CN1681852A - Modified polymer particle, packing material and column for chromatography - Google Patents
Modified polymer particle, packing material and column for chromatography Download PDFInfo
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- CN1681852A CN1681852A CNA038215861A CN03821586A CN1681852A CN 1681852 A CN1681852 A CN 1681852A CN A038215861 A CNA038215861 A CN A038215861A CN 03821586 A CN03821586 A CN 03821586A CN 1681852 A CN1681852 A CN 1681852A
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
- C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines
Abstract
An object of the present invention is to prevent an isolation of carboxyl group caused by hydrolysis of ester bond, which occurs when a polymer particle containing an ester bond is used in the presence of a strongly acidic or strongly alkaline solution to thereby improve the acid Ealkali durability of the polymer particle.When a polymer particle containing an ester bond is treated with an acid or alkali hydrous solution and thereby an ester bond which is located and exposed on the surface of the particle and is readily hydrolyzed is previously hydrolyzed to isolate a carboxyl group and then the free carboxyl group is capped by amidation, to thereby dissolve the above problem.
Description
Technical Field
The present invention relates to a polymer particle improved in acid and alkali resistance, a modified packing material for chromatography, a method for producing and modifying the same, and a chromatography column using the packing material.
Background
Conventionally, acrylate-based and methacrylate-based polymer particles have been used as ion exchange resins or packing materials for various types of chromatography. However, these polymer particles contain an ester bond in the molecule, and use of such a polymer in an acid or alkali solution causes a decrease in strength due to hydrolysis of the ester bond, or use thereof as a packing material for chromatography causes a change in analysis pattern or the like due to the separated carboxyl group. Thus, the pH range of the solution that can be used is limited.
Examples of the application of the packing material for chromatography include chromatography for anion analysis. Anion chromatography includes inhibitor methods (a method using an inhibitor) and non-inhibitor methods (a method without an inhibitor). As the eluent, an alkali solution having a pH of 10 or more, such as a carbonate buffer solution or sodium hydroxide, is used in the inhibitor method, while a weak acid solution, such as p-hydroxybenzoic acid, phthalic acid and trimesic acid, is used in the non-inhibitor method. Therefore, acrylate-based and methacrylate-based filler materials are generally limited to use only as filler materials for non-inhibitor processes (see JP-A-2000-221179 (the term "JP-A" as used herein means an "unexamined published Japanese patent application")).
Also, there are known ｃA production method of an anion exchanger, an anion exchanger and ｃA method of measuring anions using the exchangers, characterized in that an anion exchanger having ester bonds of acrylate groups and methacrylate groups is treated with an alkali solution to decompose the ester bonds, thereby producing hydroxyl groups and/or carboxyl groups (see JP-A-2002-1941117). However, in this case, in order to separate the hydroxyl group and/or the carboxyl group and adjust the anion retention time at the time of analysis by using the separated group, the treatment of the ester bond-containing polymer is performed with an acidic or basic aqueous solution.
Other examples of the use of the packing material for chromatography include reverse phase chromatography. As a packing material for a reverse phase chromatography column, silica-based particles such as silica gel treated with octadecanoic acid are mainly used. However, such a filler material has a problem in terms of chemical stability, and therefore polymer particles are also used. Examples of the acrylate-based or methacrylate-based filler material include ethylene glycol dimethacrylate/alkyl methacrylate copolymer and a homopolymer of glyceryl dimethacrylate having an octadecanoyl group introduced therein.
In the silica-based particles, unreacted silanol groups remain in many cases, and therefore, it is impossible to obtain separation performance as high as that of a reverse phase column. The degree of residual amount of silanol groups can be detected by injecting an organic base such as pyridine into a packed column and comparing the peak shape thereof. It is generally known that as the number of residual silanol groups becomes larger, the peak is more apt to tail.
In order to solve the above-mentioned problems encountered in the process of using a silica-based filler material, a method of blocking residual silanol groups with inert groups is known. Recently, for the purpose of sealing at ｃA higher density, for example, ｃA method of reacting two terminal addition agents each capable of forming ｃA complex partially in ｃA sealed vessel in an inert atmosphere (JP-A-10-72579) and ｃA method of reacting ｃA filler with ｃA chemical modifier in ｃA supercritical fluid (JP-A-9-49829) have been reported.
On the other hand, the polymer particle-packed column is advantageous in that the chemical stability is excellent as compared with the silica column, but such a column is inferior to the silica column in, for example, (1) the lot difference of the retention volume is large, (2) the reproducibility of the retention volume is poor, (3) the tailing is strong, and (4) the theoretical plate number is small. Therefore, the polymer-based distribution-adsorption column is very small in the amount of commercially available products, and the possibility of using the column is extremely limited. The above problems are particularly pronounced when using eluents which are completely salt-free. Such ｃA problem of polymer particles can be solved by ｃA method of blocking free carboxyl groups of ｃA polymer-based filler material with inert groups (see JP-A-2000-310623). However, also in this case, the acid-base resistance is not sufficiently high and the pH range of the eluent used is limited.
JP- ｃA-2003-176363 describes ｃA filler material obtained by covering polymer particles with ｃA crosslinkable epoxy compound and introducing carbon chains through ether bonds, and which has high acid-base resistance. However, even in this case, when acrylate-based or methacrylate-based particles are used as a base material gel and a strongly acidic or strongly basic solution is used as an eluent, ester bonds exposed to the particle surface are hydrolyzed, new free carboxyl groups are generated, and therefore, the pH range of the eluent usable at the time of analysis is limited.
Disclosure of Invention
An object of the present invention is to provide polymer particles improved in acid-base resistance, which can be used for performing liquid chromatography analysis by using polymer particles containing an ester bond, and which can be used even in a strongly acidic or strongly basic solution. More particularly, it is an object of the present invention to provide polymer particles improved in acid-alkali resistance, a modified packing material for chromatography, a production method thereof and a chromatography column using the packing material.
The present inventors have found that when polymer particles containing ester bonds are treated with an acidic or basic aqueous solution, thereby preliminarily hydrolyzing the ester bonds which are easily contacted with a liquid and easily hydrolyzed to separate carboxyl groups, and then blocking the free carboxyl groups by amidation, the acid and alkali resistance of the polymer particles can be improved. The present invention has been completed based on the finding.
That is, the present invention relates to, for example, the following subject matters.
[1]A modified polymer particle improved in acid-base resistance obtained by treating a polymer particle containing an ester bond with an acidic or basic aqueous solution to partially hydrolyze the ester bond and separate the carboxyl group, and blocking the free carboxyl group by amidation.
[2]The modified polymer particles improved in acid-alkali resistance as described in [1], wherein the ester bond which has been hydrolyzed is an ester bond which is easily contacted with a liquid.
[3]The modified polymer particle improved in acid-alkali resistance as described in [1], wherein the amine used for amidation is an amine represented by the formula (1):
NHR1R2(1)
(wherein, R1And R2Each independently represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
[4]The modified polymer particle improved in acid-alkali resistance as described in [3], wherein the amine used for amidation is an amine represented by the formula (2):
NH2R3(2)
(wherein, R3Represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
[5]A modified polymer particle improved in acid-alkali resistance, wherein when the polymer particle is packed in a column having an inner diameter of 4.6mm and a length of 150mm and the alkali resistance is evaluated using the column by the following method, the percentage of increase in pyridine retentivity after passing through an alkali eluent is 50% or less:
the evaluation method comprises the following steps:
(1) an eluent of acetonitrile/0.1% aqueous phosphoric acid solution (30/70) was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and the pyridine retentivity was measured by using an eluent of acetonitrile/water (30/70) at a flow rate of 0.5ml/min,
(2) an alkaline eluent of acetonitrile/0.01 mol of aqueous sodium hydroxide solution of 50/50 was passed through the same column at a column temperature of 40 ℃ for 4 hours at a flow rate of 0.5ml/min, then an eluent of acetonitrile/0.1% aqueous phosphoric acid solution of 30/70 was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃,and pyridine retentivity was measured by using an eluent of acetonitrile/water of 30/70 at a flow rate of 0.5ml/min, and
(3) the pyridine retention of (2) was compared to the retention of (1).
[6]The modified polymer particles improved in acid-alkali resistance as described in any one of [1]to [5], wherein the polymer particles have an average particle size of 1 to 50 μm.
[7]A polymer-based packing material for chromatography, which uses modified polymer particles improved in acid-base resistance, wherein the polymer particles are obtained by treating polymer particles containing ester bonds with an acidic or basic aqueous solution to partially hydrolyze the ester bonds and separate carboxyl groups, and then blocking the free carboxyl groups by amidation.
[8]The polymer-based packing material for chromatography as described in [7], wherein the ester bond that has been hydrolyzed is an ester bond that is easily contacted with a liquid.
[9]The polymer-based packing material for chromatography as described in [7], wherein the amine used for amidation is an amine represented by formula (1):
NHR1R2(1)
(wherein, R1And R2Each independently represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
[10]The polymer-based packing material for chromatography as described in [9], wherein the amine used for amidation is an amine represented by formula (2):
NH2R3(2)
(wherein, R3Represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
[11]A polymer-based packing material for chromatography, which uses modified polymer particles improved in acid-alkali resistance, so that when the polymer particles are packed in a column having an inner diameter of 4.6mm and a length of 150mm and the alkali resistance is evaluated using the column by the following method, the percentage of increase in pyridine retention after passing an alkali eluent is 50% or less:
the evaluation method comprises the following steps:
(1) an eluent of acetonitrile/0.1% aqueous phosphoric acid solution (30/70) was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and the pyridine retentivity was measured by using an eluent of acetonitrile/water (30/70) at a flow rate of 0.5ml/min,
(2) an alkaline eluent of acetonitrile/0.01 mol of aqueous sodium hydroxide solution of 50/50 was passed through the same column at a column temperature of 40 ℃ for 4 hours at a flow rate of 0.5ml/min, then an eluent of acetonitrile/0.1% aqueous phosphoric acid solution of 30/70 was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and pyridine retentivity was measured by using an eluent of acetonitrile/water of 30/70 at a flow rate of 0.5ml/min, and
(3) the pyridine retention of (2) was compared to the retention of (1).
[12]The polymer-based packing material for chromatography as described in any one of [7]to [11], wherein the average particle size of the polymer particles is 1 to 50 μm.
[13]A method for producing a modified polymer particle improved in acid-alkali resistance, which comprises treating a polymer particle containing an ester bond with an acidic oralkaline aqueous solution to partially hydrolyze the ester bond and separate the carboxyl group, and then blocking the free carboxyl group by amidation.
[14]The method for producing modified polymer particles improved in acid-alkali resistance as recited in [13], wherein the ester bond that has been hydrolyzed is an ester bond that is easily contacted with a liquid.
[15]The method for producing modified polymer particles improved in acid-alkali resistance as described in [13], wherein the amine used for amidation is an amine represented by the formula (1):
NHR1R2(1)
(wherein, R1And R2Each independently represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
[16]The method for producing modified polymer particles improved in acid-alkali resistance as described in [15], wherein the amine used for amidation is an amine represented by the formula (2):
NH2R3(2)
(wherein, R3Represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
[17]The method for producing a modified polymer particle improved in acid-alkali resistance as recited in any one of [13]to [16], wherein when the polymer particle is packed in a column having an inner diameter of 4.6mm and a length of 150mm and the alkali resistance is evaluated using the column by the following method, the percentage of increase in pyridine retentivity after passing through an alkali eluent is 50% or less:
the evaluationmethod comprises the following steps:
(1) an eluent of acetonitrile/0.1% aqueous phosphoric acid solution (30/70) was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and the pyridine retentivity was measured by using an eluent of acetonitrile/water (30/70) at a flow rate of 0.5ml/min,
(2) an alkaline eluent of acetonitrile/0.01 mol of aqueous sodium hydroxide solution of 50/50 was passed through the same column at a column temperature of 40 ℃ for 4 hours at a flow rate of 0.5ml/min, then an eluent of acetonitrile/0.1% aqueous phosphoric acid solution of 30/70 was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and pyridine retentivity was measured by using an eluent of acetonitrile/water of 30/70 at a flow rate of 0.5ml/min, and
(3) the pyridine retention of (2) was compared to the retention of (1).
[18]The process for producing modified polymer particles improved in acid-base resistance as described in any one of [13]to [16], wherein the polymer particles have an average particle size of 1 to 50 μm.
[19]A method for producing a polymer-based packing material for chromatography, which comprises producing the polymer-based packing material for chromatography described in any one of [6]to [12]by performing hydrolysis treatment with one or both of an acidic or basic aqueous solution and blocking treatment by amidation while packing the polymer-based packing material in a column.
[20]A chromatography column using the polymer-based packing material for chromatography having improved acid-base resistance described in any one of [6]to [12].
Embodiments of the invention
In the present invention, when liquid chromatography is performed using polymer particles containing ester bonds, ester bonds which are easily contacted with a liquid and easily hydrolyzed are hydrolyzed in advance to separate carboxyl groups, and the carboxyl groups are blocked by amidation, thereby inhibiting hydrolysis of esters which occurs when used in chromatography, improving the acid and alkali resistance of the polymer particles, and enabling stable analysis.
More specifically, in JP-A-2000-310623, carboxyl groups generated in the polymerization step for producing polymer particles are blocked, whereas in the present invention, ester bonds which are easily hydrolyzed are actively hydrolyzed, thereby significantly improving the acid-base resistance.
The polymer particles modified by the method of the present invention are polymer particles containing an ester bond in the molecule, and examples thereof include crosslinkable polymers containing a polyester structure. Further, even in the case of polymer particles in which an ester bond is contained as a problem in a partial structure, when it is considered that the ester bond causes a decrease in acid-base resistance, this is polymer particles modified by the method of the present invention.
Examples of the polymer particles having a polyester structure include ethylene glycol di (meth) acrylate/(meth) acrylic acid alkyl ester copolymers, ethylene glycol di (meth) acrylate homopolymers, glycerol di (meth) acrylate/(meth) acrylic acid alkyl ester copolymers, glycerol di (meth) acrylate homopolymers and modified products thereof, ethylene glycol di (meth) acrylate/glycerol di (meth) acrylate copolymers and modified products thereof, trimethylolpropane tri (meth) acrylate/(meth) acrylic acid alkyl ester copolymers, trimethylolpropane tri (meth) acrylate homopolymers, pentaerythritol tri (meth) acrylate/(meth) acrylic acid alkyl ester copolymers and modified products thereof, pentaerythritol tri (meth) acrylate homopolymers and modified products thereof, polyethylene glycol di (meth) acrylate copolymers, polyethylene glycol di, Vinyl (meth) acrylate homopolymers and hydrolysis or modification products of the ethylene oxide ring of ethylene glycol di (meth) acrylate/(meth) acrylic acid glycerol ester copolymers.
Examples of the polymer particles having an ester bond as a problem in the partial structure include polymer particles having one or more partial structures selected from amide, imide, alcohol, ether, aromatic ring, alkyl chain and the like in combination in addition to the above-mentioned ester structure.
The polymer particles contain ester bonds, and when the polymer particles are used in an acidic or basic aqueous solution, the ester bonds exposed to the surface of the particles are hydrolyzed. Therefore, the acid and alkali resistance of the polymer particles is low.
The modified polymer particles referred to in the present invention include all polymer particles containing the above-mentioned ester bond, in which the ester bond exposed to the surface and liable to be hydrolyzed is cleaved in advance by an acidic or basic aqueous solution, and the resulting free carboxyl group is blocked by amidation.
The amide bond is not easily hydrolyzed as compared with an ester bond (see "PROTECTIVE group in ORGANIC SYNTHESIS" page 442 middle column of 3 rd edition), and therefore, when an ester bond which is easily contacted with a liquid is previously cleaved and a free carboxyl group generated is blocked and converted into an amide bond by amidation, the generation of a carboxyl group is suppressed and the durability of the polymer is improved even if polymer particles are used in an acid or alkali solution.
That is, the ester bond which is easily contacted with a liquid in the present invention is an ester bond relatively close to the surface of the polymer. By converting the ester bond into an amide bond, the polymer surface is protected with the amide bond which is not easily hydrolyzed as described above, and as a result, the ester bond which is not hydrolyzed by acid or alkali treatment when used as a column or the like becomes more difficult to contact with a liquid, and it is considered that the acid and alkali resistance of the polymer particles is improved.
In the present invention, the polymer particles to be modified may have various particle sizes depending on the use. In the case of use as a packing material for chromatography, the polymer particles preferably have an average particle size of 1 to 50 μm, more preferably 1.5 to 30 μm, and still more preferably 2 to 10 μm. If the average particle size is less than 1 μm, the column pressure rises excessively beyond the strength limit of the particles, which is not preferable, whereas if the average particle size exceeds 50 μm, the separation ability is low and in practice this is not preferable.
The method of the present invention for cleaving an ester bond which is considered to be exposed to the surface of a polymer particle and which is susceptible to hydrolysis, by treatment with an acidic or basic aqueous solution will be specifically described below.
As the acidic aqueous solution, an aqueous solution of hydrochloric acid, sulfuric acid, or the like can be used. In the case where the polymer particles are less wettable in the solution, a suitable amount of a water-soluble organic solvent which does not react in a strongly acidic solution, such as dimethyl sulfoxide, may be added before the aqueous solution is used. The concentration is not particularly limited as long as the ester bond on the surface of the polymer particle can be hydrolyzed, but the polymer is suspended by appropriately controlling the concentration so that the solution has a pH of 3 or less, preferably 1 to 2. The reaction temperature is not particularly limited as long as the ester bond on the surface of the polymer particle can be hydrolyzed, but it is suitably set at 20 to 100 deg.C, preferably 30 to 80 deg.C, more preferably 40 to 60 deg.C. The reaction time is not particularly limited as long as the ester bond on the surface of the polymer particle can be hydrolyzed, but the reaction is suitably carried out under stirring for 30 minutes to 24 hours, preferably 30 minutes to 10 hours, preferably 1 to 6 hours.
As the alkaline aqueous solution, an aqueous solution of a hydroxide such as sodium hydroxide and potassium hydroxide may be used. In the case where the polymer particles are less wettable in the solution, an appropriate amount of a water-soluble organic solvent which does not react in a strongly basic solution, such as dimethyl sulfoxide, may be added before the aqueous solution is used. The concentration is not particularly limited as long as the ester bond on the surface of the polymer particle can be hydrolyzed, but the polymer is suspended by appropriately controlling the concentration so that the solution has a pH of 10 to 14, preferably 11 to 13. The reaction temperature is not particularly limited as long as the ester bond on the surface of the polymer particle can be hydrolyzed, but it is suitably set at 20 to 100 deg.C, preferably 30 to 80 deg.C, more preferably 40 to 60 deg.C. The reaction time is not particularly limited as long as the ester bond on the surface of the polymer particle can be hydrolyzed, but the reaction is suitably carried out under stirring for 20 minutes to 24 hours, preferably 30 minutes to 10 hours, preferably 1 to 6 hours.
The ranges of pH, reaction temperature and reaction time in the hydrolysis conditions of the ester bond may be adjusted and used individually, but it is preferable toadjust all the conditions in combination.
The amidation method for achieving blocking in the present invention is specifically described below.
The amine used for amidation is not substantially limited as long as the free carboxyl group can be blocked, but in view of reactivity under amidation, limitation introduced due to steric hindrance, and stability after conversion into an amide, it is preferable that the amine used is an amine represented by formula (1):
NHR1R2(1)
(wherein, R1And R2Each independently represents a hydrogen atom, may be branched or may be taken by a halogenAn alkyl group having 18 or less carbon atoms in the generation, or a phenyl group).
More preferably, the amine is a primary amine represented by formula (2):
NH2R3(2)
(wherein, R3Represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group).
The smaller substituent group volume is advantageous in that introduction efficiency is improved due to small steric hindrance and hydrophobicity of the polymer particles before modification is not greatly changed. However, in the case where the number of free carboxyl groups to be blocked is very small, the hydrophobicity changes little even if a relatively large inert group is introduced. Therefore, a substituent having a large volume to some extent may be used. More specifically, in the case of alkylamine, the alkyl group preferably has a carbon number of 18 or less, more preferably 12 or less, more preferably 6 or less, and particularly preferably 4 or less.
Examples thereof include ammonia, methylamine, ethylamine, 1-propylamine, isopropylamine, 1-butylamine, isobutylamine, tert-butylamine, 1-hexylamine, cyclohexylamine, 1-octylamine, dimethylamine, diethylamine and di (1-propyl) amine.
For amidation in the present invention, a method generally used in peptide synthesis, and the like can be used. However, it is necessary that the portion other than the free carboxyl groups of the polymer particles to be modified is not adversely affected. Further, in view of practical aspects such as introduction efficiency, ease of handling and cost, it is preferable to perform amidation by using the following combination of reagents.
(A) (i) reagents for producing mixed anhydrides, such as ethyl chloroformate; tertiary amines, such as triethylamine; and an organic solvent such as chloroform, and (ii) an amine represented by formula (1).
(B) Amines represented by formula (2), such as 1-propylamine; dehydration condensing agents such as N, N' -diisopropylcarbodiimide; and organic solvents such as toluene and N, N-dimethylformamide.
The method for modifying polymer particles having an ester bond of the present invention is characterized in that the polymer particles are treated with the above-mentioned acidic or basic aqueous solution and brought into contact with a solution or suspension containing the amidation agent.
That is, the readily hydrolyzable ester bonds believed to be exposed on the surface of the polymer particles are first hydrolyzed by treating the polymer particles with an acidic or basic aqueous solution, and then the isolated carboxyl groups are converted to amide groups by contacting the polymer particles with a solution or suspension containing an amidation agent.
The polymer particles to be modified may or may not be packed in the column beforehand. More specifically, one or both of the hydrolysis treatment with an acidic or basic aqueous solution and the blocking treatment by amidation may be performed with the polymer particles packed into a column. In order to treat the polymer in a packed state, a method of adding a solution or suspension containing a reagent into a column is used. The form of addition, temperature, rate and time are suitably selected according to the requirements for completion of the reaction.
With a conventional liquid chromatography column packed with polymer particles containing ester bonds which are easily contacted with a liquid, the elution time and peak shape of an organic base such as pyridine sometimes change greatly between before and after passing through a strongly acidic or strongly basic eluent. On the other hand, with a liquid chromatography column packed with the polymer particles of the present invention, the change in the elution time and the peak shape of an organic base such as pyridine between before and after passing through a strongly acidic or strongly basic eluent is significantly suppressed.
It is considered that a polymer filled with a polymer containing an ester bond which is easily contacted with a liquid is usedA problem encountered in conventional liquid chromatography column measurements of particles is due to the generation of free carboxyl groups resulting from hydrolysis of ester bonds exposed to the surface of the polymer particles upon passage through a strongly acidic or strongly basic eluent. As the free carboxyl group, it is considered that a proton type (R-COOH) carboxyl group and a metal type (R-COOM) carboxyl group coexist. Organic bases such as pyridine (the organic base is hereinafter referred to as "pyridine") adsorb strongly mainly to the former. This is because the pH is locally low in the vicinity of the proton type carboxylic acid (R-COOH) and the equilibrium of pyridine and pyridinium salt ions tendsto be pyridinium salt ions, and as a result, generation is likely to occur Ionic bonding of (2). This phenomenon occurs more significantly if a completely salt-free eluent is used. Since the metal is trapped and concentrated in the column when passing near the proton type carboxylic acid (R-COOH) if a small amount of the metal is mixed in the eluent, as a result, the metal type carboxylic acid (R-COOM) increases and pyridine is less adsorbed. In order to precisely evaluate the alkali resistance, it is necessary to convert the metal type carboxylic acid (R-COOM) into a proton type carboxylic acid (R-COOH). To this end, a phosphoric acid-containing acid solution may be passed through the column prior to analysis of the pyridine.
In view of this, the effect of modification can be clearly detected when pyridine analysis is performed before and after passing a strongly acidic or strongly basic eluent through the subject column to be evaluated.
More specifically, when the ester bond is hydrolyzed and a free carboxyl group is generated, the retention volume of pyridine increases and the peak shape trails, and thus, the effect of the present invention can be examined by comparing the polymer particle after modification according to the present invention with the polymer particle before modification.
By the method, the influence on the acid-base resistance of the polymer particles obtained by modification including hydrolysis treatment with an acidic or basic aqueous solution and blocking treatment by amidation can be confirmed.
Examples
The present invention is described in more detail below by referring to examples, but the present invention is not limited to these examples. In example 1, the production method of a polymer-based packing material suitable fora reversed-phase liquid chromatography column is described from the preparation of the base material gel first until the introduction of the carbon chain finally, but steps 3 and 4 are the parts mainly related to the present invention. Thus, the method of the present invention can be utilized by incorporating the method of the present invention in a series of steps for producing polymer particles.
(example 1)
<step 1: synthesis of base Material crosslinked Polymer particles
In a mixed solution containing 2,000g of glycerol dimethacrylate and 900g of 1-hexanol, 30g of 2, 2' -azobisisobutyronitrile was dissolved to prepare an oil phase. 180g of polyvinyl alcohol (kurarayploval PVA-224, manufactured by Kuraray co., ltd.) was dissolved in 3 liters of water, respectively, and 7 liters of water was added thereto, and then a solution obtained by dissolving 240g of sodium chloride in 2 liters of water and a solution obtained by dissolving 15g of sodium lauryl sulfate in 485ml of water were added, and mixed to prepare an aqueous phase. The obtained oil phase and water phase were mixed in a stainless steel vessel of 20L volume and dispersed in a high-speed disperser (homogenizer) by adjusting the number of revolutions and dispersion time so that the maximum particle size of oil droplets was 3 μm.
The obtained dispersion was reacted at 70 ℃ for 4 hours while stirring at 150 rpm. The resulting crosslinked polymer particles were centrifuged (at 2,000rpm for 10 minutes), and after removing the supernatant, the precipitate was dispersed in 12 liters of hot water at 70 ℃ (by using an ultrasonic cleaner), and then stirred at 70 ℃ for 3 hours. The resulting solution was suction-filtered, and the gel on the funnel was washed with 60 liters of hot water at 70 ℃ and then 18 liters of acetone, air-dried by dispersing it in a stainless steel bath, and further dried at 60 ℃ under reduced pressure for 24 hours. The obtained polymer particles were classified with a pneumatic classifier to obtain 716g of crosslinked polymer particles having a weight average particle size of 3 μm (hereinafter, the polymer particles are referred to as "base material gel").
<step 2: thorough cleaning>
Pure water (500ml) was added to 50g of the base material gel obtained in step 1, and heated and stirred at 60 ℃ for 5 hours. Thereafter, the collected particles were washed by filtration, successively with 2,000ml of 70 ℃ hot water, and then with 300ml of methanol, and then air-dried by dispersing the particles in a stainless steel bath, and further dried under reduced pressure at 60 ℃ for 24 hours, to obtain 49g of a thoroughly washed base material gel.
<step 3: hydrolysis treatment with an alkaline aqueous solution>
The thoroughly washed base material gel (10g) obtained in step 2 was dispersed in 50ml of a 0.1N aqueous solution of sodium hydroxide and stirred at 50 ℃ for 2 hours. The reaction liquid was suction-filtered, and the gel on the funnel was washed successively with 100ml of a 0.01N hydrochloric acid solution, with 500ml of water and with 100ml of acetone, then air-dried by dispersing the gel in a stainless steel bath, and further dried at 60 ℃ under reduced pressure for 3 hours to obtain 10g of a hydrolyzed gel.
<step 4: blocking by amidation>
The hydrolyzed gel (10g) obtained in step 3 was dispersed in 50ml of chloroform at 25 ℃. While stirring the dispersion in a water bath at 25 ℃ 2.3g of triethylamine were added, after 5 minutes 2.5g of ethyl chloroformate were added, after 30 minutes 1.6g of 1-propylamine were added. Then, they were allowed to react for 3 hours. The reaction mixture was suction-filtered, and the gel on the funnel was washed successively with 100ml of chloroform, with 500ml of water and with 100ml of acetone, then air-dried by dispersing the gel in a stainless steel bath, and further dried under reduced pressure at 60 ℃ for 3 hours to obtain 10g of amidated and blocked gel.
<step 5: surface crosslinking and epoxy Ring opening reaction>
The amidated and blocked gel obtained in step 4 (10g) and 1g of ethylene glycol diglycidyl ether were added to 50ml of toluene, and they were simultaneously stirred in a water bath at 40 ℃. 0.5g of boron trifluoride diethyl ether complex was added and they were allowed to react for 3 hours. The reaction mixture was suction filtered, and the gel on the funnel was washed with 100ml of acetone and then 500ml of water, and then the gel was transferred to a container, and 50ml of 0.1N hydrochloric acid was added thereto and reacted at 50 ℃ for 1 hour. The reaction mixture was suction-filtered, and the gel on the funnel was washed with 500ml of water and then 100ml of acetone, after which air-drying was performed by dispersing the gel in a stainless steel bath, and further dried at 60 ℃ under reduced pressure for 3 hours to obtain 11.5g of a surface-crosslinked gel.
<step 6: reaction of C18 formation>
The surface-crosslinked gel obtained in step 5 (10g) and 3g of octadecyl glycidyl ether were dispersed in 100ml of toluene, and simultaneously stirred in a water bath at 40 ℃. 0.5g of boron trifluoride diethyl ether complex was added and they were allowed to react for 3 hours. The reaction mixture was suction-filtered, and the gel on the funnel was washed successively with 100ml of toluene, with 300ml of tetrahydrofuran, with 500ml of water, and with 100ml of acetone, then air-dried by dispersing the gel in a stainless steel bath, and further dried under reduced pressure at 60 ℃ for 3 hours to obtain 10.5g ofa gel having carbon chains incorporated therein.
<filling of modified gel>
The gel into which carbon chains were introduced obtained in step 6 was packed into a stainless steel column of 4.6mm (inner diameter) × 150mm (length) by a slurry method to produce a reverse phase chromatography column (hereinafter referred to as "column a").
Comparative example 1
The column was produced by removing steps 3 and 4 in the column production method of example 1 (hereinafter referred to as "column R").
Comparative example 2
The column was produced by removing step 4 in the column production method of example 1 (hereinafter referred to as "column C").
(1. comparison of alkali resistance)
Example 1 (column a) and comparative example 1 (column B) were evaluated for alkali resistance by the following methods.
To clearly show the effect of blocking by amidation, the pyridine/phenol test results of comparative example (column C) are also shown.
1-1. alkali resistance test method
1-1-1 pyridine/phenol test in initial state
An acidic eluent was passed through the test object column under the following conditions. The above procedure is carried out to bias the free carboxyl groups, if present, to the proton form (RCOOH).
Eluent: CH (CH)3CN/0.1% phosphoric acid solution in water 30/70(v/v)
Flow rate: 0.3ml/min
Column temperature: 25 deg.C
Eluent passage time: 30 minutes
Subsequently, the conditions were changed to the following conditions, and after the liquid was displaced for 30 minutes or more, pyridine and phenol were analyzed.
Eluent: CH (CH)3CN/H2O＝30/70(v/v)
Flow rate: 1.00ml/min
Column temperature: 40 deg.C
1-1-2, passing through strong alkaline eluent
After completion of the pyridine/phenol test in the initial state, a strongly basic eluent was passed through the test object column under the following conditions. By this operation, the ester bond, if present, which is easily contacted with the liquid is hydrolyzed to generate a free carboxyl group.
Eluent: CH (CH)3CN/0.01N-NaOH(pH：12)＝50/50(v/v)
Flow rate: 0.50ml/min
Column temperature: 40 deg.C
Eluent passage time: 4 hours
1-1-3 pyridine/phenol test after passing through strongly basic eluent
After passing through the strongly basic eluent, a pyridine/phenol test was carried out by the same method as in 1-1-1 above using the test object column.
1-2 evaluation results of alkali resistance
The evaluation results of column a and column B are shown in table 1. In the table, the retention free time t is represented by0And a composite retention time trCalculating the retention k':
k’＝(tr-t0)/t0
from the peak width at 5% of the peak height according to the following formulaW0.05hAnd calculating a tailing coefficient T according to the peak width f on the rising side of the peak:
T＝W0.05h/f
TABLE 1
| Pyridine Retention k' | Phenol-retaining k' | Coefficient of pyridine tailing | ||||
| Initial state | By strong alkali Sex eluent After that | Initial state | By strong alkali Sex eluent After that | Initial state | By strong alkali Sex eluent After that | |
| Column A | 1.5 | 1.6 | 3.6 | 3.6 | 0.75 | 0.75 |
| Column B | 1.6 | 2.5 | 3.6 | 3.6 | 1.5 | 4.3 |
| Column C | 4.7 | - | 3.6 | - | 5.8 | - |
In column a and column B, the phenol retention k' was unchanged in the initial state and after passage through the strongly basic eluent, but in column B, the pyridine retention increased by 56% and the tailing factor also increased. This indicates that the ester bond is hydrolyzed and free carboxyl groups are generated during the passage through the strongly basic eluent. In contrast, in column a, the pyridine peak is hardly changed, which remarkably shows the effect of the present invention.
Further, by comparing the pyridine retentivity and tailing coefficient of the column a in the initial state with those of the column C, it can be confirmed that the carboxyl group generated by the alkali treatment in the production method of the packing material is blocked by amidation.
(2. comparison of acid resistance)
Example 1 (column a) and comparative example 1 (column B) were subjected to acid resistance by the following method.
2-1. acid resistance evaluation method
2-1-1. pyridine/phenol test in initial state
The pyridine/phenol test was carried out by the same method as in the above-mentioned 1-1-1.
2-1-2, passing through strong acid eluent
After completion of the pyridine/phenol test in the initial state, the test object column was passed through by a strongly acidic eluent under the following conditions. By this operation, the ester bond, if present, which is easily contacted with the liquid is hydrolyzed to generate a free carboxyl group.
Eluent: MeOH/0.1% trifluoroacetic acid in water (pH: 1.2) ═ 10/90(v/v)
Flow rate: 1.00ml/min
Column temperature: 40 deg.C
Eluent passage time: 70 hours
2-1-3 pyridine/phenol test after passing through strongly acidic eluent
After passing through a strongly acidic eluent, a pyridine/phenol test was performed by the same method as in 1-1-1 above using a test object column.
2-2 acid resistance evaluation results
The evaluation results of column A and column B are shown in Table 2. In the table, the retention free time t is represented by0And a composite retention time trCalculating the retention k':
k’＝(tr-t0)/t0
from the peak width W at 5% of the peak height according to the following formula0.05hAnd calculating a tailing coefficient T according to the peak width f on the rising side of the peak:
T＝W0.05h/f
TABLE 2
| Pyridine Retention k' | Phenol-retaining k' | Coefficient of pyridine tailing | ||||
| Initial state | By strong acids Sex eluent After that | Initial state | By strong acids Sex eluent After that | Initial state | By strong acids Sex eluent After that | |
| Column A | 1.4 | 1.6 | 3.6 | 3.6 | 0.75 | 0.75 |
| Column B | 1.6 | 2.6 | 3.6 | 3.6 | 1.5 | 3.6 |
In column a and column B, the phenol retention k' was not changed in the initial state and after passing through a strongly acidic eluent, but in column B, the pyridine retention rose by 63%, and the tailing factor also rose. This indicates that the ester bond is hydrolyzed and free carboxyl groups are generated during the passage through a strongly acidic eluent. In contrast, in column a, the pyridine peak is hardly changed, which remarkably shows the effect of the present invention.
The polymer particles modified by the method of the present invention are packed to produce a column for chromatography, an organic base such as pyridine is analyzed before and after passing through a strongly acidic or strongly basic eluent, and comparison is made, as a result, increase in retention and tailing of peaks are significantly suppressed, and the effect of the present invention can be confirmed.
INDUSTRIAL APPLICABILITY
In the modified polymer particles of the present invention, the ester bond which exists in the vicinity of the surface and is easily contacted with a liquid is hydrolyzed, and the generated carboxyl group is converted into an amide group, and therefore, after the treatment, an amide bond which is less easily hydrolyzed exists on the surface, and the residual ester bond becomes difficult to contact with a liquid, and as a result, it is considered that the acid-base resistance is improved.
The polymer particles of the present invention can be used as a packing material for chromatography, and a column packed with the polymer particles exhibits high resistance to acids and alkalis, and therefore, it is useful in a wide range of fields such as pharmaceutical preparations or agricultural chemical preparations, food additives, intermediates thereof, natural or synthetic polymers, additives thereof, and the separation and analysis of environmental pollutants.
Claims (20)
1. A modified polymer particle improved in acid-base resistance obtained by treating a polymer particle containing an ester bond with an acidic or basic aqueous solution to partially hydrolyze the ester bond and separate the carboxyl group, and blocking the free carboxyl group by amidation.
2. The modified polymer particle improved in acid-alkali resistance according to claim 1, wherein the ester bond that has been hydrolyzed is an ester bond that is easily contacted with a liquid.
3. The modified polymer particle improved in acid-alkali resistance of claim 1, wherein the amine used for amidation is an amine represented by formula (1):
NHR1R2(1)
wherein R is1And R2Each independently represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group.
4. The modified polymer particle improved in acid-alkali resistance of claim 3, wherein the amine used for amidation is an amine represented by formula (2):
NH2R3(2)
wherein R is3Represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group.
5. A modified polymer particle improved in acid-alkali resistance, wherein when the polymer particle is packed in a column having an inner diameter of 4.6mm and a length of 150mm and the alkali resistance is evaluated using the column by the following method, the percentage of increase in pyridine retentivity after passing through an alkali eluent is 50% or less:
the evaluation method comprises the following steps:
(1) an eluent of acetonitrile/0.1% aqueous phosphoric acid solution (30/70) was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and the pyridine retentivity was measured by using an eluent of acetonitrile/water (30/70) at a flow rate of 0.5ml/min,
(2) an alkaline eluent of acetonitrile/0.01 mol of aqueous sodium hydroxide solution of 50/50 was passed through the same column at a column temperature of 40 ℃ for 4 hours at a flow rate of 0.5ml/min, then an eluent of acetonitrile/0.1% aqueous phosphoric acid solution of 30/70 was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and pyridine retentivity was measured by using an eluent of acetonitrile/water of 30/70 at a flow rate of 0.5ml/min, and
(3) the pyridine retention of (2) was compared to the retention of (1).
6. The modified polymer particles with improved acid-base resistance of any one of claims 1 to 5, wherein the average particle size of the polymer particles is 1 to 50 μm.
7. A polymer-based packing material for chromatography, which uses modified polymer particles improved in acid-base resistance, wherein the polymer particles are obtained by treating polymer particles containing ester bonds with an acidic or basic aqueous solution to partially hydrolyze the ester bonds and separate carboxyl groups, and then blocking the free carboxyl groups by amidation.
8. The polymer-based packing material for chromatography according to claim 7, wherein the ester bond that has been hydrolyzed is an ester bond that is easily contacted with a liquid.
9. The polymer-based packing material for chromatography according to claim 7, wherein the amine used for amidation is an amine represented by formula (1):
NHR1R2(1)
wherein R is1And R2Each independently represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group.
10. The polymer-based packing material for chromatography according to claim 9, wherein the amine used for amidation is an amine represented by formula (2):
NH2R3(2)
wherein R is3Represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group.
11. A polymer-based packing material for chromatography, which uses modified polymer particles improved in acid-alkali resistance, so that when the polymer particles are packed in a column having an inner diameter of 4.6mm and a length of 150mm and the alkali resistance is evaluated using the column by the following method, the percentage of increase in pyridine retention after passing an alkali eluent is 50% or less:
the evaluation method comprises the following steps:
(1) an eluent of acetonitrile/0.1% aqueous phosphoric acid solution (30/70) was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and the pyridine retentivity was measured by using an eluent of acetonitrile/water (30/70) at a flow rate of 0.5ml/min,
(2) an alkaline eluent of acetonitrile/0.01 mol of aqueous sodium hydroxide solution of 50/50 was passed through the same column at a column temperature of 40 ℃ for 4 hours at a flow rate of 0.5ml/min, then an eluent of acetonitrile/0.1% aqueous phosphoric acid solution of 30/70 was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and pyridine retentivity was measured by using an eluent of acetonitrile/water of 30/70 at a flow rate of 0.5ml/min, and
(3) the pyridine retention of (2) was compared to the retention of (1).
12. A polymer-based packing material for chromatography as claimed in any one of claims 7 to 11, wherein the average particlesize of the polymer particles is in the range of 1 to 50 μm.
13. A method for producing a modified polymer particle improved in acid-alkali resistance, which comprises treating a polymer particle containing an ester bond with an acidic or alkaline aqueous solution to partially hydrolyze the ester bond and separate the carboxyl group, and then blocking the free carboxyl group by amidation.
14. The method for producing modified polymer particles improved in acid-alkali resistance according to claim 13, wherein the ester bond that has been hydrolyzed is an ester bond that is easily contacted with a liquid.
15. The method for producing modified polymer particles improved in acid-alkali resistance according to claim 13, wherein the amine used for amidation is an amine represented by formula (1):
NHR1R2(1)
wherein R is1And R2Each independently represents a hydrogen atom, an alkyl group having a carbon number of 18 or less which may be branched or may be substituted with a halogen, or a phenyl group.
16. The method for producing modified polymer particles improved in acid-alkali resistance according to claim 15, wherein the amine used for amidation is an amine represented by formula (2):
NH2R3(2)
wherein R is3Represents a hydrogen atom, a carbon number of 18 or less which may be branched or substituted by halogenAn alkyl group, or a phenyl group.
17. The method for producing a modified polymer particle improved in acid-alkali resistance according to any one of claims 13 to 16, wherein when the polymer particle is packed in a column having an inner diameter of 4.6mm and a length of 150mm and the alkali resistance is evaluated using the column by the following method, the percentage of increase in pyridine retention after passing through an alkali eluent is 50% or less:
the evaluation method comprises the following steps:
(1) an eluent of acetonitrile/0.1% aqueous phosphoric acid solution (30/70) was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and the pyridine retentivity was measured by using an eluent of acetonitrile/water (30/70) at a flow rate of 0.5ml/min,
(2) an alkaline eluent of acetonitrile/0.01 mol of aqueous sodium hydroxide solution of 50/50 was passed through the same column at a column temperature of 40 ℃ for 4 hours at a flow rate of 0.5ml/min, then an eluent of acetonitrile/0.1% aqueous phosphoric acid solution of 30/70 was passed at a flow rate of 0.3ml/min for 30 minutes, the column temperature was set at 40 ℃, and pyridine retentivity was measured by using an eluent of acetonitrile/water of 30/70 at a flow rate of 0.5ml/min, and
(3) the pyridine retention of (2) was compared to the retention of (1).
18. The method for producing modified polymer particles improved in acid-alkali resistance according to any one of claims 13 to 16, wherein the average particle size of the polymer particles is from 1 to 50 μm.
19. A method for producing a polymer-based packing material for chromatography, comprising producing the polymer-based packing material for chromatography described in any one of 6 to 12 by performing hydrolysis treatment with one or both of acidic or basic aqueous solutions and blocking treatment by amidation in the case of packing the polymer-based packing material in a column.
20A column for chromatography using the polymer-based packing material for chromatography having improved acid-base resistance as described in any one of 6 to 12.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002265140A JP2004099790A (en) | 2002-09-11 | 2002-09-11 | Improved polymer particle, filler for chromatography, their production method and column for chromatography |
| JP265140/2002 | 2002-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1681852A true CN1681852A (en) | 2005-10-12 |
Family
ID=32264363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038215861A Pending CN1681852A (en) | 2002-09-11 | 2003-09-11 | Modified polymer particle, packing material and column for chromatography |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1537151A1 (en) |
| JP (1) | JP2004099790A (en) |
| KR (1) | KR20050052491A (en) |
| CN (1) | CN1681852A (en) |
| AU (1) | AU2003260961A1 (en) |
| CA (1) | CA2499605A1 (en) |
| WO (1) | WO2004024784A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541537A (en) * | 2016-03-28 | 2016-05-04 | 山东成泰化工有限公司 | Conditioning agent and method for adjusting heterogeneous reaction selectivity of C4 alkene |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5858026B2 (en) * | 1976-06-25 | 1983-12-23 | 昭和電工株式会社 | Packing material for chromatography and its manufacturing method |
| CS188619B1 (en) * | 1977-01-19 | 1979-03-30 | Jaromir Lukas | Polar polymere sorbent based on glycidylic esters for gas and liquid chromatography |
| US5059659A (en) * | 1987-05-29 | 1991-10-22 | Harry P. Gregor | Surface treatments to impart hydrophilicity |
| JPS6454004A (en) * | 1987-08-26 | 1989-03-01 | Hitachi Chemical Co Ltd | Production of anion exchanger |
| ATE119170T1 (en) * | 1988-11-23 | 1995-03-15 | Cytec Tech Corp | POROUS SURFACE HYDRATED SUBSTRATES MADE OF POLYACRYLNITRIL, SUCH AS PEARL DERIVATIVES, METHOD FOR THEIR PRODUCTION AND METHOD OF USE. |
| JP2986592B2 (en) * | 1990-09-07 | 1999-12-06 | 帝人株式会社 | Method for separating 24-position epimer of 24-hydroxycholesterol derivative |
-
2002
- 2002-09-11 JP JP2002265140A patent/JP2004099790A/en active Pending
-
2003
- 2003-09-11 AU AU2003260961A patent/AU2003260961A1/en not_active Abandoned
- 2003-09-11 KR KR1020057004093A patent/KR20050052491A/en not_active Application Discontinuation
- 2003-09-11 CN CNA038215861A patent/CN1681852A/en active Pending
- 2003-09-11 WO PCT/JP2003/011635 patent/WO2004024784A1/en not_active Application Discontinuation
- 2003-09-11 EP EP03795397A patent/EP1537151A1/en not_active Withdrawn
- 2003-09-11 CA CA002499605A patent/CA2499605A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541537A (en) * | 2016-03-28 | 2016-05-04 | 山东成泰化工有限公司 | Conditioning agent and method for adjusting heterogeneous reaction selectivity of C4 alkene |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1537151A1 (en) | 2005-06-08 |
| AU2003260961A1 (en) | 2004-04-30 |
| JP2004099790A (en) | 2004-04-02 |
| WO2004024784A1 (en) | 2004-03-25 |
| KR20050052491A (en) | 2005-06-02 |
| CA2499605A1 (en) | 2004-03-25 |
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