JPH0466874B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides, for example, artificial organs, their members,
The following formula (1)', which has a reducing sugar residue in the side chain and which has not been described in the literature, is useful for forming molded products such as other similar products. However, in the formula, R ¹ is

[Formula] represents; R ² represents a group selected from the group consisting of a hydrogen atom and CH ₃ ; and X represents a group selected from the group consisting of a reducing sugar residue, its sulfate ester residue, and an alkali salt of the ester residue The structural unit represented by and the following formula (2)′ However, in the formula, R ³ , R ⁴ and R ⁵ each represent a group selected from the group consisting of a hydrogen atom and CH ₃ , and R ⁶ is

[Formula] [Here, R ⁷ is a hydrogen atom, a C ₁ to C ₁₈ alkyl group, a C ₁ to _{C 5} hydroxyalkyl group, a cyclohexyl group, a C ₁ to _{C 5} aminoalkyl group, a di(C ₁ to _C2 alkyl)amino( _C1 - _C5
alkyl) group, glycidyl group, tetrahydrofuran group, benzyl group and (-CH ₂ CH ₂ O-) _y
Indicates a group selected from the group consisting of CH ₂ CH ₂ OH group (y = positive number from 1 to 10);

[Formula] [Here, R ⁸ represents a hydrogen atom or a C ₁ to C ₄ alkyl group, and the two R ^8s may be the same or different], -CH, -OH,

[Formula] [where R ⁹ represents a C ₁ to C ₈ alkyl group],

【formula】

【formula】

[Formula] and

[Formula] [Here, R ¹⁰ represents a C ₁ to C ₅ alkyl group] A structural unit represented by The present invention relates to an N-glycoside vinyl compound useful as an intermediate for the production of polymers, which has not been described in any prior literature, and a method for producing the same. In the above formula (1)′, preferable R ¹ is

[Formula] and preferable reducing sugar residues of X are xylose, ribose, glucose,
Residues of reducing monosaccharides selected from the group consisting of galactose and mannose; selected from the group consisting of maltose, isomaltose, cellobiose, lactose, isomaltotriose, manninotriose, cellotriose, isomaltotetraose and cellotetrose Residues of reducing oligosaccharides; and starch, cellulose, dextran,
It is a residue of a reducing polysaccharide selected from the group consisting of pullulan, curdlan, and their partial hydrolysates. More specifically, the present invention provides the following formula (1) which can be used as an intermediate for producing the above-mentioned copolymer. However, in the formula, R ¹ is

[Formula] represents; R ² represents a group selected from the group consisting of a hydrogen atom and CH ₃ ; and X represents a group selected from the group consisting of a reducing sugar residue, its sulfate ester residue, and an alkali salt of the ester residue The present invention relates to an N-glycoside vinyl compound represented by: and a method for producing the same. In the above formula (1), preferred examples of R ¹ and X as reducing sugar residues are the same as those described for formula (1)'. Conventionally, a large number of polymer compounds in which a vinyl monomer is graft-copolymerized to a polysaccharide backbone polymer have already been disclosed. On the other hand, little has been disclosed about polymer compounds in which a vinyl monomer backbone polymer has a monosaccharide as a side chain. In particular, vinyl-based polymer compounds having oligosaccharides or polysaccharides in their side chains have rarely been disclosed so far because they can only be synthesized by more complicated methods. The present invention relates to a polymer compound that can be easily synthesized and has an olefinic backbone polymer with a monosaccharide, oligosaccharide, or polysaccharide as a side chain, which has not been described in any literature. The present inventors have conducted research on the development of N-glycoside/olefin compound copolymers. As a result, by reacting a reducing sugar with a vinyl monomer having an amino group, a macromer represented by the above formula (1) in which the anomeric carbon atom at the reducing end of the sugar and the nitrogen atom of the amino group are N-glucosidically bonded, which has not been described in any prior literature. discovered that it can be easily synthesized. Furthermore, by reacting the N-glycoside vinyl compound obtained in this manner with a polymerizable olefin compound in the presence or absence of a polymerization catalyst, the structural unit of formula (1)' can be obtained. formula
(2) It is possible to form an N-glycoside/olefin compound copolymer having a reducing sugar residue in the side chain, which has not been previously described in any literature, and the N-glycoside/olefin compound copolymer thus obtained has The olefin compound copolymer is a cast film-forming material, and the film has excellent anticoagulant properties and is suitable for use in forming molded articles such as artificial organs, their parts, and other similar products. I learned that it is a substance that can be expected to have excellent usefulness. Therefore, an object of the present invention is to solve the problem of N
- To provide a glycoside-olefin compound copolymer and a method for producing the same. Another object of the present invention is to provide an N-glycoside vinyl compound that is useful as an intermediate for producing the copolymer and which has not been described in the literature, and a method for producing the same. The above objects and many other objects and advantages of the present invention will become more apparent from the following description. The following formula (1), which can be used as an intermediate for producing the N-glycoside/olefin compound copolymer, However, in the formula, R ¹ is

[Formula] is shown; ^R2 represents a group selected from the group consisting of a hydrogen atom and _CH3 ; and X represents a group selected from the group consisting of a reducing sugar residue, its sulfate ester residue, and an alkali salt of the ester residue An N-glycoside vinyl compound represented by, for example, a reducing sugar and the following formula (3), However, in the formula, R ¹ is

[Formula] (-CH ₂ -) _n [where m is an integer from 1 to 5] and

[Formula] represents a group selected from the group consisting of [where n is an integer of 1 to 10]; R ² represents a group selected from the group consisting of a hydrogen atom and CH ₃ ; an amino group represented by A vinyl compound having
It can be produced by reacting in a polar organic solvent or its water-containing solvent. Examples of the above polar organic solvents include methanol,
Examples include polar alcohol solvents such as ethanol, polar amide solvents such as dimethylformamide and formamide, dimethyl sulfoxide, and mixtures thereof, and further, water-containing solvents of these and water, for example, containing about 50 V/V% or less of water. Examples include these polar organic solvents. These solvents are preferably selected and used as appropriate depending on the types of reducing sugar and vinyl compound, the properties of the compound of formula (1) to be formed, and the like. Usually, a solvent is selected that dissolves the raw materials and products and is advantageous for purification. For example, when reacting oligosaccharides such as glucose and maltose with p-aminostyrene, methanol, ethanol, formamide, dimethylformamide, dimethylsulfoxide,
A mixture thereof or a solvent containing up to about 50 V/V% of water, preferably methanol or ethanol, particularly preferably about 3 V/V% to about 10 V/V
% aqueous ethanol is preferably used. In addition, when reacting starch or dextran with p-aminostyrene, formamide, dimethylformamide, dimethyl sulfoxide, a mixture thereof, or a water-containing (approximately 50 V/V% or less) solvent thereof is used, preferably water or formamide is 20 to about 50V/V
% of dimethylformamide is preferably used. The reaction is carried out, for example, by adding reducing sugar in a polar organic solvent or a water-containing solvent thereof such as those exemplified above at a rate of about 1 to about 50 g, more preferably about 5 g, per 100 ml of the solvent.
to about 20 grams per mole of reducing sugar, such as from about 1 to about
20 moles, more preferably from about 1 to about 10 moles of the formula
(3) This can be carried out by adding an amino group-containing vinyl compound and causing a reaction. The reaction temperature can be selected as appropriate, for example from about 0° to about
Examples include temperatures such as 100°C, more preferably about
Temperatures from 30° to approximately 70°C can be adopted. The reaction is preferably carried out under stirring conditions, and can be carried out, for example, for a reaction time of about 2 to about 5 hours. During the reaction, the reaction can be carried out in the presence of a catalyst, if desired, and is preferred. It is also possible and preferred to carry out the reaction in the presence of a polymerization inhibitor, if desired. Examples of such catalysts include sulfuric acid, ammonium sulfate, ammonium chloride, etc., and the amount used is about 5 to about 5% in the reaction system.
An example of the usage amount is 100 ppm. Further, as an example of the above-mentioned polymerization inhibitor, hydroquinone can be exemplified, and the amount used is about 100 to about 100% in the reaction system.
An example of a usage amount is 5000 ppm. The N-glycoside vinyl compound of formula (1) in which X is a reducing sugar residue, which can be formed as described above, can be separated and purified, for example, as described below. For example, when a relatively low boiling point solvent is used, the solvent is distilled off under reduced pressure, and a solvent that does not dissolve the reaction target of formula (1), such as ethyl ether,
Solvents such as acetone or mixtures thereof can be washed off and dried under reduced pressure. Also, when a relatively high boiling point solvent such as dimethylformamide is used, a poor solvent such as ethyl alcohol, acetone, ethanol or a mixture thereof is preferably used, preferably about 3 to 10 parts of ethyl ether and acetone.
Adding a mixed solvent such as about 10 (V/V) in an amount of about 3 to about 10 times the amount of the half-reaction solvent (V/V) to precipitate the reaction target product of formula (1) above and separate it. I can do it. Furthermore, if necessary, dissolve the precipitate in dimethyl sulfoxide, add the same mixed solvent of ethyl ether and acetone, and reprecipitate the target product.
Further purification can be achieved by repeating this separation operation. Next, the compound of formula (1) can be separated and purified by washing with, for example, ether, acetone or ethanol and drying under reduced pressure. For example, the formula that can be obtained as above
In (1), the N-glycoside vinyl compound in which X is a reducing sugar residue is usually a white to pale yellow compound that is solid at room temperature.
^13C nuclear magnetic resonance spectrum of the compound (macromer) (solvent DMSO- _d6 ; concentration 16%;
(room temperature; 25MHz) is shown in Figure 1 of the attached drawings. As shown in Figure 1, according to the ¹³ C nuclear magnetic resonance spectrum, the chemical shift value of the anomeric carbon atom participating in the N-glucoside bond of the macromer is shifted to the high magnetic field side compared to that of the free sugar. do. For example, the chemical shift value of the reducing terminal anomer carbon of styrylaminated altose, which is an N-glucoside of maltose and p-aminostyrene, is about 85 ppm for the β type and about 82 ppm for the α type. On the other hand, the reducing end anomeric carbon of free maltose is approximately 97 ppm for the β form and 92 ppm for the α form. The same relationship also applies to N-glucoside compounds of dextran and p-aminostyrene. Furthermore, an infrared absorption spectrum diagram of the macromer shown in FIG. 1 above is shown in FIG. 2 of the accompanying drawings. As shown in FIG. 2, according to infrared absorption spectroscopy, the macromer exhibits a combination of absorption spectra of both the raw material reducing sugar and the amino group-containing vinyl monomer of formula (3), with new peaks particularly unacceptable. For example, the characteristic infrared absorption spectrum of styrylaminated maltose, which is a macromer composed of p-aminostyrene and maltose, is around 3400 cm ^-1 (O-H stretching vibration) and 1615 cm
These are peaks around ⁻¹ , around 1520 cm ⁻¹ (para-disubstituted benzene ring), and around 1030 cm ⁻¹ (O—O stretching vibration). Furthermore, by thin layer chromatography,
The macromer in which X in formula (1) is a reducing sugar residue can be confirmed. For example, 1-butanol-ethanol-
When developed with 0.1N acetic acid aqueous solution (1:1:2), p-aminostyrene-N-maltoside is
Rf = approximately 0.76, maltose has Rf = approximately 0.68,
Further, the macromer consisting of p-aminostyrene and dextran having an average octamer has Rf=about 0.76, and the average octamer dextran has an Rf=about 0.58. In the formula (1) N-glycoside vinyl compound of the present invention,
The N-glycoside vinyl compound of formula (1) in which X is a sulfate ester residue of a reducing sugar residue or an alkali salt of the ester residue is an ester of the compound of formula (1) in which X is a reducing sugar residue as described above. It can be easily formed by a conventional salt-forming reaction. The above esterification is carried out using a solvent capable of reacting in a homogeneous system, such as formamide, dimethylformamide, or a mixture thereof.
In 100 ml, a macromer in which X is a reducing sugar residue in the above formula (1) is dissolved in an amount of, for example, about 1 g to about 30 g, more preferably about 3 g to about 10 g, for example,
About -5°C to about 20°C, more preferably about 0°C to about 10°C
This can be carried out by adding a sulfuric acid esterifying agent such as chlorosulfuric acid or sulfuric anhydride under relatively low temperature conditions such as °C. At this time, it is preferable to add an amine compound, for example, a basic amine compound such as triethylamine, tributylamine or pyridine, to the reaction system as a neutralizing agent in order to prevent hydrolysis. Further, preferably, a complex of a sulfuric acid esterifying agent and an amine compound as exemplified above, such as a sulfuric anhydride-triethylamine complex, can be used as the esterifying agent. The amount of the esterifying agent to be used can be selected as appropriate. For example, if a sulfuric acid esterified macromer of formula (1) with a high degree of substitution is desired, a macromer in which X is a reducing sugar residue in formula (1) is used.
For example, it is preferable to add about 2 to about 6 moles of the sulfuric acid esterification agent per mole of OH group. Sulfuric acid esterification can thus be carried out by stirring for about 5 to about 48 hours. Next, a poor solvent such as ethyl ether, acetone, or a mixed solvent thereof can be added to the reaction system in an amount 2 to 10 times (V/V) the amount of the reaction solvent to precipitate the sulfuric acid ester. If necessary, it can be further purified by re-dissolving and reprecipitating, then thoroughly washed with a solvent such as ethyl ether, acetone, or a mixed solvent thereof, and then dried under reduced pressure for separation and purification. The sulfuric acid esterified macromer of formula (1) obtained as described above can be obtained in the form of an amine salt when the reaction is carried out in the presence of the basic amine compound. Just as the sodium salt can be obtained by dissolving it, it can also be obtained by simply converting it into a salt of another monovalent cation. In the above formula (1), the N-glycoside vinyl compound of formula (1), in which X is a sulfate ester residue of a reducing sugar residue or an alkali salt thereof, is usually a light yellow to yellowish brown compound that is solid at room temperature. In general, the degree of substitution of the sulfate ester per anhydrous monosaccharide unit is:
It is about 0.1 to about 2.5. As an example, an infrared absorption spectrum diagram of the sulfuric acid esterified macromer of Example 5 is shown in FIG. 8 of the accompanying drawings. According to the infrared absorption spectrum, the sulfate-esterified macromer exhibits the following characteristic spectrum.
For example, as shown in FIG. 8, equation (1)
In the spectrum shown by the macromer in which X is a reducing sugar residue (see Figure 7), the absorption spectrum around 3400 cm ^-1 based on the stretching vibration of the O-H group is reduced, and the stretching vibration of SO ₂ is newly observed. An absorption spectrum appears around 1250 cm ^-1 based on In addition, the sulfur content of the sulfuric acid esterified macromer varies depending on the type of counter ion of the sulfuric acid group, the type of vinyl compound (3) having an amino group forming the sulfuric acid esterified macromer, etc. Although it is difficult to quantify the S content, it is generally less than 20%, with approximately 2.5 sulfate groups per anhydrous monosaccharide unit.
It usually contains sulfur equivalent to less than The measurement of sulfur content is based on the Japanese Pharmacopoeia (No. 9).
(Revised), General Test Methods, Oxygen Flask Combustion Method. The N-glycoside/olefin compound copolymer having the structural unit represented by the formula (1)' and the structural unit represented by the formula (2)' of the present invention can be obtained, for example, as described above. The following formula (1), However, in the formula, R ¹ is

[Formula] [Here, m is integer from 1 to 5] and

[Formula] represents a group selected from the group consisting of [where n is an integer of 1 to 10]; R ² represents a group selected from the group consisting of a hydrogen atom and CH ₃ ; and X is a reducing sugar Represents a group selected from the group consisting of a residue, a sulfate ester residue thereof, and an alkali salt of the ester residue; an N-glycoside vinyl compound represented by the following formula (2) However, in the formula, R ³ , R ⁴ and R ⁵ each represent a group selected from the group consisting of a hydrogen atom and CH ₃ , and R ⁶ is

[Formula] [Here, R ⁷ is a hydrogen atom, a C ₁ to C ₁₈ alkyl group, a C ₁ to _{C 5} hydroxyalkyl group, a cyclohexyl group, a C ₁ to _{C 5} aminoalkyl group, a di(C ₁ to _C2 alkyl)amino( _C1 - _C5
alkyl) group, glycidyl group, tetrahydrofuran group, benzyl group and (-CH ₂ CH ₂ O-) _y
A group selected from the group consisting of CH ₂ CH ₂ OH group (y = positive number from 1 to 10);

[Formula] [Here, R ⁸ represents a hydrogen atom or a C ₁ to C ₄ alkyl group, and the two R ^8s may be the same or different], -CN; -OH;

[Formula] [Here, R ⁹ represents a C ₁ to C ₈ alkyl group];

【formula】

【formula】

【formula】

[Formula] and

[Formula] [Here, R ¹⁰ represents a C ₁ to C ₅ alkyl group. It can be formed by reacting in the presence of The reaction can be preferably carried out by copolymerizing the compound of formula (1) and the polymerizable olefin compound of formula (2) using a polar solvent in which the N-glycoside vinyl compound of formula (1) is soluble. The copolymerization can be carried out in any desired polymerization format, such as solution (or homogeneous) polymerization, suspension polymerization, or emulsion polymerization, and various combinations of these polymerization formats can also be employed. For example, a polar solvent in which the N-glycoside vinyl compound of formula (1) is soluble, such as dimethylformamide,
Using formamide, dimethyl sulfoxide, water, a mixed solvent of at least two of these, etc.
The compound of formula (1) is added to 100 ml of solvent, for example, from about 1 to about 50
It can be carried out by dissolving in an amount of about 5 to about 30 g, more preferably about 5 to about 30 g, adding an appropriate polymerization initiator if desired, and further adding the polymerizable olefin compound of formula (2). In this case, when the polymerization solvent is an organic solvent, it is preferable to use benzoyl peroxide, mazobisisobutyronitrile, ammonium persulfate, etc., preferably azobisisobutyronitrile, as a polymerization initiator, and the amount used is For example, about 0.005 mol/~0.5 mol/, based on the polymerization solvent.
More preferably about 0.01 mol/~0.05 mol/
An example of the usage amount is as follows. Furthermore, when water is used as the polymerization solvent, it is preferable to use ammonia persulfate, potassium persulfate, etc. as a polymerization initiator, and the amount used is, for example, about 0.001 mol/- to about 0.5 mol// to water. , more preferably about 0.005
An example of the amount used is from mol/ to about 0.05 mol/. The compound of formula (1) and the polymerizable olefin compound of formula (2) can be used singly or in combination. The amount of the compound of formula (2) to be added can be appropriately selected, for example, depending on the chain length of the reducing sugar residue X in the compound of formula (1). To name a few examples, for example, equation (1)
In the case of maltose in which the middle and X moieties are disaccharides,
The formula (1) compound is added to about 100 moles of the formula (2) compound.
The proportion is preferably 400 mol or less, preferably about 3 mol to about 100 mol. For example, in the case of dextran in which the X moiety is an octasaccharide in the formula (1), the compound of the formula (2)
About 100 mol or less of the compound of formula (1) per 100 mol,
Preferably, the proportion is about 1 mol to about 10 mol. Further, at this time, when water is used as the polymerization solvent and a water-insoluble compound of formula (2) is used, it is preferable to add an emulsifier such as sodium dodecylbenzenesulfonate to the polymerization system in advance. The addition ratio can be selected as appropriate, for example, about 10W/W% or less, preferably about 10W/W% or less based on water.
An example of a usage amount is 1 W/W% to about 5 W/W%. The reaction is preferably carried out in the substantial absence of oxygen, for example, by degassing the polymerization system and/or purging with nitrogen to create a substantially oxygen-free atmosphere. The reaction can be carried out under stirring or standing conditions, for example at a temperature of about 20° to about 100°C, more preferably about 40° to about 70°C. The polymerization time may be, for example, about 10 minutes to about 5 hours. In carrying out this copolymerization reaction, a wide range of polymerization conditions can be selected depending on the purpose. For example, if a relatively hydrophilic copolymer with a relatively high intrinsic viscosity is desired, the formula ( 2) It is preferable to use acrylonitrile as the compound, and it is further preferable to use dimethyl sulfoxide, which has a small chain transfer constant, as the polymerization solvent. By carrying out the copolymerization under such preferable conditions, the copolymerized compound having an intrinsic viscosity [η] of ²⁵ ° C. _{and DMSO} of 2 or more can be obtained relatively easily. For example, if the intrinsic viscosity is relatively high and you also want to impart hydrophobicity,
As the compound of formula (2), it is preferable to use a part of acrylonitrile, for example, about 10 mol % to about 30 mol %, in place of styrene. Furthermore, for example,
When it is desired to impart more hydrophobicity, it is preferable to use styrene as the compound of formula (2), and furthermore, dimethylformamide or a mixture of dimethylformamide and dimethylsulfoxide (1:0.5 to 2W/V) is used as the polymerization solvent. It is preferable to use After carrying out the copolymerization reaction as described above, the polymerization product system is cooled with ice water, for example, and a poor solvent such as methanol, ethanol, or acetone is added at a concentration of about 2 to about 5 times the polymerization solvent (V/ V) amount can be added to separate and collect the insoluble matter, which is a copolymer. If necessary, for example, redissolve or redisperse in dimethyl sulfoxide or dimethylformamide, then add methanol, ethanol or acetone in an amount of about 2 times to about 5 times (V/V) the amount of the solvent in which it was dissolved or dispersed, Purification can be achieved by repeating the operation of separating insoluble matter. Then, for example, insoluble matter can be washed with methanol or ethanol and dried under reduced pressure. For example, as described above, in the compound of formula (1),
The N-glycoside/olefin compound copolymer of the present invention, which can be obtained from the compound of formula (1) and the compound of formula (2) in which X is a reducing sugar residue, is usually a white to yellow compound that is solid at room temperature. However, when copolymerized in an aqueous medium, it often exhibits a brown to brown color. As an example of the N-glycoside/olefin compound copolymer obtained as described above, an infrared absorption spectrum diagram of the N-glycoside/olefin compound copolymer obtained in Example 6 is shown in FIG. 10 of the attached drawings. Indicated. As shown in FIG. 10, the N-glycoside/olefin compound copolymer is a polymerizable olefin compound copolymerized with the absorption spectrum of the compound of formula (1) (X is a reducing sugar residue). Both absorption spectra of (2) are shown together. For example, a copolymer compound of styrylaminated maltose and acrylonitrile consisting of maltose and p-aminostyrene, which is a type of macromer of the formula (1), has a characteristic spectrum of styrylaminated maltose around 3400 cm ^-1 and 1030 cm ^-1 The characteristic spectrum of acrylonitrile near 2250 cm ^-1 (-C≡N) is also shown. Furthermore, for example, a copolymer compound of styrene and styrylaminated dextran, which is a type of macromer of formula (1), and p-aminostyrene, has a characteristic spectrum of styrylaminated dextran around 3400 cm ^-1 and 1030 cm -1. Around ^-1 and around 1500 cm ^-1 which is the characteristic spectrum of styrene.

[Formula] and around 700cm ^-1

It also shows the absorption of [Formula]. Furthermore, whether or not the copolymer is actually copolymerized can be determined by the solubility of the obtained copolymer. For example, a copolymer of styrylaminated dextran and acrylonitrile containing a large number of styrylaminated dextran moieties is soluble in water, whereas polyacrylonitrile is not soluble in water. Further, for example, a copolymer of styrylaminated maltose and styrene containing a large number of styrylaminated maltose moieties dissolves in dimethyl sulfoxide, but polystyrene does not dissolve therein. Furthermore, regarding the compound shown in Figure 10 above,
^{The 13} C nuclear magnetic resonance spectrum (solvent DMSO-d ₆ concentration 15%; room temperature; 25 MHz) is shown in FIG. 9 of the accompanying drawings. As shown in FIG. 9, the compound of formula (1) (X
No signals attributed to the vinyl group having a reducing sugar residue (reducing sugar residue) or the >C=C< group of the polymerizable olefin compound (2) were observed, but signals attributed to the methine carbon and methylene carbon were observed. On the other hand, the formula
The chemical shift values of carbon atoms other than vinyl groups in the macromer (1) and the compound of formula (2) do not change much even when they are copolymerized. Furthermore, the sugar content in the copolymer can vary widely depending on the polymerization conditions used, and is generally about 80% W/W or less. The method for quantifying sugar in this case was as follows. That is, 10 mg to 50 mg of the copolymer is dissolved or dispersed in about 10 ml of a 2N aqueous hydrochloric acid solution, kept at 95 to 100°C for about 5 hours with stirring, and if there is any insoluble material, it is filtered off, and the filtrate is adjusted to 50 ml, and then dissolved or dispersed as necessary. If so, dilute it and use it as a test solution for sugar determination. Then water 25
Mix 1 ml of the test solution with 5 ml of the coloring test solution, which is made by dissolving 200 mg of Antholone in a mixture of 1.5 ml and 75 ml of sulfuric acid, and heat in a 100°C water bath for 10 minutes to develop color. Separately, a standard test solution containing the same sugar as the sample and having a known concentration is similarly colored. The absorbance of these samples was measured at a wavelength of 620 nm and
The sugar content in the copolymer compound is determined according to Beer's law. Above, in the compound of formula (1), the formula where X is a reducing sugar residue
The copolymerization mode and product of the compound (1) and the polymerizable olefin compound of formula (2) have been described above, and in the compound of formula (1), X is a sulfate ester residue of the reducing sugar or an alkali salt thereof. Formation of a copolymer of the compound of formula (1) and the compound of formula (2) can also be carried out in substantially the same manner as described above. For example, using a solvent in which the formula (1) esterification or its alkali salt macromer is soluble, such as dimethylsulfoxide, dimethylformamide, formamide, methanol, ethanol, water and combinations thereof, preferably dimethylsulfoxide or dimethylformamide, the solvent
100 ml of the esterified macromer of formula (1), preferably its N ⁺ H(C ₂ H ₅ ) ₃ salt, more preferably the formula (1) having an average degree of ester substitution of about 1 or more per anhydrous monosaccharide unit.
(1) For example, about 50 g or less of the esterified macromer,
More preferably, about 5 g to about 30 g is dissolved.
Next, a polymerization initiator such as azobisisobutyronitrile, benzoyl peroxide, ammonium peroxide, potassium peroxide, etc. is added. In this case, when an organic solvent is used as the copolymerization medium, azobisisobutyronitrile is preferable, and for example, about 0.005 mol/~0.5 mol/,
More preferably about 0.01 mol/~0.05 mol/
When water is used as the copolymerization medium, ammonium peroxide or potassium peroxide is preferred, for example about 0.001 mol/~ to the solvent.
About 0.5 mol/more preferably about 0.005 mol/
Add about 0.05 mol/about. Next, the polymerizable olefin compound of formula (2) can be added to carry out a reaction. At this time, the addition ratio of the formula (1) esterified macromer and the formula (2) compound can be selected widely depending on the purpose, but the range of addition ratio depends on the chain length of the sugar moiety of the formula (1) esterification macromer. It is recommended to change the selection as appropriate. For example, when the sugar moiety of the esterified macromer of formula (1) is maltose, the esterified macromer of formula (1) is, for example, about 200 mol or less per 100 moles of the total number of moles of the compound of formula (2), More preferably, it is used in a proportion of about 2 mol to about 50 mol. For example, when the sugar moiety of the esterified macromer of formula (1) is octamer dextran,
The esterified macromer is preferably used in an amount of, for example, about 50 mol or less, more preferably about 0.2 mol to about 10 mol, per 100 mol of the total number of moles of the compound of formula (2). Then, copolymerization can be carried out in the same substantially oxygen-free atmosphere as described above at a temperature of, for example, about 20°C to about 100°C, more preferably about 40°C to about 70°C. The polymerization time can be changed as appropriate depending on the conditions and purpose, and is generally about 30 minutes to about 7 hours. The polymerization system is then cooled and treated with a poor solvent such as ethyl ether, methanol, ethanol, or acetone, preferably ethyl ether or an ethyl ether-methanol mixture (4:
1 to 2) in about 3 to about 6 times the amount of the polymerization solvent (V/V)
The desired copolymer can be separated and collected as an insoluble matter. If necessary, the collected insoluble matter is redissolved or dispersed in, for example, dimethylformamide or dimethyl sulfoxide.
Purification can be achieved by repeating the same procedure of adding a poor solvent and re-precipitating the insoluble matter. Next, this insoluble material can be washed with an acetone-methanol mixture (1:1-2) and then dried under reduced pressure. For example, as described above, in the compound of formula (1),
The N-glycoside/olefin compound copolymer of the present invention, which can be obtained from the compound of formula (1) and the compound of formula (2) in which is a sulfate ester residue of a reducing sugar or an alkali salt thereof, usually has a dark yellow to It is a yellow compound that is solid at room temperature and may take on a brown to brown color when copolymerized in an aqueous medium. Example 9 is an example of the N-glycoside/olefin compound copolymer obtained as described above.
The infrared absorption spectrum of the N-glycoside/olefin compound copolymer obtained in the above is shown in FIG. 11. As shown in FIG. 11, the copolymer is
The characteristic absorption spectrum of the esterified macromer of formula (1) and the characteristic absorption spectrum of the copolymerized compound of formula (2) are shown together. For example, the copolymerized compound of formula (1) esterified macromer, sulfuric ester/triethylamine salt of styryl aminated dextran, and acrylonitrile has a characteristic spectrum of 1250 cm ^-1 of the sulfuric ester/triethylamine salt of styryl aminated dextran.
(SO ₂ ), an absorption peak near 1030 cm ^-1 (O-O), and an absorption peak near 2250 cm ^-1 (C≡N), which is a characteristic absorption spectrum of acrylonitrile, are shown together. Furthermore, whether or not the copolymer is actually copolymerized can be determined by the solubility of the obtained copolymer. For example, a copolymer of sulfuric acid ester/triethylamine salt of styryl aminated dextran and acrylonitrile with a small proportion of acrylonitrile dissolves in water, but polyacrylonitrile does not dissolve in water. Further, for example, a copolymer of sulfuric acid ester/triethylamine salt of styrylaminated dextran and styrene, which does not have a large proportion of styrene, dissolves in dimethyl sulfoxide, but polystyrene does not dissolve in dimethyl sulfoxide. From this, it is understood that they are not just a mixture but a copolymer. Furthermore, the sugar sulfate ester content in the copolymer is
It can be changed greatly depending on the polymerization conditions,
Generally, it is about 70 W/W% or less. In this case, the sugar sulfate ester was determined by converting the sugar content determined according to the sugar determination method described above. The N-glycoside/olefin compound copolymer of the present invention has film-forming properties, and can be molded from its solution into, for example, a film, a sheet, or any other form that can be molded by a drooling method. For example, an N-glycoside/olefin compound copolymer, preferably the sugar content of the copolymer is about
10 W/W% to about 70 W/W%, and the intrinsic viscosity [η] of the copolymer is ²⁵ ° C. _DMSO forms the copolymer of about 1 or more, more preferably the formula (1) The copolymer in which the sugar moiety in the macromer is 4 or more sugars,
Preferably about 20g or less, more preferably about 2g ~
About 10 g of dimethylformamide, dimethyl sulfoxide, etc. is dissolved in 100 ml of dimethylformamide, dimethyl sulfoxide, etc., and then the solution is cast onto a clean flat surface, such as a glass plate, and heated under reduced pressure or normal pressure, preferably at 50°C using an infrared lamp, for example. The film can be formed by drying the film, followed by peeling off the film by, for example, immersing it in water, washing it with water, and then immersing the film in methanol or ethanol and drying it. The membrane thus obtained is usually pale yellow to yellowish brown and transparent, and the infrared absorption spectrum of this membrane shows the same pattern as that of the copolymer from which it is made. Furthermore, in the present invention, an N-glycoside/olefin compound copolymer in which X in formula (1)' is a sulfuric ester residue of a reducing sugar or an alkali salt thereof is also a film-forming substance, and Similarly, it can be drool molded. That is, the content of the sulfated saccharide of the copolymerized polymer compound is preferably about 10 W/W% to about 50 W/W%, and the intrinsic viscosity of the copolymerized polymer compound [η] ²⁵ °C _DMSO is approx.
0.5 or more of the copolymerized polymer compound, more preferably, the sugar moiety of the esterified macromer of formula (1) forming the copolymerized polymer compound is 4 or more sugars, and the degree of substitution of the sulfate ester group is per anhydrous monosaccharide unit. Dissolving about 20 g or less, preferably about 2 g to about 10 g of about one or more copolymerized polymer compounds, particularly preferably triethylamine salts of the copolymerized polymer compounds, in 100 ml of dimethylformamide or dimethyl sulfoxide,
The solution is then cast onto a clean flat surface, such as a glass plate, and heated to preferably below 50° C. under reduced pressure or normal pressure, using, for example, an infrared lamp. After drying, the membrane is peeled off by immersing it in water, and after further washing with water, the membrane is immersed in methanol or ethanol and dried. The film thus obtained is pale yellow to yellowish brown and transparent, and the infrared absorption spectrum of this film shows the same pattern as that of the copolymerized polymer compound that is the raw material. Further, a film obtained from an organic amine salt, such as a triethylamine salt, of the copolymerized polymer compound can be easily converted into a sodium salt by immersing it in an aqueous sodium carbonate solution, for example. The membrane thus obtained, particularly the membrane prepared from a copolymer compound having a sulfate ester group, has excellent anti-blood coagulation properties. For example, the membrane prepared in Example 10 has m−1 compared to the solidification time of glass.
Blood coagulation time was 3.2 times longer, m-2 was 4.4 times longer, and m-3 was 6.0 times longer. The blood coagulation time was measured by the partial thromboplastin time method using rabbit plasma. That is, 50μ of rabbit plasma and platelin (General
Liagnostic, Revision of Warner-Lambert) 50 μm was added dropwise and the two liquids were mixed by shaking gently. After 3 minutes, drop 50μ of 0.025MCaCl ₂ aqueous solution, shake gently, and start the clock at the same time. The time when fibrin fibers are first observed is defined as the blood coagulation time. Hereinafter, several aspects of the present invention will be explained in more detail with reference to Examples. Example 1 3.6 g (20 mmol) of glucose, 80 mg of hydroquinone, 40 ml of ethanol containing 5 V/V% water, and p-aminostyrene are mixed and heated under reflux for about 4 hours while stirring. After cooling, it is filtered, concentrated under reduced pressure, and further dried. The residue was then dissolved in ethyl ether.
The mixture was stirred with 60 ml of acetone (2:1 V/V) mixture for about 1 hour, filtered through a glass filter, and the procedure was repeated four times, followed by drying under reduced pressure. Yield 5.4g. Elemental analysis C H N Calculated value 59.77% 6.81% 4.98% Analytical value 59.60% 6.95% 4.88% ¹³ C-NMR spectrum: Shown in FIG. IR spectrum: Shown in Figure 2. Example 2 Hydrous maltose (C ₁₂ H ₂₂ O ₁₁・H ₂ O) 3.6 g (10
mmol), hydroquinone 180 mg, methanol 36
ml, 2MH ₂ SO ₄ 36μ and p-aminostyrene
2.4 g (20 mmol) are mixed and heated under reflux for about 2 hours while stirring. After cooling, if any insoluble matter is present, it is filtered, concentrated under reduced pressure, and further dried. Next, the solid content was stirred with 60 ml of a 2:1 (V/V) mixture of ethyl ether and acetone for about 1 hour, filtered through a glass filter, and the procedure was repeated four times, followed by drying under reduced pressure. yield
4.2g. Elemental analysis C H N Calculated value 54.17% 6.59% 3.16% Analytical value 54.23% 6.67% 3.11% ¹³ C-NMR spectrum: Shown in FIG. 3. IR spectrum: Shown in Figure 4. Example 3 4.54 g (7 mmol) of dextran with an average molecular weight of 649 and 60 mg of hydroquinone were dispersed in 30 ml of DMF, then 30 μ of 2MH ₂ SO ₄ and 3.36 g (28 mmol) of p-aminostyrene were added, and the mixture was stirred for 45 min.
Keep at ℃~50℃ for 3 hours. After cooling, add 160 ml of a 1:3 (V/V) mixture of ethanol and ethyl ether,
The precipitate is centrifuged. The precipitate obtained was dissolved in 15 ml of dimethyl sulfoxide and then dissolved in 160 ml of a 1:3 (V/V) mixture of ethanol-ethyl ether.
is added and the precipitate is centrifuged. The precipitate is a 1:3 (V/V) mixture of ethanol and ethyl ether.
Stir in 60 ml for about 30 minutes, filter and filter three times, then dry under reduced pressure. Yield: 5.2g. Elemental analysis N Calculated value 1.86% Analytical value 1.90% ¹³ C-NMR spectrum: Shown in Figure 5. IR spectrum: Shown in Figure 6. Example 4 4.1 g (3.2 mmol) of dextran with an average molecular weight of 1285 and 70 ml of hydroquinone were dissolved in a mixed solvent of 21 ml of dimethylformamide and 14 ml of water, and then
Add 70 µ of 2MH ₂ SO ₄ aqueous solution and 2.3 g (19.2 mmol) of p-aminostyrene and stir for 41~
Keep at 45℃ for 5 hours. After cooling, 170 ml of a 1:2 (V/V) mixture of methanol and ethyl ether was added, and the precipitate was centrifuged. Add 100 ml of :2 (V/V) mixture and centrifuge the precipitate. The obtained precipitate was stirred in a mixture of methanol and ethyl ether (60 ml) in equal amounts for about 30 minutes, filtered and separated three times, and then dried under reduced pressure. Yield: 4.4g. Elemental analysis N, 1.01% (calculated value), 0.93%
(Analytical values) IR spectrum: Shown in FIG. 7. Example 5 10.9 g of anhydrous triethylamine sulfate complex was dissolved in a mixed solvent of 15 ml of dimethylformamide and 28 ml of formamide, and the mixture was kept at about 0°C with ice water to obtain the compound of formula (1) in the claims obtained in Example 4. Add 1.7g and stir at about 0°C for 24 hours. Then, 400 ml of an equal amount of acetone-ethyl ether mixture is added and the precipitate is separated. The precipitate is dimethylformamide 10
ml of acetone-ethyl ether 3:1
The operation of adding 100 ml of (V/V) mixed solvent and separating the precipitate was repeated three times. Next, this precipitate was stirred with 60 ml of ethyl ether for 1 hour, filtered and filtered three times, and then dried under reduced pressure. Yield: 4.4g.
S content, 11.7 W/W% (average degree of substitution per anhydrous monosaccharide unit, 1.86). IR spectrum: Shown in Figure 8. Example 6 A series of copolymerization experiments shown in Table 1 were conducted. That is, in a polymerization tube, a predetermined amount of the compound of formula (1) (abbreviated as SAM) synthesized in Example 2 and a predetermined amount of azobisisobutyronitrile corresponding to 0.5 mol% of the total monomer amount were added. of dimethyl sulfoxide (abbreviated as DMSO), then add a certain amount of acrylonitrile (abbreviated as AN), cooled to about -78°C, degassed several times, and melt-sealed. 60±
Polymerize at 0.5℃ for a specified time. After cooling in ice water, the package is opened, the polymerization system is diluted with dimethyl sulfoxide if necessary, methanol is added in an amount four times that of dimethyl sulfoxide, and the precipitate is separated. The obtained precipitate was redissolved in 5 to 15 ml of dimethyl sulfoxide, 0.05 to 0.1 ml of saturated saline was added, then 4 times the amount of methanol as dimethyl sulfoxide was added, and the precipitate was separated three times. Repeat several times. For this separation operation, filtration using a glass filter or the like or centrifugation is sufficient. Next, the precipitate was stirred in 60 ml of methanol, and the filtering operation was repeated three times, followed by drying under reduced pressure.

[Table] Here, the sugar content refers to the sugar content in the obtained copolymer. Moreover, [η] is the intrinsic viscosity number at 25°C in dimethyl sulfoxide. ¹³ C-NMR spectrum (solvent DMSO-D ₆ ; concentration 6%; room temperature; 25 MHz): Shown in FIG. IR spectrum: Shown in Figure 10. Example 7 A series of copolymerization experiments shown in Table 2 were conducted. That is, a predetermined amount of the compound of claim formula (1) synthesized in Example 3 (abbreviated as SAD [4]) and azobisisobutyronitrile corresponding to 0.5 mol% of the total monomer amount were placed in the polymerization tube. Weigh out and dissolve in a predetermined amount of dimethyl sulfoxide (abbreviated as DMSO).
Then a predetermined amount of acrylonitrile (abbreviated as AN)
is added, cooled to approximately -78°C, degassed several times, and melt-sealed. Polymerize at 60±0.5℃ for a specified time. After cooling in ice water, the package is opened, the polymerization system is diluted with dimethyl sulfoxide if necessary, methanol is added in an amount three times the amount of dimethyl sulfoxide, and the precipitate is separated. The obtained precipitate was dimethyl sulfoxide 5
Re-dissolve the precipitate in ~15 ml, add 0.05-0.1 ml of saturated saline, then add 3 times the amount of methanol as dimethyl sulfoxide, and repeat the operation 3 times to separate the precipitate.
Repeat several times. Next, the precipitate was stirred in 60 ml of methanol, filtered and filtered three times, and then dried under reduced pressure.

[Table] Here, the sugar content refers to the sugar content in the obtained copolymer. [η] is the intrinsic viscosity at 25°C in dimethyl sulfoxide. Example 8 A series of copolymerization experiments shown in Table 3 were conducted. That is, the claims synthesized in Example 4 in the polymerization tube
Weigh out a predetermined amount of the compound of formula (1) (abbreviated as SAD[8]) and azobisisobutyronitrile corresponding to 0.5 mol% of the total monomer amount, and then weigh out a predetermined amount of dimethyl sulfoxide (abbreviated as DMSO). dissolve in Then, a predetermined amount of acrylonitrile (abbreviated as AN) is added, cooled to about -78°C, degassed several times, and melt-sealed. Polymerize at 60±0.5℃ for a specified time. After cooling in ice water, open the package, dilute the polymerization system with dimethyl sulfoxide if necessary, add methanol in an amount 2.5 times the amount of dimethyl sulfoxide, and separate the precipitate. The obtained precipitate was dimethyl sulfoxide 5
The procedure of redissolving the solution in ~15 ml, adding 0.05 to 0.1 ml of saturated saline, then adding methanol in an amount 2.5 times that of dimethyl sulfoxide, and separating the precipitate is repeated three times. Next, the precipitate was stirred in 60 ml of methanol, filtered and filtered three times, and then dried under reduced pressure.

[Table] Here, the sugar content refers to the sugar content in the obtained copolymer. [η] is the intrinsic viscosity number at 25°C in dimethyl sulfoxide. Example 9 A series of copolymerization experiments shown in Table 4 were conducted. That is, the claims synthesized in Example 5 to the polymerization tube
A predetermined amount of the compound of formula (2) (abbreviated as SAD-S) and azobisisobutyronitrile corresponding to 0.5 mol% of the total monomer amount are weighed out, and then added to a predetermined amount of dimethyl sulfoxide (abbreviated as DMSO). dissolve. Acrylonitrile (abbreviated as AN) and styrene (abbreviated as St) were then added, cooled to about -78°C,
Degas several times and seal. Polymerize at 60±0.5℃ for a specified time. After cooling in ice water, open the package, dilute the polymerization system with dimethyl sulfoxide if necessary, then add an ether-methanol mixed solvent (4:1 V/V) in an amount five times that of dimethyl sulfoxide, and separate the precipitate. Then, in the case of C-31, the precipitate was stirred for 2 hours in 50 ml of a 2:1 (V/V) mixture of methanol and acetone, and the procedure of filtering out insoluble matter was repeated three times, followed by drying under reduced pressure. The other lot is methanol.
Stir in 50 ml for 2 hours, filter out insoluble matter, repeat the process three times, and then dry under reduced pressure.

[Table] Content rate
IR spectrum (C-32): Shown in FIG. 〃 〃 (C-34): Shown in Figure 12. Example 10 Prepare the following DMSO solution. n-1: 0.33 g of C-32 copolymer of Example 9
Dissolve in 3.6ml of DMSO. m-2: 0.3 g of C-32 copolymer of Example 9 and
0.15 g of polyacrylonitrile having an intrinsic viscosity of 2.18 at 25° C. in DMSO is dissolved in 5.0 ml of DMSO. m-3: 0.45 g of C-33 copolymer of Example 9
Dissolve in 4.0ml of DMSO. 1.5 ml of each of these DMSO solutions is thinly cast onto a glass plate and irradiated with an infrared lamp at a temperature below 45°C. After completely drying, it is immersed in a 2.5% aqueous sodium carbonate solution for 15 minutes, then washed three times with water, further washed three times with methanol, and dried under reduced pressure. Obtain a transparent film approximately 10 cm in diameter. IR spectrum: Shown in FIG. 13.

[Brief explanation of the drawing]

In the accompanying drawings, Figure 1 shows the compound obtained in Example 1.
¹³ C-NMR spectrum, Figure 2 is its IR spectrum, and Figure 3 is ¹³ C-NMR spectrum of the compound obtained in Example 2.
-NMR spectrum diagram, Figure 4 is its IR spectrum diagram, Figure 5 is ^{the 13} C- of the compound obtained in Example 3.
NMR spectrum diagram, Figure 6 is the IR spectrum diagram, Figure 7 is the IR spectrum diagram of the compound obtained in Example 4, Figure 8 is the IR spectrum diagram of the compound obtained in Example 5, and Figure 9 is the IR spectrum diagram of the compound obtained in Example 5. of the compound obtained in Example 6.
¹³ C-NMR spectrum, Figure 10 is the IR spectrum, Figures 11 and 12 are the IR spectrum of the compound obtained in Example 9, and Figure 13 is the IR spectrum of the compound obtained in Example 10. It is a spectrum diagram.

Claims (1)

[Claims] 1. The following formula (1) In the formula, R ¹ represents [Formula], R ² represents a group selected from the group consisting of a hydrogen atom and CH ₃ , and X represents a reducing group selected from the group consisting of xylose, ribose, glucose, galactose and mannose. Residues of monosaccharides; residues of reducing oligosaccharides selected from the group consisting of maltose, isomaltose, cellobiose, lactose, isomaltotriose, manninotriose, cellotriose, isomaltotetraose and cellotetrose;
or residues of reducing polysaccharides selected from the group consisting of starch, cellulose, dextran, pullulan, curdlan, and partial hydrolysates thereof; or sulfate ester residues of the above reducing sugar residues or alkali residues of the ester residues; An N-glycoside vinyl compound represented by: 2. The N-glycoside vinyl compound according to claim 1, wherein in the above formula (1), R ¹ is [Formula]. 3 Reducing sugar and the following formula (3) In the formula, R ¹ represents [Formula], R ² represents a group selected from the group consisting of a hydrogen atom and CH ₃ , and a vinyl compound having an amino group represented by:
The following formula (1) is characterized by being reacted in a polar organic solvent or its water-containing solvent. where R ¹ and R ² have the meanings given above; and X is the residue of a reducing monosaccharide selected from the group consisting of xylose, ribose, glucose, galactose and mannose; maltose, isomaltose, cellobiose, lactose , the residue of a reducing oligosaccharide selected from the group consisting of isomaltotriose, manninotriose, cellotriose, isomaltotetraose and cellotetrose;
or residues of reducing polysaccharides selected from the group consisting of starch, cellulose, dextran, pullulan, curdlan, and partial hydrolysates thereof; or sulfate ester residues of the above reducing sugar residues or alkali residues of the ester residues; A method for producing an N-glycoside vinyl compound represented by: