JP2017176946A - Chelating carrier and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a chelating carrier that has a high chelating power, is easy to handle, and is high in stability and safety, and further to provide a method for producing the same.SOLUTION: Provided is a chelating carrier obtained by immobilizing a ligand having a chelating capability on a solid phase carrier comprising a polymer having an amino group. The polymer is a polymer composed of at least one of a styrenic polymer, a poly(meth)acrylate-based polymer, a polyvinyl alcohol-based polymer, cellulose, and agarose. At least a part of the amino groups is a halide salt. During the production, by reacting a functional group capable of forming a chelate and a ligand having an aldehyde group with a solid phase carrier comprising a polymer having an amino group, a Schiff's base is formed, and this is reduced with a reducer, followed by treated with hydrohalic acid.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a chelating carrier in which a ligand having chelating ability is introduced into a base solid phase carrier, and a method for producing the same.

  In recent years, a new concept of chronic kidney disease (Chronic Kidney Diseases; CKD) has been pointed out and has attracted attention all over the world. As a treatment for it, biologically unstable iron (Non-Transferrin), which is the most common cause of CKD -Bound Iron (NTBI) has been found to be effective. Biologically unstable iron as used herein refers to iron ions that are not bound to transferrin and may have a harmful effect on the human body. Therefore, biologically unstable iron includes, for example, iron bound to transferrin (iron ion in transferrin iron complex; transferrin-bound iron), stored iron present in liver, spleen, and bone marrow as ferritin, and erythrocytes Hemoglobin consisting of 4 molecules of heme (porphyrin complex with iron) and 1 molecule of globin (4 polypeptide chains), a chromoprotein in the muscle that stores oxygen molecules until needed for metabolism, 1 heme Does not include myoglobin containing.

  Therapies for reducing or eliminating in vivo iron, especially in vivo unstable iron, include (1) phlebotomy, (2) iron-restricted diet, (3) drug therapy with iron chelators, and (4) extracorporeal blood. There are blood purification therapy by circulation. Although hemoptysis therapy has a good QOL (Quality of Life) for patients, the removal of whole blood including red blood cells has side effects such as anemia and hypoproteinemia, and only for patients without anemia. Adaptable. The iron-restricted diet method is a method for reducing absorption of iron from the gastrointestinal tract, but has side effects such as nutritional imbalance and can be applied only to some liver diseases.

  Various iron chelating agents for removing biological iron that have remarkable effects of pharmacotherapy have been proposed (see Patent Documents 1 to 11, etc.), and are mainly used for patients with post-transfusion iron overload. Yes. However, iron-related disorders in some organs due to mild iron overload or abnormalities in iron metabolism are not only said to have a high frequency of side effects due to overchelation, but iron chelating agents taken into the body It can be taken up by metabolic processes and adversely affect living organisms, including impaired renal function. On the other hand, blood purification therapy by extracorporeal blood circulation has a characteristic that side effects due to over-chelation are unlikely to occur because iron removal is performed only during the extracorporeal circulation of blood for treatment.

Special table 2010-31022 WO2009 / 130604 Special table 2007-532509 Special table 2006-504748 Special table 2005-509649 Special table 2000-507601 Special table 2008-520669 Special table 2002-502816 Special table 2000-506546 JP2004-203820 Special table flat 9-501144

As described above, with conventional iron chelating agents, iron chelating agents dissolved in water can be mixed in the blood and taken into metabolic processes in the body, which may still have an undesirable effect on the living body. . On the other hand, if blood purification therapy using extracorporeal blood circulation is employed, side effects are unlikely to occur. However, when a conventional iron chelating agent is applied to blood purification therapy using extracorporeal blood circulation, handling becomes a big problem.

  The present invention has been proposed in view of such conventional circumstances. For example, it can be selectively chelated to biologically unstable iron, has a high chelating power, is easy to handle, is stable and safe. It is an object to provide a chelating carrier having high properties, and further to provide a production method thereof.

  In order to achieve the aforementioned object, the chelating carrier of the present invention is a chelating carrier obtained by fixing a ligand having a chelating ability to a solid phase carrier comprising a polymer having an amino group, and the polymer comprises It is a polymer composed of at least one of styrene-based polymer, poly (meth) acrylic acid-based polymer, polyvinyl alcohol-based polymer, cellulose, and agarose, and is characterized in that at least a part of the amino group is a halide salt. It is what.

  Further, the method for producing a chelating carrier of the present invention comprises reacting the aldehyde group of a ligand having a functional group capable of forming a chelate and an aldehyde group with a solid phase carrier made of a polymer having an amino group, to give a Schiff base. Formed, reduced with a reducing agent, and then treated with hydrohalic acid. The polymer is a styrene polymer, poly (meth) acrylic acid polymer, polyvinyl alcohol polymer, cellulose, or agarose. It is a polymer composed of at least one kind.

  In the present specification, a chelating carrier converted into a halide salt is simply referred to as a “chelating carrier”, and a chelating carrier that is not converted into a halide salt is referred to as a “chelating carrier precursor”.

  The chelating carrier of the present invention is synthesized by a method different from quaternization of an amino group, and has a feature of having no toxicity at all while being a chelate compound having various functions such as iron removal function. . Further, by using the base as a solid phase carrier, it is possible to realize a chelate compound that is easy to handle. Furthermore, by using at least a part of the amino group as a halide salt, the spatial arrangement of the chelate sites becomes appropriate, the chelating power is increased, and the stability is also improved.

  In the production method of the present invention, the chelate compound is converted into a halide salt form by treatment with hydrohalic acid (for example, hydrochloric acid) after reduction with a reducing agent. In general, in the formation of the Schiff base and the reduction of the reducing agent, the remaining unreacted Schiff base compound and the reducing agent become a problem, and considerable time and labor are required to wash it. Further, in order to completely reduce the unreacted Schiff base, it is necessary to use a large amount of a reducing agent. The treatment with the hydrohalic acid (hydrochloric acid) is effective for solving these problems. For example, the treatment with hydrochloric acid decomposes unreacted Schiff base compounds and reducing agents in a short time. Completely removed.

  ADVANTAGE OF THE INVENTION According to this invention, it is possible to provide the chelation support | carrier which has high chelating power, high safety | security and stability, is easy to handle, and can be applied to various uses. Furthermore, according to the production method of the present invention, there is an effect that the unreacted Schiff base compound and the reducing agent can be completely removed in a short time, and the safety of the resulting chelating carrier can be further enhanced. it can.

In Example 1, the ion exchange resin beads (WA20) (left), the chelating carrier precursor (A-1) (center), and the chelating carrier (AH-1) (right) were immersed in water and allowed to stand. It is a photograph showing the state. In Example 1, ion exchange resin beads (WA20) (left), chelating carrier precursor (A-1) (middle), and chelating carrier (AH-1) (right) were reacted with ammonium iron citrate. It is a photograph showing the state. In Example 1, the ion exchange resin beads (WA21J) (left), the chelating carrier precursor (B-1) (center), and the chelating carrier (BH-1) (right) were immersed in water and allowed to stand. It is a photograph showing the state. In Example 1, ion exchange resin beads (WA21J) (left), chelating carrier precursor (B-1) (center), and chelating carrier (BH-1) (right) were reacted with ammonium iron citrate. It is a photograph showing the state. In Example 2, it is a photograph which shows the state which reacted the untreated aminated fiber (left), the fibrous chelation support | carrier precursor (center), and the fibrous chelation support | carrier (right) with iron ammonium citrate. The fibrous chelated carrier precursor (left) and fibrous chelated carrier (right) prepared in Example 2 are air-dried. It is a photograph which shows the state which made the fibrous chelation support | carrier precursor (left) and the fibrous chelation support | carrier (right) produced in Example 2 react with the nta-Fe solution. In Example 3, it is a photograph which shows the state which reacted the methacrylate polymer bead <8309> (left), the chelation support | carrier precursor (center), and the chelation support | carrier (right) with the iron citrate ammonium. In Example 3, it is a photograph which shows the state which reacted the methacrylate polymer bead <8415> (left), the chelation support | carrier precursor (center), and the chelation support | carrier (right) with the iron citrate ammonium. In Example 4, it is a photograph which shows the state which reacted the aminated polyvinyl alcohol bead (left), the chelation support | carrier precursor (center), and the chelation support | carrier (right) with the iron citrate ammonium. In Example 5, it is a photograph which shows the state which reacted the aminated cellulose bead (left), the chelation support | carrier precursor (center), and the chelation support | carrier (right) with the iron citrate.

  Hereinafter, embodiments of the chelating carrier to which the present invention is applied and a method for producing the same will be described in detail.

  In the chelating carrier of the present invention, a ligand having chelating ability binds to a solid phase carrier having an amino group, and at least a part of the amino group is a halide salt.

  The base solid phase carrier is a solid phase carrier made of a polymer having an amino group, and the polymer is at least one of a styrene polymer, a poly (meth) acrylic acid polymer, a polyvinyl alcohol polymer, cellulose, and agarose. A polymer composed of seeds.

  As the styrenic polymer having an amino group, monovinyl aromatic monomers such as styrene, bromobutyl styrene, vinyl toluene, chloromethyl styrene, α-methyl styrene, vinyl naphthalene, etc. constitute most, and a small part is divinyl. Polymers composed of monomers comprising at least two active vinyl groups such as benzene, divinylsulfone, butadiene, chloroprene, divinylbiphenyl, trivinylbenzenes, divinylnaphthalene, diallylamine, divinylpyridine At least a part of the monovinyl aromatic monomer is a halide such as bromobutyl styrene or chloromethyl styrene, and a polymer having an amino group introduced using halogen as a target can be used.

  As the poly (meth) acrylic acid-based polymer having an amino group, a monovinyl aromatic monomer and a monovinyl monomer selected from the group consisting of an acrylic ester and a methacrylic ester constitute the majority, and a small The portion is a polymer composed of a monomer composed of a crosslinking monomer having at least two active vinyl groups, and at least a part of the monovinyl aromatic monomer is bromobutylstyrene, chloromethylstyrene, or the like. Epoxy hydration with epichlorohydrin as a target for a hydroxyl group as a target and a polymethacrylate polymer introduced with a hydroxyl group such as Toyopearl (product of Tosoh Corp.) At least a part of the hydroxyl group is removed by a method such as amination with aqueous ammonia. Amination polymer and the like can be used.

  As polyvinyl alcohol polymers having amino groups, 1) amination in which at least a part of hydroxyl groups is aminated by epoxidation with epichlorohydrin and amination with aqueous ammonia using the hydroxyl group of polyvinyl alcohol as a target. It is a polyvinyl alcohol polymer. 2) A polyvinyl alcohol polymer comprising a saponified product of polyvinyl acetate and ethylene vinyl acetate copolymer, and amino such as a polymer in which an amino group is introduced into polyvinylamine, polyallylamine, polyethyleneimine, polylysine and polychloromethylstyrene. For example, a polymer described in JP-A-63-69835 can also be used. Moreover, it is preferable that the crosslinking monomer is included in order to maintain the permanent pore by a polyvinyl alcohol-type polymer. The crosslinking monomer is preferably a polyvinyl or polyallyl monomer unit that is chemically stable and has little nonspecific adsorption of biological substances. For example, triallyl compounds such as triallyl isocyanurate and triallyl cyanurate, di (meth) acrylates such as ethylene glycol dimethacrylate and diethylene glycol dimethacrylate, polyvinyl such as butanediol divinyl ether, diethylene glycol divinyl ether, and tetravinyl glyoxol Preference is given to polyallyl ethers such as ethers, diarylidenepentaerythrits and tetraallyloxyethanes. In addition to the crosslinking monomer, a monomer that does not affect the properties of the solid phase carrier, such as a carboxylic acid vinyl ester unit or a vinyl ether unit, may be included.

  Examples of cellulose include spherical cellulose particles such as trade name Cellulobeads (Daito Kasei Co., Ltd.) and trade name Cellufine (JNC), trade name Theolas (registered trademark), trade name Selfia (registered trademark) (all Asahi Kasei Chemicals Corporation). And the like. In any case, a polymer in which at least a part of the hydroxyl group is aminated by a method such as epoxidation with epichlorohydrin and amination with aqueous ammonia can be used as the aminated cellulose.

  Examples of the cross-linked product of agarose gel include cross-linked agarose such as trade name Sepharose (manufactured by GE Healthcare). Using a hydroxyl group of cross-linked agarose as a target, a polymer in which at least a part of the hydroxyl group is aminated by a method such as epoxidation with epichlorohydrin and amination with aqueous ammonia is used as a cross-linked product of aminated agarose gel Is possible.

  If necessary, a polymer having an arbitrary length (linker) introduced between each polymer and an amino group can be used as a solid phase carrier. Examples of the linker molecule include a polymethylene chain, an oligoethylene glycol chain, a polyethylene glycol chain, and a polyalanine chain. For example, a hydroxyl group of cellulose and a glycidyl group on one side of polyethylene glycol diglycidyl ether can be reacted and combined, and the remaining glycidyl group and aqueous ammonia can be reacted to form an amino group.

  In the polymer, the amino group is preferably a primary amino group and may be a secondary amino group. Tertiary and higher amino groups are not suitable. The content of the amino group contained in the polymer is arbitrary, but is preferably 15 μmol / mL or more, and more preferably 30 μmol / mL or more. For example, it may be 15 μmol / mL to 1000 μmol / mL.

  A polymer having an amino group can be synthesized by a known method. For example, an ion exchange resin having an amino group can be synthesized by a method disclosed in JP-A-1-14206. The ion exchange fiber can be synthesized by the method disclosed in JP-A-63-69835.

  Examples of the form of the solid phase carrier used as a base include particles, fibers, and films. The particulate solid phase carrier includes a flaky solid phase carrier and a bead solid phase carrier. When adopting a fibrous form, a woven fabric or a non-woven fabric can be used. As the membrane-like solid phase carrier, a flat membrane solid phase carrier, a hollow fiber membrane or the like can be used.

  When the solid phase carrier is granular, the average particle size is preferably larger than 50 μm. For example, when used for blood purification, the average particle size is preferably 300 μm or more and less than 2 mm. A solid phase carrier having a large surface area, such as porous or fibrous, is preferable because the amount of chelate moieties (and hence the amount of chelate) increases.

  In the chelating carrier of the present invention, a ligand having a chelating ability is bonded via an amino group of the polymer constituting the solid phase carrier, and the function as a chelating agent is exhibited by the ligand having the chelating ability. The ligand has an aromatic ring, at least one of the groups bonded to the aromatic ring is a hydroxyl group, and the other is any group selected from hydrogen, a hydroxyl group, a carboxyl group, and an alkoxy group. Therefore, a phenol derivative can be mentioned as an example of a ligand, and a specific structure can be mentioned, for example, as shown in Chemical Formulas 1 to 4.

  In the example shown in Chemical Formula 1, the chelate-forming site is an aromatic ring having two hydroxyl groups located in the ortho position, and forms a stable coordination structure of a 5-membered ring with a metal ion (for example, iron ion). Thus, a coordination bond is formed.

  In the example showing the structure in Chemical Formula 2, the chelate-forming site is an aromatic ring having one hydroxyl group and one carboxylic acid group located in the ortho position, and a stable 6-membered ring together with a metal ion (for example, an iron ion). Coordination bonds are formed so as to form a coordination structure.

  In the example showing the structure in Chemical Formula 3, the chelate-forming site is an aromatic ring having a carboxylic acid group bonded through one amino group and an amino group located in the ortho position, and a metal ion (for example, an iron ion) It becomes possible to chelate with a stable coordination structure formed from one 5-membered ring and one 6-membered ring.

  In the example shown in the chemical formula 4, the chelate-forming site is an aromatic ring having one hydroxyl group and two functional groups located at the ortho positions on both sides thereof (a carboxylic acid group bonded via an amino group). Yes, the amount of metal ions that can be chelated per chelate-forming site can be increased.

  In the chelating carrier of the present invention, in addition to having the above structure, at least a part of the amino group takes the form of a halide salt. As a result, the spatial arrangement of the chelating sites becomes appropriate, an excellent chelating power is expressed, and the chelating power is enhanced.

  The halide salt can be a salt such as HBr, HI, HF, etc. in addition to the hydrochloride, but is limited to the hydrochloride from the viewpoint of safety, for example, in use such as oral intake and medical applications. .

  Since the chelating carrier of the present invention is insoluble in water, it is excellent in handleability such as being easily separated from the reaction system. When a beaded chelating carrier is taken orally as an oral chelating agent, the chelating carrier can be excreted as feces by chelating iron while moving in the digestive tract without being digested. Even when dietary content is restricted due to restriction of iron intake, absorption of dietary iron can be suppressed by using an oral chelating agent mainly composed of the chelating carrier of the present invention. Thereby, the breadth of a meal can be enjoyed and QOL can be improved. Further, since it has a function of removing iron, a function of removing phosphate ions, and a function of removing harmful substances such as dichromic acid, it can be used, for example, for purification of well water during a disaster.

  The chelating carrier of the present invention is not particularly required to be water-soluble, so it can be used without being a halide salt (even in the state of a chelating carrier precursor), and such a form is also novel. However, it is advantageous to use a halide salt (hydrochloride) in terms of quickly removing impurities such as a reducing agent used in the synthesis process.

  The chelating carrier of the present invention not only has the above-mentioned advantages, but also performs a treatment (particularly hydrochloric acid treatment) to make a halide salt during production, so that a product with less impurities and excellent safety can be efficiently used. There is also an advantage that it can be manufactured. Hereinafter, the manufacturing method of the chelation support | carrier of this invention is demonstrated.

  In order to produce the chelated carrier of the present invention, the above-described ligand having an aromatic ring and at least a functional group capable of forming a chelate and an aldehyde group with respect to the polymer having an amino group constituting the carrier. The aldehyde group is reacted to form a Schiff base, which is reduced with a reducing agent and then treated with hydrohalic acid.

  Chemical formula 5 shows the synthesis process of the chelating carrier in the present invention. Here, a case where a phenol derivative (aromatic ring compound) having two hydroxyl groups as functional groups capable of forming a chelate and further having an aldehyde group is used as a ligand and converted into a hydrochloride by treatment with hydrochloric acid will be described as an example.

The basis of the synthesis is a condensation reaction between an amino group and an aldehyde group present in the polymer (generation of a Schiff base, -HC = NR) and a method of reducing the double bond (-CH ₂ -NH-R). Through this Schiff base generation, a chelate-forming site is introduced.

  In the above synthesis method, the ease with which a Schiff base is generated, the stability, the ease of reduction, and the stability of the reduced compound are important, and when the chelating carrier of the present invention is used as a pharmaceutical, All of these items are subject to safety and toxicity assessment. In particular, since aldehydes are highly toxic, it is necessary to pay sufficient attention to mixing them as impurities.

  In order to eliminate the possibility that aldehydes are mixed as impurities, it is better to isolate the generated Schiff base as a solid and reduce it. In order to eliminate the aldehyde toxicity, it is desirable to treat the resulting reduction product once with dilute hydrochloric acid. This is because the Schiff base that has not been reduced by this treatment is decomposed to remove the aldehyde. This ensures maximum safety.

  Moreover, this hydrochloric acid treatment enables long-term storage of the target compound and also enables recycling. In the reduced compound, some phenol groups are neutralized with sodium ions (-ONa). The phenol group in this state becomes weak against oxidation (oxygen in the air) and turns brown as time passes. Although it has been confirmed that this brown sample also exhibits the ability to remove iron ions, the ability decreases with time. To prevent this, it is desirable to store phenol in the -OH state. For this purpose, treatment with hydrochloric acid is necessary. Also from this point, the compound obtained by treatment with hydrochloric acid is very good and can be stored for a long time. Furthermore, since it can be treated with hydrochloric acid, once adsorbed iron ions are removed with dilute hydrochloric acid, and the H-type compound can be used again as an iron adsorbent, it is a very convenient compound from an economic point of view. .

Furthermore, the hydrochloric acid treatment is also effective in removing excess reducing agent used in the synthesis process. By treating with hydrochloric acid, an unreacted reducing agent (for example, NaBH ₄ ) adhering to the product can be completely removed in a short time. If hydrochloric acid is not used, this cleaning requires considerable time and effort. By performing hydrochloric acid treatment, the washing time and the like can be greatly shortened, and a high-quality chelating carrier can be produced with high productivity.

  As mentioned above, although the embodiment of the chelating carrier to which the present invention is applied and the production method thereof have been described, the present invention is not limited to the above-described embodiment, and various modifications can be made without departing from the gist of the present invention. It goes without saying that is possible.

  Hereinafter, specific examples of the present invention will be described based on experimental results.

Giving amino group to polymer (1) Giving amino group to polyvinyl alcohol 18 g of a spherical porous body made of polyvinyl acetate (Asahi Glass Co., Ltd., average particle size 100 μm) was added to dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) ) Into 180 mL, epichlorohydrin (manufactured by Wako Pure Chemical Industries, Ltd.) 137 mL, aqueous solution of sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.) (21 g / 31.5 mL) and sodium borohydride 88 mg (manufactured by Wako Pure Chemical Industries, Ltd.) was added and reacted at 30 ° C. for 5 hours to introduce an epoxy group. After the reaction, the spherical porous body into which the epoxy group was introduced was washed with methanol (manufactured by Wako Pure Chemical Industries, Ltd.) and then washed with pure water to obtain an epoxy activated carrier.

  The obtained carrier was 2 mL of a 1.0 M sodium thiosulfate aqueous solution (Wako Pure Chemical Industries, Ltd.) and 2 drops of 1% phenolphthalein ethanol solution (Wako Pure Chemical Industries, Ltd.) per 1 mL of the activated carrier Add 0.1 M hydrochloric acid (manufactured by Wako Pure Chemical Industries, Ltd.) until red coloration is not confirmed at 80 ° C., and “activate amount (epoxy group substance amount per unit resin volume) = The amount of the epoxy group introduced by the formula of “hydrochloric acid concentration (volume molar concentration) × hydrochloric acid titration amount (volume amount) / resin amount (volume amount)” was determined and confirmed to be 110 μmol / mL or more. Next, 30 mL of the epoxidized carrier was weighed, 45 mL of aqueous ammonia (concentration: 28-30%, manufactured by Kanto Chemical Co., Inc.) was added, and reacted at 40 ° C. for 90 minutes to convert the epoxy group to an amino group. The obtained aminated carrier was quantitatively confirmed to be an amino group from an epoxy group by elemental analysis. For example, what was obtained by such a method was made into the amination polyvinyl alcohol bead in this specification.

(2) Amino group imparted to cellulose Particulate crystalline cellulose [manufactured by Asahi Kasei Chemicals Co., Ltd., trade name SELFIA (registered trademark), classified to a particle size of 500 to 700 μm] 20 g of dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) The product was introduced into 50 mL, and epichlorohydrin (manufactured by Wako Pure Chemical Industries, Ltd.) 40 mL, an aqueous solution of sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.) (6 g / 9 mL) and sodium borohydride 25 mg (Wako Pure Chemical Industries, Ltd.) was added and reacted at 30 ° C. for 5 hours to introduce an epoxy group. After the reaction, the spherical porous body into which the epoxy group was introduced was washed with methanol (manufactured by Wako Pure Chemical Industries, Ltd.) and then washed with pure water to obtain an epoxy activated carrier.

  The obtained carrier was 2 mL of 1.0 M sodium thiosulfate aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.) and 2 drops of 1% phenolphthalein ethanol solution (manufactured by Wako Pure Chemical Industries, Ltd.) in 1 mL of the activated carrier. Add 0.1 M hydrochloric acid (manufactured by Wako Pure Chemical Industries, Ltd.) until red coloration is not confirmed at 80 ° C., and “activate amount (epoxy group substance amount per unit resin volume) = The amount of the epoxy group introduced by the formula of “hydrochloric acid concentration (volume molar concentration) × hydrochloric acid titration amount (volume amount) / resin amount (volume amount)” was determined and confirmed to be 44 μmol / mL. Next, 30 mL of the epoxidized carrier was weighed, 45 mL of aqueous ammonia (concentration: 28-30%, manufactured by Kanto Chemical Co., Inc.) was added, and reacted at 40 ° C. for 90 minutes to convert the epoxy group to an amino group. For example, what was obtained by such a method was made into the amination cellulose bead in this specification.

(3) Amino group attachment to polymer fiber 77 parts of polyvinyl alcohol (manufactured by Nippon Synthetic Chemical Co., Ltd.) having a solution viscosity of 13 to 16 mPa · s and a saponification rate of 99 mol% or more, and a polyethyleneimine having a molecular weight of 10,000 A spinning dope consisting of 23 parts and 300 parts of water was produced. A 250 dtex long fiber was obtained from this stock solution. This was heat-treated in hydrogen chloride gas at 120 ° C. for 1 hour to obtain a fiber having an amino group. For example, what was obtained by such a method was made into the aminated fiber in this specification.

Example 1
In this example, a chelate compound was synthesized using commercially available styrenic weakly basic anion exchange resin beads. The chemical formula of the chelate moiety is as shown in Chemical Formula 6, in which R1 = R4 = R5 = H and R2 = R3 = OH.

  Ion exchange resin beads WA20 (manufactured by Mitsubishi Chemical Corporation) were allowed to stand overnight in a graduated cylinder, and 15 ml was measured. This and 3,4-dihydroxybenzaldehyde (0.6 g) were added to methanol / water (4: 1, 50 mL) and stirred for about 1 hour. The ion exchange resin turned yellow upon condensation with the aldehyde. The ion-exchange resin colored yellow was suction filtered and washed thoroughly with methanol (to remove unreacted 3,4-dihydroxybenzaldehyde). This was suspended in a methanol / water mixed solvent (4: 1, 50 mL), and 3 g of sodium borohydride was added little by little. Yellow ion-exchange resin beads become white. After the addition was completed, the mixture was allowed to stand for 1 hour, filtered with suction, and washed well with water (to remove unreacted sodium borohydride) to obtain a chelated carrier precursor (A-1).

  The chelated carrier precursor obtained here was added to 1N hydrochloric acid solution (50 mL) and stirred for 1 hour. The product thus obtained was filtered off with suction and washed with water and then with methanol. Thus, a chelating carrier (AH-1) was obtained.

  Ion exchange resin beads (WA20), a chelating carrier precursor (A-1) using the same, and a chelating carrier (AH-1) were immersed in ultrapure water and allowed to stand overnight at room temperature. As shown in Fig. 4, the elution of impurities that are thought to have been caused by oxidation of unreacted substances (3,4-dihydroxybenzaldehyde) during chelate site synthesis from the chelated carrier precursor that is not a chloride salt continues even after washing. And the stock solution turned pale pink. In FIG. 1, the left is an ion exchange resin bead (WA20), the center is a chelating carrier precursor (A-1), and the right is a chelating carrier (AH-1).

  The ion exchange resin beads used in Example 1, the chelating carrier precursor obtained in Example 1, and the chelating carrier were suspended in 100 ml of water, and 1.0 g of ammonium iron citrate was added thereto. Stir for hours. The obtained iron chelating carrier was filtered by suction and thoroughly washed with water. Thus, an iron chelating carrier was obtained. FIG. 2 is a photograph comparing various beads reacted with ammonium iron citrate. In FIG. 2, the ion exchange resin beads (left), chelating carrier precursor (center), and chelating carrier (right) used in Example 1 were arranged in this order.

  Nonspecific ammonium iron citrate adheres to the ion-exchange resin beads, and elution is observed with time (left). The chelated carrier precursor (A-1) chelates iron, but the chelate site of this chelated carrier precursor is originally different from the color tone when iron is chelated with the correct ligand. For this reason, it turns out that the chelate power which a chelate part originally has cannot fully be demonstrated. On the other hand, in the chelating carrier (AH-1), the iron ion is correctly chelated to the ligand at the chelating site, and the chelating carrier (AH-1) changes to a black purple color that should be observed. Since the ligand appropriately chelates iron ions, the amount of chelated iron ions is large and the chelate retention power is considered high.

  The obtained iron chelating carrier binds to phosphate ions, diphosphate ions, polyphosphate ions, etc., and has a high ability to remove these ions from an aqueous solution, especially for artificial dialysis that removes phosphate. It is very promising as a material.

  In addition, when different ion-exchange resin beads WA21J (manufactured by Mitsubishi Chemical Co., Ltd.) were prepared and evaluated by the same method, the chelating carrier precursor (B-1) and the chelating carrier (BH-1) were evaluated. It was seen. The results are shown in FIGS. In each figure, the ion-exchange resin beads WA21J are on the left, the chelating complex carrier precursor (B-1) is in the center, and the chelating carrier (BH-1) is on the right.

Example 2
1.0 g of an amino group-containing fiber produced by the above-described method was suspended in 100 ml of methanol, 3,4-dihydroxybenzaldehyde (0.6 g) was added, and the mixture was stirred for about 1 hour. The aminated fiber turned yellow upon condensation with the aldehyde. The yellow colored fiber was filtered with suction and washed thoroughly with methanol (to remove unreacted 3,4-dihydroxybenzaldehyde). This was suspended in 50 mL of methanol, and 3 g of sodium borohydride was added little by little. Yellow fiber becomes white. After the addition was completed, the mixture was allowed to stand for 1 hour, filtered by suction, and washed thoroughly with water (to remove unreacted sodium borohydride) to obtain a fibrous chelated carrier precursor (D-1).

  The fibrous chelated carrier precursor thus obtained was added to 1N hydrochloric acid solution (50 mL) and stirred for 1 hour. The product obtained is filtered off with suction and washed with water and then with methanol. Thus, a fibrous chelating carrier (DH-1) was obtained.

  The fibrous chelating carrier precursor (D-1) and the fibrous chelating carrier (DH-1) were each suspended in 100 ml of water, and 1.0 g of ammonium iron citrate was added thereto, followed by stirring for 1 hour. The obtained iron chelating carrier was filtered by suction and thoroughly washed with water. Thus, a fibrous iron chelating carrier was obtained. FIG. 5 is a photograph comparing various fibers reacted with ammonium iron citrate. In FIG. 5, the aminated fiber of Example 2 (left), the fibrous chelated carrier precursor (center), and the fibrous chelated carrier (right) were arranged in this order. The fibrous chelated carrier precursor and the fibrous chelated carrier chelate iron and are strongly colored.

  FIG. 6 shows the fibrous chelated carrier precursor (D-1) prepared in Example 2 and the fibrous chelated carrier (DH-1) once air-dried. In FIG. 6, the left is the fibrous chelated carrier precursor (D-1), and the right is the fibrous chelated carrier (DH-1). 0.5 g of each was weighed and stirred in 20 ml of 0.05M nta-Fe solution. The fibrous chelating carrier precursor (D-1) and the fibrous chelating carrier (DH-1) are iron chelate compounds such as nta-Fe [Y. Nishida and S. ITO, Polyhedron, 14, 2301-2308 (1995). ))] Chelated iron ions and quickly turned black-purple. FIG. 7 shows the state of the fibrous chelated carrier precursor (left) and the fibrous chelated carrier (right) after chelating iron from nta-Fe. It can be seen that the fibrous chelating carrier prepared in the present invention can chelate iron from other strong iron chelating agents.

Example 3
In the same manner as in Example 1, a chelating carrier was synthesized using methacrylate polymer beads (trade name Lifetech (TM) ECR-8309M, manufactured by Purolite). The results of reaction with an ammonium iron citrate solution are shown in FIG. In FIG. 8, the left is untreated methacrylate polymer beads <8309>, the center is the chelating carrier precursor, and the right is the chelating carrier. The chelating carrier precursor and the chelating carrier chelate iron and are strongly colored.

  Similarly, methacrylate polymer beads (made by Purolite, trade name Lifetech (TM) ECR-8415M) with the same polymer material but different bead pore size sizes and polymethylene chains that serve as linkers between the polymer substrate and amino groups Was used to synthesize a chelating carrier. The result of the reaction with the ammonium iron citrate solution is shown in FIG. In FIG. 9, the left is an untreated methacrylate polymer bead <8415>, the center is a chelated carrier precursor, and the right is a chelated carrier. The chelating carrier precursor and the chelating carrier chelate iron and are strongly colored.

Example 4
In the same manner as in Example 1, a chelating carrier was synthesized using polyvinyl alcohol beads provided with an amino group by the method described above. The result of the reaction with the ammonium iron citrate solution is shown in FIG. In FIG. 10, the left is an aminated polyvinyl alcohol bead, the center is a chelating carrier precursor, and the right is a chelating carrier. The chelating carrier precursor and the chelating carrier chelate iron and are strongly colored.

Example 5
In the same manner as in Example 1, a chelating carrier was synthesized using cellulose beads provided with an amino group by the method described above. The result of the reaction with the ammonium iron citrate solution is shown in FIG. In FIG. 11, the left is an aminated cellulose bead, the center is a chelating carrier precursor, and the right is a chelating carrier. The chelating carrier precursor and the chelating carrier chelate iron and are strongly colored.

Claims (7)

A chelating carrier formed by immobilizing a ligand having chelating ability on a solid phase carrier made of a polymer having an amino group,
The polymer is a polymer composed of at least one of a styrene-based polymer, a poly (meth) acrylic acid-based polymer, a polyvinyl alcohol-based polymer, cellulose, and agarose,
A chelating support characterized in that at least a part of the amino group is a halide salt.   The chelating carrier according to claim 1, wherein the halide salt is hydrochloride.   2. The ligand has an aromatic ring, at least one of the groups bonded to the aromatic ring is a hydroxyl group, and the other is any group selected from hydrogen, a hydroxyl group, a carboxyl group, and an alkoxy group. 3. The chelating carrier according to 2.   The chelating carrier according to any one of claims 1 to 3, wherein the ligand forms a complex with an iron ion.   The chelate carrier according to any one of claims 1 to 4, wherein the solid phase carrier is in the form of particles, fibers, or a film. A solid phase carrier composed of a polymer having an amino group is reacted with a functional group capable of forming a chelate and the aldehyde group of a ligand having an aldehyde group to form a Schiff base, which is reduced with a reducing agent, and then halogenated. Characterized by treatment with hydrofluoric acid,
The method for producing a chelating carrier, wherein the polymer is a polymer composed of at least one of a styrene polymer, a poly (meth) acrylic acid polymer, a polyvinyl alcohol polymer, cellulose, and agarose.   7. The method for producing a chelating carrier according to claim 6, wherein the hydrohalic acid is hydrochloric acid.