WO2015064487A1 - 医用ポリオキシプロピレン重合体の製造方法および医用ポリオキシプロピレン/ポリオキシエチレンブロック共重合体の製造方法 - Google Patents
医用ポリオキシプロピレン重合体の製造方法および医用ポリオキシプロピレン/ポリオキシエチレンブロック共重合体の製造方法 Download PDFInfo
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
- C08G65/06—Cyclic ethers having no atoms other than carbon and hydrogen outside the ring
- C08G65/08—Saturated oxiranes
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
- C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2618—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing nitrogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2696—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds characterised by the process or apparatus used
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/30—Post-polymerisation treatment, e.g. recovery, purification, drying
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
- C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2203/00—Applications
- C08L2203/02—Applications for biomedical use
Definitions
- the present invention relates to a method for producing a polyoxypropylene polymer and a polyoxypropylene / polyoxyethylene block copolymer. More particularly, the present invention relates to a method for producing a high-purity polyoxypropylene polymer and a polyoxypropylene / polyoxyethylene block copolymer intended for use in medical materials.
- a polyoxyalkylene polymer obtained by ring-opening polymerization of a cyclic ether compound such as alkylene oxide on an initiator having active hydrogen is non-antigenic and excellent in biocompatibility.
- a wound dressing material In the field of medical materials, it is used for applications such as anti-adhesion materials, sustained drug release materials, and scaffold materials in regenerative medicine.
- polyoxypropylene / polyoxyethylene block copolymers have improved swelling, flexibility, mechanical strength, and cell / tissue adhesion by changing the composition of hydrophobic polyoxypropylene and hydrophilic polyoxyethylene. It can be arbitrarily adjusted and is widely used as a medical material because of its high versatility.
- the production of a polyoxyalkylene polymer is usually carried out by ring-opening polymerization of alkylene oxide on an initiator having active hydrogen in the presence of a base catalyst.
- a base catalyst when ring-opening polymerization of propylene oxide using a base catalyst, isomerization of propylene oxide occurs in parallel with the polymerization reaction of propylene oxide, and allyl alcohol is generated.
- the produced allyl alcohol serves as a new polymerization starting point and propylene oxide undergoes ring-opening polymerization.
- the polyoxypropylene polymer contains polyoxypropylene monoallyl ether.
- the polyoxypropylene / polyoxyethylene block copolymer is obtained by ring-opening polymerization of ethylene oxide with respect to the polyoxypropylene polymer.
- the polyoxypropylene polymer contains polyoxypropylene monoallyl ether derived from isomerization of propylene oxide, ethylene oxide is polymerized from the hydroxyl group of polyoxypropylene monoallyl ether, resulting in polyoxypropylene as a result.
- Monoallyl ether of polyoxyethylene block copolymer is by-produced.
- Patent Document 1 discloses a method for isomerization of allyl ether to propenyl ether using potassium hydroxide or sodium methoxide and subsequent hydrolysis of propenyl ether.
- the method described here treats at 120 ° C. using alkali metal hydroxide and alkali metal primary or secondary alkoxide as the base catalyst, but the isomerization efficiency of allyl ether to propenyl ether is low. Even after the subsequent hydrolysis of propenyl ether, a large amount of unsaturated ether remains.
- Non-patent document 2 is an example in which the unsaturated ether content can be sufficiently reduced.
- the unsaturated ether content can be sufficiently reduced.
- the method described here has a disadvantage that the polyoxypropylene polymer is likely to be colored because it is necessary to treat the allyl ether for isomerization at a high temperature of 160 ° C. for a long time. Since colored products are avoided in the field of medical materials, the development of a method capable of sufficiently reducing the unsaturated ether content and suppressing coloration is very significant.
- Patent Document 2 adjusts the pH to 2 to 4 by adding a mineral acid to the polyoxypropylene polymer after propylene oxide ring-opening polymerization, Unsaturated ether content is reduced by treating at 80-150 ° C.
- the method described here has low isomerization efficiency of allyl ether, and although it may be possible to further reduce unsaturated ether by treatment at a lower pH and high temperature, it causes quality deterioration such as generation of irritating odors. Therefore, it is not suitable as a method for producing medical materials.
- Patent Document 3 the unsaturated ether contained in the polyoxypropylene / polyoxyethylene block copolymer is removed by gel permeation chromatography, and the polyoxypropylene / polyoxyethylene block copolymer containing no unsaturated ether is removed. Used as a medical material as a unit.
- the method described here is difficult to apply to an industrial scale due to technical and cost problems.
- the production method of the polyoxypropylene polymer and the polyoxypropylene / polyoxyethylene block copolymer having a low unsaturated ether content and suppressed coloring can be easily implemented on an industrial scale. Is not known.
- An object of the present invention is to provide a method for producing a polyoxypropylene polymer and a polyoxypropylene / polyoxyethylene block copolymer having a low unsaturated ether content and suppressing coloration for use in medical materials There is to do.
- the present inventor has developed a tertiary alkali metal class with respect to a polyoxypropylene polymer obtained by ring-opening polymerization of propylene oxide to a starting material having active hydrogen.
- a tertiary alkali metal class with respect to a polyoxypropylene polymer obtained by ring-opening polymerization of propylene oxide to a starting material having active hydrogen.
- the present invention is as follows. (1) The following steps: (A) An alkali metal tertiary alkoxide is used as a starting material for a polyoxypropylene polymer containing allyl ether as an impurity obtained by ring-opening polymerization of propylene oxide to an starting material having active hydrogen that reacts with propylene oxide. Adding excess to the number of moles of active hydrogen in the mixture and heat-treating at 115 ° C. or less to isomerize allyl ether to propenyl ether; and (B) mineral acid to the product obtained in step (A) And adjusting the pH to 4 or less and treating at 70 ° C. or less to hydrolyze propenyl ether.
- a method for producing a medical polyoxypropylene polymer comprising: (2) After the step (B), (C) performing at least one of a step of washing the polyoxypropylene polymer with water and (D) a step of treating the polyoxypropylene polymer with an inorganic adsorbent composed of an oxide containing at least one of aluminum and silicon.
- (1) The method characterized by the above-mentioned.
- (3) A method for producing a medical polyoxypropylene / polyoxyethylene block copolymer, comprising a step of ring-opening polymerization of ethylene oxide with respect to the polyoxypropylene polymer obtained by the method of (1) or (2) .
- isomerization of allyl ether contained in polyoxypropylene polymer to propenyl ether can be quantitatively achieved under mild temperature conditions, resulting in extremely low unsaturated ether content and reduced coloration. Is possible. Therefore, the production method of the present invention can easily provide a high-quality polyoxypropylene polymer suitable for medical materials and a polyoxypropylene / polyoxyethylene block copolymer on an industrial scale.
- Medical use is a use to be applied to a living body, such as a wound dressing material, an adhesion prevention material, a drug sustained-release material, and a scaffold material in regenerative medicine.
- the “starting material having active hydrogen that reacts with propylene oxide” that can be used in the present invention is a starting material for causing ring-opening polymerization of propylene oxide.
- the functional group having active hydrogen is not limited as long as it is a starting point for ring-opening polymerization of propylene oxide.
- the starting material is selected from the group consisting of a hydroxyl group, an amino group, a sulfanyl group, and a carboxy group. It preferably has a selected functional group, more preferably has a hydroxyl group and / or an amino group, and most preferably has a hydroxyl group.
- Specific examples of the starting material having a hydroxyl group include the following alcohols.
- Monovalent alcohols include methanol, ethanol, propanol, isopropanol, butanol, t-butanol, phenol and benzyl alcohol.
- Divalent alcohols include ethylene glycol, diethylene glycol, propylene glycol, water, 1,4-butane.
- Diol, 1,5-pentanediol, 1,6-hexanediol, 1,4-benzenediol, etc., and trihydric or higher polyhydric alcohols include glycerin, trimethylolpropane, pentaerythritol, diglycerin, N, N, N ′, N′-tetrakis (2-hydroxypropyl) ethylenediamine, xylitol, triglycerin, dipentaerythritol, sorbitol, hexaglycerin and the like can be mentioned.
- a trihydric or higher polyhydric alcohol is used as the starting material.
- the valence of the hydroxyl group of the polyhydric alcohol is generally preferably 8 or less.
- the starting material having an amino group examples include dimethylamine, diethylamine, piperazine, morpholine, aniline, monoethanolamine, diethanolamine, triethanolamine, ammonia, ethylenediamine, toluylenediamine and diethylenetriamine.
- compounds containing two or more amino groups are used as starting materials.
- the number average molecular weight per hydroxyl group of the polyoxypropylene polymer obtained by ring-opening polymerization of propylene oxide on the starting material having active hydrogen of the present invention is preferably 300 to 10,000, more preferably 500 to 5,000. is there.
- the number average molecular weight is a number average molecular weight converted from the hydroxyl value, and is represented by 56100 ⁇ (the number of active hydrogens of the starting material) / (hydroxyl value).
- the tertiary alkoxide of alkali metal that can be used in the step (A) of the present invention is one in which the hydrogen atom of the hydroxyl group of the tertiary alcohol is substituted with an alkali metal.
- the alkali metal constituting the alkali metal tertiary alkoxide is preferably lithium, sodium, or potassium.
- the tertiary alkoxide has 4 or more carbon atoms, preferably 6 or less, and more preferably 5 or less.
- Specific examples of the alkali metal tertiary alkoxide include lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, lithium t-pentoxide, sodium t-pentoxide, potassium t-pentoxide, and sodium t-butoxide. Potassium t-butoxide, sodium t-pentoxide or potassium t-pentoxide is more preferred, and sodium t-butoxide or potassium t-butoxide is most preferred.
- the isomerization of allyl ether to propenyl ether proceeds efficiently by the action of the alkali metal tertiary alkoxide, so the amount of alkali metal tertiary alkoxide used is the activity of the starting material. It is necessary in excess of the number of moles of hydrogen. When the amount of the alkali metal tertiary alkoxide used is less than or equal to the number of moles of active hydrogen of the starting material, only the alkoxide of the polyoxypropylene polymer is produced, and the isomerization efficiency of the allyl ether is extremely lowered.
- the amount of the alkali metal tertiary alkoxide used is 1.1 times equivalent or more, more preferably 1.3 times equivalent or more, still more preferably 1.5 times equivalent to the number of moles of active hydrogen in the starting material. More preferably, it is 2.0 times equivalent or more.
- the required amount of the mineral acid used in step (B) and the complexity of the post-treatment it is preferably 5.0 times equivalent or less, more preferably 4.0 times equivalent or less.
- the treatment temperature in step (A) is 115 ° C. or lower, preferably 110 ° C. or lower, more preferably 105 ° C. or lower, and further preferably 100 ° C. or lower.
- a temperature higher than 115 ° C. is not preferable because coloring becomes strong.
- the treatment temperature in the step (A) in the present invention is preferably 70 ° C. or higher, and more preferably 80 ° C. or higher, from the viewpoint of promoting the isomerization reaction.
- Preferred examples of the mineral acid that can be used in the step (B) of the present invention are hydrochloric acid, sulfuric acid, sulfurous acid, nitric acid, phosphoric acid or hypophosphorous acid, more preferably hydrochloric acid, sulfuric acid or phosphoric acid, Preferred is hydrochloric acid or sulfuric acid.
- These mineral acids can be used after diluting to an arbitrary concentration.
- step (B) of the present invention mineral acid is added to the product obtained in step (A) to adjust the pH to 4 or less.
- the pH is preferably 3 or less, more preferably 2.5 or less, and even more preferably 2 or less. Further, when the pH is less than 0, quality deterioration such as generation of an irritating odor is caused. When the pH is higher than 4, the acid concentration is insufficient and the hydrolysis of propenyl ether is insufficient or the hydrolysis takes a long time.
- the treatment temperature in the step (B) in the present invention is 70 ° C. or less, preferably 60 ° C. or less, more preferably 50 ° C. or less, and further preferably 40 ° C. or less. Further, when the treatment temperature is less than 0 ° C., a load is applied to the stirring due to an increase in viscosity, precipitation of a neutralized salt, or the like.
- step (B) it is preferable to remove excess mineral acid and neutralized salt from the polyoxypropylene polymer after step (B), specifically, at least one of step (C) and step (D). It is preferable to do. Step (C) and step (D) may be performed alone or in combination.
- Water or alkaline aqueous solution can be used for the water washing in the step (C).
- the base that can be used for the preparation of the alkaline aqueous solution include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, etc., preferably sodium hydroxide, water Potassium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
- the above bases may be used alone or in combination, and washing with water may be repeated.
- the mineral acid is previously neutralized to near neutrality with a base in order to keep the amount of water or alkaline aqueous solution used for removing the mineral acid used in step (B) low. After that, washing with water or an alkaline aqueous solution is performed.
- a base that can be used for neutralizing mineral acids include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, preferably sodium hydroxide or hydroxide. Potassium.
- the amount of water or alkaline aqueous solution used for the water washing in the step (C) is preferably 0.5 to 10 times by mass, more preferably 1 to 8 times by mass, and further preferably 2 to 2 times the polyoxypropylene polymer. 6 times mass.
- an appropriate inorganic salt or lower alcohol may be added and washed with water to improve these.
- the inorganic salt include sodium chloride, potassium chloride, sodium bromide and potassium bromide, and sodium chloride is preferable.
- the amount of the inorganic salt used is preferably 1 to 20% by mass, more preferably 2 to 15% by mass, and further preferably 3 to 10% by mass of the water or alkaline aqueous solution used in the water washing.
- Specific alcohols include methanol, ethanol, propanol, isopropanol, butanol, and t-butanol, and methanol or ethanol is preferable.
- the amount of lower alcohol used is preferably 0.1 to 3 times, more preferably 0.2 to 2.5 times, and still more preferably 0.3 to 2 times the amount of water or alkaline aqueous solution used in washing.
- the above inorganic salts and lower alcohols may be used alone or in combination.
- the polyoxypropylene polymer may be dissolved in a suitable organic solvent and washed with water.
- the organic solvent include aprotic solvents such as toluene, benzene, xylene, ethyl acetate, hexane, diethyl ether, t-butyl methyl ether, tetrahydrofuran, chloroform and dichloromethane, preferably toluene, ethyl acetate, t-Butyl methyl ether, chloroform or dichloromethane, more preferably chloroform or dichloromethane.
- the amount of the organic solvent used is preferably 0.5 to 10 times by mass, more preferably 1 to 8 times by mass, and further preferably 2 to 6 times by mass with respect to the polyoxypropylene polymer.
- the above organic solvents may be used alone or in combination.
- the inorganic adsorbent composed of an oxide containing at least one of aluminum and silicon that can be used in the step (D) is an oxide containing one or both of aluminum and silicon in the oxide.
- Specific examples include aluminum oxide, silicon dioxide, composite oxides of aluminum oxide and silicon dioxide, composite oxides of aluminum oxide and other metals, and composite oxides of silicon dioxide and other metals.
- Other metals referred to herein include sodium, magnesium and calcium.
- an adsorbent having an acidic substance adsorbing ability is preferable for removing excess mineral acid.
- Specific examples include the Kyodo 300 series of Kyoward series manufactured by Kyowa Chemical Industry Co., Ltd. 2.5MgO ⁇ Al 2 O 3 ⁇ 0.7CO 3 ⁇ nH 2 O), Kyoward 500 (Mg 6 Al 2 (OH) 16 (CO 3 ) ⁇ 4H 2 O), Kyoward 1000 (Mg 4.5 Al 2 (OH) 13 (CO 3 ) ⁇ 3.5H 2 O).
- an adsorbent having a high salt adsorbing ability is preferable.
- Specific examples include Kyoward 2000 (4.5MgO ⁇ Al 2 O 3 ), Kyoward 200B (Al 2 O 3 ⁇ 2.0 H 2 O). These adsorbents may be used alone or in combination.
- step (D) in the present invention after removing the mineral acid in step (C), a slightly remaining base can be removed.
- adsorbents that can be used for this purpose include basic properties such as Kyoward 600 (MgO ⁇ 3SiO 2 ⁇ nH 2 O) and Kyoward 700 (Al 2 O 3 ⁇ 9SiO 2 ⁇ nH 2 O).
- These adsorbents may be used alone or in combination with other adsorbents.
- the color components slightly generated in the step (A) and the step (B) can be removed.
- adsorbents that can be used for this purpose include Kyoward 500 (Mg 6 Al 2 (OH) 16 (CO 3 ) ⁇ 4H 2 O), Kyoward 1000 (Mg 4.5 Al 2 (OH) 13 It is a dye adsorbent such as (CO 3 ) ⁇ 3.5H 2 O), preferably Kyoward 1000 (Mg 4.5 Al 2 (OH) 13 (CO 3 ) ⁇ 3.5H 2 O).
- These adsorbents may be used alone or in combination with other adsorbents.
- the amount of the inorganic adsorbent used in the step (D) of the present invention is preferably 10% by mass or less, more preferably 8% by mass or less, and further preferably 5% by mass with respect to the polyoxypropylene polymer. It is as follows. If it exceeds 10% by mass, a load is applied to the filtration operation and the filter cake increases, which is not preferable.
- the step (D) is effective for removing a slight amount of coloring components generated slightly in the steps (A) and (B), but the coloring component generated by the high-temperature treatment of the unsaturated ether shown in the comparative example.
- the effect is limited, and a considerable amount of coloring components remain without being removed. That is, it can be said that it is impossible to reduce the coloring to the level achieved by the present invention by applying only the step (D).
- the number average molecular weight per hydroxyl group of the polyoxyethylene portion is preferably 600 to 20000, and more preferably 1000 to 10,000.
- the number average molecular weight of the polyoxyethylene part is the number average molecular weight of the polyoxypropylene polymer before ethylene oxide polymerization, based on the number average molecular weight converted from the hydroxyl value of the polyoxypropylene / polyoxyethylene block copolymer. Calculated by subtracting.
- the value evaluated by the Hazen color number is used for the degree of coloring.
- the Hazen color number is a color number determined by comparing the transmitted color of the sample with a Hazen standard colorimetric solution prepared using a mixed solution of chloroplatinic acid and cobalt chloride, as described in JIS K 0071. Moreover, it can also measure using a Hazen color number measuring device. As the Hazen color number increases, the color changes from colorless to yellow, brown, and dark brown.
- the Hazen color number of the polyoxypropylene polymer and the polyoxypropylene / polyoxyethylene block copolymer in the present invention is preferably 100 or less, more preferably 80 or less, still more preferably 60 or less, 40 It is particularly preferred that
- the degree of coloring is represented by the Hazen color number, the unsaturated ether content is measured by 1 H-NMR, and the amount of unsaturated ether per 1 g of polyoxypropylene polymer and polyoxypropylene / polyoxyethylene block copolymer is measured. Expressed in equivalent (meq / g, the same applies hereinafter).
- the degree of coloring was evaluated by comparing the transmitted color with the Hazen standard colorimetric solution described in JIS K K0071 for a solution obtained by diluting the sample 4 times by mass with special grade ethanol (99.5) manufactured by Kanto Chemical Co., Ltd. .
- JNM-ECP400 or JNM-ECA600 manufactured by JEOL Datum was used, and a ⁇ 5 mm tube was used. Measurement was performed using CDCl 3 or CD 3 OD as the heavy solvent and tetramethylsilane (TMS) as the internal standard substance.
- TMS tetramethylsilane
- the values obtained for only I 2 or only I 3 are the allyl ether content or the propenyl ether content, respectively.
- Mn is the number average molecular weight converted from the hydroxyl value of the sample, 60.10 is the molecular weight of ethylenediamine, and 58.08 is the molecular weight of propylene oxide.
- Mn is the number average molecular weight converted from the hydroxyl value of the polyoxypropylene polymer before ethylene oxide polymerization, and the polyoxypropylene / polyoxyethylene block copolymer weight after ethylene oxide polymerization.
- the number average molecular weight converted from the hydroxyl value of the coalescence was calculated as Mn ′ and calculated according to the following formula.
- Unsaturated ether content (meq / g) [(I 2/2) + (I 3/3)] / (I 1 /3) ⁇ (Mn-60.10)/58.08 ⁇ 10 3 / Mn '
- polyoxypropylene polymers used in Examples and Comparative Examples were synthesized by the following propylene oxide polymerization reaction.
- Example 1 A 1 L four-necked flask equipped with a thermometer, nitrogen blowing tube, stirrer, Dean-stark tube, and cooling tube was charged with 300 g (60.0 mmol) of polyoxypropylene polymer obtained by the propylene oxide polymerization reaction and 300 g of toluene, The temperature was raised to 110 ° C. in a nitrogen atmosphere, and water was removed azeotropically with toluene. After cooling to room temperature, 53.9 g (480 mmol) of potassium t-butoxide slurried with 90 g of dehydrated toluene was added, and the reaction was performed at 100 ° C. for 2 hours in a nitrogen atmosphere.
- the aqueous layer was discarded, and the organic layer was washed with a mixed solution of 600 g of 5 mass% sodium chloride / 5 mass% aqueous sodium bicarbonate and 450 g of methanol, and then the solvent of the organic layer was distilled off. Water contained in the residue was removed by azeotropic removal with toluene, and then Kyoward 7009g and Kyoward 1000 9g made by Kyowa Chemical Industry Co., Ltd., which were slurried with 300g of toluene, were added and stirred at 40 ° C for 1 hour in a nitrogen atmosphere. After filtration through No. 5A filter paper manufactured by Toyo Filter Paper Co., Ltd., the solvent was distilled off to obtain a colorless and transparent low-viscosity liquid polyoxypropylene polymer.
- Example 2 A 5 L autoclave container was charged with 250 g (50.0 mmol) of the polyoxypropylene polymer obtained in Example 1, 282 g of toluene, and a mixed solution of 1.56 g (13.9 mmol) of 50% by weight potassium hydroxide aqueous solution and 5.5 g of methanol. After replacing the interior with nitrogen, the temperature was raised to 110 ° C., and water and methanol were removed azeotropically with toluene. Ethylene oxide (500 g, 11.4 mol) was added at 120 ° C. or lower and 0.5 MPa or lower, and the reaction was continued for 2 hours or more at the same temperature until the pressure in the vessel reached equilibrium. After removing unreacted ethylene oxide gas under reduced pressure, the mixture was cooled to 80 ° C. and neutralized with 85% by mass phosphoric acid to obtain a nearly colorless solid polyoxypropylene / polyoxyethylene block copolymer.
- Ethylene oxide 500 g, 11.4
- Comparative Example 2 120 g (24.0 mmol) of the polyoxypropylene polymer obtained in Comparative Example 1 to a 300 ml four-necked flask equipped with a thermometer, nitrogen blowing tube, stirrer, Dean-stark tube, and condenser tube, 2.5 g of ion-exchanged water, Kyowa Chemical Industry Co., Ltd. Kyoward 600 1.8g and Kyoward 700 0.6g were charged and stirred at 100 ° C for 1 hour in a nitrogen atmosphere. After cooling to 40 ° C. and filtering with No. 5A filter paper manufactured by Toyo Filter Paper Co., Ltd., the solvent was distilled off to obtain a brown transparent low-viscosity liquid polyoxypropylene polymer.
- Comparative Example 4 120 g (24.0 mmol) of the polyoxypropylene polymer obtained in Comparative Example 1 was neutralized with a 400 g / l aqueous sodium hydroxide solution according to Example 1, and then dissolved in 240 g of chloroform, 240 g of 5% by mass saline and methanol. 180 g was added and washed with a separatory funnel. The aqueous layer was discarded, and the organic layer was washed with a mixed solution of 5% by mass sodium chloride / 5% by mass sodium bicarbonate aqueous solution 240 g and methanol 180 g, and then the organic layer solvent was distilled off.
- the polyoxypropylene polymer obtained in Example 1 had a Hazen color number of 10 or less and was almost colorless.
- Comparative Examples 2 and 3 after the high-temperature treatment of Comparative Example 1 and subsequent acid hydrolysis, both had a strong Hazen color number of 500 or more and a high unsaturated ether content.
- Comparative Example 4 after-treatment was performed in the same step (D) as in Example 1, coloring was somewhat reduced, but it was impossible to reduce it to the same level as in Example 1. It was. Therefore, the coloring produced in Comparative Example 1 is considered to include components that cannot be removed by the same step (D) as in Example 1.
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Abstract
Description
ポリオキシプロピレン重合体およびポリオキシプロピレン/ポリオキシエチレンブロック共重合体において、アリルエーテルなどの不飽和エーテルの存在は、水酸基数の実質的な低下をもたらし、水酸基を他の官能基に化学変換して医用材料として用いる場合は、その機能を損なうことになる。また、不飽和エーテルは予期せぬ界面活性効果や副反応などにより、材料の物性に悪影響を及ぼす可能性もある。
(1) 以下の工程:
(A) プロピレンオキシドと反応する活性水素を有する開始物質にプロピレンオキシドを開環重合させて得られる、不純物としてアリルエーテルを含むポリオキシプロピレン重合体に対して、アルカリ金属の三級アルコキシドを開始物質の活性水素のモル数に対して過剰に加え、115℃以下で熱処理してアリルエーテルをプロペニルエーテルに異性化させる工程;および
(B) 工程(A)で得られた生成物に対して鉱酸を加えてpH4以下に調整し、70℃以下で処理してプロペニルエーテルを加水分解する工程; を有することを特徴とする、医用ポリオキシプロピレン重合体の製造方法。
(2) 前記工程(B)の後に、
(C) ポリオキシプロピレン重合体を水洗する工程と
(D) ポリオキシプロピレン重合体をアルミニウムとケイ素との少なくとも一方を含む酸化物からなる無機系吸着剤で処理する工程との少なくとも一方を実施することを特徴とする、(1)の方法。
(3) (1)または(2)の方法によって得られたポリオキシプロピレン重合体に対して、エチレンオキシドを開環重合させる工程を含む、医用ポリオキシプロピレン/ポリオキシエチレンブロック共重合体の製造方法。
医用とは、創傷被覆材、癒着防止材、薬物徐放材、再生医療における足場材料などの、生体に適用されるべき用途である。
不飽和エーテル含量(meq/g) =
[(I2/2)+(I3/3)]/(I1/3)×(Mn-60.10)/58.08×103/Mn
不飽和エーテル含量(meq/g) =
[(I2/2)+(I3/3)]/(I1/3)×(Mn-60.10)/58.08×103/Mn’
5Lオートクレーブ容器へN,N,N’,N’-テトラキス(2-ヒドロキシプロピル)エチレンジアミン146.2g (0.500mol)、50質量%水酸化カリウム水溶液9.87g (88.0mmol)、およびトルエン730gを仕込み、系内を窒素置換後、110℃に昇温し、水をトルエンで共沸除去した。110℃以下かつ0.5MPa以下でプロピレンオキシド2325g (40.0mol)を加え、同温度にて容器内の圧力が平衡に達するまで2時間以上反応を続けた。減圧にて未反応のプロピレンオキシドガスを除去後、無色透明の低粘度液状ポリオキシプロピレン重合体を得た。
温度計、窒素吹き込み管、攪拌機、Dean-stark管、および冷却管を装備した1L四つ口フラスコへプロピレンオキシド重合反応で得られたポリオキシプロピレン重合体300g (60.0mmol)とトルエン300gを仕込み、窒素雰囲気下110℃に昇温し、水をトルエンで共沸除去した。室温へ冷却後、脱水トルエン90gでスラリーにしたカリウムt-ブトキシド53.9g (480mmol)を加え、窒素雰囲気下100℃で2時間反応を行なった。40℃に冷却した後、冷却を続けながら徐々にイオン交換水80gを加えた。6N塩酸120ml(720mmol)を加えてpH 1.5に調整後、窒素雰囲気下40℃で2時間反応を行なった。冷却しながら400g/l水酸化ナトリウム水溶液14ml (140mmol)で中和後、5質量%食塩水600g、メタノール450gおよびクロロホルム600gを加えて分液漏斗で洗浄した。水層を廃棄し、有機層を5質量%食塩/5質量%炭酸水素ナトリウム水溶液600gとメタノール450gの混合溶液で洗浄した後、有機層の溶媒を留去した。残渣に含まれる水をトルエンで共沸除去した後、トルエン300gでスラリーにした協和化学工業(株)製キョーワード700 9gおよびキョーワード1000 9gを加え、窒素雰囲気下40℃で1時間撹拌した。東洋濾紙(株)製No.5A濾紙で濾過後、溶媒を留去して無色透明の低粘度液状ポリオキシプロピレン重合体を得た。
5Lオートクレーブ容器へ実施例1で得られたポリオキシプロピレン重合体250g (50.0mmol)、トルエン282g、および50質量%水酸化カリウム水溶液1.56g (13.9mmol)とメタノール5.5gの混合溶液を仕込み、系内を窒素置換後、110℃に昇温し、水とメタノールをトルエンで共沸除去した。120℃以下かつ0.5MPa以下でエチレンオキシド500g (11.4mol)を加え、同温度にて容器内の圧力が平衡に達するまで2時間以上反応を続けた。減圧にて未反応のエチレンオキシドガスを除去後、80℃に冷却し、85質量%リン酸で中和して無色に近い固体のポリオキシプロピレン/ポリオキシエチレンブロック共重合体を得た。
従来技術の中で不飽和エーテル含量が最も低いと考えられる非特許文献2に基づいて、以下の比較実験を行った。
温度計、窒素吹き込み管、攪拌機、Dean-stark管、および冷却管を装備した1L四つ口フラスコへプロピレンオキシド重合反応で得られたポリオキシプロピレン重合体360g (72.0mmol)とトルエン360g、および50質量%水酸化カリウム水溶液1.62g (14.4mmol)を仕込み、窒素雰囲気下110℃に昇温し、水をトルエンで共沸除去した。トルエンを全量留去後、窒素雰囲気下160℃で3時間反応を行なった。40℃に冷却した後、50質量%リン酸でpH 3に調整し、窒素雰囲気下100℃で1時間反応を行なった。40℃に冷却した後、3分割して下記比較例2~5の実験に使用した。
温度計、窒素吹き込み管、攪拌機、Dean-stark管、および冷却管を装備した300ml 四つ口フラスコへ比較例1で得られたポリオキシプロピレン重合体120g (24.0mmol)、イオン交換水2.5g、協和化学工業(株)製キョーワード600 1.8gおよびキョーワード700 0.6gを仕込み、窒素雰囲気下100℃で1時間撹拌した。40℃に冷却し、東洋濾紙(株)製No.5A濾紙で濾過後、溶媒を留去して褐色透明の低粘度液状ポリオキシプロピレン重合体を得た。
分液漏斗へ比較例1で得られたポリオキシプロピレン重合体120g (24.0mmol)、トルエン120gおよびイオン交換水120gを仕込み、室温で十分振り混ぜた後、静置して分液させた。下層の水層を除いた後、再度同量のイオン交換水を仕込み、同じ操作を繰り返した。次いで水層を除き、上層の有機層を減圧下濃縮して残存する水を共沸除去した後、東洋濾紙(株)製No.5A濾紙により濾過して褐色透明の低粘度液状ポリオキシプロピレン重合体を得た。
比較例1で得られたポリオキシプロピレン重合体120g (24.0mmol)を実施例1に準じて400g/l水酸化ナトリウム水溶液で中和後、クロロホルム240gに溶解し、5質量%食塩水240gおよびメタノール180gを加えて分液漏斗で洗浄した。水層を廃棄し、有機層を5質量%食塩/5質量%炭酸水素ナトリウム水溶液240gとメタノール180gの混合溶液で洗浄した後、有機層の溶媒を留去した。残渣に含まれる水をトルエンで共沸除去した後、トルエン120gでスラリーにした協和化学工業(株)製キョーワード700 3.6gおよびキョーワード1000 3.6gを加え、窒素雰囲気下40℃で1時間撹拌した。東洋濾紙(株)製No.5A濾紙で濾過後、溶媒を留去して黄色透明の低粘度液状ポリオキシプロピレン重合体を得た。
5Lオートクレーブ容器へ比較例1で得られたポリオキシプロピレン重合体100g (20.0mmol)、トルエン113g、および50質量%水酸化カリウム水溶液0.62g (5.5mmol)とメタノール2.2gの混合溶液を仕込み、系内を窒素置換後、110℃に昇温し、水とメタノールをトルエンで共沸除去した。120℃以下かつ0.5MPa以下でエチレンオキシド200g (4.5mol)を加え、同温度にて容器内の圧力が平衡に達するまで2時間以上反応を続けた。減圧にて未反応のエチレンオキシドガスを除去後、80℃に冷却し、85質量%リン酸で中和して褐色固体のポリオキシプロピレン/ポリオキシエチレンブロック共重合体を得た。
温度計、窒素吹き込み管、攪拌機、Dean-stark管、および冷却管を装備した300ml 四つ口フラスコへプロピレンオキシド重合反応で得られたポリオキシプロピレン重合体100g (20.0mmol)とトルエン100gを仕込み、窒素雰囲気下110℃に昇温し、水をトルエンで共沸除去した。室温へ冷却後、川研ファインケミカル(株)製SM-28 (28質量%ナトリウムメトキシド メタノール溶液) 30.9g (160mmol)を加え、100℃まで昇温しながらメタノールを除去した。その後、窒素雰囲気下100℃で2時間反応を行なった。
また、比較例4では、後処理を実施例1と同様の工程(D)で行ったところ、着色は幾分低減されたものの、実施例1と同等の水準まで低減することは不可能であった。したがって、比較例1で生じた着色は、実施例1と同様の工程(D)では除去できない成分を含むと考えられる。
なお、本出願は、2013年10月31日付で出願された日本国特許出願(特願2013-227328)に基づいており、その全体が引用により援用される。また、ここに引用されるすべての参照は全体として取り込まれる。
Claims (3)
- 以下の工程:
(A) プロピレンオキシドと反応する活性水素を有する開始物質にプロピレンオキシドを開環重合させて得られる、不純物としてアリルエーテルを含むポリオキシプロピレン重合体に対して、アルカリ金属の三級アルコキシドを前記開始物質の前記活性水素のモル数に対して過剰に加え、115℃以下で熱処理してアリルエーテルをプロペニルエーテルに異性化させる工程;および
(B) 工程(A)で得られた生成物に対して鉱酸を加えてpH 4以下に調整し、70℃以下で処理してプロペニルエーテルを加水分解する工程; を有することを特徴とする、医用ポリオキシプロピレン重合体の製造方法。 - 前記工程(B)の後に、
(C) ポリオキシプロピレン重合体を水洗する工程と
(D) ポリオキシプロピレン重合体をアルミニウムとケイ素との少なくとも一方を含む酸化物からなる無機系吸着剤で処理する工程との少なくとも一方を実施することを特徴とする、請求項1記載の方法。 - 請求項1または2記載の方法によって得られた前記ポリオキシプロピレン重合体に対して、エチレンオキシドを開環重合させる工程を含む、医用ポリオキシプロピレン/ポリオキシエチレンブロック共重合体の製造方法。
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EP14856839.7A EP3064525B1 (en) | 2013-10-31 | 2014-10-24 | Method for producing medical polyoxypropylene polymer, and method for producing medical polyoxypropylene/polyoxyethylene block copolymer |
KR1020167011487A KR102119198B1 (ko) | 2013-10-31 | 2014-10-24 | 의료용 폴리옥시프로필렌 중합체의 제조방법 및 의료용 폴리옥시프로필렌/폴리옥시에틸렌 블록 공중합체의 제조방법 |
CN201480059927.0A CN105683247B (zh) | 2013-10-31 | 2014-10-24 | 医用聚氧丙烯聚合物的制造方法和医用聚氧丙烯/聚氧乙烯嵌段共聚物的制造方法 |
US15/033,303 US9777113B2 (en) | 2013-10-31 | 2014-10-24 | Production method of medical polyoxypropylene polymer and production method of medical polyoxypropylene/polyoxyethylene block copolymer |
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2013
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2014
- 2014-10-24 US US15/033,303 patent/US9777113B2/en not_active Expired - Fee Related
- 2014-10-24 EP EP14856839.7A patent/EP3064525B1/en not_active Not-in-force
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- 2014-10-24 CN CN201480059927.0A patent/CN105683247B/zh active Active
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KR20160079790A (ko) | 2016-07-06 |
EP3064525B1 (en) | 2018-06-20 |
EP3064525A1 (en) | 2016-09-07 |
US9777113B2 (en) | 2017-10-03 |
CN105683247B (zh) | 2018-05-04 |
JP6202471B2 (ja) | 2017-09-27 |
CN105683247A (zh) | 2016-06-15 |
EP3064525A4 (en) | 2017-05-17 |
KR102119198B1 (ko) | 2020-06-04 |
JP2015086320A (ja) | 2015-05-07 |
US20160264730A1 (en) | 2016-09-15 |
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