glycidyl ether; and hydroxyl group-containing cyclic alkyl ethers such as glycidol. Examples of suitable cyclic ether compounds include ether compounds (preferably hydroxy group-containing cyclic ether compounds having a total of 2 to 80 carbon atoms); aromatic group-containing cyclic ether compounds such as styrene oxide, benzyl glycidyl ether, and 2-biphenylyl glycidyl ether (preferably aromatic group-containing cyclic ether compounds having a total of 8 to 80 carbon atoms); silicon-containing cyclic ether compounds such as diethoxy(3-glycidyloxypropyl)methylsilane and 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (preferably silicon-containing cyclic ether compounds having a total of 4 to 80 carbon atoms); and cyclic ether group-containing organic salts such as glycidyltrimethylammonium chloride (preferably cyclic ether group-containing organic salts having a total of 4 to 80 carbon atoms). One of these compounds may be used alone in the reaction, or two or more of them may be used in combination in the reaction.

[0041] Examples of low molecular weight compounds having one cyclic ether group and one other polymerizable functional group in the molecule include glycidyl (meth)acrylate, 3,4-epoxycyclohexylmethyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate glycidyl ether, tetrahydrofurfuryl (meth)acrylate, 3-oxiranylpropyl (meth)acrylate, 4-oxiranylbutyl (meth)acrylate, 5-oxiranylpentyl (meth)acrylate, 6-oxiranylhexyl (meth)acrylate, 7-oxiranylheptyl (meth)acrylate, 8-oxiranyloctyl (meth)acrylate, (3-methyloxiranyl)methyl (meth)acrylate, glycerin mono(meth)acrylate glycidyl ether, 3,4-epoxycyclohexylethyl (meth)acrylate, and 3,4-epoxycyclohexylpropyl (meth)acrylate. Examples of the monomer include (meth)acrylate monomers having a cyclic ether group such as α-(meth)acryl-ω-glycidyl polyethylene glycol (preferably a (meth)acrylate monomer having a cyclic ether group having a total of 6 to 80 carbon atoms); aromatic vinyl monomers having a cyclic ether group such as vinylbenzyl glycidyl ether (preferably an aromatic vinyl monomer having a cyclic ether group having a total of 10 to 80 carbon atoms); allyl ether monomers having a cyclic ether group such as allyl glycidyl ether (preferably an allyl ether monomer having a cyclic ether group having a total of 6 to 80 carbon atoms), as well as vinyl alkylene oxide monomers such as 3,4-epoxy-1-butene and alkylene oxide monomers having a triple bond such as 2,3-epoxypropyl propargyl ether. One of these monomers may be used alone in the reaction, or two or more of them may be used in combination in the reaction.

[0042] Examples of low molecular weight compounds having two cyclic ether groups in a molecule but no other polymerizable functional groups include diglycidyl ethers (preferably diglycidyl ethers having a total carbon number of 7 to 80) such as 1,4-butanediol diglycidyl ether, 1,6-hexanediol diglycidyl ether, bisphenol A diglycidyl ether, ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, tripropylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, and glycerin diglycidyl ether; diglycidyl dicarboxylates such as diglycidyl-cyclohexanedicarboxylate, diglycidyl phthalate, diglycidyl terephthalate (preferably diglycidyl dicarboxylates having a total of 8 to 80 carbon atoms); diepoxyalkanes such as 1,3-butadiene diepoxide (preferably diepoxyalkanes having a total of 4 to 80 carbon atoms); compounds having two epoxycyclohexyl groups in the molecule such as 1,3-bis[2-(7-oxabicyclo[4.1.0]heptan-3-yl)ethyl]-1,1,3,3-tetramethyldisiloxane (preferably compounds having two epoxycyclohexyl groups in the molecule having a total of 12 to 80 carbon atoms), and the like. Among these, one kind may be used alone in the reaction, or two or more kinds may be used in combination in the reaction.

[0043] An example of a low molecular weight compound having two cyclic ether groups and one other polymerizable functional group in the molecule is diglycidyl 4-cyclohexene-1,2-dicarboxylate.

[0044] An example of a low molecular weight compound having two cyclic ether groups and two other polymerizable functional groups in the molecule is diglycidyl bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate.

[0045] Examples of low molecular weight compounds having three cyclic ether groups in the molecule but no other polymerizable functional groups include triglycidyl ethers such as trimethylolpropane triglycidyl ether and glycerol triglycidyl ether (preferably triglycidyl ethers having a total carbon number of 10 to 80), as well as triglycidyl isocyanurate, triglycidyl cyanurate, and triglycidyl 1,2,4-benzenetricarboxylate. One of these may be used alone in the reaction, or two or more of them may be used in combination in the reaction.

[0046] Examples of low molecular weight compounds having four cyclic ether groups in the molecule but no other polymerizable functional groups include tetraglycidyl ethers (preferably tetraglycidyl ethers having a total of 13 to 80 carbon atoms) such as methanetetrayltetrakis(glycidyl ether), sorbitol tetraglycidyl ether, and pentaerythritol tetraglycidyl ether, and one of these may be used alone in the reaction, or two or more of them may be used in combination in the reaction.

[0047] -Cyclic ether group-containing polymer compound- Next, the cyclic ether group-containing polymer compound will be specifically described. In this specification, the term "cyclic ether group-containing polymer compound" refers to a cyclic ether group-containing compound that contains repeating structural units and has a large molecular weight. The weight average molecular weight of the cyclic ether group-containing polymer compound is preferably 750 or more, more preferably 1000 or more, even more preferably 2500 or more, and particularly preferably 5000 or more, and is preferably 2.5 million or less, more preferably 1 million or less, and particularly preferably 500,000 or less. The weight average molecular weight can be measured, for example, by NMR, GPC, etc. As the cyclic ether group-containing polymer compound, a polymer compound having a structural unit having a cyclic ether group is preferred, and a polymer compound having a structural unit having a cyclic ether group in a side chain is more preferred. In addition, the monomer that induces the structural unit having a cyclic ether group may be a non-crosslinkable monomer or a crosslinkable monomer.

[0048] The total number of carbon atoms of the monomer from which the structural unit having a cyclic ether group is derived is preferably 2 to 80, more preferably 2 to 40, even more preferably 3 to 35, still more preferably 3 to 30, and particularly preferably 4 to 25, in order to improve the solubility and viscosity in the reaction system and thereby improve the reaction efficiency. As the monomer from which the structural unit having a cyclic ether group is derived, one having "another polymerizable functional group" such as a polymerizable unsaturated group is preferred. The number of the other polymerizable functional groups in one monomer molecule is preferably 1 to 10, more preferably 1 to 6, even more preferably 1 to 2, and particularly preferably 1.

[0049] Examples of monomers that induce structural units having a cyclic ether group include monomers having one each of a cyclic ether group and another polymerizable functional group in the molecule, and monomers having two or more cyclic ether groups in the molecule.Specific examples of such monomers include those having one each of a cyclic ether group and another polymerizable functional group in the molecule, and those having two or more cyclic ether groups in the molecule, among the compounds listed above as the "cyclic ether group-containing low molecular weight compounds."The low molecular weight compounds having two or more cyclic ether groups in the molecule may or may not have the above-mentioned "other polymerizable functional groups."

[0050] The content of the structural unit having a cyclic ether group is preferably from 0.1 to 100 mass %, and more preferably from 10 to 90 mass %, of all the structural units contained in the polymer compound.

[0051] In addition, the cyclic ether group-containing polymer compound may have a structural unit other than the structural unit having a cyclic ether group. The monomer that derives such a structural unit (hereinafter also referred to as "other monomer MO1") may be a polymerizable unsaturated group-containing monomer that does not have a cyclic ether group. The other monomer MO1 is roughly classified into a non-crosslinkable monomer and a crosslinkable monomer, and either one of them may be used or they may be used in combination. The content of the structural units provided by the other monomer MO1 is preferably from 0 to 99.9 mass %, more preferably from 10 to 90 mass %, of all the structural units contained in the polymer compound.

[0052] Examples of the non-crosslinkable monomer include (meth)acrylate-based non-crosslinkable monomers, (meth)acrylamide-based non-crosslinkable monomers, aromatic vinyl-based non-crosslinkable monomers, vinyl ketone-based non-crosslinkable monomers, (meth)acrylonitrile-based non-crosslinkable monomers, N-vinylamide-based non-crosslinkable monomers, and unsaturated dicarboxylic anhydride-based non-crosslinkable monomers. These can be used alone or in combination of two or more. Among the non-crosslinkable monomers, (meth)acrylate-based non-crosslinkable monomers and aromatic vinyl-based non-crosslinkable monomers are preferred.

[0053] Examples of the (meth)acrylate-based non-crosslinkable monomer include methyl (meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate, 4-tert-butyl (meth)acrylate, isobutyl (meth)acrylate, n-octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, cyclohexyl (meth)acrylate, methoxyethyl (meth)acrylate, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, glycerol mono(meth)acrylate, trimethylolethane mono(meth)acrylate, trimethylolpropane mono(meth)acrylate, butanetriol mono(meth)acrylate, polyethylene glycol mono(meth)acrylate, methoxypolyethylene glycol (meth)acrylate, pentaerythritol mono(meth)acrylate, dipentaerythritol mono(meth)acrylate, and inositol mono(meth)acrylate. These can be used alone or in combination of two or more.

[0054] Examples of the (meth)acrylamide-based non-crosslinkable monomer include (meth)acrylamide, dimethyl(meth)acrylamide, hydroxyethyl(meth)acrylamide, (meth)acryloylmorpholine, diacetone(meth)acrylamide, etc. These may be used alone or in combination of two or more.

[0055] Examples of the aromatic vinyl non-crosslinkable monomer include styrenes such as styrene, α-methylstyrene, halogenated styrene, 4-methylstyrene, 2,4-dimethylstyrene, 2,4,6-trimethylstyrene, ethylvinylbenzene, 4-isopropylstyrene, 4-n-butylstyrene, 4-isobutylstyrene, and 4-tert-butylstyrene; vinylnaphthalenes such as 1-vinylnaphthalene and 2-vinylnaphthalene; and the like. These may be used alone or in combination of two or more.

[0056] Examples of the vinyl ketone-based non-crosslinkable monomer include ethyl vinyl ketone, propyl vinyl ketone, isopropyl vinyl ketone, etc. These may be used alone or in combination of two or more. Examples of the (meth)acrylonitrile-based non-crosslinkable monomer include acrylonitrile, methacrylonitrile, etc. These may be used alone or in combination of two or more. Examples of the N-vinylamide non-crosslinkable monomer include N-vinylacetamide, N-vinylpropionamide, etc. These may be used alone or in combination of two or more. Examples of the unsaturated dicarboxylic anhydride-based non-crosslinkable monomer include maleic anhydride, methylmaleic anhydride, glutaconic anhydride, etc. These may be used alone or in combination of two or more.

[0057] Examples of the crosslinkable monomer include (meth)acrylate crosslinkable monomers, aromatic vinyl crosslinkable monomers, and allyl crosslinkable monomers. These may be used alone or in combination of two or more. As the crosslinkable monomer, di- to penta-functional crosslinkable monomers are preferred, and di- or tri-functional crosslinkable monomers are more preferred. Among the crosslinkable monomers, (meth)acrylate crosslinkable monomers and aromatic vinyl crosslinkable monomers are preferred.

[0058] Examples of the (meth)acrylate crosslinkable monomer include ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, tripropylene glycol di(meth)acrylate, tetrapropylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate, 1,4-butanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, glycerin di(meth)acrylate, trimethylolethane di(meth)acrylate, trimethylolpropane di(meth)acrylate, trimethylolpropane tri(meth)acrylate, acrylate, butanetriol di(meth)acrylate, pentaerythritol di(meth)acrylate, pentaerythritol tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, glucose di(meth)acrylate, glucose tri(meth)acrylate, glucose tetra(meth)acrylate, dipentaerythritol di(meth)acrylate, dipentaerythritol tri(meth)acrylate, dipentaerythritol tetra(meth)acrylate, dipentaerythritol penta(meth)acrylate, inositol di(meth)acrylate, inositol tri(meth)acrylate, inositol tetra(meth)acrylate, mannitol di(meth)acrylate, mannitol tri(meth)acrylate, mannitol tetra(meth)acrylate, mannitol penta(meth)acrylate, etc. These can be used alone or in combination of two or more.

[0059] In addition, the aromatic vinyl crosslinkable monomer may be, for example, divinylbenzene, trivinylbenzene, divinyltoluene, divinylxylene, divinylethylbenzene, divinylnaphthalene, etc. In addition, the compound represented by formula (β) of the present invention may also be used as an aromatic vinyl crosslinkable monomer. These may be used alone or in combination of two or more.

[0060] Examples of the allyl-based crosslinkable monomer include diallyl phthalate, diallyl isophthalate, diallyl terephthalate, diallyl maleate, diallyl fumarate, diallyl itaconate, diallyl trimellitate, triallyl trimellitate, triallyl cyanurate, diallyl isocyanurate, triallyl isocyanurate, etc. These may be used alone or in combination of two or more. Further, in addition to the above-mentioned examples, examples of the crosslinkable monomer include dehydration condensation products of aminoalcohols such as diaminopropanol, trishydroxymethylaminomethane, and glucosamine with (meth)acrylic acid, and conjugated diolefins such as butadiene and isoprene.

[0061] The cyclic ether group-containing polymer compound may have a one-dimensional structure or a multidimensional structure, and may be any of a linear polymer compound, a branched polymer compound, a plate-like polymer compound, and a network polymer compound. When the cyclic ether group-containing polymer compound is a copolymer, the arrangement of the structural units is arbitrary, and may be any of a random copolymer, an alternating copolymer, a block copolymer, a graft copolymer, and the like.

[0062] In addition, carriers and supports used in various purification methods such as affinity purification, detection of biological substances, in vitro diagnosis, etc. can also be used as cyclic ether group-containing polymer compounds in the thio group introduction reaction. Examples of the form of the carrier or support include particles, monoliths, membranes, chips, etc. The above carriers and supports may be commercially available products or may be prepared by referring to known methods described in International Publication No. 2015 / 119255, etc.

[0063] (Thiocarboxylate) The method for producing an organic sulfur compound of the present invention involves reacting a thiocarboxylate with a cyclic ether group-containing compound, thereby allowing the reaction of opening two cyclic ether groups and introducing a thio group between them to proceed safely and efficiently. The thiocarboxylate may be present as an ion in the reaction system. In addition, the "reaction of a cyclic ether group-containing compound with a thiocarboxylate" in the present invention also includes the creation of a state in which a thiocarboxylate or its ion is present in the reaction system by, for example, adding a basic substance to the reaction system together with the thiocarboxylate.

[0064] Examples of the salt of thiocarboxylic acid include alkali metal salts such as sodium salt, potassium salt, lithium salt, etc.; salts with Group 2 elements such as calcium salt, magnesium salt, etc.; ammonium salt, pyridinium salt, imidazolium salt, morpholinium salt, piperidinium salt, pyrrolidinium salt, phosphonium salt, sulfonium salt, etc. Among these, alkali metal salts are preferred in order to efficiently obtain the desired compound.

[0065] As the thiocarboxylate, one represented by the following formula (13) is preferred in order to efficiently obtain the desired compound.

[0066] [ka]

[0067] [In formula (13), R 22 represents a hydrogen atom or a monovalent organic group, M represents a cation that forms a thiocarboxylate.

[0068] In formula (13), R 22 R represents a hydrogen atom or a monovalent organic group, and is preferably a monovalent organic group in order to efficiently obtain the desired compound. Examples of the monovalent organic group include substituted or unsubstituted hydrocarbon groups.22 The hydrocarbon group in the above is a concept including aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, and aromatic hydrocarbon groups. Among these, in order to efficiently obtain a desired compound, aliphatic hydrocarbon groups and aromatic hydrocarbon groups are preferred, and aliphatic hydrocarbon groups are more preferred. The number of carbon atoms in the aliphatic hydrocarbon group is preferably 1 to 20, more preferably 1 to 12, even more preferably 1 to 6, and particularly preferably 1 to 3, in order to efficiently obtain the desired compound. The aliphatic hydrocarbon group may be linear or branched. In addition, as the aliphatic hydrocarbon group, an alkyl group is preferable in order to efficiently obtain the desired compound. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, and a dodecyl group.

[0069] In order to efficiently obtain a desired compound, the number of carbon atoms in the alicyclic hydrocarbon group is preferably 3 to 12, and more preferably 3 to 8. Specific examples of the alicyclic hydrocarbon group include cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. In order to efficiently obtain a desired compound, the number of carbon atoms in the aromatic hydrocarbon group is preferably 6 to 12, and more preferably 6 to 8. Specific examples of the aromatic hydrocarbon group include aryl groups such as a phenyl group, a tolyl group, a xylyl group, and a naphthyl group.

[0070] R 22 Examples of the substituent in include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0071] Furthermore, M represents a cation that forms a thiocarboxylate. Examples of M include alkali metal ions such as sodium ion, potassium ion, and lithium ion; ions of Group 2 elements such as calcium ion and magnesium ion; and ammonium ion, pyridinium ion, imidazolium ion, morpholinium ion, piperidinium ion, pyrrolidinium ion, phosphonium ion, and sulfonium ion. Among these, alkali metal ions are preferred in order to efficiently obtain the desired compound.

[0072] Specific examples of thiocarboxylates include thioformates, thioacetates, propanethioates, butanethioates, pentanethioates, hexanethioates, octanethioates, nonanethioates, decanethioates, dodecanethioates, thiobenzoates, etc. Among these, in order to efficiently obtain a desired compound, thioacetates are preferred, and alkali metal salts of thioacetic acid are particularly preferred. The thiocarboxylate may be used alone or in combination of two or more kinds in the reaction. The thiocarboxylate may be a commercially available product or may be prepared by referring to a known method.

[0073] The amount of the thiocarboxylate used is preferably 0.01 mol or more, more preferably 0.05 mol or more, more preferably 0.1 mol or more, more preferably 0.25 mol or more, and particularly preferably 0.5 mol or more, relative to 1 mol of the cyclic ether group in order to efficiently obtain the desired compound. Also, in order to efficiently obtain the desired compound, the amount is preferably 5 mol or less, more preferably 2.5 mol or less, more preferably 1 mol or less, and particularly preferably 0.75 mol or less, relative to 1 mol of the cyclic ether group in order to efficiently obtain the desired compound. When the amount of the thiocarboxylate used is 0.75 mol or less, relative to 1 mol of the cyclic ether group, the desired compound can be obtained particularly efficiently. As a specific range, 0.01 mol or more and 5 mol or less are preferred, 0.05 mol or more and 2.5 mol or less are more preferred, 0.1 mol or more and 1 mol or less are more preferred, and 0.25 mol or more and 0.75 mol or less are particularly preferred.

[0074] (Reaction conditions, etc.) The reaction between a cyclic ether group-containing compound and a thiocarboxylate (thio group introduction reaction) can be carried out in the presence or absence of a solvent, but is preferably carried out in the presence of a solvent in order to efficiently obtain the desired compound. Examples of the solvent include water; alcohols such as methanol, ethanol, propanol, isopropyl alcohol, and n-butyl alcohol; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate and butyl acetate; amides such as N,N-dimethylformamide; and nitriles such as acetonitrile. One of these may be used alone, or two or more may be used in combination. As the solvent, a water-containing solvent (water or a mixture of water and a solvent other than water) is preferable in order to efficiently obtain the desired compound. In the water-containing solvent, the content of water is preferably 3 to 100% by mass, more preferably 20 to 100% by mass in order to efficiently obtain the desired compound. Among these solvents, in order to efficiently obtain the desired compound, one or more solvents selected from water, alcohols, sulfoxides, ketones, ethers, and amides are preferred, and one or more solvents selected from water, alcohols, and sulfoxides are particularly preferred. The amount of the solvent used is usually 0 to 10,000 parts by mass, and preferably 10 to 2,000 parts by mass, based on 100 parts by mass of the cyclic ether group-containing compound.

[0075] The thio group introduction reaction may be carried out using a basic catalyst such as N,N-diisopropylethylamine, but the reaction can also be carried out without using a catalyst.

[0076] The reaction conditions for the thio group introduction reaction include basic conditions, neutral conditions, and acidic conditions, but in order to efficiently obtain the desired compound, the thio group introduction reaction is preferably carried out under neutral to basic conditions. The pH of the thio group introduction reaction is preferably 6 or more, more preferably 6 to 14, and particularly preferably 7 to 14, in order to efficiently obtain the desired compound. Here, the above-mentioned "under neutral to basic conditions" refers to a state in which a neutral to basic state is created in the reaction system during the reaction between a cyclic ether group-containing compound and a thiocarboxylate, and whether or not a component (basic substance, etc.) other than the cyclic ether group-containing compound and the thiocarboxylate is added, if a neutral to basic state is created in the reaction system, it corresponds to a reaction under "neutral to basic conditions". In other words, "under neutral to basic conditions" includes, for example, the reaction between a cyclic ether group-containing compound and a thiocarboxylate spontaneously making the system basic, adding a basic substance separately to make the reaction system neutral to basic, adding a thiocarboxylate together with a basic substance instead of a thiocarboxylate to the reaction system to create a state in which a thiocarboxylate or its ion is present in the reaction system, and the like to make the reaction system neutral to basic. The same applies to the pH mentioned above. For example, "pH 6 or higher" means that a state of pH 6 or higher is created in the reaction system during the reaction between a cyclic ether group-containing compound and a thiocarboxylate. Regardless of whether or not a component (such as a basic substance) other than the cyclic ether group-containing compound and the thiocarboxylate is added, if a state of pH 6 or higher is created in the reaction system, this corresponds to a reaction at "pH 6 or higher."

[0077] The reaction temperature for the thio group introduction reaction is usually 0 to 120°C, preferably 20 to 80°C. The reaction time for the thio group introduction reaction is usually 0.01 to 24 hours, preferably 0.5 to 8 hours. The reaction pressure for the thio group introduction reaction is not particularly limited, and the reaction can be carried out at normal pressure.

[0078] According to the above-mentioned thio group introduction reaction, a wide variety of sulfide compounds (X in formula (21)) can be obtained depending on the type of cyclic ether group-containing compound. 2is a thio group). For example, a cyclic ether group-containing compound and a cyclic ether group-containing compound that is a different molecule from the compound (these cyclic ether group-containing compounds may be the same or different) can be ring-opened to introduce a thio group between them to link them, or two cyclic ether groups contained in one molecule can be ring-opened to introduce a thio group between them to introduce a crosslinked structure into the molecule. More specifically, when a low molecular weight compound having one cyclic ether group and one other polymerizable functional group in the molecule (e.g., glycidyl (meth)acrylate, vinylbenzyl glycidyl ether, etc.) is used as the cyclic ether group-containing compound, a sulfide compound having another polymerizable functional group can be obtained. Furthermore, when a low molecular weight compound having two cyclic ether groups in the molecule (e.g., 1,4-butanediol diglycidyl ether, bisphenol A diglycidyl ether, ethylene glycol diglycidyl ether, etc.) is used as the cyclic ether group-containing compound, a cyclic sulfide compound or a chain sulfide compound can be obtained. Furthermore, when a low molecular weight compound having three or more cyclic ether groups in the molecule (eg, triglycidyl isocyanurate, etc.) is used as the cyclic ether group-containing compound, a thio group-containing network polymer can be obtained. Furthermore, when a polymer compound having two or more cyclic ether groups is used as the cyclic ether group-containing compound, a polymer compound having a crosslinked structure containing a divalent group represented by formula (21) can be obtained.

[0079] The sulfide compound obtained as described above may be isolated, if necessary, by an appropriate combination of conventional means such as filtration, washing, drying, recrystallization, reprecipitation, dialysis, centrifugation, extraction with various solvents, neutralization, chromatography, and the like.

[0080] In addition, X in formula (21) 2 In the case of producing a compound in which is a sulfinyl group or a sulfonyl group, X in the formula (21) obtained by the above thio group introduction reaction is 2The compound having a thio group (sulfide compound) can be oxidized. The oxidation may be carried out with reference to known methods described in International Publication No. 2015 / 119255, JP 2016-50897 A, etc., and specifically, a method using an oxidizing agent may be mentioned. Examples of the oxidizing agent include organic oxidizing agents such as peracetic acid, perbenzoic acid, metachloroperbenzoic acid, and tert-butyl hydroperoxide; and inorganic oxidizing agents such as hydrogen peroxide, chromic acid, and permanganate. These oxidizing agents may be used alone or in combination of two or more.

[0081] In addition, when a polymer compound having a structural unit having a cyclic ether group is used as a cyclic ether group-containing compound in a thio group introduction reaction, a cyclic ether group may remain in the product of the thio group introduction reaction, but the remaining cyclic ether group may be ring-opened by a known method. Specifically, a method of reacting a cyclic ether group with an alcohol containing a mercapto group such as mercaptoethanol or thioglycerol, or a polyhydric alcohol such as glycerol, may be mentioned. In addition, when the product of the thio group introduction reaction has another polymerizable functional group, this product can be polymerized, and in this case, it may be copolymerized with another monomer MO1.

[0082] When the compound containing a divalent group represented by the following formula (21) obtained by the method for producing an organic sulfur compound of the present invention is a low molecular weight compound, it is useful, for example, as an organic solvent, surfactant, hydrophilizing agent, dispersion stabilizer, crosslinking agent, etc. When the compound is a high molecular weight compound, it is useful, for example, as a carrier or support therefor, dispersion stabilizer, gelling agent, hardener, etc. used in various purifications such as affinity purification, detection of biological substances, in vitro diagnosis, etc.

[0083] [ka]

[0084] [In formula (21), R 51 and R 52each independently represents a divalent group formed by ring-opening of a cyclic ether group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, * indicates a bond.

[0085] In addition, R 51 and R 52 The divalent group formed by ring-opening of the cyclic ether group represented by the formula: corresponds to the cyclic ether group contained in the cyclic ether group-containing compound. For example, when the cyclic ether group contained in the cyclic ether group-containing compound is an epoxy group, it is a ring-opened epoxy group represented by the formula: -CHOH-CH-.

[0086] Among the compounds containing a divalent group represented by formula (21) obtained by the method for producing an organic sulfur compound of the present invention, the compound represented by the following formula (β) is a novel compound. Since this compound (β) has a plurality of polymerizable unsaturated groups, it is useful as a crosslinkable monomer, and can be used, for example, as a raw material monomer for carriers used in various purifications such as affinity purification, detection of biological substances, in vitro diagnosis, etc. In addition, it has properties such as higher structural flexibility and hydrophilicity than the crosslinkable monomer divinylbenzene, and is particularly useful as an alternative monomer for divinylbenzene, etc.

[0087] [ka]

[0088] [In formula (β), R 51 and R 52 each independently represents a divalent group formed by ring-opening of a cyclic ether group, R 53 and R 54 each independently represents a hydrogen atom or a methyl group, R 55 and R 56 each independently represents a halogen atom or an organic group, R 57 and R 58each independently represents a single bond or a divalent linking group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, n1 and n2 each independently represent an integer of 0 to 4.

[0089] In formula (β), R 51 and R 52 Each independently represents a divalent group formed by opening a cyclic ether group. 51 and R 52 is R in Eq. (21). 51 and R 52 is synonymous with.

[0090] R 55 and R 56 each independently represents a halogen atom or an organic group. R 55 and R 56 Examples of the halogen atom represented by the formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. R 55 and R 56 Examples of the organic group represented by the formula (I) include substituted or unsubstituted hydrocarbon groups and groups in which a portion of the carbon atoms of the substituted or unsubstituted hydrocarbon group is replaced by one or more bonds selected from ether bonds, amide bonds and ester bonds, with substituted or unsubstituted hydrocarbon groups being preferred. Note that in the group in which a portion of the carbon atoms of the substituted or unsubstituted hydrocarbon group is replaced by one or more bonds selected from ether bonds, amide bonds and ester bonds, the number of ether bonds, amide bonds and ester bonds may be one or more. Also, R 55 and R 56 The total number of carbon atoms in the organic group represented by the formula: is preferably 1 to 20, more preferably 1 to 10, further preferably 1 to 6, and particularly preferably 1 to 3. R 55 and R 56 The "hydrocarbon group" in the formula (13) may or may not have a substituent. The substituted or unsubstituted hydrocarbon group is, for example, R 22In addition, when n1 is an integer of 2 to 4, n1 R 55 may be the same or different, and when n2 is an integer of 2 to 4, n2 R 56 may be the same or different. n1 and n2 each independently represent an integer of 0 to 4, preferably 0 or 1, and more preferably 0.

[0091] R 57 and R 58 each independently represents a single bond or a divalent linking group, preferably a divalent linking group, and more preferably a divalent organic group. R 57 and R 58 The divalent organic group represented by the formula (I) is preferably a substituted or unsubstituted divalent hydrocarbon group, or a group in which a portion of the carbon atoms of the substituted or unsubstituted divalent hydrocarbon group is replaced by one or more bonds selected from an ether bond, an amide bond, and an ester bond, and more preferably a substituted or unsubstituted divalent hydrocarbon group, or a group in which a portion of the carbon atoms of the substituted or unsubstituted divalent hydrocarbon group is replaced by an ether bond. In addition, in a group in which a portion of the carbon atoms of a substituted or unsubstituted divalent hydrocarbon group is replaced with one or more bonds selected from an ether bond, an amide bond, and an ester bond, the number of the ether bond, amide bond, or ester bond may be one or more. The divalent organic group preferably has a total of 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, further preferably 1 to 6 carbon atoms, and particularly preferably 1 to 3 carbon atoms.

[0092] Also, R 57 and R 58 The "divalent hydrocarbon group" in the above formula may be any of a divalent aliphatic hydrocarbon group, a divalent alicyclic hydrocarbon group, and a divalent aromatic hydrocarbon group, with a divalent aliphatic hydrocarbon group being preferred.

[0093] The number of carbon atoms in the divalent aliphatic hydrocarbon group is preferably 1 to 20, more preferably 1 to 10, even more preferably 1 to 6, and particularly preferably 1 to 3. The divalent aliphatic hydrocarbon group may be linear or branched. In addition, the divalent aliphatic hydrocarbon group is preferably an alkanediyl group. Examples of the alkanediyl group include a methane-1,1-diyl group, an ethane-1,1-diyl group, an ethane-1,2-diyl group, a propane-1,1-diyl group, a propane-1,2-diyl group, a propane-1,3-diyl group, a propane-2,2-diyl group, a butane-1,4-diyl group, a pentane-1,5-diyl group, and a hexane-1,6-diyl group. Examples of a substituted or unsubstituted divalent hydrocarbon group in which a part of the carbon atoms is replaced by an ether bond include -(R g O) q2 R h A group represented by - is preferred. Here, R g and R h R each independently represents a divalent hydrocarbon group (preferably an alkanediyl group) having 1 to 8 carbon atoms (preferably 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms), and q2 represents an integer of 1 to 6 (preferably an integer of 1 to 3, more preferably 1 or 2). g and R h The alkanediyl group represented by the above R 57 and R 58 In addition, when q2 is an integer of 2 to 6, q2 R g may be the same or different. Such a -(R g O) q2 R h Specific examples of the group represented by - include -CH2-O-CH2-, -CH2-O-CH2-O-CH2-, -CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2-, -CH2CH2-O-CH2CH2-O-CH2CH2-, and the like.

[0094] R 57 and R 58 Examples of the substituent in include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0095] <Carrier> The carrier of the present invention contains a polymer having a crosslinked structure that contains a divalent group represented by the following formula (1) (hereinafter also referred to as "divalent group (1)").

[0096] [ka]

[0097] [In formula (1), R 1 ~R 4 each independently represents a single bond or a divalent hydrocarbon group, R 5 and R 6 each independently represents a hydrogen atom or a hydrocarbon group, X is a thio group, a sulfinyl group, a sulfonyl group, an oxy group, >N(-R 31 ), >Si(-R 32 )2,>P(-R 33 ),>P(=O)(-R 34 ), >B(-R 35 ), or >C(-R 36 )2 indicates (R 31 ~R 36 each independently represents a hydrogen atom or a hydrocarbon group; * indicates a bond. However, R 1 and R 3 When both are divalent hydrocarbon groups, R 1 and R 3 may be joined together to form a ring with adjacent carbon atoms, R 2 and R 4 When both are divalent hydrocarbon groups, R 2 and R 4 may be joined together with the adjacent carbon atoms to form a ring.

[0098] (Specific crosslinked structure) The specific crosslinked structure contains the above divalent group (1). In formula (1), R 1 ~R 4 each independently represents a single bond or a divalent hydrocarbon group. R 1 ~R 4 The number of carbon atoms in the divalent hydrocarbon group represented by the formula (I) is preferably 1 to 20, more preferably 1 to 10, even more preferably 1 to 4, and particularly preferably 1 or 2, in order to improve pressure resistance, dynamic binding capacity for the target substance, and target substance separation ability.

[0099] R 1 ~R 4 The divalent hydrocarbon group represented by may be a divalent saturated hydrocarbon group or a divalent unsaturated hydrocarbon group. Examples of the divalent hydrocarbon group include a divalent aliphatic hydrocarbon group, a divalent alicyclic hydrocarbon group, and a divalent aromatic hydrocarbon group, but in order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability, a divalent aliphatic hydrocarbon group is preferred. The divalent aliphatic hydrocarbon group may be linear or branched.

[0100] R 1 ~R 4 When the divalent hydrocarbon group represented by the formula (I) is a divalent aliphatic hydrocarbon group, in order to improve the pressure resistance, the dynamic binding capacity for the target substance, and the target substance separation ability, the number of carbon atoms is preferably 1 to 20, more preferably 1 to 10, still more preferably 1 to 4, and particularly preferably 1 or 2. Examples of the divalent aliphatic hydrocarbon group include an alkanediyl group and an alkenediyl group, and in order to improve the pressure resistance, the dynamic binding capacity for the target substance, and the target substance separation ability, the alkanediyl group is preferred. Specific examples of the alkanediyl group include a methane-1,1-diyl group, an ethane-1,1-diyl group, an ethane-1,2-diyl group, a propane-1,1-diyl group, a propane-1,2-diyl group, a propane-1,3-diyl group, a propane-2,2-diyl group, a butane-1,1-diyl group, a butane-1,2-diyl group, a butane-1,3-diyl group, a butane-1,4-diyl group, a pentane-1,4-diyl group, a pentane-1,5-diyl group, a hexane-1,2-diyl group, a hexane-1,5-diyl group, a hexane-1,6-diyl group, a heptane-1,7-diyl group, an octane-1,8-diyl group, a nonane-1,9-diyl group, a decane-1,2-diyl group, and a decane-1,10-diyl group.

[0101] R 1 ~R 4 When the divalent hydrocarbon group represented by the formula (I) is a divalent alicyclic hydrocarbon group, the number of carbon atoms therein is preferably 3 to 20, more preferably 3 to 14, still more preferably 3 to 10, and particularly preferably 3 to 8. Examples of the divalent alicyclic hydrocarbon group include cycloalkanediyl groups such as a cyclohexanediyl group, a methylcyclohexanediyl group, and a cycloheptanediyl group, as well as divalent bridged ring hydrocarbon groups such as an adamantylene group. R 1 ~R 4 When the divalent hydrocarbon group represented by the formula (I) is a divalent aromatic hydrocarbon group, the number of carbon atoms therein is preferably 6 to 18, and more preferably 6 to 12. The divalent aromatic hydrocarbon group is preferably an arylene group, and specific examples thereof include a phenylene group and a naphthylene group. The bonding site of the divalent alicyclic hydrocarbon group and the bonding site of the divalent aromatic hydrocarbon group may be on any carbon atom on the ring.

[0102] Also, R 1 and R 3 , R 2 and R 4Examples of the ring that may be formed by combining with each other include cycloalkane rings having a total of 3 to 10 carbon atoms (preferably a total of 5 to 7 carbon atoms), such as a cyclopentane ring, a cyclohexane ring, a methylcyclohexane ring, a cycloheptane ring, and a cyclooctane ring. Among these, a cyclopentane ring and a cyclohexane ring are preferred. The site to which the hydroxyl group and X in formula (1) are bonded may be any carbon on the ring.

[0103] R 1 ~R 4 The divalent hydrocarbon group represented by may or may not have a substituent. Examples of the substituent include halogen atoms such as chlorine atoms, bromine atoms, and fluorine atoms, and hydroxyl groups. The substitution position and number of the substituents are optional, and when there are two or more substituents, the substituents may be the same or different.

[0104] R 1 ~R 4 In order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability, the following combinations are used: R 1 and R 2 is a single bond, and R 3 and R 4 are each independently a divalent hydrocarbon group; R 1 is a single bond, and R 2 , R 3 and R 4 are each independently a divalent hydrocarbon group; R 2 and R 4 taken together with adjacent carbon atoms to form a ring, R 2 is a single bond, and R 1 , R 3 and R 4 are each independently a divalent hydrocarbon group; R 1 and R 3 taken together with adjacent carbon atoms to form a ring, R 1 ~R4 are each independently a divalent hydrocarbon group; R 1 and R 3 are taken together with the adjacent carbon atoms to form a ring, and R 2 and R 4 are preferably combined with adjacent carbon atoms to form a ring, R 1 and R 2 is a single bond, and R 3 and R 4 are each independently a divalent hydrocarbon group; R 1 ~R 4 are each independently a divalent hydrocarbon group; R 1 and R 3 are taken together with the adjacent carbon atoms to form a ring, and R 2 and R 4 are more preferably combined with adjacent carbon atoms to form a ring, R 1 and R 2 is a single bond, and R 3 and R 4 are each independently a divalent hydrocarbon group, R 1 and R 2 is a single bond, and R 3 and R 4 are each independently a divalent hydrocarbon group having 1 to 10 carbon atoms, R 1 and R 2 is a single bond, and R 3 and R 4 are each independently an alkanediyl group having 1 to 4 carbon atoms.

[0105] R 5 and R 6 each independently represents a hydrogen atom or a hydrocarbon group. Among these, a hydrogen atom is preferred in order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability. R5 and R 6 The hydrocarbon group represented by the formula (I) encompasses an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aromatic hydrocarbon group, and may be a saturated or unsaturated hydrocarbon group. The number of carbon atoms in the hydrocarbon group is preferably 1 to 4, more preferably 1 or 2. The hydrocarbon group is preferably an aliphatic hydrocarbon group, more preferably an alkyl group. The alkyl group may be linear or branched, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group.

[0106] X is a thio group, a sulfinyl group, a sulfonyl group, an oxy group, >N(-R 31 ), >Si(-R 32 )2,>P(-R 33 ),>P(=O)(-R 34 ), >B(-R 35 ), or >C(-R 36 Of these, a thio group, a sulfinyl group or a sulfonyl group is preferred, and a thio group is particularly preferred. R 31 ~R 36 R each independently represents a hydrogen atom or a hydrocarbon group. 31 ~R 36 The hydrocarbon group represented by R 5 Examples of the hydrocarbon group include those similar to those represented by the following formula:

[0107] Furthermore, the specific crosslinked structure is not particularly limited as long as it contains the above-mentioned divalent group (1), and may be a divalent crosslinked structure or a trivalent or higher crosslinked structure. In order to improve the pressure resistance performance, the dynamic binding capacity for the target substance, and the target substance separation ability, a divalent to hexavalent crosslinked structure is preferred, a divalent to trivalent crosslinked structure is more preferred, and a divalent crosslinked structure is particularly preferred. In addition, the number of divalent groups represented by formula (1) in one specific crosslinked structure is preferably 1 to 9, more preferably 1 to 5, and particularly preferably 2 or 3, in order to improve pressure resistance, dynamic binding capacity for a target substance, and target substance separation ability. In addition, in order to improve the pressure resistance performance, the dynamic binding capacity for the target substance, and the target substance separation ability, the total carbon number of the specific crosslinked structure is preferably 2 or more, more preferably 3 or more, even more preferably 4 or more, even more preferably 5 or more, and particularly preferably 6 or more, and is preferably 60 or less, more preferably 40 or less, even more preferably 30 or less, even more preferably 20 or less, and particularly preferably 18 or less.

[0108] A specific preferred example of the specific crosslinked structure is a crosslinked structure represented by the following formula (2).

[0109] [ka]

[0110] [In formula (2), Y 1 , Y 2 and Y 3 each independently represents a single bond or a divalent linking group, n represents an integer of 0 or greater. The other symbols are as defined above.]

[0111] In formula (2), n represents an integer of 0 or more. In order to improve pressure resistance, dynamic binding capacity for the target substance, and target substance separation ability, n is preferably an integer of 0 to 8, more preferably an integer of 0 to 4, and particularly preferably 1 or 2. When n is an integer of 2 or more, n Y 2 may be the same or different. When n is an integer of 1 or more, the n+1 X's in formula (2) may be the same or different. 1 ~R 6 The same applies to.

[0112] In formula (2), Y 1 ~Y 3 Examples of the divalent linking group represented by the formula (I) include an alkanediyl group, an alkanediyl group having two or more carbon atoms and an ether bond between the carbon atoms, a thio group, a sulfinyl group or a sulfonyl group, an arylene group, -C(=O)OR 7-**, -C(=O)NH-R 8 -**, -Ar-R 9 -** or -Ar-OR 10 -** etc. Here, Ar represents an arylene group. 1 , Y 3 The ** in may be a bond bonded to the carbon atom in formula (2) or a bond at the other end, but is preferably a bond bonded to the carbon atom in formula (2). 2 The ** in the figure indicates R in formula (2). 2 Y may be bonded to either of the carbon atoms adjacent to 1 ~Y 3 Examples of the arylene group represented by Ar include a phenylene group, a naphthylene group, and a phenanthrenylene group. Also, R 7 ~R 10 each independently represents an alkanediyl group, or an alkanediyl group having 2 or more carbon atoms which has an ether bond, a thio group, a sulfinyl group or a sulfonyl group between carbon atoms.

[0113] Y 1 ~Y 3 , R 7 ~R 10The number of carbon atoms of the alkanediyl group represented by the formula (I) is preferably 1 to 12, more preferably 1 to 6, and particularly preferably 1 to 3. The alkanediyl group may be linear or branched. Specific examples of the alkanediyl group include a methane-1,1-diyl group, an ethane-1,1-diyl group, an ethane-1,2-diyl group, a propane-1,1-diyl group, a propane-1,2-diyl group, a propane-1,3-diyl group, a propane-2,2-diyl group, a butane-1,1-diyl group, a butane-1,2-diyl group, a butane-1,3-diyl group, a butane-1,4-diyl group, and a pentane-1,1-diyl group. group, pentane-1,2-diyl group, pentane-1,3-diyl group, pentane-1,4-diyl group, pentane-1,5-diyl group, hexane-1,1-diyl group, hexane-1,2-diyl group, hexane-1,3-diyl group, hexane-1,4-diyl group, hexane-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group, and octane-1,8-diyl group.

[0114] Y 1 ~Y 3 , R 7 ~R 10 The "group having an ether bond, a thio group, a sulfinyl group or a sulfonyl group between carbon atoms of an alkanediyl group having two or more carbon atoms" represented by the formula: a (X a R b ) t X b R c A group represented by the formula - (R a , R b and R c each independently represents an alkanediyl group having 1 to 4 carbon atoms; a and X b each independently represents an ether bond, a thio group, a sulfinyl group or a sulfonyl group, and t represents an integer of 0 to 30. R a , R b and R cThe alkanediyl group represented by the formula may be linear or branched. Specific examples include methane-1,1-diyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl. t is preferably an integer of 0 to 20, more preferably an integer of 0 to 10, even more preferably an integer of 0 to 5, and particularly preferably 0. When t is an integer of 2 to 30, t R b may be the same or different. X a The same applies to. Preferable specific examples of the alkanediyl group having 2 or more carbon atoms and having an ether bond, a thio group, a sulfinyl group or a sulfonyl group between the carbon atoms include -R a X b R c - is an example of a group represented by the formula: In addition, Y 1 ~Y 3 , R 7 ~R 10 and an alkanediyl group having 2 or more carbon atoms and having an ether bond, a thio group, a sulfinyl group, or a sulfonyl group between the carbon atoms thereof may or may not have a substituent. Examples of the substituent include a hydroxyl group.

[0115] Y 1 , Y 3 is a divalent linking group, the divalent linking group is -C(=O)OR 7 -** is particularly preferred. Also, Y 2 In order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability, the alkyl group is preferably a single bond, or a group having an ether bond, a thio group, a sulfinyl group, or a sulfonyl group between the carbon-carbon atom of an alkanediyl group having two or more carbon atoms, more preferably a single bond, or a group having a thio group, a sulfinyl group, or a sulfonyl group between the carbon-carbon atom of an alkanediyl group having two or more carbon atoms, and particularly preferably a single bond.

[0116] The content of the specific crosslinked structure is preferably 0.1 to 90 mass%, more preferably 1 to 60 mass%, and particularly preferably 3 to 50 mass%, based on the total mass of the polymer in order to improve pressure resistance, dynamic binding capacity for the target substance, and target substance separation ability. The content of each structure in the polymer can be measured by elemental analysis, pyrolysis gas chromatography, or the like.

[0117] (polymer) The polymer contained in the carrier of the present invention is not particularly limited as long as it has a specific crosslinked structure in the molecule, and may be a synthetic polymer or a natural polymer, but is preferably a synthetic polymer. In addition, the polymer is preferably a water-insoluble polymer. Examples of synthetic polymers include polymers having one or more selected from structural units derived from (meth)acrylate monomers, structural units derived from (meth)acrylamide monomers, structural units derived from (meth)acrylonitrile monomers, structural units derived from aromatic vinyl monomers, structural units derived from vinyl ether monomers, structural units derived from vinyl ketone monomers, structural units derived from N-vinylamide monomers, structural units derived from vinyl alkylene oxide monomers, structural units derived from alkylene oxide monomers having triple bonds, structural units derived from allyl monomers, structural units derived from unsaturated dicarboxylic anhydride monomers, structural units derived from epoxy monomers, and structural units derived from unsaturated polyalkylene glycol ether monomers. Examples of natural polymers include those composed of polysaccharides such as agarose, cellulose (such as crystalline cellulose), and dextran. The content of the polymer in the carrier of the present invention is preferably 80 to 100% by mass, more preferably 90 to 100% by mass, and particularly preferably 99 to 100% by mass.

[0118] Furthermore, the polymer contained in the carrier of the present invention may have a reactive functional group σ in the molecule in addition to the specific crosslinked structure. The reactive functional group σ is preferably one that can react with a sulfanyl group or a thiocarboxylate, or one that can react with an antibody. For example, one or more functional groups selected from the group consisting of a cyclic ether group, a carboxy group, -C(=O)-OC(=O)-, an N-succinimidyl group, a formyl group, an isocyanate group, a maleimide group, and a haloacetyl group (such as an iodoacetyl group or a bromoacetyl group) can be mentioned. Among them, in order to improve the pressure resistance performance, the dynamic binding capacity for the target substance, and the target substance separation ability, a cyclic ether group or an N-succinimidyl group is preferred, and a cyclic ether group is particularly preferred. The "cyclic ether group" is the same as the "cyclic ether group" contained in the cyclic ether group-containing compound used in the method for producing an organic sulfur compound of the present invention. As the cyclic ether group, a cyclic ether group represented by formula (3) is preferred in order to improve the reaction efficiency.

[0119] The molar ratio [(b) / (a)] of the content (b) of reactive functional groups σ in the polymer to the content (a) of specific crosslinked structures in the polymer is preferably 0 to 10, more preferably 0 to 1, and particularly preferably 0 to 0.1, in order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability.

[0120] Furthermore, the polymer contained in the carrier of the present invention preferably has two or more divalent groups formed by ring-opening of the above-mentioned cyclic ether group, and these groups preferably constitute part of the specific cross-linked structure, and more preferably constitute both ends of the specific cross-linked structure.

[0121] In addition to the above, the polymer contained in the carrier of the present invention may have a monovalent group containing one or more selected from the group consisting of an ether bond, a thio group, a sulfinyl group, a sulfonyl group, a hydroxyl group, and a sulfanyl group in the molecule. As such a monovalent group, a group represented by the following formula (9), a monovalent group containing a sulfanyl group, and a hydroxyl group are preferred, and a group represented by the formula (9) and a monovalent group containing a sulfanyl group are more preferred. Examples of the monovalent group containing a sulfanyl group include a sulfanyl group and a group represented by the following formula (30). When such a monovalent group containing a sulfanyl group is present in a molecule, it is possible to fix a ligand such as an antibody by chemical bonding. When an antibody is fixed in this way, it is useful for detecting or diagnosing a target substance that binds to the antibody. The fixation of a ligand such as an antibody can be performed by a simple method such as reacting a crosslinker (e.g., N-succinimidyl 4-maleimidobutyrate, etc.) having a reactive functional group that reacts with a sulfanyl group and a reactive functional group that reacts with a ligand such as an antibody.

[0122] [ka]

[0123] [In formula (9), R 15 represents a q+1 valent hydrocarbon group, Y 4 represents an ether bond, a thio group, a sulfinyl group or a sulfonyl group, Y 5 represents a hydrophilic group, q represents an integer of 0 or more, * indicates a bond.

[0124] [ka]

[0125] (In formula (30), * represents a bond, and other symbols are as defined above.)

[0126] In formula (9), R 15 represents a q+1 valent hydrocarbon group. That is, when q=0, R 15 is a monovalent hydrocarbon group, and when q=1, R 15 is a divalent hydrocarbon group, and when q=2, R 15 is a trivalent hydrocarbon group. R 15 The monovalent hydrocarbon group represented by R5 The hydrocarbon groups represented by R 15 The divalent hydrocarbon group represented by R 1 The divalent hydrocarbon group represented by R 15 The number of carbon atoms in the trivalent hydrocarbon group represented by the formula (I) is preferably 1 to 12, and more preferably 1 to 6. As the trivalent hydrocarbon group, an alkanetriyl group such as a methane-1,1,1-triyl group, an ethane-1,1,1-triyl group, an ethane-1,1,2-triyl group, a propane-1,2,3-triyl group, or a propane-1,2,2-triyl group is preferable.

[0127] In formula (9), Y 4 represents an ether bond, a thio group, a sulfinyl group or a sulfonyl group, with an ether bond or a thio group being preferred. Y 5 Examples of the hydrophilic group represented by the formula (I) include a hydroxy group, a sulfanyl group, a carboxy group, an amino group, and a group that forms an organic ammonium salt, with a hydroxy group being preferred. q represents an integer of 0 or more, preferably an integer of 0 to 4, and more preferably an integer of 0 to 2. When q is an integer of 2 or more, q Y 5 may be the same or different.

[0128] The molar ratio [(c) / (a)] of the content (c) of monovalent groups containing one or more selected from the group consisting of ether bonds, thio groups, sulfinyl groups, sulfonyl groups, hydroxy groups and sulfanyl groups in the polymer to the content (a) of the specific crosslinked structure in the polymer is preferably 0 to 16, and more preferably 0.1 to 4, in order to improve the pressure resistance performance, the dynamic binding capacity for the target substance, and the target substance separation ability.

[0129] In addition, the polymer contained in the carrier of the present invention includes those in which the structural units contained in the polymer are crosslinked with a specific crosslinking structure, and those in which the structural units contained in the polymer are crosslinked with a specific crosslinking structure. In order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability, it is preferable that the structural units contained in the polymer are crosslinked with a specific crosslinking structure, and it is more preferable that the side chains of the structural units contained in the polymer are crosslinked with a specific crosslinking structure. In addition, the polymer contained in the carrier of the present invention may have a structural unit (B) having a reactive functional group σ, or a structural unit (C) having a monovalent group containing one or more selected from the group consisting of an ether bond, a thio group, a sulfinyl group, a sulfonyl group, a hydroxyl group, and a sulfanyl group, in addition to the structural unit (A) crosslinked with a specific crosslinking structure.

[0130] The structural unit (A) is preferably a structural unit represented by the following formula (10), the structural unit (B) is preferably a structural unit represented by the following formula (11), and the structural unit (C) is preferably a structural unit represented by the following formula (12).

[0131] [ka]

[0132] [In formula (10), R 16 represents a hydrogen atom or a methyl group, R 17 represents a single bond or a divalent linking group, ** indicates a bond that bonds to the specific cross-linked structure, and means that the polymer is cross-linked via the specific cross-linked structure.

[0133] [ka]

[0134] [In formula (11), R 18 represents a hydrogen atom or a methyl group, R 19represents a single bond or a divalent linking group, Z 1 represents a reactive functional group σ.

[0135] [ka]

[0136] [In formula (12), R 20 represents a hydrogen atom or a methyl group, R 21 represents a single bond or a divalent linking group, Z 2 represents the residue of a reactive functional group σ, Z 3 represents a monovalent group containing one or more groups selected from the group consisting of an ether bond, a thio group, a sulfinyl group, a sulfonyl group, a hydroxy group, and a sulfanyl group.

[0137] R in Equation (10) 17 , R in Equation (11) 19 , R in Eq. (12) 21 is a divalent linking group represented by Y in formula (2). 1 In addition, when two structural units represented by formula (10) are crosslinked by a crosslinked structure represented by formula (2), Y in formula (2) is preferably the same as the divalent linking group represented by formula (10). 1 , Y 3 is a single bond, and R in formula (10) 17 is a divalent linking group, or Y 1 , Y 3 is a divalent linking group, and R in formula (10) 17 is preferably a single bond.

[0138] Z 1 , Z 2 The "reactive functional group σ" in is the same as the reactive functional group σ described above, and Z 3The monovalent group containing one or more selected from the group consisting of an ether bond, a thio group, a sulfinyl group, a sulfonyl group, a hydroxy group, and a sulfanyl group, as shown in the formula (I), is the same as the monovalent group containing one or more selected from the group consisting of an ether bond, a thio group, a sulfinyl group, a sulfonyl group, a hydroxy group, and a sulfanyl group. Specific examples of the residue of the reactive functional group σ include divalent groups formed by opening a cyclic ether group, -C(=O)-, -NH-C(=O)-, and divalent groups formed by opening a cyclic ether group are preferred. When the cyclic ether group is an epoxy group, the divalent group formed by opening a cyclic ether group is a ring-opened epoxy group as shown in the formula (I).

[0139] As the monomer that gives the structural units (A) to (C), a monomer having a reactive functional group σ in the molecule is preferable, and a monomer having a cyclic ether group in the molecule is more preferable. In addition, this monomer may be a non-crosslinkable monomer or a crosslinkable monomer, and may further have a polymerizable functional group other than the reactive functional group σ. An example of the "polymerizable functional group other than the reactive functional group σ" is a polymerizable unsaturated group. The number of reactive functional groups σ in one monomer molecule is preferably 1 to 20, more preferably 1 to 6, still more preferably 1 to 4, and particularly preferably 1 to 2. The number of polymerizable functional groups other than the reactive functional group σ in one monomer molecule is preferably 1 to 10, more preferably 1 to 6, still more preferably 1 to 2, and particularly preferably 1. Examples of monomers that provide the structural units (A) to (C) include a monomer having one each of a cyclic ether group and a polymerizable functional group other than the reactive functional group σ in the molecule, a monomer having two cyclic ether groups in the molecule but no polymerizable functional group other than the reactive functional group σ, a monomer having two cyclic ether groups and one polymerizable functional group other than the reactive functional group σ in the molecule, a monomer having two cyclic ether groups and two polymerizable functional groups other than the reactive functional group σ in the molecule, a monomer having three cyclic ether groups in the molecule but no polymerizable functional group other than the reactive functional group σ, and a monomer having four cyclic ether groups in the molecule but no polymerizable functional group other than the reactive functional group σ. In addition, (meth)acrylate-based monomers having an isocyanate group such as isocyanatoethyl (meth)acrylate; unsaturated dicarboxylic acid anhydride-based monomers such as maleic anhydride, methylmaleic anhydride, and glutaconic anhydride, as well as (meth)acrylic acid, etc. may be used. These monomers can be used alone or in combination of two or more. Among these monomers, a monomer having one cyclic ether group and one polymerizable functional group other than the reactive functional group σ in the molecule is preferred in order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability.

[0140] Examples of the monomer having one each of a cyclic ether group and one each of a polymerizable functional group other than the reactive functional group σ in the molecule include the same as those exemplified as the "low molecular weight compound having one each of a cyclic ether group and one other polymerizable functional group in the molecule" that can be used in the production method of the organic sulfur compound of the present invention, and one type may be used alone in the reaction, or two or more types may be used in combination in the reaction.

[0141] Examples of the monomer having two cyclic ether groups in the molecule but having no polymerizable functional groups other than the reactive functional group σ include the same as those exemplified as the "low molecular weight compound having two cyclic ether groups in the molecule but having no other polymerizable functional groups" that can be used in the production method for the organic sulfur compound of the present invention, and one type may be used alone in the reaction, or two or more types may be used in combination in the reaction.

[0142] An example of a monomer having two cyclic ether groups and one polymerizable functional group other than the reactive functional group σ in the molecule is diglycidyl 4-cyclohexene-1,2-dicarboxylate.

[0143] An example of a monomer having two cyclic ether groups and two polymerizable functional groups other than the reactive functional group σ in the molecule is diglycidyl bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate.

[0144] Examples of monomers having three cyclic ether groups in the molecule but no polymerizable functional group other than the reactive functional group σ include triglycidyl ethers such as trimethylolpropane triglycidyl ether and glycerol triglycidyl ether (preferably triglycidyl ethers having a total of 10 to 80 carbon atoms), as well as triglycidyl isocyanurate, triglycidyl cyanurate, and triglycidyl 1,2,4-benzenetricarboxylate. One of these may be used alone in the reaction, or two or more of them may be used in combination in the reaction.

[0145] Examples of monomers having four cyclic ether groups in the molecule but no polymerizable functional group other than the reactive functional group σ include tetraglycidyl ethers (preferably tetraglycidyl ethers having a total of 13 to 80 carbon atoms) such as methanetetrayltetrakis(glycidyl ether), sorbitol tetraglycidyl ether, and pentaerythritol tetraglycidyl ether, and among these, one kind may be used alone in the reaction, or two or more kinds may be used in combination in the reaction.

[0146] The total content of the structural units (A) to (C) in the polymer is preferably 0 to 100,000 parts by mass, more preferably 10 to 50,000 parts by mass, and particularly preferably 100 to 10,000 parts by mass, based on 100 parts by mass of the specific crosslinked structure.

[0147] In addition, the polymer contained in the carrier of the present invention may have a structural unit other than the specific crosslinked structure and the structural units (A) to (C). Examples of monomers that provide such structural units (hereinafter also referred to as other monomers MO2) include polymerizable unsaturated group-containing monomers that do not have a reactive functional group σ. The other monomers MO2 are roughly classified into non-crosslinkable monomers and crosslinkable monomers, and either one of them may be used or they may be used in combination.

[0148] Examples of the non-crosslinkable monomer include (meth)acrylate-based non-crosslinkable monomers, (meth)acrylamide-based non-crosslinkable monomers, aromatic vinyl-based non-crosslinkable monomers, vinyl ketone-based non-crosslinkable monomers, (meth)acrylonitrile-based non-crosslinkable monomers, and N-vinyl amide-based non-crosslinkable monomers. These can be used alone or in combination of two or more. Among the non-crosslinkable monomers, (meth)acrylate-based non-crosslinkable monomers and aromatic vinyl-based non-crosslinkable monomers are preferred.

[0149] Examples of the (meth)acrylate-based non-crosslinking monomer, (meth)acrylamide-based non-crosslinking monomer, aromatic vinyl-based non-crosslinking monomer, vinyl ketone-based non-crosslinking monomer, (meth)acrylonitrile-based non-crosslinking monomer, and N-vinyl amide-based non-crosslinking monomer include the same as those exemplified as the (meth)acrylate-based non-crosslinking monomer, (meth)acrylamide-based non-crosslinking monomer, aromatic vinyl-based non-crosslinking monomer, vinyl ketone-based non-crosslinking monomer, (meth)acrylonitrile-based non-crosslinking monomer, and N-vinyl amide-based non-crosslinking monomer in "Other monomers MO1".

[0150] The content of the structural unit provided by the non-crosslinkable monomer in the polymer is preferably 1 to 500 parts by mass, and more preferably 1 to 100 parts by mass, based on 100 parts by mass of the specific crosslinked structure.

[0151] Examples of the crosslinkable monomer include (meth)acrylate crosslinkable monomers, aromatic vinyl crosslinkable monomers, and allyl crosslinkable monomers. These may be used alone or in combination of two or more. As the crosslinkable monomer, di- to penta-functional crosslinkable monomers are preferred, and di- or tri-functional crosslinkable monomers are more preferred. Among the crosslinkable monomers, (meth)acrylate crosslinkable monomers and aromatic vinyl crosslinkable monomers are preferred.

[0152] The above (meth)acrylate crosslinking monomers, aromatic vinyl crosslinking monomers, and allyl crosslinking monomers include the same ones as those exemplified as the (meth)acrylate crosslinking monomers, aromatic vinyl crosslinking monomers, and allyl crosslinking monomers in "other monomers MO1". In addition to the above-exemplified crosslinking monomers, examples of the crosslinking monomers include dehydration condensation products of amino alcohols such as diaminopropanol, trishydroxymethylaminomethane, and glucosamine with (meth)acrylic acid, and conjugated diolefins such as butadiene and isoprene.

[0153] The content of the structural unit provided by the crosslinkable monomer in the polymer is preferably 1 to 1,000 parts by mass, and more preferably 10 to 500 parts by mass, based on 100 parts by mass of the specific crosslinked structure.

[0154] The carrier of the present invention may be in any form that can be used as a solid phase carrier. Examples of such forms include particles, monoliths, plates, membranes (including hollow fibers), fibers, cassettes, chips, etc., and the particles are preferred. The particulate carrier may be magnetic particles that have been given magnetism or latex particles with a small particle size. The carrier of the present invention is preferably a porous carrier such as porous particles, and the porous particles are preferably porous polymer particles.

[0155] When the carrier of the present invention is a particulate carrier, the average particle size (volume average particle size) is preferably 0.01 to 150 μm, more preferably 20 to 100 μm, and the coefficient of variation of the average particle size is preferably 40% or less, more preferably 30% or less. The specific surface area of ​​the carrier of the present invention is preferably 1 to 500 m 2 / g, more preferably 10 to 300m 2 / g. The volume average pore diameter of the support of the present invention is preferably 10 to 300 nm. The average particle size, coefficient of variation, specific surface area and volume average pore size can be measured by laser diffraction / scattering particle size distribution measurement or the like.

[0156] (Ligand) The carrier of the present invention can be used with or without immobilizing a ligand other than the specific cross-linked structure, but even if no ligand other than the specific cross-linked structure (such as a protein ligand or a peptide ligand) is immobilized, it has a large dynamic binding capacity for the target substance and has high performance in separating the target substance from a biological sample.

[0157] When the ligand is immobilized for use (i.e., when the ligand is used as the ligand-immobilized carrier of the present invention), the ligand other than the specific crosslinked structure may be any molecule that binds to a target substance, and examples of such ligands include proteins such as protein A, protein G, and avidin; peptides such as insulin; nucleic acids such as DNA and RNA; enzymes; chelating compounds such as iminodiacetic acid; antibodies; antigens; hormones; carbohydrates such as heparin, Lewis X, and gangliosides; receptors; aptamers; vitamins such as biotin and its derivatives; metal ions; synthetic dyes; and low molecular weight compounds such as 2-aminophenylboronic acid, 4-aminobenzamidine, and glutathione. The ligands exemplified above may be used in their entirety, or fragments thereof obtained by recombinant or enzyme treatment may be used. Artificially synthesized peptides and peptide derivatives may also be used. When used in immunoassays (immunoassay methods) such as CLIA and CLEIA, the ligand is preferably an antibody. On the other hand, when an antibody is used as a target substance, an antibody affinity ligand is usually used, and the antibody affinity ligand is preferably an immunoglobulin-binding protein. Examples of antibody affinity ligands include peptide ligands, protein ligands, and chemically synthesized ligands (synthetic compounds). More specifically, examples include protein A, protein G, protein L, protein H, protein D, protein Arp, protein FcγR, antibody-binding synthetic peptide ligands, and related substances thereof.

[0158] The immobilized amount of the ligand other than the specific crosslinked structure is preferably 0 to 300 mg, more preferably 0 to 150 mg, even more preferably 0 to 75 mg, still more preferably 0 to 25 mg, and particularly preferably 0 to 10 mg per gram of dry weight of the carrier. Even in the case of such a low immobilized amount, the carrier of the present invention has a large dynamic binding capacity for the target substance and has a high performance in separating the target substance from a biological sample. The amount of immobilized ligands other than the specific cross-linked structure may be measured by the BCA method, Bradford method, Lowry method, or the like.

[0159] The immobilization of the ligand to the carrier may be performed according to a conventional method such as a covalent bond method, an ionic bond method, a physical adsorption method, or an embedding method. Specifically, a method of binding the ligand to a functional group capable of immobilizing the ligand may be mentioned. This method may be performed with reference to the descriptions in WO 2015 / 119255, WO 2015 / 041218, etc. More specifically, a method of binding a cyclic ether group, a carboxy group, -C(=O)-OC(=O)-, a formyl group, etc. of the carrier to an amino group, etc. of the ligand may be mentioned. In addition, when the polymer of the carrier has a monovalent group containing a sulfanyl group in the molecule, the ligand may be immobilized using a crosslinker having a reactive functional group that reacts with a sulfanyl group and a reactive functional group that reacts with the ligand, such as 4-maleimidobutyric acid N-succinimidyl. Furthermore, the ligand may be immobilized using a method of controlling the orientation of the ligand (U.S. Pat. No. 6,399,750; Ljungquist C. et al., rEur. J. Biochem., 1989, Vol. 186, pp. 557-561), a method of immobilizing the ligand on the carrier via a linker (spacer) (U.S. Pat. No. 5,260,373; JP-A Nos. 2010-133733 and 2010-133734), or a method of accumulating the ligand on the carrier using an associative group (JP-A No. 2011-256176).

[0160] <Method of manufacturing the carrier> The carrier of the present invention can be produced by appropriately combining conventional methods, but the following carrier production method PR2-1 and carrier production method PR2-2 are preferred as carrier production methods in order to obtain the desired carrier safely, efficiently, and with a simple operation. Among carrier production method PR2-1 and carrier production method PR2-2, carrier production method PR2-1 is preferred in order to obtain the desired carrier safely, efficiently, and with a simple operation. [Carrier Production Method PR2-1] A production method comprising the step of reacting a polymer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by the following formula (α) in the molecule: [Support Production Method PR2-2] A production method including the following steps B-1 and B-2. (Step B-1) A step of reacting a monomer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by the following formula (α) in the molecule: (Step B-2) A step of preparing a carrier using the crosslinkable monomer obtained in step B-1

[0161] [ka]

[0162] [In formula (α), R 2 , R 4 , R 6 and * are as defined above.

[0163] -Carrier manufacturing method PR2-1- Here, the carrier production method PR2-1 of the present invention will be described in detail. (Polymer having a cyclic ether group in the molecule) The polymer having a cyclic ether group in the molecule used in the carrier production method PR2-1 may be a commercially available product or may be prepared by referring to a known method. Such a polymer may be obtained, for example, by (co)polymerizing a monomer having a cyclic ether group in the molecule. The (co)polymerization method is preferably suspension polymerization. Examples of the monomer having a cyclic ether group in the molecule include the same monomers having a cyclic ether group in the molecule as exemplified as the monomers that give the structural units (A) to (C). In addition, the monomer having a cyclic ether group in the molecule may be copolymerized with the other monomer MO2 (non-crosslinkable monomer, crosslinkable monomer). The total amount of monomers having a cyclic ether group in the molecule is preferably 1 to 99 parts by mass, more preferably 20 to 95 parts by mass, and particularly preferably 40 to 90 parts by mass, per 100 parts by mass of the total amount of monomers, in order to improve pressure resistance, dynamic binding capacity for target substances, and target substance separation ability. The total amount of the non-crosslinkable monomers is preferably 0 to 50 parts by mass, more preferably 0.1 to 25 parts by mass, relative to 100 parts by mass of the total monomers, in order to improve pressure resistance, dynamic binding capacity for the target substance, and target substance separation ability. The total amount of the crosslinkable monomers is preferably 1 to 70 parts by mass, more preferably 3 to 60 parts by mass, relative to 100 parts by mass of the total monomers, in order to improve pressure resistance, dynamic binding capacity for the target substance, and target substance separation ability.

[0164] Specific examples of the (co)polymerization method include a method in which a polymerization initiator is dissolved in a mixed solution (monomer solution) containing a monomer and, if necessary, a porosifier, and the solution is suspended in an aqueous medium and heated to a predetermined temperature to polymerize; a method in which a polymerization initiator is dissolved in a mixed solution (monomer solution) containing a monomer and, if necessary, a porosifier, and the solution is added to an aqueous medium heated to a predetermined temperature to polymerize; and a method in which a mixed solution (monomer solution) containing a monomer and, if necessary, a porosifier is suspended in an aqueous medium and heated to a predetermined temperature, a polymerization initiator is added, and the like.

[0165] The polymerization initiator is preferably a radical polymerization initiator. Examples of the radical polymerization initiator include azo initiators, peroxide initiators, and redox initiators, and specifically include azobisisobutyronitrile, methyl azobisisobutyrate, azobis-2,4-dimethylvaleronitrile, benzoyl peroxide, di-tert-butyl peroxide, and benzoyl peroxide-dimethylaniline. The total amount of the polymerization initiator used is usually about 0.01 to 10 parts by mass relative to 100 parts by mass of the total amount of monomers.

[0166] The porosity-inducing agent is used to produce porous particles, and in the polymerization in the oil droplets, it exists together with the monomer and plays a role of forming holes as a non-polymerized component. The porosity-inducing agent is not particularly limited as long as it is easily removable from the porous surface, and examples thereof include linear polymers that are soluble in various organic solvents and mixed monomers, and these may be used in combination.

[0167] Examples of the porosifying agent include aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, and undecane; alicyclic hydrocarbons such as cyclopentane and cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene, naphthalene, and ethylbenzene; halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane, and chlorobenzene; aliphatic alcohols such as butanol, pentanol, hexanol, heptanol, 4-methyl-2-pentanol, and 2-ethyl-1-hexanol; Examples of the porosifier include alicyclic alcohols such as cyclohexanol, aromatic alcohols such as 2-phenylethyl alcohol and benzyl alcohol, ketones such as diethyl ketone, methyl isobutyl ketone, diisobutyl ketone, acetophenone, 2-octanone and cyclohexanone, ethers such as dibutyl ether, diisobutyl ether, anisole and ethoxybenzene, esters such as isopentyl acetate, butyl acetate, 3-methoxybutyl acetate and diethyl malonate, and linear polymers such as homopolymers of non-crosslinkable vinyl monomers. The porosifier can be used alone or in combination of two or more kinds. The total amount of the porosifying agents used is usually about 40 to 600 parts by mass per 100 parts by mass of the total amount of monomers.

[0168] The aqueous medium may, for example, be an aqueous solution of a water-soluble polymer, and examples of the water-soluble polymer include hydroxyethyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, polyvinylpyrrolidone, starch, and gelatin. The total amount of the aqueous medium used is usually about 200 to 7,000 parts by mass per 100 parts by mass of the total amount of the monomers. When water is used as the dispersion medium of the aqueous medium, a dispersion stabilizer such as sodium carbonate, calcium carbonate, sodium sulfate, calcium phosphate, or sodium chloride may be used.

[0169] In addition, in the (co)polymerization, various surfactants including anionic surfactants such as alkyl sulfate salts, alkylaryl sulfate salts, alkyl phosphate salts, and fatty acid salts may be used. In addition, polymerization inhibitors such as nitrites such as sodium nitrite, iodide salts such as potassium iodide, tert-butylpyrocatechol, benzoquinone, picric acid, hydroquinone, copper chloride, and ferric chloride may be used. In addition, a polymerization regulator such as dodecyl mercaptan may be used.

[0170] The polymerization temperature may be determined depending on the type of polymerization initiator, but is usually about 2 to 100° C., and when azobisisobutyronitrile is used as the polymerization initiator, the temperature is preferably 50 to 100° C., more preferably 60 to 90° C. The polymerization time is usually 5 minutes to 48 hours, and preferably 10 minutes to 24 hours.

[0171] (Sulfanyl compounds) As the sulfanyl compound having two or more groups represented by formula (α) in the molecule, those having two groups represented by formula (α) in the molecule are preferable. 2 may be the same or different. 4 , R 6 The same applies to. Such a sulfanyl compound is preferably one represented by the following formula (14).

[0172] [ka]

[0173] (The symbols in formula (14) are as defined above.)

[0174] Examples of the sulfanyl compound include dithiothreitol, dithioerythritol, 1,2-dimercapto-1,2-ethanediol, 2,3-dimercapto-1,4-butanediol, 1,4-dimercaptobutane-2,3-diol, 3,3'-thiobis(1-mercaptopropan-2-ol), etc. One kind may be used alone in the reaction, or two or more kinds may be used in combination in the reaction. The sulfanyl compound to be used may be a commercially available product or one prepared by referring to a known method.

[0175] (Thiocarboxylate) Examples of the salt of thiocarboxylic acid include alkali metal salts such as sodium salt, potassium salt, lithium salt, etc.; salts with Group 2 elements such as calcium salt, magnesium salt, etc.; ammonium salt, pyridinium salt, imidazolium salt, morpholinium salt, piperidinium salt, pyrrolidinium salt, phosphonium salt, sulfonium salt, etc. Among these, alkali metal salts are preferred in order to efficiently obtain the desired support.

[0176] As the thiocarboxylate, in order to efficiently obtain the desired carrier, one represented by the following formula (13) is preferred.

[0177] [ka]

[0178] [R in formula (13)] 22 and M has the same meaning as above.]

[0179] Specific examples of thiocarboxylates include thioformates, thioacetates, propanethioates, butanethioates, pentanethioates, hexanethioates, octanethioates, nonanethioates, decanethioates, dodecanethioates, thiobenzoates, etc. Among these, in order to efficiently obtain the desired support, thioacetates are preferred, and alkali metal salts of thioacetic acid are particularly preferred. The thiocarboxylate may be used alone or in combination of two or more kinds in the reaction. The thiocarboxylate may be a commercially available product or may be prepared by referring to a known method.

[0180] The total amount of the compound selected from the thiocarboxylate and the sulfanyl compound having two or more groups represented by formula (α) in the molecule is preferably 0.01 mol or more, more preferably 0.05 mol or more, more preferably 0.1 mol or more, more preferably 0.25 mol or more, particularly preferably 0.5 mol or more, relative to 1 mol of the cyclic ether group in order to efficiently obtain the desired carrier, and is preferably 5 mol or less, more preferably 2.5 mol or less, more preferably 1 mol or less, particularly preferably 0.75 mol or less, relative to 1 mol of the cyclic ether group in order to efficiently obtain the desired carrier. When the total amount of the compound selected from the thiocarboxylate and the sulfanyl compound having two or more groups represented by formula (α) in the molecule is 0.75 mol or less relative to 1 mol of the cyclic ether group, the desired carrier can be obtained particularly efficiently.

[0181] (Crosslinking reaction) Here, the carrier production method PR2-1 of the present invention is to react a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by formula (α) in the molecule with a polymer having a cyclic ether group in the molecule (hereinafter, this reaction is also simply referred to as a "crosslinking reaction").By this crosslinking reaction, a carrier in which X in formula (1) is a thio group can be obtained. Furthermore, as exemplified by the following reaction formula, when a thiocarboxylate is used, two cyclic ether groups contained in the polymer are opened and a thio group is introduced between them.

[0182] [ka]

[0183] (The symbols in the formula are as defined above.)

[0184] On the other hand, as exemplified in the following reaction formula, when a sulfanyl compound having two or more groups represented by formula (α) in the molecule is used, the sulfanyl compound acts as a crosslinking agent, and two cyclic ether groups contained in the polymer are opened, and a residue of the sulfanyl compound is introduced between them.

[0185] [ka]

[0186] [Each symbol in the formula has the same meaning as above. Note that, in one crosslinked structure of the support obtained by the above reaction formula, a divalent group represented by formula (1) (wherein R 1 = single bond, R 3 =-CH2-, R 5 = hydrogen atom, X = thio group).

[0187] The above crosslinking reaction can be carried out in the presence or absence of a solvent, but is preferably carried out in the presence of a solvent in order to efficiently obtain the desired carrier. Examples of the solvent include the same solvents as those usable in the "thio group introduction reaction" in the method for producing an organosulfur compound of the present invention. The amount of the solvent used is usually 0 to 10,000 parts by mass, and preferably 10 to 2,000 parts by mass, based on 100 parts by mass of the polymer having a cyclic ether group in the molecule.

[0188] The reaction temperature for the crosslinking reaction is usually 0 to 120°C, and preferably 20 to 80°C. The reaction time for the crosslinking reaction is usually 0.01 to 24 hours, preferably 0.5 to 8 hours. The reaction pressure for the crosslinking reaction is not particularly limited, and the reaction can be carried out at normal pressure.

[0189] In addition, when a sulfanyl compound having two or more groups represented by formula (α) in the molecule is used, the crosslinking reaction may be carried out in the presence of a basic catalyst. Examples of the basic catalyst include triethylamine, N,N-dimethyl-4-aminopyridine, and diisopropylethylamine, and one type may be used alone or two or more types may be used in combination.

[0190] In addition, when a thiocarboxylate is used in a crosslinking reaction, the thiocarboxylate may be present as an ion in the reaction system. In addition, the "reaction of a polymer having a cyclic ether group in the molecule with a thiocarboxylate" also includes the creation of a state in which a thiocarboxylate or its ion is present in the reaction system by, for example, adding a basic substance to the reaction system together with a thiocarboxylic acid. The reaction conditions for the crosslinking reaction include basic conditions, neutral conditions, and acidic conditions, but when reacting with a thiocarboxylate, it is preferable to carry out the reaction under neutral to basic conditions in order to efficiently obtain the desired carrier. When reacting with a thiocarboxylate, the pH of the crosslinking reaction is preferably 6 or more, more preferably 6 to 14, and particularly preferably 7 to 14 in order to efficiently obtain the desired carrier. Here, the above-mentioned "under neutral to basic conditions" refers to a state in which a neutral to basic state is created in the reaction system during the reaction between a polymer having a cyclic ether group in the molecule and a thiocarboxylate, and whether or not a component (basic substance, etc.) other than the polymer having a cyclic ether group in the molecule and the thiocarboxylate is added, if a neutral to basic state is created in the reaction system, it corresponds to a reaction under "neutral to basic conditions". In other words, "under neutral to basic conditions" includes, for example, the reaction between a polymer having a cyclic ether group in the molecule and a thiocarboxylate spontaneously makes the system basic, adding a basic substance separately to make the reaction system neutral to basic, adding thiocarboxylic acid to the reaction system together with a basic substance instead of a thiocarboxylate to create a state in which a thiocarboxylate or its ion is present in the reaction system, and the like to make the reaction system neutral to basic. The same applies to the pH described above. For example, "pH 6 or higher" means that a state of pH 6 or higher is created in the reaction system during the reaction between a polymer having a cyclic ether group in its molecule and a thiocarboxylate. Regardless of whether or not a component (such as a basic substance) other than a polymer having a cyclic ether group in its molecule and a thiocarboxylate is added, the reaction is considered to be "pH 6 or higher" as long as a state of pH 6 or higher is created in the reaction system.

[0191] -Carrier manufacturing method PR2-2- Next, the carrier production method PR2-2 of the present invention will be described. (Process B-1) Step B-1 in the carrier production method PR2-2 is a step of reacting a monomer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by formula (α) in the molecule. Step B-1 may be carried out in the same manner as the crosslinking reaction in the carrier production method PR2-1, except that a monomer having a cyclic ether group in the molecule is used instead of a polymer having a cyclic ether group in the molecule. Examples of the monomer having a cyclic ether group in the molecule include the same monomers having a cyclic ether group in the molecule as those exemplified as monomers that give the structural units (A) to (C). According to the step B-1, a monomer having a cyclic ether group in the molecule and a monomer having a cyclic ether group in the molecule that is different from the monomer (these monomers may be the same or different) can be ring-opened to introduce a thio group or a residue of a sulfanyl compound between them to link them. As illustrated in the following reaction formula, for example, when a monomer having a cyclic ether group in the molecule and a polymerizable functional group other than the reactive functional group σ is used as a monomer having a cyclic ether group in the molecule, a crosslinkable monomer having two polymerizable functional groups other than the reactive functional group σ in the molecule can be obtained.

[0192] [ka]

[0193] (The symbols in the formula are as defined above.)

[0194] (Process B-2) Step B-2 in the carrier production method PR2-2 is a step of preparing a carrier using the crosslinkable monomer obtained in step B-1. Step B-2 may be carried out in the same manner as in the preparation of the "polymer having a cyclic ether group in its molecule" in the carrier production method PR2-1, except that the crosslinkable monomer obtained in step B-1 is used instead of the monomer having a cyclic ether group in its molecule. By step B-2, a support in which X in formula (1) is a thio group can be obtained.

[0195] Furthermore, when producing a carrier in which X in formula (1) is a sulfinyl group or a sulfonyl group, the carrier in which X in formula (1) is a thio group obtained in the crosslinking reaction in carrier production method PR2-1 or in step B-2 in carrier production method PR2-2 may be oxidized. The oxidation may be carried out with reference to known methods described in International Publication No. 2015 / 119255, JP 2016-50897 A, etc., and specifically, a method using an oxidizing agent may be mentioned. Examples of the oxidizing agent include organic oxidizing agents such as peracetic acid, perbenzoic acid, metachloroperbenzoic acid, and tert-butyl hydroperoxide; and inorganic oxidizing agents such as hydrogen peroxide, chromic acid, and permanganate. These oxidizing agents may be used alone or in combination of two or more.

[0196] In addition, when a carrier in which X in formula (1) is an oxy group is produced, the above-mentioned cyclic ether groups may be crosslinked under acidic or alkaline conditions, and X in formula (1) may be >N(-R 31 In the case of producing a carrier having a structure of >Si(-R), the cyclic ether groups may be crosslinked with a primary or secondary amine or the like. 32 )2,>P(-R 33 ),>P(=O)(-R 34 ), >B(-R 35 ), or >C(-R 36When a carrier having the formula 2 is produced, the above cyclic ether groups may be crosslinked with a crosslinking agent corresponding to X.

[0197] In addition, cyclic ether groups may remain in the product of the crosslinking reaction in the carrier production method PR2-1 or in the step B-2 in the carrier production method PR2-2, or in the carrier after the oxidation, and these remaining cyclic ether groups may be ring-opened by a known method, specifically, a method of reacting a cyclic ether group with an alcohol containing a mercapto group, such as mercaptoethanol or thioglycerol, or a polyhydric alcohol, such as glycerol, may be mentioned.

[0198] The products obtained in each of the above reactions may be isolated, if necessary, by an appropriate combination of conventional means such as filtration, washing, drying, recrystallization, reprecipitation, dialysis, centrifugation, extraction with various solvents, neutralization, chromatography, etc.

[0199] The carrier of the present invention that can be produced as described above has excellent pressure resistance, and even if a protein ligand is not immobilized, it has a large dynamic binding capacity for a target substance and has high performance in separating the target substance from a biological sample. In addition, the target substance can be captured without using a capture promoter such as a lyotropic salt. For example, a biologically relevant substance such as an antibody can be adsorbed by physical adsorption without chemical bonding. Furthermore, the carrier of the present invention has excellent selective separation ability because it can specifically recognize and adsorb the Fc region of an antibody. In addition, the specific adsorption to such an Fc region can realize highly oriented antibody adsorption on the carrier, and as a result, it can be made into a carrier that can efficiently recognize an antigen.

[0200] Therefore, the carrier and ligand-immobilized carrier of the present invention are useful as a chromatography carrier, and are suitable for isolating a target substance selected from proteins and peptides, and are particularly suitable for protein purification. Furthermore, the carrier and ligand-immobilized carrier of the present invention can also be used for detection and diagnosis of target substances (for example, immunoassays (immunoassay methods) such as CLIA and CLEIA), and are also useful as carriers for in vitro diagnostic agents or carriers for detecting biologically relevant substances in research in the field of biochemistry, etc. More specifically, the support portion can be made into magnetic particles or latex particles and used in immunoassays, and can be used as a substrate in ELISA, and are useful as carriers for immunodiagnosis. Note that examples of "biologically relevant substances" that can be detected by carriers for detecting biologically relevant substances include the same target substances as the biologically relevant substances described below, and specifically include proteins, peptides, amino acids, sugars, polysaccharides, lipids, vitamins, nucleic acids (DNA, RNA), etc., with proteins, peptides, and amino acids being particularly preferred.

[0201] <Chromatography column> The chromatography column of the present invention comprises a column container packed with the carrier of the present invention or the ligand-immobilized carrier of the present invention. The chromatography column of the present invention is suitable for the isolation of target substances selected from proteins and peptides, and is particularly suitable for protein purification.

[0202] <Method for detecting or isolating a target substance> The method for detecting or isolating a target substance of the present invention is characterized by using the carrier of the present invention or the ligand-immobilized carrier of the present invention. Examples of detection of a target substance include detection by immunoassays such as hemagglutination, latex agglutination, radioimmunoassay, enzyme immunoassay, fluorescent immunoassay, and chemiluminescence immunoassay. Detection of a target substance may be performed with reference to known methods described, for example, in JP 2009-031061 A. Isolation of the target substance can be performed by chromatography. In addition, the isolation of the target substance can be performed in the same manner as known isolation using a carrier immobilizing a protein ligand, except that the carrier of the present invention or the ligand-immobilized carrier of the present invention is used. For example, the isolation can be performed with reference to known methods described in International Publication No. 2015 / 119255 and the like. Methods for isolating a target substance include a method comprising a step of contacting the carrier of the present invention or the ligand-immobilized carrier of the present invention with a sample containing the target substance (this step preferably uses a buffer having a pH (25°C) in the range of preferably 5 to 10, more preferably 6 to 9). After separating impurities from the target substance in this step, it is preferable to carry out an elution step in which the target substance captured on the carrier is eluted. In the elution step, a dissociation liquid that dissociates the ligand and the target substance is usually used (this step preferably uses a dissociation liquid having a pH (25°C) in the range of preferably 2 to 7, more preferably 3 to 5). Alternatively, the isolation may be carried out using the chromatography column of the present invention. Such a method includes a step of passing a sample containing the target substance through the chromatography column of the present invention, and it is preferable to separate impurities from the target substance by this step, and then carry out an elution step in the same manner as described above.

[0203] Examples of target substances include biologically relevant substances such as proteins, peptides, amino acids, sugars, polysaccharides, lipids, vitamins, and nucleic acids (DNA, RNA), with proteins and peptides being preferred, and proteins being more preferred. Examples of target proteins include antigens, antibodies, Fc fusion proteins, antibody-drug conjugates (ADCs), and virus particles, with antigens, antibodies, Fc fusion proteins, and antibody-drug conjugates (ADCs) being more preferred. Examples of antibodies include polyclonal antibodies, monoclonal antibodies, bispecific antibodies, synthetic antibodies, humanized antibodies, chimeric antibodies, single-chain antibodies, Fab fragments, Fab' fragments, F(ab')2 fragments, Fc fragments, Fv fragments, Fv' fragments, fragments produced by Fab expression libraries, anti-idiotype (anti-Id) antibodies, and any of the above epitope-binding fragments. Examples of antibody classes include IgG, IgE, IgM, IgD, and IgA. The subclass is not particularly limited. Among such proteins, proteins having an Fc region are preferred, and antibodies having an Fc region are more preferred.Specific examples include polyclonal antibodies having an Fc region, monoclonal antibodies having an Fc region, bispecific antibodies having an Fc region, synthetic antibodies having an Fc region, humanized antibodies having an Fc region, chimeric antibodies having an Fc region, Fc fragments, anti-idiotype (anti-Id) antibodies having an Fc region, any of the above epitope-binding fragments, Fc fusion proteins, and antibody-drug conjugates (ADCs) having an Fc region.

[0204] Examples of samples containing a target substance include various liquids such as whole blood, serum, plasma, blood components, various blood cells, blood clots, platelets, and other blood components; urine, semen, breast milk, sweat, interstitial fluid, interstitial lymph fluid, bone marrow fluid, tissue fluid, saliva, gastric juice, synovial fluid, pleural effusion, bile, ascites, and amniotic fluid; bacterial fluid, cell culture medium, cell culture supernatant, and tissue and cell homogenate. Examples of contaminants include non-target proteins, enzymes, etc. Specifically, when an antibody is the target substance, contaminants are proteins and enzymes other than antibodies. Also, when a virus particle is the target substance, contaminants are DNA and host cell-derived proteins.

[0205] With respect to the above-described embodiment, the present invention further discloses the following manufacturing method and the like. <a1>A method for producing a compound containing a divalent group represented by the following formula (21), comprising a step of reacting a cyclic ether group-containing compound with a thiocarboxylate salt:

[0206] [ka]

[0207] [In formula (21), R 51 and R 52 each independently represents a divalent group formed by ring-opening of a cyclic ether group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, * indicates a bond.

[0208] <a2>The thiocarboxylate is represented by the following formula (13): <a1>The manufacturing method described in

[0209] [ka]

[0210] [In formula (13), R 22 represents a hydrogen atom or a monovalent organic group, M represents a cation that forms a thiocarboxylate. <a3>The thiocarboxylate is a thioacetate. <a1>or <a2>The manufacturing method described in <a4>The thiocarboxylate is an alkali metal salt of thioacetic acid. <a1> ~ <a3>13. The method for producing a semiconductor device according to any one of the preceding claims.

[0211] <a5>The cyclic ether group is a cyclic ether group represented by the following formula (3): <a1> ~ <a4>13. The method for producing a semiconductor device according to any one of the preceding claims.

[0212] [ka]

[0213] [In formula (3), R 11 ~R 13 each independently represents a hydrogen atom or an alkyl group, * indicates a bond.

[0214] <a6>The reaction is carried out under neutral to basic conditions. <a1> ~ <a5>13. The method for producing a semiconductor device according to any one of the preceding claims. <a7>X 2 is a thio group; <a1> ~ <a6>13. The method for producing a semiconductor device according to any one of the preceding claims. <a8>X 2 is a sulfinyl group or a sulfonyl group, and the method further comprises a step of oxidizing the sulfide compound obtained in the above step. <a1> ~ <a6>13. The method for producing a semiconductor device according to any one of the preceding claims. <a9>the amount of the thiocarboxylate used is 0.75 mol or less relative to 1 mol of the cyclic ether group; <a1> ~ <a8>13. The method for producing a semiconductor device according to any one of the preceding claims.

[0215] <a10> <a1> ~ <a9>A compound containing a divalent group represented by formula (21), obtained by the production method according to any one of the above. <a11>A compound represented by the following formula (β):

[0216] [ka]

[0217] [In formula (β), R 51 and R 52 each independently represents a divalent group formed by ring-opening of a cyclic ether group, R 53 and R 54 each independently represents a hydrogen atom or a methyl group, R 55 and R 56 each independently represents a halogen atom or an organic group, R 57 and R 58 each independently represents a single bond or a divalent linking group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, n1 and n2 each independently represent an integer of 0 to 4.

[0218] <a12>R 51 and R 52 is a ring-opened epoxy group; <a11>The compound according to claim 1, <a13>R 57 and R 58 is a substituted or unsubstituted divalent hydrocarbon group, or a group in which a part of the carbon atoms of the substituted or unsubstituted divalent hydrocarbon group is replaced by an ether bond, <a11>or <a12>The compound according to claim 1, <a14>X 2 is a thio group; <a11> ~ <a13>2. The compound according to claim 1 ,

[0219] <b1>A support comprising a polymer having a crosslinked structure containing a divalent group represented by the following formula (1):

[0220] [ka]

[0221] [In formula (1), R 1 ~R 4 each independently represents a single bond or a divalent hydrocarbon group, R 5 and R 6 each independently represents a hydrogen atom or a hydrocarbon group, X is a thio group, a sulfinyl group, a sulfonyl group, an oxy group, >N(-R 31 ), >Si(-R 32 )2,>P(-R 33 ),>P(=O)(-R 34 ), >B(-R 35 ), or >C(-R 36 )2 indicates (R 31 ~R 36 each independently represents a hydrogen atom or a hydrocarbon group; * indicates a bond. However, R 1 and R 3 When both are divalent hydrocarbon groups, R 1 and R 3 may be joined together to form a ring with adjacent carbon atoms, R 2 and R 4 When both are divalent hydrocarbon groups, R 2 and R 4 may be joined together with the adjacent carbon atoms to form a ring.

[0222] <b2>R 1 ~R 4 are each independently a single bond or a divalent hydrocarbon group having 1 to 10 carbon atoms; <b1>The carrier described in . <b3>R 1 and R 2 is a single bond, and R 3 and R 4 are each independently a divalent hydrocarbon group having 1 to 10 carbon atoms; <b1>or <b2>The carrier described in . <b4>R 1 and R 2 is a single bond, and R 3 and R 4 are each independently an alkanediyl group having 1 to 4 carbon atoms; R 5 and R 6 is a hydrogen atom, <b1> ~ <b3>2. A carrier according to any one of the preceding claims.

[0223] <b5>Each crosslinked structure contains 1 to 5 divalent groups represented by formula (1). <b1> ~ <b4>2. A carrier according to any one of the preceding claims. <b6>X is a thio group, a sulfinyl group, or a sulfonyl group; <b1> ~ <b5>2. A carrier according to any one of the preceding claims. <b7>X is a thio group; <b1> ~ <b5>2. A carrier according to any one of the preceding claims. <b8>A support on which the protein ligand is not immobilized. <b1> ~ <b7>2. A carrier according to any one of the preceding claims. <b9>A particulate carrier, <b1> ~ <b8>2. A carrier according to any one of the preceding claims.

[0224] <b10>A chromatography carrier, an in vitro diagnostic carrier, or a carrier for detecting biologically related substances. <b1> ~ <b9>2. A carrier according to any one of the preceding claims. <b11>A protein purification chromatography support, <b1> ~ <b9>2. A carrier according to any one of the preceding claims.

[0225] <b12> <b1> ~ <b9>13. A ligand-immobilized support comprising the support according to any one of claims 1 to 12 and a ligand, wherein the ligand is immobilized on the support. <b13>The ligand is an immunoglobulin-binding protein, an antibody or an antigen; <b12>The ligand-immobilized carrier according to claim 1. <b14>the polymer of the carrier has a residue of a monovalent group containing a sulfanyl group in the molecule, and the ligand is fixed to the residue via a linking group derived from a crosslinking agent having a reactive functional group that reacts with a sulfanyl group and a reactive functional group that reacts with a ligand; <b12>or <b13>The ligand-immobilized carrier according to claim 1. <b15>A chromatography carrier, an in vitro diagnostic carrier, or a carrier for detecting biologically related substances. <b12> ~ <b14>2. The ligand-immobilized carrier according to claim 1 , <b16>A protein purification chromatography support, <b12> ~ <b14>2. The ligand-immobilized carrier according to claim 1 ,

[0226] <b17> <b1> ~ <b16>1. A chromatography column comprising a column container packed with the carrier or ligand-immobilized carrier described in any one of the above. <b18> <b1> ~ <b16>2. A method for detecting or isolating a target substance, comprising using the carrier or ligand-immobilized carrier described in any one of claims 1 to 11.

[0227] <b19> <b1> ~ <b11>The present invention relates to a method for producing a carrier according to any one of the above items 1 to 5, comprising the step of reacting a polymer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by the following formula (α) in the molecule:

[0228] [ka]

[0229] [In formula (α), R 2 , R 4 , R 6 and * are as defined above.

[0230] <b20> <b1> ~ <b11>The method for producing the carrier according to any one of the above items B-1 and B-2 includes the following steps B-1 and B-2: (Step B-1) A step of reacting a monomer having a cyclic ether group in the molecule with a compound selected from a thiocarboxylate and a sulfanyl compound having two or more groups represented by the following formula (α) in the molecule: (Step B-2) A step of preparing a carrier using the crosslinkable monomer obtained in step B-1

[0231] [ka]

[0232] [In formula (α), R 2 , R 4 , R 6 and * are as defined above. EXAMPLES

[0233] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0234] (Example 1: Production of organic sulfur compound) Compound (E1) was obtained according to the following synthetic route.

[0235] [ka]

[0236] That is, in a reaction vessel, 0.50 g of (S)-glycidyl methyl ether (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 2.5 g of pure water, and 0.33 g of potassium thioacetate (manufactured by Tokyo Chemical Industry Co., Ltd.) dissolved in 2.5 g of pure water was added thereto, and the reaction was carried out by stirring at room temperature for 4 hours. As the reaction progressed, the reaction system spontaneously changed from neutral to basic, and then returned to near neutrality. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and the solvent was distilled off to obtain compound (E1) in a yield of 0.55 g. Regarding the obtained compound (E1), 1 Identification was carried out by H-NMR spectroscopy (apparatus: Bruker nuclear magnetic resonance apparatus, 600 MHz).

[0237] 1 H NMR (600MHz, D2O): δ2.63(dd, J=7.8, 13.8 Hz,2H), 2.75(dd, J= 5.4, 13.8 Hz,2H), 3.37(s, 6H), 3.47(dd, J= 6.6, 13.8 Hz,2H), 3.54(dd, J= 3.6, 10.8 Hz,2H), 3.94(m,2H)

[0238] (Example 2: Production of organic sulfur compounds) The same procedure as in Example 1 was carried out except that the amount of potassium thioacetate used was changed from 0.33 g to 0.65 g, to obtain compound (E1) in a yield of 0.52 g. Regarding the obtained compound (E1), 1 Identification was carried out by H-NMR spectroscopy (apparatus: Bruker nuclear magnetic resonance apparatus, 600 MHz).

[0239] 1 H NMR (600MHz, D2O): δ2.63(dd, J=7.8, 13.8 Hz,2H), 2.75(dd, J= 4.8, 13.8 Hz,2H), 3.37(s, 6H), 3.47(dd, J= 6.6, 13.8 Hz,2H), 3.54(dd, J= 3.6, 10.2 Hz,2H), 3.94(m,2H)

[0240] The appearance of each product obtained after all the procedures in the above Examples 1 and 2 was confirmed. In addition, the yield of compound (E1) in Examples 1 and 2 was calculated. These results are shown in Table 1.

[0241] [Table 1]

[0242] As shown in Table 1, the production method of Example 1 had a particularly high yield. In addition, the product had a transparent appearance, and it was presumed that there was a particularly small amount of by-products.

[0243] (Example 3: Production of organic sulfur compounds) Compound (E2) was obtained according to the following synthetic route.

[0244] [ka]

[0245] That is, in a reaction vessel, 10.0 g of vinylbenzyl glycidyl ether (a mixture of (3-vinylbenzyl) glycidyl ether and (4-vinylbenzyl) glycidyl ether) was dissolved in a mixed solvent of 17.5 g of pure water and 47.5 g of methanol. Separately, 3.30 g of potassium thioacetate was dissolved in a mixed solvent of 17.5 g of pure water and 47.5 g of methanol, which was added to the reaction vessel and stirred at room temperature for 4 hours to carry out the reaction. As the reaction proceeded, the reaction system spontaneously changed from neutral to basic, and then returned to near neutral. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and the solvent was distilled off to obtain compound (E2) in a yield of 10.80 g. Regarding the obtained compound (E2), 1 Identification was carried out by H-NMR spectroscopy (apparatus: Bruker nuclear magnetic resonance apparatus, 600 MHz).

[0246] 1 H NMR (600 MHz, CDCl3) : δ2.65(m,2H), 2.76(m, 2H), 3.07(br, 1H), 3.50(m, 2H), 3.93(m, 1H), 4.53(d, J= 7.8, 2H), 5.25(dd, J= 8.4, 10.8, 1H), 5.75(dd, J= 10.2, 18.0, 1H), 6.70(m, 1H), 7.30(m, 4H)

[0247] (Example 4: Production of organic sulfur compounds) Compound (E3) was obtained according to the following synthetic route. Note that most of the compounds (E3) obtained were those in which p in the formula was an integer of 1 to 5.

[0248] [ka]

[0249] That is, in a reaction vessel, 0.115 g of 1,4-butanediol diglycidyl ether (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in a mixed solvent of 0.18 g of pure water and 0.33 g of methanol. Separately, 0.068 g of potassium thioacetate was dissolved in a mixed solvent of 0.18 g of pure water and 0.33 g of methanol, and this was added to the reaction vessel. The reaction was carried out by stirring at room temperature for 8 hours. As the reaction progressed, the reaction system spontaneously changed from neutral to basic, and then returned to near neutral. After the reaction was completed, the solvent was removed to obtain compound (E3). Regarding the obtained compound (E3), 1 Identification was performed by H-NMR spectrum measurement (apparatus: Bruker nuclear magnetic resonance apparatus 600 MHz) and MALDI-TOF mass measurement (apparatus: AB SCIEX TOF / TOF(TM) 5800 system).

[0250] 1 H NMR (600 MHz, D2O, CD3OD): δ1.68(br s,4H), 2.66(m, 2H), 2.94(m, 2H), 3.51(m, 8H), 3.88(m, 2H)

[0251] MALDI-TOF mass (Matrix: Dithranol): p=1[M+Na] + : Found m / z = 495.14, calculated(C20H40O8S2Na) 495.64. p=2[M+Na] + : Found m / z = 731.21, calculated(C30H60O12S3Na) 731.97. p=3[M+Na] + : Found m / z = 967.30, calculated(C40H80O16S4Na) 968.29. p=4[M+Na] + : Found m / z = 1203.39, calculated(C50H100O20S5Na) 1204.62. p=5[M+Na] + : Found m / z = 1439.49, calculated(C60H120O24S6Na) 1440.95.

[0252] (Example 5: Production of organic sulfur compounds) In a reaction vessel, 1.0 g of triglycidyl isocyanurate (Tokyo Chemical Industry Co., Ltd.) was dissolved in a mixed solvent of 1.0 g of pure water and 5.0 g of dimethyl sulfoxide (DMSO). Separately, 0.58 g of potassium thioacetate was dissolved in a mixed solvent of 1.0 g of pure water and 5.0 g of DMSO, which was added to the reaction vessel and stirred at room temperature. The viscosity gradually increased, and finally a gel was formed in a state where the solvent was thickened.

[0253] (Example 6: Production of organic sulfur compounds) In a reaction vessel, 1.93 g of bisphenol A diglycidyl ether (Tokyo Chemical Industry Co., Ltd.) was dissolved in 5.0 g of DMSO, and 0.65 g of potassium thioacetate dissolved in 5.0 g of DMSO was added and stirred at room temperature. The viscosity gradually increased, and finally a cured material in which the solvent was solidified was formed.

[0254] (Example 7: Production of organic sulfur compounds) (1) 2.69 g of polyvinyl alcohol (PVA-217, manufactured by Kuraray Co., Ltd.) was added to 448 g of pure water, and the mixture was heated and stirred to dissolve the polyvinyl alcohol. After cooling, 0.045 g of sodium dodecyl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was added and stirred to prepare an aqueous solution S. On the other hand, a monomer composition consisting of 3.63 g of divinylbenzene (manufactured by Wako Pure Chemical Industries, Ltd.), 0.36 g of 1-ethyl-4-vinylbenzene (manufactured by ChemSampCo., Ltd.) and 14.15 g of glycidyl methacrylate (manufactured by Mitsubishi Gas Chemical Co., Ltd.) was dissolved in 29.38 g of 2-octanone (manufactured by Toyo Gosei Co., Ltd.) to prepare a monomer solution. Next, the entire amount of the aqueous solution S was poured into a separable flask, a thermometer, a stirring blade and a cooling tube were attached, the flask was placed in a hot water bath, and stirring was started under a nitrogen atmosphere. The entire amount of the monomer solution was poured into the separable flask, and the flask was heated in a hot water bath. When the internal temperature reached 85°C, 1.34 g of 2,2'-azoisobutyronitrile (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the internal temperature was raised to 86°C.

[0255] (2) After that, the mixture was stirred for 3 hours while maintaining the temperature at 86°C. The reaction solution was then cooled, filtered, and washed with pure water and ethanol. The washed particles were dispersed in pure water and decanted three times to remove small particles. The particles were then dispersed in pure water to a particle concentration of 10% by mass, to obtain a porous particle dispersion. (3) Then, 2.51 g of potassium thioacetate was added to 100 g of the porous particle dispersion, and the mixture was stirred at room temperature for 2 hours. As the reaction proceeded, the reaction system spontaneously changed from neutral to basic, and then returned to near neutral. The reaction solution was then filtered and washed with pure water to obtain a porous crosslinked particle dispersion. The reaction in step (3) is shown below, and the results of FT-IR measurement and alkaline hydrolysis (5M NaOH) of the extract were as follows: 1 Introduction of a crosslinked structure was confirmed by H-NMR spectroscopy (apparatus: Bruker nuclear magnetic resonance apparatus 600 MHz, D2O).

[0256] [ka]

[0257] (Example 8: Production of organic sulfur compounds) The same operations as in steps (1) to (3) of Example 7 were carried out to obtain a porous crosslinked particle dispersion. (4) Next, 47.5 g of α-thioglycerol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5.67 g of diisopropylethylamine were added to the total amount of the dispersion, and the mixture was heated to 70° C. and stirred for 3 hours while maintaining the temperature at 70° C. Thereafter, the reaction liquid was filtered and washed with pure water. (5) Next, 4.06 g of glycerol was added, and the mixture was heated to 70° C. and stirred for 3 hours while maintaining the temperature at 70° C. After that, the reaction liquid was filtered and washed with pure water. The particles were dispersed in pure water so that the particle concentration was 10% by mass, to obtain a porous crosslinked particle dispersion.

[0258] (Example 9) Production of organic sulfur compounds A porous crosslinked particle dispersion was obtained by carrying out the same operations as in steps (1) to (3) of Example 7, except that in step (1) of Example 7, 3.63 g of divinylbenzene was changed to 11.56 g of the compound (E2) obtained in Example 3.

[0259] Comparative Example 1 The same procedure as in Example 1 was carried out, except that 0.33 g of potassium thioacetate in Example 1 was changed to 0.22 g of thioacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd.). After the operation is completed, 1 H-NMR spectrum measurement (apparatus: Bruker nuclear magnetic resonance apparatus 600 MHz) was performed, but the compound containing the divalent group represented by formula (21) was not obtained.

[0260] 1 H NMR (600 MHz, D2O): δ2.39(s, 3H), 2.95(dd, J=6.6, 14.4 Hz,1H), 3.10(dd, J= 5.4, 14.4 Hz,1H), 3.37(s, 3H), 3.45(dd, J= 4.2, 10.8 Hz,1H), 3.49(dd, J= 3.6, 10.2 Hz,1H), 3.92(m,1H)

[0261] (Example A1 Carrier) A porous crosslinked particle dispersion was obtained by carrying out the same operations as in steps (1) to (5) of Example 8. The porous crosslinked particles contained in this dispersion are referred to as "chromatography carrier V1."

[0262] (Example A2 Carrier) In step (3), 2.51 g of potassium thioacetate was replaced with 3.39 g of DL-dithiothreitol and 5.67 g of diisopropylethylamine, and the reaction temperature and reaction time were changed to 70°C and 3 hours, respectively, and the same operations as steps (1) to (5) of Example 8 were carried out to obtain a porous crosslinked particle dispersion. The porous crosslinked particles contained in this dispersion are referred to as "chromatography carrier V2". The crosslinking reaction using DL-dithiothreitol is shown below, and the results of FT-IR measurement and alkaline hydrolysis (5M NaOH) of the extract were obtained. 1 Introduction of a crosslinked structure was confirmed by H-NMR spectroscopy (apparatus: Bruker nuclear magnetic resonance apparatus 600 MHz, D2O).

[0263] [ka]

[0264] (Comparative Example B1) In step (3), 2.51 g of potassium thioacetate was replaced with 4.00 g of 3,6-dioxa-1,8-octanedithiol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 5.67 g of diisopropylethylamine, and the reaction temperature and reaction time were changed to 70°C and 3 hours, respectively, and the same operations as in steps (1) to (5) of Example 8 were carried out to obtain a porous crosslinked particle dispersion. The porous crosslinked particles contained in this dispersion are referred to as "chromatography carrier X1". The crosslinking reaction using 3,6-dioxa-1,8-octanedithiol is shown below.

[0265] [ka]

[0266] (Comparative example B2) A porous particle dispersion was obtained by carrying out the same operations as in steps (1) to (5) of Example 8, except that steps (3) and (5) were not carried out. The porous particles contained in this dispersion are referred to as "chromatography carrier X2."

[0267] [Test Example 1-1] The carriers V1 to V2 and X1 to X2 of each of the Examples and Comparative Examples were used for isolating and purifying antibodies without binding a protein ligand, and their performance was evaluated. The specific procedure is shown below. -Equilibration process- That is, each carrier was packed to a packing height of about 5 cm in a column container with a capacity of 1 mL (5 mmφ×50 mm length) to prepare a column. The obtained columns were connected to AKTA Prime Plus manufactured by GE Healthcare, and equilibrated by passing 4 column volumes (4 times the column volume) of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. -Adsorption process- Next, the monoclonal antibody Trastuzumab (hereinafter, in each test example, the monoclonal antibody Trastuzumab will be simply referred to as "monoclonal antibody") and BSA were dissolved in 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5), and 100 μL of this sample (monoclonal antibody: 5 g / L, BSA: 5 g / L) was passed through the column at a linear flow rate of 300 cm / hr. -Cleaning process- Next, the carrier was washed by passing 10 column volumes of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. The liquid recovered from the column in this washing step was measured for the presence or absence of monoclonal antibodies by size exclusion chromatography (column: TSKgel UP-SW3000, eluent: 100 mM sodium phosphate (pH 6.7) / 100 mM sodium sulfate / 0.05% sodium azide, flow rate: 0.35 mL / min, detection UV: 280 nm), and the antibody adsorption performance during washing was evaluated according to the following criteria. The results are shown in Table 2. (Antibody adsorption performance evaluation standard during washing) A: No peaks that could be attributed to monoclonal antibodies were identified. B: A peak deemed to be derived from a monoclonal antibody was confirmed. -Elution process- Thereafter, 6 column volumes of 50 mM sodium citrate buffer (pH 3.2) were passed through the column at a linear flow rate of 300 cm / hr, and the eluted fraction with Abs.280>5 mAu was collected. The amount of monoclonal antibody contained in the collected fraction was then measured using a spectrophotometer (SmartSpec Plus spectrophotometer manufactured by Bio-Rad) to calculate the antibody recovery rate (%). Furthermore, this antibody recovery rate (%) was evaluated according to the following criteria. The results are shown in Table 2. (Antibody recovery rate evaluation criteria) AA: Antibody recovery rate is 90% or more A: Antibody recovery rate is 70% or more but less than 90% B: Antibody recovery rate is 20% or more but less than 70% C: Antibody recovery rate is less than 20%

[0268] [Test Example 1-2] A column was prepared by packing the carriers V1 to V2 and X1 to X2 of each Example and Comparative Example in a column container with a capacity of 1 mL (5 mmφ×50 mm length) to a packing height of about 5 cm. The obtained columns were connected to AKTA Prime Plus manufactured by GE Healthcare, and equilibrated by passing 4 column volumes (4 times the column volume) of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. Next, BSA was dissolved in 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5), and 100 μL of this sample (BSA: 5 g / L) was passed through the column at a linear flow rate of 300 cm / hr. Next, 10 column volumes of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) were passed through the column at a linear flow rate of 300 cm / hr to wash the carrier. The absorbance of the liquid was measured using a spectrophotometer attached to AKTA Prime Plus manufactured by GE Healthcare. As a result, a peak derived from BSA was confirmed in all the carriers V1-V2 and X1-X2 of the examples and comparative examples. Then, 50 mM sodium citrate buffer (pH 3.2) was passed through the column at a linear flow rate of 300 cm / hr with 6 column volumes, and the absorbance of the solution was measured using a spectrophotometer attached to the AKTA Prime Plus. As a result, no peak derived from BSA was confirmed when any of the carriers V1-V2 and X1-X2 of the examples and comparative examples were used.

[0269] [Test Example 1-3] A column was prepared by packing the carriers V1 to V2 and X1 to X2 of each Example and Comparative Example in a column container with a capacity of 1 mL (5 mmφ×50 mm length) to a packing height of about 5 cm. The obtained columns were connected to AKTA Prime Plus manufactured by GE Healthcare, and equilibrated by passing 4 column volumes (4 times the column volume) of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. Next, the monoclonal antibody was dissolved in 150 mM sodium chloride buffer (pH 7.5), and 100 μL of this sample (monoclonal antibody: 5 g / L) was passed through the column at a linear flow rate of 300 cm / hr. Next, 10 column volumes of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) were passed through the column at a linear flow rate of 300 cm / hr, and the absorbance of the solution was measured using a spectrophotometer attached to AKTA Prime Plus manufactured by GE Healthcare. As a result, when carriers V1 and V2 of the examples were used, no peaks derived from the monoclonal antibodies were observed, whereas when carriers X1 and X2 of the comparative examples were used, peaks derived from the monoclonal antibodies were observed.

[0270] [Test Example 1-4] A column was prepared by packing the carriers V1 to V2 and X1 to X2 of each Example and Comparative Example in a column container with a capacity of 1 mL (5 mmφ×50 mm length) to a packing height of about 5 cm. The obtained columns were connected to AKTA Prime Plus manufactured by GE Healthcare, and equilibrated by passing 4 column volumes (4 times the column volume) of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. Next, the Fc fusion protein Etanercept was dissolved in 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5), and 100 μL of this sample (Fc fusion protein: 5 g / L) was passed through the column at a linear flow rate of 300 cm / hr. Next, the carrier was washed by passing 10 column volumes of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. The absorbance of the liquid was measured using a spectrophotometer attached to AKTA Prime Plus manufactured by GE Healthcare. As a result, when carriers V1 to V2 of the examples were used, no peaks derived from the Fc fusion protein were confirmed. On the other hand, when carriers X1 to X2 of the comparative examples were used, peaks derived from the Fc fusion protein were confirmed. Thereafter, 6 column volumes of 50 mM sodium citrate buffer (pH 3.2) were passed through the column at a linear flow rate of 300 cm / hr, and the absorbance of the solution was measured using a spectrophotometer attached to the AKTA Prime Plus. As a result, when the carriers V1 and V2 of the embodiment were used, peaks derived from the Fc fusion protein were confirmed. On the other hand, when the carriers X1 and X2 of the comparative example were used, no peaks derived from the Fc fusion protein were confirmed.

[0271] [Test Example 1-5] The same procedure as in Test Example 1-3 was carried out, except that the monoclonal antibody was changed to lysozyme. As a result, a peak derived from lysozyme was confirmed in all of the carriers V1 to V2 and X1 to X2 of the examples and comparative examples. Moreover, the same procedure as in Test Example 1-3 was performed except that the monoclonal antibody was changed to albumin (derived from human serum). As a result, a peak derived from albumin (derived from human serum) was confirmed in all cases where carriers V1 to V2 and X1 to X2 in the examples and comparative examples were used. Moreover, the same procedure as in Test Example 1-3 was performed except that the monoclonal antibody was changed to α-chymotrypsinogen A. As a result, a peak derived from α-chymotrypsinogen A was confirmed in all cases where carriers V1 to V2 and X1 to X2 in the examples and comparative examples were used.

[0272] [Test Example 1-6] A commercially available MAbsorbent A2P HF (Prometic Bioseparations) was prepared as a carrier having a non-proteinaceous synthetic ligand represented by the following formula: This carrier is also referred to as "Carrier of Comparative Example B3" and "Carrier Y1".

[0273] [ka]

[0274] A column was prepared by packing the carrier Y1 to a packing height of about 5 cm in a column container with a capacity of 1 mL (5 mmφ×50 mm length). The obtained column was connected to AKTA Prime Plus manufactured by GE Healthcare, and equilibrated by passing 4 column volumes (4 times the column volume) of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) through the column at a linear flow rate of 300 cm / hr. Next, the monoclonal antibody, Fc fusion protein, BSA, lysozyme, albumin (derived from human serum) and α-chymotrypsinogen A were each dissolved in 150 mM sodium chloride buffer (pH 7.5), and 100 μL of each of these samples (monoclonal antibody, Fc fusion protein, BSA, lysozyme, albumin (derived from human serum) or α-chymotrypsinogen A: 5 g / L) were passed through the column at a linear flow rate of 300 cm / hr. Next, 10 column volumes of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) were passed through the column at a linear flow rate of 300 cm / hr, and the absorbance of the solution was measured using a spectrophotometer attached to an AKTA Prime Plus manufactured by GE Healthcare Co., Ltd. As a result, when the carrier Y1 of the comparative example was used, no peaks derived from the monoclonal antibody, Fc fusion protein, BSA, lysozyme, albumin (derived from human serum), or α-chymotrypsinogen A were observed, regardless of whether these were used. Next, the solution was passed through the column at a linear flow rate of 300 cm / hr, stepwise from 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) to 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 5.0) at pH 0.5 each, and the absorbance of the solution was measured using a spectrophotometer attached to AKTA Prime Plus manufactured by GE Healthcare Co., Ltd. As a result, as in the above, no peaks derived from monoclonal antibodies, Fc fusion proteins, BSA, lysozyme, albumin (derived from human serum), or α-chymotrypsinogen A were confirmed when any of these were used.

[0275] The presence or absence of adsorption when 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) was used as the mobile phase in Test Examples 1-2 to 1-6 is summarized in Table 3. Cases where adsorption was observed were marked with "A," and cases where adsorption was not observed were marked with "B."

[0276] [Test Example 2 (DBC Measurement)] Using AKTAprime plus manufactured by GE Healthcare, the DBC of carriers V1 to V2 and X1 to X2 of each Example and Comparative Example for a protein (human IgG antibody, HGG-1000 manufactured by Equitech Bio) at a linear flow rate of 300 cm / hr was measured. A column container with a capacity of 4 mL (5 mmφ×200 mm length) and a protein dissolved at 5 mg / mL in 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) were used, and the DBC was calculated from the protein capture amount at 10% breakthrough at the elution tip and the column packing volume. The results are shown in Table 2.

[0277] [Test Example 3 (Measurement of consolidation line flow velocity)] Carriers V1 to V2 and X1 to X2 obtained in each Example and Comparative Example were packed in a column container to an inner diameter of 16 mm and a packing height of 100 mm, and this column was connected to an AKTA pilot manufactured by GE Healthcare Biosciences. Next, pure water was passed through at a linear flow rate of 100 cm / hr, and the linear flow rate was increased stepwise by 100 cm / hr every minute, and the linear flow rate when it reached 2.0 MPa was recorded as the compaction linear flow rate. The compaction linear flow rate was then evaluated according to the following criteria. The results are shown in Table 2.

[0278] (Evaluation criteria for consolidation line velocity) A: Consolidation line velocity is 3000 cm / hr or more B: Consolidation line velocity is less than 3000 cm / hr

[0279] [Table 2]

[0280] [Table 3]

[0281] As shown in Table 3, carriers V1 and V2 of the examples successfully adsorbed monoclonal antibodies having an Fc region and Fc fusion proteins. Therefore, carriers V1 and V2 of the examples are considered to adsorb monoclonal antibodies by specifically recognizing the Fc region, similar to protein A, and are presumed to adsorb antibodies and proteins having an Fc region. Furthermore, carriers V1 and V2 of the examples adsorbed monoclonal antibodies and Fc fusion proteins, but did not adsorb model proteins (BSA, lysozyme, albumin (derived from human serum), and α-chymotrypsinogen A), confirming their adsorption selectivity. On the other hand, carrier Y1, which is commercially available as a carrier having a non-proteinaceous synthetic ligand, adsorbed all of the samples tested, confirming that its adsorption selectivity is insufficient.

[0282] [Test Example 4 Adsorption Rate Test] 400 μL of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) containing 0.4 mg of each antibody shown in Table 4 was added to 20 μL of carriers V1 to V2 of the example. After incubating for 30 minutes, the supernatant was collected. Next, after washing with 400 μL of 20 mM phosphate buffer (pH 7.5), the washing solution was collected. The total amount of antibody in the supernatant and washing solution was calculated by measuring absorbance, and the adsorption rate (%) [= (1-(total amount of antibody in the supernatant and washing solution) / total amount of antibody) × 100] was calculated from the ratio to the total amount of antibody. It was also confirmed that the antibody was eluted by adding 400 μL of 50 mM sodium citrate buffer (pH 3.2) after washing.

[0283] [Table 4]

[0284] From the results of Test Example 4, it was confirmed that the carriers V1 and V2 of the present invention adsorb antibodies derived from various animals.

[0285] [Test Example 5-1 Preparation of antibody-immobilized particles 1] (1) 50 μL of DMSO in which 47 μg of N-succinimidyl 4-maleimidobutyrate was dissolved was added to 20 μL of porous crosslinked particles prepared by the same procedure as in steps (1) to (3) of Example 7, and the mixture was allowed to stand at room temperature for 2 hours. The mixture was washed three times with 400 μL of DMSO to obtain particles with N-succinimidyl groups introduced therein. (Note that the amount of sulfanyl groups on the particles before and after this reaction was quantified using Ellman's reagent, and the amount of sulfanyl groups was found to have decreased significantly. This confirmed that N-succinimidyl groups had been introduced by the addition reaction between the maleimide moiety and the sulfanyl groups on the particles.) (2) The obtained particles were subjected to solvent replacement twice with 400 μL of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5), after which 400 μL of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5) containing 1.2 mg of monoclonal antibody was added thereto and allowed to stand for 15 hours at 4° C. The reaction solution was collected, and then washed successively with 400 μL each of 20 mM sodium phosphate / 150 mM sodium chloride buffer (pH 7.5), 50 mM sodium citrate buffer (pH 3.2), 0.01 M aqueous sodium hydroxide solution, and 20% aqueous ethanol solution, to obtain antibody-immobilized particles.

[0286] [Test Example 5-2: Preparation of antibody-immobilized particles 2] In step (3), 2.51 g of potassium thioacetate was replaced with 3.39 g of DL-dithiothreitol and 5.67 g of diisopropylethylamine, and the reaction temperature and reaction time were changed to 70°C and 3 hours, respectively, and the same operations as steps (1) to (3) of Example 7 were carried out to prepare porous crosslinked particles. 50 μL of DMSO in which 106 μg of 4-maleimidobutyric acid N-succinimidyl was dissolved was added to 20 μL of the above porous crosslinked particles, and the mixture was allowed to stand at room temperature for 2 hours. After washing three times with 400 μL of DMSO, the same operation as step (2) of Test Example 5-1 was carried out to obtain antibody-immobilized particles.

[0287] From the results of Test Examples 5-1 and 5-2, it was revealed that the above-mentioned porous crosslinked particles used in Test Examples 5-1 and 5-2 have sulfanyl groups in the polymer molecules in addition to the specific crosslinked structure, and are not only capable of physically adsorbing antibodies, but also capable of immobilizing antibodies by chemical bonding when reacted with a crosslinker having a reactive functional group that reacts with sulfanyl groups and a reactive functional group that reacts with antibodies, such as N-succinimidyl 4-maleimidobutyrate, and it was confirmed that the particles can be used as carriers for immunodiagnosis, etc. < / b1> < / b20> < / b1> < / b19> < / b1> < / b18> < / b1> < / b17> < / b12> < / b12> < / b1> < / b12> < / b1> < / b1> < / b1> < / b1> < / b1> < / b1> < / b1> < / b1> < / a11> < / a1> < / a10> < / a1> < / a1> < / a1> < / a1> < / a1> < / a1>

Claims

1. A method for producing a compound containing a divalent group represented by the following formula (21), comprising a step of reacting an epoxy group-containing compound with a thiocarboxylate in the presence of an aqueous solvent, wherein the epoxy group-containing compound is an epoxy group-containing polymeric compound having a weight average molecular weight of 750 or more, or a low molecular weight compound containing an epoxy group and a polymerizable unsaturated group and having a molecular weight of less than 750, and the aqueous solvent used has a water content of 3 to 100 mass %. 【Chemistry 1】 [In formula (21), R 51 and R 52 each independently represents a ring-opened epoxy group, X 2 represents a thio group, a sulfinyl group, or a sulfonyl group, * indicates a bond.

2. The method according to claim 1 , wherein the thiocarboxylate is represented by the following formula (13): 【Chemistry 2】 [In formula (13), R 22 represents a hydrogen atom or a monovalent organic group, M represents a cation that forms a thiocarboxylate.

3. The method according to claim 1 or 2, wherein the thiocarboxylate is a thioacetate.

4. The method according to any one of claims 1 to 3, wherein the amount of the thiocarboxylate used is 0.01 mol or more and 5 mol or less per 1 mol of the epoxy group.

5. The method according to any one of claims 1 to 4, wherein the amount of the water-containing solvent used is 10 to 2000 parts by mass based on 100 parts by mass of the epoxy group-containing compound.

6. The process according to any one of claims 1 to 5, wherein the step is carried out at a pH of 6 to 14.

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