JP7004990B2 - Method for Producing Cyclic Peptide NMP Initiator and Multiblock Polymer - Google Patents

Description

The present invention relates to a cyclic peptide NMP initiator and a method for producing a multi-block polymer using the initiator.

Artificial peptides are attractive biopolymers that can be easily designed for higher-order structures and various functions (stimulation responsiveness, cell affinity, etc.) based on amino acid sequences. On the other hand, synthetic polymers such as vinyl polymers are mass-produced in terms of mechanical properties, processability, and synthetic scale advantages, and are indispensable materials for our daily lives.

In recent years, there has been a demand for higher functionality of materials while maintaining the superiority of general-purpose polymers, and a hybrid strategy for introducing highly functional peptides into synthetic polymers has been proposed, for example, non-patented. Documents 1 and 2 describe the synthesis method.

By the way, the conventional radical polymerization consists of four elementary reactions: an initiation reaction, a growth reaction, an termination reaction, and a chain transfer reaction. When the initiator is decomposed by various stimuli such as heat, light, oxidation / reduction, etc. and a radical is generated, it reacts with the monomer one after another (growth reaction), and at the same time, the growth terminal radical undergoes a recombination reaction or disproportionation. It becomes a dead polymer by undergoing a termination reaction due to the conversion reaction. The generation of the initiator radical proceeds irreversibly, and the termination reaction occurs at a rate close to the diffusion rate-determining rate. Therefore, each of the generated radical species undergoes a rapid termination reaction and loses the activity of the polymerization terminal.

On the other hand, living radical polymerization is characterized in that the growth terminal radicals are reversibly generated from dormant species having a functional group suitable for radical generation. That is, the generation of active species P radicals from the resting species PY (activation reaction), the reaction with the monomer (growth reaction), and the conversion reaction to the resting species by recombination with Y (inactivation reaction). It consists of three elementary reactions.

Living radical polymerization includes atom transfer radical polymerization (ATRP), nitroxide-mediated radical polymerization (hereinafter abbreviated as NMP (Nitroxide-mediated Polymerization)), reversible addition cleavage chain transfer (RAFT) polymerization, and organic tellurium compounds. There are mediated living radical polymerization (TERP) and the like.

The polymerization mechanism of NMP is a reversible dissociation-recombination reaction between P radicals and nitroxyl radicals (Non-Patent Document 3). The carbon-oxygen bond of the alkoxyamine derivative is cleaved to generate a P radical and a nitroxyl radical which is a stable radical, and the P radical reacts with the monomer to extend the polymer chain. In addition, living polymerization occurs by reaching a steady state in which a heterocoupling reaction between P radicals and nitroxyl radicals selectively occurs at an extremely fast stage of polymerization due to the stable radical effect. In addition, various initiators for NMP have been proposed (Patent Documents 1 and 2, Non-Patent Document 4).

Multi-block synthesis with the peptide repeatedly in the vinyl polymer main clavicle has not been realized, contrary to its attractive structural properties. This is because, in general, multi-block type synthesis is limited to systems that utilize the reaction between polymer terminal groups, and it is difficult to utilize this synthesis strategy in chain polymerization (vinyl polymer) systems.

Special Table 2006-514133 Special Table 2006-516669 Gazette

K.Luo et al., Macromolecules, 2011,44,2481 S.E.Grieshaber et al., Soft Matter, 2013,9,1589. A.Goto, T.Fukuda, Macromolecules, 30, 5183-5186, (1997). N.Ide, T.Fukuda, Macromolecules, 30, 4268-4271, (1997).

The present invention has been made in view of such problems, and an object of the present invention is to provide a new synthetic method capable of easily producing a multi-block type polymer composed of an artificial peptide and a vinyl polymer.

A multi-block polymer having a peptide in the main chain of a vinyl polymer is produced by polymerizing a vinyl monomer using a cyclic peptide NMP initiator having the following formula.

S1及びS2は、-O-CH₂-CH₂-部分を有するスペーサーであり(l及びmはそれぞれ1～4)、X2は、両端にカルボキシル基を有するアミノ酸、若しくは、両端にカルボキシル基を有するアミノ酸誘導体であり、Zは、開環によりニトロキシラジカルを発生する化合物である。 Here, in the above formula, X1 is a peptide (-NH-CHR _X - CO-) consisting of amino acids that may be the same or different or derivatives thereof (n is 1 to 20), where R _x is the following formula . Consists of

S1 and S2 are spacers with -O-CH ₂ -CH ₂ -parts (l and m are 1 to 4 respectively), and X2 is an amino acid having a carboxyl group at both ends or a carboxyl group at both ends. An amino acid derivative, Z is a compound that generates a nitroxy radical by ring opening.

According to the present invention, a multi-block polymer composed of an artificial peptide and a vinyl polymer can be easily produced.

It is a figure which shows the GPC measurement result which compared the multi-block copolymer of cyclic (Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1) and styrene, and the fragment thereof. It is a figure which shows the FT-IR measurement result which compared the multi-block copolymer of cyclic (Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1) and styrene, and the fragment thereof. It is a figure which shows the 1H NMR spectrum measurement result which compared the multi ^- block copolymer of cyclic (Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1) and styrene, and the fragment thereof. It is a figure which shows the GPC measurement result which compared the copolymer of styrene and acrylonitrile using cyclic (Asp-deg-(Leu-Gly) ₂ -deg-TEMPO) (CyPI 2), and the fragment thereof. The figure which shows the FT-IR measurement result which compared the copolymer of styrene and acrylonitrile using cyclic (Asp-deg-(Leu-Gly) ₂ -deg-TEMPO) (CyPI 2) and the fragment thereof. be. The figure which shows the ¹ H NMR spectrum measurement result which compared the copolymer of styrene and acrylonitrile using cyclic (Asp-deg-(Leu-Gly) ₂ -deg-TEMPO) (CyPI 2), and the fragment thereof. Is.

Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings, but the embodiments are for facilitating the understanding of the principles of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiments, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.

Through diligent research, the present inventor has found that a multi-block polymer composed of an artificial peptide and a vinyl polymer can be easily produced by combining solid-phase peptide synthesis and nitroxide-mediated polymerization. That is, a cyclic peptide NMP initiator in which an NMP moiety that reversibly generates stable radicals by heat is introduced into the peptide main chain skeleton is newly designed and synthesized, and various vinyl monomers are radically polymerized using this.

The cyclic peptide NMP initiator is represented by the following formula.

Here, in the above formula, X1 is a peptide consisting of amino acids or derivatives thereof which may be the same or different (n is 1 to 20), and S1 and S2 are spacer groups (l and m are 0 to 0, respectively). 4), X2 is an amino acid or an amino acid derivative having a side chain functional group capable of reacting with an amino group or a carboxyl group.

Z is a compound capable of generating a nitroxyl radical, and is preferably represented by the following formula.

Here, R1 to R4 are alkyl groups that may be the same or different, and the alkyl group is a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, or an alkoxyalkyl group. , Esther group, ester alkyl group, or phenyl group, pyridyl group, amino group, hydroxyl group, fluorine atom, chlorine atom), which may have one or more linear chains or branches having 1 to 6 carbon atoms. It is an alkyl group of the chain.

When Z is represented by the above formula, the cyclic peptide NMP initiator is represented by the following formula.

Z is more preferably TEMPO represented by the following formula. TEMPO is an abbreviation for 2,2,6,6-tetramethylpiperidine 1-oxyl, a type of nitroxyl radical (R ₂ NO?).

Note that Z is not limited to the above formula, and for example, those shown below can also be used (note that, as described above, R1 to R4 are alkyl groups which may be the same or different. Yes, this alkyl group may have a substituent as described above).

As Z, 2,2,5-trimethyl-4-phenyl-3-azahexane nitroxide (TIPNO) and N-tert-butyl-1-diethylphosphono-2,2-dimethylpropylnitroxide (DEPN) can also be used.

As described above, X1 is a peptide consisting of amino acids or derivatives thereof which may be the same or different, and the peptide is preferably abbreviated as SPPS (Solid-phase peptide synthesis). It can be synthesized by.). Here, the peptide solid-phase synthesis method generally uses beads or the like of a polystyrene polymer gel having a diameter of about 0.1 mm whose surface is modified with an amino group as a solid phase, from which amino acid chains are extended one by one by a dehydration reaction. When the sequence of the target peptide is completed, it is cut out from the surface of the solid phase to obtain the target substance.

Amino acids are compounds having an amino group and a carboxy group in the same molecule, and branched amino acids are also included. Here, the branched amino acid means an amino acid having a carbon chain branched into a side chain. The amino acid derivative means an amino acid in which an amino group or a carboxy group is modified with a protecting group. The protecting group is not particularly limited as long as it is generally used as a protecting group for an amino group and a carboxy group. Specifically, examples of the amino acid protective group include a formyl group, an acetyl group, a trichloroacetyl group, an α-chloroacetyl group, a trifluoroacetyl group, a benzoyl group, a t-butyloxycarbonyl group and a benzyloxycarbonyl group. Examples thereof include a tosyl group, a methethylen sulphonyl group, a trityl group, a xanthyl group and the like. Examples of the protective group of the carboxylic acid include a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a benzyl group, an O-benzyl group, a nitrobenzyl group and the like.

As mentioned above, S1 and S2 are spacer groups. As the spacer group, either a hydrophobic or hydrophilic spacer can be used, but a hydrophilic spacer is preferable. The hydrophilic spacer is preferably an ethylene glycol group, more preferably a diethylene glycol group. Further, alkylene, aryl, alkylene ether groups and the like can also be used.

X2 is an amino acid or an amino acid derivative having a side chain functional group capable of reacting with an amino group or a carboxyl group, but can be widely used as long as it has a side chain capable of reacting with the terminal of the peptide chain and cyclizing. Amino acid having a carboxyl group at both ends, or an amino acid derivative having a carboxyl group at both ends is preferable. Here, the amino acid having a carboxyl group at both ends is, for example, glutamic acid or aspartic acid. Amino acid derivatives having carboxyl groups at both ends include, for example, a lysine derivative in which a carboxyl group is introduced into the N-terminal of lysine via a peptide bond, and a serine derivative in which a carboxyl group is introduced into a hydroxy group of serine via an ester bond. Examples thereof include a serine derivative in which a carboxyl group is introduced into a hydroxy group of threonine via an ester bond. It is also possible to bind the azide to the alkyne by a click reaction, in which case X2 has, for example, a 1,2,3-triazole structure.

Next, a method for synthesizing the cyclic peptide NMP initiator according to the present embodiment will be shown. Cyclic peptide NMP initiator is used to react the radically polymerizable monomer X-CHCH ₂ . Radical-polymerizable monomers include, for example, acrylonitrile, methacrylonitrile, methylmethacrylate, ethylmethacrylate, butylmethacrylate, propylmethacrylate, hydroxyethylmethacrylate, hydroxypropylmethacrylate, glycidylmethacrylate, acrylamide, methacrylamide, styrene, parachlorostyrene, penta. Fluorostyrene, 4-vinylpyridine, 2-vinylpyridine and the like can be mentioned. Cyclic peptide NMP initiators reversibly generate stable radicals by thermal dissociation. The reaction temperature is, for example, 90 ° C. or higher, preferably 110 ° C. or higher. This is because the activation reaction of NMP is relatively slow, so that the polymerization temperature is preferably relatively high. The NMP activation mechanism is the thermal dissociation reaction of the carbon-oxygen bond of the alkoxyamine derivative, which is a dormant species. When P radicals and Y radicals are generated from dormant species PX by thermal dissociation, the P radicals react with the monomer to extend the molecular chain, which then undergoes a coupling reaction with the nitroxyl radicals to inactivate them into dormant species. Will be done. During the polymerization reaction, the stable radical effect rapidly reaches a steady state in which a heterocoupling reaction between P radicals and nitroxyl radicals selectively occurs, and the formation of dead polymers due to homocoupling between P radicals is suppressed. Radical. Since this heterocoupling reaction, that is, the inactivation reaction, occurs at a sufficiently high rate as compared with the addition reaction of the P radical monomer, the molecular weight distribution is controlled.

(1) 4-((((9H-fluoren-9-yl) methoxy) carbonyl) amino)-(2,2,6,6-tetramethylpiperidine-1-oxyl) free radical (Fmoc-NH-TEMPO) synthesis As shown below, NH ₂ -TEMPO 1.62 g (9.45 mmol), Fmoc-OSu 3.04 g (9 mmol) and triethylamine 1.25 mL (9 mmol) were dissolved in 20 mL of dichloromethane and reacted at room temperature for 20 hours. After the reaction, the reaction solution was added to 100 mL of a mixed solution of hexane / ethyl acetate (v / v = 3/7) and washed 3 times with 100 mL of dilute hydrochloric acid at pH 2, so that unreacted NH ₂ -TEMPO and triethylamine and triethylamine were washed. The hydrochloride was removed. The organic layer was recovered and dehydrated with anhydrous sodium sulfate. After dehydration, sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation was performed by silica gel column chromatography using a mixed solvent of hexane / acetone (v / v = 7/3) as the developing solvent, and a fraction with an Rf value of 0.65 (TLC) was recovered. By removing the solvent from the recovered solution under reduced pressure, the desired Fmoc-NH-TEMPO 3.05 g (7.74 mmol) was obtained as an orange solid (yield: 86.0%). It is impossible to detect in the ¹ H NMR spectrum due to the influence of electron spin. Therefore, the structure was determined by DART-MS spectral measurement.

(2) tert-butyl 2-((4-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,2,6,6-tetramethylpiperidine-1-yl) oxy) -2- Synthesis of methylpropanoate (Fmoc-NH-TEMPO-COOtBu) Fmoc-NH-TEMPO 0.98 g (2.48 mmol), tert-butyl 2-bromo-2-methylpropanoic acid 0.92 mL (4.96 mmol), reducing agent as shown below. Cu (0) 0.158 g (2.48 mmol), Cu (OTf) ₂ 18 mg (5.96 × 10 ^-2 mmol) as catalyst and N, N, N', N ”, N” -pentamethyldiethylenetriamine 41.6 μL (0.20) Ethyl) was dissolved in 20 mL of methanol, the solution was transferred to a test tube, and the mixture was frozen and degassed to remove oxygen from the system. After degassing, the tube was sealed and reacted at 60 ° C. for 24 hours under a nitrogen atmosphere. After the reaction, add the reaction solution to 100 mL of hexane / ethyl acetate (v / v = 1/1) mixed solution, and wash 3 times each with 100 mL of 0.1 M EDTA _aq (pH 8.0) and 100 mL of distilled water. This removed copper, the ligand and its complex. The organic layer was recovered and dehydrated with anhydrous sodium sulfate. After dehydration, sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation was performed by silica gel column chromatography using a mixed solvent of hexane / diethyl ether (v / v = 2/1) as the developing solvent, and a fraction with an Rf value of 0.32 (TLC) was recovered. By removing the solvent from the recovered solution under reduced pressure, 0.84 g (1.56 mmol) of the desired Fmoc-NH-TEMPO-COOtBu was obtained as an orange solid (yield: 69.2%). The structure was determined by ¹ H NMR spectrum measurement.

(3) 2-((4-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,2,6,6-tetramethylpiperidine-1-yl) oxy) -2-methylpropanoic acid ( Synthesis of Fmoc-NH-TEMPO-COOH) Fmoc-NH-TEMPO-COOtBu 0.81 g (1.51 mmol) with 2,2,2-trifluoroacetic acid / dichloromethane / triisopropylsilane (v / v / v) as shown below = 8.5 / 1 / 0.5) Dissolved in 30 mL of mixed solution and reacted at room temperature for 12 hours. Remove 2,2,2-trifluoroacetic acid and dichloromethane from the reaction solution under reduced pressure, and recrystallize from 30 mL of hexane / acetone (v / v = 2/1) to obtain the desired Fmoc-NH-TEMPO-COOH 0.36 g. (0.75 mmol) was obtained as a white solid (yield: 49.8%). The structure was determined by ¹ H NMR spectrum measurement.

(4) Synthesis of Cyclic Peptide NMP Initiator Cyclic Peptide NMP Initiator cyclic (Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1), cyclic (Asp-deg- (Leu-Gly) ₂ ) -deg-TEMPO) (CyPI 2) and cyclic (Asp-deg- (Glu (OBz)) ₄ -deg-TEMPO) (CyPI 3) were synthesized by the Fmoc peptide solid phase synthesis method, respectively. First, Fmoc-NH-SAL MBHA Resin 0.30 g (0.20 mmol) was swollen with 5 mL of DMF for 3 hours. The resin was then treated with a mixed solution of piperidine / DMF (v / v = 1/4) to deprotect the Fmoc groups and washed repeatedly with 5 mL of DMF until neutral. There, Fmoc-Asp (OAl) -OH 0.24 g (0.60 mmol) dissolved in 5 mL of DMF as a solvent, DIPC 0.076 g (0.60 mmol) as a condensing agent, and HOBt 0.081 g (0.60 mmol) as a condensation accelerator were added. In addition, amino acid coupling was performed by reacting at room temperature for 3 hours. After coupling, it was repeatedly washed with 5 mL of DMF to remove unreacted residual reagents. By repeating the Fmoc group deprotection and amino acid condensation reaction cycle using various Fmoc-amino acids, Fmoc-NH-deg-COOH and Fmoc-NH-TEMPO-COOH, the linear peptide of the desired sequence is placed on the resin. Was synthesized. Next, the resin was treated in 10 mL of dichloromethane with tetrakistriphenylphosphine palladium 0.023 g (0.020 mmol) as a catalyst and phenylsilane 0.25 mL (2.0 mmol) as an allyl supplement, and treated at room temperature for 3 hours to obtain OAl. The group was deprotected. After the reaction, the Fmoc group was deprotected by washing with 5 mL of DMF 10 times and treating with a mixed solution of piperidine / DMF (v / v = 1/4). Repeatedly wash with 5 mL of DMF until neutral, and add 0.076 g (0.60 mmol) of DIPC as a condensing agent and 0.081 g (0.60 mmol) of HOBt as a condensation accelerator to the linear peptide on the resin in 5 mL of DMF at room temperature. By allowing it to act for 6 hours, an intramolecular cyclization reaction of the peptide was carried out on the resin. After the cyclization reaction, wash several times with 5 mL of DMF and 5 mL of dichloromethane, respectively, and then 2,2,2-trifluoroacetic acid / dichloromethane / triisopropylsilane (v / v / v = 8.5 / 1 / 0.5) mixed solution 10 mL was added and the reaction was carried out at room temperature for 4 hours, and the peptide was excised from the resin. The resin was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. Finally, purification was performed by a reprecipitation method using diethyl ether as a non-solvent to obtain the desired CyPIs 1, 2 and 3 as white solids, respectively. The structure was determined by MALDI-TOF MS spectrum and ¹ H NMR spectrum measurement.

The cyclic peptide NMP initiator cyclic (Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1) obtained by synthesis is shown below.

In addition, the cyclic peptide NMP initiator cyclic (Asp-deg- (Leu-Gly) ₂ -deg-TEMPO) (CyPI 2) synthesized and obtained as described above is shown below.

The cyclic peptide NMP initiator cyclic (Asp-deg- (Glu (OBz)) ₄ -deg-TEMPO) (CyPI 3) synthesized as described above is shown below.

(5) Synthesis of multi-block copolymer using cyclic peptide NMP initiator Styrene, parachlorostyrene, 4-vinylpyridine and styrene-acrylonitrile using cyclic peptide NMP initiators CyPI 1, 2 and 3 as shown below. A multi-block polymer (Entry AF) composed of a polymer was synthesized. The reaction conditions and molecular weight are shown in the table below.

First, CyPI 0.010 mmol and monomer 1.0 mmol were dissolved in DMF so that the monomer concentration was 6 M, the solution was transferred to a test tube, and oxygen was removed from the system by freezing and degassing. After degassing, the tube was sealed and reacted at 110 or 120 ° C. under a nitrogen atmosphere for 18 to 144 hours. After the reaction, the target polymer was obtained as a white solid by reprecipitation from methanol or diethyl ether. The molecular weight and polydispersity were determined by GPC, and the structure was determined by FT-IR and ¹ H NMR spectrum measurements.

Fragmentation of the polymer chain was performed to confirm that the obtained polymer (Entry AF) had a multi-block structure as shown below. First, 10 mg of polymer and 40 mg (> 400 eq) of TEMPO in excess are dissolved in 100 μL of N-methyl-2-pyrrolidone, and the solution is transferred to a test tube and frozen and degassed to remove oxygen from the system. did. After degassing, the tube was sealed and reacted at 110 ° C. under a nitrogen atmosphere. After the reaction, reprecipitation from methanol or diethyl ether gave the desired fragmented polymer as an orange or brown solid. The molecular weight and polydispersity were determined by GPC, and the structure was determined by FT-IR and ¹ H NMR spectrum measurements.

(5-1) Polymerization of Styrene Using Cyclic Peptide NMP Initiator cyclic (Asp-deg-Leu4-deg-TEMPO) (CyPI 1) As an example of synthesis of a multi-block copolymer, cyclic peptide NMP initiator cyclic (Asp- The polymerization of styrene using deg-Leu ₄ -deg-TEMPO) (CyPI 1) is shown below. In the same manner as above, CyPI 1 0.010 mmol and styrene monomer 1.0 mmol were dissolved in DMF so that the monomer concentration was 6 M.

It was also confirmed that the obtained polymer had a multi-block structure as shown below.

The molecular weight and polydispersity were determined by GPC, and the structure was determined by FT-IR and ¹ H NMR spectrum measurements. FIG. 1 shows the GPC measurement results comparing the multi-block copolymer and the fragment. The polydispersity index PDI = Mw / Mn. FIG. 2 shows the FT-IR measurement results comparing the multi-block copolymer and the fragment. FIG. 3 shows the ¹ H NMR spectrum measurement results comparing the multi-block copolymer and the fragment.
(5-2) Polymerization of 4-vinylpyridine using cyclic peptide NMP initiator cyclic (Asp-deg-Leu4-deg-TEMPO) (CyPI 1) As an example of synthesis of a multiblock copolymer, the cyclic peptide NMP initiator cyclic The polymerization of 4-vinylpyridine using (Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1) is shown below. In the same manner as above, CyPI 1 0.010 mmol and 4-vinylpyridine 1.0 mmol were dissolved in DMF so that the monomer concentration was 6 M.

(5-3) Polymerization of Parachlorostyrene Using Cyclic Peptide NMP Initiator cyclic (Asp-deg-Leu4-deg-TEMPO) (CyPI 1) As an example of synthesis of a multi-block copolymer, cyclic peptide NMP initiator cyclic (5-3) The polymerization of parachlorostyrene using Asp-deg-Leu ₄ -deg-TEMPO) (CyPI 1) is shown below. In the same manner as above, CyPI 1 0.010 mmol and parachlorostyrene 1.0 mmol were dissolved in DMF so that the monomer concentration was 6 M.

(5-4) As an example of the synthesis of a copolymerized multiblock copolymer of styrene and acrylonitrile using the cyclic peptide NMP initiator cyclic (Asp-deg- (Leu-Gly) ₂ -deg-TEMPO) (CyPI 2). The copolymerization of styrene and acrylonitrile using the cyclic peptide NMP initiator cyclic (Asp-deg- (Leu-Gly) ₂ -deg-TEMPO) (CyPI 2) is shown below. CyPI 2 0.010 mmol, styrene 0.8 mmol and acrylonitrile 0.2 mmol were dissolved in DMF to a monomer concentration of 6 M.

The molecular weight and polydispersity were determined by GPC, and the structure was determined by FT-IR and 1H NMR spectral measurements. FIG. 4 shows the GPC measurement results comparing the multi-block copolymer and the fragment. FIG. 5 shows the FT-IR measurement results comparing the multi-block copolymer and the fragment. FIG. 6 shows the ¹ H NMR spectrum measurement results comparing the multi-block copolymer and the fragment.

It can be used for the production of multi-block type polymers.

Claims (7)

Cyclic peptide NMP initiator consisting of the following formula

(Here, in the above formula,
X1 is a peptide (-NH-CHR _X - CO-) consisting of amino acids that may be the same or different or derivatives thereof (n is 1 to 20), where R _x is composed of the following formula.

S1 and S2 are spacers with -O-CH ₂ -CH ₂ -parts (l and m are 1 to 4 respectively).
X2 is an amino acid having a carboxyl group at both ends or an amino acid derivative having a carboxyl group at both ends.
Z is a compound that generates a nitroxy radical by ring opening. ). The cyclic peptide NMP initiator according to claim 1, which comprises the following formula.

(Here, R1 to R4 are alkyl groups that may be the same or different.). The cyclic peptide NMP initiator according to claim 1, wherein the compound that generates a nitroxy radical by ring opening is TEMPO, TIPNO or DEPN. The cyclic peptide NMP initiator according to claim 1 or 2, which comprises the following formula.

The cyclic peptide NMP initiator according to claim 1 or 2, which comprises the following formula.

The cyclic peptide NMP initiator according to claim 1 or 2, which comprises the following formula.

A method for producing a multi-block polymer having a peptide in the main chain of a vinyl polymer, which comprises polymerizing a vinyl monomer using the cyclic peptide NMP initiator according to any one of claims 1 to 6. ..

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