Method for producing highly-pure branched polyethylene glycol compound

Abstract

The present invention provides a method for producing a highly-pure branched PEG compound, the method comprising: a step (1a) for mixing, in the presence of a solvent, a porous metal complex with a mixture containing a branched PEG compound and, as an impurity, a linear PEG compound to adsorb the linear PEG compound on the porous metal complex; a step (2a) for removing the porous metal complex having adsorbed the linear PEG compound from the mixture containing the branched PEG compound and the porous metal complex having adsorbed the linear PEG compound to obtain a solution containing the branched PEG compound; and a step (3) for recovering the branched PEG compound from the solution containing the branched PEG compound.

Description

Method for producing high purity branched polyethylene glycol compound

[0001] The present invention relates to a method for producing a high-purity branched polyethylene glycol compound.

[0002] Polyethylene glycol compounds are widely used as materials for drug delivery systems and medical hydrogels, and polyethylene glycol compounds with minimal impurities are required for such medical use.

[0003] For example, monomethoxypolyethylene glycol, a type of polyethylene glycol compound, is known to contain, as an impurity, a linear polyethylene glycol having hydroxy groups at both ends (hereinafter sometimes referred to as a "diol form"), which is produced by a reaction between water molecules and ethylene oxide (see, for example, Patent Document 1).

[0004] Since diols are produced even when a trace amount of water is present in the system during the production of polyethylene glycol compounds, it is difficult to completely suppress their production, and therefore there is a strong demand for a method for reducing the amount of diols in polyethylene glycol compounds.

[0005] Meanwhile, a method using a porous metal complex is known as a method for separating multiple polymer compounds from one another (see, for example, Patent Document 2). In the method described in Patent Document 2, multiple polymer compounds are mixed with a porous metal complex, and the porous metal complex is then filtered to recover a specific polymer material present in the pores of the porous metal complex, thereby concentrating or separating the target polymer compound. In addition, porous metal complexes such as metal organic frameworks (MOFs) are known to be capable of separating and storing gases (see, for example, Patent Document 3).

[0006] Japanese Patent Laid-Open No. 11-335460 International Publication No. 2019 / 078171 Special Publication No. 2017-500204

[0007] The method described in Patent Document 2 separates a plurality of polymer compounds from each other based on differences in terminal functional groups. However, Patent Document 2 does not disclose separation of branched polyethylene glycol compounds and linear polyethylene glycol compounds based on differences in branched or linear structures.

[0008] The present invention has been made in view of the above-mentioned circumstances, and an object of the present invention is to obtain a high-purity branched polyethylene glycol compound in which the content of linear polyethylene glycol compounds (for example, the above-mentioned diol form) as impurities has been reduced.

[0009] As a result of intensive studies, the present inventors have found that by using a porous metal complex, it is possible to remove a linear polyethylene glycol compound from a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity, thereby obtaining a highly pure branched polyethylene glycol compound. The present invention, based on this finding, is as follows.

[0010] [1] A method for producing a high-purity branched polyethylene glycol compound, comprising: (1a) a step of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the presence of a solvent, and allowing the linear polyethylene glycol compound to be adsorbed onto the porous metal complex; (2a) a step of removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from the mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon, and the branched polyethylene glycol compound, to obtain a solution containing the branched polyethylene glycol compound; and (3) a step of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.

[0011] [2] A method for producing a high-purity branched polyethylene glycol compound, comprising: (1b) a step of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the absence of a solvent, thereby allowing the linear polyethylene glycol compound to be adsorbed onto the porous metal complex; (2b) a step of mixing a mixture containing the porous metal complex to which the linear polyethylene glycol compound has been adsorbed and the branched polyethylene glycol compound with a solvent, and removing the porous metal complex to which the linear polyethylene glycol compound has been adsorbed from the mixture thus obtained, thereby obtaining a solution containing the branched polyethylene glycol compound; and (3) a step of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.

[0012] [3] A method for producing a high-purity branched polyethylene glycol compound, comprising: (1) mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the presence or absence of a solvent, and allowing the linear polyethylene glycol compound to be adsorbed onto the porous metal complex; (2a) removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from the mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon and the branched polyethylene glycol compound, when the mixing in step (1) is carried out in the presence of a solvent, to obtain a solution containing the branched polyethylene glycol compound; or (2b) mixing the mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon and the branched polyethylene glycol compound with a solvent, and removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from the mixture thus obtained, to obtain a solution containing the branched polyethylene glycol compound, when the mixing in step (1) is carried out in the absence of a solvent; (3) recovering the branched chain polyethylene glycol compound from the solution containing the branched chain polyethylene glycol compound.

[0013] [4] The branched polyethylene glycol compound is represented by formula (I):

[0014]

[0015] (wherein m is 0 or 1, when m is 0, s is an integer of 3 to 9, and when m is 1, s is an integer of 2 to 8, s n's each independently represent a number of 20 to 2000, Y and s X's each independently represent a hydroxy group which may be substituted with a substituent, and E represents an (s+m)-valent linker).

[0016] [5] The method according to [4], wherein the substituent is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group. [6] The method according to [4] or [5], wherein E is a linker having a structure obtained by removing a hydroxy group from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, pentaerythritol, dipentaerythritol, tetritol, pentitol, or hexitol.

[0017] [7] The method according to any one of [1] to [6] above, wherein the solvent used in step (1a) or step (2b) is at least one selected from the group consisting of N,N-dimethylformamide, ethanol, ethyl acetate, chloroform, and toluene.

[0018] [8] The method for producing the branched chain polyethylene glycol compound according to any one of [1] to [7], wherein the number average molecular weight of the branched chain polyethylene glycol compound is 4,000 to 80,000. [9] The method for producing the branched chain polyethylene glycol compound according to any one of [1] to [7], wherein the number average molecular weight of the branched chain polyethylene glycol compound is 5,000 to 80,000.

[0019]

[10] The method for producing the linear polyethylene glycol compound according to any one of [1] to [9], wherein the number-average molecular weight of the linear polyethylene glycol compound is 1,500 to 90,000.

[11] The method for producing the linear polyethylene glycol compound according to any one of [1] to [9], wherein the number-average molecular weight of the linear polyethylene glycol compound is 2,000 to 90,000.

[0020] According to the present invention, a highly pure branched polyethylene glycol compound can be obtained by removing the linear polyethylene glycol compound from a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity.

[0021] The present invention will be described below in order. Note that the descriptions in this specification can be combined with each other unless it is clear that they cannot be combined.

[0022] The present invention relates to a method for producing a high-purity branched polyethylene glycol compound. More specifically, the present invention relates to a method for producing a high-purity branched polyethylene glycol compound by removing a linear polyethylene glycol compound from a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity. Therefore, more precisely, the term "high-purity branched polyethylene glycol compound" in the present invention means a mixture containing the branched polyethylene glycol compound (purity: less than 100%) in which the purity of the branched polyethylene glycol compound is improved compared to the mixture containing the branched polyethylene glycol compound and linear polyethylene glycol compound used in the present invention, or the branched polyethylene glycol compound itself (purity: 100%).

[0023] In the present invention, the "purity" of a "high-purity branched polyethylene glycol compound" means "100 x mass of the branched polyethylene glycol compound / mass of the entire mixture containing the branched polyethylene glycol compound." When the purity is 100%, the "mixture containing the branched polyethylene glycol compound" in the above formula is the branched polyethylene glycol compound.

[0024] In the present invention, the "purity" of the "branched polyethylene glycol compound" is preferably 90% or more, more preferably 92% or more, and even more preferably 95% or more. The upper limit of this purity is 100%.

[0025] (Polyethylene Glycol Compound) In the present invention, the term "branched polyethylene glycol compound" refers to a compound having two or more polyethylene glycol chains and having a branched structure.

[0026] In the present invention, a "linear polyethylene glycol compound" refers to a compound having a polyethylene glycol chain and a linear structure. The "linear polyethylene glycol compound" may have only one polyethylene glycol chain or may have two or more polyethylene glycol chains (for example, a compound having a linear structure in which two linear polyethylene glycol chains are linked by one linker). The "linear polyethylene glycol compound" is preferably a compound having one polyethylene glycol chain and a linear structure (for example, the above-mentioned diol form).

[0027] The number average molecular weight (hereinafter sometimes abbreviated as "Mn") of the branched polyethylene glycol compound is, from the viewpoint of separation of the branched polyethylene glycol compound and the linear polyethylene glycol compound (hereinafter sometimes abbreviated as "viewpoint of separation"), preferably 4,000 or more, more preferably 5,000 or more, even more preferably 20,000 or more, and is preferably 90,000 or less, more preferably 80,000 or less.

[0028] From the viewpoint of separation, the Mn of the linear polyethylene glycol compound is preferably 1,500 or more, more preferably 2,000 or more, even more preferably 10,000 or more, particularly preferably 20,000 or more, and is preferably 90,000 or less, more preferably 80,000 or less, even more preferably 40,000 or less.

[0029] The Mn of the polyethylene glycol compound was measured by gel permeation chromatography (GPC) (standard: polyethylene glycol (HO-(C２ H ５ O) ｎ -H)).

[0030] The mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound can be obtained by a known method for producing a branched polyethylene glycol compound.

[0031] Examples of methods for producing branched polyethylene glycol compounds include: (i) a method of using a polyhydric alcohol having three or more hydroxy groups as a starting material and adding ethylene oxide thereto (see, for example, JP 2004-197077 A); and (ii) a method of reacting a linear polyethylene glycol compound having a hydroxy group with a compound having three or more functional groups capable of reacting with the hydroxy group (see, for example, JP 9-504299 A). In the method (i) above, if water is present during the addition of ethylene oxide, a linear polyethylene glycol having hydroxy groups at both ends is formed as a by-product. In the method (ii) above, the starting linear polyethylene glycol compound may remain as an impurity.

[0032] The branched polyethylene glycol compound is preferably represented by formula (I):

[0033]

[0034] (wherein m is 0 or 1, when m is 0, s is an integer of 3 to 9, and when m is 1, s is an integer of 2 to 8, s n's are each independently a number of 20 to 2000, Y and s X's are each independently a hydroxy group which may be substituted with a substituent, and E is an (s+m)-valent linker.) Here, the term "branched compound" refers to a compound having a branched structure. Therefore, compound (I) specifically refers to a compound represented by formula (I) and having a branched structure.

[0035] The symbols in formula (I) will be explained below in order. When m in formula (I) is 0, it means that Y in formula (I) is absent. In formula (I), n is the number of repeating oxyethylene units. This number of repeating units is an average value and may be a decimal number.

[0036] In formula (I), when m is 0, s is an integer of 3 to 9, preferably an integer of 3 to 5. In formula (I), when m is 1, s is an integer of 2 to 8, preferably an integer of 2 to 4. Therefore, there are a plurality of n's and a plurality of X's in formula (I). The s n's may be the same as or different from each other. Similarly, the s X's may be the same as or different from each other.

[0037] In formula (I), the s n's are each independently a number from 20 to 2000, preferably a number from 200 to 1000. From the viewpoint of ease of production of compound (I), it is preferred that the s n's are the same as each other.

[0038] In formula (I), Y and s X's each independently represent a hydroxy group which may be substituted with a substituent. From the viewpoint of ease of production of compound (I), it is preferred that the s X's are the same.

[0039] In the present invention, the term "a hydroxy group which may be substituted with a substituent" means a hydroxy group or a hydroxy group substituted with a substituent, and the term "a hydroxy group substituted with a substituent" means a hydroxy group (-OR) in which the hydrogen atom (H) of the hydroxy group (-OH) is substituted with a substituent (R).

[0040] The substituent of the hydroxy group is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, more preferably a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, and even more preferably a benzyl group.

[0041] The s Xs are preferably each independently a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group, heptyl group, isoheptyl group, phenyl group, benzyl group, trityl group, tert-butyldimethylsilyl group, or hydroxy group which may be substituted with a tert-butyldiphenylsilyl group; more preferably each independently a hydroxy group which may be substituted with a benzyl group, trityl group, tert-butyldimethylsilyl group, or tert-butyldiphenylsilyl group; and even more preferably both are hydroxy groups (i.e., unsubstituted hydroxy groups).

[0042] Y is preferably a hydroxy group optionally substituted with a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, more preferably a hydroxy group optionally substituted with a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, and even more preferably a hydroxy group substituted with a benzyl group.

[0043] E in formula (I) is an (s+m)-valent linker, i.e., a trivalent to nonavalent linker. E is preferably a linker having a structure obtained by removing a hydroxy group from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, pentaerythritol, dipentaerythritol, tetritol, pentitol, or hexitol.

[0044] The above-mentioned diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and heptaglycerin are compounds generally collectively referred to as "polyglycerin (also known as polyglycerol)." "Polyglycerin" refers to a compound having a structure in which multiple glycerins (also known as glycerols) are bonded via ether bonds. Specifically, "diglycerin" refers to a compound having a structure in which two glycerins are bonded via ether bonds, and "heptaglycerin" refers to a compound having a structure in which seven glycerins are bonded via ether bonds. "Triglycerin," "tetraglycerin," "pentaglycerin," and "hexaglycerin" also have the same meaning as "diglycerin" and "heptaglycerin." The polyglycerol may have a structure in which a plurality of glycerols are bonded in a linear chain, or may have a structure in which a plurality of glycerols are bonded in a branched chain.

[0045] In the present invention, "tetritol" refers to a compound represented by the formula: C ４ H ６ (OH) ４ In the present invention, the term "pentitol" refers to a tetrahydric sugar alcohol represented by the formula: C, for example, erythritol. ５ H ７ (OH) ５ In the present invention, the term "hexitol" refers to a pentavalent sugar alcohol represented by the formula: C, for example, xylitol. ６ H ８ (OH) ６An example of the hexavalent sugar alcohol is mannitol.

[0046] In formula (I), when m is 0, s is an integer of 3 to 5, when m is 1, s is an integer of 2 to 4, and E is a group represented by formula (IIa) to formula (IIc):

[0047]

[0048] (wherein * indicates the bonding position). Note that * indicates the bonding position, not the carbon atom. In other words, "*-" indicates a single bond.

[0049] The linker represented by formula (IIa) is a linker having a structure obtained by removing a hydroxy group from glycerin, the linker represented by formula (IIb) is a linker having a structure obtained by removing a hydroxy group from pentaerythritol, and the linker represented by formula (IIc) is a linker having a structure obtained by removing a hydroxy group from a pentitol (e.g., xylitol).

[0050] In formula (I), when m is 0, s is an integer of 3 or 4, and when m is 1, s is an integer of 2 or 3, and E is more preferably a linker represented by formula (IIa) or formula (IIb).

[0051] (Porous Metal Complex) In the present invention, the separation of a branched polyethylene glycol compound and a linear polyethylene glycol compound using a porous metal complex is achieved by adsorption of the linear polyethylene glycol compound onto the porous metal complex. Here, the term "porous metal complex" refers to a metal complex having a porous three-dimensional structure formed by metal ions and organic bridging ligands connecting them. Only one type of porous metal complex may be used, or two or more types may be used in combination.

[0052] The pore diameter of the porous metal complex is preferably 0.3 nm or more, more preferably 0.4 nm or more, even more preferably 0.5 nm or more, and is preferably 5 nm or less, more preferably 3 nm or less, even more preferably 2 nm or less, particularly preferably 1.5 nm or less. The pore diameter can be measured by nitrogen gas adsorption, single crystal X-ray diffraction, or powder X-ray diffraction.

[0053] Examples of porous metal complexes include: (i) a metal complex having a structure in which polyhedra composed of metal ions and first organic bridging ligands are three-dimensionally connected, with pores formed between the polyhedra; and (ii) a metal complex having a structure in which two-dimensional sheets composed of metal ions and first organic bridging ligands form layers, with bidentate second organic bridging ligands coordinating to metal cations present in each layer to connect adjacent sheets, with pores formed between them. Note that the metal complex (i) differs from the metal complex (ii) in that it does not contain a second organic bridging ligand.

[0054] The porous metal complexes used in the present invention broadly include porous metal complexes known as MOFs. The pores of the porous metal complexes are preferably linear tunnel-shaped pores.

[0055] Examples of metal ions of the porous metal complex include ions of metals belonging to Groups 1 to 13 of the periodic table. Examples of metals include zinc, copper, aluminum, gold, platinum, silver, ruthenium, tin, palladium, rhodium, iridium, osmium, nickel, cobalt, iron, yttrium, magnesium, manganese, titanium, zirconium, hafnium, calcium, cadmium, vanadium, chromium, molybdenum, and scandium. The metal ion is preferably an ion of a metal belonging to Groups 6 to 13, more preferably a zinc ion, copper ion, or aluminum ion, and even more preferably a zinc ion.

[0056] Examples of the first organic bridging ligand of the porous metal complex include: (i) a compound in which two, three, or four carboxy groups are bonded to an aromatic compound such as benzene, naphthalene, anthracene, phenanthrene, fluorene, indane, indene, pyrene, 1,4-dihydronaphthalene, tetralin, biphenylene, triphenylene, acenaphthylene, or acenaphthene (the compound may contain a halogen atom (e.g., F, Cl, Br, or I), a nitro group, an amino group, an acylamino group (e.g., an acetylamino group), a cyano group, a hydroxy group, or a methylenedioxy group (—O—CH ２ -O-), ethylenedioxy group (-O-CH ２ CH ２ -O-), a linear or branched alkoxy group having 1 to 4 carbon atoms (for example, a methoxy group or an ethoxy group), a linear or branched alkyl group having 1 to 4 carbon atoms (for example, a methyl group, an ethyl group, a propyl group, a tert-butyl group or an isobutyl group), -SH, a trifluoromethyl group, a sulfo group, a carbamoyl group, an alkylamino group (for example, a methylamino group), or a dialkylamino group (for example, a dimethylamino group), which may be substituted with 1 to 3 substituents selected from the group consisting of: (i) an anion of a cyclic saturated aliphatic polycarboxylic acid having 5 to 12 carbon atoms (for example, 1,2-cis-cyclopropanedicarboxylic acid, 1,2-trans-cyclopropanedicarboxylic acid, 1,3-cis-cyclobutanedicarboxylic acid, 1,3-trans-cyclobutanedicarboxylic acid, 1,4-cis-cyclohexanedicarboxylic acid, 1,4-trans-cyclohexanedicarboxylic acid, or 1,3-adamantanedicarboxylic acid), (iii) Anions of unsaturated dicarboxylic acids (for example, (1α,2α,4α)-1,2,4-cyclohexanetricarboxylic acid, fumaric acid, maleic acid, citraconic acid, and itaconic acid).

[0057] The first organic bridging ligand is preferably an isophthalate ion, a 5-methoxyisophthalate ion, a 5-methylisophthalate ion, a 5-fluoroisophthalate ion, a 5-chloroisophthalate ion, a 5-bromoisophthalate ion, a 5-iodoisophthalate ion, a 5-nitroisophthalate ion, a 5-cyanoisophthalate ion, a terephthalate ion, a 2-methylterephthalate ion, a 2-methoxyterephthalate ion, a 2-nitroterephthalate ion, a dihydrocyclobuta[1,2-b]terephthalate ion, 4,4′-dicarboxydiphenylsulfone, a 1,4-naphthalenedicarboxylic acid ion, a 2,6 ... dicarboxylate ion, 9,10-anthracenedicarboxylate ion, 2,3-pyrazinedicarboxylate ion, tetrafluoroterephthalate ion, 4,4'-bibenzoate ion, octafluoro-4,4'-bibenzoate ion, 4,4'-biphenyldicarboxylate ion, 2,7-fluorenedicarboxylate ion, 2,7-pyrenedicarboxylate ion, 4,5,9,10-tetrahydropyrene-2,7-dicarboxylate ion, succinate ion, maleate ion, fumarate ion, acetylenedicarboxylate, and the like, and more preferably terephthalate ion or 1,4-naphthalenedicarboxylate ion.

[0058] The porous metal complex comprises a monodentate ligand (e.g., O ２－ , H ２ O, OH － , OF － , F － The use of monodentate ligands allows for the control of the crystal size of the complex.

[0059] As the monodentate ligand, a monodentate organic ligand may be used. Examples of the monodentate organic ligand include monocarboxylic acid ions. Examples of the monocarboxylic acid include formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, pyruvic acid, butanoic acid, pentanoic acid, hexanoic acid, and cyclohexanecarboxylic acid.

[0060] Examples of the second organic bridging ligand of the porous metal complex include pyrazine, trans-1,2-bis(4-pyridyl)ethylene, 1,4-dicyanobenzene, 4,4'-dicyanobiphenyl, 1,2-dicyanoethylene, 1,4-bis(4-pyridyl)benzene, triethylenediamine, 4,4'-bipyridine, diazapyrene, 2,5-dimethylpyrazine, 2,2'-dimethyl-4,4'-bipyridine, 1,2-bis(4-pyridyl)ethyne, 1,4-bis(4-pyridyl)butadiyne, 1,4-bis(4-pyridyl)benzene, and 3,6-di(4-pyridyl)-1,2,4,5-tetramethylpyrazine. azine, 2,2'-bi-1,6-naphthyridine, phenazine, 2,6-di(4-pyridyl)-benzo[1,2-c:4,5-c']dipyrrole-1,3,5,7(2H,6H)-tetrone, N,N'-di(4-pyridyl)-1,4,5,8-naphthalenetetracarboxydiimide, trans-1,2-bis(4-pyridyl)ethene, 4,4'-azopyridine, 1,2-bis(4-pyridyl)ethane, 4,4'-dipyridyl sulfide, 1,3-bis(4-pyridyl)propane, 1,2-bis(4-pyridyl)glycol, and N-(4-pyridyl)isonicotinamide. Of these, triethylenediamine is preferred.

[0061] Porous metal complexes that can be used include those described in known literature (e.g., Angew. Chem. Int. Ed. 2004, 43, 2334-2375; Angew. Chem. Int. Ed. 2008, 47, 2-14; Chem. Soc. Rev., 2008, 37, 191-214; PNAS, 2006, 103, 10186-10191; Chem. Rev., 2011, 111, 688-764; Nature, 2003, 423, 705-714).

[0062] Examples of porous metal complexes include, but are not limited to, CD-MOF-1, CD-MOF-2, CD-MOF-3, CPM-13, FJI-1, FMOF-1, HKUST-1, IRMOF-1, IRMOF-2, IRMOF-3, IRMOF-6, IRMOF-8, IRMOF-9, IRMOF-13, IRMOF-20, JUC-48, JUC-62, MIL-101, MIL-100, MIL-125, MIL-53, MIL-88 (MIL- 88A, MIL-88B, MIL-88C, MIL-88D series), MOF-5, MOF-74, MOF-177, MOF-210, MOF-200, MOF-205, MOF-505, MOROF-2, MOROF-1, NOT T-100, NOTT-101, NOTT-102, NOTT-103, NOTT-105, NOTT-106, NOTT-107, NOTT-109, NOTT-110, NOTT-111, NOTT-112, NOTT-113, NOTT -114, NOTT-140, NU-100, rho-ZMOF, PCN-6, PCN-6', PCN9, PCN10, PCN12, PCN12', PCN14, PCN16, PCN-17, PCN-21, PCN46, PCN66, PCN6 8, PMOF-2 (Cu), PMOF-3, SNU-5, SNU-15', SNU-21S, SNU-21H, SNU-50, SNU-77H, UiO-66, UiO-67, soc-MOF, sod-ZMOF, TUDMOF-1, UMCM -2, UMCM-150, UTSA-20, ZIF-2, ZIF-3, ZIF-4, ZIF-8, ZIF-9, ZIF- 10, ZIF-11, ZIF-12, ZIF-14, ZIF-20, ZIF-21, ZIF-23, ZIF-60, ZIF -61, ZIF-62, ZIF-64, ZIF-65, ZIF-67, ZIF-68, ZIF-69, ZIF-70, Z IF-71, ZIF-72, ZIF-73, ZIF-74, ZIF-75, ZIF-76, ZIF-77, ZIF-90.

[0063] Specific examples of porous metal complexes include: Zn ２ (1,4-benzenedicarboxylate) ２Triethylenediamine (Zn2(1,4-benzenedicarboxylate)2triethylenediamine) (pore diameter = 7.5 Å), Zn ２ (1,4-naphthalenedicarboxylate) ２ Triethylenediamine (Zn2(1,4-naphthalenedicarboxylate)2triethylenediamine) (pore diameter = 5.7 Å), IRMOF-1, i.e., Zn ４ O (BDC) ３ (BDC = 1,4-benzenedicarboxylate, pore size = 15.0 Å), MOF-69C, i.e., Zn ３ (OH) ２ (BDC) ２ (pore diameter = 6.5 Å), MOF-74, i.e., M ２ (DOBDC) (DOBDC = 2,5-dihydroxyterephthalate, M = Zn, Co, Ni, or Mg, pore size = 11.0 Å), HKUST-1, i.e., Cu ３ (BTC) ２ (BTC = 1,3,5-benzenetricarboxylate, pore size = 9.0 Å), MOF-177, i.e., Zn ４ O (BTB) ２ (BTB = 4,4',4"-benzene-1,3,5-triyl-tribenzoate, pore size = 11.8 Å), MOF-508, i.e., Zn(BDC)(bpy) ０．５ (bpy = 4,4'-bipyridine, pore size = 4.0 Å), Zn-BDC-DABCO, i.e., Zn ２ (BDC) ２ (DABCO) (DABCO = (1,4-diazabicyclo[2.2.2]-octane), pore size = 7.5 Å), Cr-MIL-101, i.e., Cr ３ F (H ２O) ２ O (BDC) ３ (pore diameter = 29.0 Å), Al-MIL-110, i.e., Al ８ (OH) １２ [(OH) ３ (H ２ O) ３ ](BTC)3 (pore diameter = 16.0 Å), MIL-103, i.e., M(BTB) (M = light rare-earth element = any of La (lanthanum) to Ho (holmium), pore diameter = 10.7 Å), Al-MIL-53, i.e., Al(OH)(BDC) (pore diameter = 8.5 Å), ZIF-8, i.e., Zn(MeIM) ２ (MeIM = 2-methylimidazole, pore size = 12.0 Å), MIL-88B, i.e., Cr ３ OF (BDC) ３ (pore diameter = 15.6 Å), MIL-88C, i.e., Fe ３ O (NDC) ３ (NDC = 2,6-naphthalenedicarboxylate, pore size = 18.7 Å), MIL-88D, i.e., Cr ３ OF (BPDC) ３ (BPDC = 4,4'-biphenyldicarboxylate, pore size = 20.5 Å), CID-1, i.e., Zn ２ (ip) ２ (bpy) ２ (ip = isophthalate, bpy = 4,4'-bipyridine, pore size = 5.0 Å), ZrO(BPCD) (pore size = 6.4 Å), Al(OH)(NDC) (pore size = 8.5 Å).

[0064] The porous metal complex is preferably Zn ２ (1,4-benzenedicarboxylate) ２ Triethylenediamine and Zn ２ (1,4-naphthalenedicarboxylate) ２triethylenediamine, and more preferably Zn ２ (1,4-benzenedicarboxylate) ２ Triethylenediamine or Zn ２ (1,4-naphthalenedicarboxylate) ２ It is triethylenediamine.

[0065] The porous metal complex can be produced by a known method (for example, the method described in Chun, H. et al., Chem. Eur. J. 2005, 11, 3521-3529).

[0066] (Method for Producing High-Purity Branched Polyethylene Glycol Compound) The method for producing a high-purity branched polyethylene glycol compound (hereinafter sometimes abbreviated as "branched PEG compound") of the present invention comprises: a step (1) of mixing a mixture containing a branched PEG compound and a linear polyethylene glycol compound (hereinafter sometimes abbreviated as "linear PEG compound") as an impurity with a porous metal complex in the presence or absence of a solvent, thereby allowing the linear PEG compound to be adsorbed onto the porous metal complex; and, when the mixing in step (1) is carried out in the presence of a solvent, a step (2a) of removing the porous metal complex having the linear PEG compound adsorbed thereon from the mixture containing the porous metal complex having the linear PEG compound adsorbed thereon and the branched PEG compound, thereby obtaining a solution containing the branched PEG compound; or When the mixing in step (1) is carried out in the absence of a solvent, the method includes step (2b) of mixing a mixture containing the porous metal complex having adsorbed thereon a linear PEG compound and the branched PEG compound with a solvent, and removing the porous metal complex having adsorbed thereon the linear PEG compound from the mixture thus obtained to obtain a solution containing the branched PEG compound; and step (3) of recovering the branched PEG compound from the solution containing the branched PEG compound.

[0067] <Step (1)> The mixing in step (1) is carried out in the presence or absence of a solvent. In this specification, "step (1) in which mixing is carried out in the presence of a solvent" may be referred to as "step (1a)," and "step (1) in which mixing is carried out in the absence of a solvent" may be referred to as "step (1b)."

[0068] The amount of the porous metal complex used in step (1a) or step (1b) is preferably 15 to 105 parts by mass, more preferably 25 to 95 parts by mass, per 100 parts by mass of the branched-chain PEG compound, from the viewpoints of operability and separability.

[0069] Step (1) is preferably step (1a). Therefore, the production method of the present invention preferably includes steps (1a), (2a), and (3). The solvent used in step (1a) is preferably at least one selected from the group consisting of N,N-dimethylformamide (DMF), ethanol, ethyl acetate, chloroform, and toluene, and more preferably DMF or toluene.

[0070] The amount of the solvent used in step (1a) is preferably 250 to 400 parts by mass, more preferably 300 to 360 parts by mass, per 100 parts by mass of the branched chain PEG compound, from the viewpoint of the viscosity of the mixture in step (1).

[0071] The mixing temperature in step (1a) or step (1b) is preferably 25 to 150°C, more preferably 60 to 100°C, and the mixing time is preferably 1 to 24 hours, more preferably 2 to 8 hours.

[0072] The mixing in step (1a) or (1b) may be performed in an air atmosphere or an inert atmosphere (e.g., a nitrogen atmosphere). From the viewpoint of simplicity, the mixing in step (1a) or (1b) is preferably performed in an air atmosphere.

[0073] <Step (2a) or Step (2b)> Step (2a) is carried out after step (1a), and step (2b) is carried out after step (1b).

[0074] A solvent may be added to the mixture obtained in step (1a), and the resulting mixture (i.e., a diluted product) may be used in step (2a). The solvent is at least one selected from the group consisting of N,N-dimethylformamide (DMF), ethanol, ethyl acetate, chloroform, and toluene, and more preferably DMF, chloroform, or toluene. From the viewpoint of the viscosity of the diluted product, the amount of the solvent used is preferably 500 to 2,000 parts by mass, more preferably 1,000 to 1,400 parts by mass, per 100 parts by mass of the branched PEG compound.

[0075] In step (2a), the porous metal complexes having adsorbed linear PEG compounds are removed from a mixture containing the porous metal complexes having adsorbed linear PEG compounds and the branched PEG compounds (e.g., the mixture obtained in step (1a) or a dilution thereof), to obtain a solution containing the branched PEG compounds.

[0076] In step (2b), a mixture containing the porous metal complex having the linear PEG compound adsorbed thereon and the branched PEG compound is mixed with a solvent, and the porous metal complex having the linear PEG compound adsorbed thereon is removed from the resulting mixture to obtain a solution containing the branched PEG compound.

[0077] The solvent used in step (2b) is preferably at least one selected from the group consisting of N,N-dimethylformamide (DMF), ethanol, ethyl acetate, chloroform, and toluene, more preferably chloroform. The amount of the solvent used in step (2b) is preferably 1,000 to 1,200 parts by mass, more preferably 800 to 1,000 parts by mass, per 100 parts by mass of the branched PEG compound, from the viewpoint of the viscosity of the mixture in step (2b).

[0078] In step (2b), the temperature for mixing the mixture containing the porous metal complex having the linear PEG compound adsorbed thereon and the branched PEG compound with the solvent is preferably 20 to 50°C, more preferably 25 to 45°C, and the mixing time is preferably 5 to 30 minutes, more preferably 10 to 20 minutes.

[0079] The mixing in step (2b) may be performed in an air atmosphere or an inert atmosphere (e.g., a nitrogen atmosphere). From the viewpoint of simplicity, the mixing in step (2b) is preferably performed in an air atmosphere.

[0080] In step (2a) or step (2b), the means for removing the porous metal complex to which the linear PEG compound has been adsorbed is not particularly limited, and the porous metal complex can be removed by known means (e.g., filtration or centrifugation).

[0081] <Step (3)> In step (3), the branched PEG compound is recovered from the solution containing the branched PEG compound. The recovery means is not particularly limited, and the branched PEG compound can be recovered by known means (e.g., solid-liquid separation by solvent distillation or addition of a poor solvent).

[0082] When the solvent is distilled off from the solution containing the branched PEG compound, the temperature is preferably 20 to 60°C, more preferably 35 to 45°C, the pressure is preferably 2 to 20 kPa, more preferably 5 to 15 kPa, and the time is preferably 0.5 to 4 hours, more preferably 1 to 2 hours.

[0083] The poor solvent for solid-liquid separation is preferably at least one selected from the group consisting of n-hexane, diethyl ether, and methyl tert-butyl ether, more preferably n-hexane. The amount of the poor solvent used is preferably 100 to 200 parts by mass, more preferably 120 to 180 parts by mass, per 100 parts by mass of the solvent in the solution containing the branched chain PEG compound. The temperature when the poor solvent is added to the solution containing the branched chain PEG compound is preferably 25 to 45°C, more preferably 30 to 40°C.

[0084] The solid containing the branched PEG compound precipitated by the addition of the anti-solvent can be recovered by known means (for example, filtration or centrifugation).

[0085] The mixture containing a branched PEG compound and a linear PEG compound used in step (1a) or (1b) is preferably obtained by the following steps (P1) and (P2). That is, the production method of the present invention preferably includes steps (P1), (P2), (1a), (2a), and (3), or steps (P1), (P2), (1b), (2b), and (3), and more preferably includes steps (P1), (P2), (1a), (2a), and (3).

[0086] <Step (P1)> Step (P1) is a step of alcoholating a portion of a polyol compound represented by any one of the following formulas (iia) to (iic) (hereinafter sometimes abbreviated as "polyol compound").

[0087]

[0088] The reactant for alcoholating the polyol compound is preferably an alkali metal salt such as sodium methoxide or potassium hydroxide. The amount of the reactant (preferably the alkali metal salt) used relative to the polyol compound is preferably 5 to 50 mol %, more preferably 15 to 40 mol %, from the viewpoint of the rate of addition polymerization of ethylene oxide in step (P2). Here, "the amount of the reactant used relative to the polyol compound" means "100 × amount of reactant (mol) / amount of polyol compound (mol)".

[0089] If the amount of reactant (preferably an alkali metal salt) used for the polyol compound in step (P1) is less than 5 mol%, the rate of addition polymerization of ethylene oxide in step (P2) will be slow, increasing thermal history and generating impurities such as terminal vinyl ethers. Therefore, it is advantageous to set the amount used to 5 mol% or more in order to produce a high-quality polymer. On the other hand, if the amount used exceeds 50 mol%, the viscosity of the reaction mixture will increase or solidify during the alcoholation reaction, reducing stirring efficiency and tending not to promote alcoholation.

[0090] The reaction temperature between the polyol compound and the reactant (preferably an alkali metal salt) is preferably 10 to 50°C, more preferably 20 to 40°C. If the reaction temperature is higher than 50°C, the polyol compound undergoes a decomposition reaction, producing low-molecular-weight impurities. If the reaction temperature is lower than 10°C, the reaction mixture tends to become viscous or solidify, making it difficult to handle.

[0091] The reaction time for the alcoholation in step (P1) is preferably 1 to 24 hours, more preferably 6 to 18 hours. If the reaction time is shorter than 1 hour, the alcoholation reaction may not proceed sufficiently. If the reaction time is longer than 24 hours, decomposition of the polyol compound may occur.

[0092] The alcoholation reaction in step (P1) is preferably carried out in the presence of an aprotic solvent. Examples of aprotic solvents include toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, dimethyl sulfoxide, N,N-dimethylformamide, and dimethylacetamide. The aprotic solvent may be used alone or in combination of two or more. Toluene is preferred as the aprotic solvent. The alcoholation reaction in step (P1) may also be carried out in the absence of a solvent.

[0093] When an aprotic solvent is used, the amount thereof is preferably 1,000 to 3,000 parts by mass, more preferably 1,500 to 2,500 parts by mass, per 100 parts by mass of the polyol compound.

[0094] In step (P1), in order to promote the alcoholation reaction, the alcoholation reaction is carried out while removing low-molecular-weight compounds produced in the alcoholation reaction (for example, methanol produced by the reaction of a polyol compound with sodium methoxide, or water produced by the reaction of a polyol compound with potassium hydroxide) under reduced pressure. Therefore, the pressure during the alcoholation reaction is preferably 5 to 35 kPa, more preferably 10 to 30 kPa.

[0095] In the step (P1), a mixture containing a polyol compound and an alcoholate (hereinafter abbreviated as "the mixture of the step (P1)") is obtained.

[0096] <Step (P2)> Step (P2) is a step of carrying out addition polymerization of ethylene oxide. Specifically, step (P2) is a step of carrying out addition polymerization by supplying ethylene oxide to the mixture of step (P1). From the viewpoints of reaction pressure and safety, the supply rate of ethylene oxide (g / h / mol) is preferably 50 to 250 g / h / mol, more preferably 100 to 200 g / h / mol. The "supply rate of ethylene oxide (g / h / mol)" refers to the amount of ethylene oxide supplied (g) per hour per mol of the total of the polyol compound and the alcoholate.

[0097] The temperature for the addition polymerization of ethylene oxide is preferably 50 to 130°C, more preferably 60 to 120°C. If this temperature is lower than 50°C, the rate of addition polymerization is slow and the thermal history increases, which tends to reduce the quality of the resulting branched-chain PEG compound. If this temperature is higher than 130°C, side reactions such as vinyl etherification of the terminals tend to occur during the addition polymerization, which tends to reduce the quality of the resulting branched-chain PEG compound. There are no particular limitations on the addition polymerization time, and the addition polymerization may be carried out until a branched-chain PEG compound having the desired molecular weight is obtained.

[0098] The addition polymerization of ethylene oxide is preferably carried out in the presence of an aprotic solvent. Examples of aprotic solvents include toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, dimethyl sulfoxide, N,N-dimethylformamide, and dimethylacetamide. The aprotic solvent may be used alone or in combination of two or more. Toluene is preferred as the aprotic solvent.

[0099] When an aprotic solvent is used, the amount thereof is preferably 200 to 1800 parts by mass, more preferably 500 to 1500 parts by mass, per 100 parts by mass of the mixture in step (P1).

[0100] After the addition polymerization in step (P2), it is preferable to treat the reaction mixture with an acid such as phosphoric acid. Such acid treatment gives a mixture containing a branched PEG compound, compound (I) of formula (I), in which m is 0, s is 3 to 5, s n's are each a number from 20 to 2000, s X's are hydroxy groups, and E is a linker represented by any one of formulas (IIa) to (IIc), and a linear PEG compound as an impurity (hereinafter abbreviated as the "mixture of step (P2)").

[0101] When the addition polymerization of ethylene oxide in step (P2) is carried out in the presence of an aprotic solvent, the mixture of step (P2) can be recovered from a solution containing the mixture of step (P2), and the obtained mixture can be used to carry out step (1) (i.e., step (1a) or step (1b)). There are no particular limitations on the means for this recovery, and the mixture of step (P2) can be recovered by known means (for example, solid-liquid separation by distilling off the solvent or adding a poor solvent).

[0102] When the solvent is distilled off from the solution containing the mixture in step (P2), the temperature is preferably 30 to 70°C, more preferably 40 to 60°C, the pressure is preferably 2 to 20 kPa, more preferably 5 to 15 kPa, and the time is preferably 0.5 to 4 hours, more preferably 1 to 2 hours.

[0103] The poor solvent for solid-liquid separation is preferably at least one selected from the group consisting of n-hexane, diethyl ether, and methyl tert-butyl ether, more preferably n-hexane. The amount of the poor solvent used is preferably 500 to 3,000 parts by mass, more preferably 1,000 to 3,000 parts by mass, per 100 parts by mass of the solvent in the solution containing the mixture of step (P2). The temperature when the poor solvent is added to the solution containing the mixture of step (P2) is preferably 25 to 45°C, more preferably 30 to 40°C.

[0104] The mixture of step (P2) can be used to carry out step (1) (i.e., step (1a) or step (1b)). That is, in step (1), the mixture of step (P2) and a porous metal are mixed in the presence or absence of a solvent, thereby allowing the linear PEG compound to be adsorbed onto the porous metal complex.

[0105] When the addition polymerization of ethylene oxide in step (P2) is carried out in the presence of an aprotic solvent, the solution containing the mixture obtained in step (P2) can be used to carry out step (1a). That is, in step (1a), the solution containing the mixture of step (P2) is mixed with a porous metal, thereby allowing the linear PEG compound to be adsorbed onto the porous metal complex.

[0106] The present invention will be described in more detail below based on examples, but the present invention is not limited to the embodiments of the examples.

[0107] In the examples, the following porous metal complexes were used: MOF(1): Zn ２ (1,4-benzenedicarboxylate) ２ Triethylenediamine (Zn2(1,4-benzenedicarboxylate)2triethylenediamine) (pore size: 0.75 nm) ("AP3025" manufactured by Atomis Co., Ltd.) MOF (2): Zn ２ (1,4-naphthalenedicarboxylate) ２ Triethylenediamine (Zn2(1,4-naphthalenedicarboxylate)2triethylenediamine) (pore diameter: 0.57 nm) (produced by the method described in Nature Communication (2018) 9; 3635). The pore diameters of MOF (1) and MOF (2) were measured by nitrogen gas adsorption.

[0108] Hereinafter, "polyethylene glycol" may be abbreviated as "PEG." In the following Examples 1 to 9, "PEG mixture" refers to a mixture containing a branched PEG compound and a linear PEG compound that has not been treated with a porous metal complex. The PEG mixture does not contain a solvent. In the following Examples 1 to 9, "main fraction purity" refers to the purity of the branched PEG compound, and "linear PEG content" refers to the content of the linear PEG compound.

[0109] In the following Comparative Example 1, "PEG mixture" refers to a mixture containing a high molecular weight branched PEG compound with an Mn of 40,000 and a low molecular weight branched PEG compound with an Mn of 20,000 that has not been treated with a porous metal complex. The PEG mixture does not contain a solvent. In the following Comparative Example 1, "main fraction purity" refers to the purity of the high molecular weight branched PEG compound, and "low molecular weight PEG content" refers to the content of the low molecular weight branched PEG compound.

[0110] (Evaluation Method) (i) Mn of the PEG compounds used in the following Examples 1 to 9 and Comparative Example 1, and (ii) the main fraction purity, linear PEG content (or low-molecular-weight PEG content), and polydispersity (hereinafter abbreviated as "Mw / Mn") of the raw materials (PEG mixtures) and the target products obtained in the following Examples 1 to 7 and 9 and Comparative Example 1 were calculated by gel permeation chromatography (GPC) measurement (standard: polyethylene glycol) under the following conditions. Note that the Mw / Mn of the raw materials (PEG mixtures) and the target products obtained in Example 8 were not calculated. <GPC Measurement Conditions> Apparatus: "Prominence" manufactured by Shimadzu Corporation Detector: RI Column: PLgel 5 μm MIXED-D 300 × 7.5 mm (two columns connected) Mobile phase: N,N-dimethylformamide Flow rate: 0.7 mL / min

[0111] The purity of the main fraction and the linear PEG content of the raw material (PEG mixture) used in Example 8 and the target product obtained were calculated by derivatizing the hydroxyl groups at the PEG terminals with 3,5-dinitrobenzoyl chloride and then performing reverse-phase high-performance liquid chromatography (RP-HPLC) measurement under the following conditions: <RP-HPLC Measurement Conditions> Apparatus: "Alliance" manufactured by Waters Corporation Detector: UV (210 nm) Column: Zorbax 300SB-C18 (3.0 x 150 mm) Mobile phase A: Water Mobile phase B: Acetonitrile Flow rate: 0.6 mL / min Gradient conditions: As shown in Table 1.

[0112]

[0113] Example 1 A PEG mixture (main fraction purity = 95.98%, linear PEG content = 3.32 mass%, Mw / Mn = 1.033, 0.3 g) containing a branched PEG compound represented by the following formula (III) (Mn = 41,223) and a linear PEG compound represented by the following formula (IV) (Mn = 20,857) and MOF (2) (0.1 g) were weighed into a glass flask and mixed with N,N-dimethylformamide (DMF) (0.9 g). The mixture was stirred at 80°C for 5 hours, cooled, diluted with chloroform (3 g), and centrifuged to separate MOF (2) and a solution containing branched PEG. The solvent of the resulting solution was distilled off at a temperature of 40°C and a pressure of 10 KPa for 1 hour to obtain the target product. The purity of the main fraction of the target product was 97.04%, the linear PEG content was 2.36% by mass, and Mw / Mn was 1.029.

[0114]

[0115]

[0116] Example 2 A PEG mixture (main fraction purity = 88.05%, linear PEG content = 11.63% by mass, Mw / Mn = 1.068) containing a branched PEG compound represented by formula (III) (Mn = 40,376, main fraction purity = 99.33%, linear PEG content = 0% by mass, Mw / Mn = 1.024, 0.27 g) and a linear PEG compound represented by formula (V) (Mn = 20,598, 0.03 g) was weighed into a glass flask and mixed with N,N-dimethylformamide (0.9 g). The mixture was stirred at 80°C for 2 hours, cooled, diluted with chloroform (3 g), and centrifuged to separate MOF (2) and a solution containing the branched PEG compound. The solvent in the resulting solution was distilled off at a temperature of 40°C under a pressure of 10 kPa for 1 hour to obtain the target product, which had a main fraction purity of 92.19%, a linear PEG content of 7.30% by mass, and an Mw / Mn of 1.051.

[0117]

[0118] In Example 2, a PEG mixture was used, obtained by adding a linear PEG compound represented by formula (V) to a branched PEG compound represented by formula (III). The terminal functional groups of both the branched PEG compound and the linear PEG compound are a hydroxyl group and a benzyloxy group, and the difference between these two PEG compounds is their branched or linear structure. The main fraction purity of the target product obtained by the method of Example 2 was improved compared to the main fraction purity of the PEG mixture, demonstrating that the production method of the present invention can remove linear PEG compounds from a PEG mixture to obtain high-purity branched PEG compounds, regardless of the difference in terminal functional groups.

[0119] Example 3 A PEG mixture (main fraction purity = 87.74%, linear PEG content = 11.62% by mass, Mw / Mn = 1.042) containing a branched PEG compound represented by the following formula (VI) (Mn = 34,302, main fraction purity = 95.74%, linear PEG content = 3.32% by mass, Mw / Mn = 1.044, 0.27 g) and a linear PEG compound represented by the above formula (IV) (Mn = 21,172, 0.03 g) was weighed into a glass flask and mixed with N,N-dimethylformamide (0.9 g). The mixture was stirred at 80°C for 2 hours, cooled, diluted with N,N-dimethylformamide (3 g), and filtered to separate the solution containing MOF (2) and branched PEG. To the resulting solution, n-hexane (6.0 g) was added at 35°C to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product was 92.55%, the linear PEG content was 7.00% by mass, and Mw / Mn was 1.032.

[0120]

[0121] In Example 3, a PEG mixture was used, obtained by adding a linear PEG compound represented by formula (IV) to a branched PEG compound represented by formula (VI). The terminal functional groups of both the branched PEG compound and the linear PEG compound are hydroxy groups, and the differences between these two PEG compounds are the presence or absence of a branched structure and their molecular weights. The main fraction purity of the target product obtained by the method of Example 3 was improved compared to the main fraction purity of the PEG mixture, demonstrating that the production method of the present invention can remove linear PEG compounds from a PEG mixture to obtain high-purity branched PEG compounds, regardless of the difference in terminal functional groups.

[0122] Example 4 A PEG mixture (main fraction purity = 89.28%, linear PEG content = 10.22% by mass, Mw / Mn = 1.077) containing the branched PEG compound represented by formula (III) (Mn = 40,488, main fraction purity = 99.33%, linear PEG content = 0% by mass, Mw / Mn = 1.024, 0.27 g) and the linear PEG compound represented by formula (IV) (Mn = 18,945, 0.03 g) was weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and branched PEG. To the resulting solution, n-hexane (6.0 g) was added at 35°C to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product obtained was 99.41%, the linear PEG content was 0% by mass, and Mw / Mn was 1.020.

[0123] Example 5 A PEG mixture containing the branched PEG compound represented by the formula (III) (Mn = 19,774, main fraction purity = 98.27%, linear PEG content = 1.72% by mass, Mw / Mn = 1.038, 0.27 g) and the linear PEG compound represented by the formula (IV) (Mn = 9,943, 0.03 g) (main fraction purity = 88.07%, linear PEG content = 11.93% by mass, Mw / Mn = 1.070), and MOF (1) (0.225 g) were weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and branched PEG. To the resulting solution, n-hexane (6.0 g) was added at 35°C to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product obtained was 98.95%, the linear PEG content was 0% by mass, and Mw / Mn = 1.027.

[0124] Example 6 A PEG mixture (main fraction purity = 90.73%, linear PEG content = 9.37% by mass, Mw / Mn = 1.132) containing the branched PEG compound represented by formula (III) (Mn = 5,386, main fraction purity = 100.00%, linear PEG content = 0% by mass, Mw / Mn 1.021, 0.27 g) and the linear PEG compound represented by formula (IV) (Mn = 1,829, 0.03 g) was weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and branched PEG. To the resulting solution, n-hexane (6.0 g) was added at 35°C to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product obtained was 100%, the linear PEG content was 0% by mass, and Mw / Mn = 1.021.

[0125]

[0126] Example 7 A PEG mixture (main fraction purity = 90.11%, linear PEG content = 9.89% by mass, Mw / Mn = 1.108) containing the branched PEG compound represented by formula (VII) (Mn = 4,689, main fraction purity = 100.00%, linear PEG content = 0% by mass, Mw / Mn = 1.020, 0.27 g) and the linear PEG compound represented by formula (IV) (Mn = 1,810, 0.03 g) was weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and branched PEG. To the resulting solution, n-hexane (6.0 g) was added at 35°C to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product obtained was 100%, the linear PEG content was 0% by mass, and Mw / Mn = 1.020.

[0127] Example 8 A PEG mixture (main fraction purity = 90.03%, linear PEG content = 9.97% by mass) containing the branched PEG compound represented by formula (VI) (Mn = 18,091, main fraction purity = 97.30%, linear PEG content = 2.70% by mass, 0.27 g) and the linear PEG compound represented by formula (IV) (Mn = 18,628, 0.03 g) was weighed into a glass flask and mixed with toluene (0.9 g). The mixture was stirred at 80 ° C for 2 hours, cooled, diluted with toluene (3 g), and then filtered to separate the solution containing MOF (1) and the branched PEG. n-Hexane (6.0 g) was added to the resulting solution at 35 ° C to precipitate the branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The purity of the main fraction of the target product obtained was 95.93%, and the linear PEG content was 4.07% by mass.

[0128] A PEG mixture containing branched and linear PEG compounds having similar Mn values ​​was used in Example 8. The purity of the main fraction of the target product obtained by the method of Example 8 was improved compared to the purity of the main fraction of the PEG mixture, indicating that the production method of the present invention can remove linear PEG compounds from a PEG mixture to obtain a highly pure branched PEG compound, even if the branched and linear PEG compounds contained in the PEG mixture have similar Mn values.

[0129] Example 9 A PEG mixture (main fraction purity = 96.21%, linear PEG content = 3.33 mass%, Mw / Mn = 1.034, 0.1 g) containing the branched PEG compound represented by formula (III) (Mn = 40,971) and the linear PEG compound represented by formula (IV) (Mn = 20,487) was weighed and mixed in a glass flask with MOF (2) (0.085 g). The mixture was stirred at 80°C for 2 hours, cooled, diluted with chloroform (3 g), and centrifuged to separate MOF (2) and a solution containing the branched PEG compound. The solvent from the resulting solution was distilled off at a temperature of 40°C and a pressure of 10 kPa for 1 hour to obtain the target product. The purity of the main fraction of the target product obtained was 97.08%, the linear PEG content was 2.45% by mass, and Mw / Mn was 1.029.

[0130] Comparative Example 1 A PEG mixture (main fraction purity = 88.58%, low molecular weight PEG content = 10.81% by mass, Mw / Mn = 1.068) containing a high molecular weight branched PEG compound represented by formula (III) (Mn = 40,551, main fraction purity = 95.98%, low molecular weight PEG content = 3.32% by mass, Mw / Mn = 1.033, 0.27 g) and a branched PEG compound having a molecular weight represented by formula (III) (Mn = 20,124, 0.03 g) was weighed into a glass flask and mixed with N,N-dimethylformamide (0.9 g). The mixture was stirred at 80 ° C. for 2 hours, cooled, diluted with N,N-dimethylformamide (3 g), and filtered to separate the solution containing MOF (2) and branched PEG. To the resulting solution, n-hexane (6.0 g) was added at 35°C to precipitate a branched PEG compound. The precipitated solid was collected by filtration to obtain the target product. The main fraction purity of the target product obtained was 88.87%, the low-molecular-weight PEG content was 10.84% ​​by mass, and Mw / Mn = 1.067.

[0131] In Comparative Example 1, a PEG mixture was used, obtained by adding a branched PEG compound represented by formula (III) above with a different molecular weight. Both of these PEG compounds have a branched structure, and the difference between them is their molecular weight. The main fraction purity of the target product obtained by the method of Comparative Example 1 was not improved compared to the main fraction purity of the PEG mixture, indicating that the PEG compound having a branched structure cannot sufficiently remove PEG compounds having branched structures with different molecular weights, and therefore a highly pure branched PEG compound could not be obtained.

[0132] Table 2 below lists the branched PEG compounds, linear PEG compounds (low molecular weight branched PEG compounds in Comparative Example 1) used in Examples 1 to 9 or Comparative Example 1, the porous metal complexes used (referred to as "MOF" in Table 2), the solvents used in step (1a) (referred to as "solvent" in Table 2), the mixing temperatures in step (1a) or step (1b) (referred to as "mixing temperature" in Table 2), the means for removing the porous metal complexes (referred to as "MOF removal" in Table 2), the main fraction purity and Mw / Mn of the PEG mixture, and the main fraction purity and Mw / Mn of the target product. Note that in Example 8, the Mw / Mn of the PEG mixture and the Mw / Mn of the target product were not calculated.

[0133]

[0134] According to the present invention, a highly pure branched polyethylene glycol compound can be obtained. Such a highly pure branched polyethylene glycol compound can be used, for example, for medical purposes.

[0135] This application is based on Japanese Patent Application No. 2023-169554, the contents of which are incorporated in their entirety herein.

Claims

1. A method for producing a high-purity branched polyethylene glycol compound, comprising: a step (1a) of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the presence of a solvent to allow the linear polyethylene glycol compound to be adsorbed onto the porous metal complex; a step (2a) of removing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon from the mixture containing the porous metal complex having the linear polyethylene glycol compound adsorbed thereon, and the branched polyethylene glycol compound, to obtain a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.

2. A method for producing a high-purity branched polyethylene glycol compound, comprising: a step (1b) of mixing a mixture containing a branched polyethylene glycol compound and a linear polyethylene glycol compound as an impurity with a porous metal complex in the absence of a solvent, and allowing the linear polyethylene glycol compound to be adsorbed onto the porous metal complex; a step (2b) of mixing a mixture containing the porous metal complex to which the linear polyethylene glycol compound has been adsorbed and the branched polyethylene glycol compound with a solvent, and removing the porous metal complex to which the linear polyethylene glycol compound has been adsorbed from the mixture thus obtained, thereby obtaining a solution containing the branched polyethylene glycol compound; and a step (3) of recovering the branched polyethylene glycol compound from the solution containing the branched polyethylene glycol compound.

3. The branched polyethylene glycol compound has the formula (I): (wherein m is 0 or 1; when m is 0, s is an integer of 3 to 9, and when m is 1, s is an integer of 2 to 8; s n's are each independently a number from 20 to 2000; Y and s X's are each independently a hydroxy group which may be substituted with a substituent; and E is a linker having a valence of (s+m).

4. The method according to claim 3, wherein the substituent is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an isoheptyl group, a phenyl group, a benzyl group, a trityl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group.

5. The method according to claim 3, wherein E is a linker having a structure obtained by removing a hydroxy group from glycerin, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, pentaerythritol, dipentaerythritol, tetritol, pentitol, or hexitol.

6. The process according to claim 1 or 2, wherein the solvent used in step (1a) or step (2b) is at least one selected from the group consisting of N,N-dimethylformamide, ethanol, ethyl acetate, chloroform, and toluene.

7. The method according to claim 1 or 2, wherein the branched polyethylene glycol compound has a number average molecular weight of 4,000 to 80,000.

8. The method according to claim 1 or 2, wherein the branched polyethylene glycol compound has a number average molecular weight of 5,000 to 80,000.

9. The method according to claim 1 or 2, wherein the number average molecular weight of the linear polyethylene glycol compound is 1,500 to 90,000.

10. The method according to claim 1 or 2, wherein the number average molecular weight of the linear polyethylene glycol compound is 2,000 to 90,000.

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