JPH044017B2 - - Google Patents

Description

[Detailed description of the invention]

(a) Technical Field The present invention relates to a method for producing a novel adsorbent, particularly a polymer adsorbent made of a crosslinked polymer containing a structural unit of an amino acid having a specific amide group and having a high degree of selectivity. (b) Prior art and problems to be solved Optical resolution, that is, the separation of racemic mixtures into optical antipodes, is a very important technique in the pharmaceutical, agrochemical, food, and other industries. The usual method is to convert a racemic mixture into a mixture of diastereomers and separate the diastereomer mixtures based on their physical property differences, but the types of racemic mixtures that can be separated by this method are is limited. In addition to these conventional methods, techniques for resolving racemic mixtures by chromatography have recently been developed.
It is being actively researched. However, all of the ones that have been put to practical use use porous silica gel as a carrier, and they are no more than analytical tools and are not durable enough to withstand industrial use. Therefore, as of now, no method has been found that is satisfactory in terms of durability, price, ease of manufacture, etc., and therefore, it is difficult to apply such a method to the separation of racemates from an industrial and technical point of view. It is difficult to In order to solve these problems and provide a new polymer adsorbent, the present inventor conducted intensive research and developed a cross-linked polymer containing an optically active synthetic polyamino acid as a constituent component. However, we were able to provide an adsorbent with unprecedented performance as an adsorbent for optical resolution, etc. Due to the unique steric structure of the polyamino acid component and the asymmetric environment based thereon, this adsorbent can preferentially adsorb one side of the racemic mixture and perform optical resolution with high efficiency. In addition, as a result of further studies, the present inventor found that among the various types of adsorbents, those having an amide group in the side chain of the polyamic acid component are particularly effective for hydrogen bonding between the amide group and the separation target. It has already been discovered that racemic mixtures can be effectively optically resolved by such interactions. Based on these findings, the present inventors realized that in order to effectively perform optical resolution, it is necessary to introduce amide groups having various substituents suitable for the separation target into the side chains of polyamino acid components. It has arrived. One of the methods for introducing an amide group into the side chain of a polyamino acid is to introduce an amide group into the side chain of the aspartic acid or glutamic acid that constitutes the polyamino acid.

There is a method to make [Formula] (R′, R″ are H or organic groups). Regarding this method, two
There are three literatures, among which the simplest and most practical method is a method in which the benzyl ester of the side chain -COOH is aminolysed with an amine. Using this method, the present inventor succeeded in aminolysing poly(acidic amino acid benzyl ester) supported on a crosslinked polymer carrier with benzylamine and converting it into benzylamide.
59-44065, JP-A-60-193538). However, this method has the drawback that the reaction only proceeds with amines that have an affinity for the crosslinked polymer, such as benzylamine, and that the reaction rate becomes extremely slow if diluted with a solvent or the like during the reaction. have. Therefore, the above-mentioned method was not fully satisfactory because it was not possible to introduce amide groups having various substituents suitable for the separation target into the side chains of polyamino acids in crosslinked polymers. Furthermore, in the conventional method, it is not possible to use poly(γ-methyl-L-glutamate) obtained starting from industrially advantageous raw materials as the poly(acidic amino acid ω-ester) in the crosslinked polymer. However, when considering actual industrialization, it was not completely satisfactory. On the other hand, poly(γ-methyl-L-glutamate)
There is a report on a method for converting the side chain methyl ester of into an amide group using a homogeneous solution of the uncrosslinked polyamino acid itself as a raw material [Shin Okawara, Journal of the Chemical Society of Japan, Vol. 9, No. 1770]
Page (1973)]. However, as mentioned above, this method involves a reaction in a homogeneous solution of polyamino acids that are not crosslinked, and there is no description of polyamino acids in crosslinked polymers that are crosslinked and insolubilized in solvents. As mentioned above, there have been no reports on the aminolysis of polyamino acid esters in crosslinked polymers using conventionally known methods. There are no reports regarding its superiority. (c) Means for solving the problems An object of the present invention is to provide a novel method for producing an adsorbent that can solve the above-mentioned problems, and a novel adsorbent obtained by the method. As a result of extensive studies, the present inventor first replaced the side chain ester moiety of poly(acidic amino acid ω-ester) in the crosslinked polymer with one active ester,
Then, by performing aminolysis, aminolysis will proceed at a high reaction rate in the case of an amine that has an affinity for the crosslinked polymer, and aminolysis will proceed easily even in the case of an aliphatic amine that does not have an affinity for the crosslinked polymer. It was discovered that an amide group could be introduced, leading to the present invention. As a result, they discovered that it is possible to produce various adsorbents having an amide group attached to a substituent suitable for the separation target in the side chain of a polyamino acid. The present invention has been made based on the above findings, and includes a general formula whose main constituent unit is an optically active acidic amino acid ω-ester, (In the formula, n is an integer of 5 or more, R is an organic group having an ester group at the end, and R' is H or an alkyl group.) amino acid omega
- The terminal ester in R of the ester constitutional unit is first converted into an active ester, and then the ester is amidated by aminolysis, in which R
The present invention relates to a method for producing an adsorbent characterized by introducing an amide group into the adsorbent. Examples of the optically active acidic amino acid ω-ester, which is the main structural unit of the synthetic polyamino acid that is a component of the adsorbent of the present invention, include β- or γ-esters of aspartic acid or glutamic acid. Specific examples of esters include esters substituted with methyl groups, ethyl groups, propyl groups, butyl groups, benzyl groups, etc., but any ester can be used as long as it can be easily transesterified. good. The adsorbent of the present invention can contain an amino acid other than the acidic amino acid ω-ester as a constituent unit. The composition ratio of acidic amino acid ω-ester and other amino acids is 0.5 to 1.0. Synthetic polyamino acid constituent units other than the above-mentioned acidic amino acid ω-esters include optically active amino acids constituting proteins, such as D- or L-forms of protein-constituting amino acids such as alanine, valine, leucine, phenylalanine, and proline. , optically active α-aminocarboxylic acids (e.g. sarcosine) other than amino acids constituting proteins and derivatives thereof are used. In the constituent components of the above general formula, n is 4 or more and generally 100 or less, but especially 10 to
40 is preferred. The active ester in the present invention refers to an ester bond that can be easily aminolysed with an amine and converted into an amide bond, and has activated reactivity toward aminolysis reaction compared to a normal ester bond. This refers to a high ester bond. Specific examples of these include aliphatic or aromatic esters having electron-withdrawing groups such as halogen, nitrile, and nitro, as described below. The excellent substrate selectivity of the adsorbent of the present invention is derived from its constituent optically active synthetic polyamino acids and/or derivatives thereof.
The other constituent components may be any polymer as long as they are polymers. However, the present adsorbent is required to swell in the solvent used in the adsorption operation. That is, when water is used as a solvent, it is preferable to use a hydrophilic polymer, and when an organic compound such as benzene or toluene is used as a solvent, a hydrophobic polymer is preferably used as a constituent other than the polyamino acid. The synthetic polyamino acid component constituting the adsorbent of the present invention and other components may be bonded in any manner as long as the bonded product is a crosslinked polymer. Typical examples thereof include those in which a polyamino acid component is graft-bonded to a crosslinked polymer carrier, or those in which the polyamino acid component itself constitutes a crosslinking portion. For polyamino acid components linked at one end,
Preferable results may be obtained by protecting the other unbonded end with a protecting group. In this case, a protective group that is chemically stable and difficult to eliminate is preferred. The molecular weight, crosslinking density, etc. of the crosslinked polymer that is the adsorbent of the present invention can be selected as appropriate depending on the object to be adsorbed, and the ratio of the synthetic polyamino acid component in the adsorbent can also be selected as appropriate;
%, preferably 10-60%. The adsorption effect of the adsorbent of the present invention varies depending on the solvent system used as described above, but it also depends on the functional groups, stericity, etc. of the substance to be adsorbed. The type of amino acid, crosslinking density, etc. can be changed as appropriate. The adsorptivity of the adsorbent of the present invention can be adjusted by crosslinking density or porosity, and the crosslinking density can be changed as appropriate depending on the substance to be adsorbed, but in general, the crosslinking density tends to decrease as the molecular weight of the substance to be adsorbed increases. There is. Further, the adsorbent of the present invention can be made porous by using a diluent or the like as described later. The crosslink density of the adsorbent of the present invention changes depending on whether or not it is made porous, but the crosslink density when it is not made porous is
The crosslinking density is 0.01 to 50%, preferably 0.5 to 10%, and the crosslinking density in the case of making it porous is 0.1 to 100%, preferably 5 to 30%. The crosslinked polymer containing as a constituent a synthetic polyamino acid having an optically active acidic amino acid ω-ester as a main constituent unit of the present invention can be produced, for example, by the following known method. First, the general formula (In the formula, R is an organic group having an ester group at the end,
R' is H or an alkyl group) N-carboxy anhydride (hereinafter referred to as NCA) of an optically active acidic amino acid ω-ester or a mixture of the acidic amino acid ω-ester and another amino acid is Synthesize by method.
Details of this method are described, for example, in M. Goodman, Biopolymers, Vol. 15, p. 1869 (1976). Next, a crosslinked polymer carrier having a functional group convertible into an amino group or into which an amino group can be introduced is produced by a known method, and the functional group is converted into an amino group or an amino group is introduced. The above NCA is polymerized using the carrier having an amino group as an initiator to obtain a crosslinked polymer in which an optically active synthetic polyamino acid is supported on the carrier. As a crosslinked polymer carrier having a functional group that can be converted into an amino group or into which an amino group can be introduced,
Examples include chloromethylstyrene-styrene-divinylbenzene copolymer, acrylamide-methylenebisacrylamide copolymer, etc., but in short, monomers having a functional group convertible to an amino group such as chloromethylstyrene, or Any crosslinked polymer may be used as long as it is polymerized using as a monomer component a monomer having a functional group into which an amino group can be introduced, such as cidyl methacrylate. Suspension polymerization of these copolymers is carried out, for example, by the following method. First, the reaction raw material is dissolved in an inert organic solvent, preferably an aromatic hydrocarbon such as benzene or toluene, an aliphatic hydrocarbon such as n-octane, or an alcohol such as cyclohexanol or lauryl alcohol. The amount of organic solvent should be 1 if the monomer can be completely dissolved.
It is particularly advantageous to use 1 part by weight of solvent per part by weight of reaction raw materials, but generally 0 to 3 parts by weight of solvent are used. This reaction solution is a protective colloid aqueous solution, especially a polyvinyl alcohol aqueous solution,
For example, for 1 part by weight of this reaction solution, 2 to 25
Parts by weight of the aqueous solution are used and mixed well with an efficient stirrer. This stirred mixture was heated under an atmosphere of non-reactive gas, especially nitrogen, for about 40 minutes.
Heat to between 100°C and 100°C, preferably about 70°C. Polymerization time is about 4 hours to 72 hours, preferably about 10 hours. In this case, a porous spherical gel can be obtained by adding a suitable diluent to the monomer phase.
As for the type of diluent, organic solvents that have low swelling properties for the resulting gel are suitable. For example, in the case of a chloromethylstyrene-styrene-divinylbenzene copolymer, octane, decane, dodecane, etc. are preferred. Alternatively, instead of a diluent, a linear polymer such as polystyrene, polymethylstyrene, polymethyl acrylate, etc. may be present in the coexistence for polymerization, and then the linear polymer may be extracted and removed from the resulting spherical gel to form a porous spherical gel. can. Porous formation is applied to materials with low or high crosslinking density, but is generally applied to materials with high crosslinking density. This is preferable because it facilitates contact with the group. Further, those having a high degree of crosslinking are very preferable because they have little swelling and shrinkage and have high mechanical strength, and are particularly preferable in the case of chromatography. Conversion reaction of functional groups in the copolymer to amino groups,
Further, details of the amino group introduction reaction are described, for example, in R.B. Merrifield, Journal of the American Chemical Society (JACS), Vol. 98, p. 7357 (1976). After washing, the obtained crosslinked polymer carrier having amino groups is completely dehydrated by Soxhlet extraction or the like, and thoroughly dried under heating and reduced pressure. The type of amino group that initiates the polymerization of NCA is usually a primary or secondary amino group.
When a primary amino group is used as an initiator, it is particularly preferable because the polyamino acid can be supported quantitatively. Next, the acidic amino acid side chain ester in the crosslinked polymer containing as a constituent component the synthetic polyamino acid whose main constituent unit is the optically active acidic amino acid ω-ester obtained by the above method is converted into an active ester. , then shows how to aminolyse. Conversion to active esters involves converting the crosslinked polymer into 2
Swell with ~20 times the amount of solvent, then add an alcohol with an electron-withdrawing group and an acidic catalyst,
This can be done by heating to ℃ and reacting for 10 to 40 hours. In this case, the reaction can be promoted by reducing the pressure in the reaction system and distilling off the alcohol produced by the reaction together with the solvent. Examples of the solvent include benzene, toluene, methylene chloride, chloroform, dichloroethane, dioxane, acetonitrile, benzonitrile, etc., and it is desirable to dehydrate and purify it before use. Examples of alcohols having an electron-withdrawing group include:
Examples include ethylene chlorohydrin, ethylene cyanohydrin, 2-fluoroethanol, 2,2,2-trifluoroethanol, 2,2,2-trichloroethanol, and the like. Generally, active esters are more susceptible to aminolysis as their substituents have higher electron-withdrawing properties. That is, 2,2,2-trichloroethyl ester has much higher reactivity than monochloroethyl ester. However, the inventors have found that polyamino acid side chain esters in crosslinked polymers are more affected by steric effects than electronic effects. Therefore, active esters having substituents that are not sterically noble and have high electron-withdrawing properties to some extent are preferred. Examples of the acidic solvent used in the transesterification reaction include concentrated sulfuric acid and p-toluenesulfonic acid. The reaction product can be easily removed from the reaction system by filtration and purified by washing with a solvent. Progress of the reaction is confirmed by the fact that the absorption of the ester shifts to the higher wavenumber side in the infrared absorption spectrum of the product, or by the observation of the absorption of nitrile at 2250 cm ^-1 in the case of cyanoethyl ester. The reaction rate is determined from the nitrogen content or halogen content by elemental analysis. The thus obtained active ester is converted into an amide group by aminolysis using various amines in the following manner. First, the active esterified crosslinked polymer is swollen with 2 to 20 times the amount of solvent, and then a desired amine is added and reacted at 20 to 80°C for 10 to 40 hours. In addition, in this case, the amine may be used as a reaction reagent and a solvent. Particularly when the amine has an affinity for crosslinked polymers, it is a preferred method to use the amine as both a reaction reagent and a solvent. The inventors of the present invention have found that in this reaction, the reactivity or the degree of occurrence of side reactions is completely different depending on the type of solvent. Namely, toluene, dioxane,
The reaction is extremely difficult to proceed in solvents such as acetonitrile and dichloroethane, and conversely, the reaction proceeds easily in aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. I found out. In particular, in order to suppress side reactions such as cleavage of the main chain of polyamino acids, it has been found that a solvent that is difficult to decompose such as N,N-dimethylacetamide is one of the particularly preferable solvents. The amines that can be used include various primary or secondary amines, such as linear alkylamines such as ethylamine and n-butylamine, branched alkylamines such as isopropylamine and t-butylamine, and cyclic alkylamines such as cyclohexylamine. Primary amines such as alkylamines having an aromatic ring such as alkylamines, benzylamine, p-hydroxybenzylamine, α-phenylethylamine, secondary amines such as diethylamine, diisopropylamine, ethylenediamine, hexamethylene diamine, etc. , polyamines such as diethylenetriamine, and amines having functional groups such as monoethanolamine. As exemplified in the examples, even weakly basic or sterically noble amines react easily. Furthermore, in the method of the present invention, since the amine can be diluted with a solvent, the reaction can easily proceed with aliphatic amines that have little affinity with the crosslinked polymer carrier. The reaction temperature or reaction time is closely related to the basicity and steric grandeur of the amine used, and as the basicity increases and the steric grandeur decreases, the suitable reaction temperature becomes In addition, the reaction time becomes shorter. Reacting with a strongly basic amine at high temperature for a long period of time is not a preferable method because it only causes a side reaction of severing the main chain of the polyamino acid. The amidated crosslinked polymer obtained as described above can be easily taken out of the reaction system by filtration and purified by washing with a solvent. The progress of the reaction is determined by the infrared absorption spectrum of the product.
Absorption of esters near 1740 cm ^-1 decreases, and conversely
This is confirmed by the increase in amide absorption near 1650 cm ^-1 . Although the reaction rate cannot be determined accurately because a small amount of cleavage of the polyamino acid main chain occurs,
It can be estimated from the amount of decrease in ester absorption in the infrared spectrum or the nitrogen content determined by elemental analysis. (d) Effects of the Invention The method of the present invention makes it possible to introduce various substituents into the amide groups of polyamino acid side chains in crosslinked polymers, which was difficult to do with conventional methods, and makes it possible to introduce adsorbents suitable for the separation target. It became possible to provide
That is, the adsorbent obtained by the method of the present invention has hydrogen bonds between the polyamino acid side chain amide group in the crosslinked polymer and the object to be separated, and steric bonds between the substituents bonded to the amide and the object to be separated. By combining interactions such as obstacles, various mixtures can be efficiently separated and purified. In particular, when performing advanced separation such as optical resolution of racemic mixtures, it is necessary to manufacture an adsorbent in which a substituent suitable for the separation target is bonded to the amide group of the polyamino acid side chain. This method is extremely useful in such cases. Furthermore, by the method of the present invention, poly(γ-methyl-L-glutamate) obtained starting from γ-methyl-L-glutamate NCA, which is an industrially advantageous raw material, can be used as poly(acidic amino acid ω-ester) in a crosslinked polymer. Since it becomes possible to use L-glutamate), the present invention can provide an industrially extremely advantageous method. (e) Examples The present invention will be specifically explained in the following production examples and examples, but the present invention is not limited only to these examples. Example 1 2.0 g of chloromethylstyrene, 2.74 g of 55% divinylbenzene (crosslinking agent), 95.26 g of styrene, 75
Add a solution of 0.67 g of % dibenzoyl peroxide to a solution of 4.0 g of polyvinyl alcohol and 400 g of water,
The mixture was stirred at 1000 rpm for 10 hours at 70° C. under nitrogen to produce a copolymer of chloromethylstyrene-styrene-divinylbenzene copolymer. The crosslinked polymer was a translucent spherical gel. 85.8g of this crosslinked polymer was added to phthalimide potassium
After mixing 85.8 g with 686 ml of DMF and stirring at 120°C for 6 hours, the crosslinked polymer was taken out, washed and dried.
Next, the crosslinked polymer was mixed with 68.6 ml of hydrazine hydrate and 686 ml of dioxane, and after stirring at 90°C for 6 hours,
The crosslinked polymer in which chloromethyl groups were converted to aminomethyl groups was taken out, thoroughly washed, and completely dried.
The nitrogen content of this product was 0.17%. 81 g of the obtained gel-like crosslinked polymer carrier was dispersed in a solution of 32.4 g of β-benzyl-L-aspartate NCA and 648 ml of dioxane, and the mixture was heated at 35°C under nitrogen for 72 hours.
The mixture was stirred for an hour to polymerize NCA. When a part of the crosslinked polymer was isolated and analyzed after purification, the nitrogen content was found to be 1.81%, and the amount of poly(β-benzyl-L-aspartate) supported in the crosslinked polymer calculated from this value was 26.1%. and its degree of polymerization is
It was 12.4. After the polymerization reaction, 88.2 g of ethylene chlorohydrin and 3.5 g of 97% sulfuric acid as a catalyst were added to the crosslinked polymer dispersion, and the mixture was stirred at 60° C. for 10 hours to perform a transesterification reaction. After the reaction, the chloroethyl esterified crosslinked polymer was isolated, thoroughly washed, and completely dried. The elemental analysis values of this product were as follows. C: 82.25% H: 7.30% N: 1.71% Cl: 3.41% The reaction rate (conversion rate from benzyl ester to chloroethyl ester) calculated from the elemental analysis value (chlorine 3.41%) was 78.6%. Furthermore, the degree of polymerization of the chloroethyl esterified polyaspartic acid calculated from the nitrogen content (1.71%) is 11.7, which indicates that cleavage of the polyamino acid main chain hardly occurs. This chloroethyl esterified crosslinked polymer
40 g was dispersed in 320 ml of dioxane, 40 g of cyclohexylamine was added, and the mixture was stirred at 40°C for 24 hours, followed by isolation and purification. 1740 in the infrared absorption spectrum
The absorption peak of the ester in cm ^-1 decreases, 1640 ~
The amide absorption peak at 1660 cm ^-1 increased. The elemental analysis results were as follows: chlorine content decreased and nitrogen content increased. Elemental analysis values: C: 82.46% H: 7.38% N: 2.10% Cl: 2.45% The above results indicate that a portion of chloroethyl ester was partially converted to cyclohexylamide by aminolysis. The conversion rate calculated from elemental analysis values was about 23%. Thus, it can be seen that the method of the present invention makes it possible to produce an adsorbent having an amide group substituted with an alicyclic hydrocarbon in the side chain of the supported polyamino acid, which could not be obtained by conventional methods. Examples 2 to 12 4.74 g of chloromethylstyrene, 58.54 g of 55% divinylbenzene (crosslinking agent), 294.5 g of styrene, 75
A solution of 4.78 g of % dibenzoyl peroxide and 304.12 g of n-octane (diluent) was added to a solution of 20.0 g of polyvinyl alcohol and 2000 g of water. The mixture was stirred at 1000 rpm for 10 hours at 70° C. under nitrogen. The obtained crosslinked chloromethylstyrene-styrene-divinylbenzene copolymer was isolated in the same manner as in Production Example 1. The crosslinked polymer was a porous white spherical gel. A crosslinked polymer in which chloromethyl groups were converted to aminomethyl groups was obtained by the same method as in Production Example 1. The nitrogen content of this product was 0.12%. 223 g of the obtained porous crosslinked polymer carrier was mixed with γ-methyl-L.
-Glutamate NCA was dispersed in a solution of 69 g of NCA and 2007 ml of 1,2-dichloroethane and stirred under nitrogen at 30°C for 40 hours to polymerize NCA. When a part of the crosslinked polymer was isolated and analyzed after purification, the nitrogen content was found to be 2.03, and the content of poly(γ-methyl-L-glutamate) in the processed polymer calculated from this value was 19.7%. , and its degree of polymerization is 19.3
It was hot. After the polymerization reaction, 338 g of ethylene cyanohydrin, 223 g of dichloroethane, and 123 g of p-toluenesulfonic acid (monohydrate) as a catalyst were added to the crosslinked polymer dispersion, stirred at 60°C for 3 hours, and then the reaction system was depressurized. The mixture was further stirred for 6 hours while methanol produced by the reaction was distilled off together with the solvent to carry out a transesterification reaction. After the reaction, the cyanoethyl esterified crosslinked polymer was isolated, thoroughly washed, and completely dried. Since the yield after the reaction was slightly lower than the theoretical yield, it is estimated that about 10% of the supported polyamino acid main chain was cleaved as a side reaction during the reaction. The elemental analysis values of this product were as follows. C: 82.97% H: 7.39% N: 3.10% Based on the elemental analysis value (nitrogen 3.10%), the reaction rate (conversion rate from methyl ester to cyanoethyl ester) is estimated to be about 70%. Figure 1 shows the infrared absorption spectrum of this product, and characteristic absorption of nitrile groups is observed at 2250 cm ^-1 . The absorptions near 1650 cm ^-1 and 1550 cm ^-1 are characteristic absorptions of amides and amides based on supported polyamino acids. This cyanoethyl esterified crosslinked polymer was reacted with various amines in the same manner as in Example 1 to produce various adsorbents. The results are shown in Table 1. The progress of the reaction with the amine is indicated by the disappearance of the nitrile absorption at 2250 cm ^-1 in the infrared absorption spectrum.
This is determined by the decrease in ester absorption around 1740 cm ^-1 and the increase in amide absorption around 1650 cm ^-1 . Figure 2 shows the infrared absorption spectrum of the adsorbent obtained in Example 9, and it shows that nitrile absorption disappears, ester absorption decreases, amide absorption increases, and a wide range of hydroxyl absorption is observed around 3300 cm ^-1 . from,
It can be seen that an amide group having a hydroxyethyl group as a substituent is certainly introduced into the supported polyamino acid side chain. As described above, according to the method of the present invention, it is possible to produce various adsorbents suitable for separation targets, and the present invention

【table】

[Table] It can be seen that this method is a useful manufacturing method for adsorbents. Example 13 A crosslinked polymer having a supported amount of poly(γ-methyl-L-glutamate) of 30.5% and a degree of polymerization of 15.1 was produced in the same manner as in Example 2. Next, 18 g of the crosslinked polymer was dispersed in 180 ml of dichloroethane, and ethylene chlorohydrin was added.
Add 30.57 g and 1.94 g of 97% sulfuric acid as a catalyst,
The mixture was stirred at 60° C. for 3 hours, and then the reaction system was reduced in pressure and stirred for an additional 4 hours while methanol was distilled off to carry out a transesterification reaction. After the reaction, the chloroethyl esterified crosslinked polymer was isolated, thoroughly washed, and completely dried. The elemental analysis values of this product were as follows. C: 73.07% H: 6.94% N: 2.91% Cl: 7.00% From the elemental analysis values (chlorine 7.00%), it is estimated that transesterification proceeded almost quantitatively. 18g of this chloroethyl ester crosslinked polymer
Aminolysis was performed by dispersing the solution in 108 ml of benzylamine and stirring at 60°C for 30 hours. After the reaction, the product was isolated and purified, and its infrared absorption spectrum was measured. As a result, the ester absorption peak at 1740 cm ⁻¹ disappeared, and the amide absorption peak at 1640 to 1660 cm ¹ increased. The results of elemental analysis of this product are as follows. C: 80.34% H: 7.34% N: 5.15% Cl: 0.3% From the above results, it can be seen that the chloroethyl ester group was almost quantitatively converted into a benzylamide group by aminolysis. Thus, it can be seen that the method of the present invention makes it possible to quantitatively introduce amide groups into side acids of supported polyamino acids, which was difficult to do using conventional methods. Next, the obtained benzylamide crosslinked polymer
By dispersing 10 g in a solution of 60 ml of dioxane and 2 ml of acetic anhydride and stirring at 30°C for 24 hours, the amino group at the end of the unbonded main chain of the supported polyamino acid was protected with an acetyl group. . In order to evaluate the crosslinked polymer obtained in this way as an adsorbent for optical resolution, the inner diameter was 7.6 mm and the length was 50 mm.
was packed into a stainless steel column. Next, using this packed column, the resolving power of the adsorbent was evaluated by chromatography. Shimadzu LC for liquid delivery and detection
A type-4A liquid chromatography device was used.
The conditions for chromatography are as follows. Eluent: 3:2 toluene-dioxane mixture Flow rate: 0.5ml/min Temperature: 10°C Detection: Differential refractometer and optical rotation detector A racemic mixture of isopropylhydantoin (sample amount: 200μ of 1% solution) was evaluated. When the separation was carried out using
After a few minutes, the S-isomer with − optical rotation is eluted and completely R
It became clear that it can be divided into a body and an S body. Thus, it can be seen that the adsorbent of the present invention has an unprecedented optical resolution ability. Comparative Example 1 A crosslinked polymer having a supported amount of poly(γ-benzyl-L-glutamate) of 30.5% and a degree of polymerization of 15.1 was produced in exactly the same manner as in Example 13.
Next, without going through an active esterification reaction,
Aminolysis of the side chain benzyl ester was immediately performed with benzylamine, and the substitution rate was 70% after reacting at 60°C for 30 hours. When the reaction temperature was raised to further increase the substitution rate, the main chain of the polyamino acid was cleaved, resulting in a decrease in the amount of polyamino acid supported. Therefore, it was impossible to increase the substitution rate with this method. The benzylamidated crosslinked polymer obtained by this method was treated in exactly the same manner as in Example 13 to acetylate the terminal amino group of the supported polyamino acid. When the adsorbent thus obtained was packed into a column in exactly the same manner as in Example 13 and the racemic mixture of isopropylhydantoin was separated, a single elution curve with a peak top at 45 minutes was obtained. Although the R isomer and the S isomer were eluted at a late stage, complete resolution was not successful, and all of them were eluted as a mixture of the R and S isomers. As described above, it can be seen that the adsorbent of this comparative example obtained by the conventional method performs less efficient partitioning than the adsorbent of Example 13.

[Brief explanation of drawings]

Figure 1 shows the side chain ω of poly(γ-methyl-L-glutamate) supported on cross-linked polystyrene beads.
- This is an infrared absorption spectrum of a crosslinked polymer obtained by transesterifying an ester and converting it into a cyanoethyl ester. FIG. ,
This is an infrared absorption spectrum of an adsorbent into which an amide group having a 2-hydroxyethyl group as a substituent is introduced.

Claims (1)

[Claims] 1. A general formula containing an optically active acidic amino acid ω-ester as a main structural unit, (In the formula, n is an integer of 5 or more, R is an organic group having an ester group at the end, and R' is H or an alkyl group.) A method for producing an adsorbent, which comprises first converting the terminal ester in R of the amino acid ω-ester constituent unit into an active ester, then amidating the ester by aminolysis, and introducing an amide group into R in the formula. .