JPH03236395A - N-glycoside vinyl compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is formula II, -(CH2)m (m is 1-5) or formula III (n is 1-10); R<2> is H or CH3; X is reducing sugar residue, sulfuric acid ester thereof or alkali salt of the ester residue]. USE:A production intermediate for N-glycoside olefin based compound copolymer. PREPARATION:A reducing sugar is reacted with a vinyl compound having an amino group expressed by formula IV in a polar organic solvent or water- containing solvent thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the following materials, which have not been described in prior literature, and which have reducing sugar residues in their side chains and are useful for forming molded products such as artificial organs, their parts, and other similar products. Formula (1)′ 2 where, 1 is an integer from 1 to 5] and −fcHz−0−C−[
Here, n is an integer from 1 to 10 and represents a group selected from the group consisting of; R2 represents a group selected from the group consisting of a hydrogen atom and CH3; and X represents a reducing sugar residue, its sulfate ester Represents a group selected from the group consisting of a residue and an alkali salt of the ester residue; and a structural unit represented by the following formula (2)'3 ft5 4 R8, where R3, R4 and R5 are a hydrogen atom and a hydrogen atom, respectively. represents a group selected from the group consisting of CHI, 1 R6 is -C-0-R7 [where R7 is a hydrogen atom, C
1 to CI8 alkyl group, C1 to C5 hydroxyalkyl group, cyclohexyl group, C+-Cs aminoalkyl group, di(C+ to C2 alkyl)amino(C, to C5
alkyl) group, glycidyl group, tetrahydrofuran group,
R8 represents a hydrogen atom or a group; -C-N(R")z [Here, C, -C, alkyl are the same or different -Cal, -0ff, -0-C-R' [Here, R9 is a C1-C8 alkyl group [Here, RIG represents a group selected from the group consisting of C1 to C5 alkyl groups] N- which is useful as an intermediate in the production of polymers and which has not been described in the literature
This invention relates to glycoside vinyl compounds and their production methods.

In the above formula (1)', R1 is preferably 0 or
+CH2) and preferred reducing sugar residues of X are residues of reducing monosaccharides selected from the group consisting of xylose, ribose, glucose, galadose and mannose; maltose, inmaltose, cellobiose, lactose, isomalt Triose, Manninotriose,
Residues of reducing oligosaccharides selected from the group consisting of cellotriose, isomaltotetraose and cellotetrose;
and starch, cellulose, dextran, pullulan,
It is a residue of a reducing polysaccharide selected from the group consisting of curdlan and their partial hydrolysates.

More specifically, the present invention provides compounds of the following formula (1), in which 1 is an integer of 1 to 5, which can be used as intermediates for producing the copolymer, and the C1112i0-C- [where n is 1 R2 represents a group selected from the group consisting of a hydrogen atom and CH3; and X represents a reducing sugar residue, its sulfate ester residue and the ester residue; This invention relates to an N-glycoside vinyl compound represented by: a group selected from the group consisting of alkali salts of the group and a method for producing the same.

In the above formula (1), preferred examples of R1 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 with oligosaccharides or polysaccharides in their side chains can only be synthesized by more complicated methods, and so far, little has been disclosed. .

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 in its side chain, which has not been previously 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 amine group are N-glucoside bonded, which has not been described in any prior literature. discovered that it can be easily synthesized.

Furthermore, by reacting the thus obtained N-glycoside vinyl compound and a polymerizable olefin compound in the presence or absence of a polymerization catalyst, the formula (1)' structural unit and the formula ( 2) N having a reducing sugar residue in its side chain, which has not been described in the literature,
- A glycoside/olefin compound copolymer can be formed, and the N-glycoside/olefin compound copolymer thus obtained is a cast film-forming material, and furthermore, the film has excellent anticoagulant performance. It has been found that this material is expected to have excellent usefulness in forming molded articles such as artificial organs, their parts, and other similar products.

Accordingly, an object of the present invention is to provide an N-glycoside/olefin compound copolymer that has not been described in the literature 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 formulas (1) and 2 which can be used as production intermediates for the N-glycoside/olefin compound copolymer, where 1 is an integer from 1 to 5] and -fcHzh-0-C- [where,
n represents a group selected from the group consisting of [an integer of 1 to 10]; R2 represents a group selected from the group consisting of a hydrogen atom and CH3; and X represents a reducing sugar residue, its sulfate ester residue and The N-glycoside vinyl compound represented by: represents a group selected from the group consisting of alkali salts of the ester residues, for example,
Reducing sugar and the following formula (3), 2 (3) H2N-R'-C=CB2, where: 1 an integer from 1 to 5] and 6CB21O-C- [where, n
represents a group selected from the group consisting of [an integer of 1 to 10]; R2 represents a group selected from the group consisting of a hydrogen atom and CH, and a vinyl compound having an amino group represented by It can be produced by reacting in a solvent or a water-containing solvent thereof.

Examples of the above-mentioned polar organic solvents include polar alcohol solvents such as methanol and ethanol, polar amide solvents such as dimethylformamide and formamide, dimethyl sulfoxide, and mixtures thereof, as well as water-containing solvents of these and water. For example, these polar organic solvents containing about 50 V/V% or less of water can be mentioned. 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 or maltose with p-aminostyrene, methanol, ethanol, formamide, dimethylformamide, dimethyl sulfoxide, a mixture thereof, or a mixture thereof, or about 50 V/min.
V% or less of a water-containing solvent, preferably methanol or ethanol, particularly preferably about 3V/V% to about 10V/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 solution (approximately 50%
V/V% or less), preferably water or dimethylformamide containing formamide in an amount of about 20 to about 50 V/V%.

The reaction is carried out, for example, in a polar organic solvent or its water-containing solvent as exemplified above, containing reducing sugar in an amount of about 1 to about 50 g, more preferably about 5 to about 20 g, per 10 Qml of the solvent. Forming a solution or dispersion, adding, for example, about 1 to about 20 moles, more preferably about 1 to about 10 moles of the amino group-containing vinyl compound of the formula (3) per mole of the reducing sugar, and reacting. This can be done by

The reaction temperature can be selected as appropriate, for example from about 0° to about 100°C.
Examples include temperatures such as, more preferably about 30° to about 7°
A temperature of 0°C can be used. 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 100 ppm in the reaction system.

Further, as an example of the above-mentioned polymerization inhibitor, hydroquinone can be exemplified, and the amount used is about 100 to about 5% in the reaction system.
An example of the usage amount is 000 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) above, such as a solvent such as ethyl ether, acetone, or a mixture thereof, is used. It can be washed with water 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 in a ratio of about 3 to about 10 parts of ethyl ether and acetone.
0 (V/V) of the half-reacting solvent.
By adding about 10 times the amount (V/V), the target product of the reaction of formula (1) can be precipitated and separated. Furthermore, if necessary, dissolve the precipitate in dimethyl sulfoxide,
Add a similar mixed solvent of ethyl ether and acetone,
Further purification can be achieved by repeating the procedure of reprecipitating and separating the target product. 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 N-glycoside vinyl compound of formula (1) in which X is a reducing sugar residue, which can be obtained as described above, is usually a white to pale yellow compound that is solid at room temperature. As, the compound of Example 1 (macromer)
13C nuclear magnetic resonance spectrum for (solvent DMS)
O-d, concentration 16%; room temperature; 25 MHz) is shown in FIG. 1 of the accompanying drawings.

As shown in FIG. 1, according to the 130 nuclear magnetic resonance spectrum, the chemical shift value of the anomeric carbon atom participating in the N-glucoside bond of the macromer shifts to the high magnetic field side compared to that of the free sugar. . For example, the chemical shift value of the reducing terminal anomer carbon of styrylaminated maltose, which is an N-glucoside of maltose and p-aminostyrene, is approximately 85 ppm for the β type and approximately s2pp for the α type.
It is m.

On the other hand, the reducing end anomeric carbon of free maltose is approximately 97 ppm for the β type and 92 ppm for the α type.

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 is composed of reducing sugar as a raw material and formula (3).
) The absorption spectra of both amino group-containing vinyl monomers are combined, and no new peaks are particularly observed. For example, the characteristic infrared absorption spectrum of styrylaminated maltose, a macromer consisting of p-aminostyrene and maltose, is around 3400c'1 (0-H stretching vibration), around 1615cr' and around 1520cm-' (
(2-substituted benzene ring) and 1030c (around 1 (O
−〇Stretching vibration).

Furthermore, formula (1) can also be obtained by thin layer chromatography.
The macromer in which X is a reducing sugar residue can be confirmed. For example, 1-
Butanol-ethanol-0, IN acetic acid aqueous solution (1:
1:2), p-aminostyrene-N-maltoside has Rf = approximately 0.76, and maltose has Rf =
f=about 0.68, and the macromer consisting of p-aminostyrene and dextran having an average octamer has an Rf=about 0276, and the average octamer dextran has an Rf=about 0°5.
It is 8.

In the N-glycoside vinyl compound of formula (1) of the present invention, the N-glycoside vinyl compound of formula (1) in which X is a sulfuric ester residue of a reducing sugar residue or an alkali salt of the ester residue, It can be easily formed by esterification of a compound of formula (1) in which is a reducing sugar residue, and further by a conventional salt-forming reaction thereof.

The above esterification is carried out using a solvent capable of reacting in a homogeneous system, such as formamide, dimethylformamide, or a mixture thereof. is dissolved in an amount of, for example, about 1 g to about 30° C., more preferably about 3 g to about 10 g, at a relatively low temperature, e.g., about -5° C. to about 20° C., more preferably about 10° 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 certain conditions. 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,
OHH of a macromer in which X is a reducing sugar residue in formula (1)
For example, it is preferable to add about 2 to about 6 moles of the sulfuric acid esterifying agent based on the base mole.

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, further purify by redissolving and reprecipitating, then ethyl ether,
It can be separated and purified by thoroughly washing with a solvent such as acetone or a mixed solvent thereof and then drying under reduced pressure.

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. The degree of substitution of the sulfate ester is generally about 0.1 to about 2.5 per anhydrous monosaccharide unit.

- 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, in formula (1),
The spectrum shown by the macromer in which X is a reducing sugar residue (
(see Figure 7), < 340 based on the stretching vibration of the O-H group.
The absorption spectrum near 0c11 shrinks and a new SO2
Based on the stretching vibration of <1250a, an absorption spectrum appears near 1.

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 content, it generally contains 20% or less of sulfur, which corresponds to about 2.5 or less sulfate groups per anhydrous monosaccharide unit.Measurement of sulfur content was in accordance with the Japanese Pharmacopoeia (9th revision), general test methods, and oxygen flask combustion method.

The N-glycoside/olefin compound copolymer having the structural unit represented by the formula (1)' and the authoritative unit represented by the formula (2)' of the present invention can be obtained, for example, as described above. The following formula (1) (1) % formula % However, in the formula, 1 is an integer from 1 to 5] and -fCHzh-0-C- [mini,
n represents a group selected from the group consisting of [an integer of 1 to 10]; R2 represents a group selected from the group consisting of a hydrogen atom and CH3; and X represents a reducing sugar residue, its sulfate ester residue and represents a group selected from the group consisting of alkali salts of the ester residues; an N-glycoside vinyl compound represented by the following formula (
2) In the formula, R3, R4 and R5 each represent a group selected from the group consisting of a hydrogen atom and CH, and 1 R6 is -C-0-R' [where R7 is a hydrogen atom, CI to CI 11 alkyl group, C, -C, hydroxyalkyl group, cyclohexyl group, C1 to C6 aminoalkyl group, di(C, to C, alkyl)amino (
C, ~C, alkyl) group, glycidyl group, tetrahydrofuran group, benzyl group and (CH2CH20 juice C112
1 group selected from the group consisting of CH20H group (y = positive number of 1 to 10); -C-NCR')2 [where R8
represents a hydrogen atom or a C1-C, alkyl group, and the two R8s may be the same or different, -CN
, -OH,-〇-C-R91 [Here, R9 represents a C1 to C8 alkyl group, O [Here, RIO represents a C1 to C6 alkyl group selected from the group consisting of It can be formed by reacting the represented polymerizable olefin compound in the presence or absence of a polymerization initiator.

The reaction preferably uses a polar solvent in which the N-glycoside vinyl compound of formula (1) is soluble, and the compound of formula (1) and the N-glycoside vinyl compound of formula (2) are reacted.
) It can be carried out by copolymerizing with a polymerizable olefin compound. The copolymerization is carried out in solution (or homogeneously)
Any polymerization method such as polymerization, suspension polymerization, emulsion polymerization, etc. can be used, and various combinations of these polymerization methods can also be employed.

For example, using a polar solvent in which the N-glycoside vinyl compound of formula (1) is soluble, such as dimethylformamide, formamide, dimethyl sulfoxide, water, or a mixed solvent of at least two thereof, the compound of chain formula (1) is added to the solvent 100a+1. For example, by dissolving in an amount of about 1 to about 50 g, preferably about 5 to about 30 g, adding an appropriate polymerization initiator if desired, and further adding the polymerizable olefin compound of formula (2). I can do it.

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, from about 0.005 mol/l to the polymerization solvent.
Approximately 0.5 mol/l.

More preferably about 0.01 mol/l to about 0.05 mol/l
An example of the usage amount is 1. 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/l to water. about 0.5 mol/l, more preferably about 0.005 mol/l to about 0.5 mol/l.
For example, the amount used may be 0.05 mol/l.

The compound of formula (1) and the polymerizable olefin compound of formula (2) can be used singly or in plurality. The amount of the compound of chain formula (2) to be added can be selected as appropriate, for example, depending on the chain length of the reducing sugar residue X in the compound of formula (1). To give a few examples, for example, in the case of maltose in which the X moiety in formula (1) is a disaccharide, compound 1 of chain formula (2)
The ratio of the compound of chain formula (1) to 00 moles is about 400 moles or less, preferably about 3 moles to about 100 moles. For example, in the case of dextran in which the X moiety in chain formula (1) is an octasaccharide, the chain formula (1) compound is added to about 100 mol or less, preferably about 1 mol or less, per 100 mol of the chain formula (2) compound.
A ratio of about 1 mole to about 10 moles is preferable. 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 LOW/W% or less based on water, preferably about I
An example of a usage amount is 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 is carried out under stirring or standing conditions, e.g.
It can be carried out at a temperature of from 100°C to about 100°C, more preferably from about 40' to about 70°C. The polymerization time may be, for example, about 10 minutes to about 5 hours.

When carrying out this copolymerization reaction, a wide range of polymerization conditions can be selected depending on the purpose. For example, if a relatively high intrinsic viscosity and relatively hydrophilic copolymer is desired,
It is preferable to use acrylonitrile as the compound of chain formula (2), 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 extreme 25° C. limiting viscosity [η] of 2 or more can also be obtained relatively easily. For example, if the intrinsic viscosity is relatively high and you also want to impart hydrophobicity, use the chain formula (
2) It is preferable to use a part of acrylonitrile as a compound, 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 chain formula (2) compound, and as the polymerization solvent, dimethylformamide or a mixed solution of dimethylformamide and dimethyl sulfoxide (1:0.5~ 2W/V) is preferably used.

After carrying out the copolymerization reaction as described above, for example, the polymerized product system is cooled with ice water, etc., and then mixed with, for example, methanol,
A poor solvent such as ethanol or acetone is added in an amount approximately 2 to 5 times (V/V) the amount of the polymerization solvent, and the insoluble matter, which is the copolymer, can be separated and collected. If necessary, for example, redissolve or redisperse in dimethyl sulfoxide or dimethyl formamide, then methanol, ethanol, or acetone from about 2 times to about 5 times the solvent in which it was dissolved or dispersed.
Purification can be achieved by repeating the operation of adding twice the amount (V/V) and separating the insoluble matter. Then, for example, insoluble matter can be washed with methanol or ethanol and dried under reduced pressure.

For example, as described above, the N-glycoside-olefin compound copolymer of the present invention which can be obtained from the compound of formula (1) in which X is a reducing sugar residue and the compound of formula (2) The copolymer is usually a white to yellow compound that is solid at room temperature, and often exhibits a brown to brown color when copolymerized in an aqueous medium.

As an example of the N-glycoside/olefin compound copolymer obtained as described above, the N-glycoside/olefin compound copolymer obtained in Example 6 is
- The infrared absorption spectrum of the glycoside/olefin compound copolymer is shown in FIG. 10 of the attached drawings.

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 with chain formula (1), has a characteristic spectrum of styrylaminated maltose.
It shows the absorption near 400 cm-', near 1030 cm-', and near 2250C11 (-CmiN), which is the characteristic spectrum of acrylonitrile. Furthermore, for example,
Dextran, a type of macromer with chain formula (1), and p-
A copolymer compound of styrylaminated dextran consisting of aminostyrene and styrene has a characteristic spectrum of styrylaminated dextran near 3 400c "1" and 103103O', and a characteristic spectrum of styrene near cm-' (- 1＠ > absorption is also shown.

Furthermore, whether the copolymer is actually copolymerized or not,
It can also 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. Furthermore, 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 in this solvent.

Furthermore, 13 (nuclear magnetic resonance spectrum diagram (solvent DMSO-d6 concentration 15%) for the compound shown in FIG. 10 above;
(room temperature; 25 MHz) is shown in FIG. 9 of the attached drawings.

As shown in Internuclear 9, signals attributed to the vinyl group of the compound of formula (1) (X is a reducing sugar residue) or the >C=C< group of the polymerizable olefin compound (2) are not recognized. However, signals assigned to methine carbon and methylene carbon are observed.

On the other hand, the chemical shift values of carbon atoms other than vinyl groups in the macromer of chain formula (1) and the compound of chain 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 was added to 2N
Dissolve or disperse in approximately 10 ml of hydrochloric acid aqueous solution and stir for 95 minutes.
The mixture is maintained at ~100°C for about 5 hours, and if any insoluble matter is present, it is filtered out, the filtrate is adjusted to 5 ml, and diluted if necessary to use as a test solution for sugar determination. Next, 1 mA' of the test solution is mixed with 5 mA' of a coloring test solution prepared by dissolving 200 mg of Antholone in a mixture of 25 ml of water and 75 mA' of sulfuric acid, and heated in a water bath at 100° C. 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. Regarding these,
The absorbance is measured at a wavelength of 620 nm, and the sugar content in the copolymer compound is determined according to Lambert-Beer's law.

As mentioned above, in the compound of formula (1), X is a reducing sugar residue.
) compound and the polymerizable olefin compound of formula (2) and the product have been described. Formation of a copolymer of the compound 1) and the compound of chain formula (2) can also be carried out in substantially the same manner as described above.

For example, using chain formula (1) esterification or its alkali salt macromer-soluble solvent such as dimethylsulfoxide, dimethylformamide, formamide, methanol, ethanol, water and combinations thereof, preferably dimethylsulfoxide or dimethylformamide, In 100 mA' of the solvent, an esterified macromer of the chain formula (1), preferably its N''H(C2H5)! salt, more preferably an esterified macromer of the chain formula (1) having an average degree of ester substitution of about 1 or more per anhydrous monosaccharide unit For example, about 50 g or less, more preferably about 59 to about 30 q, is dissolved. Next, as a polymerization initiator, for example, azobisisobutyronitrile, benzoyl peroxide, ammonium peroxide, potassium peroxide, etc. are added. In this case, when an organic solvent is used as the copolymerization medium, azobisisobutyronitrile is preferable, and for example, about 0.0%
05 mol/l to about 0.5 mol/l, more preferably about 0
．． Adding about 0.01 mol/l to about 0.05 mol/l,
When water is used as the copolymerization medium, ammonium peroxide or potassium peroxide is preferred, for example about 0.001 mol/I! based on the solvent. ~about 0.5 mol/l.

More preferably, it is added in an amount of about 0.005 mol/I to about 0.05 mol/l. Next, a polymerizable olefin compound having the chain formula (2) can be added to carry out a reaction. At this time, the addition ratio of the esterified macromer with chain formula (1) and the compound with chain formula (2) 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 esterified macromer with chain formula (1). It is recommended to change the selection as appropriate. For example, chain formula (1)
When the sugar moiety of the esterified macromer is maltose, the esterified macromer of the chain formula (1) is added, for example, to about 200 mol or less, more preferably from about 2 mol to 100 moles of the total number of moles of the chain formula (2) compound. It is preferable to use it in a proportion of about 50 moles. For example, when the sugar moiety of the esterified macromer of chain formula (1) is octamer dextran, the esterified macromer is used in an amount of, for example, about 50 moles per 100 moles of the total number of moles of the compound of chain formula (2). Hereinafter, it is more preferably used in a ratio of about 0.2 mol to about 10 mol. Then, in the same substantially oxygen-free atmosphere as described above, for example, about 0°C to about 100°C, more preferably about 0°C.
The copolymerization can be carried out under temperature conditions such as from 0.degree. C. to about 70.degree. 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
-2) is added in an amount of about 3 to about 6 times the polymerization solvent (■/V), and the desired copolymer can be separated and collected as an insoluble matter. If necessary, it can be purified by repeating the procedure of re-dissolving or dispersing the collected insoluble matter in dimethylformamide, dimethyl sulfoxide, etc., adding a poor solvent in the same manner, and re-precipitating it as an 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, the N- Glycoside/olefin compound copolymers are usually dark yellow to yellow compounds that are solid at room temperature, and may exhibit a brown to brown color when copolymerized in an aqueous medium.

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 9 is shown in FIG. 11 of the attached drawings. Ta.

As shown several times in 11, the copolymer has the formula (1
) Characteristic absorption spectra of esterified macromers,
The characteristic absorption spectrum of the copolymerized compound of formula (2) is also shown. For example, the copolymerized compound of formula (1), a sulfate/triethylamine salt of styryl-aminated dextran, which is an esterified macromer, and acrylonitrile has a characteristic spectrum of the sulfuric ester/triethylamine salt of styryl-aminated dextran12
50c "1 (SO2) and around 1030cm-' (O
-○) absorption peak and the characteristic absorption spectrum of acrylonitrile around 2 250c “1 (CEN)
The absorption peak of

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. moreover,
For example, a copolymer of sulfuric acid ester/triethylamine salt of styrylaminated dextran and styrene with a small 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 can vary greatly depending on the polymerization conditions, and is generally 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 formed from its solution into a film, sheet, or any other shape that can be formed by a casting method. .

For example, an N-glycoside/olefin compound copolymer, preferably, the sugar content of the copolymer is about 10 W/W% to
The sugar moiety in the macromer of formula (1) forming the copolymerized MSO product, more preferably the copolymer, at about 70 W/W% and having an intrinsic viscosity [η] of about 1 or more at 25°C. is 4 or more sugars, preferably about 20 g or less, more preferably about 2 g to about 10 g
9, for example, dimethylformamide, dimethyl sulfoxide, etc., and then cast the solution on a clean flat surface, such as a glass plate, under reduced pressure or normal pressure, for example, with an infrared lamp, preferably below 50°C. The membrane can then be peeled off by, for example, immersing it in water, and after further washing with water, the membrane can be immersed in methanol or ethanol and dried to form a membrane. 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, Similarly, flow molding is possible. That is, the content of the sulfated sugar in the copolymerized polymer compound, preferably, is about LOW/W% to about 50W/W%.
W% and the intrinsic viscosity of the copolymerized polymer compound, more preferably the formula (1) forming the copolymerized polymer compound.
The copolymerized polymeric compound in which the sugar moiety of the esterified macromer is 4 or more sugars and the degree of substitution of the sulfuric ester group is about 1 or more per anhydrous monosaccharide unit, particularly preferably the triethylamine salt of the copolymerized polymeric compound is about 209 Preferably about 2 or less
9 to about 10 g are dissolved in 100 ml of dimethylformamide or dimethyl sulfoxide, and the solution is then cast onto a clean flat surface, for example a glass plate, and heated under reduced pressure or normal pressure, preferably with an infrared lamp, to below 50°C. . 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 film prepared in Example 10 has m-1 of 3.2 times and m-2 of 4.4 times the solidification time of glass.
times, m-3 showed 6.0 times the blood clotting time. The blood coagulation time was measured by the partial thromboplastin time method using rabbit plasma. That is, 50 μl of rabbit plasma and platelin (Gen
Eral Liagnostic, Livision
of Warner-Lambert) 50 μl
Add it dropwise and shake it gently to mix the two liquids. 3 minutes later 0
．． Add 50 μl of 025MCaCl2 aqueous solution dropwise, 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 3.69 (20 mmol) of glucose, 80 u 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-acetone (2:1v/
v) Stir the mixture at 60 mA' for about 1 hour, filter it through a glass filter four times, and then dry under reduced pressure.

Yield: 5.4g.

Elemental analysis CHN Calculated value 59.77% 6.81% 4.98%
Analysis value 59.60% 6.95% 4688%
13C-NMR spectrum: Shown in FIG.

IR spectrum: Shown in Figure 2.

Example 2 Hydrous maltose (CI 2H2201□・H,O) 3
．． 69 (10 mmol), hydroquinone 180 mg,
36 ml of methanol, 0436 ul of 2 MH2S and 2.49 (20 mmol) of p-aminostyrene are mixed and heated under reflux for about 2 hours with stirring. After cooling, if any insoluble matter is present, it is filtered, concentrated under reduced pressure, and further dried. Next, the solid content is 2 + 1 (V/
V) Stir 601 ml of the mixed solution for about 1 hour, filter it through a glass filter four times, and then dry under reduced pressure. Yield: 4.2g.

Elemental analysis CHN Calculated value 54.17% 6.59% 3.16%
Analysis value 54.23% 6.67% 3.11%
The C-NMR spectrum is shown in Figure 3.

IR spectrum: Shown in Figure 4.

Example 3 4.549 (7 mmol) of dextran with an average molecular weight of 649 and 60 mmol of hydroquinone were dispersed in DMF 301111, then 30 μl of 2MH2SO4 and 3.36 g (28 mmol) of p-aminostyrene were added, and the mixture was heated at 45°C with stirring. Keep at ~50°C for 3 hours. After cooling, 160 ml of a 1:3 (V/V) heating medium of ethanol-ethyl ether is added, and the precipitate is centrifuged.

The resulting precipitate was dissolved in 15 mA' of dimethyl sulfoxide and then diluted with 1:1 of ethanol-ethyl ether.
3 (V/V) Add 160 mA' of hot medium and centrifuge the precipitate. The precipitate is 1 of ethanol-ethyl ether.
: 3 (V/V) Stir in hot medium 60a+1 for about 30 minutes, remove to zero, and repeat 3 times, then dry under reduced pressure. Yield: 5.2g.

elemental minute hand Calculated value: 1.86% Analysis value 1.90% The C-NMR spectrum is shown in Figure 5.

The IR spectrum is shown in Figure 6.

Example 4 4.19 (3°2 mmol) of dextran with an average molecular weight of 1285 and 70 mA' of hydroquinone were dissolved in a mixed solvent of 21 ml of dimethylformamide and 14 mA' of water.
Then 70 μl of a 2 MH 2 SO 4 aqueous solution and 2.3 g (19.2 mmol) of p-aminostyrene are added and kept under stirring at 41-45° C. for 5 hours. After cooling, a 1:2 (V/V) heating medium of methanol-ethyl ether (170 mA') was added, the precipitate was centrifuged, the obtained precipitate was dissolved in 20 ml of dimethyl sulfoxide, and then a mixture of methanol-ethyl ether 1: 2 (V/V) Hot medium lOOm
I! is added and the precipitate is centrifuged. The obtained precipitate was stirred in a methanol-ethyl ether equivalent hot medium (60 ml) for about 30 minutes, and the operation was repeated three times.
Dry under reduced pressure. Yield: 4.4g.

Elemental analysis N, 1.01% (calculated value), 0.93%
(Analytical values) The IR spectrum is shown in Figure 7.

Example 5 10.99 ml of anhydrous triethylamine sulfate complex was dissolved in a mixed solvent of 15 ml of dimethylformamide and 28 ml of formamide and kept at about 0°C with ice water. Add 1.7 g of compound and stir at about 0° C. for 24 hours. Then an equal volume of 400 ral of acetone-ethyl ether hot medium is added and the precipitate is separated. The precipitate was dissolved in dimethylformamide lQmA',
The operation of adding 100 mA' of a 3:1 (V/V) mixed solvent of acetone-ethyl ether and separating the precipitate is repeated three times.

Next, this precipitate was stirred with 60 m/ml of ethyl ether for 1 hour, and the operation of removing the precipitate was repeated three times, followed by drying under reduced pressure.

Yield: 4.4g. S content, 11.7 W/W% (average degree of substitution per anhydrous monosaccharide unit, 1.86).

The IR spectrum is shown in Figure 8.

Example 6 A series of copolymerization experiments shown in Table 1 were conducted. That is, a predetermined amount of the claimed claim (1) synthesized in Example 2 was placed in the polymerization tube.
) compound (abbreviated as SAM) and the total monomer amount of 0.
5 mol% of azobisisobutyronitrile is dissolved in a predetermined amount of dimethyl sulfoxide (abbreviated as DMSO), and then a predetermined amount of acrylonitrile (abbreviated as AN) is dissolved.
is added, cooled to about -78°C, degassed several times, and melt-sealed.

Polymerization is carried out at 60±0.5°C for a predetermined 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 the amount of dimethyl sulfoxide, and the precipitate is separated. The obtained precipitate was redissolved in dimethyl sulfoxide 5 to 15 mA', and saturated saline was dissolved at 0.05 to 0°1111! The operation of adding methanol in an amount four times that of dimethyl sulfoxide and separating the precipitate is repeated three times. For this separation operation, filtration using a glass filter or the like or centrifugation is sufficient.

The precipitate was then stirred in 60 ml of methanol, and the other operation was repeated three times, followed by drying under reduced pressure.

Redissolve in 5-15 ml of sulfoxide and saturated table salt.

The operation of adding 0.05 to 1 mA' of 0.05 to 1 mA', then adding methanol in an amount three times that of dimethyl sulfoxide, and separating the precipitate is repeated three times. Next, a precipitate;.

After stirring in 60 ID/methanol, the operation of zero separation was repeated twice, and the mixture was dried under reduced pressure.

The sugar content in mini refers to the content of sugar in the obtained copolymer. Also, [η] is 25°C in dimethyl sulfoxide.
is the limiting viscosity number at

1''C-NMR spectrum (solvent DMSO-D6; concentration 6%; room temperature; 25 MHz): Shown in FIG.

The IR spectrum is shown in Figure 10.

Example 7 A series of copolymerization experiments shown in Table 2 were conducted. That is, in the polymerization tube, a predetermined amount of the compound of formula (1) (abbreviated as SAD [4]) synthesized in Example 3 and azobisisobutyro corresponding to 0.5 mol% of the total monomer amount were added. nitrile and a predetermined amount of dimethyl sulfoxide (DM
(abbreviated as SO). Then, a predetermined amount of acrylonitrile (abbreviated as AN) is added, cooled to about -78°C, degassed several times, and melt-sealed. Polymerization is carried out at 60±0.5°C for a predetermined 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 resulting precipitate is dimethylsaccharide, where the sugar content refers to the content of sugar in the resulting 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, a predetermined amount of the compound of formula (1) (abbreviated as SAD [8]) synthesized in Example 4 and azobisisobutyronitrile corresponding to 0.5 mol% of the total monomer amount were added to the polymerization tube. and a predetermined amount of dimethyl sulfoxide (DMS).
(abbreviated as O). Then, a predetermined amount of acrylonitrile (abbreviated as AN) is added, cooled to about -78°C, degassed several times, and melt-sealed. Polymerization is carried out at 60±0.5°C for a predetermined 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 2.5 times the amount of dimethyl sulfoxide, and the precipitate is separated.

The obtained precipitate contains 5 to 15 ml of dimethyl sulfoxide.
The procedure of adding 0.05 to 1 ml of saturated saline, then adding methanol in an amount 2.5 times the amount of dimethyl sulfoxide, and separating the precipitate is repeated three times.

Next, the precipitate was stirred in 60 ml of methanol, and the operation was repeated three times, followed by drying under reduced pressure.

The sugar content in mini refers to the content of sugar in the obtained copolymer. [η] is the intrinsic viscosity at 25° C. in dimethyl sulfoxide.

Example 9 A series of copolymerization experiments shown in Table 4 were conducted. That is, a predetermined amount of the compound of formula (2) (abbreviated as SAD-8) synthesized in Example 5 and 0 of the total monomer amount were added to the polymerization tube.
．． 5 mol % of azobisisobutyronitrile is weighed out and dissolved in a predetermined amount of dimethyl sulfoxide (abbreviated as DMSO). Acrylonitrile (abbreviated as AN) and styrene (abbreviated as St) are then added to approximately -78
Cool to ℃, degas several times and melt seal. Polymerize at 60±0°5°C for a predetermined time. After cooling in ice water, the package is opened, the polymerization system is diluted with dimethyl sulfoxide if necessary, and then an ether-methanol mixed solvent (4: IV/V) in an amount five times that of dimethyl sulfoxide is added to separate the precipitate.

In the case of C-31, the precipitate was then stirred for 2 hours in a 2:1 (V/V) methanol-acetone mixture 5QmA';
Insoluble matter is separated out three times and then dried under reduced pressure.

The paternal lot was stirred in 50 ml of methanol for 2 hours,
Insoluble matter is dried under reduced pressure after repeating the operation three times.

IR spectrum (C-32): Shown in FIG. 11.

“　　　” (C-34): Shown in FIG. 12.

Example 10 Prepare the following DMSO solution.

n-1=7-0.33 g of C-32 copoly of Example 9 is dissolved in 3.6 ml of DMSO.

m-2: Copoly7-0.39 and D of C-32 of Example 9
0.159 of polyacrylonitrile with intrinsic viscosity 2.18 at 25° C. in MSO is dissolved in DMS 05, Qml.

m-3 = C-33 copoly v-0, 45 g of Example 9 is dissolved in DMSO4,0-.

1.5 mA' 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, add 15% to 2.5% sodium carbonate aqueous solution.
Soak for a minute, then wash three times with water, three times with methanol, and dry under reduced pressure. Hang a transparent membrane 10 cm in diameter.

The IR spectrum is shown in Figure 13.

[Brief explanation of drawings]

In the accompanying drawings, Figure 1 shows the 13C-
NMR spectrum diagram, Figure 2 is its IR spectrum diagram,
Figure 3 is a C-NMR spectrum diagram of the compound obtained in Example 2, Figure 4 is its IR spectrum diagram, Figure 5 is a 13C-NMR spectrum diagram of the compound obtained in Example 3, and Figure 6 is Figure 7 is an IR spectrum diagram of the compound obtained in Example 4, Figure 8 is an IR spectrum diagram of the compound obtained in Example 5, and Figure 9 is a 13C spectrum diagram of the compound obtained in Example 6. -NMR spectrum, Figure 10 is its IR spectrum, Figures 11 and 12 are IR spectrum of the compound obtained in Example 9, and Figure 13 is IR spectrum of the compound obtained in Example 10. Figure 3 Figure 5 I, ppm Procedural Amendment Shobo Ceremony) March 27, 1991

Claims (1)

[Claims] 1. The following formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) However, in the formula, R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas , tables, etc. ▼ [Here, m is an integer from 1 to 5] and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Here, n is an integer from 1 to 10]. 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 An N-glycoside vinyl compound represented by: 2. In the above formula (1), R^1 is ▲ mathematical formula, chemical formula,
The N-glycoside vinyl compound according to claim 1, which has tables, etc. ▼ or ▲ has mathematical formulas, chemical formulas, tables, etc. ▼. 3. In the above formula (1), the reducing residue of X is a reducing monosaccharide residue selected from the group consisting of xylose, ribose, glycol, galactose, and mannose; Residues of reducing oligosaccharides selected from the group consisting of maltotriose, manninotriose, cellotriose, isomaltotetraose and cellotetrose; or from starch, cellulose, dextran, pullulan, curdlan and partial hydrolysates thereof The N-glycoside vinyl compound according to claim 1, which is a residue of a reducing polysaccharide selected from the group consisting of: 4. Reducing sugar and the following formula (3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) However, in the formula, R^1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas, tables, etc. There is a group selected from the group consisting of ▼ [where m is an integer from 1 to 5] and ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ [where n is an integer from 1 to 10] R^2 represents a group selected from the group consisting of a hydrogen atom and CH_3, and the vinyl compound having an amino group represented by the following formula is reacted in a polar organic solvent or its water-containing solvent ( 1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) However, in the formula, R^1, R^2 and X have the above meanings; and X is a reducing sugar residue, its sulfate ester residue, and 1. Preparation of an N-glycoside vinyl compound represented by: a group selected from the group consisting of alkali salts of said ester residues.