WO2012029630A1

WO2012029630A1 - Novel polymer, novel n-carboxy-amino acid anhydride, and method for manufacturing same

Info

Publication number: WO2012029630A1
Application number: PCT/JP2011/069188
Authority: WO
Inventors: 遠藤　剛; 孝一古賀; 須藤　篤
Original assignee: Jsr株式会社
Priority date: 2010-08-31
Filing date: 2011-08-25
Publication date: 2012-03-08
Also published as: JP2013234207A

Abstract

Provided are a novel polymer, a novel compound, and a method for manufacturing same; specifically, a polymer having structural units represented by formula (A), an N-carboxy-amino acid anhydride represented by formula (B), and a method for manufacturing same. (In formulae (A) and (B), R¹ represents an optionally substituted monovalent hydrocarbon group, R² represents a hydrogen atom or an optionally substituted monovalent hydrocarbon group, and R³ represents an optionally substituted divalent hydrocarbon group.)

Description

NOVEL POLYMER, NOVEL N-carboxyamino acid anhydride, and production method thereof

The present invention relates to a novel polymer, a novel N-carboxyamino acid anhydride, and a method for producing them.

Amino acid-N-carboxyanhydrides are useful as intermediate raw materials for synthesizing polypeptides from amino acids.
Many methods for producing the amino acid-N-carboxyanhydride have been known for a long time. Recently, the present inventors have reported that an amino acid carbamate compound obtained from an amino acid or an ester thereof and diphenyl carbonate is N -Found useful as a raw material for the synthesis of carboxyamino acid anhydrides, and filed a patent application (Patent Document 1).

JP 2007-22932 A

However, the polypeptide obtained by polymerization of the N-carboxyamino acid anhydride is a normal polypeptide, and further development of a new polypeptide type polymer has been desired.
An object of the present invention is to provide a novel polymer, a novel N-carboxyamino acid anhydride, and a method for producing them.

Accordingly, the present inventors have made various studies on N-carboxyamino acid anhydrides and polymers thereof. As a result, an α-amino acid derivative having a substituted carbamoyl group is used as an N-carboxyamino acid anhydride via an amino acid carbamate compound. Thus, by polymerizing this, it was found that a novel polymer having a substituted carbamoyl group in the side chain, which is useful as a polyamide resin having biodegradability, biocompatibility, etc., was obtained, and the present invention was completed.

That is, the present invention provides a polymer having a structural unit represented by the following formula (A).

(In Formula (A), R ¹ represents a monovalent hydrocarbon group which may have a substituent, and R ² represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R ³ represents a divalent hydrocarbon group which may have a substituent.)

The present invention also provides a method for producing a polymer represented by the above formula (A), characterized by polymerizing an N-carboxyamino acid anhydride represented by the following formula (B).

(In Formula (B), R ¹ represents a monovalent hydrocarbon group which may have a substituent, and R ² represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R ³ represents a divalent hydrocarbon group which may have a substituent.)

The present invention also provides an N-carboxyamino acid anhydride represented by the following formula (B).

The present invention also provides a method for producing an N-carboxyamino acid anhydride represented by the above formula (B), wherein the amino acid carbamate compound represented by the following formula (C) is cyclized.

(In Formula (C), R ¹ represents a monovalent hydrocarbon group which may have a substituent, and R ² represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R ³ represents a divalent hydrocarbon group which may have a substituent, and R ⁴ represents a monovalent hydrocarbon group which may have a substituent.

The present invention further comprises a step of reacting an amino acid organic salt compound represented by the following formula (2) with a carbonic acid diester represented by the formula (3) to obtain an amino acid carbamate compound represented by the formula (C). And a process for producing an N-carboxyamino acid anhydride represented by the formula (B).

(In Formula (2), R ¹ represents a monovalent hydrocarbon group which may have a substituent, and R ² represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R ³ represents a divalent hydrocarbon group which may have a substituent, and AX ⁺ represents an organic onium ion.

(In Formula (3), R ⁴ and R ⁵ each independently represents a monovalent hydrocarbon group which may have a substituent.)

Furthermore, the present invention provides a biocompatible material having a polymer having a structural unit represented by the formula (A).

The polymer of the present invention is a polypeptide type polymer, and has a substituted carbamoyl group in the side chain. Therefore, the polymer of the present invention has the same properties as various polyamide resins, has biodegradability and biocompatibility, It can also be applied as a material.

<Polymer of the present invention>
The polymer of the present invention has a structural unit represented by the following formula (A).

In the formula (A), the monovalent hydrocarbon group which may have a substituent represented by R ^{1 or} R ² has an alkyl group which may have a substituent, or a substituent. An alkenyl group that may have a substituent, an cycloalkyl group that may have a substituent, an aryl group that may have a substituent, an arylalkyl group that may have a substituent, and a substituent. And a heterocyclic group which may be substituted or a heterocyclic alkyl group which may have a substituent. Examples of groups that can be substituted for these hydrocarbon groups include halogen atoms such as chlorine and fluorine, hydroxy groups, mercapto groups, amino groups, nitro groups, carboxy groups, alkoxy groups, alkoxycarbonyl groups, aralkyloxy groups, and aralkyls. An oxycarbonyl group, an epoxy group, etc. are mentioned.

The alkyl group which may have a substituent in the above R ¹ and R ² means an alkyl group in which any part of the alkyl group may be substituted, and may have a substituent. Preferred alkyl groups having 1 to 20 carbon atoms are preferable, and preferred specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group. , Trichloroethyl group, methyl mercaptoethyl group, hydroxymethyl group, hydroxyethyl group, mercaptomethyl group, mercaptoethyl group, methyl mercaptoethyl group, carboxymethyl group, carboxyethyl group, aminopropyl group, aminobutyl group, aminocarbonylmethyl group, aminocarbonyl ethyl group, pentyl group, heptyl group, octyl group, _- _(CH 2) 3 -NH- _{_{_{(= NH) -NH 2, -}}} (CH 2) 3 NH-CO-NH 2 and the like.
The alkenyl group which may have a substituent means an alkenyl group in which a part of the alkenyl group may be substituted, and the alkenyl group having 2 to 20 carbon atoms which may have a substituent. The group is preferable, and preferable specific examples include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and an octenyl group.

Further, the cycloalkyl group which may have a substituent means a cycloalkyl group in which a part of the cycloalkyl group may be substituted, and may have a substituent having 3 to 3 carbon atoms. 20 cycloalkyl groups are preferred, and preferred specific examples include cyclopropyl group, cyclopropylmethyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexylmethyl group, cycloheptyl group, cyclooctyl group, adamantyl group and the like. It is done.

Further, the aryl group which may have a substituent means an aryl group in which any part of the aryl group may be substituted, and may have a substituent having 6 to 14 carbon atoms. Aryl groups are preferred. As a preferred specific example, an optionally substituted phenyl group is preferable, and a phenyl group, tolyl group, methoxyphenyl group, benzyloxyphenyl group, ethylphenyl group, chlorophenyl group, fluorophenyl group, hydroxyphenyl group And nitrophenyl group.

Further, the arylalkyl group which may have a substituent represents an arylalkyl group in which a part of the arylalkyl group may be substituted, and preferred specific examples include a fluorenylmethyl group, benzyl Group, nitrobenzyl group, aminobenzyl group, bromobenzyl group, methoxybenzyl group, hydroxybenzyl group, dihydroxybenzyl group, phenacyl group, methoxyphenacyl group, cinnamyl group, phenethyl group and the like.

Further, the heterocyclic group which may have a substituent means a heterocyclic group in which a part of the heterocyclic group may be substituted, and preferred specific examples thereof include a tetrahydropyranyl group, a tetrahydrofuran group. Nyl group, tetrahydrothienyl group, piperidyl group, morpholinyl group, piperazinyl group, pyrrolyl group, pyrrolidinyl group, furyl group, thienyl group, pyridyl group, furfuryl group, tenenyl group, pyrimidyl group, pyrazyl group, imidazolyl group, indolyl group, isoquinolyl group Group, quinolyl group, thiazolyl group and the like.
In addition, the heterocyclic alkyl group which may have a substituent means a heterocyclic alkyl group in which a part of the heterocyclic alkyl group may be substituted, and preferred specific examples include a pyridylmethyl group. Imidazolylmethyl group, indolylmethyl group and the like.

In Formula (A), R ³ is a divalent hydrocarbon group that may have a substituent, and the divalent hydrocarbon group that may have a substituent has a substituent. An alkylene group which may be present. Examples of groups that can be substituted with these hydrocarbon groups include halogen atoms such as chlorine and fluorine, hydroxy groups, mercapto groups, amino groups, carboxyl groups, alkoxycarbonyl groups, and aralkyloxycarbonyl groups.

The alkylene group that may have a substituent in R ³ means an alkylene group in which any part of the alkylene group may be substituted, and the number of carbons that may have a substituent. 1 to 20 alkylene groups are preferred, and preferred specific examples include a methylene group, an ethylene group, a propylene group, a trimethylene group, a butylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and a trichloroethylene group.

R ¹ is preferably an aryl group having 6 to 14 carbon atoms which may have a substituent. Examples of the aryl group include a phenyl group, a tolyl group, and a naphthyl group, and a phenyl group is more preferable. Specifically, halogen atoms, hydroxy groups, mercapto groups, amino groups, nitro groups, carboxyl groups, alkoxycarbonyl groups, alkyl groups, alkoxy groups, aralkyloxy groups, aralkyloxycarbonyl groups, epoxy groups, etc. are substituted. A good phenyl group is preferred. Further, halogen atoms, hydroxy groups, mercapto groups, amino groups, nitro groups, carboxyl groups, alkyl groups having 1 to 6 carbon atoms, alkoxycarbonyl groups having 1 to 6 carbon atoms, benzyloxy groups, benzyloxycarbonyl groups, epoxy A phenyl group which may be substituted with a group or the like is more preferable, and a phenyl group is particularly preferable.

R ² is particularly preferably a hydrogen atom.

R ³ is preferably an alkylene group having 1 to 20 carbon atoms which may have a substituent, and more preferably an alkylene group having 1 to 6 carbon atoms which may have a substituent. These alkylene groups that can be substituted are preferably halogen atoms, hydroxy groups, mercapto groups, amino groups, carboxyl groups, alkoxycarbonyl groups, and aralkyloxycarbonyl groups. Specific examples of R ³ include a methylene group, an ethylene group, a propylene group, a trimethylene group, a butylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group.

In addition, since the polymer of the present invention has an asymmetric carbon atom, an optical isomer exists, but the polymer of the present invention includes any of L-form, D-form and racemate. .

The polymer of the present invention preferably has a weight average molecular weight of 500 to 500,000, more preferably 1,000 to 100,000, and a molecular weight distribution (Mw / Mn) of 1.1 to 8.0 is preferable. .3 to 3.5 is more preferable.
The weight average molecular weight can be easily adjusted by the polymerization temperature, the addition amount of the catalyst / initiator, and the molecular weight distribution can be easily adjusted by the ratio of the raw material and the solvent, the stepwise change of the polymerization temperature, and the like.

<Method for producing polymer of the present invention>
The polymer (A) of the present invention can be obtained by polymerizing an N-carboxyamino acid anhydride represented by the following formula (B).

(In the formula ^(B), R 1, ^{R 2} and ^{R 3} have the same meaning as ^R 1, ^{R 2} and ^{R 3} in formula (A).)

The reaction for polymerizing the compound represented by the above formula (B) according to the present invention can be carried out in the presence or absence of a solvent. Usually, examples of the solvent include dimethylacetamide, dimethylformamide, and N-methylpyrrolidone. Amide solvents; Sulfoxide solvents such as dimethyl sulfoxide; Ketone solvents such as methyl ethyl ketone and acetone; Ester solvents such as ethyl acetate and butyl acetate; Nitrile solvents such as acetonitrile; Halogen solvents such as chloroform and dichloromethane; Tetrahydrofuran, And ether solvents such as cyclopentane monomethyl ether.
The amount of the solvent used is preferably 20 to 2,000 parts by weight, more preferably about 100 to 1,500 parts by weight with respect to 100 parts by weight of the compound represented by the above formula (B). If the amount is less than 20 parts by weight, the compound represented by the above formula (B) may not be sufficiently dissolved in the solvent, while if it exceeds 2,000 parts by weight, the reaction rate may decrease.

The reaction for polymerizing the compound represented by the above formula (B) of the present invention can be carried out in the presence or absence of a catalyst, but the catalyst can be remarkably increased in reaction rate and reaction temperature. It is preferable to carry out in the presence. The catalyst is not particularly limited as long as it is a basic compound, but more preferably, zeolites such as molecular sieves; basic alkali metal salts such as sodium hydrogen carbonate; primary or secondary amine compounds; triethylamine, 1 , 8-diazabicyclo [5.4.0] undec-7-ene, tertiary amine compounds such as 1,4-diazabicyclo [2.2.2] octane; aromatic amine compounds such as pyridine; methylpyrrolidone, polyvinylpyrrolidone Pyrrolidone compounds such as are used.
Examples of the primary or secondary amine compound include primary or secondary amines having a hydrocarbon group having 1 to 24 carbon atoms, cyclic amines, aromatic amines, etc., for example, n-butylamine, isobutylamine, triethylene Examples thereof include tetramine, aniline, chitosan, terminal amino group-substituted polyethylene glycol, terminal amino group-substituted polypropylene glycol, and terminal amino group-substituted liquid rubber.
The amount of the catalyst added is preferably 0.01% by weight to 10% by weight, more preferably 0.05% by weight to 3% by weight in the reaction solution.

The reaction temperature of the reaction for polymerizing the compound represented by the above formula (B) of the present invention is preferably 0 to 110 ° C., more preferably 10 to 80 ° C., further preferably 20 to 70 ° C. It is preferably 1 to 200 hours, more preferably 0.5 to 72 hours, and even more preferably 1 to 48 hours.
When the reaction temperature is less than 0 ° C. in the presence of a catalyst, the reaction does not proceed sufficiently. On the other hand, when the reaction temperature exceeds 110 ° C., the compound represented by the above formula (B) as a raw material may be decomposed. When the reaction time is less than 0.1 hour, the polymerization reaction does not proceed sufficiently. On the other hand, when it exceeds 200 hours, an undesirable secondary reaction may proceed.

<Method for Producing N-Carboxyamino Acid Anhydride of the Present Invention>
The N-carboxyamino acid anhydride represented by the above formula (B) can be obtained by cyclizing an amino acid carbamate compound represented by the following formula (C). Specifically, for example, an amino acid organic salt compound represented by the following formula (2) obtained from an amino acid derivative represented by the following formula (1) and a carbonic acid diester represented by the formula (3) are reacted: The step of obtaining the amino acid carbamate compound represented by the formula (C) and the obtained amino acid carbamate compound are cyclized and dehydrated by a known method described in, for example, the above-mentioned Japanese Patent Application Laid-Open No. 2007-22932. This is a method for obtaining an N-carboxyamino acid anhydride represented by (B).

(In the formula, AX ⁺ represents an organic onium ion, R ⁴ and R ⁵ each independently represents a monovalent hydrocarbon which may have a substituent, R ¹ , R ² and R ^3. Is synonymous in the formula (A).)

Hereinafter, each reaction process will be described.

(First step)
In the first step, an amino acid having a substituted carbamoyl group (R ¹ NHCO-) represented by the formula (1) and a cationic hydroxy compound represented by AX.OH are reacted in an organic solvent to form the formula (2) Is a step of obtaining an amino acid organic salt compound represented by the formula:

The amino acid derivative represented by the formula (1) can be produced by a known means such as a method of reacting an acidic amino acid such as glutamic acid with an amine (for example, R ¹ NH ₂ ).

A commercially available hydroxy compound can be used as the cationic hydroxy compound represented by AX.OH. For example, quaternary ammonium hydroxide, specifically, tetraalkylammonium hydroxide such as tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrapentylammonium hydroxide, tetrahexylammonium hydroxide, tetraoctylammonium hydroxide, etc. In addition to trimethylphenylammonium hydroxide, trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, tetrabutylphosphonium hydroxide, trimethylsulfonium hydroxide, and the like can be given. Accordingly, AX ⁺ includes these cations, for example, quaternary ammonium ions such as tetraalkylammonium.

Examples of organic solvents include amide solvents such as dimethylacetamide, dimethylformamide, and N-methylpyrrolidone; sulfoxide solvents such as dimethyl sulfoxide; ketone solvents such as 2-butanone, methyl ethyl ketone, and acetone; esters such as ethyl acetate and butyl acetate Examples thereof include nitrile solvents such as acetonitrile; halogen solvents such as chloroform and dichloromethane; ether solvents such as tetrahydrofuran and cyclopentane monomethyl ether; alcohol solvents such as methanol, ethanol, and butanol.

The reaction is preferably performed in the presence of a dehydrating agent. Examples of the dehydrating agent include synthetic zeolite such as molecular sieve 4A, molecular sieve 3A, or molecular sieve 5A, anhydrous sodium sulfate, anhydrous magnesium sulfate, or anhydrous calcium sulfate. The reaction can usually be carried out under air, but it is desirable to carry out under an inert gas atmosphere such as argon or nitrogen. This reaction can be carried out under normal pressure, reduced pressure, or increased pressure. The reaction temperature is usually selected from the range of −70 ° C. to 120 ° C., preferably −10 to 100 ° C. The reaction time usually requires 0.1 to 100 hours.

The amino acid organic salt compound represented by the formula (2) can be produced by other known methods. For example, as described in JP-A No. 2004-269414, the AX ⁺ halide of the cation moiety is dissolved in an aqueous solvent, and is exchanged with a hydroxy compound through, for example, an anion exchange resin, which becomes an anion moiety. It is obtained by adding an amino acid to react. More specifically, 1 part by mass of a halide of AX ⁺ is dissolved in an aqueous solvent and converted to a hydroxy compound through an anion exchange resin, and the amino acid represented by the formula (1) is converted into about 1 to 1.1 parts by mass, preferably about 1.0 part by mass is added, the resulting mixed solution is stirred under ice-cooling, the solvent is distilled off under reduced pressure, and unreacted amino acids are removed from the residue by an appropriate method. A desired amino acid organic salt compound can be produced.

(Second step)
The second step is a step of obtaining the amino acid carbamate compound represented by the formula (C) by reacting the amino acid organic salt compound of the formula (2) with the carbonic acid diester of the formula (3).

The monovalent hydrocarbon group which may have a substituent in the formula (3) representing the carbonic acid diester used in the second step includes an alkyl group which may have a substituent, and a substituent. A cycloalkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkenyl group which may have a substituent, an aryl group which may have a substituent, or a substituent An arylalkyl group which may be present.

Examples of groups that can be substituted with these hydrocarbon groups include nitro groups; halogen atoms such as chlorine atoms and fluorine atoms; perfluoroalkyl groups (wherein alkyl groups are straight-chain, Branched and cyclic saturated and unsaturated alkyl groups, etc.); a perchloroalkyl group (wherein the alkyl group is the same as the perfluoroalkyl group); a halogenated alkyl group; An ester group; an acyl group having 2 to 15 carbon atoms such as an acetyl group and a benzoyl group; a cyano group, a nitro group, a halogen atom, a halogen-substituted alkyl group (wherein the alkyl group includes a perfluoroalkyl group and The same may be mentioned).

In the above “optionally substituted alkyl group”, examples of the “alkyl group” include an alkyl group having 1 to 20 carbon atoms, and an alkyl group having 1 to 10 carbon atoms is particularly preferable. Examples of the alkyl group include straight-chain and branched alkyl groups. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, Examples thereof include a tert-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, and an n-decanyl group.

In the “cycloalkyl group optionally having substituent (s)”, examples of the “cycloalkyl group” include a cycloalkyl group having 3 to 20 carbon atoms, particularly a cycloalkyl group having 3 to 10 carbon atoms. preferable. Specific examples include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
In the above “optionally substituted alkenyl group”, examples of the “alkenyl group” include alkenyl groups having 2 to 18 carbon atoms, with alkenyl groups having 2 to 10 carbon atoms being particularly preferred. Specific examples include a vinyl group, a propenyl group, and 3-butenyl.

In the “optionally substituted cycloalkenyl group”, examples of the “cycloalkenyl group” include a cycloalkenyl group having 5 to 18 carbon atoms, and a cycloalkenyl group having 5 to 10 carbon atoms is particularly preferable. . Specific examples include cyclohexenyl, cyclooctenyl, cyclododecenyl and the like.
In the “aryl group optionally having substituent (s)”, examples of the “aryl group” include aryl groups having 6 to 14 carbon atoms, and aryl groups having 6 to 10 carbon atoms are particularly preferable. Specific examples include phenyl, tolyl, naphthyl and the like.

In the “arylalkyl group optionally having substituent (s)”, examples of the “arylalkyl group” include arylalkyl groups having 7 to 13 carbon atoms, particularly arylalkyl groups having 7 to 9 carbon atoms. preferable. Specific examples include benzyl, phenethyl, naphthylmethyl, naphthylethyl and the like.

As the hydrocarbon group, an aryl group which may have a substituent is suitably used. Specific examples of the carbonic acid diester include diphenyl carbonate, bis (4-nitrophenyl) carbonate, bis (2-nitrophenyl) carbonate, bis (2,4-dinitrophenyl) carbonate, bis (2,4,6-trinitro Phenyl) carbonate, bis (pentafluorophenyl) carbonate, bis (4-chlorophenyl) carbonate, bis (2,4-dichlorophenyl) carbonate, bis (2,4,6-trichlorophenyl) carbonate and the like. Particularly preferably used.
In addition, the carbonic acid diester mentioned above can be manufactured by a well-known method, and can use a commercially available thing.

In the second step, the amount of the carbonic acid diester represented by the formula (3) to 1 mol of the amino acid organic salt compound represented by the formula (2) is preferably 1 to 10 mol, and more preferably 1 to 3 mol.

The second step can be performed in the presence or absence of a catalyst, and is usually performed in the presence of a solvent.
Solvents include amide solvents such as dimethylacetamide, dimethylformamide, and N-methylpyrrolidone; sulfoxide solvents such as dimethyl sulfoxide; ketone solvents such as 2-butanone, methyl ethyl ketone, and acetone; ester solvents such as ethyl acetate and butyl acetate. Solvents; nitrile solvents such as acetonitrile; halogen solvents such as chloroform and dichloromethane; ether solvents such as tetrahydrofuran and cyclopentane monomethyl ether; alcohol solvents such as methanol, ethanol, and butanol, etc., 2-butanone, acetonitrile , Dichloromethane, chloroform, methanol and ethanol are preferred, 2-butanone, acetonitrile and dichloromethane are more preferred, 2-butanone and acetonitrile But more preferable.
The amount of the solvent used is usually 100 to 3000 parts by weight, preferably 1000 to 2000 parts by weight, based on 100 parts by weight of the total amount of the amino acid organic salt compound and the carbonic acid diester.

The reaction temperature in the second step is preferably −30 ° C. to 35 ° C., more preferably −20 ° C. to 25 ° C. The reaction time is preferably 0.01 to 15 hours, more preferably 0.1 to 8 hours.
In addition, manufacture of the amino acid carbamate compound represented by Formula (C) can also be performed in 1 pot with manufacture of the amino acid organic salt compound represented by Formula (2).

(Third step)
The third step is a step of cyclizing the amino acid carbamate of formula (C) to obtain the N-carboxyamino acid anhydride of formula (B).

The third step is not particularly limited, but it is preferable to carry out the reaction in the presence of a weakly basic inorganic compound or a protonic acid from the viewpoint of obtaining the N-carboxyamino acid anhydride (B) in a high yield.

Examples of weakly basic inorganic compounds that can be used include solid basic compounds such as crystalline aluminosilicates, sodium hydrogen carbonate, alumina, zeolites, ion exchange resins, and silica gel. Specific examples include molecular sieves and sodium hydrogen carbonate. The amount of the weakly basic inorganic compound used is preferably 1 to 1000 parts by weight, particularly 1 to 10 parts by weight, per 100 parts by weight of the amino acid carbamates (C).

Examples of the protonic acid used include phenols, phosphoric acids, sulfonic acids, and compounds represented by general formula (10).
R ¹⁰ (C (R ¹¹ ) (R ¹² )) _n COOH (10)

(Wherein R ¹⁰ , R ¹¹ and R ¹² are each independently a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, a halogen atom, a hydroxyl group or an alkoxy; A group, an aryloxy group, a ketone group, an ester group or a carboxyl group; n represents a number from 0 to 10. However, when n = 0, R ¹⁰ may have a hydrogen atom or a substituent. (It is an aryl group which may have an alkyl group or a substituent.)

Of these, phenols and compounds represented by the above general formula (10) are preferred. Examples of phenols include electron-withdrawing group-substituted phenols such as 2,4-dinitrophenol, pentafluorophenol, cyanophenol, and (2-butanone) phenol.

In the general formula (10), examples of the alkyl group represented by R ¹⁰ , R ¹¹ , and R ¹² include linear or branched alkyl groups having 1 to 12 carbon atoms. Examples of the aryl group include aryl groups having 6 to 14 carbon atoms, and a phenyl group, a naphthyl group, and the like are preferable. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Examples of the alkoxy group include linear or branched alkoxy groups having 1 to 12 carbon atoms. Examples of the aryloxy group include aryloxy groups having 6 to 14 carbon atoms, and a phenoxy group is preferable. Examples of the group that can be substituted on the alkyl group or aryl group include 1 to 5 groups selected from a halogen atom, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an alkoxy group, and the like.

In the compound represented by the general formula (10), preferably R ¹⁰ , R ¹¹ and R ¹² are each independently selected from a hydrogen atom and an aryl group which may have a substituent, and n is 0 or 1 It is. Further, when n = 0, R ¹⁰ is an optionally substituted phenyl group, and when n = 1, R ¹⁰ , R ¹¹ and R ¹² are each independently a hydrogen atom or a substituent. Particularly preferred is a phenyl group which may have a group. Specifically, benzoic acid, p-nitrobenzoic acid, pentafluorobenzoic acid, 2,4-dinitrobenzoic acid, phenylacetic acid, diphenylacetic acid and the like are preferably used.

Examples of phosphoric acids include phosphoric acid, phosphorous acid, and hypophosphorous acid.
Examples of the sulfonic acids include aliphatic sulfonic acids and aromatic sulfonic acids. Specifically, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid are preferably used.

The amount of the protonic acid used is preferably 0.1 to 10 mol, particularly preferably 0.5 to 10 mol, per 1 mol of the amino acid carbamate (C).
In this reaction, it is considered that the weakly basic inorganic compound acts as a catalyst, and the protonic acid suppresses the decomposition of amino acid-N-carboxyanhydride.

The reaction is preferably performed in an organic solvent. Specific examples of the organic solvent that can be used in the present invention include ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and ethylene glycol dimethyl ether; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; ethyl acetate and acetic acid. Esters such as butyl; Ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; Aromatic hydrocarbons such as benzene, toluene, and xylene; Nitriles such as acetonitrile and propionitrile; Carbonates such as dimethyl carbonate; Hexane, Aliphatic hydrocarbons such as petroleum ether; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene. The use of an organic solvent is not essential and there is no particular limitation on the amount used. These solvents may be used alone or in combination of two or more.

The reaction conditions in the step of cyclizing the amino acid carbamate are not particularly limited. The reaction can usually be carried out in the atmosphere, but it is desirable to carry out the reaction under an inert gas atmosphere such as argon or nitrogen because the compounds and products used are decomposed by moisture. This reaction can be carried out under normal pressure, reduced pressure, or increased pressure. The reaction temperature is usually selected from the range of −70 ° C. to 120 ° C., preferably −10 to 100 ° C. The reaction time usually requires 0.1 to 100 hours.

The target compound should be separated from the reaction system by isolation and purification by appropriately combining conventional means such as filtration, washing, drying, recrystallization, centrifugation, activated carbon treatment, extraction with various solvents, chromatography, etc. Can do.

The polymer (A) of the present invention forms a stronger network structure than conventional polypeptides. Further, it is useful as a polyamide resin having biodegradability and biocompatibility. More specifically, it is useful as a material for biodegradable materials, biocompatible materials, for example, containers for handling biomaterials, and test instruments.

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Synthesis Example 1-1 Synthesis of N5-phenyl-L-glutamine L-glutamic acid (10.0 g, 68.0 mmol) was added to p-toluenesulfonic acid monohydrate (19.4 g, 102 mmol) trichloroethanol (15 0.2 g, 102 mmol) and toluene (200 mL) were added, and the mixture was stirred at 140 ° C. for 10 hours and filtered to obtain a p-toluenesulfonic acid salt of a compound represented by the following formula (a).
The obtained p-toluenesulfonate (18.03 g, 40.0 mmol) of the compound represented by the following formula (a) was suspended in 2-propanol (200 mL), and triethylamine (4.86 g, 48.0 mmol) was suspended. Of 2-propanol (20 mL) was added and stirred for 10 minutes, followed by filtration to obtain a glutamate of formula (a). This was reacted in dichloromethane containing aniline (3.72 g, 40.0 mmol) at 40 ° C. for 3 hours. The reaction was traced by TLC (EtOAc / Hexane / MeOH = 5/5/1) and concentrated after completion of the reaction to recover 16.86 g of product, which was purified by reprecipitation and purified by N5-phenyl-L-glutamine. Was obtained as a white solid. (82%, 7.76 g, mp: 209-211 ° C. (literature value mp: 210-211 ° C.)

Synthesis Example 1-2 Synthesis of N5-phenyl-L-glutamine tetrabutylammonium salt N5-phenyl-L-glutamine (0.489 g, 2.2 mmol) was suspended in 10 mL of ion-exchanged water, and tetrabutyl was added thereto. A methanol solution (1.334 g, 2.0 mmol) containing 38.7% ammonium hydroxide and 10 mL of methanol were added, and the mixture was stirred at room temperature for 1 hour. TLC tracking did not confirm aniline spots. After concentration, acetonitrile was added to remove the excess N5-phenyl-L-glutamine that had precipitated. The obtained filtrate was concentrated to obtain a tetrabutylammonium salt of N5-phenyl-L-glutamine as a solid. (94%, 0.871g)
¹ H-NMR (CDCl ₃ ) 1.00 (t, 12H), 1.44 (m, 8H), 1.65 (m, 8H), 2.02-2.16 (m, 1H), 2. 28-2.40 (m, 1H), 2.48-1.73 (m, 2H), 3.3 (m, 8H), 3.62 (m, 1H), 5.91 (d, 1H) , 7.26-7.40 (m, 5H).

Synthesis Example 1-3 Synthesis of N5-phenyl-L-glutamine-N1-phenylcarbamate N5-phenyl-L-glutaminetetra-tetrahydrofuran was added to an acetonitrile solution (7.3 ml) of diphenyl carbonate (0.370 g, 1.73 mmol). A reaction was started by adding an acetonitrile solution (10 mL) of butylammonium salt (0.800 g, 1.73 mmol). The progress of the reaction was confirmed by TLC (Hexane / EtOAc = 3/1). After 5 minutes from the start of the reaction, the disappearance of diphenyl carbonate was confirmed, and 1N HCl was added to stop the reaction. After concentration, extraction, washing and drying yielded the product. Next, purification by column chromatography gave N5-phenyl-L-glutamine-N1-phenylcarbamate. Isolated yield: 521.2 mg, isolated yield: 88%.

Synthesis Example 1-4 Synthesis of N5-phenyl-L-glutamine-N1-carboxy anhydride N5-phenyl-L-glutamine-N1 was placed in a 100 mL two-necked round bottom flask equipped with a Dimroth condenser under a nitrogen atmosphere. -514 mg (1.5 mmol) of phenyl carbamate, 313 mg (1.5 mmol) of diphenylacetic acid and 15 mL of 2-butanone were added and stirred at 80 ° C for 20 hours. Next, purification by column chromatography gave N5-phenyl-L-glutamine-N1-carboxyanhydride. Isolated yield: 283.0 mg, isolated yield: 76%.

(Synthesis Example 1-5) Synthesis of poly (N5-phenyl-L-glutamine) In a nitrogen atmosphere, 140 mg (0.5 mmol) of N5-phenyl-L-glutamine-N1-carboxy anhydride and 0.5 mL of dichloroethane were added to a polymerization tube. N-Butylamine (0.025 mmol, 5 mol%) was added as a polymerization initiator, and the mixture was stirred at 30 ° C. for 3 hours. After completion of the reaction, reprecipitation was performed with methanol-hexane to obtain poly (N5-phenyl-L-glutamine) as a white precipitate. When the obtained product was analyzed by IR, absorption indicating the presence of the amide bond of the main chain and the amide group of the side chain appeared at 1665 cm ⁻¹ and 1683 cm ⁻¹ , respectively, and poly (N5-phenyl- It was confirmed that (L-glutamine) was obtained.
The resulting polypeptide is insoluble in highly polar solvents such as dimethyl sulfoxide and does not dissolve even when trifluoroacetic acid is added. Therefore, it has a strong network due to hydrogen bonding between amide groups and stacking of phenyl groups. The formation of structure was suggested.

Claims

A polymer having a structural unit represented by the following formula (A).

(In Formula (A), R 1 represents a monovalent hydrocarbon group which may have a substituent, and R 2 represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R 3 represents a divalent hydrocarbon group which may have a substituent.)
R 1 is an aryl group having 6 to 14 carbon atoms which may have a substituent; R 2 is a hydrogen atom; R 3 may have 1 to 20 carbon atoms which may have a substituent The polymer according to claim 1, which is an alkylene group of
R 1 is a halogen atom, a hydroxy group, a mercapto group, an amino group, a nitro group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a benzyloxy group, a benzyloxycarbonyl group, and 3. The heavy group according to claim 1, wherein the phenyl group may have a substituent selected from an epoxy group; R 2 is a hydrogen atom; and R 3 is an alkylene group having 1 to 6 carbon atoms. Coalescence.
The method for producing a polymer according to claim 1, wherein an N-carboxyamino acid anhydride represented by the following formula (B) is polymerized.

(In Formula (B), R 1 represents a monovalent hydrocarbon group which may have a substituent, and R 2 represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R 3 represents a divalent hydrocarbon group which may have a substituent.)
R 1 is an aryl group having 6 to 14 carbon atoms which may have a substituent; R 2 is a hydrogen atom; R 3 may have 1 to 20 carbon atoms which may have a substituent The production method according to claim 4, wherein the alkylene group is
R 1 is a halogen atom, a hydroxy group, a mercapto group, an amino group, a nitro group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a benzyloxy group, a benzyloxycarbonyl group, and 6. The production method according to claim 4 or 5, which is an optionally substituted phenyl group selected from an epoxy group; R 2 is a hydrogen atom; and R 3 is an alkylene group having 1 to 6 carbon atoms.
N-carboxyamino acid anhydride represented by the following formula (B).

(In Formula (B), R 1 represents a monovalent hydrocarbon group which may have a substituent, and R 2 represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R 3 represents a divalent hydrocarbon group which may have a substituent.)
R 1 is an aryl group having 6 to 14 carbon atoms which may have a substituent; R 2 is a hydrogen atom; R 3 may have 1 to 20 carbon atoms which may have a substituent The compound according to claim 7, which is an alkylene group of
R 1 is a halogen atom, a hydroxy group, a mercapto group, an amino group, a nitro group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a benzyloxy group, a benzyloxycarbonyl group, and The compound according to claim 7 or 8, which is an optionally substituted phenyl group selected from epoxy groups; R 2 is a hydrogen atom; and R 3 is an alkylene group having 1 to 6 carbon atoms.
The method for producing an N-carboxyamino acid anhydride according to claim 3, wherein the amino acid carbamate compound represented by the following formula (C) is cyclized.

(In Formula (C), R 1 represents a monovalent hydrocarbon group which may have a substituent, and R 2 represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R 3 represents a divalent hydrocarbon group which may have a substituent, and R 4 represents a monovalent hydrocarbon group which may have a substituent.
. )
5. The process of obtaining the amino acid carbamate compound represented by Formula (C) by reacting the amino acid organic salt compound represented by following formula (2), and the carbonic acid diester represented by Formula (3). A process for producing an N-carboxyamino acid anhydride.

(In Formula (2), R 1 represents a monovalent hydrocarbon group which may have a substituent, and R 2 represents a monovalent hydrocarbon group which may have a hydrogen atom or a substituent. R 3 represents a divalent hydrocarbon group which may have a substituent, and AX + represents an organic onium ion.

(In Formula (3), R 4 and R 5 each independently represents a monovalent hydrocarbon group which may have a substituent.)
R 1 is an aryl group having 6 to 14 carbon atoms which may have a substituent; R 2 is a hydrogen atom; R 3 may have 1 to 20 carbon atoms which may have a substituent The production method according to claim 10 or 11, wherein the alkylene group is.
R 1 is a halogen atom, a hydroxy group, a mercapto group, an amino group, a nitro group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a benzyloxy group, a benzyloxycarbonyl group, and The production method according to claim 10 or 11, which is an optionally substituted phenyl group selected from epoxy groups; R 2 is a hydrogen atom; and R 3 is an alkylene group having 1 to 6 carbon atoms.
A biocompatible material comprising the polymer according to any one of claims 1 to 3.