Patent Application
20250101146
The present invention relates to an oxyethylene chain-containing polymer.
A vinyl ether polymer is conventionally used as a compounding component of a chemical product such as an adhesive, coating material, or lubricant. It is known that a vinyl ether generally contains an electron-donating substituent, and thus, produces a vinyl ether polymer through cationic polymerization. For the purpose of modifying a vinyl ether polymer, a polymerization method of introducing a functional group into an end has been studied. For example, it is disclosed that an acetal group is introduced into an end of a vinyl ether polymer (see Patent Literature 1 and 2).
In addition, an oxyethylene chain-containing polymer is a material having extremely excellent biocompatibility. To utilize an oxyethylene chain-containing polymer as a biomaterial, it is vital to introduce a highly reactive functional group into the polymer. However, there is no known oxyethylene chain-containing polymer having a highly reactive functional group introduced into an end thereof. Because of this, there is a demand for development of an oxyethylene chain-containing polymer having excellent biocompatibility and still having excellent reactivity.
Accordingly, an object of the present invention is to provide an oxyethylene chain-containing polymer having excellent biocompatibility and still having excellent reactivity.
The present inventors have vigorously made studies to solve the above-described problem, and consequently completed the present invention through the discovery that introducing a specific highly reactive functional group into one end (w end) of an oxyethylene chain-containing polymer can solve the above-described problem.
That is, the present invention provides the following inventions.
[1] An oxyethylene chain-containing polymer represented by the following general formula (1):
[2] The oxyethylene chain-containing polymer according to [1],
[3] The oxyethylene chain-containing polymer according to [1],
[4] The oxyethylene chain-containing polymer according to [1], wherein, in the general formula (1), R1 is —(CH2)p—NH2, and p is an integer of 1 to 3;
[5] The oxyethylene chain-containing polymer according to [1],
[6] The oxyethylene chain-containing polymer according to any one of [1] to [5], wherein the number-average molecular weight (Mn) of the oxyethylene chain-containing polymer is 500 or more and 100,000 or less.
[7] The oxyethylene chain-containing polymer according to any one of [1] to [6], wherein the ratio of the weight-average molecular weight (Mw) of the oxyethylene chain-containing polymer to the number-average molecular weight (Mn) of the polymer is 1.0 or more and 3.0 or less.
The present invention can provide an oxyethylene chain-containing polymer having excellent biocompatibility and still having excellent reactivity. Such an oxyethylene chain-containing polymer has excellent reactivity, and thus, can more easily modify a base material, microparticles, or the like, and can give biocompatibility to a base material, microparticles, or the like.
An oxyethylene chain-containing polymer according to the present invention is represented by the following general formula (1).
In the general formula (1), R1 is —(CH2)p—SH, —(CH2)p—N3, (CH2)p—NH2, or —(CH2)p—COOH.
p is an integer of 1 to 5, preferably an integer of 1 to 3, more preferably 1 or 2.
R2 to R4 are each independently hydrogen or a C1-10 alkyl group, preferably hydrogen or a C1-4 alkyl group, more preferably hydrogen or a C1-3 alkyl group, still more preferably hydrogen or a C1-2 alkyl group, still more preferably hydrogen.
R5 is a C1-10 alkyl group, preferably a C1-10 alkyl group, more preferably a C1-4 alkyl group, still more preferably a C1-2 alkyl group.
R6 is hydrogen or a C1-5 alkyl group, preferably a C1-2 alkyl group, more preferably a methyl group.
R7 is a C1-10 alkyl group, preferably a C1-7 alkyl group, more preferably a C1-4 alkyl group.
n is an integer of 5 to 1000, preferably an integer of 10 to 500, more preferably an integer of 20 to 400.
m is an integer of 1 to 10, preferably an integer of 1 to 5, more preferably an integer of 1 to 3.
q is an integer of 0 to 5, preferably an integer of 0 to 2, more preferably an integer of 0 to 1.
In this regard, the above-described alkyl group may be linear or branched.
An oxyethylene chain-containing polymer according to the present invention has a highly reactive functional group introduced into one end (ω end) thereof, in which the functional group is a thiol group, azido group, amino group, or carboxyl group. Thus, the polymer has excellent biocompatibility and still can modify a base material, microparticles, or the like. Because of this, the polymer can give biocompatibility to a base material, microparticles, or the like. In addition, such a highly reactive functional group can be further converted to further enhance capabilities such as reactivity and a modifying capability.
Examples of a preferable embodiment of an oxyethylene chain-containing polymer represented by the general formula (1) include the below-described polymers. In the following formula, n is an integer of 5 to 1000, preferably an integer of 10 to 500, more preferably an integer of 20 to 400.
The number-average molecular weight (Mn) of an oxyethylene chain-containing polymer according to the present invention is preferably 500 or more and 100,000 or less. The lower limit of the number-average molecular weight (Mn) is more preferably 700 or more, still more preferably 1,000 or more, still more preferably 1,500 or more, and the upper limit is more preferably 70,000 or less, still more preferably 50,000 or less, still more preferably 30,000 or less, particularly preferably 20,000 or less. The oxyethylene chain-containing polymer having a number-average molecular weight (Mn) in the above-described ranges has excellent biocompatibility, and in addition, can more easily modify a base material, microparticles, and the like, and more easily give biocompatibility.
The ratio (the molecular-weight distribution, Mw/Mn) of the weight-average molecular weight (Mw) of an oxyethylene chain-containing polymer according to the present invention to the number-average molecular weight (Mn) of the polymer is preferably 1.0 or more and 3.0 or less, more preferably 1.0 or more and 2.0 or less, still more preferably 1.0 or more and 1.5 or less, still more preferably 1.0 or more and 1.3 or less. The oxyethylene chain-containing polymer having a molecular-weight distribution (Mw/Mn) in the above-described ranges makes it easier to keep the capability of the polymer uniformly.
In this regard, the number-average molecular weight (Mn) and the weight-average molecular weight (Mw) in the present invention can be calculated from a standard polystyrene calibration curve based on a gel permeation chromatography (GPC) method.
Embodiments of a method of producing an oxyethylene chain-containing polymer according to the present invention will be described. First, using a vinyl ether as a raw-material monomer, for example, an oxyethylene chain-containing polymer having a carbonyl group at one end thereof and represented by the following general formula (2) is synthesized through living cationic polymerization in the presence of a polymerization initiator. Upon completion of the polymerization, a small amount of water is added, so that the end cation reacts with the water, thus enabling a carbonyl group to be introduced. Subsequently, the carbonyl group at one end of the oxyethylene chain-containing polymer represented by the following general formula (2) is converted to thereby enable a reactive functional group (thiol group, azido group, amino group, or carboxyl group) to be introduced.
In this regard, R2 to R7, n, m, and q in the general formula (2) are the same as R2 to R7, n, m, and q in the general formula (1).
In addition, preferable aspects of R2 to R7, n, m, and q in the general formula (2) are the same as preferable aspects of R2 to R7, n, m, and q in the general formula (1).
A vinyl ether usable as a raw-material monomer is, for example, a vinyl ether represented by the following general formula (3).
R2 to R5 and m in the general formula (3) are the same as R2 to R5 and m in the general formula (1).
In addition, preferable aspects of R2 to R5 and m in the general formula (2) are the same as preferable aspects of R2 to R5 and m in the general formula (1).
Examples of a vinyl ether represented by the general formula (3) include 2-methoxyethylvinyl ether (MOVE), 2-ethoxyethylvinyl ether (EOVE), diethylene glycol monoethylmonovinyl ether (EOEOVE), and triethylene glycol monomethylvinyl ether (TEGMVE).
A polymerization initiator to be used in the polymerization of an oxyethylene chain-containing polymer is not particularly limited, subject to being a polymerization initiator that advances cationic polymerization in a living manner. The initiator may be a conventionally known polymerization initiator. Examples of a polymerization initiator to be suitably used, for example, a living cationic polymerization initiator for vinyl ethers, include HI/I2-based initiators (for example, in JP S60-228509A) and polymerization initiators (for example, in JP3096494B2, JP H07-002805B2, JP S62-257910A, JP H01-108202A, and JP H01-108203A) obtained by combining a Lewis-acid catalyst (organic aluminum compound or the like) with an additive (ether or the like) such as a base.
The usage of the polymerization initiator is preferably 0.001 to 20 mol %, more preferably 0.01 to 10 mol %, particularly preferably 1 mol % or less, with respect to the total amount of the raw-material monomers.
In addition, the living cationic polymerization reaction is preferably performed in the presence of, or may be performed in the absence of, a suitable organic solvent. Examples of an organic solvent that is usable include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; aliphatic hydrocarbon solvents such as propane, n-butane, isobutane, n-pentane, isopentane, n-hexane, n-heptane, n-octane, isooctane, decane, hexadecane, and cyclohexane; halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride, and carbon tetrachloride; and ether solvents such as diethyl ether, dibutyl ether, tetrahydrofuran (THF), dioxane, and ethylene glycol diethyl ether. These organic solvents may be used singly or in combination of two or more kinds thereof, as necessary. In addition, among these organic solvents, hydrocarbon solvents such as aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents are preferable, and toluene, THF, and the like are preferable.
The polymerization temperature in the living cationic polymerization reaction depends, for example, on the kinds of a polymerization initiator, monomer, and solvent that are used, and is usually −80 to 150° C., preferably −50 to 100° C., particularly preferably −20 to 80° C. In addition, the polymerization time depends, for example, on the polymerization initiator, monomer, and solvent that are used and on the reaction temperature, and is usually approximately 10 minutes to 100 hours. The polymerization reaction may be suitably performed using any of a batch method and a continuous method. After the polymerization reaction, a purification treatment, if desired, may be performed using a known method in order to remove an unreacted monomer.
Below, one example of polymerization reaction of an oxyethylene chain-containing polymer (PMOVE) is illustrated, in which 2-methoxyethylvinyl ether (MOVE) is used as a raw-material monomer. First, a PMOVE having a carbonyl group at one end thereof is synthesized from an MOVE in the presence of a polymerization initiator in accordance with the following reaction formula (I). Upon completion of the polymerization, a small amount of water is added, so that the end cation reacts with the water, thus enabling a carbonyl group to be introduced. In respect of the polymerization reaction conditions and the like for the following reaction formula (I), J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 468-472 can be referred to. In the following reaction formulae (I) to (V), n in PMOVE is an integer of 5 to 1000, preferably an integer of 10 to 500, more preferably an integer of 20 to 400, as in the general formula (1).
Below, a method (a reaction formula) of synthesizing a PMOVE will be described in respect of each kind of reactive functional group. A catalyst, polymerization initiator, solvent, and the like in the following series of reactions may be suitably selected with reference to a conventional known method. In addition, the polymerization reaction conditions such as a polymerization temperature and a polymerization time may be set suitably.
In a case where the reactive functional group is a thiol group, the carbonyl group at one end of the PMOVE obtained as described above can be converted in accordance with the following reaction formula (II) to synthesize a PMOVE having a thiol group at one end thereof. In respect of the polymerization reaction conditions and the like for the following reaction formula (II), Journal of Colloid and Interface Science, 428 (2014), 276-285 can be referred to. In the following reaction formula (II), EtOH represents ethanol, MsCl represents methanesulfonyl chloride, TEA represents triethylamine, KSAc represents potassium thioacetate, DMSO represents dimethyl sulfoxide, MeOH represents methanol, and NaOH represents sodium hydroxide.
In a case where the reactive functional group is an azido group, the carbonyl group at one end of the PMOVE obtained as described above can be converted in accordance with the following reaction formula (III) to synthesize a PMOVE having an azido group at one end thereof. In respect of the polymerization reaction conditions and the like for the following reaction formula (III), Med Chem Res (2016) 25:824-833 can be referred to. In the following reaction formula (III), NaN3 is sodium azide, and the other abbreviations are the same as the abbreviations in the above-described reaction formula (II).
In a case where the reactive functional group is an amino group, the carbonyl group at one end of the PMOVE obtained as described above can be converted in accordance with the following reaction formula (IV) to synthesize a PMOVE having an amino group at one end thereof. In respect of the polymerization reaction conditions and the like for the following reaction formula (IV), Med Chem Res (2016) 25:824-833 can be referred to. In the following reaction formula (IV), PPh3 is triphenylphosphine, and the other abbreviations are the same as the abbreviations in the above-described reaction formula (II).
In a case where the reactive functional group is a carboxyl group, the carbonyl group at one end of the PMOVE obtained as described above can be converted in accordance with the following reaction formula (IV) to synthesize a PMOVE having a carboxyl group at one end thereof. In the following reaction formula (V), NaClO2 represents sodium chlorite, and NaH2PO4 represents sodium dihydrogenphosphate.
Next, the present invention will be described in more detail with reference to Examples and Comparative Examples. The present invention should not be restricted to these Examples or the like in any way.
In Examples and Comparative Examples, the structure of a polymer was determined from the results of 1H-NMR analysis. In addition, the number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of a polymer were determined from the results of GPC analysis of the molecular weight (in terms of polystyrene). The analytical device, measurement conditions, and the like in each measurement are described below.
Using 2-methoxyethylvinyl ether (MOVE) as a raw-material monomer, a PMOVE having a carbonyl group at one end thereof (PMOVE-CHO) was obtained in accordance with the above-described reaction formula (I). Specifically, 5.8 mL of MOVE as a raw-material monomer, 147 μL of MOEA, namely an acetic acid adduct of MOVE, as a polymerization initiator, 90 mL of toluene, 1.6 mL of THF, 108 μL of 2,6-di-tert-butylpyridine, 2.2 mL of ethyl aluminum sesquichloride (25% in a toluene solution), and 1.0 ml of tin chloride (IV) (1.0 M in a heptane solution) were mixed, and allowed to undergo polymerization reaction. Upon completion of the polymerization, 1.0 ml of water was mixed, and a carbonyl group was introduced into one end. The solvent was removed using an evaporator, the residue was redissolved in ethanol, and then purified using a 0.45 μm syringe filter. The solvent was again removed to give a PMOVE-CHO.
Herein, a polymer having a functional group at one end is referred to as a “polymer name-functional group name”.
Then, the carbonyl group at one end of PMOVE was converted into a thiol group in accordance with the above-described reaction formula (II). Specifically, 1.0 g of PMOVE-CHO, 0.3 g of sodium borohydride, and 20 mL of ethanol were first mixed, and the resulting mixture was stirred overnight. The resulting mixture was dissolved in water, and dialytically purified through a dialysis membrane having an MWCO of 3,500 to give a PMOVE-OH. Subsequently, 500 mg of PMOVE-OH, 12 mL of CH2Cl2, 63 μL of TEA, and 23 μL of MsCl were mixed, allowed to react under argon at 0° C. for 0.5 hours, and further allowed to react at room temperature for 3.5 hours. The resulting solution was washed with water and saturated saline, and the solvent was removed with an evaporator to give a PMOVE-Ms. Subsequently, 500 mg of PMOVE-Ms, 12 mL of dehydrated DMSO, and 57 mg of KSAc were mixed and allowed to react under argon at 40° C. for 18 hours. The resulting solution was quenched with 1.0 M hydrochloric acid, and then, the solvent was removed. The resulting product was redissolved in water, and dialytically purified through a dialysis membrane having an MWCO of 3,500 to give a PMOVE-SAc. Finally, 500 mg of PMOVE-SAc and 12 mL of dehydrated methanol were mixed and sparged with argon. To the resulting solution, 20 mg of NaOH and 46 mg of dithiothreitol were mixed, and allowed to react for 1 hour. The resulting solution was quenched with 1.0 M hydrochloric acid, and the resulting solution was dialytically purified through a dialysis membrane having an MWCO of 3,500 at 4° C. in a refrigerator to give a PMOVE-SH.
The resulting reaction product (PMOVE-SH) and a precursor thereof (PMOVE-SAc) were subjected to a 1H-NMR measurement under the above-described conditions to give 1H-NMR spectra illustrated in
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-SH obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.05.
A PMOVE-CHO was obtained in the same manner as in Example 1. Then, the carbonyl group at one end of PMOVE was converted into an azido group in accordance with the above-described reaction formula (III). Specifically, 500 mg of PMOVE-Ms, 12 mL of dehydrated DMSO, and 39 mg of NaN3 were mixed and allowed to react under argon at 70° C. for 18 hours. The resulting solution was quenched with water, and then, the solvent was removed. The resulting product was redissolved in water, and dialytically purified through a dialysis membrane having an MWCO of 3,500 to give a PMOVE-N3.
The resulting reaction product (PMOVE-N3) and a precursor thereof (PMOVE-Ms) were subjected to a 1H-NMR measurement under the above-described conditions to give 1H-NMR spectra illustrated in
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-N3 obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.05.
A PMOVE-CHO was obtained in the same manner as in Example 1. Then, the carbonyl group at one end of PMOVE was converted into an amino group in accordance with the above-described reaction formula (IV). Specifically, 500 mg of PMOVE-N3, 525 mg of PPh3, 8.7 mL of MeOH, and 3.3 ml of water were mixed, and allowed to react for 5 hours under reflux at 90° C. The resulting solution was quenched with 1.0 M hydrochloric acid, and then, the solvent was removed. The resulting product was redissolved in water, and dialytically purified through a dialysis membrane having an MWCO of 3,500 to give a PMOVE-NH2.
The PMOVE-NH2 obtained as described above was quantitated through a cation-exchange column (SP-5PW), using GPC (an RI detector: RI-2031 Plus (manufactured by JASCO Corporation); a GPC pump: PU-1580 (manufactured by JASCO Corporation; mobile phase, an aqueous solution of 2 mM NaCl). The ratio of introduction of an amino group into one end was approximately 100%. Additionally, from this result, it is estimated that the ratio of introduction of an azido group into one end was approximately 100% also in the polymer having an azido group at one end in Example 2, in which the polymer was a precursor of the polymer having an amino group at one end in Example 3.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-NH2 obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.05.
A PMOVE-CHO was obtained in the same manner as in Example 1. Then, the carbonyl group at one end of PMOVE was converted into a carboxyl group in accordance with the above-described reaction formula (V). Specifically, 500 mg of PMOVE-CHO, 5.5 mL of ethanol, and 0.2 mL of 2-methyl-2-butene were mixed, and cooled to 0° C. with good stirring. Subsequently, 34 mg of NaClO2, 36 mg of NaH2PO4, and 0.9 ml of water were mixed to another flask, and stirred well. This aqueous solution was dropped into the ethanol solution, stirred for 5 minutes, and then further allowed to react at room temperature for 15 hours. The resulting solution was quenched with saturated saline, and the resulting solution was dialytically purified through a dialysis membrane having an MWCO of 3,500 to give a PMOVE-COOH.
The PMOVE-COOH obtained as described above was subjected to measurement by 1H-NMR, verifying that a carboxyl group had been introduced into one end. In addition, the ratio of introduction of a carboxyl group into one end was approximately 100%.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-COOH obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.05.
A PMOVE-SH was obtained in the same manner as in Example 1 except that 55.7 μL of MOEA was mixed.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-SH obtained as described above were measured with the results as follows: Mn=12,000; and Mw/Mn=1.04.
A PMOVE-SH was obtained in the same manner as in Example 1 except that 3.5 mL of MOVE, 230 μL of MOEA, 138 mL of toluene, 2.4 mL of THF, 162 μL of 2,6-di-tert-butylpyridine, 3.3 mL of ethyl aluminum sesquichloride (25% in a toluene solution), and 1.5 mL of tin chloride (IV) (1.0 M in a heptane solution) were mixed.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-SH obtained as described above were measured with the results as follows: Mn=2,000; and Mw/Mn=1.06.
A PEOVE-SH was obtained in the same manner as in Example 1 except that 6.5 mL of 2-ethoxyethylvinyl ether (EOVE) as a raw-material monomer and 203 μL of EOEA namely an acetic acid adduct of EOVE as an initiator were mixed.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PEOVE-SH obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.08.
A PEOEOVE-SH was obtained in the same manner as in Example 1 except that 8.7 mL of 2-(2-ethoxy) ethoxyethylvinyl ether (EOEOVE) as a raw-material monomer and 333 μL of EOEOEA namely an acetic acid adduct of EOEOVE as an initiator were mixed.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PEOEOVE-SH obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.06.
A PTEGMVE-SH was obtained in the same manner as in Example 1 except that 9.6 mL of triethylene glycol monomethylvinyl ether (TEGMVE) as a raw-material monomer and 450 μL of TEGMEA namely an acetic acid adduct of TEGMVE as an initiator were mixed.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PTEGMVE-SH obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.08.
A PMOVE-CHO was obtained in the same manner as in Example 1.
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PMOVE-CHO obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.05.
A PNBVE-SH was obtained in the same manner as in Example 1 except that n-butylvinyl ether (NBVE) as a raw-material monomer was used in place of 2-methoxyethylvinyl ether (MOVE).
The number-average molecular weight (Mn) and molecular-weight distribution (Mw/Mn) of the PNBVE-SH obtained as described above were measured with the results as follows: Mn=5,000; and Mw/Mn=1.10.
With the PMOVE-SH obtained in Example 1, gold microparticles having an average particle diameter of 150 nm were modified to give gold microparticles coated with PMOVE (PMOVE-coated gold microparticles). Specifically, the following test was performed.
A dispersion of 150 nm gold microparticles modified with citric acid was concentrated by centrifugation, and then dispersed in 90 μL of water. Subsequently, 10 μL of the PMOVE-SH prepared at a concentration such that the average density of the polymer modification would become 1.12 pcs/nm2 to gold microparticles was mixed. The resulting mixture was allowed to react at 60° C. for 1 hour. After the reaction, the resulting solution was concentrated by centrifugation, and the supernatant liquid was removed. Then, the resulting solution was washed several times with water containing 0.25 mM sodium citrate and 0.05 v/v % Tween 20.
The average particle diameter of the PMOVE-coated gold microparticles obtained in the above-described test was measured by dynamic light scattering using a particle diameter measurement device (Model No.: Zetasizer Nano ZS, manufactured by Malvern Panalytical Ltd.). The average particle diameter was found to have been increased to 175.6 nm. From this result, it is estimated that the surfaces of the gold microparticles were successfully modified with the PMOVE.
In accordance with the above-described testing method, an attempt was made to modify gold microparticles with the PMOVE-CHO obtained in Comparative Example 1. However, the polymer had low reactivity with gold microparticles, and thus, did not allow an end thereof to bind with gold microparticles, failing to modify the gold microparticles.
In accordance with the above-described testing method, an attempt was made to modify gold microparticles with the PNBVE-SH obtained in Comparative Example 2. However, the polymer was hydrophobic, and thus, was condensed, failing to modify the gold microparticles.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2022-082856 | May 2022 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2023/018694 | 5/19/2023 | WO |
