JPH0425503A - Production of cyclodextrin-immobilized polymer - Google Patents

Abstract

PURPOSE:To obtain the title polymer which is highly reactive even in a polymer reaction by converting cyclodextrin into monohydroxycyclodextrin and reacting it with an alpha,beta-unsaturated acid halide as a monomer. CONSTITUTION:One of the methylol groups of cyclodextrin is iodinated by, for example, reacting cyclodextrin with p-toluenesulfonyl chloride to tosylate one of the methylol groups and reacting it with potassium iodide. A protective group is introduced into the obtained derivative by reacting it with an alcohol acting as a protectiv group (e.g. benzyl alcohol) and the derivative is then etherified or esterified. The protective group is eliminated, and the obtained monohydroxycyclodextrin is reacted with an alpha,beta-unsaturated acid halide (e.g. methacryloyl chloride) as a monomer to obtain a cyclodextrin-immobilized polymer desirable as, e.g. a packing for chromatographic separation.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a method for producing a cyclodextrin-immobilized polymer, and more specifically, to a method for producing a cyclodextrin-immobilized polymer, and more specifically, to immobilize one unit of cyclodextrin per basic monomer unit. The present invention relates to a method for producing a cyclodextrin-immobilized polymer.

[Prior Art] Cyclodextrin contains 6 or more units of glucose α-1.
4-linked cyclic oligosaccharide with 6.7.8 glucose units
These are particularly well known, and there are many published documents regarding their applications. All of these application examples utilize the selective inclusion ability due to the fact that the inside of the cyclodextrin ring is hydrophobic and the size of this ring is determined by the amount of glucose units. It is used as a chemical agent, catalyst, or food additive, to mask off-flavors, to retain volatile substances, and to solubilize poorly soluble substances.

It is easy to predict that such selective inclusion ability would be an effective means for separating and extracting hydrophobic substances. It is difficult to separate the clathrate from the system and to separate the clathrate from the cyclodextrin.

If cyclodextrin is immobilized while retaining its inclusion ability, it can be packed into a column, and the components can be separated, recovered, and removed by adsorption, flam operation, or chromatography operation in the same way as ion exchange resins and activated carbon. can be easily done.

Therefore, various methods have been attempted to immobilize cyclodextrin, but the utilization rate of immobilized cyclodextrin is low, and the base polymer on which cyclodextrin is immobilized adsorbs hydrophobic substances. Furthermore, they were unsuitable for effective industrial use, as they had insufficient selectivity and required a great deal of cost to manufacture.

[Fill to be solved by the invention] For example, Japanese Patent Publication No. 55-2γ083, No. 55-4164
No. 3 and No. 5B-15806 each describe a method for producing a polystyrene polymer having a cyclodextrin derivative, and according to this method, one unit of the cyclodextrin derivative is always fixed to the styrene monomer. However, in the polymer reaction, the reactivity is low and the amount immobilized is not sufficient. Furthermore, in various publications such as JP-A-55-75402 and JP-A-63-314201, immobilization is carried out by subjecting a glycidyl group or its epoxy ring to a polymeric reaction with a cyclodextrin. In this method, in order to bind sufficient cyclodextrin to the parent body, the long FtrrR reaction must be carried out, and the cyclodextrin actually bound is only a part of the amount charged, and it is necessary to It was not possible to immobilize a single cyclodextrin, and there was an economical problem in utilizing the excellent inclusion ability of cyclodextrin for various purposes.

Therefore, the object of the present invention is to use an acid halide of an α,β unsaturated acid as a monomer, immobilize one unit of a cyclodextrin derivative on the monomer, and to provide a cyclodextrin that exhibits high reactivity in the polymer reaction. An object of the present invention is to provide a method for producing an immobilized polymer.

[f! ! Means for Solving li] The present inventors have solved the above l! As a result of intensive research in view of the above problems, the above object of the present invention is to react a cyclodextrin derivative obtained by iodizing one of the methylol groups of cyclodextrin with an alcohol serving as a protecting group, and to react the cyclodextrin derivative with an alcohol serving as a protecting group. The method is characterized in that the monohuman 0-oxycyclodextrin obtained by introducing a protecting group and then etherifying or esterifying it and then removing the protecting group is reacted with an acid oxygenated monomer of an α,β unsaturated acid. We have found that this can be achieved by a method for producing a cyclodextrin-immobilized polymer.

The present invention will be explained in more detail below.

The present invention relates to cyclodextrin (hereinafter abbreviated as CD)
Selectively iodinate only one of the methylol groups possessed by the molecule to introduce a protective group therein, then etherify or esterify the remaining hydroxyl groups, and then remove the protective group by elimination, etc. to obtain monohydroxy-CD,
By reacting this with an acid halide monomer of an α,β unsaturated acid, one unit of CD is added to the monomer.
A CD-immobilized polymer on which a derivative is immobilized is obtained.

In the present invention, as a method for selectively iodizing one of the methylol groups of CD, for example, CD is reacted with para-toluenesulfonic acid chloride to tosylate one of the methylol groups, and then reacted with potassium iodide or the like. A method of iodination is used.

In addition, as a compound used to introduce a protecting group into 1082 group of the obtained CD derivative, preferably benzyl alcohol or benzyloxyalkyl ether is mentioned, and among these, benzyloxyalkyl ether is as follows A compound represented by the formula is used.

Here, n is an integer of 2 to 10, preferably 2 to 5
is an integer.

As described above, after the protective group is introduced, esterification such as etherification, acetylation, benzoylation, etc. is performed to methylate the other remaining hydroxyl groups. Such etherification or esterification is carried out, for example, by reaction with methyl iodide, acetic anhydride, benzoyl chloride, or the like.

After this, in order to remove the protecting group to obtain a hydroxyl group,
Hydrogenation is carried out using Pd/C as a catalyst.

As a result, monohydroxy CD having one hydroxyl group is obtained.

Other compounds used to introduce a protecting group into the 10821 group of CD derivatives include the following compounds: CH, =CHC
H20H CH2=CHCH20-f-CH2i0HCH.

These can be introduced into CD derivatives by reacting with β-CD monoiodide in a NaH, DMF system.

Next, each of the above compounds (1), (2>, (3), (10) and 11) is etherified or esterified to block all remaining hydroxyl groups, and then the protective groups are removed as follows. It can be removed.

That is, water/ethanol system HgCl2 was used for (1) and (2), water/methanol system A (INO3) was used for (3), and (10) and (11)
The protecting group can be removed using (n-04H9)4N+F- in THF.

Also, compounds (4), (5), (6), (7).

After each of (8) and (9) is etherified to block all remaining hydroxyl groups, the protective group can be removed as follows. That is, (4) and (5
) for (6), (7), (8) and (9) using water/ethanol based Ts OH (toluenesulfonic acid).
), the protecting group can be removed using a chloroform/HCffi system.

In the present invention, such monohydroxy CD is
One unit of the cyclodextrin derivative can be immobilized on the monomer by reacting it with an acid halide monomer of a β-unsaturated acid. HMi compound or the like is used, and after reacting these monomers with monohydroxy-CD, a CD-immobilized polymer can be produced by polymerizing or copolymerizing with methyl methacrylate or the like. In addition, after synthesizing a copolymer containing the acid chloride in advance, the copolymer is reacted with monohydroxy-CD and C
A method of immobilizing D is also possible.

Furthermore, the CDs used in the present invention include α-CD, β-
Either CD, γ-CD, etc. can be used.

The method for synthesizing the CD-immobilized polymer of the present invention and specific synthesis examples of the production method of the present invention are listed below.

(Synthesis Example 1) β-CD is dissolved in pyridine at room temperature, and paratoluenesulfone chloride dissolved in pyridine is added dropwise thereto at 20°C. After completion of the dropwise addition, the mixture was stirred at room temperature for one day and night, and after the completion of the reaction, pyridine was distilled off under reduced pressure at 40° C. or below, and the residue was added to a large amount of acetone for reprecipitation. The precipitate is collected and purified by repeated recrystallization from water (yield: 25%). The obtained β
-CD monotosylate with Kl in DMF at 70-80°C
After the reaction was completed, DMF was distilled off under reduced pressure and the residue was reprecipitated from a large amount of acetone. The precipitate is purified by recrystallization from n-butanol/ethanol/water (yield:
60%).

Next, benzyl alcohol ((I)-CH20H) and NaH were reacted in DMF in a nitrogen atmosphere, and then β-CD monoiodide was reacted with DMF at room temperature.
Add the solution and then react at 70-80°C for 24 hours. After the reaction is completed, DMF is distilled off under reduced pressure, and the residue is reprecipitated from a large amount of acetone. The precipitate was collected and dried under reduced pressure. The obtained precipitate was dissolved in DMF, and NaH was added thereto for 3 hrs. at room temperature.
After reacting for an hour, methyl iodide is added at 0°C to methylate the hydroxyl groups. Note that methylation is performed in a dark room for 24 hours. After the reaction is completed, it is filtered, the filtrate is distilled off under reduced pressure, and the residue is extracted with a water/chloroform system. The chloroform layer is concentrated under reduced pressure, ethanol is added to the crude product to dissolve it, and reprecipitation is performed from a large amount of water. After filtering the obtained precipitate,
The linear reaction is purified by column chromatography to obtain monobenzyl-methyl β-CD (mono-6-benzyl-ber0-methyl β-CD) (yield near 5%).

The obtained target product was dissolved in ethanol, hydrogenated using Pd/C as a catalyst, and the solvent was concentrated under reduced pressure to obtain monohydroxy-methyl β-CD (mono-6-CD).
Hydroxy-ber0-methyl β-CD) is obtained (yield:
95%).

In the above case, monobenzyl-acetyl β-CD is obtained by dissolving monobenzyl β-CD (crude product) in pyridine and reacting with acetic anhydride, and monobenzylbenzoyl β-CD is obtained by reacting with benzoyl chloride. CD can be obtained (esterification).

Thereafter, hydrogenation is performed in the same manner to obtain a monohydroxy derivative.

(Synthesis Example 2) β-CD is dissolved in pyridine at room temperature, and paratoluenesulfonic acid chloride dissolved in pyridine is added dropwise thereto at 20°C. After completion of the dropwise addition, the mixture was stirred at room temperature for one day and night, and after the reaction was completed, pyridine was distilled off under reduced pressure at a temperature below 40°C, and the residue was added to a large amount of acetone for reprecipitation. The precipitate is collected and purified by repeated recrystallization from water (yield: 25%). The obtained β
-CD monotosylate with Kl in DMF at 70-80°C
After the reaction was completed, DMF was distilled off under reduced pressure and the residue was reprecipitated from a large amount of acetone. The precipitate is purified by recrystallization from n-butanol/ethanol/water (yield:
60%).

Next, add a DMF solution of Do in DMF, and then react at 70 to 80°C for 24 hours. After the reaction is completed, DMF- is distilled off under reduced pressure, and the residue is reprecipitated from a large amount of acetone. The precipitates were collected and dried under reduced pressure, and the obtained precipitates were dissolved in DMF, NaH was added thereto, and the mixture was allowed to react at room temperature for 3 hours. Then, methyl iodide was added at 0° C. to methylate the water II groups. Note that methylation is performed in a dark room for 24 hours. After the reaction is completed, it is filtered, the filtrate is distilled off under reduced pressure, and the residue is extracted with a water/chloroform system. The chloroform layer is concentrated under reduced pressure, ethanol is added to the crude product to dissolve it, and reprecipitation is performed from a large amount of water. After filtering the obtained precipitate, the linear mixture is purified by column chromatography to obtain β-CD (mono-6o-trityl-ber-0-methyl β-CD) (yield near 5%).

The obtained target product was dissolved in chloroform, a small amount of hydrochloric acid was added and shaken, and after the reaction was completed, the chloroform layer was neutralized.
By washing with water, drying, and concentrating the solvent under reduced pressure, monohydroxy-medyl-β-CD (mono-6-hydroxylper-0-methyl β-G[)) is obtained (yield:
95%).

(Synthesis Example 3) (1) CH,=CHCH20H (2) Method for introducing and removing CH2=CHCH20-fCH2'j-OH React the above (1) or (2) with NaH in DMF at room temperature under nitrogen atmosphere. A DMF solution of β-CD monoiodide was added thereto, followed by reaction at 70 to 80°C for 24 hours. After completion of the reaction, DMF was distilled off under reduced pressure, and the residue was reprecipitated from a large amount of acetone. The precipitate was collected and dried under reduced pressure.

Yield: (1) → 35% (2) → 55% (n=2) Methylation was carried out in the same manner as in Synthesis Example 1.

Yield: (1) → 60% (2) → 70% (n=2) Next, monoallyl-methyl β-CD (derivative 10 of (1)
nO-5-allyl-per-0-1ethyl
β-CD) is dissolved in DMSO and isomerized using t-3u OK by stirring at 50° C. for 1 hour and then at room temperature for 24 hours. The system was then heated at 1-1°C12 in the presence of HgO.
Add aqueous solution. Subsequently, the mixture is stirred at room temperature for 6 hours. After completion, it is filtered and the solution is concentrated under reduced pressure.

Add chloroform to the residue, filter it again, distill off the chloroform under reduced pressure, and separate the residue using silica gel column chromatography to obtain monohydroxyethyl-methyl β-C.
D (mono-6-hydroxyethyl-p
er -i+ethy+β-CD) (yield: (1
) → 25%, (2) → 35%).

(Synthesis Example 4) Introduction method and removal method (3) (n = 2) and N
aH is reacted, and D of β-CD monoiodide is reacted therewith.
A MF solution was added, and the mixture was then reacted at 30 to 40°C for 600 hours. After completion of the reaction, DMF was distilled off under reduced pressure, and the residue was reprecipitated from a large amount of acetone. The precipitate was collected and dried under reduced pressure. (
(Yield: 40%) Note that methylation was performed in the same manner as in Synthesis Example 1. (Yield: 55%) Next, mono-tetrahydro-2-thiopyranyloxyethyl-methyl β-CD ((3) derivative 1110nO-
6-tetrahydro-2-thtopyrar
+yloxyethy1-Eler -0-1ethy
lβ-CD) is dissolved in acetonitrile and an aqueous AU NO3 solution is added at room temperature. After the addition, the mixture was further stirred at room temperature for 6 hours. The monomer was then filtered, the solution was concentrated under reduced pressure, and the residue was separated by silica gel chromatography.
Hydroxyethyl-methyl β-CD is obtained. (Yield: 4
5%) (Synthesis Example 5) (10) (CH3)3S + C) + cH2←
OH(11) (t-Bu)(CH,)2S r
O÷CH,←Method for introducing and removing OH In DMF at room temperature in a nitrogen atmosphere Incompound (10) (n=2
> or (11) and NaH were reacted, and then a DMF solution of β-CD monoiodide was added, followed by reaction. After completion of the reaction, DMF was distilled off under reduced pressure, and the residue was reprecipitated from methanol. The precipitate was collected and dried under reduced pressure. (
Yield: (10)→40%, (11)→30%) The methylation was performed in the same manner as in Synthesis Example 1. (Yield: (1G) → 50%, (11) → 55%) Next, monotrimethylsilyloxymethyl-methyl β-CD (
(1G) derivative mono-5-trimethyl
5ilyloxyethyl -per -o
--ethvlβ-CD) was dissolved in THF, and tetrabutylammonium fluoride ((n-C4Hs)4N"F-) dissolved in THF was added dropwise at room temperature. After the dropwise addition, the mixture was allowed to react under reflux for 6 hours. Then, THF is distilled off under reduced pressure. Monohydroxyethylmethyl β-CD is obtained by separating the residue by silica gel column chromatography. (Yield: (10) → 25%,
(11) →30%) Identification can be performed by NMR spectrum, mass spectrum, and elemental analysis.

Further, the above method can be applied to other CD derivatives as well.

[Effects of the Invention] As explained in detail above, the present invention has high reactivity because it is a reaction between an acid halide and an alcohol, and also because it immobilizes one unit of a CD derivative to an acid halide monomer. , it is possible to provide a method for producing a CD-immobilized polymer that is easy to quantify.

Claims (1)

[Claims] A cyclodextrin derivative obtained by iodizing one of the methylol groups of cyclodextrin is reacted with an alcohol serving as a protecting group, and after introducing the protecting group into the cyclodextrin derivative, etherification or esterification is performed,
A method for producing a cyclodextrin-immobilized polymer, characterized in that the monohydroxycyclodextrin obtained by removing the protecting group is then reacted with an acid halogenated monomer of an α,β unsaturated acid.