JP3485394B2 - Aspartic acid-based copolymer having sugar structure in side chain and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention enables the targeted delivery of drugs to specific disease sites,
The present invention relates to an aspartic acid-based copolymer having a sugar structure in its side chain, which is a novel compound useful in a drug delivery system (DDS), and a method for producing the same.

[0002]

2. Description of the Related Art The effects and side effects of a drug in therapy are largely due not only to the physiological activity of the drug, but also to the behavior of the drug in the body (in vivo fate) after administration. In recent years, a so-called drug delivery system (DD) has been attempted to optimize drug treatment by delivering a drug to a disease site under a desired concentration-time pattern.
The idea of S) is drawing attention. Among the DDS studies, targeting is a technique in which the drug is delivered only to a target site by controlling the distribution process of the drug that has reached the systemic circulation.

[0003] In targeting using a polymer as a drug carrier, it is considered useful to have a structure having a certain affinity with a target site in the structure of the polymer to be used. Above all, introducing a sugar chain structure into the polymer,
Attempts have already been made to take up carrier macromolecules into specific cells by utilizing the highly specific sugar chain recognition mechanism possessed by glycoprotein receptors on the cell surface, and they are promising.

Further, it is easily presumed that the use of a polyamino acid as a carrier polymer will be a system advantageous for drug release because the carrier is easily biodegraded after being taken up by cells.

From the above viewpoint, for example, Hirabayashi et al. Have reported that poly-L-glutamic acid (PLGA) having an average molecular weight of about 25,000.
In which galactose is introduced as a sugar chain is disclosed (Abstracts of the 10th Annual Meeting of the Pharmaceutical Society of Japan, p132-1).
33, 1994). This polymer is synthesized by introducing ethylenediamine into PLGA using a water-soluble carbodiimide in advance and binding the hydroxyl group at the 1-position of galactose to a functional group that reacts with an amine. .

[0006] However, this method uses expensive polyglutamic acid as a raw material and requires at least 4 steps of reaction until the sugar and the polyamino acid are bound, which is industrially extremely disadvantageous and can be obtained. Since the polymer has an unnecessary bonding group between the sugar chain and the polyamino acid, it undergoes biodegradation when administered in vivo,
Undesirable components other than sugars and amino acids are generated in the body
It circulates and is extremely unsuitable as a drug carrier for DDS.

In the field of biochemistry, in the study of glycoproteins, which are said to be greatly involved in various intricate reactions and interactions in the living body, a protein having an oligosaccharide chain (polysaccharide) should be used as a model compound. Various attempts have been made to synthesize amino acids), but in any of the synthetic methods, as in the above-mentioned techniques, many take a complicated and multi-step synthetic route,
It has been desired to provide a manufacturing method that is simple and can obtain a model compound that is as close as possible to an actual glycoprotein.

[0008]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
It is intended to provide a polyamino acid derivative having a sugar chain, a precursor thereof and an inexpensive and efficient production method thereof, which are useful as a drug carrier for S or as a glycoprotein model compound for biochemical research.

[0009]

Means for Solving the Problems As a result of intensive studies for solving the above-mentioned problems, the present inventors have found that an amino sugar having an amino group at the anomeric carbon at the reducing end can be produced at a relatively low cost. The present inventors have found that the target polyamino acid derivative and its precursor, a polysuccinimide derivative, can be obtained by a simple method of reacting with succinimide, and arrived at the present invention.

That is, in the present invention, at least the general formula (13) (formula 13) or the general formula (14) is used as a monomer unit.
The other monomer unit is a unit represented by the general formula (15) to (19) (Chemical Formula 15 to 19), which is a unit group having at least one unit represented by the chemical formula (14). It is an aspartic acid-based copolymer having a sugar structure in the side chain and having a monomer unit in the molecule of 0 to 99 mol%.

[0011]

[Chemical 13]

[0012]

[Chemical 14] (R ¹ in the formula is an oligosaccharide having a degree of polymerization of 1 to 10 having an anomeric carbon at the reducing end as a binding carbon)

[0013]

[Chemical 15]

[0014]

[Chemical 16]

[0015]

[Chemical 17]

[0016]

[Chemical 18]

[0017]

[Chemical 19] (In the formula, R ² and R ³ are hydrogen, an aliphatic hydrocarbon group having 1 to 18 carbon atoms or a monovalent group selected from a cycloalkyl group, a phenyl group and a benzyl group, which may be the same or different from each other. R4 represents hydrogen or an alkali metal) Another invention is a method of introducing a sugar chain as a side chain into polyaspartic acid, which is a anomeric carbon at a reducing terminal to polysuccinimide. The method for producing an aspartic acid-based copolymer having a sugar structure in the side chain is characterized in that a sugar having an amino group is reacted with. The aspartic acid-based copolymer of the above invention can also be produced by this production method.

The sugar chain in the present invention is a low polymer (oligosaccharide) in which one type of monosaccharide or a plurality of types of monosaccharides are linked by a glycoside bond, and monosaccharides are also included. The present invention is carried out as follows. The polysuccinimide used as a raw material in the production method of the present invention is a polymer represented by the following general formula (20).

[0019]

[Chemical 20] In the general formula (20), the structure of the terminal group varies depending on the method for producing the polysuccinimide and is not particularly specified.

The aspartic acid-based copolymer referred to in the present invention is a polymer having at least 1 mol% or more of the monomer unit represented by the general formula 20 in the polymer structure, and polysuccinimide. A publicly known method can be used as a method for producing. For example, J. Amer. Che
m. Soc, 80 , 3361 (1958) discloses a method of heating and condensing aspartic acid at 200 ° C. for 2 to 3 hours. In addition, Japanese Examined Japanese Patent Publication 48-206
No. 38 discloses a method of obtaining a high molecular weight polysuccinimide by carrying out a reaction in a thin film form using a rotary evaporator with 85% phosphoric acid as a catalyst. U.S. Pat. No. 5,057,597 discloses a method for industrially obtaining polysuccinimide by heating and condensing aspartic acid in a fluidized bed.

When the molecular weight of the polysuccinimide used is too low, the molecular weight of the obtained aspartic acid-based copolymer also becomes low, and the polymer does not exhibit its properties as a polymer.
It can be said that it is not suitable for medical applications such as DS and various other applications. On the other hand, when the molecular weight is too high, the solubility in the reaction solvent is lowered and the viscosity of the reaction solution becomes too high, which is not preferable. Considering this point, the molecular weight of the polysuccinimide used is preferably about 5,000 or more and 300,000 or less. More preferably, it is 10,000 or more and 200,000 or less.

The method for producing a sugar having an amino group at the anomeric carbon at the reducing end (hereinafter simply referred to as aminated sugar) used as another raw material is not particularly limited. For example, the reducing end of the corresponding sugar is It is preferable to produce it by substituting the hydroxyl group of (4) with an amino group.

The sugar may be a low polymer (oligosaccharide) in which one kind of monosaccharide or a plurality of kinds of monosaccharide is bound by a glycosidic bond and has a reducing hydroxyl group, and the degree of polymerization thereof is 1 to several tens. However, from the viewpoint of reactivity and the like, those up to the decamer are preferable. Examples of oligosaccharides that can be used are glucose, lactose, fructose, maltose, galactose, galactobiose, maltotriose, cellobiose, isomaltose, melibiose, chitobiose, N, N-diacetylchitobiose,
Examples thereof include chitotriose and xylobiose. Preferably lactose, N, N-diacetylchitobiose,
Glucose and the like.

In the method of aminating the hydroxyl group at the reducing end of the sugar, known aminating agents can be used, but ammonium hydrogen carbonate is preferably used in consideration of reactivity and prevention of side reactions. . The aminating agent is 10 times or more moles, more preferably 20 moles, relative to the number of moles of sugar.
It is preferable to use an excess amount such that the molar ratio is not less than the molar amount.
The upper limit is not particularly limited, but it is 100 in consideration of economical efficiency.
It is preferably up to a molar ratio.

The reaction solvent used in the amination reaction may be any solvent that can dissolve the aminating agent, but water or a mixed solvent of water and a water-soluble alcohol is preferably used. The reaction temperature is preferably around 0 to 50 ° C, more preferably around 20 to 40 ° C.

The production method of the present invention is characterized by reacting the above polysuccinimide with an aminated sugar.
As the reaction solvent, a solvent that dissolves at least one of aminated sugar and polysuccinimide can be used. In order to accelerate the reaction, it is preferable to use a solvent that dissolves both polysuccinimide and aminated sugar, for example, dimethyl sulfoxide, N, N-dimethylformamide (DMF), N-methylpyrrolidone, N, A mixed solvent of N-dimethylacetamide, N, N′-dimethylimidazolidinone, sulfolane, and another solvent containing them as a main component is preferably used. Particularly preferably, dimethyl sulfoxide and DMF are used.

The starting materials (polysuccinimide, aminated sugar) and reaction solvent used are preferably dried in advance to remove water. In particular, since all the raw materials used are hygroscopic, they often contain about several percent of water. When a large amount of water is present, side reactions occur simultaneously during the reaction, and it becomes impossible to obtain an aspartic acid-based copolymer having a desired structure. The amount of water contained in the reaction system composed of the raw material and the solvent is preferably less than 18% with respect to the weight of the charged polysuccinimide. More preferably, it is less than 1%.

The composition ratio of aminated sugar to polysuccinimide is in the range of 1 to 150 mol% based on the number of moles of imide ring of polysuccinimide. It is appropriately determined according to the composition ratio of sugar chains. That is, when the composition ratio of aminated sugar to polysuccinimide increases, the molar composition of the sugar chain in the produced aspartic acid-based copolymer increases.

The concentration of the reaction system is not particularly limited as long as the progress of the reaction can be substantially maintained. The concentration of the reaction system is selected based on the concentration of polysuccinimide with respect to the reaction solvent, and generally the concentration of polysuccinimide is selected from the range of 1 to 40% by weight. Further, the optimum concentration of the aminated sugar to be used can be selected from the range of the polysuccinimide concentration of 1 to 40% by weight.

The reaction between the polysuccinimide and the aminated sugar proceeds without using a catalyst, but a basic catalyst may be used if necessary. Examples of usable catalysts include aliphatic tertiary amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, triethanolamine and triethylenediamine (DABCO), alicyclic tertiary amines such as N-methylmorpholine, and dimethyl. Examples thereof include aromatic tertiary amines such as aniline and diethylaniline, and tetramethylguanidine, which can be used alone or in combination.

If the reaction temperature is too high, the polysuccinimide may cause a side reaction with impurities in the reaction system or the aminated sugar may be modified, which is not preferable. Even if the reaction temperature is too low, the reaction proceeds. Is slow, which is not preferable. Considering this point, the reaction temperature is preferably about 0 to 100 ° C. More preferably, it is 20-80 degreeC.

The method for isolating the aspartic acid-based copolymer from the reaction solution after completion of the reaction, which is used in the production method according to the present invention, can substantially isolate the reaction product in a desired purity. If there is, it is not particularly limited. Generally, isolation operations such as concentration and reprecipitation are adopted. As a specific example, an excess poor solvent is added to the reaction solution after the reaction to form a precipitate, the precipitate is isolated by a method such as filtration and decantation, further washed with a poor solvent, and then dried. Is mentioned. Preferred poor solvents include, for example, acetone, methanol, ethanol, isopropanol, ethyl acetate, hexane, diethyl ether, tetrahydrofuran, and mixed solvents thereof. Preferred are methanol, acetone, and an acetone / hexane mixed solvent.

In the method for producing an aspartic acid-based copolymer according to the present invention, a part of polysuccinimide is treated with another substance having active hydrogen before or after reacting the polysuccinimide with an aminated sugar. It also includes opening the imide ring. As the other substance having active hydrogen, any substance capable of opening the imide ring may be used, but if exemplified, ammonia, amine, water and the like can be mentioned, and the amine has 1 to 1 carbon atoms. 18
Aliphatic hydrocarbon group, cycloalkyl group, phenyl group,
Examples thereof include primary or secondary amines having a substituent selected from the benzyl group.

Illustrating a preferred embodiment, a polymer produced by reacting 99 mol% or less of an aminated sugar with respect to the imide ring of polysuccinimide in a solvent is isolated,
Alternatively, without isolation, water is added under basic conditions such as sodium hydroxide to hydrolyze the unreacted imide ring in the polymer to give the structure of the general formula 13 or 14 and the structure of the general formula 18 or 19. An aspartic acid-based copolymer having is obtained.

Another preferred embodiment is, for example, 25 mol% based on the imide ring of polysuccinimide in a solvent.
By reacting a degree of aminated sugar, and then reacting another primary or secondary amine compound with the remaining 75 mol% of unreacted imide ring, the structure of general formula 13 or 14
An aspartic acid-based copolymer having 5 mol% and 75 mol% of the structure represented by the general formula 16 or 17 can be produced. Here, when the amount of the other amine to be reacted with the remaining unreacted imide ring is set to, for example, about 25 mol%, the general formula 13 or 14
25 mol% of the structure of, 50 mol% of the structure of the general formula 15,
It is possible to obtain an aspartic acid-based copolymer having 25 mol% of the structure of the general formula 16 or 17.

In the aspartic acid-based copolymer of the present invention, a sugar chain structure as a side chain is bonded to the polyamino acid skeleton of the main chain through only an amide bond, and those known so far (for example, the above-mentioned ones). Hirabayashi et al.'S polyglutamic acid −
(Galactose-based polymer), which has an extra linking group between the polyamino acid skeleton and the sugar chain. This means that this copolymer is suitable for use in biochemical applications, pharmaceutical applications and the like. Further, the aspartic acid-based copolymer according to the present invention generally has α
The amide type monomer unit and the β-amide type monomer unit are mixed, and the ratio of the two is not particularly limited.

If the molecular weight of this copolymer is too low, the strength as a biomedical material will be reduced, or a conformation peculiar to a polymer will be caused and the expression of a biorecognition effect cannot be expected. . On the other hand, if the molecular weight is too high, the solubility in the solvent is lowered, and the viscosity of the solution becomes too high, which is not preferable in handling. Considering this point, the molecular weight of the aspartic acid-based copolymer of the present invention is preferably about 5,000 or more and 300,000 or less. Particularly preferably, it is about 10,000 or more and 200,000 or less.

[0038]

EXAMPLES The present invention will be described in detail below with reference to examples. The physical properties shown in the examples were measured as follows. (1) Weight average molecular weight of polymer The weight average molecular weight of polymer (hereinafter referred to as Mw) is determined by gel permeation chromatography (hereinafter referred to as GP).
It is measured under the conditions of (a) or (b) below. (A) DMF-based GPC solvent: 0.01M LiBr / DMF standard substance: polystyrene device: JASCO 880-PU detector: Shodex RID-300 column: Shodex KD-804, KD-80M concentration: 0.5% by weight injection Volume: 20 μl Flow rate: 1.0 ml / min (b) Water-based GPC Solvent: 0.01 M KCl / water / methanol = 8: 2 mixed solvent Standard substance: Polyethylene oxide Device: JASCO 880-PU Detector: JASCO 830- RI column: Shodex OHpak B-804 Concentration: 0.5% by weight Injection amount: 20 μl Flow rate: 1.0 ml / min (2) Nuclear magnetic resonance spectrum (NMR spectrum) Nuclear magnetic resonance measurement device (manufactured by JEOL Ltd., Format FX-9
0) was used to dissolve the sample in deuterated dimethyl sulfoxide or deuterated water (concentration 3% by weight), and 1H-N at room temperature.
The MR spectrum (90 MHz) was measured.

Preparation Example 1 (Synthesis of β-lactosylamine) 43.2 g (0.12 mol) of lactose monohydrate was placed in a 1 l separable flask.
Then, 500 ml of water was added and dissolved, and ammonium hydrogencarbonate was added with stirring until it became supersaturated (saturated and a small amount of crystals remained at the bottom of the flask). Then, with the flask open, stir 2 while maintaining the temperature at 37 ° C in a warm water bath.
Continued for days. Meanwhile, ammonium hydrogencarbonate crystals were added little by little, taking care that the crystals remained at the bottom of the flask. The total amount of ammonium hydrogen carbonate added is 272.
It was g (3.44 mol).

The progress of the reaction was followed by thin layer chromatography (hereinafter referred to as TLC). (As a developing solvent for TLC, ethyl acetate: acetic acid: methanol: water = 4:
A mixed solvent of 3: 3: 2 (volume ratio) was used. The Rf value of lactose is 0.58, and the Rf value of β-lactosylamine is 0.34).

Two days after the reaction was started, spots of lactose were almost disappeared in TLC.
The reaction solution was concentrated under reduced pressure with a rotary evaporator.
In order to remove excess ammonium hydrogencarbonate, 500 ml of water was further added and the mixture was concentrated again under reduced pressure, which was repeated 5 times until the smell of ammonia disappeared. Finally β-lactosylamine was obtained in powder form. Yield 99%. Soluble in methanol.

Preparation Example 2 (Synthesis of glucosylamine) 10.8 g (0.06 mol) of glucose was placed in a separable flask of 500 ml, and 250 ml of water was added to dissolve it. Crystals remain on the bottom of the flask) and are added under stirring. Then, with the flask open, stirring was continued for 2 days while maintaining the temperature at 37 ° C. in a warm water bath. Meanwhile, ammonium hydrogencarbonate crystals were added little by little, taking care that the crystals remained at the bottom of the flask. The total amount of ammonium hydrogen carbonate added is 140 g
(1.77 mol).

The progress of the reaction was followed by thin layer chromatography (hereinafter referred to as TLC). (As a developing solvent for TLC, ethyl acetate: acetic acid: methanol: water = 4:
A mixed solvent of 3: 3: 2 (volume ratio) was used. The Rf value of glucose is 0.80, and the Rf value of glucosylamine is 0.42).

Two days after the reaction was started, glucose spots disappeared in TLC.
The reaction solution was concentrated under reduced pressure with a rotary evaporator.
In order to remove excess ammonium hydrogencarbonate, 250 ml of water was further added and the mixture was concentrated again under reduced pressure, and this was repeated 5 times until the smell of ammonia disappeared. Finally, glucosylamine was obtained in powder form. Yield 89%. Soluble in methanol.

Preparation Example 3 (Synthesis of N, N'-diacetylchitobiosylamine) 1
0.2 g (0.5 mmol) of N, N′-diacetylchitobiose was placed in a 00 ml eggplant-shaped flask, 10 ml of water was added and dissolved, and ammonium hydrogencarbonate was added with stirring until supersaturated. Then, with the flask open, stirring was continued for 3 days while maintaining the temperature at 37 ° C. in a warm water bath. Meanwhile, ammonium hydrogencarbonate crystals were added little by little, taking care that the crystals remained at the bottom of the flask.
The total amount of ammonium hydrogen carbonate added is 41.4 g.
(0.52 mol).

The progress of the reaction was followed by TLC.
(A mixed solvent of ethyl acetate: acetic acid: methanol: water = 2: 2: 1: 1 (volume ratio) was used as a developing solvent for TLC. The Rf value of N, N′-diacetylchitobiose was 0.49. , N, N′-diacetylchitobiosylamine has an Rf value of 0.38).

Three days after the reaction was started, spots of N, N'-diacetylchitobiose in TLC almost disappeared, so the reaction solution was concentrated under reduced pressure by a rotary evaporator. In order to remove excess ammonium hydrogencarbonate, 50 ml of water was further added and the mixture was concentrated again under reduced pressure, which was repeated three times until the smell of ammonia disappeared. Finally, N, N'-diacetylchitobiosylamine was obtained in powder form. Yield 98%.

Example 1 Polysuccinimide as a raw material (DMF-based GPC-based Mw
= 97000) was dried well under reduced pressure at 60 ° C. and dried well. As the other raw material, β-lactosylamine used was the one obtained in Preparation Example 1, which was well dried by heating under reduced pressure at 40 ° C. A molecular sieve was added to the reaction solvent, and dry nitrogen gas was blown into the reaction solvent overnight to use well dried dimethyl sulfoxide.

2.43 g of the above polysuccinimide was placed in a 50 ml separable flask, and 20 ml of dimethyl sulfoxide was added and dissolved. 2.13 g of the above β-lactosylamine (25 mol% based on the imide ring)
Was added and stirred until the system became uniform (about 5 minutes). At this point, the water content in the reaction system was measured and found to be 0.9% based on the charged polysuccinimide. The reaction system was heated with an oil bath while stirring and reacted at 75 ° C. for 3 hours.

After completion of the reaction, the reaction solution is stirred 4
The mixture was poured into 00 ml of methanol, and the white precipitate formed was collected by suction filtration. Yield about 97%. DMF GP
Mw by C = 26000. In the 1H-NMR spectrum, absorption peaks derived from the methine proton and the methylene proton of the imide ring of polysuccinimide are observed at 5 to 5.8 ppm and 2.2 to 3.7 ppm, respectively. In addition, a peak of 3.2 ppm, which seems to be derived from the methylene proton at the opened portion of the imide ring, and a unique multiplet peak extending from 3.5 to 4.9 ppm derived from the proton of lactose were observed.

Example 2 A reaction was conducted in the same manner as in Example 1 except that the glucosylamine obtained in Preparation Example 2 was used in place of lactosylamine in an amount of 40 mol% based on the number of moles of imide ring of polysuccinimide. It was

After completion of the reaction, the reaction solution is stirred 4
The mixture was poured into 00 ml of methanol, and the white precipitate formed was collected by suction filtration. Yield about 90%. DMF GP
Mw by C: 53000. In the 1H-NMR spectrum, absorption peaks derived from the methine proton and the methylene proton of the imide ring of polysuccinimide are observed at 5 to 5.8 ppm and 2.2 to 3.7 ppm, respectively. In addition, a peak of 3.2 ppm, which seems to be derived from the methylene proton at the opened portion of the imide ring, and a unique multiplet peak extending from 3.5 to 4.9 ppm derived from the proton of glucose were observed.

Example 3 Instead of lactosylamine, N obtained in Preparation Example 3,
The reaction was performed in the same manner as in Example 1 except that N′-diacetylchitobiosylamine was used in an amount of 5 mol% based on the number of imide ring mols of the polysuccinimide. After completion of the reaction, the reaction solution was put into 400 ml of stirring methanol, and the produced white precipitate was collected by suction filtration. Yield about 98%. Mw = 76000 by DMF system GPC. 1
In the H-NMR spectrum, absorption peaks derived from the methine proton and the methylene proton of the imide ring of polysuccinimide are observed at 5 to 5.8 ppm and 2.2 to 3.7 ppm, respectively. A peak of 3.2 ppm, which seems to be derived from the methylene proton of the ring-opening part, and a unique multi-line peak extending from 3.5 to 4.9 ppm, which was derived from the proton of N, N′-diacetylchitobease, were observed.

Example 4 2.28 g of the polymer obtained in Example 1 was placed in a 100 ml flask and dissolved in 20 ml of DMF. 0.74 g of n-propylamine was added thereto while stirring at room temperature.
Was added. Immediately after the addition, the temperature of the reaction solution slightly increased, and the progress of the reaction was observed. After 20 hours, the reaction solution was poured into an acetone / hexane mixed solvent for reprecipitation purification. Yield 90%. Mw 49000. 1H-
In the NMR spectrum, almost no unique peak derived from the methine proton of the imide ring of polysuccinimide at 5 to 5.8 ppm was observed, and it was confirmed that the imide ring was almost completely opened by the amine.

Example 5 1 g of the polymer obtained in Example 1 was placed in a 100 ml flask and 40 ml of water was added to suspend it. While measuring the pH of the suspension, a 2N aqueous sodium hydroxide solution was added dropwise thereto. The pH increases with each drop,
When the dropping was stopped, the pH dropped slowly. When the hydrolysis was continued slowly while adjusting the dropping rate so that the pH did not exceed 13, the liquid gradually became transparent. After several hours, the hydrolysis was completed when the pH did not drop even after the dropping was stopped. The reaction solution was concentrated to about 20 ml, poured into methanol for reprecipitation, and the precipitated polymer was recovered and dried. Yield 82%. Water-based GP
Mw by C is 52000.

[0056]

The present invention provides a novel aspartic acid-based copolymer. Since this aspartic acid-based copolymer has a sugar chain having a cell recognition function in its side chain and has a biodegradable polysuccinimide or polyaspartic acid structure in its main chain, for example, by incorporating and binding a drug. , Is a promising material for DDS that can target drugs to target cells. In addition, this aspartic acid-based copolymer can be a model compound for glycoprotein in the field of biochemistry, and has a wide range of applications. Also,
The present invention provides a simple method for producing an aspartic acid-based copolymer having a sugar structure in its side chain. This manufacturing method is
It is a method for quantitatively producing an aspartic acid-based copolymer with a small number of reaction steps, a high yield, and has a high industrial utility value.

─────────────────────────────────────────────────── ─── Continuation of front page (56) Reference JP-A-7-238162 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C08G 73/00-73/26 CAPLUS (STN ) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A method for producing an aspartic acid-based copolymer having a sugar structure in a side chain, which comprises reacting a polysuccinimide with a sugar having an amino group at the anomeric carbon at the reducing terminal. 2. A polysuccinimide is reacted with a sugar having an amino group at the anomeric carbon at the reducing end, in an amount of 99 mol% or less with respect to the imide ring of the polysuccinimide to open the remaining imide ring. 2. The method according to claim 1, wherein
For producing an aspartic acid-based copolymer having a sugar structure in its side chain.