JPH02133401A - Manufacture of saccharide derivative - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to derivatives of saccharides, more specifically chitosan and its decomposition products, and natural polysaccharides having free amino groups and their decomposition products with aldehyde groups such as saccharides. The present invention relates to the production of sugar derivatives into which a compound with a saccharide is introduced as a side chain.

[Prior Art and its Problems] Chitin is a homopolysaccharide in which the amino sugar N-acetylcurcosamine is linked with β-(1,4), and its deacetylated product is chitosan. Such amino sugars are contained in structural polysaccharides and glycoproteins of living organisms in the living world. Chitin and chitosan also form the skeletal structures of arthropods such as crabs, shrimp, and insects, as well as fungi.The amount of chitin and chitosan produced is said to be 1×109 to 10”) per year in the natural world, which is almost comparable to cellulose, and is produced by humans. It is attracting attention as the last biomass.In particular, chitosan, which is a deacetylated product of chitin, has a highly reactive free amino group (Nl2 group) in the molecule, and can be subjected to various chemical modifications, and the entire molecule is basic. It is expected to become an important material in various industrial fields because it has very useful properties such as interaction with biological materials, especially proteins and nucleic acids, and is expected to have physiological activity. However, until now, chitosan, like chitin, has extremely high crystallinity, which has made research and development extremely difficult due to problems with physical properties such as solubility.

Conventionally, as a means to improve the solubility of chitosan, carboxymethyl chitosan (JP-A-63-110201
There have been reports of derivatives in which a compound having an aldehyde group is introduced into the free amino group of chitosan by reductive alkylation (US Pat. No. 4,424,346). Among these, the above-mentioned US patent discloses a method of introducing a saccharide that becomes a hydrophilic side chain into chitosan by reductive alkylation.

Reductive alkylation is carried out by a catalytic hydrogenation method or a reaction in the presence of a reducing agent, sodium borohydride. When reducing a base, there are problems with reaction selectivity (production of sugar alcohol) and reactivity under acidic conditions necessary for dissolving chitosan. This problem is solved in the above-mentioned US patent by using sodium cyanoborate as a reducing agent. However, sodium cyanoborohydride is extremely toxic to living organisms, and there is a risk that similarly toxic cyanide compounds may remain as a reaction by-product.

Therefore, there is a risk that the range of application of the sugar derivative will be significantly limited.

[Means to solve the problem]

The present inventors have discovered that the free amino group (-NH2 group) of chitosan
In the reductive alkylation between and the aldehyde group of the sugar,
As a result of intensive research into a method that has no problems with reaction selectivity or reactivity under acidic conditions and is safer for living organisms, in other words, a method with a wider range of applications, we have found that a borane complex can be used as a reducing agent. We developed a method to use this method.

That is, the present invention involves subjecting a compound selected from chitosan and its decomposition products, natural polysaccharides having free amino groups and their decomposition products, and a compound having an aldehyde group to a reductive alkylation reaction in the presence of a borane complex. The present invention relates to a method for producing a sugar derivative characterized by the following.

In particular, the present invention aims to produce chitosan derivatives having side chains by performing reductive alkylation between chitosan, its decomposition products, and saccharides with reducing ends in the presence of a borane complex type reducing agent. It is something.

The borane complex used in the present invention refers to a complex of various amines and borane, and can be obtained by a conventional method by reacting diborane, sodium borohydride, etc. with amines [Burg, 81. ; Schlesinger, H.
,,J,Am,Chem,Soc,, 5
9.780° (1937), Hutchins, R.
0,, et al,, Org, Prep.

Proced, Int., 16.5.335-37
2 (1984)). More specifically, it refers to reducing agents such as ammonia borane, monomethyl borane, dimethyl borane, trimethyl borane, triethylamine borane, tert-butylamine borane, pyridine borane, and morpholine borane, and one or more of them. can be used in the reaction. Examples of saccharides used as side chains include monosaccharides such as glucose, galactose, arabinose, xylose, and N-acetylglucosamine, oligosaccharides such as maltose, lactose, and cellobiose, and various natural polysaccharides and their decomposition products. . Furthermore, the production method of the present invention is also effective when introducing other general compounds having aldehyde groups such as aromatic and aliphatic aldehydes as side chains.

In addition, like chitosan, we can also treat other natural polysaccharides that have free amino groups (NL groups) in their molecules, such as deacetylated products of hyaluronic acid and chondroitin, and their decomposition products.
By the method of the present invention, side chains can be introduced to produce sugar derivatives.

By making these derivatives, the solubility of chitosan and its decomposition products, natural polysaccharides with 7 free amino groups and its decomposition products can be adjusted arbitrarily, and when made into an aqueous solution, it can increase the viscosity, It can impart properties such as gelation, and can be used as a thickener or gelling agent in cosmetics, hair products, etc. to improve the feel.

Specifically, the manufacturing method can be carried out as shown below.

First, chitosan and its decomposition product, or a natural polysaccharide having a free amine group in its molecule and its decomposition product, are dissolved in distilled water or, if necessary, an organic acid aqueous solution (e.g., acetic acid), and then a compound having an aldehyde group is dissolved. (such as a saccharide with a reducing end) and further dilute with alcohol (eg methanol) if necessary. Next, one or more of the borane complexes exemplified above are added and stirred. After the reaction, if necessary, it can be neutralized with an alkali and purified by precipitation with alcohol, organic solvent, etc., or if necessary, it can be purified by column chromatography such as gel filtration.

The degree of substitution of the resulting sugar derivative can be determined by potentiometric titration in which unreacted free amino groups are titrated with alkali. The degree of substitution is expressed as a percentage, with the case of complete substitution being 1.0.

In the following description, all proportions, percentages, ratios, etc. are by weight unless otherwise specified.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples.
It goes without saying that the present invention is not limited in any way by this explanation.

Example 1 Chitosan (Kimitsukitosan F1, manufactured by Kimitsu Chemical Industry Co., Ltd., hereinafter the same) Ig was dissolved in 30-1% acetic acid, 2 g of glucose was added and dissolved, and the mixture was diluted with 30 ml of methanol. Next, 2.5 g of dimethylamine borane (
Chitosan (at a ratio of 7 mol to 1 mol of glucosamine) was dissolved in 20 ml of methanol, and the mixture was stirred at room temperature using a magnetocooler. The reaction solution turned into a transparent gel in 1 to 2 hours and could no longer be stirred. Thereafter, when the reaction was continued by standing still, the gel turned white, water separated, and became insolubilized after 3 hours. Therefore, the reaction time was determined as Ll, 5.3.8 hours, and when each reaction was completed, O, IN
75ml of NaOH? Add 400mf of ethanol to neutralize acetic acid! was added to finely crush the reaction product while precipitating it, and the mixture was collected by filtration. The precipitate was washed 3 to 5 times with 200% 90% ethanol, further washed with ether, and then dried under reduced pressure at room temperature. Table 1 shows the degree of substitution of reactants at each reaction time.

Example 2 After dissolving 1 g of chitosan in 30-1% acetic acid, 5 g of N-acetylglucosamine was added and dissolved, and 3 g of methanol was added.
Diluted with 0rnl. Next, 2.5 g of dimethylamine borane (7 moles per 1 mole of glucosamine in chitosan), which is a reducing agent, was dissolved in 20 mf of methanol and added.
Stir with a magnetic stirrer at room temperature. The reaction solution is 3
It started thickening in ~5 hours and became a clear gel in 9-13 hours. Thereafter, when the gel was allowed to stand still and the reaction was continued, the gel turned white, and after 20 hours, the gel was completely water-separated and insolubilized. During the above reaction process, when the reaction system thickened (after 4 hours),
When it became a transparent gel (after 13 hours) and when it became white and water separated (after 24 hours), 0. lNNa Kano 75mj! Add ethanol to neutralize the acetic acid, and add 4 ethanol to neutralize the acetic acid.
00- was added, the reaction product was finely crushed while precipitating, and collected by filtration. The precipitate was washed 3 to 5 times with 200 ml of 90% ethanol, further washed with ether, and then dried under reduced pressure at room temperature. Table 1 shows the degree of substitution of reactants at each reaction time.
Shown below.

Example 3 Low-molecular chitosan (molecular 116.0
After dissolving 2 g (by intrinsic viscosity method) in 60 d of 1% acetic acid, 4 g of N-acetylglucosamine was added, dissolved, and diluted with methanol 60 d. Next, 5 g of dimethylamine borane (7 moles per mole of glucosamine in chitosan) as a reducing agent was dissolved in 40 ml of methanol and stirred at room temperature using a magnetic cooler. For the reaction time set at 4, 7, and 18 hours, neutralization of acetic acid, ethanol precipitation, washing, and drying under reduced pressure were performed in the same manner as in Example 1.2, and the degree of substitution of the obtained reaction product is shown. 1
Shown below.

Example 4 2.5 g of chitosan oligo a obtained by decomposing chitosan by the method of JP-A-61-21102 and 2.5 g of glucose were added to 60 ml of distilled water. dissolved in. Next, 2.5 g of dimethylamine borane (ratio of 1.4 mol to 1 mol of glucosamine in chitosan) as a reducing agent was dissolved in 30 d of methanol, and the mixture was stirred at room temperature using a magnetic cooler. The reaction solution became cloudy 4 to 5 hours after the start of the reaction. Stirring was stopped after 6 hours, and 120% of acetone was added to precipitate the oligosaccharide reaction product. After collecting the precipitate by filtration, acetone 200
After washing with mf 5 times, it was dried under reduced pressure at room temperature.

Table 1 shows the degree of substitution of the reactants.

Example 5 After dissolving 1 g of chitosan in 30 ml of 1% acetic acid, N-
5 g of acetylglucosamine was added, dissolved, and diluted with 30 d of methanol. Next, 2.5 g of trimethylamine borane (at a ratio of 5.5 moles to 1 mole of glucosamine in chitosan), which is a reducing agent, was dissolved in 20 jaws of methanol, and the mixture was stirred at room temperature for 24 hours using a magnetic stirrer.

The reaction solution thickened after 24 hours and became slightly cloudy. After the reaction, it was purified in the same manner as in the previous example. Table 1 shows the degree of substitution of the reactants.

Example 6 After dissolving 1 g of chitosan in 30 d of 1% acetic acid, 2 g of glucose was added, dissolved, and diluted with 30 ml of methanol. Next, 2.5 g of trimethylamine borane, which is a reducing agent.
(Ratio of 5.5 mol to 1 mol of glucosamine in chitosan) and 20 m7 of methanol! The mixture was added to the solution and stirred with a magnetic stirrer at room temperature for 24 hours. The reaction solution is 2
After 4 hours, the viscosity increased and the mixture became slightly cloudy. After the reaction, it was purified in the same manner as in the previous example. Table 1 shows the degree of substitution of the reactants.

Claims (1)

[Claims] 1. Reductive alkylation of a compound selected from chitosan and its decomposition products, natural polysaccharides having free amino groups and their decomposition products, and a compound having an aldehyde group in the presence of a borane complex. A method for producing a sugar derivative, characterized by a reaction. 2. The method for producing a sugar derivative according to claim 1, wherein the compound having an aldehyde group is a sugar having a reducing end.