Method for producing multi-arm polyethylene glycol derivatives

Abstract

To provide a manufacturing method capable of manufacturing a high purity multi-arm type polyethylene glycol derivative at good efficiency industrially.SOLUTION: There is provided a manufacturing method of a multi-arm type polyethylene glycol derivative having a special structure, conducting processes (A), (B), (C), (D), (E) in this order. (A): keeping only a hydroxyl group at 1-position of polyvalent alcohol having odd numbered hydroxyl groups remain and protecting other even numbered hydroxyl group with cyclic benzylidene acetalization. (B): connecting 2 molecules of the resulting compound and a specific bi-functional compound by an etherification reaction. (C): de-protecting a cyclic benzylidene acetal structure of a terminal of the resulting compound, and release 8 or 12 hydroxyl groups. (D): polymerizing 3 to 600 mole of ethylene oxide to each hydroxyl group of the resulting compound to obtain the multi-arm type polyethylene glycol derivative. (E): functionalizing a hydroxyl group of a terminal of the resulting multi-arm type polyethylene glycol derivative.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a multi-arm polyethylene glycol derivative having a narrow molecular weight distribution. [Background technology]

[0002] Drug delivery systems (DDS) are being developed as an ideal drug administration form for the treatment of various diseases. In particular, the development of drugs that can be modified with polyethylene glycol to improve blood retention has been extensively carried out, and drugs in which cytokines such as interferon and GCSF are modified with polyethylene glycol have been marketed. Until now, polyethylene glycol derivatives with one reactive functional group at the end of the polyethylene glycol were common, but in recent years, multi-arm polyethylene glycols in which multiple functional groups have been introduced into one molecule have come to be used. Since this multi-arm polyethylene glycol has multiple reaction points with drugs, it has the advantage of being able to increase the amount of drug administered per unit weight. However, when polyethylene glycol derivatives with different numbers of functional groups are included, the number of drugs modified in one polyethylene glycol molecule is different, which causes the problem of inconsistency as a pharmaceutical product.

[0003] Taking advantage of the high water solubility and biocompatibility of polyethylene glycol, the development of water-swellable polyethylene glycol hydrogels, which combine polyethylene glycol with other molecules, is also progressing. Polyethylene glycol hydrogels are being considered for various applications in the biomedical field, such as adhesives and hemostatic agents, adhesion inhibitors, drug sustained release carriers, and regenerative medicine materials. For these hydrogels, multi-arm polyethylene glycols with more reactive sites for forming crosslinked structures with other molecules are useful. In particular, when using hydrogels as drug sustained release carriers or regenerative medicine materials, a narrower molecular weight distribution is desired in order to strictly control the permeation and diffusion rate of drugs and proteins, which are cell growth factors, from the gel.

[0004] As a raw material for multi-arm polyethylene glycol, a polyhydric alcohol according to the desired number of functional groups is generally used. For example, ethylene oxide is ring-opened and polymerized using glycerin, etc. for 3-arm polyethylene glycol, and pentaerythritol, etc. for 4-arm polyethylene glycol. These low molecular weight raw materials contain almost no impurities, so it is possible to produce high-quality polyethylene glycol with a relatively narrow molecular weight distribution. On the other hand, 6-arm and 8-arm polyethylene glycols are known to be produced using polyglycerols such as tetraglycerol and hexaglycerol as low molecular weight raw materials. These polyglycerols are usually mixtures containing multiple polymerization degrees and isomers, but because of their high polarity, it is difficult to purify them into single components, so when ethylene oxide is added, low-quality multi-arm polyethylene glycol with a wide molecular weight distribution is produced. Therefore, a method for producing multi-arm polyethylene glycol derivatives with a narrow molecular weight distribution even in more highly branched types is required.

[0005] As such a high-purity 8-arm polyethylene glycol derivative, Patent Document 1 describes a multi-arm polyethylene glycol derivative having a narrow molecular weight distribution. In the method for producing a multi-arm polyethylene glycol derivative described in this document, the low molecular weight compound to which ethylene oxide is added is a compound obtained by protecting the hydroxyl group of a polyhydric alcohol such as xylitol or volemitol by isopropylidene acetalization. However, although not specified in Patent Document 1, when the hydroxyl group of such a polyhydric alcohol is isopropylidene acetalized, an isomer is generally produced as a by-product, and in Patent Document 2, the isomer is removed by purification such as distillation or column chromatography. Thus, in the method of isopropylidene acetalization of the hydroxyl group of a polyhydric alcohol, an isomer is produced as a by-product, and a multi-stage purification process is required to remove the isomer, resulting in a significant decrease in yield. Therefore, further improvement is required for industrial production.

[0006] Non-Patent Document 1 describes the protection of xylitol by benzylidene acetalization. In the protection of xylitol by benzylidene acetalization, the isomer generated in isopropylidene acetalization is not produced as a by-product, and the hydroxyl group at position 1 is left, while the other hydroxyl groups can be protected. However, the document describes only the protection of xylitol, and does not describe a reaction in which a multi-arm polyethylene glycol derivative is synthesized using a protected compound as a raw material. Furthermore, the solubility of benzylidene acetalized xylitol is extremely low, and it is almost insoluble in both water and organic solvents, so that it is very difficult to efficiently convert the hydroxyl group at position 1 by reaction. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Arthur T. Ness, Raymond M. Hann, CS Hudson, J. Am. Chem. Soc., 75,132-134 (1953) [Patent documents]

[0008] [Patent Document 1] JP 2013-227543 A [Patent Document 2] JP 2012-214747 A Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to provide a method for industrially producing, with good yield, high purity multi-arm polyethylene glycol derivatives having a narrow molecular weight distribution, which are suitable for use as materials in DDS and the biomedical fields. [Means for solving the problem]

[0010] As a result of intensive studies to solve the above problems, the present inventors have established a method for producing a multi-arm polyethylene glycol derivative having the following configuration.

[0011] That is, the present invention is as follows.

[0012] (1) A method for producing a multi-arm polyethylene glycol derivative represented by the following formula (1), which comprises carrying out the following steps (A), (B), (C), (D) and (E) in this order: [ka] (In formula (1), L represents a group selected from the group consisting of linear or branched alkylene groups having 3 to 8 carbon atoms, substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and cycloalkylene groups having 6 to 12 carbon atoms; k is 1 or 2, n is the average number of moles of oxyethylene groups added, and n is an integer of 3 to 600. X represents an alkylene group which may have a single bond, an ester bond, a urethane bond, an amide bond, an ether bond, a carbonate bond, a secondary amino group, a urea bond, a thioether bond, or a thioester bond in the chain or at an end thereof; Y represents a chemically reactive functional group.

[0013] Process (A): A process for protecting the even-numbered hydroxyl groups other than the 1-position hydroxyl group of a polyhydric alcohol having an odd number of hydroxyl groups by cyclic benzylidene acetalization, leaving only the 1-position hydroxyl group Process (B): Two molecules of the compound obtained in the above step (A) are linked to a compound represented by the following formula (2) by an etherification reaction to obtain a compound, Woji Purifying by recrystallization in methylformamide [ka] (In formula (2), L represents a group selected from the group consisting of linear or branched alkylene groups having 3 to 8 carbon atoms, substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and cycloalkylene groups having 6 to 12 carbon atoms; A represents a halogen atom selected from chlorine, bromine, or iodine, or a sulfone-based leaving group. Process (C): A step of deprotecting the terminal cyclic benzylidene acetal structure of the compound obtained in step (B), which produces 8 hydroxyl groups when k=1 and 12 hydroxyl groups when k=2. Process (D): A step of polymerizing 3 to 600 moles of ethylene oxide to each hydroxyl group of the compound obtained in the step (C) to obtain a multi-arm polyethylene glycol derivative. Process (E): A step of functionalizing the terminal hydroxyl groups of the multi-arm polyethylene glycol derivative obtained in the step (D).

[0014] (2) The method according to (1), wherein the step (A) is carried out using an acidic solution as a solvent.

[0015] ( 3 The method according to (1), wherein the step (C) is carried out under acidic conditions. Effect of the Invention

[0016] The present invention is a novel method for producing multi-arm polyethylene glycol derivatives suitable for material applications in the new bio-medical field, not limited to DDS. In this production method, even-numbered hydroxyl groups of the raw material polyhydric alcohol such as xylitol or volemitol can be efficiently protected by benzylidene acetalization while leaving the hydroxyl group at the first position. The compound in which the protector is bonded with a linker has very high crystallinity, and can be purified by recrystallization alone without the need for specific purification, as compared with the conventional method via isopropylidene protector. Then, by removing the benzylidene acetal, a low-molecular-weight raw material with almost no impurities having different numbers of functional groups can be obtained. In addition, by polymerizing ethylene oxide to the low-molecular-weight raw material, a high-purity multi-arm polyethylene glycol derivative can be obtained. Then, the terminal hydroxyl groups of the obtained polyoxyethylene chain can be functionalized to effectively modify multiple drugs, and a multi-arm polyethylene glycol derivative that can be used as a hydrogel can be obtained. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The multi-arm polyethylene glycol derivative according to the present invention is represented by the following formula (1):

[0018] [ka]

[0019] In the formula (1) of the present invention, L represents a group selected from a linear or branched alkylene group having 3 to 8 carbon atoms, a substituted or unsubstituted arylene group having 6 to 12 carbon atoms, and a cycloalkylene group having 6 to 12 carbon atoms.

[0020] Examples of the alkylene group include alkylene groups having 3 to 8 carbon atoms, and specific examples thereof include, for example, ethylene, propylene, isopropylene, n-butylene, s-butylene, t-butylene, pentamethylene, hexamethylene, heptamethylene, and octamethylene. Examples of the arylene group include substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and examples thereof include phenylene, naphthylene, and anthrylene. Examples of the cycloalkylene group include cycloalkylene groups having 6 to 12 carbon atoms, and specific examples thereof include, for example, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, and cyclodecylene. If the carbon number of L is less than 3, the effect of the hydrophobic group is not obtained, and the polymer is not dispersed in an organic solvent when ethylene oxide is added, and the molecular weight distribution may become broad. Furthermore, when the number of carbon atoms in L is greater than 12, the surface activity of the molecule increases, and there is a risk that the expected performance will not be exhibited when considering application to a pharmaceutical modifying agent. L is preferably a propylene group, an isopropylene group, an n-butylene group, an s-butylene group, a t-butylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, or an octamethylene group, and more preferably an n-butylene group.

[0021] In formula (1), k represents 1 or 2, and is preferably 1. When k is 1, the structure is a xylitol structure, and when k is 2, the structure is a volemitol structure.

[0022] In formula (1), n ​​is the average number of moles of oxyethylene groups added, and n is usually 3 to 600, preferably 5 to 300, and more preferably 12 to 250. The molecular weight of the compound of formula (1) that is suitably used is 1,500 to 160,000, and preferably 4,000 to 140,000.

[0023] X is a linker between the polyoxyethylene group and the reactive functional group Y. The linker may not be present, in which case it is defined as a single bond. There is no particular limitation as long as it is a covalent bond, and any bond that is usually used as a linker may be used, but preferred examples include an alkylene group alone, or an alkylene group having an ether bond, an ester bond, a urethane bond, an amide bond, a carbonate bond, a secondary amino group, a urea bond, a thioether bond, or a thioester bond in the alkylene chain or at the end. The number of carbon atoms in the alkylene group is preferably 1 to 12.

[0024] A preferred example of the alkylene group is a structure such as (x1). A preferred example of the alkylene group having an ether bond is a structure such as (x2). A preferred example of the alkylene group having an ester bond is a structure such as (x3). A preferred example of the alkylene group having a urethane bond is a structure such as (x4). A preferred example of the alkylene group having an amide bond is a structure such as (x5). A preferred example of the alkylene group having a carbonate bond is a structure such as (x6). A preferred example of the alkylene group having a secondary amino group is a structure such as (x7). A preferred example of the alkylene group having a urea bond is a structure such as (x8). A preferred example of the alkylene group having a thioether bond is a structure such as (x9). A preferred example of the alkylene group having a thioester bond is a structure such as (x10).

[0025] [ka]

[0026] In each formula, s is an integer of 0 to 12. The range of s is 0 to 12. For example, when binding is desired in a hydrophobic environment such as the inside of a protein, a larger s is preferable, whereas when binding is desired in a hydrophilic environment, a smaller s is preferable. The s in (x5), (x6), (x7), (x8), (x9), and (x10) may be the same or different.

[0027] Y represents a chemically reactive functional group, and is preferably a functional group capable of reacting with a hydroxyl group, an amino group, a mercapto group, an aldehyde group, a carboxyl group, a triple bond, or an azide group to form a chemical bond with another substance. For example, see "POLY(ETYLENE GLYCOL) CHEMISTRY" by J. Milton Harris and "Bioconjugate Techniques second edition” (2008) and “Pegylated Protein Drug: basic science and clinical” by Francesco M. Veronese. Examples of the functional groups include those described in “Applications” (2009) and others.

[0028] More specifically, functional groups include those containing carboxylic acid, active ester, active carbonate, aldehyde, amine, oxyamine, hydrazide, azide, unsaturated bond, thiol, dithiopyridine, sulfone, maleimide, vinyl sulfone, α-iodoacetyl, acrylate, isocyanate, isothiocyanate, epoxide, and the like.

[0029] Y is preferably a group shown below. [ka]

[0030] (In the formula, R represents a hydrocarbon group having 1 to 10 carbon atoms which may contain a fluorine atom.)

[0031] In a preferred embodiment of the reaction of the compound of the present invention with another substance, Y is a group represented by the following group (i), group (ii), group (iii), group (iv), group (v) or group (vi).

[0032] Group (i): Functional groups capable of reacting with the hydroxyl groups of other substances The above (a), (b), (cm)

[0033] Group (ii): Functional groups capable of reacting with the amino groups of other substances The above (a), (b), (c), (d), (e), (m), (n)

[0034] Group (iii): Functional groups capable of reacting with the mercapto group of other substances The above (a), (b), (c), (d), (e), (j), (k), (l), (m), (n), (o), (p)

[0035] Group (iv): Functional groups capable of reacting with the aldehyde or carboxyl groups of other substances The above (f), (g), (h), (k)

[0036] Group (v): Functional groups capable of reacting with the triple bond of other substances The above (f), (g), (h), (i), (k)

[0037] Group (vi): Functional groups capable of reacting with the azide group of other substances (j) above

[0038] The multi-arm polyethylene glycol derivative of the present invention can be produced, for example, by carrying out steps (A), (B), (C), (D) and (E) in this order as follows.

[0039] Step (A) is a step in which only the 1-position hydroxyl group of a polyhydric alcohol having an odd number of hydroxyl groups is left, and the even-numbered hydroxyl groups are protected by cyclic benzylidene acetalization.

[0040] Step (B) is a step of bonding two molecules of the compound obtained in step (A) to a compound represented by the following formula (2) as a linker by an etherification reaction. [ka]

[0041] (In formula (2), L represents a group selected from the group consisting of linear or branched alkylene groups having 3 to 8 carbon atoms, substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and cycloalkylene groups having 6 to 12 carbon atoms, and A represents a halogen atom selected from chlorine, bromine, or iodine, or a sulfone-based leaving group.)

[0042] Step (C) is a step of deprotecting the terminal cyclic benzylidene acetal structure of the compound obtained in step (B), thereby generating 8 hydroxyl groups when k=1, and 12 hydroxyl groups when k=2.

[0043] Step (D) is a step of polymerizing 3 to 600 moles of ethylene oxide to each hydroxyl group of the compound obtained in step (C) to obtain a multi-arm polyethylene glycol derivative.

[0044] Step (E) is a step of functionalizing the terminal hydroxyl groups of the multi-arm polyethylene glycol derivative obtained in step (D).

[0045] By carrying out the above steps (A), (B), (C), (D) and (E), the polyoxyethylene derivative (1) represented by formula (1) is produced.

[0046] A preferred specific example of the method for producing such a multi-arm polyethylene glycol derivative (1) will be further described below. However, since the derivative where k=1 and the derivative where k=2 can be produced by the same method, the following description will focus on the derivative where k=1, i.e., the multi-arm polyethylene glycol derivative represented by the following formula (3) (multi-arm polyethylene glycol derivative (3)).

[0047] [ka] (In formula (3), L, X, Y, and n are as defined above.)

[0048] The multi-arm polyethylene glycol derivative (3) can be produced by carrying out the following steps (A), (B), (C), (D) and (E) in this order.

[0049] In step (A), only the hydroxyl group at the 1st position of xylitol, which has 5 hydroxyl groups, is left, and the other 4 hydroxyl groups are protected by cyclic benzylidene acetalization. In this step, high-purity 2,3,4,5-dibenzylidene xylitol can be obtained. 1,2,4,5-dibenzylidene xylitol, which is an isomer with the hydroxyl group at the 3rd position remaining, is not produced in step (A).

[0050] The acetalization method is PROTECTIVE GROUPS IN There are no particular limitations on the method for protecting a hydroxyl group, so long as it is a general method such as that described in ORGANIC SYNTHESIS (THEODORA W. GREENE et al.), etc.; specifically, 2,3,4,5-dibenzylidene xylitol can be obtained by reacting xylitol with benzaldehyde in the presence of an acid catalyst such as sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, or p-toluenesulfonic acid monohydrate.

[0051] The amount of acid used is 5 x 10 for xylitol. -6 ~5×10 -3Equivalents are preferred, 5 x 10 -5 ~5×10 -4 An equivalent amount is more preferred. In order to dissolve xylitol, a large amount of acid may be used as a solvent, and in this case, the amount is preferably 5 to 100 times by weight, more preferably 10 to 50 times by weight, relative to xylitol. The type of acid is sulfuric acid, hydrochloric acid, or phosphoric acid, preferably sulfuric acid or hydrochloric acid, and more preferably sulfuric acid.

[0052] The amount of benzaldehyde used is preferably 2.0 to 5.0 equivalents relative to xylitol, and more preferably 2.5 to 4.0 equivalents.

[0053] The reaction can be carried out using a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, etc., with dimethylformamide and tetrahydrofuran being preferred. The reaction temperature is usually 0 to 60° C., preferably 10 to 50° C. The reaction time is preferably 3 to 24 hours. If the reaction time is too short, the reaction will be insufficient.

[0054] It is preferable to remove xylitol and impurities that were not acetalized in the reaction. 2,3,4,5-dibenzylidene xylitol produced in the reaction crystallizes in the reaction solution, so it can be purified simply by filtration. Since the obtained crystals have low solubility in all solvents, impurities can be removed by suspending the crystals in a solvent, stirring, and repeating filtration to further increase the purity. Solvents used in this suspension washing are preferably water, methanol, ethanol, diethyl ether, methyl t-butyl ether, THF (tetrahydrofuran), acetonitrile, and the like, and mixtures of these may also be used. The washing temperature is usually 0 to 60°C, preferably 10 to 50°C. The stirring time is preferably 10 minutes to 3 hours. If the stirring time is short, purification will be insufficient.

[0055] The step (B) is not particularly limited, but is preferably an etherification step of two molecules of 2,3,4,5-dibenzylidene xylitol and the compound (2) by the Williamson reaction.

[0056] In the compound (2) of the reaction, A may be any leaving group, such as a halogen atom, such as chlorine, bromine, or iodine, or a sulfone-based leaving group, such as a methanesulfonyl group, a p-toluenesulfonyl group, or a trifluoromethanesulfonyl group. As the base for etherification, an alkali metal alkoxide salt may be formed, such as t-butoxypotassium, sodium hydride, potassium hydride, metallic sodium, hexamethyldisilazane, or potassium carbonate. L represents a group selected from a linear or branched alkylene group having 3 to 8 carbon atoms, a substituted or unsubstituted arylene group having 6 to 12 carbon atoms, and a cycloalkylene group having 6 to 12 carbon atoms. Examples of the alkylene group include alkylene groups having 3 to 8 carbon atoms, and specific examples thereof include, for example, ethylene, propylene, isopropylene, n-butylene, s-butylene, t-butylene, pentamethylene, hexamethylene, heptamethylene, and octamethylene. Examples of the arylene group include substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and examples thereof include phenylene, naphthylene, and anthrylene. Examples of the cycloalkylene group include cycloalkylene groups having 6 to 12 carbon atoms, and specific examples thereof include, for example, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, and cyclodecylene. If the carbon number of L is less than 3, the effect of the hydrophobic group is not obtained, and the polymer is not dispersed in an organic solvent when ethylene oxide is added, and the molecular weight distribution may become broad. Furthermore, when the number of carbon atoms in L is greater than 12, the surface activity of the molecule increases, and there is a risk that the expected performance will not be exhibited when considering application to a pharmaceutical modifying agent. L is preferably a propylene group, an isopropylene group, an n-butylene group, an s-butylene group, a t-butylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, or an octamethylene group, and more preferably an n-butylene group. The reaction solvent is not particularly limited as long as it is an aprotic solvent, and examples thereof include tetrahydrofuran, dimethyl ether, methylene chloride, chloroform, dimethylformamide, toluene, and benzene, with toluene and dimethylformamide being more preferred.

[0057] The crystals obtained by this reaction can be purified by recrystallization, using a solvent such as tetrahydrofuran or dimethylformamide, preferably dimethylformamide. The amount of the solvent used for recrystallization is preferably 9 to 30 times by weight, more preferably 18 to 26 times by weight, relative to compound (2). The temperature for recrystallization is -10°C to 20°C, preferably 0°C to 10°C. If the temperature exceeds 20°C, the crystals may not be sufficiently generated, and the yield may decrease. The recrystallization time is preferably 1 hour or more. If the time is less than 1 hour, the removal of impurities may be insufficient.

[0058] Step (C) is a step of deprotecting the terminal cyclic benzylidene acetal structure of the compound obtained by the etherification in step (B).

[0059] The method for deprotecting the cyclic acetal is not particularly limited as long as it is a general deprotection method such as that described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (THEODORA W. GREENE et al.), etc., but specifically, deprotection can be performed in the presence of an acid catalyst. Examples of the acid catalyst include acetic acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc., and preferably hydrochloric acid, phosphoric acid, and trifluoroacetic acid, and more preferably trifluoroacetic acid.

[0060] The amount of the acid used is preferably 0.05 to 2 times by weight, more preferably 0.1 to 1 times by weight, relative to the compound obtained in step (B). The solvent used in the deprotection reaction is water, methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide, or dimethylacetamide, and water or methanol is preferred. The amount of the solvent used is 1 to 50 times by weight, preferably 2 to 35 times by weight, and more preferably 5 to 20 times by weight, relative to the compound obtained in step (B).

[0061] The reaction time is preferably 1 to 24 hours. If the reaction time is shorter than 1 hour, the deprotection reaction will be insufficient. The reaction temperature is usually 0 to 60°C, preferably 10 to 40°C.

[0062] Step (D) is an addition polymerization step of ethylene oxide to a compound having a hydroxyl group newly generated by deprotection of the cyclic acetal structure. Although not particularly limited, it can be preferably produced through the following steps (D1) and (D2).

[0063] Step (D1) is a step in which the deprotected compound is dissolved in an aqueous solution containing preferably 50 mol % to 250 mol % of an alkali catalyst, and then an organic solvent is added to carry out azeotropic dehydration preferably at 50 to 130°C.

[0064] Step (D2) is a step of reacting the deprotected compound with ethylene oxide in the presence of an organic solvent, preferably at 50 to 130° C., to obtain a multi-arm polyethylene glycol derivative having a hydroxyl group at the terminal.

[0065] The alkali catalyst in step (D1) is not particularly limited, and examples thereof include metallic sodium, metallic potassium, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, and potassium methoxide. As a solvent for dissolving the alkali catalyst, protic polar solvents such as methanol and ethanol, in addition to water, can be used. The concentration of the alkali catalyst is preferably 50 mol% to 250 mol% based on the deprotected compound. If it is less than 50 mol%, the polymerization reaction rate of ethylene oxide slows down, the heat history increases, and impurities such as terminal vinyl ethers are generated, so that it is advantageous to set it to 50 mol% or more in terms of producing a high-quality polymeric substance. If the catalyst exceeds 250 mol%, the viscosity of the reaction solution increases or solidifies during the alcoholation reaction, the stirring efficiency decreases, and alcoholation tends not to be promoted.

[0066] The organic solvent for azeotropic dehydration is not particularly limited as long as it is an aprotic solvent such as toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, dimethyl sulfoxide, dimethylformamide, or dimethylacetamide, but toluene, which has a boiling point close to that of water, is preferred. The azeotropic temperature is preferably 50 to 130°C. If the temperature is lower than 50°C, the viscosity of the reaction liquid increases and water tends to remain. The remaining water generates polyethylene glycol compounds derived from water, which may cause the molecular weight distribution to widen and the quality to decrease. If the temperature is higher than 130°C, a condensation reaction may occur. If water remains, it is preferable to repeatedly perform azeotropic dehydration.

[0067] Step (D2) is carried out in an organic solvent. The reaction solvent is not particularly limited as long as it is an aprotic solvent such as toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, dimethylsulfoxide, dimethylformamide, or dimethylacetamide, but toluene is preferred because it can be easily removed by crystallization and vacuum drying after the reaction. The reaction time is preferably 1 to 24 hours. If the reaction time is shorter than 1 hour, the catalyst may not be completely dissolved. If the reaction time is longer than 24 hours, the above-mentioned decomposition reaction may occur.

[0068] The reaction temperature is preferably 50 to 130°C. If the temperature is lower than 50°C, the polymerization reaction rate is slow and the thermal history increases, which tends to reduce the quality of the multi-arm polyethylene glycol derivative having a hydroxyl group at the end. If the temperature is higher than 130°C, side reactions such as vinyl etherification of the terminals occur during polymerization, which tends to reduce the quality of the multi-arm polyethylene glycol derivative having a hydroxyl group at the end. During polymerization, as the molecular weight increases, the viscosity of the reaction solution increases, so an aprotic solvent, preferably toluene, may be added as appropriate.

[0069] Step (D2) may be repeated several times. In that case, ethylene oxide may be added to the reaction mixture remaining in the reaction vessel and the reaction may be carried out under the same conditions as above. By adjusting the number of repetitions, the average number of moles added n can be adjusted.

[0070] The compound of formula (3) of the present invention has a polydispersity Mw / Mn from the elution start point to the elution end point when subjected to gel permeation chromatography. Mw / Mn≦1.05 More preferably, Mw / Mn≦1.03 This is the case when the following is satisfied.

[0071] When Mw / Mn>1.05, it means that the compound has a wide molecular weight distribution due to the inclusion of polyethylene glycols with different arm numbers or the non-uniform addition of ethylene oxide. This is because when it is combined with a bio-related substance, the number of modifications of the bio-related substance in one polyethylene glycol molecule is different, and when it is used as a drug sustained release carrier or a raw material for hydrogels in regenerative medicine materials, it is difficult to strictly control the permeation and diffusion speed of the substance, which may cause side effects as a medicine or biomaterial.

[0072] Step (E) is a step of functionalizing the terminal hydroxyl groups of the multi-arm polyethylene glycol derivative obtained in step (D).

[0073] A method for introducing a functional group into the terminal hydroxyl group of a multi-arm polyethylene glycol derivative will be described in detail below. In the following description, the compounds of formula (3) in which the functional groups Y are (a) to (p) may be referred to as (a) form...(p) form, or as "amine form (f)" with the name of the functional group added, respectively.

[0074] [Method for producing compound (3) in which Y is (d) or (m)] The p-nitrophenyl carbonate (d) or sulfonate (m) can be obtained by reacting the terminal hydroxyl group of the multi-arm polyethylene glycol derivative with an organic base such as triethylamine, pyridine, or 4-dimethylaminopyridine, or an inorganic base such as sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium acetate, potassium carbonate, or potassium hydroxide, and any of the compounds represented by the following general formulas (d1) and (m1) in an aprotic solvent such as toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, t-butyl-methyl ether, tetrahydrofuran, chloroform, methylene chloride, dimethyl sulfoxide, dimethylformamide, or dimethylacetamide, or without a solvent. The organic base or inorganic base may not be used. The ratio of the organic base or inorganic base used is not particularly limited, but is preferably equimolar or more relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The organic base may be used as a solvent. W in (d1) and (m1) is a halogen atom selected from chlorine, bromine, and iodine, and is preferably chlorine. The proportion of the compound represented by the general formula (d1) and (m1) used is not particularly limited, but is preferably equimolar or more with respect to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative, and more preferably in the range of equimolar to 50 mol. The reaction temperature is preferably 0 to 300°C, and more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, and more preferably 30 minutes to 24 hours. The produced compound may be purified by purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0075] [ka]

[0076] (W represents a halogen atom selected from chlorine, bromine, and iodine. R represents a hydrocarbon group having 1 to 10 carbon atoms which may contain a fluorine atom.)

[0077] [Production method of compound (3) in which Y is (o)] The divinyl sulfone body (o) can be obtained by reacting the terminal hydroxyl group of the multi-arm polyethylene glycol derivative with divinyl sulfone in an aprotic solvent such as toluene under a base catalyst. The base catalyst may be either an inorganic base or an organic base, and is not particularly limited, but examples thereof include potassium t-butoxide, sodium hydride, potassium hydride, metallic sodium, hexamethyldisilazane, and potassium carbonate. The proportion of the base catalyst used is not particularly limited, but it is preferably used in the range of 0.1 to 50 moles relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The proportion of divinyl sulfone used is not particularly limited, but it is preferably an equimolar amount or more relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative, and it is preferable to use an excess amount of 10 equivalents or more to prevent the by-production of a dimer. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 40°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, or supercritical extraction.

[0078] [Method for producing compound (3) in which Y is (a)] The carboxyl body (a) can be obtained by reacting the terminal hydroxyl group of the multi-arm polyethylene glycol derivative or the amine body (f) described below with a dicarboxylic acid anhydride such as succinic anhydride or glutaric anhydride in the above-mentioned aprotic solvent or without a solvent. The proportion of the dicarboxylic acid anhydride used is not particularly limited, but is preferably equimolar or more relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative, more preferably equimolar to 5 moles. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours.

[0079] In the reaction, an organic base such as triethylamine, pyridine, or dimethylaminopyridine, or an inorganic base such as sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium acetate, potassium carbonate, or potassium hydroxide may be used as a catalyst. The proportion of the catalyst used is preferably 0.1 to 50% by mass, more preferably 0.5 to 20% by mass, based on the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The compound thus produced may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, or supercritical extraction, or may be used as it is when used as a raw material for a condensation reaction.

[0080] The carboxyl body (a) can be obtained by reacting the terminal hydroxyl group of the multi-arm polyethylene glycol derivative with a halogen-substituted carboxylate such as ethyl 6-bromohexanoate or ethyl 7-bromoheptanoate in the above-mentioned aprotic solvent or without a solvent. The proportion of the halogen-substituted carboxylate used is not particularly limited, but is preferably equimolar or more relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative, more preferably equimolar to 30 mol. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. In the reaction, an organic base such as triethylamine, pyridine, or dimethylaminopyridine, or an inorganic base such as sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium acetate, potassium carbonate, or potassium hydroxide may be used as a catalyst. The proportion of the catalyst used is preferably 0.1 to 500% by mass, more preferably 0.5 to 300% by mass, relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. After the etherification, an aqueous solution of sodium hydroxide or potassium hydroxide is added in the case of an organic base, or water is added in the case of an inorganic base to hydrolyze the ester. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 100°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. After the reaction, the reaction mixture is neutralized with hydrochloric acid, sulfuric acid, or the like. The compound may be purified by the above-mentioned purification means in this way, or may be used as it is when used as a raw material for a condensation reaction.

[0081] [Method for producing compound (3) in which Y is (b)] The succinimide (b) can be obtained by condensing the carboxyl (a) with N-hydroxysuccinimide in the presence of a condensing agent such as DCC (dicyclohexylcarbodiimide) or EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) in the above-mentioned aprotic solvent or without a solvent. The condensing agent is not particularly limited, but is preferably DCC. The proportion of DCC used is preferably equimolar or more with respect to the carboxyl group, more preferably equimolar to 5 mol. The proportion of N-hydroxysuccinimide used is preferably equimolar or more with respect to the carboxyl group, more preferably equimolar to 5 mol. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0082] [Method for producing compound (3) in which Y is (c)] The succinimide carbonate body (c) can be obtained by reacting the terminal hydroxyl group of the multi-arm polyethylene glycol derivative with an organic base such as triethylamine, pyridine, or 4-dimethylaminopyridine, or an inorganic base such as sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium acetate, potassium carbonate, or potassium hydroxide, and N,N'-disuccinimide carbonate in the above-mentioned aprotic solvent or without a solvent. The organic base or inorganic base may not be used. The ratio of the organic base or inorganic base used is not particularly limited, but is preferably equimolar or more with respect to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The organic base may also be used as a solvent. The ratio of N,N'-disuccinimide carbonate used is preferably equimolar or more with respect to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative, more preferably equimolar to 5 moles. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0083] [Method for producing compound (3) in which Y is (f)] The amine body (f) can be obtained by adding acrylonitrile or the like to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative in a solvent such as water or acetonitrile using an inorganic base such as sodium hydroxide or potassium hydroxide as a catalyst to obtain a nitrile body, and then hydrogenating the nitrile group in an autoclave under a nickel or palladium catalyst. The proportion of the inorganic base used in obtaining the nitrile body is not particularly limited, but is preferably 0.01 to 50 mass% relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The proportion of acrylonitrile or the like used is not particularly limited, but is preferably equimolar or more relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative, more preferably equimolar to 50 moles. Acrylonitrile may also be used as a solvent. The reaction temperature is preferably -50 to 100°C, more preferably -20 to 60°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The reaction solvent in the subsequent hydrogenation reaction of the nitrile is not particularly limited as long as it is a solvent that does not participate in the reaction, but is preferably toluene. The proportion of nickel or palladium catalyst used is not particularly limited, but is 0.05 to 30 mass% and preferably 0.5 to 20 mass% based on the nitrile. The reaction temperature is preferably 20 to 200°C, more preferably 50 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The hydrogen pressure is preferably 2 to 10 MPa, more preferably 3 to 8 MPa. Ammonia may be added to the reaction system to prevent dimerization. The ammonia pressure when adding ammonia is not particularly limited, but is 0.1 to 10 MPa, more preferably 0.3 to 2 MPa. The produced compound may be purified by purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0084] The amine (f) can also be obtained by reacting the sulfonate (m) with aqueous ammonia. The reaction is carried out in aqueous ammonia, and the concentration of the ammonia is not particularly limited, but is preferably in the range of 10 to 40% by mass. The proportion of aqueous ammonia used is preferably 1 to 300 times the mass of the sulfonate (m). The reaction temperature is preferably 0 to 100°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 72 hours, more preferably 1 to 36 hours.

[0085] The amine body (f) can also be obtained by reacting the sulfonate body (m) with ammonia in an autoclave. The reaction solvent is not particularly limited, but preferred examples include methanol and ethanol. The amount of ammonia is preferably 10 to 300% by mass, more preferably 20 to 200% by mass, based on the sulfonate body (m). The reaction temperature is preferably 50 to 200°C, more preferably 80 to 150°C. The reaction time is preferably 10 minutes to 24 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by the above-mentioned purification means.

[0086] The amine body (f) can also be obtained by binding the terminal hydroxyl group of the multi-arm polyethylene glycol derivative with phthalimide in an aprotic solvent using the Mitsunobu reaction, and deprotecting the resulting compound with a primary amine. The reaction conditions for the Mitsunobu reaction are not particularly limited, but the reaction solvent is preferably chloroform or dichloromethane. The proportion of triphenylphosphine and azocarboxylate used is not particularly limited, but is equimolar or more, preferably equimolar to 50molar, relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The reaction temperature is preferably 0 to 100°C, more preferably 10 to 50°C. The reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 6 hours.

[0087] Regarding the deprotection, the primary amine to be used is not particularly limited, but preferably includes ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclohexylamine, ethanolamine, propanolamine, butanolamine, ethylenediamine, etc. Of course, these primary amines may be used as a solvent. The ratio of the primary amine to be used is not particularly limited, but it is preferable to use an equimolar amount or more, preferably an equimolar amount to 500 moles, relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The reaction solvent is not particularly limited, but methanol is preferable. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 72 hours, more preferably 1 to 10 hours. The produced compound may be purified by the above-mentioned purification means.

[0088] [Method for producing compound (3) in which Y is (g)] The oxyamine (g) can be obtained by reacting the active carbonate (c) or (d) with a compound (g1) represented by the following general formula in the presence of a base catalyst such as triethylamine or pyridine to convert it into an oxyphthalimide, and then dephthalimidizing it in the presence of a primary amine. The reaction solvent for oxyphthalimidization is not particularly limited as long as it is a non-solvent or a polar solvent, but is preferably dimethylformamide. The proportion of the base catalyst used is not particularly limited, but is preferably equimolar or more with respect to the active carbonate group, and more preferably in the range of equimolar to 20 moles. The proportion of the compound (g1) used is preferably equimolar or more with respect to the active carbonate group, and more preferably equimolar to 20 moles. The reaction temperature is preferably 0 to 100°C, and more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, and more preferably 30 minutes to 12 hours. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, supercritical extraction, etc., or may be advanced to the next step without purification.

[0089] The reaction solvent for dephthalimidization is not particularly limited, but methanol is preferred. The primary amine used is not particularly limited, but preferably includes ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclohexylamine, ethanolamine, propanolamine, butanolamine, ethylenediamine, etc. Of course, these primary amines may be used as a solvent. The proportion of the primary amine used in the presence of the primary amine is not particularly limited, but is preferably equimolar or more relative to the active carbonate group, more preferably in the range of equimolar to 50 moles. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by the above-mentioned purification means.

[0090] [ka] (Q represents a linear alkylene group having 1 to 7 carbon atoms.)

[0091] [Method for producing compound (3) in which Y is (n)] The maleimide (n) can be obtained by reacting the amine (f) with maleic anhydride in the above-mentioned aprotic solvent or without solvent to obtain a maleamide, and then carrying out a ring-closing reaction using acetic anhydride and sodium acetate as catalysts. The proportion of maleic anhydride used in the maleamidation reaction is not particularly limited, but is preferably equimolar or more relative to the amino group, more preferably equimolar to 5 moles. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 120°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, supercritical extraction, etc., or may be advanced to the next step without purification.

[0092] The reaction solvent in the subsequent ring-closing reaction is not particularly limited, but an aprotic solvent or acetic anhydride is preferable. The proportion of sodium acetate used is not particularly limited, but is preferably equimolar or more relative to the maleamide group, more preferably equimolar to 50 moles. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by the above-mentioned purification means.

[0093] The maleimide body (n) can also be obtained by reacting a compound (n1) represented by the following general formula with an amine body (f) in the above-mentioned aprotic solvent or without a solvent. The proportion of (n1) used is preferably equimolar or more with respect to the amino group (f), more preferably equimolar to 5 moles. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The reaction may be performed in the dark. The resulting compound may be purified by the above-mentioned purification means.

[0094] [ka] (Q represents a linear alkylene group having 1 to 7 carbon atoms.)

[0095] [Method for producing compound (3) in which Y is (e)] The aldehyde (e) can be obtained by reacting the sulfonate (m) with the compound (e1) represented by the following general formula in the above-mentioned aprotic solvent or without a solvent to obtain an acetal, and then hydrolyzing it under acidic conditions. The proportion of (e1) used is preferably equimolar or more with respect to the sulfonate group, more preferably equimolar to 50 moles. (e1) can be prepared from the corresponding alcohol using metallic sodium, metallic potassium, sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide, or the like. The reaction temperature is preferably 0 to 300°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours.

[0096] In addition, when compound (e2) is used, the terminal hydroxyl group of the multi-arm polyethylene glycol derivative is converted to an alcoholate by the above-mentioned method, and then the acetal body can be obtained by reacting (e2) in an aprotic solvent or without a solvent in an equimolar amount or more, preferably equimolar to 100mol, relative to the terminal hydroxyl group of the multi-arm polyethylene glycol derivative. The reaction temperature is preferably 0 to 300°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, particularly preferably 30 minutes to 24 hours.

[0097] In addition, when compound (e3) is used, an acetal form can be obtained by reacting (e3) with a carboxyl form (a), a succinimide form (b), or an activated carbonate form (c) or (d). In the reaction with (e3), the solvent is not particularly limited, but it is preferably carried out in an aprotic solvent. The proportion of (e3) used is preferably equimolar or more of the carboxyl group, succinimide group, or active carbonate group, more preferably equimolar to 10 mol. The reaction temperature is preferably -30 to 200°C, more preferably 0 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. When the carboxyl body (a) is used, a condensing agent such as DCC or EDC may be used as appropriate. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, or supercritical extraction, or may be advanced to the next step without purification.

[0098] The subsequent aldehyde-forming reaction can be obtained by hydrolyzing the acetal body in a 0.1-50% aqueous solution adjusted to pH 1-4 with an acid such as acetic acid, phosphoric acid, sulfuric acid, or hydrochloric acid. The reaction temperature is preferably -20 to 100°C, and more preferably 0 to 80°C. The reaction time is preferably 10 minutes to 24 hours, and more preferably 30 minutes to 10 hours. The reaction may be performed in the dark. The produced compound may be purified by the above-mentioned purification means.

[0099] [ka]

[0100] (In the formula, R 2 , R 3 are hydrocarbon groups having 1 to 3 carbon atoms, and may be the same or different. They may also be joined together to form a ring. M is sodium or potassium, A is a halogen atom selected from chlorine, bromine, or iodine, or a sulfone-based protecting group, and t is an integer of 1 to 12.

[0101] [Method for producing compound (3) in which Y is (k)] The mercapto body (k) can be obtained by reacting the sulfonate body (m) with a thiazolium salt and a thiazolium salt-forming agent such as thiourea, followed by hydrolysis under alkaline conditions. The thiazolium salt-forming reaction is carried out in water, acetonitrile, or an alcohol solvent such as methanol, ethanol, or 2-propanol, or in the absence of a solvent. The proportion of the thiazolium salt used is preferably equimolar or more relative to the sulfonate group, more preferably in the range of equimolar to 50 mol. The reaction temperature is preferably 0 to 300°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The subsequent hydrolysis can be obtained by hydrolyzing the thiazolium salt in a 0.1 to 50% aqueous solution adjusted to pH 10 to 14 with an alkali such as sodium hydroxide, potassium hydroxide, or potassium carbonate. The reaction temperature is preferably -20 to 100°C, more preferably 0 to 80°C. The reaction time is preferably 10 minutes to 24 hours, more preferably 30 minutes to 10 hours. The reaction may be performed in the dark. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0102] The mercapto compound (k) can also be obtained by reacting the sulfonate compound (m) with the compound (k1) represented by the following general formula in the above-mentioned aprotic solvent or without a solvent, and decomposing it with a primary amine. The proportion of (k1) used is preferably equimolar or more with respect to the sulfonate group, more preferably in the range of equimolar to 50 moles. The reaction temperature is preferably 0 to 300°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The subsequent alkali decomposition with a primary amine is carried out in an aprotic solvent or without a solvent. The primary amine used is not particularly limited, but preferably includes ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclohexylamine, ethanolamine, propanolamine, butanolamine, ethylenediamine, and the like. Of course, these primary amines may be used as a solvent. The resulting compound may be purified by the above-mentioned purification means.

[0103] [ka]

[0104] [Production method of compound (3) in which Y is (l)] The dipyridyl disulfide (l) can be obtained by reacting the mercapto (k) with 2,2-dipyridyl disulfide. The reaction solvent is not particularly limited, but is preferably carried out in an alcohol solvent such as methanol, ethanol, or 2-propanol. The proportion of 2,2-dipyridyl disulfide used is preferably equimolar or more with respect to the mercapto group, more preferably equimolar to 50 mol. The reaction temperature is preferably -30 to 100°C, more preferably 0 to 60°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The produced compound may be purified by purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0105] [Method for producing compound (3) in which Y is (p)] The iodoacetyl form (p) can be obtained by reacting the amine form (f) with iodoacetic anhydride in the above-mentioned aprotic solvent or without a solvent. The ratio of iodoacetic anhydride used is not particularly limited, but is preferably equimolar or more with respect to the amino group, more preferably equimolar to 5 moles. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 120°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0106] The iodoacetyl form (p) can also be obtained by subjecting the amine form (f) to a condensation reaction with iodoacetic acid in the presence of a condensing agent such as DCC or EDC in the above-mentioned aprotic solvent or in the absence of a solvent. The condensing agent is not particularly limited, but is preferably DCC. The proportion of DCC used is preferably at least equimolar to the amino group, more preferably equimolar to 5 mol. The proportion of iodoacetic acid used is preferably at least equimolar to the amino group, more preferably equimolar to 5 mol. The reaction temperature is preferably 0 to 100°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by the above-mentioned purification means.

[0107] [Method for producing compound (3) in which Y is (h)] The hydrazide (h) can be obtained by reacting the succinimide (b) or the activated carbonate (c) or (d) with t-butyl carbazate in the above-mentioned aprotic solvent or without a solvent, and then deprotecting the t-butylcarbonyl group. The proportion of t-butyl carbazate used is not particularly limited, but is preferably equimolar or more of the succinimide group or the activated carbonate group, more preferably equimolar to 10 mol. The reaction temperature is preferably 0 to 200°C, more preferably 20 to 80°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours. The produced compound may be purified by purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0108] [Method for producing compound (3) in which Y is (j)] The acetylene compound (j) can be obtained by reacting the succinimide compound (b) or the activated carbonate compounds (c) and (d) with the compound (j1) represented by the following general formula in the above-mentioned aprotic solvent or without a solvent. The proportion of (j1) used is not particularly limited, but is equimolar or more, preferably equimolar to 50 mol of (j1) to the succinimide group or the activated carbonate group. The reaction temperature is preferably 0 to 300°C, more preferably 20 to 150°C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The produced compound may be purified by a purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, and supercritical extraction.

[0109] [ka] (In the formula, u is an integer of 1 to 5. 4 represents a hydrogen atom or a hydrocarbon group having 1 to 5 carbon atoms.

[0110] [Production method of compound (3) in which Y is (i)] The azide compound (i) can be obtained by reacting the sulfonate compound (m) with sodium azide in the above-mentioned aprotic solvent or without a solvent. The usage ratio of sodium azide is equimolar or more based on the sulfonate group, preferably equimolar to 50 moles. The reaction temperature is preferably 0 to 300 ° C, more preferably 20 to 150 ° C. The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 24 hours. The produced compound may be purified by purification means such as extraction, recrystallization, adsorption treatment, reprecipitation, column chromatography, supercritical extraction, etc.

[0111] According to the present invention, a high-purity multi-arm polyethylene glycol derivative (1) can be industrially produced more efficiently than the conventional production method.

Examples

[0112] Hereinafter, the present invention will be described more specifically based on examples. For the analysis and identification of the compounds in the examples, 1 1H-NMR and GPC were used.

[0113] < 1 <1H-NMR analysis method> 1 In the 1H-NMR analysis, JNM-ECP400 manufactured by JEOL Datum Co., Ltd. was used. The integral values in the NMR measurement values are theoretical values.

[0114] <GPC analysis method> In the GPC analysis, the measurement was performed in a system using either DMF or water as the eluent. The respective measurement conditions are shown below.

[0115] (In the case of DMF system) Apparatus: Shimadzu LC-10Avp Column: PL gel MIXED-D × 2 (Polymer Laboratory) Eluent: Dimethylformamide Flow rate: 0.7 ml / min Column temperature: 65 ° C Detector: RI Sample amount: 1 mg / g, 100 μl

[0116] (In the case of aqueous system) Apparatus: alliance (Waters) Column: ultrahydrogel500 + ultrahydrogel250 (Waters) Developing solvent: 100 mM sodium acetate, 0.02% NaN3 buffer (pH 5.2) Flow rate: 0.5 ml / min Column temperature: 30 °C Detector: RI Sample amount: 5 mg / g, 20 μl

[0117] The GPC measurement value is the analytical value at the main peak obtained by vertically cutting the baseline from the inflection point of the elution curve to remove high-molecular-weight impurities and low-molecular-weight impurities. The fraction % is the ratio with respect to the entire peak from the elution start point to the elution end point of the main peak, M n is the number-average molecular weight, M w is the weight-average molecular weight, M p is the peak-top molecular weight, and Mw / Mn indicates the polydispersity.

[0118] <Molecular weight measurement by TOF-MS> Measurement was performed using TOF-MS (manufactured by Bruker, autoflexIII), with dithranol as the matrix and sodium trifluoroacetate as the salt. Analysis was performed using FlexAnalysis, and molecular weight distribution analysis was performed using Polytools. The obtained centroid value was described as the molecular weight value.

[0119] <Molecular weight measurement by hydroxyl value measurement> In accordance with JIS K1557-1, the hydroxyl value was measured by Method A (acetic anhydride / pyridine). The molecular weight was calculated from the measured hydroxyl value using the following formula. (Molecular weight) = 56.1 × 1,000 × 8 / (hydroxyl value)

[0120] (Example 1) Synthesis of compounds (I), (II), (III), and (IV) (L=n-butylene group, k=1, molecular weights of approximately 5,000, 10,000, 20,000, and 40,000) [ka]

[0121] (Example 1-1) Synthesis of 2,3,4,5-dibenzylidene xylitol 150g of xylitol and 3700g of 6M sulfuric acid were placed in a reactor equipped with a thermometer, a nitrogen inlet tube, and a stirrer, and xylitol was dissolved at room temperature. After 315g of benzaldehyde was added, the mixture was heated to about 30°C and stirred continuously, causing crystals to precipitate. Stirring was continued for 6 hours or more. 4.5L of cooled distilled water was added, and the precipitate was collected by filtration. The crystals were suspended in 3L of an aqueous ethanol solution, neutralized by adding an aqueous 10N sodium hydroxide solution, and filtered. The obtained crystals were further washed and suspended in an aqueous ethanol solution, an ethanol / methyl t-butyl ether (MTBE) mixture, and MTBE, and then repeatedly filtered. After drying under reduced pressure, 260g of 2,3,4,5-dibenzylidene xylitol was obtained. 1 H-NMR (CDCl3, internal standard TMS) δ (ppm): 3.80-4.40 (7H, m, -C H 2-O-, -C H -O-), 5.59 (1H, s, Ph-C H -O-), 5.67 (1H, s, Ph-C H -O-), 7.30-7.65 (10H, m, Ph -CH-O-)

[0122] (Example 1-2) Synthesis of 1,1'-butylenebis(2,3,4,5-dibenzylidenexylitol) 266g (0.81mol) of 2,3,4,5-dibenzylidene xylitol, 2400g of dimethylformamide (DMF) and 1600g of toluene were added to a 5000ml round bottom flask equipped with a thermometer, a nitrogen inlet tube and a stirrer, and dissolved under a nitrogen atmosphere, then azeotropically dehydrated at 110-120°C. After azeotropically dehydrated, the mixture was cooled, 94.8g (0.84mol) of t-butoxy potassium was added, and the mixture was stirred at 30-40°C for 30 minutes. Meanwhile, 80g (0.33mol) of 1,4-butanediol dimethanesulfonate was dissolved in 660g of dehydrated DMF, and then added dropwise to the reaction solution at 30-40°C over 30 minutes with stirring, and after the dropwise addition was completed, the temperature was raised to 50°C and the mixture was reacted for 2 hours. After the reaction was completed, the reaction solution was cooled to below 10°C and stirred for 30 minutes, at which point crystals precipitated, and the mixture was stirred for 1 hour. The precipitate was collected by filtration, suspended in 2.5L of an aqueous ethanol solution, and the suspension washing and filtration were repeated three times. Next, 4800g of DMF was added and the mixture was recrystallized. The obtained crystals were further added with 2560g of methyl t-butyl ether (MTBE), and the suspension washing and filtration were repeated twice, after which the mixture was dried under reduced pressure to obtain 150g of 1,1'-butylenebis(2,3,4,5-dibenzylidenexylitol). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.61 (4H, quint, -OCH2C H 2C H 2CH2-O-), 3.44-4.38 (18H, m, -OC H 2CH2CH2C H 2-O-, -C H 2-O-, -C H -O-), 5.57 (2H, s, Ph-C H -O-), 5.63 (2H, s, Ph-C H -O-), 7.30-7.65 (20H, m, Ph -CH-O-)

[0123] (Examples 1-3) Synthesis of 1,1'-butylenebisxylitol In a 3000 ml round-bottom flask equipped with a thermometer, a nitrogen blowing tube, and a stirrer, 290 g (0.41 mol) of 1,1'-butylenebis(2,3,4,5-dibenzylidene xylitol) obtained in Example 1-2, 870 g of trifluoroacetic acid (TFA), and 290 g of ion-exchanged water were added and heated to 50°C, followed by stirring for 4 hours. The mixture was cooled to 30°C or lower, 1450 g of toluene was added, and the mixture was stirred for 30 minutes or more. After stopping the stirring, the mixture was separated, the toluene layer was removed, and 1450 g of toluene was added to the water layer and washed again by separation. This separation operation was repeated a total of seven times. Next, TFA was concentrated and distilled off under reduced pressure, and then 1450 g of ethanol was added and azeotropic dehydration was repeated three times. 870 g of methanol was added to the concentrated liquid to homogenize it, and then Kyoward 1000 (manufactured by Kyowa Chemical Co., Ltd.) was added, stirred for 30 minutes, and filtered. An ion exchange resin (SMN-1, manufactured by Mitsubishi Chemical Corporation) was added to the filtrate, which was stirred for 30 minutes and then filtered. The filtrate was concentrated to obtain 126 g of 1,1'-butylene bis xylitol (V) having the following structure. 1 H-NMR (D2O, internal standard TMS) δ(ppm): 1.66 (4H, quint, -OCH2C H 2C H 2CH2-O-), 3.56-3.75 (14H, m, -OC H 2CH2CH2C H 2-O-, -C H 2-O-, -C H -O-), 3.79-3.82 (2H, m, -C H -O-), 3.91-3.93 (2H, m, -C H -O-)

[0124] [ka]

[0125] (Examples 1 to 4) Synthesis of compound (I) (molecular weight 5,000) 60 g of 1,1'-butylene bis xylitol (V) obtained in Example 1-3 was heated and washed with 41 g of methanol while being charged into a 5 L autoclave. Subsequently, 5.8 g of potassium hydroxide and 12 g of ion-exchanged water were added to a 50 ml beaker to prepare an aqueous potassium hydroxide solution, which was then charged into a 5 L autoclave. Next, 600 g of dehydrated toluene was added, and azeotropic dehydration was repeated three times at 80 ° C. and slightly reduced pressure. After azeotropic dehydration, 1594 g of dehydrated toluene was added and the system was replaced with nitrogen, and then 740 g (16.8 mol) of ethylene oxide was added at 80 to 150 ° C. and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60 ° C. and 604 g of the reaction solution was extracted from the kettle, and the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution to obtain the following compound (I). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.66 (8H, br, -O H ), 3.40 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (430H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system): Main fraction: 99.5%, Mn:3,838, Mw:3,905, Mw / Mn:1.017, Mp:3,903 Molecular weight (TOF-MS); 4,974 Molecular weight (hydroxyl value): 5,026

[0126] [ka]

[0127] (Examples 1 to 5) Synthesis of compound (II) (molecular weight 10,000) In Example 1-4, 615 g (14.0 mol) of ethylene oxide was added to about 1764 g of the reaction solution remaining in the reaction vessel at 80 to 150°C and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60°C and 1529 g of the reaction solution was extracted from the vessel, the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and the toluene was distilled off to obtain the following compound (II). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.365 (8H, br, -O H ), 3.40 (4H, s, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (878H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system) Main fraction: 99.0%, Mn:7,123, Mw:7,262, Mw / Mn:1.019, Mp:7,282 Molecular weight (TOF-MS); 10,418 Molecular weight (hydroxyl value): 9,968

[0128] [ka]

[0129] (Examples 1 to 6) Synthesis of compound (III) (molecular weight 20,000) In Example 1-5, 390 g (8.85 mol) of ethylene oxide was added to about 809 g of the reaction solution remaining in the reaction vessel at 80 to 150°C and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60°C, and 978 g of the reaction solution was extracted from the vessel, the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and the toluene was distilled off to obtain the following compound (III). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.57 (8H, br, -O H ), 3.40 (4H, s, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (1774H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system) Main fraction: 98.4%, Mn:14,140, ​​Mw:14,499, Mw / Mn:1.025, Mp:14,910 Molecular weight (TOF-MS);20,233 Molecular weight (hydroxyl value): 19,858

[0130] [ka]

[0131] (Examples 1 to 7) Synthesis of compound (IV) (molecular weight 40,000) In Example 1-6, 103 g (2.34 mol) of ethylene oxide was added to about 199 g of the reaction solution remaining in the reaction vessel at 80 to 150°C and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60°C and the entire reaction solution was removed from the vessel, the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and the toluene was distilled off to obtain the following compound (IV). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.589 (8H, br, -O H ), 3.40 (4H, s, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (3598H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system): Main fraction: 96.6%, Mn:27,158, Mw:27,691, Mw / Mn:1.020, Mp:27,945 Molecular weight (TOF-MS); 40,071 Molecular weight (hydroxyl value): 39,932

[0132] [ka]

[0133] (Example 2-1) Synthesis of cyanoethyl derivative (molecular weight approximately 10,000) 50g (5mmol) of compound (II) obtained in the above Example 1-5 and 50g of ion-exchanged water were added to a 500ml round-bottom flask equipped with a thermometer, a nitrogen blowing tube, a stirrer, and a cooling tube, and dissolved by heating to 40°C. After dissolution, the mixture was cooled to below 10°C, and 5g of 50% potassium hydroxide aqueous solution was added. Then, 42.5g (800mmol) of acrylonitrile was added dropwise over 2 hours while maintaining the temperature at 5-10°C. After the dropwise addition, the mixture was reacted for another 4 hours, 50g of ion-exchanged water was added, and 3g of 85% phosphoric acid aqueous solution was added dropwise to neutralize. 75g of ethyl acetate was added, stirred, and then allowed to stand, and the upper ethyl acetate layer was discarded. This ethyl acetate extraction was repeated 9 times. After the extraction, the mixture was extracted using 250g of chloroform. The obtained chloroform layer was dried with 25g of magnesium sulfate, filtered, and concentrated. 150g of ethyl acetate was added to the concentrated liquid to dissolve it, and hexane was added until crystals were precipitated. The crystals were filtered off, dissolved again in 150 g of ethyl acetate under heating, cooled to room temperature, and then hexane was added until crystals precipitated. The crystals were filtered off and dried to obtain the following cyanoethyl compound (VI). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.63 (16H, t, -C H 2CH2CN), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (894H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H2O) n H , -C H 2-OCH2CH2CH2CH2O-C H 2-, -CH2C H 2CN)

[0134] [ka]

[0135] (Example 2-2) Synthesis of propylamino derivative (molecular weight approx. 10,000) In a 1L autoclave, 46 g of the cyanoethyl compound (VI) obtained in Example 2-1 above, 533 g of toluene, and 4.1 g of nickel (5136p manufactured by NEM Cat Co.) were added, and the temperature was raised to 60°C. The mixture was pressurized with ammonia until the internal pressure reached 1 MPa, and then hydrogen was pressurized until the internal pressure reached 4.5 MPa, and the reaction was carried out at 130°C for 3 hours. After the reaction, the reaction solution was cooled to 80°C, and nitrogen purging was repeated until the ammonia odor disappeared. The entire reaction solution was removed and filtered, and the filtrate was cooled to room temperature, and hexane was added until crystals precipitated. The crystals were filtered and dried to obtain the following amine (VII). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 1.72(16H, quint, -CH2C H 2CH2NH2), 2.79(16H, t, -CH2CH2C H 2NH2), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (894H, m, -C H 2O (C H 2C H 2O) n H, CH O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-, -C H 2CH2CH2NH2) GPC analysis (aqueous) Main fraction: 96.9%, Mn:6,781, Mw:6,896, Mw / Mn:1.017, Mp:6,874

[0136] [ka]

[0137] (Example 3-1) Synthesis of cyanoethyl derivative (molecular weight approximately 20,000) 50g (2.5mmol) of compound (III) obtained in Example 1-6 above and 50g of ion-exchanged water were added to a 500ml round-bottom flask equipped with a thermometer, a nitrogen blowing tube, a stirrer, and a cooling tube, and dissolved by heating to 40°C. After dissolution, the mixture was cooled to below 10°C, and 5g of 50% potassium hydroxide aqueous solution was added. Then, 21.2g (400mmol) of acrylonitrile was added dropwise over 2 hours while maintaining the temperature at 5-10°C. After the dropwise addition, the mixture was reacted for another 4 hours, 50g of ion-exchanged water was added, and 3g of 85% phosphoric acid aqueous solution was added dropwise to neutralize. 75g of ethyl acetate was added, stirred, and then allowed to stand, and the upper ethyl acetate layer was discarded. This ethyl acetate extraction was repeated 9 times. After the extraction was completed, extraction was performed using 250g of chloroform. The obtained chloroform layer was dried with 15g of magnesium sulfate, filtered, and concentrated. The concentrate was dissolved in 150 g of ethyl acetate, and hexane was added until crystals precipitated. The crystals were collected by filtration, dissolved again in 150 g of ethyl acetate by heating, cooled to room temperature, and then hexane was added until crystals precipitated. The crystals were collected by filtration and dried to obtain the following cyanoethyl compound (VIII). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.63 (16H, t, -C H 2CH2CN), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (1790H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H , -C H 2-OCH2CH2CH2CH2O-C H 2-, -CH2C H 2CN)

[0138] [ka]

[0139] (Example 3-2) Synthesis of propylamino derivative (molecular weight approximately 20,000) In a 1L autoclave, 20 g of the cyanoethyl compound of compound (VIII) obtained in Example 3-1 above, 555 g of toluene, and 1.8 g of nickel (5136p manufactured by NEM Cat Co.) were added, and the temperature was raised to 60°C. The mixture was pressurized with ammonia until the internal pressure reached 1 MPa, and then hydrogen was pressurized until the internal pressure reached 4.5 MPa, and the reaction was carried out at 130°C for 3 hours. After the reaction, the reaction solution was cooled to 80°C, and nitrogen purging was repeated until the ammonia odor disappeared. The entire reaction solution was removed, filtered, and the filtrate was cooled to room temperature, and hexane was added until crystals precipitated. The crystals were filtered and dried to obtain the following amine (IX). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2CH 2C H 2CH2-O-), 1.72 (16H, quint, -CH2C H 2CH2NH2), 2.79 (16H, t, -CH2CH2C H 2NH2), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (1790H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-, -C H 2CH2CH2NH2) GPC analysis (water system) メインフラクション:97.5%, Mn:13,844, Mw:14,133, Mw / Mn:1.021, Mp:14,203

[0140]

change

[0141] (Example 4-1) Synthesis of cyanoethyl derivative (molecular weight approximately 40,000) 50g (1.25mmol) of compound (IV) obtained in the above Example 1-7 and 50g of ion-exchanged water were added to a 500ml round-bottom flask equipped with a thermometer, a nitrogen blowing tube, a stirrer, and a cooling tube, and dissolved by heating to 40°C. After dissolution, the mixture was cooled to below 10°C, and 5g of 50% aqueous potassium hydroxide solution was added. Then, 26.5g (499mmol) of acrylonitrile was added dropwise over 2 hours while maintaining the temperature at 5-10°C. After the dropwise addition, the mixture was reacted for another 4 hours, 50g of ion-exchanged water was added, and 3g of 85% aqueous phosphoric acid solution was added dropwise to neutralize. 75g of ethyl acetate was added, stirred, and then allowed to stand, and the upper ethyl acetate layer was discarded. This ethyl acetate extraction was repeated 9 times. After the extraction was completed, extraction was performed using 250g of chloroform. The obtained chloroform layer was dried with 15g of magnesium sulfate, filtered, and concentrated. The concentrated solution was dissolved in 150 g of ethyl acetate, and hexane was added until crystals precipitated. The crystals were collected by filtration, dissolved again in 150 g of ethyl acetate by heating, cooled to room temperature, and then hexane was added until crystals precipitated. The crystals were collected by filtration and dried to obtain the following cyanoethyl compound (X). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.63 (16H, t, -C H 2CH2CN), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (3614H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H , -C H 2-OCH2CH2CH2CH2O-C H 2-, -CH2C H 2CN)

[0142] [ka]

[0143] (Example 4-2) Synthesis of propylamino derivative (molecular weight approximately 40,000) In a 1L autoclave, 30 g of the cyanoethyl compound of compound (X) obtained in Example 4-1 above, 545 g of toluene, and 2.7 g of nickel (5136p manufactured by NEM Cat Co.) were added, and the temperature was raised to 60°C. The mixture was pressurized with ammonia until the internal pressure reached 1 MPa, and then hydrogen was pressurized until the internal pressure reached 4.5 MPa, and the reaction was carried out at 130°C for 3 hours. After the reaction, the reaction solution was cooled to 80°C, and nitrogen purging was repeated until the ammonia odor disappeared. The entire reaction solution was removed, filtered, and the filtrate was cooled to room temperature, and hexane was added until crystals precipitated. The crystals were filtered and dried to obtain the following amine (XI). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 1.72 (16H, quint, -CH2C H 2CH2NH2), 2.79 (16H, t, -CH2CH2C H 2NH2), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (894H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-, -C H2CH2CH2NH2) GPC analysis (aqueous) Main fraction: 96.5%, Mn:28,201, Mw:28,796, Mw / Mn:1.021, Mp:28,661

[0144] [ka]

[0145] Example 5 Synthesis of NHS glutaric acid (molecular weight approximately 20,000) In a 200 ml round-bottom flask equipped with a thermometer, a nitrogen inlet tube, and a stirrer, 50 g (2.5 mmol) of the compound (III) obtained in Example 1-6, BHT 33mg, sodium acetate 250mg, toluene 100g were added and PEG was dissolved under nitrogen atmosphere, then heated to reflux at 110℃ to remove moisture. After cooling, 3.46g (30.3mmol) of glutaric anhydride was added and reacted at 110℃ for 8 hours. Next, the reaction solution was cooled to 40℃, N-hydroxysuccinimide 4.88g (42.4mmol) and 1,3-dicyclohexylcarbodiimide 8.34g (40.4mmol) were added and reacted for 3 hours. After 3 hours, the reaction solution was filtered, and hexane was added to the filtrate until crystals precipitated. The crystals were collected by filtration, dissolved in ethyl acetate by heating, and hexane was added until crystals precipitated, and the crystals were collected by filtration and dried to obtain the target compound (XII). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.07 (16H, quint, -CH2C H 2CH2C(O)O-), 2.50 (16H, t, -C H 2CH2CH2C(O)O-), 2.72 (16H, t, -CH2CH2CH 2C(O)O-), 2.84 (32H, br, -C(O)C H 2C H 2C(O)-), 3.40 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.51-3.64 (1758H, m, -C H 2O (C H 2C H 2O) n H, C H O (C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-,) 4.25 (16H, t, -OCH2C H 2OC(O)-) GPC analysis (DMF system) Main fraction: 97.7%, Mn:14,297, Mw:14,650, Mw / Mn:1.025, Mp:15,160

[0146] [ka]

[0147] Comparative Example 1 The above compounds (I), (II), (III) and (IV) were synthesized by the production methods described in Patent Documents 1 and 2. (L=n-butylene group, k=1, molecular weight approximately 5,000, 10,000, 20,000, 40,000)

[0148] (Comparative Example 1-1) Compound (XIII) (VIX): Synthesis of diisopropylidene xylitol A 5L round-bottom flask equipped with a thermometer, nitrogen inlet tube, and stirrer was charged with 1000g of hexylitol, 1916g of 2,2-dimethoxypropane, and 37.5mg of p-toluenesulfonic acid monohydrate, and the reaction was carried out at 65℃ while blowing in nitrogen. The solvent was removed from the reaction solution, and the solution was purified by distillation (bp 108℃ / 0.15mmHg) to obtain 1527g of an isomer mixture of 1,2,3,4-diisopropylidene xylitol (formula (XIII)) and 1,2,4,5-diisopropylidene xylitol (formula (XIV)). 1 H-NMR (CDCl3, internal standard TMS) δ (ppm): 1.37-1.44 (12H,m,-C(C H 3)2), 3.59-3.65 (1H,m,-C H -O-), 3.81-3.90 (2H,m,-C H 2-O-), 3.98-4.01 (1H,m,-C H -O-), 4.04-4.10 (2H,m,-C H 2-O-) 4.11-4.23(1H, m, -C H -O-)

[0149] [ka]

[0150] (Comparative Example 1-2) Synthesis of compound (XV): 1,2,3,4-diisopropylidene-5-(t-butyldiphenylsilyl)xylitol In a 2L round-bottom flask equipped with a thermometer, nitrogen inlet tube, and stirrer, 250g of diisopropylidene xylitol (mixture of isomers) purified in 1-1, 1000g of dichloromethane, 26g of 4-dimethylaminopyridine, and 109g of triethylamine were placed and dissolved at room temperature while blowing in nitrogen, cooled to below 10°C, and 297g of t-butylchlorodiphenylsilane was added dropwise. After the dropwise addition, the mixture was returned to room temperature and reacted for 2 hours, after which it was washed with a saturated aqueous solution of sodium bicarbonate, dehydrated with magnesium sulfate, the solvent was distilled off, and 1,2,4,5-diisopropylidene xylitol was removed at 135°C under reduced pressure (0.2mmHg), to obtain 200g of 1,2,3,4-diisopropylidene-5-(t-butyldiphenylsilyl)xylitol (formula (XV)). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.06 (9H,m, -Si-C- (CH 3 ) 3) 1.37, 1.42, 1.43 (12H,s, -OCC H 3) 3.72-3.82 (1H,m,-C H -O-, -C H 2-O-) 3.95 (1H,dd, -C H -O-) 3.99-4.06 (2H,m,-C H 2-O-) 4.11-4.15 (1H,m,-C H -O-) 7.36-7.54 (6H,m, Ph -Si(- Ph )-O-) 7.66-7.70 (4H,m, Ph -Si(- Ph )-O-)

[0151] [ka]

[0152] (Comparative Example 1-3) Synthesis of compound (XIII): 1,2,3,4-diisopropylidene xylitol In a 2L round-bottom flask equipped with a thermometer, a nitrogen blowing tube, and a stirrer, 500g of 1,2,3,4-diisopropylidene-5-(t-butyldiphenylsilyl)xylitol obtained in 1-2 and 440g of dehydrated tetrahydrofuran were placed, and the mixture was homogenized at room temperature while blowing in nitrogen. After cooling to below 20°C, 1270ml of tetrabutylammonium fluoride (1mol / L tetrahydrofuran solution) was added dropwise. After the dropwise addition, the mixture was returned to room temperature and reacted for 2 hours, and the solvent was distilled off under reduced pressure. After dissolving in 2000g of ethyl acetate, the ethyl acetate layer was washed with purified water, dehydrated with magnesium sulfate, and the solvent was distilled off. 150g of 1,2,3,4-diisopropylidene xylitol (formula (XIII)) was obtained by column chromatography using chloroform and methanol as solvents and silica gel as a packing material. 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.39, 1.44 (12H,s,-C H 3) 3.62 (1H,dd,-C H -O-), 3.08-3.89 (2H,m,-C H 2-O-), 3.98-4.08 (1H,m,-C H -O-,2H,m,-C H 2O-), 4.18-4.23 (1H,m,-C H -O-)

[0153] [ka]

[0154] (Comparative Examples 1-4) Synthesis of compound (XIV): 1,1'-butylenebis(2,3,4,5-diisopropylidenexylitol) In a 5000 ml round-bottom flask equipped with a thermometer, nitrogen blowing tube, and stirrer, 130.3 g (0.56 mol) of 1,2,3,4-diisopropylidene xylitol and 1650 g of dehydrated toluene were added and dissolved under a nitrogen atmosphere, and then 65.4 g (0.58 mol) of t-butoxy potassium was added and stirred at room temperature for 30 minutes. Meanwhile, 55.2 g (0.22 mol) of 1,4-butanediol dimethanesulfonate was dissolved in 660 g of dehydrated DMF, and then dropped into the reaction solution at 40°C or less over 30 minutes while stirring. After the dropwise addition was completed, the temperature was raised to 50°C and the reaction was allowed to proceed for 6 hours. After the reaction was completed, the reaction solution was cooled, 1100 g of ion-exchanged water was added, stirred for 20 minutes, and then allowed to stand, and the aqueous layer was removed. 830 g of ion-exchanged water was added again, and the water washing process of stirring and standing was repeated 8 times to remove DMF and unreacted raw materials. After washing with water, the organic layer was concentrated, 27.6 g of magnesium sulfate was added, dehydrated, and filtered. The filtrate was concentrated again and purified by silica gel column chromatography (Wakogel C-200, developing solvent ethyl acetate:hexane = 10:3 (v / v)) to obtain 76.9 g of 1,1'-butylenebis(2,3,4,5-diisopropylidenexylitol) (XVI) having the following structure. 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.39, 1.41, 1.42, 1.44 (24H, s, -OCC H 3) 1.65 (4H, quint, -OCH2C H 2C H 2CH2-O-), 3.49 (4H, m, -OC H 2CH2CH2C H 2-O-), 3.54-3.58 (4H, m, -C H 2-O-), 3.85 (2H, t, -C H -O-), 3.89 (2H, dd, -C H -O-), 4.02-4.07 (4H, m, -C H 2-O-), 4.17 (2H, dd, -C H -O-)

[0155] [ka]

[0156] (Comparative Examples 1-5) Synthesis of 1,1'-butylenebisxylitol(V) In a 1000ml round-bottom flask equipped with a thermometer, a nitrogen inlet tube, and a stirrer, 76.8g (0.15mol) of 1,1'-butylenebis(2,3,4,5-diisopropylidene xylitol) (XVI) obtained in Example 1-1, 456g of methanol, and 45g of ion-exchanged water were added and dissolved under a nitrogen atmosphere, and then 76.4g of Dowex 50W-8H (Dow Chemical Co.) dispersed in 76g of methanol was added, and the mixture was heated to reflux to azeotropically remove the by-product acetone. The reaction solution was filtered, and the filtrate was concentrated to obtain 53.6g of the above compound 1,1'-butylenebisxylitol (V). 1 H-NMR (D2O, internal standard TMS) δ(ppm): 1.66 (4H, quint, -OCH2C H 2C H 2CH2-O-), 3.56-3.75 (14H, m, -OC H 2CH2CH2C H 2-O-, -C H 2-O-, -C H -O-), 3.79-3.82 (2H, m, -C H -O-), 3.91-3.93 (2H, m, -C H -O-)

[0157] (Comparative Examples 1-6) Synthesis of compound (I) (molecular weight 5,000) 52 g of 1,1'-butylene bis xylitol (V) obtained in Comparative Example 1-5 was heated and washed with 34 g of methanol while being charged into a 5 L autoclave. Next, 4.9 g of potassium hydroxide and 10 g of ion-exchanged water were added to a 50 ml beaker to prepare an aqueous potassium hydroxide solution, which was then charged into a 5 L autoclave. Next, 500 g of dehydrated toluene was added, and azeotropic dehydration was repeated three times at 80 ° C. and slightly reduced pressure. After azeotropic dehydration, 1423 g of dehydrated toluene was added and the system was replaced with nitrogen, and then 654 g (14.85 mol) of ethylene oxide was added at 80 to 150 ° C. and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60 ° C., 945 g of the reaction solution was extracted from the kettle, and the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, to obtain the above compound (I). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.66 (8H, br, -O H ), 3.40 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (430H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system) Main fraction: 100%, Mn:3,971, Mw:4,059, Mw / Mn:1.022, Mp:4,105 Molecular weight (TOF-MS); 4,991 Molecular weight (hydroxyl value): 5,097

[0158] (Comparative Examples 1-7) Synthesis of compound (II) (molecular weight 10,000) In Comparative Example 1-6, 370 g (8.40 mol) of ethylene oxide was added to about 1345 g of the reaction solution remaining in the reaction vessel at 80 to 150°C and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60°C, and 1045 g of the reaction solution was extracted from the vessel, the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and the toluene was distilled off to obtain the above compound (II). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.365 (8H, br, -O H ), 3.40 (4H, s, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (878H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system) Main fraction: 100%, Mn:7,264, Mw:7,429, Mw / Mn:1.023, Mp:7,513 Molecular weight (TOF-MS); 10,033 Molecular weight (hydroxyl value): 10,158

[0159] (Comparative Examples 1-8) Synthesis of compound (III) (molecular weight 20,000) In Comparative Example 1-7, 182 g (4.13 mol) of ethylene oxide was added to about 524 g of the reaction liquid remaining in the reaction vessel at 80 to 150°C and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction liquid was cooled to 60°C and 620 g of the reaction liquid was extracted from the vessel, the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and the toluene was distilled off to obtain the above compound (III). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.57 (8H, br, -O H ), 3.40 (4H, s, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (1774H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system) Main fraction: 99.3%, Mn:13,965, Mw:14,392, Mw / Mn:1.031, Mp:14,724 Molecular weight (TOF-MS); 20,083 Molecular weight (hydroxyl value): 20,225

[0160] (Comparative Examples 1-9) Synthesis of compound (IV) (molecular weight 40,000) In Comparative Example 1-8, 138 g (3.13 mol) of ethylene oxide was added to about 221 g of the reaction solution remaining in the reaction vessel at 80 to 150°C and a pressure of 1 MPa or less, and the reaction was continued for another hour. After the reaction, the reaction solution was cooled to 60°C and the entire reaction solution was removed from the vessel, the pH was adjusted to 7.5 with an 85% aqueous phosphoric acid solution, and the toluene was distilled off to obtain the above compound (IV). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.589 (8H, br, -O H ), 3.40 (4H, s, -OC H 2CH2CH2C H 2-O-), 3.50-3.81 (3598H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-) GPC analysis (DMF system): Main fraction: 97.3%, Mn:28,595, Mw:29,392, Mw / Mn:1.028, Mp:30,103 Molecular weight (TOF-MS); 41,450 Molecular weight (hydroxyl value): 38,590

[0161] (Comparative Example 2-1) Synthesis of cyanoethyl derivative (molecular weight approximately 10,000) In a 500 ml round bottom flask equipped with a thermometer, a nitrogen blowing tube, a stirrer, and a cooling tube, 30 g (3 mmol) of the compound (II) obtained in the above Comparative Example 1-4 and 30 g of ion-exchanged water were added and dissolved by heating to 40°C. After dissolution, the mixture was cooled to 10°C or less, and 3 g of 50% potassium hydroxide aqueous solution was added. Then, 25.5 g (480 mmol) of acrylonitrile was added dropwise over 2 hours while maintaining the temperature at 5 to 10°C. After the dropwise addition, the mixture was reacted for another 4 hours, 30 g of ion-exchanged water was added, and 1.8 g of 85% phosphoric acid aqueous solution was added dropwise to neutralize. 45 g of ethyl acetate was added, stirred, and then allowed to stand, and the upper ethyl acetate layer was discarded. This ethyl acetate extraction was repeated 9 times. After the extraction, the mixture was extracted using 150 g of chloroform. The obtained chloroform layer was dried with 15 g of magnesium sulfate, filtered, and concentrated. 90 g of ethyl acetate was added to the concentrated liquid to dissolve it, and hexane was added until crystals were precipitated. The crystals were filtered off, dissolved again in 90 g of ethyl acetate under heating, cooled to room temperature, and then hexane was added until crystals precipitated. The crystals were filtered off and dried to obtain the above cyanoethyl compound (VI). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.63 (16H, t, -C H 2CH2CN), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (894H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H , -C H 2-OCH2CH2CH2CH2O-C H 2-, -CH2C H 2CN)

[0162] (Comparative Example 2-2) Synthesis of propylamino derivative (molecular weight approx. 10,000) In a 1L autoclave, 13 g of the cyanoethyl compound (VI) obtained in Example 2-1 above, 560 g of toluene, and 1.2 g of nickel (5136p manufactured by NEM Cat Co.) were added, and the temperature was raised to 60°C. The mixture was pressurized with ammonia until the internal pressure reached 1 MPa, and then hydrogen was pressurized until the internal pressure reached 4.5 MPa, and the reaction was carried out at 130°C for 3 hours. After the reaction, the reaction solution was cooled to 80°C, and nitrogen purging was repeated until the ammonia odor disappeared. The entire reaction solution was removed, filtered, and the filtrate was cooled to room temperature, and hexane was added until crystals precipitated. The crystals were filtered and dried to obtain the above amine (VII). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 1.72 (16H, quint, -CH2C H 2CH2NH2), 2.79 (16H, t, -CH2CH2C H 2NH2), 3.39 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.50-3.80 (894H, m, -C H 2O (C H 2C H 2O) n H, C H O(C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-, -C H 2CH2CH2NH2) GPC analysis (aqueous) Main fraction: 97.9%, Mn:6,334, Mw:6,477, Mw / Mn:1.022, Mp:6,571

[0163] Comparative Example 3 Synthesis of NHS glutaric acid (molecular weight approximately 20,000) In a 200 ml round-bottom flask equipped with a thermometer, a nitrogen inlet tube, and a stirrer, 25 g (1.25 mmol) of the compound (III) obtained in Comparative Example 1-5, 25 mg of BHT, 125 mg of sodium acetate, and 60 g of toluene were added to dissolve the PEG under a nitrogen atmosphere, and then the mixture was heated to reflux at 110°C to remove moisture. After cooling, 1.71 g (15.0 mmol) of glutaric anhydride was added and reacted at 110°C for 8 hours. Next, the reaction solution was cooled to 40°C, and 3.45 g (30.0 mmol) of N-hydroxysuccinimide and 4.33 g (21.0 mmol) of 1,3-dicyclohexylcarbodiimide were added and reacted for 3 hours. After 3 hours, the reaction solution was filtered, and hexane was added to the filtrate until crystals precipitated. The crystals were collected by filtration, dissolved in ethyl acetate by heating, and then hexane was added until crystals precipitated. The crystals were collected by filtration and dried to obtain the target compound (XII). 1 H-NMR (CDCl3, internal standard TMS) δ(ppm): 1.57 (4H, br, -OCH2C H 2C H 2CH2-O-), 2.07 (16H, quint, -CH2C H 2CH2C(O)O-), 2.50 (16H, t, -C H 2CH2CH2C(O)O-), 2.72 (16H, t, -CH2CH2C H 2C(O)O-), 2.84 (32H, br, -C(O)C H 2C H 2C(O)-), 3.40 (4H, br, -OC H 2CH2CH2C H 2-O-), 3.51-3.64 (1758H, m, -CH 2O (C H 2C H 2O) n H, C H O (C H 2C H 2O) n H, -C H 2-OCH2CH2CH2CH2O-C H 2-,) 4.25 (16H, t, -OCH2C H 2OC(O)-) GPC analysis (DMF system) Main fraction: 97.5%, Mn:14,711, Mw:15,116, Mw / Mn:1.028, Mp:15,635

[0164] The purity and total yield of the propylamino compound (VII) obtained in Example 2-2 and Comparative Example 2-2 are shown in Table 1.

[0165] [Table 1]

[0166] The results of the polydispersity (Mw / Mn) of the main fraction obtained by GPC analysis in Examples 1-4 to 7, 2-2, and 5 and Comparative Examples 1-6 to 9, 2-2, and 3 are summarized in Table 2.

[0167] [Table 2]

[0168] In the conventional manufacturing method, three steps are required to obtain a high-purity xylitol-protected product, and the yield is significantly reduced because column chromatography is used in the purification process. On the other hand, in the manufacturing method of the present invention, a high-purity xylitol-protected product can be obtained in one step and no special purification process is required, so the total molar yield can be significantly improved. In addition, it was shown that the polydispersity and purity of the multi-arm polyethylene glycol derivative and its intermediate of the present invention are of the same quality.

Claims

1. A method for producing a multi-arm polyethylene glycol derivative represented by the following formula (1), which comprises carrying out the following steps (A), (B), (C), (D) and (E) in this order: 【Chemistry 1】 (In formula (1), L represents a group selected from the group consisting of linear or branched alkylene groups having 3 to 8 carbon atoms, substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and cycloalkylene groups having 6 to 12 carbon atoms; k is 1 or 2, n is the average number of moles of oxyethylene groups added, and n is an integer between 3 and 600. X represents an alkylene group which may have a single bond, an ester bond, a urethane bond, an amide bond, an ether bond, a carbonate bond, a secondary amino group, a urea bond, a thioether bond, or a thioester bond in the chain or at an end thereof; Y represents a chemically reactive functional group. Process (A): A step of protecting the even-numbered hydroxyl groups other than the 1-position hydroxyl group of a polyhydric alcohol having an odd number of hydroxyl groups by cyclic benzylidene acetalization, while leaving only the 1-position hydroxyl group Process (B): A step of linking two molecules of the compound obtained in the above step (A) with a compound represented by the following formula (2) by an etherification reaction to obtain a compound, and purifying this compound by recrystallization in dimethylformamide. 【Chemistry 2】 (In formula (2), L represents a group selected from the group consisting of linear or branched alkylene groups having 3 to 8 carbon atoms, substituted or unsubstituted arylene groups having 6 to 12 carbon atoms, and cycloalkylene groups having 6 to 12 carbon atoms; A represents a halogen atom selected from chlorine, bromine, or iodine, or a sulfone-based leaving group. Process (C): A step of deprotecting the terminal cyclic benzylidene acetal structure of the compound obtained in the step (B), which produces 8 hydroxyl groups when k=1 and 12 hydroxyl groups when k=2. Process (D): A step of polymerizing 3 to 600 moles of ethylene oxide to each hydroxyl group of the compound obtained in the step (C) to obtain a multi-arm polyethylene glycol derivative. Process (E): A step of functionalizing the terminal hydroxyl groups of the multi-arm polyethylene glycol derivative obtained in the step (D).

2. 2. The method according to claim 1, wherein step (A) is carried out using an acidic solution as a solvent.

3. The method according to claim 1, wherein the step (C) is carried out under acidic conditions.

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