JPS62275102A - Production of aminated cyclodextrin polymer - Google Patents

Abstract

PURPOSE:To obtain the title polymer useful as an intermediate for the production of a highly functional cyclodextrin polymer, by reducing a specified copolymer with triphenylphosphine. CONSTITUTION:beta-Cyclodextrin (a) is polymerized at 50-65 deg.C by using 10-30 equivalent, per equivalent of component (a), of an epichlorohydrin (b) to obtain a polymer of component (a). this polymer is tosylated by reaction with tosyl chloride (c) and the product is agitated at 10-40 deg.C for 1-24hr in the presence of sodium azide (d) to obtain a copolymer (A) consisting of C-6-monoazido-beta- cyclodextrin and component (a). 1g of a component A is reduced with 0.1-1g of triphenylphosphine (B) at room temperature for 1-24hr to obtain the title polymer which is a copolymer consisting of C-6-monoamino-beta-cyclodextrin and component (a).

Description

Detailed Description of the Invention 3. Detailed Description of the Invention [Field of Industrial Application] The present invention provides a copolymer (hereinafter referred to as aminated CD polymer) consisting of C-6-monoamino-β-cyclodextrin and β-cyclodextrin. ). More specifically, a copolymer consisting of C-6-N-alkyldihydronicotinamide-β-cyclodextrin and β-cyclodextrin (hereinafter referred to as N-alkyldihydronicotinamide CD polymer), which is expected to have a function as an artificial enzyme. ), which are useful as intermediates for the production of aminated CD polymers.

[Conventional technology]

CD polymers in which cyclodextrin (hereinafter referred to as CD) is three-dimensionally crosslinked with a crosslinking agent are already known. Examples of crosslinking agents include shrimp chlorohydrin and diisocyanate.

All of these polymers have the specific inclusion effect of CD. The advantage of CD polymers lies in their insolubility, which allows the molecular recognition ability of CDs to be repeatedly and continuously exerted on reactive substrates.

For example, Nozakura et al. reported the asymmetric resolution of mandelic acid, which is sterically compatible with the cyclodextrin cavity, using 1 cD epichlorohydrin bridge as a packing material for liquid chromatography (J, Polym, Sci.

Poly, Chem, Ed, 16. 189
(1978)).

Furthermore, by adding a similar epichlorohydrin crosslinked CD polymer to the reaction system, Hirai et al. specifically obtained 4-hydroxybenzoic acid from phenol in the same way as cyclodextrin alone (Journal of the Society of Organic Synthetic Chemistry, Vol. Volume 44, 4
9 (1986)).

However, in previous reports, polymerized CD
There was no chemical modification of the river other than the addition of a cross-linking agent. Therefore, conventional CD polymers have been mostly used for separation and purification purposes, and those involved in the reaction have been used only for reaction control to control the orientation of the benzene ring. was.

On the other hand, CD is a cylindrical molecule, and a number of chemically modified IJs have been reported in which the hydroxyl groups around the CD are chemically modified. It has both the molecular recognition ability of CD and the reaction activity, making it promising as a selective reaction catalyst.

The present inventors discovered that C-6 of the pyranose ring of β-cyclodextrin (hereinafter referred to as β-CD) in an alkaline aqueous solution.
A nicotinamide CD was synthesized by stereospecifically monotosylating the position, then introducing an amine group while maintaining the modified position, and making an amide bond with this amino group. Nicotinamide group is one of the vitamin B group, and is an important molecule involved in the reduction of ketones as a coenzyme of alcohol dehydratase in living organisms. This conversion of the nicotinamide group into the active form, that is, the dihydronicotinamide form, is carried out enzymatically in vivo, but the present inventors used sodium dithionite (Na2S20.) to chemically convert the active form into the dihydronicotinamide form. As a model reaction of the electron transport chain, which is an important metabolic pathway for energy acquisition in living organisms, we conducted a reduction reaction on various dye molecules to investigate the three-dimensional structure and reaction rate of the dye. We found a correlation between This reduction reaction is a model experiment for elucidating the metabolic pathway of living organisms, and at the same time is a very useful reaction as an industrial method for selective alcohol production.

However, in order for chemically modified CD to work effectively, it must be added to the reaction system at a high concentration, and it is difficult to extract the product from the reaction system. There were problems in using it on an industrial level, such as that it was difficult to remove it from water and use it again.

[Problem that the invention seeks to solve]

In addition to the ability to form inclusion complexes due to the hydrophobic field of CD, the present invention has the advantage that the pyranose ring C on the cyclodextrin of CD polymer
Amination that is useful as an intermediate for producing more practical highly functional cyclodextrin polymers that chemically modify only one of the 6-position hydroxyl groups and have reactivity with chemical modification groups such as asymmetric reduction reactivity. It is an object of the present invention to provide a method for producing CD polymer.

[Means for solving problems]

That is, the present invention provides C-6-monoamino-β-cyclodextrin and β-cyclodextrin, which are obtained by reducing a copolymer containing C-6-monoazide-β-cyclodextrin and β-cyclodextrin as constituent components. The present invention relates to a method for producing a copolymer having as a constituent component.

The manufacturing method of the present invention will be explained below according to Scheme 1.

Scheme 1 , β ゛, (β-CD) ≠, -21/pa, (tosylated β-CD polymer) ninny-7-2, pa', (azide β-CD polymer) -1111 112,,,/'v,,,1. , , (aminated β
-CD Polymer) A (1) Copolymer containing C-6-monoazide-β-cyclodextrin and β-cyclodextrin as constituent components ■ Polymerization of β-CD (β-cyclodextrin) In the present invention As β-CD, a commercially available product obtained by, for example, treating starch with a CD-generating enzyme can be used as it is.

β-CD β-CD can be obtained by polymerizing by a known method using epichlorohydrin as a crosslinking agent. The amount of epichlorohydrin mixed into β-CD during the reaction is about 10 to 30 equivalents, preferably about 15 to 25 equivalents, of epichlorohydrin to β-CD. The amount of epichlorohydrin mixed during the reaction is 10
If the amount is less than the equivalent amount, an aqueous polymer with a low degree of crosslinking tends to be produced.

Further, the polymerization reaction is preferably carried out at a temperature of about 50°C to 65°C while stirring the reaction mixture. The reaction temperature is about 50℃
By doing the above, an insoluble polymer gel can be obtained in a relatively short time (for example, within about 2 hours). Further, by controlling the temperature to about 65° C. or lower, a colorless polymer can be obtained.

The β-CD polymer thus obtained has -0-C, which is a crosslinked structure derived from epichlorohydrin, in its structure.
It has H2CHOHCH20-. The number of crosslinked structures contained in the β-CD polymer varies depending on the reaction conditions, but is usually about 3 to 5 per CD.

(2) Tosylation of β-CD polymers β-CD polymers are tosylated by reacting with tosyl chloride. The tosylation reaction is carried out using an alkaline aqueous solution or pyridine as a solvent.

In the method using an alkaline aqueous solution as a solvent, the pH is approximately 13.
This can be carried out by dispersing the β-CD polymer in an aqueous alkaline solution of 1, then adding tosyl chloride, and stirring the reaction at room temperature for about 1 hour. By this reaction, β
A tosyl group is introduced only at the C-6 position of β-CD of the -CD polymer. Furthermore, two or more tosyl groups are never introduced into one molecule of β-CD. The rate of introduction of the tosyl group into the C-6 position varies depending on the reaction conditions, but is about 10 to 40%.

Furthermore, tosylation using pyridine as a solvent can be carried out in substantially the same manner as in the case of an alkaline aqueous solution.

The amount of tosyl chloride used is about 0.5 to 2 g per 1 g of β-CD polymer.

■ Azide tosylated β-C of tosylated β-CD polymer
By reacting the D polymer with sodium azide, an azide β-CD polymer can be obtained. The reaction is carried out in a solvent such as DMF at about 10 to 40°C and about 1 to 1
It is carried out under stirring for 0 hours. The amount of IJium used is about 0.5 to 2 g per 1 g of β-CD polymer.

(2) C-6-amino-β-cyclodextrin and β-
Copolymer consisting of cyclodextrin (aminated β
-CD Polymer) Aminated β-CD polymers can be obtained by reducing azide β-CD polymers with triphenylphosphine. The reduction reaction is performed using dimethylformamide (
DMF) as solvent in the presence of ammonia. The reaction is preferably carried out at room temperature with stirring for about 1 to 24 hours.

Amination of the azide β-CD polymer proceeds almost quantitatively.

The amount of triphenylphosphine used in the reaction is suitably about 0.1 to 1 g per 1 g of azide β-CD polymer.

The aminated β-CD polymer thus obtained is
Various active groups can be introduced into the amine group.

β-CD polymers into which active groups have been introduced can stereospecifically participate in various reactions. The activated dihydronicotinamide β-CD polymer will be explained below.

(3) Production of activated dihydronicotinamide β-CD polymer ■ Nicotinamide of aminated β-CD polymer Nicotinamide β-CD polymer is a
D polymer and nicotinic acid chloride in DMF-Et3N
It can be obtained by reacting in a solvent such as at about 70 to 90° C. for about 1 to 24 hours with stirring.

The amount of nicotinic acid chloride used for the aminated β-CD polymer is approximately 0 per gram of the aminated β-CD polymer.
．． It is appropriate that the amount of nicotinamide β-CD polymer is 1 to 1 g. It is obtained by reacting in a solvent at a temperature of about 50 to 70° C. for about 1 to 10 hours with stirring.

The amount of CH,I to be used in the nicotinamide β-CD polymer is suitably about 0.1 to 1 g per 1 g of the nicotinamide β-CD polymer.

■ Dihydration of N-methylnicotinamide β-CD polymer N-methyldihydronicotinamide β-CD polymer (activated dihydronicotinamide β-CD polymer)
is N-methylnicotinamide β-CD polymer and Na
2S20. and about 10 to 4 in an aqueous Na2CO3 solution.
It is obtained by reacting at a temperature of 0° C. for about 1 to 24 hours with stirring.

Na2S, 0. The amount of N-methylnicotinamide β-CD polymer used is
-Appropriately, the amount is about 0.3 to 1.5 g per gram of CD polymer. Also, Na2Co, Na2C in aqueous solution
Suitably, the O3 concentration is about 5-15% by weight.

The activated dihydronicotinamidated β-CD polymer thus obtained is, for example, benzoylformic acid (BFA).
) can be used for the stereoselective reduction of chemically active mandelic acid.

Tosylated β-CD polymer described above, azide β-C
D polymer, aminated β-CD polymer, nicotinamide β-CD polymer, N-methylnicotinamide β
Both the -CD polymer and the N-methyldihydronicotinamidated β-CD polymer are new materials.

The present invention will be explained below using reference examples and examples.

Reference Example 1 50 g of β-cyclodextrin and 0.07 g of sodium borohydride were added to a 50 W/V% sodium hydroxide solution 6
The mixture was kneaded at 0- while cooling with cold water.

Shrimp chlorohydrin (40 mj7) was added dropwise to this paste-like mixture while keeping it at 50° C. and stirring vigorously. 2
After some time, a gel-like polymer was obtained.

The product was washed with acetone followed by water and dried.

Yield was 50g. 12g of this polymer at pH 13
of sodium hydroxide, 16 g of p-)
Ursulfonyl chloride was added and stirred at room temperature for about 45 minutes. This reaction solution was neutralized with diluted hydrochloric acid and separated by filtration. The filtrate was washed with acetone to remove ill p-)IJ sulfonyl chloride, and then vacuum-dried.

Yield was log.

As a result of elemental analysis, this gel-like polymer was found to be cross-linked by the reaction of 5 molecules of epichlorohydrin to 1 molecule of β-CD, and further contains p-tolylsulfonyl groups (tosyl groups).
and cyclodextrin ratio was 1:3. The polymer was therefore composed of 33% C-6-cetyl-β-cyclodextrin and 60% β-cyclodextrin.

Reference Example 2 10 g of the polymer containing tosylated-β-cyclodextrin obtained in Reference Example 1 was suspended in dehydrated and purified DMF, 5 g of sodium azide was added, and the reaction system was kept at 80° C. and stirred for 7 hours. The solvent was filtered off and thoroughly washed with acetone to give an azide-β-cyclodextrin polymer with a yield of 13.
4 g was obtained. According to an infrared absorption spectrum, this product was found to have an absorption characteristic of an azide compound at 2100 Cm-'.

The polymer obtained in Example Reference Example 2 was suspended in DMF again,
3.5 g of triphenylphosphine was added and stirred at room temperature for 1 hour. Further, 3.5 mβ of concentrated ammonia water was added and stirred for 12 hours. The solvent was filtered, and the filtrate was washed repeatedly with acetone and pure water, and then dried. Yield was lO, 2g. Add this polymer to 0. Suspended in hydrochloric acid at 0.0% IN. Neutralization titration with IN sodium hydroxide solution revealed that the gel had an equivalence point at pH 9.9 and that 1 g of dry gel contained 209 μmol as amino groups.

When converted to the number of molecules, 33% of C-6-monoamino-β-
It was composed of cyclodextrin and 67% β-cyclodextrin.

Reference Example 3 2 g of the polymer containing amino-β-cyclodextrin obtained in Reference Example 2 was suspended in 25 mA of dehydrated and purified DMF, and 1 ml of triethylamine and 1 g of nicotinic acid chloride were added.
Stirred at room temperature for 12 hours.

The solvent was removed by filtration, the gel was washed with acetone and methanol, and then vacuum dried. Yield was 1.8g. Dehydrate this gel again! ! Suspended in DMF, 0
．． The N-position of the nicotinamide group was methylated with 3 g of methyl iodide. The resulting polymer gel was composed of approximately 33% N-(N-methylnicotinic acid)-amino-β-cyclodextrin and 67% β-cyclodextrin according to elemental analysis.

Reference Example 4 1 g of the N-(N-methylnicotinic acid)-amino-β-cyclodextrin gel obtained in Reference Example 3 was dissolved in a 10% aqueous sodium carbonate solution and 0.7 g of dinithionic acid was added.
The mixture was stirred at room temperature overnight. Excess sodium dithionite was washed with water followed by methanol. After mixing this gel with an iodine solution and performing redox titration with sodium thiosulfate, the result was that it had a reducing power of 209 μg equivalent per 1 g of dry polymer, and considering that it was derived from nicotinamide groups, it had a reducing power of 209 μmol/Ig・dry.
It was confirmed that it had the dihydronicotinamide group of gel.

Reference Example 5 N-(N-methyldihydronicotinic acid)-amino-β-cyclodextrin gel (N-Me
-NA)! -β-CDE) 0.5g (9,35X 10
-5mot) was suspended in a solvent, and benzoylformic acid (B
FA) was added as a substrate and incubated for 24 hours in a nitrogen atmosphere, shielded from light.
The reaction was carried out at ℃ for 60 hours, the gel was removed by filtration, and the filtrate was analyzed by liquid chromatography. As a reaction solvent, M/40-phosphate, M/20 Na2B
Four types were used: 4O7, ethanol, and acetonitrile.

The reaction yielded mandelic acid as the main product as shown below. However, as a solvent M/20-Na
2B, 0. When ethanol was used, benzoic acid and phenol were detected as other by-products.

H 1゜ H-C-[001-1 The reaction conditions and product analysis results are shown in Table 1.

Furthermore, analysis by high performance liquid chromatography revealed that the production of mandelic acid by this reaction has asymmetric selectivity.

Claims (5)

[Claims] (1) C-6-monoamino-β-cyclodextrin and β-cyclodextrin, which are obtained by reducing a copolymer containing C-6-monoazide-β-cyclodextrin and β-cyclodextrin as constituent components. A method for producing a copolymer. (2) The production method according to claim (1), which comprises reducing a copolymer containing C-6-monoazide-β-cyclodextrin and β-cyclodextrin with triphenylphosphine. (3) The production method according to claim (1) or (2), wherein the reduction reaction is carried out in the presence of ammonia. (4) The production method according to any one of claims (1) to (3), wherein the reduction reaction is carried out in dimethylformamide. (5) A copolymer consisting of C-6-monoazide-β-cyclodextrin and β-cyclodextrin is obtained by tosylating a β-cyclodextrin polymer obtained by crosslinking β-cyclodextrin with epichlorohydrin,
The manufacturing method according to any one of claims (1) to (4), which is obtained by subsequent azination.