JP3029640B2 - Adsorbent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial application> The present invention relates to an advanced optics suitable for industrially producing an optically active substance, particularly by optical resolution of a racemic mixture by chromatography. The present invention relates to a novel optical resolution adsorbent having a resolution and a method for producing the same.

The present invention also relates to an adsorbent having high separation performance suitable for ion exchange, partition, adsorption, hydrophobicity, affinity and molecular exclusion chromatography, and separation of biopolymers and the like.

<Prior Art> Optical resolution, that is, a method of dividing a racemic mixture which is a mixture of optical enantiomers into respective optical enantiomers, is used in the pharmaceutical, agricultural, and food industries. And
The usual industrial resolution method involves converting a racemic mixture to a mixture of diastereomers and resolving the diastereomer mixture by differences in their physical properties. In addition to this method, a method of resolving a racemic mixture by chromatography has been actively studied in recent years.
Chromatographic separation methods include optically active adsorbents, for example, porous silica gel coated with cellulose derivatives such as cellulose triacetate, optically active poly (triphenylmethyl) methacrylate, or porous silica gel. A method is known in which a substance to which active polyacrylamide is bonded is used as a stationary phase (for example, Yoshio Okamoto Bunseki No. 2 (1990)
See page 96).

<Problems to be Solved by the Invention> The types of racemic mixtures that can be converted into diastereomeric mixtures and resolved by differences in their physical properties are limited.

In the method of separation by chromatography, the optically active adsorbent used as the stationary phase has a low concentration, amount, etc. of the racemic mixture solution that can be treated per unit volume of the adsorbent, which is sufficient for industrial use. It is hard to say that it has performance. Further, there is a problem in durability and ease of manufacture in industrial use.

An object of the present invention is to provide a novel adsorbent having high separation performance suitable for ion exchange, partition, adsorption, hydrophobicity, affinity and molecular exclusion chromatography, optical resolution, and separation of biopolymers and the like.

The present invention particularly in an adsorbent in which an optically active polymer is supported on a crosslinked polymer carrier, it is possible to improve the separation function of the supported optically active polymer component and increase the amount of the polymer supported, It is an object of the present invention to provide a novel adsorbent for optical resolution having a high resolution even under a high load of a racemic mixture.

<Means for Solving the Problems> First, to solve these problems, the present inventors have found that a crosslinked polymer obtained by grafting an optically active synthetic polyamino acid onto a crosslinked polymer carrier is adsorbed by optical resolution or the like. As an agent, it has been found that it has an unprecedented superior performance and has been proposed (see JP-B-63-53855).

Furthermore, the present inventors have conducted research on the adsorbent obtained by the above method, and as a result, the crosslinked polymer carrier obtained by the conventional method has a thick skin layer formed on its surface, and the skin layer has It has been found that it is desirable that such a skin layer be as absent as possible, as this will affect the loading of the polymer that can impart adsorption capacity. Then, by adjusting the type and amount of the diluent used at the time of polymerization of the crosslinked polymer carrier, it was found that there was no skin layer, or even if there was, a very thin carrier could be produced, and there was no skin layer thus obtained. It has been found that an adsorbent loaded with a polymer capable of imparting adsorption ability to a carrier exhibits high separation performance, and that the separation ability is not impaired even if more polymer is loaded depending on the application, and the present invention has been reached. did.

The present invention provides an adsorbent comprising a polymer capable of imparting adsorption ability supported on a crosslinked polymer carrier, wherein the carrier is a porous particle, the surface area of which is 1 to 2000 m ² / g, and the particle surface A crosslinked polymer having no or no more than 300 ° C skin layer.

 Hereinafter, the present invention will be described in detail.

In the present invention, the crosslinked polymer carrier is not particularly limited as long as it can support a polymer capable of imparting adsorption ability by graft polymerization or the like, and is appropriately selected from styrene (meth) acrylic crosslinked polymers. For example, chloromethylstyrene-styrene-divinylbenzene copolymer, acrylamide-methylenebisacrylamide copolymer,
Glycidyl (meth) acrylate-ethylene glycol di (meth) acrylate copolymer, vinylbenzyl glycidyl ether-divinylbenzene copolymer, vinylbenzyl glycidyl ether-ethylene glycol di (meth) acrylate copolymer, ethylene glycol di Examples include (meth) acrylate polymers, pt-butoxystyrene-divinylbenzene copolymers, and glycerin mono (meth) acrylate-divinylbenzene copolymers.

The degree of crosslinking of the crosslinked polymer carrier is usually 15% or more and 100% or more.
%, Preferably 20% or more and 99.5% or less.
The degree of crosslinking referred to here is represented by the weight ratio of the crosslinkable monomer to the total polymerizable monomer.

Further, in order to obtain an adsorbent having high separation ability, the physical structure of the crosslinked polymer carrier needs to be a porous type,
In particular, it has a surface area of 1 to 2000 m ² / g, and does not have a skin layer on the surface of the carrier or has a thickness of 300 mm or less. Further, a crosslinked polymer carrier without a skin layer is particularly preferable in order to increase the amount of the polymer capable of imparting the adsorptivity. Here, the thickness of the skin layer can be measured by observing the cross section of the dried crosslinked polymer particles with an electron microscope.

Specifically, for example, in an electron micrograph of a cross section of the crosslinked polymer particles, the thickness is determined by measuring and averaging five arbitrary thicknesses of the skin layer.

The skin layer referred to in the present invention is a dense layer whose surface is clearly different from the internal porous structure and can be discriminated by observation with an electron microscope.

The crosslinked polymer carrier having such a skin layer has a smooth surface that is clearly different from the porous structure when the particle surface is observed with a scanning electron microscope at a magnification of 100,000.

As a general method for producing a porous carrier, for example, by adding a suitable diluent to the monomer phase, by separating the polymer and diluent generated in the course of the polymerization by adding a suitable diluent to the porous polymer, A method of obtaining a porous carrier by carrying out polymerization by coexisting a linear polymer such as polystyrene, polymethylstyrene, and polymethyl acrylate in the monomer phase, and then extracting and removing the linear polymer from the resulting spherical gel. And the like.

In general, when a porous cross-linked polymer carrier is produced by suspension polymerization, the skin layer is also formed depending on the nature of the dispersion bath and the type of dispersion stabilizer, but in the course of polymerization, a polymer formed and a diluent When the phase separation between the polymer and the polymer is remarkable, or when the linear polymer is allowed to coexist with the monomer phase for polymerization, the polymer is formed when the concentration of the linear polymer causing the phase separation with the polymer is high in the monomer phase. Often formed on the surface of a porous carrier.

Therefore, in the present invention, as the diluent and the linear polymer to be added when the crosslinked polymer is produced, a substance having good compatibility with the produced crosslinked polymer is selected as long as the produced crosslinked polymer is made porous, or these diluents are used. When the linear polymer uses a material having poor compatibility with the crosslinked copolymer, reduce the amount thereof or use another diluent having good compatibility in combination with the target porous material without a skin layer. A crosslinked polymer can be obtained.

For example, when a mixed solution of toluene and n-dodecane is used as a diluent in the production of a chloromethylstyrene-styrene-divinylbenzene copolymer, n-dodecane having a strong phase separation property with the produced polymer is used. When the ratio is high, a skin layer is formed. Further, when only n-dodecane is used as a diluent, the thickness of the skin layer further increases.

In addition, when a linear primary alcohol is used as a diluent in the production of a glycerin monomethacrylate-divinylbenzene copolymer, when the number of carbon atoms of the primary alcohol increases, the phase separation with the produced polymer occurs. Becomes stronger and the carbon number
Using 14 tetradecanol forms a skin layer.

In the case of an adsorbent in which a polymer capable of imparting adsorbability is supported on a crosslinked polymer carrier, in order to obtain a material having high separation performance, the carrier has no skin layer on the particle surface or has no skin layer. However, it is necessary to use carrier particles having a thickness of 300 mm or less. When using a carrier having a thick skin layer,
The polymer capable of imparting the adsorptivity is mainly supported only on the surface, and the separation performance is low. When the loading amount is increased by strictly increasing the reaction conditions, the polymer capable of imparting the adsorbing ability covers the surface of the carrier densely, the inside of the porous carrier is not used, the available effective surface area is reduced, and the separating ability is also remarkable. descend.

In the present invention, by using a carrier having no skin layer or having a very thin skin layer even if it is present, the polymer capable of imparting adsorption ability is uniformly carried on the surface and inside of the carrier, thereby increasing the amount of the carrier. In addition, high separation performance can be maintained.

The crosslinked polymer carrier used in the present invention is usually spherical, and by using crosslinked polymer particles having a narrower particle size distribution as the carrier, the adsorbent obtained by supporting a polymer capable of imparting adsorption ability also has a narrower particle size distribution. In particular, when used in a column chromatography method, a high theoretical plate number can be obtained, which is advantageous.

The size of the crosslinked polymer particles varies depending on the purpose of use, but usually a particle size of 1 to 1000 μm is selected.

As the polymer capable of imparting the adsorptivity, a polymer capable of being supported on a crosslinked polymer carrier is suitably used. In particular, examples of the optically active polymer include an optically active polyamino acid and a poly (meth) acrylamide having an optically active amino acid ester or an amine in a side chain. More specifically, poly (N ⁵ - benzyl -L- glutamine), poly (N-1-phenylethyl (meth) acrylamide) or poly (N- benzyl ethoxycarbonylmethyl) (meth) acrylamide), and the like Can be
The method of supporting a polymer or the like capable of imparting an adsorption ability on a crosslinked polymer carrier may be a chemical method or a physical method. As a physical method, a polymer or the like capable of imparting the adsorptive power is dissolved in a soluble solvent, mixed well with a carrier, and the solvent is distilled off by an air stream under reduced pressure or heating. Dissolvable polymer etc. in a soluble solvent,
After mixing well with a carrier, there is a method in which the solvent is stirred and dispersed in a liquid incompatible with the solvent, and the solvent is distilled off. The chemical method varies depending on the properties of the polymer or the like capable of imparting the adsorbing ability to be carried, but is appropriately determined from a method known per se. A method in which a polymer capable of imparting an adsorptive ability having a reactive functional group and a carrier having a group capable of reacting with the functional group are bonded by a polymer-polymer reaction, For example, a method of bonding a polymer capable of imparting the above by graft polymerization.

The supported amount of the polymer capable of imparting the adsorption ability supported on the crosslinked polymer carrier is preferably 5 to 70% by weight, particularly preferably 10 to 60% by weight.
% By weight is preferred. The amount supported here is represented by the weight ratio of the unit derived from the polymer capable of imparting the adsorptivity in the obtained adsorbent.

The polymer produced according to the above method is used as an adsorbent, and methods for evaluating adsorption performance prior to use include a batch method and a column chromatography method. When performing difficult separation such as separation of an optically active substance, it is preferable to perform evaluation by column chromatography.

Usually, the column chromatography method is performed in the following procedure. First, the adsorbent is suspended in the solvent used for elution,
Transfer the suspension to the column. The substance to be separated is dissolved in a small amount of solvent, this solution is injected into the upper part of the column, and then the eluate is passed through this column, and the eluate from the column is separated and collected by a conventional method. In the case of a racemic mixture, the degree of resolution of the racemate can be determined by measuring the light intensity of each fraction.

The adsorbent of the present invention is ion exchange, partition, adsorption, hydrophobic,
It has a high degree of separation performance suitable for affinity and molecular exclusion chromatography, optical resolution, and separation of biopolymers and the like.

In particular, when the adsorbent of the present invention is used for optical resolution, it is possible to efficiently resolve many types of racemic mixtures, and particularly to process a highly concentrated racemic mixture solution. Further, it is possible to treat a larger amount of the racemic mixture at a time than the conventional one per unit volume of the adsorbent.
It is also suitably used for separating and removing an optical antipode partially mixed as an impurity in the optically active substance.

When the racemic mixture is separated into the optically active enantiomers using the adsorbent of the present invention, there are a batch method and a column chromatography method, but it is usually advantageous to use column chromatography.

The separation method by column chromatography is the same as the method described as the evaluation method. At this time, the solvent used for column packing and elution varies depending on the type of the compound to be separated and the type of the adsorbent, but there is no particular limitation except for the solvent that dissolves or reacts with the adsorbent. In particular, in the case of optical resolution, the solvent is generally selected from solvents that sufficiently dissolve the target compound and swell the adsorbent. Specific examples of such a solvent include aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether, dioxane, tetrahydrofuran and t-butyl methyl ether, and halogenated hydrocarbons such as dichloroethane, trichloromethane and carbon tetrachloride. Hydrogen and the like can be used, and these can be used alone or in combination. In addition, solvents that do not swell the adsorbent, for example, hydrocarbons such as pentane and hexane, alcohols such as ethanol and 2-propanol, and water are also used by partially mixing with the organic solvent that swells the adsorbent. I can do it.

<Action> In an adsorbent comprising a polymer capable of imparting adsorption ability to a crosslinked polymer carrier, the surface area of the carrier is 1 to 2000 m ^2.
By using carrier particles having a thickness of 300 mm / g and no or no skin layer on the particle surface, the resulting adsorbent can be used for ion exchange, distribution, adsorption, hydrophobicity, affinity and molecular exclusion chromatography. Graphy, optical resolution,
And separation of biopolymers and the like.

In particular, the resulting adsorbent has a high resolving power and exhibits a high optical resolving power even when the racemic mixture is under a high load. Therefore, the use of the adsorbent according to the present invention enables industrialization of optical resolution of a racemic mixture by chromatography.

<Examples> The present invention will be specifically described with reference to the following examples and application examples, but the present invention is not limited only to these examples and application examples.

Example 1 A solution prepared by adding 0.5 g of chloromethylstyrene, 99.5 g of 55% divinylbenzene (crosslinking agent) and 1.67 g of benzoyl peroxide to 100 g of toluene and 50 g of n-dodecane as a diluent was used for 7.5 g of polyvinyl alcohol and 750 g of water. Was added to the solution. This mixture was stirred for 30 minutes at 2000 rpm, and then stirred at 80 ° C. for 8 hours under a nitrogen stream at about 150 rpm for suspension polymerization. The resulting crosslinked polymer was filtered, washed with deionized water, acetone, toluene and methanol, and dried under reduced pressure at about 80 ° C. The obtained crosslinked polymer was spherical particles insoluble in ordinary organic solvents. This product has a surface area of 551 m ² / g measured by the nitrogen adsorption method using Micromeritics Flowsorb 2300,
It was a porous crosslinked polymer having a pore volume of 1.47 ml / g as measured by a mercury intrusion method using an Audpore 9200 manufactured by Micromeritics Company.

Next, a scanning electron microscope observation was performed to examine the surface structure of the crosslinked polymer particles. The surface vapor deposition was performed for about 25 seconds at a voltage of 1.4 kV and a current of 6 mA for about 25 seconds using an Au (60%)-Pd (40%) target using an ion coater 1B-3 manufactured by Eiko Engineering Co., Ltd. The scanning electron microscope used Hitachi S-900. Observation at a magnification of 100,000 revealed that the product was porous up to the particle surface and had no skin layer, as shown in FIG.

Next, 54 g of 2-ethylhexanol was added to 12.0 g of the crosslinked polymer, and the mixture was stirred in an ultrasonic washer at about 300 rpm for about 30 minutes to form a slurry solution. 9.14 g of hexamethylene diamine was added to the slurry solution, and 90
The mixture was stirred at 150 ° C. for 4 hours at 150 ° C. to convert a chloromethyl group in the crosslinked polymer into an N- (aminohexyl) aminomethyl group. After the reaction, the crosslinked polymer is filtered,
After sequentially washing with acetone, 0.1N-hydrochloric acid, deionized water, 0.1N-sodium hydroxide aqueous solution, deionized water and methanol, the resultant was dried under reduced pressure at 80 ° C for 8 hours. The nitrogen content of this product was 0.120% by weight.

10 g of the obtained aminated crosslinked polymer carrier was dispersed in a solution of 3.44 g of L-glutamic acid-γ-methyl ester-N-carboxylic anhydride (hereinafter referred to as γ-MLG-NCA) and 161.3 ml of dichloroethane (hereinafter referred to as EDC). , 10 at 25 ° C
After stirring for an hour, the mixture was further stirred at 30 ° C. for 20 hours to polymerize NCA.

After the polymerization reaction, 12.6 g of ethylene chlorohydrin and 0.7% of concentrated sulfuric acid as a catalyst were added to the crosslinked polymer dispersion carrying poly (γ-methyl-L-glutamate) (hereinafter referred to as PMLG).
1 g was added, and the mixture was stirred at 60 ° C. for 3 hours. Then, the reaction system was depressurized, and the mixture was further stirred for 4 hours while distilling off methanol to be purified by the reaction together with the solvent, to thereby carry out a transesterification reaction. After the reaction, the cross-linked polymer supported by poly (γ-2-chloroethyl-L-glutamate) (hereinafter referred to as PCIEG) was filtered, washed with EDC, acetone, methanol and water in that order, and dried under reduced pressure.

10.0 g of the PCIEG-supported crosslinked polymer was added to benzylamine 60.0.
The mixture was dispersed at 60 ° C. and stirred at 60 ° C. for 30 hours to perform aminolysis. After the reaction, the crosslinked polymer supported by poly (γ-N-benzyl-L-glutamine) (hereinafter referred to as PBLGN) was filtered, washed with methanol and acetone in that order, and purified. In the infrared absorption spectrum, the absorption of the ester around 1740 cm ^-1 disappeared, and the absorption of the amide around 1650 cm ^-1 increased, indicating that the ester of the polyamino acid side chain was converted to benzylamide.

10.0 g of the PBLGN-supported crosslinked polymer was 70.0 ml of dioxane,
It was dispersed in a solution of 10.0 g of acetic anhydride and stirred at 30 ° C. for 24 hours to protect the terminal amino group with an acetyl group. After the reaction, the polyamino acid-supported crosslinked polymer in which the terminal amino group was protected was filtered, washed with dioxane, acetone and methanol in that order and purified. Its elemental analysis values were as follows.

C: 82.67 (%) H: 7.68 N: 3.05 From the nitrogen content, the supported amount of polyamino acid is 23.1% by weight
It is estimated to be.

Example 2 A crosslinked polymer was synthesized and isolated in the same manner as in Example 1 except that 80% divinylbenzene was used instead of 55% divinylbenzene as a crosslinking agent. The surface area of this crosslinked polymer was 609 m ² / g, and the pore volume was 1.68 ml / g. In addition, observation with a scanning electron microscope at a magnification of 100,000 revealed that there was no skin layer on the particle surface (FIG. 2).

Using this crosslinked polymer, a polyamino acid-supported crosslinked polymer was synthesized in the same manner as in Example 1 below. Its elemental analysis values were as follows.

C: 82.56 (%) H: 7.52 N: 3.02 From the nitrogen content, the supported amount of polyamino acid is 22.9% by weight
It is estimated to be.

Example 3 A crosslinked polymer was synthesized and isolated in the same manner as in Example 1 except that 75 g of toluene and 75 g of n-dodecane were used as diluents.

The surface area of the crosslinked polymer was 459 m ² / g, and the pore volume was 1.61 ml / g. The absence of a skin layer on the surface was confirmed by observation with a scanning electron microscope.

Using the crosslinked polymer, a polyamino acid-supported crosslinked polymer was synthesized in the same manner as in Example 1. Its elemental analysis values were as follows.

C: 82.66 (%) H: 7.58 N: 2.68 Based on the nitrogen content, the supported amount of polyamino acid is 20.3% by weight
It is estimated to be.

Example 4 55% divinylbenzene was used in place of 80% divinylbenzene as a crosslinking agent, and 75 g of toluene was used as a diluent.
A crosslinked polymer was synthesized and isolated in the same manner as in Example 1 except for using 75 g of dodecane. The surface area of this crosslinked polymer was 488 m ² / g. Further, the absence of a skin layer on the surface was confirmed by observation with a scanning electron microscope at a magnification of 100,000.

Using this crosslinked polymer, a polyamino acid-supported crosslinked polymer was synthesized in the same manner as in Example 1. Its elemental analysis values were as follows.

C: 83.86 (%) H: 7.66 N: 2.45 From the nitrogen content, the loading amount of the polyamino acid is estimated to be 18.56% by weight.

Example 5 A solution obtained by adding 100 g of toluene and 50 g of n-dodecane as a diluent to 1.0 g of chloromethylstyrene, 99 g of 80% divinylbenzene (crosslinking agent) and 1.67 g of benzoyl peroxide was added to 7.5 g of polyvinyl alcohol and 750 g of water. Added to the solution. This mixture was dispersed and polymerized in the same manner as in Example 1 to synthesize and isolate a crosslinked polymer. The surface area of this crosslinked polymer was 431 m ² / g. Further, the absence of a skin layer on the surface was confirmed by observation with a scanning electron microscope at a magnification of 100,000.

Further, 12.0 g of the obtained crosslinked polymer was aminated in the same manner as in Example 1. The nitrogen content of this product was 0.090% by weight.

9.0 g of the obtained aminated crosslinked polymer carrier was used in γ-MLG-N
After dispersing in a solution of 6.67 g of CA and 188.0 ml of EDC and stirring at 25 ° C. for 10 hours, the mixture was further stirred at 30 ° C. for 20 hours to polymerize NCA. After the polymerization reaction, the PMLG-supported crosslinked polymer dispersion was sequentially reacted in the same manner as in Example 1 to obtain a polyamino acid-supported crosslinked polymer. Its elemental analysis values were as follows.

C: 78.26 (%) H: 7.33 N: 4.87 Based on the nitrogen content, the supported amount of polyamino acid was 36.9% by weight
It is estimated to be.

Example 6 9.0 g of the aminated crosslinked polymer carrier obtained in Example 5 was dispersed in a solution of 12.39 g of γ-MLG-NCA and 256.6 ml of EDC, and the dispersion was performed at 25 ° C.
After stirring for 10 hours at
A was polymerized.

After the polymerization reaction, the PMLG-supported crosslinked polymer dispersion was sequentially reacted in the same manner as in Example 1 to obtain a polyamino acid-supported crosslinked polymer. Its elemental analysis values were as follows.

C: 75.99 (%) H: 7.18 N: 6.25 Based on the nitrogen content, the supported amount of polyamino acid is 47.4% by weight.
It is estimated to be.

Example 7 A solution obtained by adding 75 g of toluene and 75 g of n-dodecane as a diluent to 1.0 g of chloromethylstyrene, 99 g of 80% divinylbenzene (crosslinking agent) and 1.67 g of benzoyl peroxide was added to 7.5 g of polyvinyl alcohol and 750 g of water. Added to the solution. This mixture was dispersed and polymerized in the same manner as in Example 1,
A crosslinked polymer was synthesized and isolated. The surface area of this crosslinked polymer was 431 m ² / g. Further, the absence of a skin layer on the surface was confirmed by observation with a scanning electron microscope at a magnification of 100,000.

Further, 12.0 g of the obtained crosslinked polymer was aminated in the same manner as in Example 1. The nitrogen content of this product was 0.040% by weight.

The obtained aminated crosslinked polymer carrier was converted into a PMLG-supported crosslinked polymer in the same manner as in Example 6, and then reacted sequentially to obtain a polyamino acid-supported crosslinked polymer. Its elemental analysis values were as follows.

C: 76.90 (%) H: 7.19 N: 5.99 Based on the nitrogen content, the loading amount of the polyamino acid is estimated to be 46.7%.

Example 8 A solution of 1.0 g of chloromethylstyrene, 99 g of 80% divinylbenzene (crosslinking agent) and 1.67 g of benzoyl peroxide and 50 g of toluene and 100 g of n-dodecane as a diluent was added to 7.5 g of polyvinyl alcohol and 750 g of water. Added to the solution. This mixture was dispersed and polymerized in the same manner as in Example 1,
A crosslinked polymer was synthesized and isolated. The surface area of this crosslinked polymer was 400 m ² / g, and the pore volume was 1.61 ml / g.

Next, in order to examine the surface structure of the crosslinked polymer particles, a magnification using a scanning electron microscope was performed in the same manner as in Example 1.
Observation of the surface at a magnification of 100,000 times (Fig. 3) and a cross section of the particles using a transmission electron microscope H-9000 made by Hitachi, Ltd.
(Figure 5) and 78000 (Figure 5). As a result, the thickness of the skin layer was 200 to 300 mm.

Further, 12.0 g of the obtained crosslinked polymer was aminated in the same manner as in Example 1. The nitrogen content of this product was 0.040% by weight.

The obtained aminated crosslinked polymer carrier was converted into a PMLG-supported crosslinked polymer in the same manner as in Example 6, and then reacted sequentially to obtain a polyamino acid-supported crosslinked polymer. Its elemental analysis values were as follows.

C: 81.34 (%) H: 7.63 N: 3.30 From the nitrogen content, it is estimated that the loading amount of the polyamino acid is 25.% by weight.

Example 9 40.0 g of glycerin monomethacrylate, 60.0 g of 80% divinylbenzene (crosslinking agent), 1.6 g of benzoyl peroxide
7 g, a solution obtained by adding 150 g of n-octanol as a diluent, calcium chloride 225 g, polyvinyl alcohol 7.5 g,
Added to a solution of 750 g of water. After stirring the mixture at 1800 rpm for 30 minutes, the mixture was stirred at 80 ° C. for 8 hours under a nitrogen stream for about 15 hours.
The mixture was stirred at 0 revolutions / minute to perform suspension polymerization. The resulting crosslinked polymer was collected by filtration, washed with deionized water, acetone, toluene and methanol, and dried under reduced pressure at about 80 ° C. The obtained crosslinked polymer was spherical particles insoluble in ordinary organic solvents. The surface area of this crosslinked polymer is 278 m ² / g,
The pore volume was 1.30 ml / g. The absence of a skin layer on the surface was confirmed by observation with a scanning electron microscope.

8.0 g of the porous polymer particles was added to a solution of 8.0 g of (S) -N (1-phenylethyl) -methacrylamide monomer in 24.0 g of methyl ethyl ketone, and left at room temperature for 1 hour to impregnate the monomer. Then, it was dispersed in 100.8 g of water. Furthermore, in this polymer particle dispersion, 0.
After adding 12.6 ml of 5N-NHO ₃ aqueous solution, the mixture was heated to 50 ° C under nitrogen. Then, 12.6 ml of 0.05N- (NH ₄ ) ₂ Ce (NO ₂ ) ₆ aqueous solution was added, and the mixture was stirred for 6 hours at 150 rpm to carry out polymerization. Thereafter, 50 ml of a 1000 ppm methanol solution of 4-t-butylbenzoylcatechol (TBC) was added to terminate the polymerization. The produced polymer was collected by filtration, washed with hot water, methanol, acetone and toluene in that order and purified.

In the infrared absorption spectrum of the resulting polymer, absorption derived from an amide of the optically active polymer supported at around 1650 cm ^-1 was observed. Its elemental analysis values were as follows.

C: 75.54 (%) H: 7.65 N: 2.54 Calculated from the nitrogen content, the amount of the supported polyamide is estimated to be 34.3% by weight.

Application Example 1 The adsorbent produced in Example 1 was packed in a stainless steel column under the following conditions. A liquid pump LC-8A for high performance liquid chromatography manufactured by Shimadzu was used as a filling pump, and a large packer manufactured by Gas Chromo Corporation was used as a filling device.
The liquid was sent by a constant flow rate method.

Column: inner diameter 7.6 mm x height 500 mm Filling liquid: methanol Flow rate: 8 ml / min Temperature: room temperature This adsorbent was packed without any problems under the above packing conditions, and there was no problem of consolidation. Next, using this packed column, a racemic mixture of 5-isopropylhydantoin (hereinafter referred to as IPH) was subjected to optical resolution by a chromatography method. For liquid sending and detection, a semi-dispersed liquid chromatograph manufactured by Waters was used. Chromatography conditions are as follows.

Eluent: (1) (mixture of toluene / dioxane = 50/50 (volume ratio)) (2) (toluene / isopropanol = 80/2
(Mixture of 0 (volume ratio)) (3) (mixture of toluene / dioxane = 75/25 (weight ratio)) Flow rate: 1.0 ml / min Temperature: 10 ° C, 20 ° C (Application Example 9) Detection : Differential refractive index detector and light intensity detector Sample amount: 200 μl of 1.0% solution The results of optical resolution by chromatography of a racemic mixture of IPH are shown in Table 1.

 The retention capacity ratio and the separation coefficient in the table were calculated by the following equations.

T ⁺ : Retention time of (+) − IPH T ⁻ : Retention time of (−) − IPH T ₀ : Retention time of toluene When the separation coefficient α = 1, it indicates that there is no optical resolution, and it indicates that the optical resolution increases as the difference from 1 increases.

Application Examples 2 to 7 The adsorbents produced in Examples 2 to 4, 6 to 8 were packed in a stainless steel column under the same conditions as in Application Example 1, and divided.
Table 1 shows the results of the optical resolution of the racemic mixture of IPH.

Application Example 8 The adsorbent produced in Example 9 was packed in a stainless steel column under the same conditions as in Application Example 1, and divided. Table 2 shows the results of the optical resolution of the racemic mixture of 1,1'-binaphthol.

Comparative Example 1 A crosslinked polymer was synthesized and isolated in the same manner as in Example 1 except that 100 g of n-dodecane was used as a diluent.

The surface area of this crosslinked polymer was 222 m ² / g, and the pore volume was 0.53 ml / g.

The surface was observed at a magnification of 100,000 times with a scanning electron microscope, and it was found that there was a skin layer on the surface of the particles (No. 6).
Figure). Further, in the same manner as in Example 8, the cross section of the particles was observed with a transmission electron microscope at a magnification of 23,000 (FIG. 7) and a magnification of 78000.
Observation at 2: 1 (FIG. 8) revealed that there was a skin layer having a thickness of about 2000 mm on the surface.

Using this crosslinked polymer, a polyamino acid-supported crosslinked polymer was synthesized in the same manner as in Example 1.

Its elemental analysis values were as follows.

C: 83.81 (%) H: 8.07 N: 2.65 Based on the nitrogen content, the supported amount of polyamino acid is 20.1% by weight
It is estimated to be.

The adsorbent was filled under the same conditions as in Application Example 1. Next, the optical resolution of the racemic mixture of IPH was performed in the same manner as in Application Example 1, and the results are shown in Table 3. As a result, it can be seen that an adsorbent obtained by using a carrier having a thicker skin layer cannot obtain a material having high separation performance even when the amount of polyamino acid carried is 20% by weight.

<Effects of the Invention> By making the carrier surface area and the particle surface area of the present invention have no or extremely thin skin layer, high-performance adsorption separation can be performed, and ion exchange, distribution, adsorption, hydrophobicity, affinity, and molecular exclusion chromatography can be performed. It can be used for chromatography, optical resolution and separation of biopolymers and the like. In particular, in optical resolution, many kinds of racemic mixtures can be efficiently resolved, and particularly, a highly concentrated racemic mixture solution can be processed. In addition, it is possible to treat a large amount of the racemic mixture per unit volume of the adsorbent, and it is possible to separate and remove a trace amount of the optically active substance mixed in the optically active substance.

Since the adsorbent of the present invention has a high separation ability and a high optical resolution even under high load of the racemic mixture, it has an excellent effect that the optical resolution of the racemic mixture by chromatography can be industrialized. It is.

[Brief description of the drawings]

FIGS. 1 and 2 are scanning electron micrographs showing the particle structure of the crosslinked polymer carriers produced in Examples 1 and 2, respectively. 1 to 5 are transmission electron micrographs showing the particle structure of the crosslinked polymer carrier produced in Example 8. 6 to 8 are electron micrographs showing the particle structure of the crosslinked polymer carrier produced in Comparative Example 1.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07C 37/82 C07C 37/82 39/14 39/14 C07D 233/74 C07D 233/74 (72) Inventor Tsunehiko Kurata Yokohama, Kanagawa 1000 Kamoshita-cho, Midori-ku, Tokyo Mitsubishi Chemical Corporation Research Institute (56) References JP-A-63-77458 (JP, A) JP-A-58-12656 (JP, A) JP-A-1-254247 (JP, A) JP-A-1-199643 (JP, A)

Claims (1)

(57) [Claims] 1. An adsorbent comprising a styrene-based or (meth) acrylic-based crosslinked polymer carrier carrying a polymer capable of imparting adsorptivity, said carrier being porous particles having a surface area of 1 to 1. An adsorbent characterized by being a crosslinked polymer having a particle size of 2000 m ² / g and having no or no skin layer on the particle surface, but having a particle size of 300 mm or less.