WO2001087986A1

WO2001087986A1 - Functionalized polysaccharides

Info

Publication number: WO2001087986A1
Application number: PCT/NL2001/000359
Authority: WO
Inventors: Theodoor Maximiliaan Slaghek; Johannus Wilhelmus Timmermans; Kees Fester Gotlieb
Original assignee: Instituut Voor Agrotechnologisch Onderzoek (Ato-Dlo)
Priority date: 2000-05-11
Filing date: 2001-05-11
Publication date: 2001-11-22
Also published as: NL1015159C2; AU5686301A

Abstract

Functionalised carbohydrates can be obtained if a carbohydrate is caused to react with an epoxy compound which also contains a double carbon-carbon bond, such as allyl glycidyl ether, to form a hydroxyalkenyl derivative of the carbohydrate. This derivative can then be epoxidised to form a hydroxy-epoxyalkyl derivative of the carbohydrate. This epoxyalkyl derivative is particularly suitable for further functionalisation of the carbohydrate. The invention relates both to the processes and to the products obtainable thereby.

Description

FUNCTIONA I ZED POLYSACCHARIDES

The invention relates to novel functionalised polysaccharides and to a process for preparing them. Functionalisation of polysaccharides such as starch and cellulose is widely used to modify the physical and chemical characteristics of the polysaccharides. Chemical modification of- the characteristics is desirable, for example, for ^• coupling the polysaccharide to other substances such as reagents (immobilisation of reagents) or excipients. Such reagents and excipients can, for example, couple via an amino or hydroxyl function (alcohols and phenols) or via other groups which can react with an epoxide to form bonds, such as carboxyl, thiol, sulphite, phosphate and the like. Examples of such reagents and excipients are carbohydrates (possibly the polysaccharide itself), proteins and the like.

A method of modifying polysaccharides which has been known for a long time is functionalisation with alkylene oxides. For example, US 2,516,632 and 2,516,633 describe the reaction of starch with ethylene oxide to form hydroxyalkyl starch. The introduction of unsaturated groups into polysaccharides can take place, for example, via a reaction with suitable alkenyl halides, as described in US 3,062,810 for the reaction of starch with allyl chloride in aqueous suspension. The reaction of polysaccharides with such halides has the drawback, however, that considerable chain shortening of the polysaccharide takes place and that isolation and salt load present problems. From US 2,455,083 it is known to add epoxybutene under vacuum, after activation using 20% strength sodium hydroxide solution, and to oxidise the product with permanganate to produce a trihydroxybutyl derivative. US 3,746,699 describes the crosslinking of starch and dextrin by the addition of glycidyl methacrylate with sodium hydroxide solution at elevated temperature.

Epoxy groups can be introduced into polysaccharides by successive reaction with an allyl halide and epoxidation with peracetic acid. For example, Lin and Huang describe the preparation of glycidyl cellulose having a high degree of substitution (2.58) inJ Polymer Sc. A, 30, 2303-2312 (1992). The reaction of cellulose with allyl bromide, however, was carried out by them in homogeneous solution in lithium chloride with dimethylacetamide and the epoxidation was performed in dichloromethane; neither of these two media, however, are particularly suitable for large-scale reaction, owing to purification problems and environmental problems. Moreover, this method results in a lower molecular weight of the cellulose.

We have now found that carbohydrates (mono-, di-, oligo- and polysaccharides) and derivatives thereof can effectively be provided with an epoxide function via a reaction of the carbohydrate with an epoxy compound which also contains a double carbon-carbon bond, followed by reaction with an epoxidant. The reaction is particularly suitable for functionalising moderately soluble carbohydrates such as starch, especially non-gelatinised starch. The non-gelatinised starch permits the reactions to take place on the starch grain, thus allowing impurities to be removed by washing in accordance with conventional methods.

Apart from starch, the carbohydrate can also be some other mono-, oligo- or polysaccharide, such as other -glucanes, β-glucanes (cellulose), fructanes, (galacto- or gluco)mannanes and the like. Alternatively, the carbohydrate can be a prefunctionalised derivative such as, for example, a hydroxyalkyl carbohydrate or a cationic (amino alkyl) carbohydrate.

The epoxy compound which also contains a double carbon-carbon bond can be a compound of formula 1 :

RHC<°>CR-A-CR=CHR, 1 wherein C<°>C represents an epoxide ring (oxirane), A represents a direct bond or a Cι-C₂₈ alkylene group which may or may not be punctuated by one or more oxygen atoms, ester or amide bonds or cycloalkylene or phenylene groups and each R, independently of the others, represents a hydrogen atom or a methyl group. Relevant examples are an α,β-epoxy-(ω-l)-alkene, such as l,2-epoxy-5-hexene or an epoxyalkyl ester or amide such as allyl glycidate, glycidyl (meth)acrylate, glycidyl(meth)acryl- amide. In particular it is an epoxyalkyl alkenyl ether such as allyl glycidyl ether.

The reaction of the carbohydrate with the epoxy compound which also contains a double carbon-carbon bond (such as allyl glycidyl ether) can be carried out in such a way that the chain length of the carbohydrate is not significantly reduced. The reaction is preferably carried out in water or an aqueous solvent, at a temperature above 0°C and below 100°C, in particular, for example for starch, below 60°C. Preferably, a base is used as a catalyst, for example in the form of a 0.01-1 M solution of a base such as a hydroxide or carbonate of an alkali metal or alkaline earth metal, or ammonia or an organic amine. The amount of epoxy compound depends on the desired degree of substitution in the product, an excess of 25-150% of epoxy compound normally being used. The degree of substitution of the reaction product is advantageously 0.001-1.0, depending on the intended use. For starch derivatives, a useful degree of substitution is 0.001-0.15, for cellulose derivatives 0.001-0.1, for oligosaccharides 0.1-3 and for mono- and disaccharides 0.1-4.

The resulting hydroxyalkenyl derivative of the carbohydrate can be epoxidised in a manner known per se, using a peracid or hydrogen peroxide. The epoxidation is carried out, for example, using hydrogen peroxide under slightly alkaline conditions at a temperature of 0-60°C, preferably at 10-40°C. The epoxidation preferably proceeds in water which, if required, is admixed with an auxiliary solvent. In addition it has been found that a nitrile such as acetonitrile can promote epoxidation; preferably, a quantity of nitrile of 0.02-50, in particular 1-10 equivalent based on the peroxide or peracid, is used.

The hydroxy-epoxyalkyl derivative obtainable via the process according to the invention is a reactive derivative which is able to react under mild conditions with many types of functional groups such as hydroxyl groups and other oxygen-containing groups (for example carboxyl groups), primary and secondary amino groups, mercapto groups and the like. Such groups can be present in compounds having a desired functionality (such as anionic or cationic functions, coupling functions, complexing functions, crosslinking functions and the like). Examples are polyols, hydroxy acids, poly- carboxylic acids, sulphate, phosphate, polyamines, amino acids, peptides, amino sugars such as chitosans, carboxy sugars such as carboxymethyl cellulose etc. The hydroxy- epoxyalkyl derivative can also advantageously serve as a basis for crosslinking of the carbohydrate itself, the epoxy group reacting with hydroxyl groups of the carbohydrate. Such reactions can be induced, for example, by basic catalysis. The derivatives can be used for various purposes, for example as a flocculant, complexant, as a pharmaceutical or diagnostic aid, etc.

Other derivatives according to the invention are hydroxy-haloalkoxyalkyl derivatives containing a pendent group in the form of a group having the formula: -CHR-C(R)OH-A-C(R)OH-CHRX, wherein X is a halogen atom and A and R have the above-mentioned meanings. These derivatives can be obtained by the addition of hypohalite to the above-mentioned hydroxyalkenyl derivative or by addition of hydrogen halide to the above-mentioned hydroxy-epoxyalkyl derivative. These reactive halogen derivatives can likewise serve as a starting material for further functionalisation.

Examples Example 1: 1.1: Allyl starch

400 g of starch (17% water, 2.05 mol of anhydroglucose) were suspended in a sodium hydroxide solution of 0.12 mol/l, which contained 10% Na₂SO₄. After the suspension had been brought to a temperature of 44°C, 80 g (0.70 mol) of allyl glycidyl ether were added over a period of 1 hour, followed by vigorous stirring for 15 hours. After cooling in a water/ice bath, 300 g of ice were added, followed by neutralisation with 2.5 M hydrochloric acid. After filtration (glass filter, G3), the allyl starch was washed four times with 1.21 of water. The product was then washed a further 3 times with 1.2 1 of ethanol and finally a further 3 times with 1.2 1 of acetone. The white powder obtained was dried for one night at room temperature and then stored at 4°C. This afforded 375.0 g of allyl starch (13% water, yield 91%). Analysis of the number of double bonds indicated 0.60 mmol of allyl groups per g of (allyl) starch (dry), which corresponds to a DS of 0.11.

1.2: Epoxy starch

A solution of 22 mg of sodium carbonate and 4.4 g of sodium bicarbonate in 438 ml of water was prepared. Added to this were 350 g of allyl starch (from example 1.1, 11% water, 1.79 mol of anhydroglucose) and 109 ml of acetonitrile (2.1 mol), and the temperature was then, with stirring, brought to 30°C. Over a period of 10 hours, 47.8 ml (0.50 mol) of hydrogen peroxide (35% m/v) were then added. After the mixture had been stirred at 30°C for a further 6 hours, it was cooled to room temperature, followed by the addition of 300 ml of water. The product was isolated with the aid of a glass filter (G3) and washed 5 times with 1.5 1 of water. The product was then washed a further 4 times with 1.5 1 of ethanol and finally a further 4 times with 1.5 1 of acetone. The white powder obtained was dried for one night at room temperature and then stored at 4°C. This afforded 331.9 g of epoxy starch (8.1% water, yield 91%). Analysis of the number of epoxy groups indicated 0.26 mmol of epoxy groups per g of (epoxy) starch (dry), which corresponds to a DS of 0.043 (39%).

Example 2: 2.1: Allyl starch 700 g of starch (16% water, 3.65 mol of anhydroglucose) were suspended in a sodium hydroxide solution of 0.12 mol/l, which contained 10% Na₂SO . After the suspension had been brought to a temperature of 44°C, 140 g (1.23 mol) of allyl glycidyl ether were added over a period of 1 hour, followed by vigorous stirring for 15 hours. After cooling in a water/ice bath, 300 g of ice were added, followed by neutralisation with 2.5 M hydrochloric acid. After filtration (glass filter, G3), the allyl starch was washed 4 times with 2.4 1 of water. The product was then washed a further 4 times with 2.4 1 of ethanol and finally a further 3 times with 2.4 1 of acetone. The white powder obtained was dried for one night at room temperature and then stored at 4°C. This afforded 701.9 g of allyl starch (10% water, yield 99%). Analysis of the number of double bonds indicated 0.66 mmol of allyl groups per g of (allyl) starch (dry), which corresponds to a DS of 0.12.

2.2: Epoxy starch

A solution of 31 mg of sodium carbonate and 6.3 g of sodium bicarbonate in 625 ml of water was prepared. Added to this were 500 g of allyl starch (from example 2.1, 10% water, 2.56 mol of anhydroglucose) and 156 ml of acetonitrile (3.0 mol), and the temperature was then, with stirring, brought to 30°C. Over a period of 20 hours, 255 ml (2.67 mol) of hydrogen peroxide (35% m/v) were then added. After the mixture had been stirred at 30°C for a further 6 hours, it was cooled to room temperature, followed by the addition of 400 ml of water. The product was isolated with the aid of a glass filter (G3) and washed 5 times with 1.3 1 of water. The product was then washed a further 4 times with 1.3 1 of ethanol and finally a further 3 times with 1.3 1 of acetone. The white powder obtained was dried for one night at room temperature and then stored at -20°C. This afforded 490.4 g of epoxy starch (9.9% water, yield 98%). Analysis of the number of epoxy groups indicated 0.35 mmol of epoxy groups per g of (epoxy) starch (dry), which corresponds to a DS of 0.062 (52%).

Claims

1. A process of preparing a functionalised carbohydrate, wherein the carbohydrate is caused to react with an epoxy compound which also contains a double carbon-carbon bond, and the resulting hydroxyalkenyl derivative of the carbohydrate is epoxidised to form a hydroxy-epoxyalkyl derivative of the carbohydrate.

2. A process according to Claim 1, wherein the epoxy compound which also contains a double carbon-carbon bond is a compound of formula 1,

RHC<°>CR-A-CR=CHR, 1 wherein C<°>C represents an epoxide ring, A represents a direct bond or a C].-C₂8 alkylene group which may or may not be punctuated by one or more oxygen atoms, ester or amide bonds or cycloalkylene or phenylene groups and each R, independently of the others, represents a hydrogen atom or a methyl group.

3. A process according to Claim 2, wherein the epoxy compound which also contains a double carbon-carbon bond is allyl glycidyl ether.

4. A process according to any one of Claims 1-3, wherein the carbohydrate is starch.

5. A process according to any one of Claims 1-4, wherein the resulting hydroxy- epoxyalkyl derivative of the carbohydrate is then caused to react with a compound having a group -OH, -COOH, -NH₂, -NHR (wherein R represents alkyl or substituted alkyl) and/or -SH.

6. A process according to Claim 5, wherein the resulting derivative of the carbohydrate is caused to react with a carbohydrate.

7. Epoxy derivative of a carbohydrate which represents 0.001-1.0 group having the formula -CHR-C(R)OH-A-CR<°>CHR, wherein A represents a direct bond or a Cι-C₂₈-alkylene group which may or may not be punctuated by one or more oxygen atoms, ester or amide bonds or cycloalkylene or phenylene groups and each R, independently of the others, represents a hydrogen atom or a methyl group, per monosaccharide unit.

8. Allyloxy-hydroxyalkyl derivative of a carbohydrate which represents 0.001-1.0 group having the formula -CHR-C(R)OH-CH₂-O-CH₂-CR=CHR, wherein each R, independently of the others, represents a hydrogen atom or a methyl group, per monosaccharide unit.

9. Derivative according to Claim 7 or 8, wherein the carbohydrate is starch.

10. Coupling product of a carbohydrate with another molecule, wherem the coupling comprises the formula -CHR-C(R)OH-A-C(R)OH-CHR-, wherein A represents a direct bond or a C₁-C₂₈-alkylene group which may or may not be punctaated by one or more oxygen atoms, ester or amide bonds or cycloalkylene or phenylene groups and each R, independently of the others, represents a hydrogen atom or a methyl group.