JP2015021038A - Phosphorylcholine group-containing polymer and method for producing the same - Google Patents

Abstract

Disclosed is a phosphorylcholine group-containing polymer which is excellent in biocompatibility and biodegradability and is suitable as a carrier material for drug delivery systems, a scaffold material for regenerative medicine, an anti-adhesion material and the like. An α-amino acid and glycolic acid alternating polyester amide having a phosphorylcholine group represented by the formula (7) in the side chain, or a polyether ester amide having a polyether group in the main chain. (In the formula, Z represents an arbitrary linking group with an α-amino acid, and A4 represents a divalent organic group. [Selection] None

Description

  The present invention relates to a phosphorylcholine group-containing polymer that can be used in the medical field and the like, and a method for producing the same.

  Since the phosphorylcholine group has a phospholipid-like structure derived from a biological membrane, a material having a phosphorylcholine group is excellent in biocompatibility. Therefore, a material having a phosphorylcholine group is suitable for application in a field related to a living body such as a medical field.

  For example, Patent Documents 1 and 2 disclose techniques for coating various medical materials with a copolymer of 2-methacryloyloxyethyl phosphorylcholine and (meth) acrylate or the like.

  Patent Document 3 discloses a technique for forming a layer of 2-methacryloyloxyethyl phosphorylcholine polymer on the surface of a metal or ceramic material used for an artificial joint.

  Further, Patent Document 4 discloses a technique using a polymer of a phosphorylcholine group-containing diol compound and a diisocyanate compound as a material having a phosphorylcholine group from the viewpoint of water resistance and mechanical strength.

JP-A-9-183819 JP 2005-006704 A JP 2007-260247 A JP 2011-162522 A

  Among materials used in vivo, there are materials that are required to have biodegradability that can be decomposed under in vivo conditions as well as biocompatibility. Examples of such materials include carrier materials for drug delivery systems and scaffold materials for regenerative medicine.

  The phosphorylcholine group-containing polymers described in Patent Documents 1 to 4 are excellent in biocompatibility because they have a phosphorylcholine group, but have poor biodegradability because their main chain skeleton is alkyl or urethane.

  In view of the above circumstances, an object of the present invention is to provide a phosphorylcholine group-containing polymer excellent in biocompatibility and biodegradability and a method for producing the same.

  In order to achieve the above object, a phosphorylcholine group-containing polymer according to an embodiment of the present invention includes a repeating unit represented by the formula (1).

（式中、Ａ１は２価の有機基を示し，Ａ２はＡ１とは独立の２価の有機基を示し、Ｘは−Ｏ−、−Ｃ（Ｏ）Ｏ−、−ＮＨＣＯ−、−ＮＨＣ（Ｏ）Ｏ−、−Ｓ−、または−ＮＨ−を示す。）

(In the formula, A1 represents a divalent organic group, A2 represents a divalent organic group independent of A1, and X represents —O—, —C (O) O—, —NHCO—, —NHC ( O) represents O-, -S-, or -NH-.

  The manufacturing method of the phosphorylcholine group containing polymer which concerns on one form of this invention includes producing | generating the intermediate polymer containing the repeating unit represented by Formula (2). Moreover, the manufacturing method of the said phosphorylcholine group containing polymer includes making the produced | generated said intermediate polymer react with the phosphorylcholine group modifier represented by Formula (3).

（式中、Ａ３は２価の有機基を示し、Ｙはカルボキシル基、アミノ基、またはビニル基を示す。）

(In the formula, A3 represents a divalent organic group, and Y represents a carboxyl group, an amino group, or a vinyl group.)

（式中、Ａ４は２価の有機基を示し、Ｚは式（４）〜（９）で表される官能基の群から選択される官能基を示す。）

(In the formula, A4 represents a divalent organic group, and Z represents a functional group selected from the group of functional groups represented by formulas (4) to (9).)

  -SH (8)

  A phosphorylcholine group-containing polymer excellent in biocompatibility and biodegradability and a method for producing the same can be provided.

  The phosphorylcholine group-containing polymer according to an embodiment of the present invention includes a repeating unit represented by the formula (10).

（式中、Ａ１は２価の有機基を示し，Ａ２はＡ１とは独立の２価の有機基を示し、Ｘは−Ｏ−、−Ｃ（Ｏ）Ｏ−、−ＮＨＣＯ−、−ＮＨＣ（Ｏ）Ｏ−、−Ｓ−、または−ＮＨ−を示す。）

(In the formula, A1 represents a divalent organic group, A2 represents a divalent organic group independent of A1, and X represents —O—, —C (O) O—, —NHCO—, —NHC ( O) represents O-, -S-, or -NH-.

  According to this configuration, high biocompatibility can be obtained by the action of the phosphorylcholine group, and high biodegradability can be obtained by the action of the hydrolyzable deptylpeptide skeleton. Therefore, a phosphorylcholine group-containing polymer having excellent biocompatibility and biodegradability can be obtained.

  The phosphorylcholine group-containing polymer may contain at least one type of repeating unit selected from the group of repeating units represented by formulas (11) to (14).

（式中、Ｒ^１は−（ＣＨ_２）_ａ−で示される有機基を示し、ａは３、４、または５である。）

(In the formula, R ¹ represents an organic group represented by — (CH ₂ ) _a —, and a is 3, 4, or 5.)

（式中、Ｒ^２は、水素原子またはメチル基を示す。）

(In the formula, R ² represents a hydrogen atom or a methyl group.)

（式中、Ｒ^３は水素原子、メチル基、メチロール基、ベンジル基、２−プロピル基、２−メチルプロピル基、または２−ブチル基を示す。）

(In the formula, R ³ represents a hydrogen atom, a methyl group, a methylol group, a benzyl group, a 2-propyl group, a 2-methylpropyl group, or a 2-butyl group.)

— (R ⁴ —O) — (14)
(In the formula, R ⁴ —O represents an oxyethylene group or an oxypropylene group.)

  According to this configuration, a phosphorylcholine group-containing polymer having excellent biocompatibility and biodegradability and other necessary performance can be obtained.

  The manufacturing method of the phosphorylcholine group containing polymer which concerns on one form of this invention includes producing | generating the intermediate polymer containing the repeating unit represented by Formula (15). Moreover, the manufacturing method of the said phosphorylcholine group containing polymer includes making the produced | generated said intermediate polymer react with the phosphorylcholine group modifier represented by Formula (16).

（式中、Ａ３は２価の有機基を示し、Ｙはカルボキシル基、アミノ基、またはビニル基を示す。）

(In the formula, A3 represents a divalent organic group, and Y represents a carboxyl group, an amino group, or a vinyl group.)

（式中、Ａ４は２価の有機基を示し、Ｚは式（１７）〜式（２２）で表される官能基の群から選択される官能基を示す。）

(In the formula, A4 represents a divalent organic group, and Z represents a functional group selected from the group of functional groups represented by formulas (17) to (22).)

-SH (21)

  The polymer may be a random copolymer. With this configuration, a phosphorylcholine group-containing polymer having a higher molecular weight than the homopolymer of formula (15) is obtained.

  The polymer may be a block copolymer. With this configuration, the phosphorylcholine group-containing polymer can be easily controlled in shape when producing micelles or tube-like assemblies.

  Embodiments of the present invention will be described below.

[Outline of Phosphorylcholine Group-Containing Polymer]
The outline | summary of the phosphorylcholine group containing polymer which concerns on one Embodiment of this invention is demonstrated.
The phosphorylcholine group-containing polymer according to this embodiment includes a repeating unit represented by the formula (23).

  Since the phosphorylcholine group-containing polymer according to this embodiment includes a repeating unit represented by the formula (23), it has a main chain skeleton including a depsipeptide skeleton composed of the repeating unit represented by the formula (24). In addition, Formula (24) shows only a depsipeptide skeleton, and the part below the broken line is omitted in Formula (24).

  Since the depsipeptide skeleton containing the repeating unit represented by the formula (24) is easily hydrolyzed, it is easily degraded in vivo, that is, has high biodegradability.

  Moreover, since the phosphorylcholine group-containing polymer according to the present embodiment includes a repeating unit represented by the formula (23), the polymer has a phosphorylcholine group represented by the formula (25). In addition, Formula (25) shows only a phosphorylcholine group, and the part above the broken line is omitted in Formula (25).

  Since the phosphorylcholine group represented by the formula (25) is a phospholipid-like structure derived from a biological membrane, it contributes to biocompatibility. Further, the phosphorylcholine group promotes hydrolysis of the depsipeptide skeleton containing the repeating unit represented by the formula (24).

  Thus, since the phosphorylcholine group-containing polymer according to the present embodiment has a main chain skeleton including a depsipeptide skeleton and a phosphorylcholine group, the polymer is excellent in biodegradability and biocompatibility.

Since the phosphorylcholine group-containing polymer according to this embodiment is excellent in biocompatibility, it is suitable for use in vivo.
Moreover, since this polymer is excellent in biodegradability, it is decomposed with time in vivo to become a compound that can be metabolized and excreted.

  Furthermore, since the phosphorylcholine group-containing polymer according to the present embodiment contains a hydrophilic phosphorylcholine group, hydrolysis of the depsipeptide skeleton is promoted. That is, the phosphorylcholine group acts to increase the biodegradability of the phosphorylcholine group-containing copolymer.

The phosphorylcholine group-containing polymer according to this embodiment can be widely applied, for example, in the medical field because of the above properties.
Specific techniques suitable for the application of this phosphorylcholine group-containing polymer include, for example, carrier materials for drug delivery systems, hydrogels for drug loading / sustained release, absorbable sutures / bone fixation materials, post-surgery Materials for preventing tissue adhesion, and scaffold materials for regenerative medicine.

  Since the phosphorylcholine group represented by the formula (25) has extremely high hydrophilicity, the monomer having the phosphorylcholine group tends to be inhibited from growing during polymerization. Therefore, even if a monomer obtained by modifying a cyclic depsipeptide with a phosphorylcholine group modifier is polymerized, it is difficult to obtain a polymer having a high molecular weight phosphorylcholine group.

  On the other hand, in this embodiment, a cyclic depsipeptide not modified with a phosphorylcholine group modifier is polymerized. Thereby, an intermediate polymer polymerized well is obtained. And the high molecular weight phosphorylcholine group containing polymer is obtained by modifying the obtained intermediate polymer with a phosphorylcholine group modifier.

[Details of phosphorylcholine group-containing polymer]
Details of the phosphorylcholine group-containing polymer according to this embodiment will be described.

<About A1>
A1 in Formula (23) represents a divalent organic group. Examples of the divalent organic group suitable as A1 include organic groups represented by formula (26) and formula (27). However, the organic group applicable as A1 is not limited to these.

-(CH ₂ ) _b1- (26)
(Wherein b1 represents an integer of 1 to 4)

—CH ₂ —O— (CH ₂ ) _b2 − (27)
(In the formula, b2 represents an integer of 3 to 10.)

<About A2>
A2 in Formula (23) represents a divalent organic group. A2 is independent of A1. Examples of the divalent organic group suitable as A2 include organic groups represented by formula (28) to formula (41). However, the organic group applicable as A2 is not limited to these.

— (CH ₂ ) _c1 − (28)
(Wherein c1 represents an integer of 2 to 18)

_{- (CH 2) c2 -O- (} CH 2) d1 - ··· (29)
(Wherein c2 and d1 each independently represents an integer of 1 to 10)

（式中、ｃ３は１〜１０の整数を表す。）

(Wherein c3 represents an integer of 1 to 10)

（式中、ｃ４は１〜１０の整数を表す。）

(Wherein c4 represents an integer of 1 to 10)

（式中、ｃ５，ｄ２はそれぞれ独立して１〜１０の整数を表す。）

(Wherein c5 and d2 each independently represents an integer of 1 to 10)

（式中、ｃ６，ｄ３はそれぞれ独立して１〜１０の整数を表す。）

(Wherein c6 and d3 each independently represents an integer of 1 to 10)

（式中、ｃ７，ｄ４はそれぞれ独立して１〜１０の整数を表す。）

(Wherein c7 and d4 each independently represents an integer of 1 to 10)

（式中、ｃ８，ｄ５はそれぞれ独立して１〜１０の整数を表す。）

(In the formula, c8 and d5 each independently represents an integer of 1 to 10.)

（式中、ｃ９，ｄ６はそれぞれ独立して１〜１０の整数を表す。）

(Wherein c9 and d6 each independently represents an integer of 1 to 10)

（式中、ｃ１０は２〜１０の整数を表し、ｄ７は０〜１０の整数を表す。）

(In the formula, c10 represents an integer of 2 to 10, and d7 represents an integer of 0 to 10.)

（式中、ｃ１１は２〜１０の整数を表し、ｄ８は１〜１０の整数を表す。）

(In the formula, c11 represents an integer of 2 to 10, and d8 represents an integer of 1 to 10.)

（式中、ｃ１２は２〜１０の整数を表し、ｄ９は１〜１０の整数を表す。）

(In the formula, c12 represents an integer of 2 to 10, and d9 represents an integer of 1 to 10.)

（式中、ｃ１３は２〜１０の整数を表し、ｄ１０は１〜１０の整数を表す。）

(In the formula, c13 represents an integer of 2 to 10, and d10 represents an integer of 1 to 10.)

（式中、ｅは１〜１０００の整数を表す。）

(In the formula, e represents an integer of 1 to 1000.)

<About X>
X in the formula (23) represents —O—, —C (O) O—, —NHCO—, —NHC (O) O—, —S—, or —NH—.

<About the combination of “A1-X-A2”>
The combination of “A1-X-A2” is preferably represented by Formula (42) to Formula (46) from the viewpoints of availability of raw materials and ease of synthesis. In addition, the broken line in each formula is a line which shows the boundary between A1, X, and A2.

（式中、ｆ１は１〜８の整数を表す。）

(In the formula, f1 represents an integer of 1 to 8.)

（式中、ｆ２は１または２を、ｇは１〜８の整数を表す。）

(In the formula, f2 represents 1 or 2, and g represents an integer of 1 to 8.)

（式中、ｆ３は１〜８の整数を表す。）

(In the formula, f3 represents an integer of 1 to 8.)

<Repeating units other than formula (23)>
In addition to the repeating unit represented by the formula (23), the phosphorylcholine group-containing polymer according to this embodiment is one or more types of repeating units among the repeating units represented by the formulas (47) to (50). May be included.

  With this configuration, functions other than those derived from the depsipeptide skeleton and the phosphorylcholine group can be added to the phosphorylcholine group-containing polymer. For example, when a highly hydrophilic organic group is employed, the hydrophilicity of the phosphorylcholine group-containing polymer is increased.

^{- (R 4 -O) - ···} (50)

R ¹ in the formula (47) represents an organic group represented by — (CH ₂ ) _a —. a represents 3, 4 or 5. From the viewpoint of easy availability of raw materials, it is preferable that a = 5.

R ² in formula (48) represents a hydrogen atom or a methyl group.

R ³ in formula (49) represents a hydrogen atom, a methyl group, a methylol group, a benzyl group, a 2-propyl group, a 2-methylpropyl group, or a 2-butyl group.
Since a methylol group has an action of improving hydrophilicity, it is preferable to select a methylol group as R ^{3 in} the case of application to the medical field.

R ⁴ —O in the formula (50) represents an oxyethylene group or an oxypropylene group. From the viewpoint of easy availability of raw materials, R ⁴ —O is preferably an oxyethylene group.

[Method for Producing Phosphorylcholine Group-Containing Polymer]
<Outline>
A method for producing the phosphorylcholine group-containing polymer according to this embodiment will be described.
In order to prepare a phosphorylcholine group-containing polymer containing a repeating unit represented by the formula (23), an intermediate polymer containing a repeating unit represented by the formula (51) is represented by the formula (52). It can be obtained by reacting a phosphorylcholine group modifier.

  Thus, in the method for producing a phosphorylcholine group-containing polymer according to this embodiment, an intermediate polymer containing a repeating unit represented by the formula (51) is generated before modification with a phosphorylcholine group.

  Then, this intermediate polymer is modified with a phosphorylcholine group modifier represented by the formula (52). That is, Y in formula (51) and Z in formula (52) react to form a bond represented by X in formula (23). That is, A3-Y in Formula (51) and A4-Z in Formula (52) become A1-X-A2 in Formula (23).

<Repeating unit represented by formula (51)>
A3 in Formula (51) represents a divalent organic group. Examples of the divalent organic group suitable as A3 include organic groups represented by formula (53) and formula (54). However, the organic group applicable as A3 is not limited to these.

-(CH ₂ ) _h1- (53)
(In the formula, h1 represents an integer of 1 to 4.)

—CH ₂ —O— (CH ₂ ) _{h 2} − (54)
(In the formula, h2 represents an integer of 1 to 8.)

  Y in the formula (51) represents a carboxyl group, an amino group or a vinyl group.

  The combination of “A3-Y” in Formula (51) is preferably represented by Formula (55) to Formula (57) from the viewpoints of availability of raw materials and ease of synthesis. In addition, the broken line in each formula is a line which shows the boundary between A3 and Y.

（式中、ｉは１または２を表す。）

(Wherein i represents 1 or 2)

<Phosphorylcholine group modifier represented by Formula 52>
A4 in Formula (52) represents a divalent organic group. Examples of the divalent organic group suitable as A4 include organic groups represented by formula (58) to formula (67). However, the organic group applicable as A4 is not limited to these.

− (CH ₂ ) _j1 − (58)
(Wherein j1 represents an integer of 1 to 10)

_{- (CH 2) j2 -O- (} CH 2) k1 - ··· (59)
(Wherein j2 and k1 each independently represents an integer of 1 to 10)

（式中、ｊ３，ｋ２はそれぞれ独立して１〜１０の整数を表す。）

(Wherein j3 and k2 each independently represents an integer of 1 to 10)

（式中、ｊ４，ｋ３はそれぞれ独立して１〜１０の整数を表す。）

(Wherein j4 and k3 each independently represents an integer of 1 to 10)

（式中、ｊ５，ｋ４はそれぞれ独立して１〜１０の整数を表す。）

(Wherein j5 and k4 each independently represents an integer of 1 to 10)

（式中、ｊ６，ｋ５はそれぞれ独立して１〜１０の整数を表す。）

(Wherein j6 and k5 each independently represents an integer of 1 to 10)

（式中、ｊ７，ｋ６はそれぞれ独立して１〜１０の整数を表す。）

(Wherein j7 and k6 each independently represents an integer of 1 to 10)

（式中、ｊ８，ｋ７はそれぞれ独立して１〜１０の整数を表す。）

(In the formula, j8 and k7 each independently represents an integer of 1 to 10.)

（式中、ｊ９，ｋ８はそれぞれ独立して１〜１０の整数を表す。）

(In the formula, j9 and k8 each independently represents an integer of 1 to 10.)

（式中、ｔは１〜１０００の整数を表す。）

(In the formula, t represents an integer of 1 to 1000.)

  Z in the formula (52) represents a functional group. Examples of functional groups suitable as Z include functional groups represented by formula (68) to formula (73).

-SH (72)

  The combination of “A4-Z” in Formula (52) is preferably represented by Formula (74) to Formula (78) from the viewpoint of easy availability of raw materials and ease of synthesis. In addition, the broken line in each formula is a line which shows the boundary between A4 and Z.

（式中、ｕ１は１〜８の整数を表す。）

(Wherein u1 represents an integer of 1 to 8)

（式中、ｕ２は１〜８の整数を表す。）

(In the formula, u2 represents an integer of 1 to 8.)

（式中、ｕ３は１〜８の整数を表す。）

(In the formula, u3 represents an integer of 1 to 8.)

<Method for Producing Intermediate Polymer Containing Repeating Unit Represented by Formula (51)>
As a method for producing an intermediate polymer containing a repeating unit represented by the formula (51), a known method can be used.

  Such a method is described, for example, in Macromol. Chem. Phys. 2011.11.809-820, J. MoI. Polym. Sci A: Plym. Chem. 1997.35.1901-1907, Japanese Patent Application Laid-Open No. 2008-120888, collection of polymer papers. 2002.59.8.484-498. Is disclosed.

  An example of a method for producing an intermediate polymer containing the repeating unit represented by the formula (51) will be described.

  First, a raw material amino acid is reacted with bromoacetyl bromide to synthesize a bromo compound. Subsequently, a cyclic depsipeptide (hereinafter also simply referred to as “cyclic depsipeptide”) as a monomer is obtained by intramolecular cyclization reaction of the bromo compound.

  To the obtained cyclic depsipeptide, a tin-based catalyst such as tin 2-ethylhexanoate or tin octylate, a metal alkoxide prepared from potassium naphthalene or the like, or 1,5,7-triaza-bicyclo [4.4.0] By adding and polymerizing an organic polymerization catalyst such as dece-5-ene (TBD), an intermediate polymer containing a repeating unit represented by the formula (51) is obtained.

  If necessary, appropriate protection and deprotection operations are performed according to the type of amino acid.

  The amino acid used as a raw material is preferably lysine, aspartic acid, glutamic acid, or serine. From the viewpoint of use in the medical field, the amino acid used as a raw material is preferably an L-form amino acid.

  Moreover, when using only a cyclic depsipeptide as a monomer, the homopolymer which consists of a repeating unit represented by Formula (51) is obtained. On the other hand, when a cyclic depsipeptide and another monomer are used in combination as a monomer, a random copolymer or block copolymer containing a repeating unit represented by the formula (51) is obtained.

  More specifically, in order to obtain a random copolymer containing the repeating unit represented by the formula (51), a cyclic depsipeptide and other monomers are polymerized simultaneously.

  In order to obtain a block copolymer containing the repeating unit represented by the formula (51), first, a polymer obtained by homopolymerizing a cyclic depsipeptide or other monomer is purified. Then, another monomer is polymerized from the purified polymer again using the terminal hydroxyl group as a starting point.

  Examples of the other monomers include ε-caprolactone, glycolide, and lactide. The other monomer may be a cyclic depsipeptide composed of glycolic acid and any one of glycine, alanine, serine, phenylalanine, isoleucine, and leucine. Furthermore, the other monomer may be ethylene glycol, propylene glycol, or a single terminal alkoxy form thereof.

  When ε-caprolactone is used as another monomer, a random copolymer or block copolymer containing a repeating unit represented by the formula (47) is obtained.

  When glycolide or lactide is used as the other monomer, a random copolymer or block copolymer containing a repeating unit represented by the formula (48) is obtained.

  When the cyclic depsipeptide consisting of any one of glycine, alanine, serine, phenylalanine, isoleucine, and leucine and glycolic acid is used as the other monomer, the random co-polymer containing the repeating unit represented by the formula (49) A coalescence or block copolymer is obtained.

  As other monomers, polyethylene glycol and polypropylene glycol are used, and when the terminal hydroxyl group of these one-terminal alkoxy compounds is the starting point, a block copolymer containing a repeating unit represented by the formula (50) is used. Can be obtained.

  Two or more other monomers may be used depending on the required performance.

  The composition ratio of the repeating unit represented by the formula (51) in the random copolymer or block copolymer to the repeating unit represented by the formula (47) to the formula (50) depends on required performance and the like. It can be determined accordingly.

  In this embodiment, when the repeating unit represented by Formula (51) is 1, the amount of the repeating unit represented by Formula (47) to Formula (50) is preferably 1 to 200. More preferably, it is -100.

  The number average molecular weight (Mn) of the phosphorylcholine group-containing polymer according to the present embodiment can be adjusted by, for example, the polymerization conditions of the intermediate polymer according to the required performance. In this embodiment, it is preferable that the number average molecular weight (Mn) of a phosphorylcholine group containing polymer is 2000-100000, and it is still more preferable that it is 3000-50000.

  The polymer containing the repeating unit represented by the formula (51) thus obtained may be used after purification or without purification. Examples of the polymer purification method include reprecipitation and gel filtration chromatography.

<Method for Producing Phosphorylcholine Group Modifier Represented by Formula (52)>
As a method for producing the phosphorylcholine group modifier represented by the formula (52), a known method can be used.

  Such a method is disclosed in, for example, JP 2009-242289 A, JP 2005-187456 A, and US Pat. No. 5,144,045.

  The obtained phosphorylcholine group modifier represented by the formula (52) may be used after purification or without purification. Examples of the method for purifying the modifier include recrystallization and silica gel column chromatography.

<Method of Modifying Polymer Containing Repeating Unit Represented by Formula (51) with a Phosphorylcholine Group Modifier Represented by Formula (52)>
A polymer containing a repeating unit represented by the formula (51) is modified with a phosphorylcholine group modifying agent represented by the formula (52) to thereby add a phosphorylcholine group-containing polymer containing the repeating unit represented by the formula (23). Coalescence is obtained.

  The reaction between the polymer containing the repeating unit represented by formula (51) and the phosphorylcholine group modifier represented by formula (52) depends on Y in formula (51) and Z in formula (52). A known method is used. At this time, a phosphorylcholine group-containing polymer containing a repeating unit represented by the formula (23) having X corresponding to Y in the formula (51) and Z in the formula (52) is obtained.

  As an example, when Y in Formula (51) is an amino group and Z in Formula (52) is reacted with a phosphorylcholine group modifier represented by Formula (69), X is —NHC (O) O—. A phosphorylcholine group-containing polymer containing a repeating unit represented by formula (23) is obtained.

  As another example, when Y in formula (51) is an amino group and Z in formula (52) is reacted with a phosphorylcholine group modifier represented by formula (68), X is —NH—. A phosphorylcholine group-containing polymer containing the repeating unit represented by (23) is obtained.

  As another example, when Y in Formula (51) is a carboxyl group and Z in Formula (52) is reacted with a phosphorylcholine group modifier represented by Formula (71), X is —C (O) O. A phosphorylcholine group-containing polymer containing a repeating unit represented by the formula (23) which is-is obtained.

  As another example, when Y in Formula (51) is a vinyl group and Z in Formula (52) is reacted with a phosphorylcholine group modifier represented by Formula (72), X is —S—. A phosphorylcholine group-containing polymer containing the repeating unit represented by (23) is obtained.

  As another example, when Y in Formula (51) is an amino group and Z in Formula (52) is reacted with a phosphorylcholine group modifier represented by Formula (70) or Formula (73), X is- A phosphorylcholine group-containing polymer containing a repeating unit represented by the formula (23) which is NHCO- is obtained.

  Hereinafter, although a specific manufacturing method is shown, it is not limited to these.

(Specific example 1)
First, the case where Y in formula (51) is an amino group and Z in formula (52) is a phosphorylcholine group modifier represented by formula (69) will be described.

  In this case, the functional group represented by the formula (69) reacts with the amino group in the formula (51) by a ring-opening addition reaction. Thereby, the phosphorylcholine group containing polymer containing the repeating unit represented by Formula (23) whose X is -NHC (O) O- is obtained.

  The ring-opening addition reaction can be performed in various solvents. The solvent used for the ring-opening addition reaction only needs to dissolve the polymer represented by formula (51) and the phosphorylcholine group modifier represented by formula (52).

  Examples of the solvent used in the ring-opening addition reaction include various organic solvents such as water, buffer solution, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and mixtures thereof. From the viewpoint that the phosphorylcholine group modifier represented by the formula (52) has high polarity, chloroform and methanol are preferable.

  The amount of the solvent used in the ring-opening addition reaction is usually 1 to 100 times, preferably 1 to 50 times, most preferably 1 to 30 times the mass ratio of the polymer represented by formula (51). It is.

  The amount of the phosphorylcholine group modifier represented by the formula (52) used in the ring-opening addition reaction is, for example, “functional group (mol) represented by the formula (69)” / “amino group in the formula (51)”. The molar ratio calculated by “(mol)” is usually 0.1 to 8.0, preferably 0.5 to 5.0, and most preferably 0.8 to 3.0.

When this molar ratio is less than 0.1, the nature of the phosphorylcholine group may not be exhibited.
Moreover, when this molar ratio is larger than 8.0, a phosphorylcholine group modifier that is wasted without contributing to the ring-opening addition reaction is generated. In this case, it becomes difficult to remove and purify the phosphorylcholine group modifier that does not contribute to the ring-opening addition reaction.

  A catalyst can be used in the ring-opening addition reaction of the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52). Examples of the catalyst include a base catalyst.

  Examples of the base catalyst include tertiary amines such as triethylamine, tributylamine, diazabicycloundecene (DBU), diazabicyclooctane (DABCO), pyridine, lithium chloride, lithium bromide, lithium fluoride, sodium chloride. And alkali metal salts.

  Examples of the base catalyst include alkaline earth metal salts such as calcium chloride, quaternary ammonium salts such as tetrabutylammonium chloride and tetraethylammonium bromide, carbonates such as potassium carbonate and sodium carbonate, zinc acetate and acetic acid. Examples thereof include metal acetates such as lead, copper acetate and iron acetate, metal hydrides such as calcium hydride, metal oxides such as calcium oxide, magnesium oxide and zinc oxide, and phosphonium salts such as tetrabutylphosphonium chloride.

  The amount of the catalyst used for the ring-opening addition reaction is usually 0.05 to 10 times, preferably 0.10 to 8 times the molar ratio of the phosphorylcholine group modifier represented by the formula (52). The most preferred amount is 0.15 to 5 times.

  The reaction temperature for the ring-opening addition reaction of the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52) is usually 0 to 120 ° C., preferably 10 to 100 ° C., most preferably Is in the range of 15-80 ° C.

  The reaction time for the ring-opening addition reaction of the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52) varies depending on the reaction temperature, catalyst and other conditions, but is usually 1 to 48. It is preferable that it is about time.

  By the above, the phosphorylcholine group containing polymer whose X in Formula (23) is -NHC (O) O- is obtained. The obtained phosphorylcholine group-containing polymer may be used as it is without purification, or may be isolated and purified by treatment such as reprecipitation or gel filtration chromatography.

(Specific example 2)
Next, the case where Y in formula (51) is an amino group and Z in formula (52) is a phosphorylcholine group modifier represented by formula (68) will be described.

  In this case, the functional group represented by the formula (68) reacts with the amino group in the formula (51) by being reduced through an imine by a reductive amination reaction. Thereby, the phosphorylcholine group containing polymer containing the repeating unit represented by Formula (51) whose X is -NH- is obtained.

  The reductive amination reaction can be performed in various solvents. The solvent used for the reductive amination reaction only needs to dissolve the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52).

  Examples of the solvent used for the reductive amination reaction include various organic solvents such as water, buffer solution, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, chloroform, and mixtures thereof. From the viewpoint that the phosphorylcholine group modifier represented by the formula (52) has high polarity, chloroform and methanol are preferable.

  The amount of the solvent used for the reductive amination reaction is usually 1 to 100 times, preferably 1 to 50 times, most preferably 1 to 30 times the mass ratio of the polymer represented by the formula (51). Amount.

  The amount of the phosphorylcholine group modifier represented by the formula (52) used in the reductive amination reaction is, for example, “functional group represented by the formula (68) (mol)” / “amino in the formula (51)”. The molar ratio calculated by “group (mol)” is usually 0.1 to 8.0, preferably 0.5 to 5.0, and most preferably 0.8 to 3.0.

When this molar ratio is less than 0.1, the nature of the phosphorylcholine group may not be exhibited.
On the other hand, when the molar ratio is greater than 8.0, a phosphorylcholine group modifier that is wasted without contributing to the reductive amination reaction is generated. In this case, it becomes difficult to remove and purify the phosphorylcholine group modifier that does not contribute to the reductive amination reaction.

  Examples of the reducing agent include 2-picoline borane, sodium cyanoborohydride, and sodium triacetoxyborohydride.

  The amount of the reducing agent used in the reductive amination reaction is usually 1.0 to 5.0 times, preferably 1.0, in molar ratio with respect to the phosphorylcholine group modifier represented by the formula (52). The amount is ˜4.0 times, most preferably 1.0 to 3.0 times.

  The reaction temperature when the reductive amination reaction between the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52) is usually 0 to 60 ° C., preferably 0 to 40 ° C., Most preferably, it is the range of 0-30 degreeC.

  The reaction time for the reductive amination reaction between the polymer represented by the formula (51) and the phosphorylcholine group modifying agent represented by the formula (52) varies depending on the conditions such as the reaction temperature, but usually 30 minutes to It is preferably about 24 hours.

  By the above, the phosphorylcholine group containing polymer whose X in Formula (23) is -NH- is obtained. The obtained phosphorylcholine group-containing polymer may be used as it is without purification, or may be isolated and purified by treatment such as reprecipitation or gel filtration chromatography.

(Specific example 3)
Next, the case where Y in formula (51) is a carboxyl group and Z in formula (52) is a phosphorylcholine group modifier represented by formula (71) will be described.

  In this case, the functional group represented by formula (71) reacts with the carboxyl group in formula (51) by a ring-opening addition reaction. Thereby, the phosphorylcholine group containing polymer containing the repeating unit represented by Formula (23) whose X is -C (O) O- is obtained.

  The ring-opening addition reaction can be performed in various solvents. The solvent used for the ring-opening addition reaction only needs to dissolve the polymer represented by formula (51) and the phosphorylcholine group modifier represented by formula (52).

  Examples of the solvent used in the ring-opening addition reaction include various organic solvents such as water, buffer solution, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and mixtures thereof. From the viewpoint that the phosphorylcholine group modifier represented by the formula (52) has high polarity, chloroform and methanol are preferable.

  The amount of the solvent used in the ring-opening addition reaction is usually 1 to 100 times, preferably 1 to 50 times, most preferably 1 to 30 times the mass ratio of the polymer represented by formula (51). It is.

  The amount of the phosphorylcholine group modifier represented by the formula (52) used in the ring-opening addition reaction is, for example, “functional group (mol) represented by the formula (71)” / “amino group in the formula (51)”. The molar ratio calculated by “(mol)” is usually 0.1 to 8.0, preferably 0.5 to 5.0, and most preferably 0.8 to 3.0.

When this molar ratio is less than 0.1, the nature of the phosphorylcholine group may not be exhibited.
Moreover, when this molar ratio is larger than 8.0, a phosphorylcholine group modifier that is wasted without contributing to the ring-opening addition reaction is generated. In this case, it becomes difficult to remove and purify the phosphorylcholine group modifier that does not contribute to the ring-opening addition reaction.

  A catalyst can be used in the ring-opening addition reaction of the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52). Examples of the catalyst include tertiary amines, imidazole compounds, and organic phosphine catalysts.

  Examples of the tertiary amine catalyst include triethylamine, diisopropylethylamine, pyridine, triethanolamine, triethylenediamine, DBU, and salts thereof.

  Examples of the imidazole compound catalyst include 2-undecylimidazole, 2-heptadecylimidazole, 2-phenylimidazole, 1-benzyl-2-methylimidazole, 1-cyanoethyl-2-methylimidazole, 1-cyanoethyl-2- Examples include undecyl imidazole and 2-phenyl-4,5-dihydroxymethylimidazole.

  Examples of organic phosphine catalysts include triphenylphosphine, triorthotolylphosphine, triparatolylphosphine, tris (paramethoxyphenyl) phosphine, tris (2,6-dimethoxyphenyl) phosphine, tributylphosphine, and triphenylphosphine oxide. Can be mentioned.

  The amount of the catalyst used for the ring-opening addition reaction is usually 0.05 to 10 times, preferably 0.10 to 8 times the molar ratio of the phosphorylcholine group modifier represented by the formula (52). The most preferred amount is 0.15 to 5 times.

  The reaction temperature in the ring-opening addition reaction between the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52) is usually in the range of 40 to 180 ° C, preferably 50 to 150 ° C. It is.

  The reaction time in the ring-opening addition reaction between the polymer represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52) varies depending on conditions such as the reaction temperature, but is usually 1 to 24 hours. It is preferable that it is a grade.

  By the above, the phosphorylcholine group containing polymer whose X in Formula (23) is -C (O) O- is obtained. The obtained phosphorylcholine group-containing polymer may be used as it is without purification, or may be isolated and purified by treatment such as reprecipitation or gel filtration chromatography.

(Specific example 4)
Next, the case where Y in Formula (51) is a vinyl group and Z in Formula (52) is a phosphorylcholine group modifier represented by Formula (72) will be described.

  In this case, the functional group represented by Formula (57) reacts with the vinyl group in Formula (51) by ene-thiol reaction. Thereby, the phosphorylcholine group containing polymer containing the repeating unit represented by Formula (52) whose X is -S- is obtained.

  The ene-thiol reaction can be performed in various solvents. The solvent used for the ene-thiol reaction only needs to dissolve the polymer represented by formula (51) and the phosphorylcholine group modifier represented by formula (52).

  Examples of the solvent used for the ene-thiol reaction include various organic solvents such as water, buffer solution, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and mixtures thereof. From the viewpoint that the phosphorylcholine group modifier represented by the formula (52) has high polarity, chloroform and methanol are preferable.

  The amount of the solvent used for the ene-thiol reaction is usually 1 to 100 times, preferably 1 to 50 times, most preferably 1 to 30 times the mass ratio of the polymer represented by the formula (51). It is.

  The amount of the phosphorylcholine group modifier represented by the formula (52) used in the ene-thiol reaction is, for example, “functional group (mol) represented by the formula (72)” / “amino group in the formula (51)”. The molar ratio calculated by “(mol)” is usually 0.1 to 8.0, preferably 0.5 to 5.0, and most preferably 0.8 to 3.0.

When this molar ratio is less than 0.1, the nature of the phosphorylcholine group may not be exhibited.
Moreover, when this molar ratio is larger than 8.0, a phosphorylcholine group modifier that is wasted without contributing to the ene-thiol reaction is generated. In this case, it becomes difficult to remove and purify the phosphorylcholine group modifier that does not contribute to the ene-thiol reaction.

  In the ene-thiol reaction between the polymer represented by the formula (51) and the phosphorylcholine group modifying agent represented by the formula (52), a thermal radical generator or a photo radical generator is used. As the thermal radical generator, a peroxide or an azo compound is preferable.

  Examples of the peroxide include tert-butyl hydroperoxide, dibenzoyl peroxide, tert-butylperoxy-2-ethylhexanoate, and dilauroyl peroxide.

  Examples of the azo compound include azobis (iso-butyronitrile), 2,2′-azobis (2-methylbutanenitrile), 2,2′-azobis (2-methylbutanenitrile) 2,2′-azobis (2- Amidinopropane) hydrochloride.

  Examples of the photo radical generator include sulfonium salts, iodonium salts, metallocene compounds, and benzoin tosylate. Examples of these commercially available products include Cyracure UVI-6970, UVI-6974, and UV-6990 (both trade names manufactured by Union Carbide, USA), Irgacure 264 (manufactured by Ciba Specialty Chemicals), CIT-1682 (Japan) Soda Co., Ltd.).

  The amount of the thermal radical generator or photoradical generator used for the ene-thiol reaction is usually 0.05 to 10 times, preferably in molar ratio with respect to the phosphorylcholine group modifier represented by the formula (52). Is 0.10 to 8 times, most preferably 0.15 to 5 times.

  The reaction temperature in the ene-thiol reaction between the polymer containing the repeating unit represented by the formula (51) and the phosphorylcholine group modifier represented by the formula (52) is used when a thermal radical generator is used. It is preferable that the 10-hour half-life temperature of the thermal radical generator to be ± 20 ° C. Although reaction time at this time changes with conditions, such as reaction temperature, it is preferable that it is normally about 1 to 48 hours.

  The reaction temperature in the ene-thiol reaction between the polymer represented by the formula (51) and the phosphorylcholine group modifying agent represented by the formula (52) is usually 0 to 60 ° C., and the photoradical generator used Depending on the absorption wavelength, radicals are separately generated using a device that emits ultraviolet light, such as a high-pressure mercury lamp or an LED laser. The ultraviolet irradiation time varies depending on the type of the photo radical generator and the conditions of the device that emits ultraviolet light, but is preferably 1 hour or less.

  By the above, the phosphorylcholine group containing polymer whose X in Formula (23) is -S- is obtained. The obtained phosphorylcholine group-containing polymer may be used as it is without purification, or may be isolated and purified by treatment such as reprecipitation or gel filtration chromatography.

[Method for evaluating phosphorylcholine group-containing polymer]
Hereinafter, the evaluation method of the phosphorylcholine group-containing polymer according to this embodiment will be described. In this embodiment, biocompatibility is evaluated by a modification rate (Q) described later, and biodegradability is evaluated by a hydrolysis test.

  In this embodiment, when producing the phosphorylcholine group-containing polymer containing the repeating unit represented by the formula (23) as described above, among the polymers containing the repeating unit represented by the formula (51), the formula The modification rate (Q) is adopted as an index representing the ratio of the repeating unit modified by the phosphorylcholine group modifier represented by (52).

  The modification rate (Q) is defined by the formula (A).

  (Q) = (P1) / (P2) Expression (A)

  In formula (A), (P1) represents the phosphorus element content (mol) per gram of the phosphorylcholine group-containing polymer. The phosphorus element content can be measured by the molybdenum blue method. The phosphorus element content can be measured, for example, according to the method described in JIS K 0102 46.3.

  Phosphorus per gram of the phosphorylcholine group-containing polymer, assuming that all the repeating units of the polymer containing the repeating unit represented by the formula (51) are modified by the phosphorylcholine group modifying agent represented by the formula (52) The theoretical value of element content (mol) is shown.

  This theoretical value can be calculated from the molecular weight of the repeating unit when a polymer consisting only of the repeating unit represented by the formula (51) is used.

  Further, this theoretical value is described in, for example, Japanese Patent Application Laid-Open No. 2008-120888 when a random copolymer or a block copolymer is used as the polymer containing the repeating unit represented by the formula (51). It can be calculated by a method.

Specifically, this theoretical value is derived from the result of calculating the composition ratio of this polymer by measuring ¹ H NMR of the polymer containing the repeating unit represented by formula (51) or its precursor. Is possible.

  The modification rate (Q) can be determined as appropriate based on the required performance and can be adjusted depending on the reaction conditions and the like. The modification rate (Q) is usually 0.1 to 1.0, preferably 0.3 to 1.0, and more preferably 0.5 to 1.0.

  The higher the modification rate (Q), the greater the number of phosphorylcholine groups, so that the biodegradability of the phosphorylcholine group-containing polymer increases, and the biocompatibility of the phosphorylcholine group-containing polymer also increases.

  The phosphorylcholine group-containing polymer according to this embodiment has a composition corresponding to the modification rate (Q).

  For example, the phosphorylcholine group-containing polymer is produced using a polymer containing only the repeating unit represented by the formula (51), and represented by the formula (23) when the modification rate (Q) is 1.0. Consists only of repeating units. When the modification rate (Q) is less than 1.0, the phosphorylcholine group-containing polymer includes a repeating unit represented by the formula (23) and a repeating unit represented by the formula (51).

  Moreover, a phosphorylcholine group containing polymer may be manufactured using the random copolymer containing the repeating unit represented by Formula (51). In this case, when the modification rate (Q) is 1.0, all the repeating units represented by the formula (51) are modified with the phosphorylcholine group modifier represented by the formula (52). On the other hand, when the modification rate (Q) is less than 1.0, a part of the repeating unit represented by the formula (51) remains unmodified by the phosphorylcholine group modifier represented by the formula (52).

  Furthermore, the phosphorylcholine group-containing polymer may be produced using a block copolymer containing a repeating unit represented by the formula (51). In this case, when the modification rate (Q) is 1.0, all of the repeating units represented by the formula (51) are modified with the phosphorylcholine group modifier represented by the formula (52), and represented by the formula (51). The block of the repeating unit is the block of the repeating unit represented by the formula (23). On the other hand, when the modification rate (Q) is less than 1.0, a part of the repeating unit represented by the formula (51) remains unmodified by the phosphorylcholine group modifier represented by the formula (52), and the formula (51) The block of the repeating unit represented by 51) is a block composed of the repeating unit represented by the formula (23) and the repeating unit represented by the formula (51).

  The hydrolyzability of the phosphorylcholine group-containing polymer is measured with respect to the phosphorylcholine group-containing polymer according to the present embodiment by measuring the number average molecular weight (Mn) of the sample before the test (0 days), after the test, after 7 days, and after 30 days. It was evaluated by.

[Modified example of phosphorylcholine group-containing polymer]
In addition to the homopolymer, a copolymer (random copolymer or block copolymer) can be used as an intermediate polymer when producing the phosphorylcholine group-containing polymer according to the present embodiment. Thereby, a high molecular weight phosphorylcholine group-containing polymer is obtained.

  Furthermore, the phosphorylcholine group-containing polymer is produced from a block copolymer containing a repeating unit represented by the formula (51), if necessary. Thereby, the shape control of the phosphorylcholine group-containing polymer is facilitated when producing a micelle or a tube-like aggregate.

  The number average molecular weight (Mn) of the phosphorylcholine group-containing polymer according to the present embodiment is appropriately determined so that the required performance can be exhibited. The number average molecular weight (Mn) of the phosphorylcholine group-containing polymer can be adjusted by the polymerization conditions and the like.

  Although the number average molecular weight (Mn) of the phosphorylcholine group-containing polymer varies depending on the modification rate (Q), it is usually in the range of 2200 to 120,000, and preferably in the range of 3300 to 70000.

  The phosphorylcholine group-containing polymer according to this embodiment can be used alone, mixed with other biodegradable materials or the like, or used after chemical modification.

  The phosphorylcholine group-containing polymer according to this embodiment can be applied as a carrier material for a drug delivery system by forming aggregates such as micelles or tubes and encapsulating a drug.

  In addition, this phosphorylcholine group-containing polymer can be used by mixing with a synthetic polymer such as polylactic acid or a natural polymer such as collagen. In addition, it can be crosslinked using a polyfunctional isocyanate or the like. Therefore, it is also possible to use it after adjusting its gelation or physical properties. Therefore, this phosphorylcholine group-containing polymer can be used as an adhesion preventing material, a scaffold material for regenerative medicine, and the like.

  As described above, the phosphorylcholine group-containing polymer according to this embodiment is widely useful as a material in the medical field. Furthermore, since this phosphorylcholine group-containing polymer has a high moisturizing property derived from the phosphorylcholine group, it is useful not only in the medical field but also in the cosmetic field as a raw material for cosmetics.

  Moreover, the manufacturing method of the phosphorylcholine group containing polymer which concerns on this embodiment makes the polymer containing the repeating unit represented by Formula (51) react with the phosphorylcholine group modifier represented by Formula (52), A phosphorylcholine group-containing polymer can be easily obtained. Furthermore, in the method for producing the phosphorylcholine group-containing polymer, the modification rate (Q) can be easily adjusted.

  In addition, it is also possible by a production method in which a monomer (cyclic depsipeptide) corresponding to the repeating unit represented by the formula (51) is reacted with the phosphorylcholine group modifier represented by the formula (52) and then subjected to ring-opening polymerization. A phosphorylcholine group-containing polymer is obtained.

  However, in this production method, the hydrophilicity of the phosphorylcholine group is extremely high, so that the growth during polymerization is easily inhibited, and it is difficult to obtain a high molecular weight product. On the other hand, in the method for producing a phosphorylcholine group-containing polymer according to this embodiment, a high molecular weight product can be obtained.

  EXAMPLES Hereinafter, although an Example demonstrates this invention still in detail, this invention is not limited to these.

[Measurement of molecular weight by gel permeation chromatography (GPC) analysis]
Using a trade name “Prominence” manufactured by Shimadzu Corporation, column: PL gel manufactured by Polymer Laboratory (trade name “MIXED-B”), column temperature: 40 ° C., sample concentration: 0.2 wt%, injection amount: The measurement was performed under the conditions of 70 μl, eluent: chloroform, flow rate: 1.0 ml / min, detector: differential refractometer (RI), standard: polystyrene.

Ｈ−Ｌｙｓ（Ｃｂｚ）−ＯＨ → ＢｒＡｃ−Ｌｙｓ（Ｃｂｚ）−ＯＨ
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Production Example 1-1]
<Synthesis of Cyclic Depsipeptide: Lys (Cbz)>

H-Lys (Cbz) -OH → BrAc-Lys (Cbz) -OH
(In the formula, Cbz represents a benzyloxycarbonyl group.)

  H-Lys (Cbz) -OH (5.6 g, 20 mmol), 4N NaOH 6.0 ml, p-dioxane 21 ml, and water 21 ml were added to the eggplant flask and cooled to -5 ° C. A mixed solution of bromoacetyl bromide (4.1 g, 20 mmol) and 6.0 g of p-dioxane and 8.4 ml of 4N NaOH were added dropwise simultaneously over 10 minutes. After completion of the addition, the mixture was stirred at −5 ° C. for 5 minutes. After 5 minutes, 4N HCl was added to adjust the pH to 2 or less, followed by extraction with ethyl acetate and washing with water. After the obtained organic layer was dehydrated with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain BrAc-Lys (Cbz) -OH as a brominated product.

ＢｒＡｃ−Ｌｙｓ（Ｃｂｚ）−ＯＨ → Ｌｙｓ（Ｃｂｚ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。）

BrAc-Lys (Cbz) -OH → Lys (Cbz)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

Sodium bicarbonate (4.4 g, 52 mmol) and 250 ml of DMF were added to the eggplant flask and stirred at 60 ° C. A mixture of BrAc-Lys (Cbz) -OH (3.6 g, 8.9 mmol) and DMF 30 ml was added dropwise over 3 hours, and the mixture was stirred for 4 hours after the completion of the addition. After completion of the reaction, sodium bicarbonate was removed and DMF was distilled off under reduced pressure. Ethyl acetate was added to perform washing with saturated aqueous NaHCO ₃ and saturated aqueous sodium chloride. The obtained organic layer was dehydrated with magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a white solid cyclic depsipeptide (Lys (Cbz)).

  As described above, in this production example, the total yield was 33%.

The NMR measurement results for this cyclic depsipeptide are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.6ppm (m, 4H, -CH 2 - CH 2 - CH 2 -CH 2 -), 1.8-2.0ppm (m, 2H, -CH 2 _{-CH 2 -CH 2 - CH 2 -CH} -), 3.1-3.3ppm (m, 2H, - CH 2 -CH 2 -CH 2 -CH 2 -CH -), 4.1ppm (m, 1H _{, -CH 2 - CH -CO -)} , 4.7ppm (d, 2H, -O- CH 2 -CO -), 5.1ppm (s, 2H, Ph- CH 2 -), 5.3ppm (m, _{1H, -CO- NH -CH 2 -)} 7.3-7.4ppm (m, 5H, Ph -CH 2 -), 8.0ppm (s, 1H, -CH- NH -CO-)

Ｈ−Ａｓｐ（ＯＢｎ）−ＯＨ → Ａｓｐ（ＯＢｎ）
（式中、Ｂｎはベンジル基を表す。） [Production Example 1-2]
<Synthesis of Cyclic Depsipeptide: Asp (OBn)>

H-Asp (OBn) -OH → Asp (OBn)
(In the formula, Bn represents a benzyl group.)

  H-Asp (OBn) -OH (5.9 g, 22 mmol), triethylamine (6.3 ml, 45 mmol), and 50 ml of p-dioxane were added to the eggplant flask and cooled to 5 ° C. A mixed solution of bromoacetyl bromide (9.9 g, 45 mmol) and p-dioxane 6.0 g was added dropwise over 30 minutes. After completion of the addition, the mixture was warmed to room temperature and stirred for 5 hours. After completion of the reaction, ethyl acetate extraction and water washing were performed. After the obtained organic layer was dehydrated with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain BrAc-Lys (Cbz) -OH as a brominated product.

Sodium bicarbonate (7.4 g, 89 mmol) and 1000 ml of DMF were added to the eggplant flask and stirred at 60 ° C. A mixture of BrAc-Asp (OBn) -OH (7.6 g, 22 mmol) and 230 ml of DMF was added dropwise over 3 hours, and the mixture was stirred for 4 hours after completion of the addition. After completion of the reaction, sodium bicarbonate was removed and DMF was distilled off under reduced pressure. Ethyl acetate was added to perform washing with saturated aqueous NaHCO ₃ and saturated aqueous sodium chloride. The obtained organic layer was dehydrated with magnesium sulfate, the solvent was distilled off under reduced pressure, and recrystallization was performed with ethyl acetate and hexane to obtain a white solid cyclic depsipeptide (Asp (OBn)).

  As described above, in this production example, the total yield was 32%.

The NMR measurement results for this cyclic depsipeptide are as follows.
^{_{1 H NMR (CDCl 3):}} 3.0ppm (d, 2H, - CH 2 -CH -), 4.5ppm (t, 1H, -CH 2 - CH -), 4.7ppm (d, 2H, -O _{- CH 2 -CO -), 5.1ppm} (s, 2H, Ph- CH 2 -), 7.3ppm (m, 5H, Ph -CH 2 -)

Ｈ−Ｓｅｒ（Ｏａｌｌｙｌ）−ＯＨ → Ｓｅｒ（Ｏａｌｌｙｌ） [Production Example 1-3]
<Synthesis of Cyclic Depsipeptide: Ser (Oallyl)>

H-Ser (Oallyl) -OH → Ser (Oallyl)

  A white solid cyclic depsipeptide (Ser (Oallyl)) was prepared in the same manner as in Production Example 1-2 except that H-Ser (Oallyl) -OH was used instead of H-Asp (OBn) -OH as a raw material. Obtained.

  As described above, in this production example, the total yield was 33%.

The NMR measurement results for this cyclic depsipeptide are as follows.
^{_{1 H NMR (CDCl 3):}} 3.8-3.9ppm (m, 2H, -O- CH 2 -CH-CO -), 4.1-4.3ppm (m, 3H, -CH 2 - CH - _{CO-, CH 2 = CH- CH 2} -), 4.5-4.6ppm (m, 2H, -O- CH 2 -CO -), 5.2-5.3ppm (m, 2H, CH 2 = _{CH-CH 2 -), 5.8-5.9ppm} (m, 1H, CH 2 = CH -CH 2 -), 8.3ppm (s, 1H, -CH- NH -CO-)

Ｈ−Ｓｅｒ（ＯＢｎ）−ＯＨ → Ｓｅｒ（ＯＢｎ）
（式中、Ｂｎはベンジル基を表す。） [Production Example 2-1]
<Synthesis of Monomer of Formula (50): Ser (OBn)>

H-Ser (OBn) -OH → Ser (OBn)
(In the formula, Bn represents a benzyl group.)

  A white solid cyclic depsipeptide (Ser (OBn)) was prepared by the same operation as in Production Example 1-2 except that H-Ser (OBn) -OH was used instead of H-Asp (OBn) -OH as a raw material. Obtained.

  As described above, in this production example, the total yield was 35%.

The NMR measurement results for this cyclic depsipeptide are as follows.
^{_{1 H NMR (CDCl 3):}} 3.7-3.8ppm (m, 2H, -O- CH 2 -CH -), 4.2-4.3ppm (m, 1H, -CH 2 - CH -CO- ), 4.5-4.6 ppm (m, 2H, —O— CH ₂ —CO—), 4.8 to 4.9 ppm (m, 2H, Ph— CH ₂ —O—), 7.3-7 .4 ppm (m, 5H, Ph— CH ₂ —O—), 8.4 ppm (s, 1H, —CH— NH— CO—)

[Production Example 3-1]
<Phosphorylcholine group modifier of formula (52): (2-hydroxy-3- (2-mercaptoethylcarbamoyloxy) propyl phosphorylcholine and 2-hydroxymethyl-2- (2-mercaptoethylcarbamoyloxy) ethyl phosphorylcholine mixture) Synthesis>

  To the eggplant flask were added 2-aminoethanethiol (7.7 g, 100 mmol), 2-oxo-1,3-dioxolan-4-yl-methylphosphorylcholine (14.2 g, 50 mmol), and 125 ml of ethanol, and 24 hours at room temperature. Stir. After completion of the reaction, decantation using hexane and purification by silica gel column chromatography were performed to obtain 2-hydroxy-3- (2-mercaptoethylcarbamoyloxy) propylphosphorylcholine and 2-hydroxymethyl-2- (2-mercapto). A mixture of ethylcarbamoyloxy) ethyl phosphorylcholine was obtained.

  As described above, in this production example, the yield was 42%.

  The NMR measurement results for this mixture are as follows.

¹ H NMR (CD ₃ OD): 3.0 ppm (m, 2H, HS—CH ₂ —CH ₂ —NH—), 3.2 ppm (s, 9H, —CH ₂ —N ⁺ — (CH ₃ ) ₃ ) _{, 3.6-4.1ppm (m, 7H, -} CH 2 - CH - CH 2 -, - CH 2 -N + - (CH 3) 3), 4.3ppm (m, 2H, -O- CH 2 _{-CH 2 -), 5.0ppm (m} , 2H, HS- CH 2 -CH 2 -)
³¹ P NMR [CD3OD]: 0.7-1.1 ppm

Ｌｙｓ（Ｃｂｚ） ＋ ＬＡ → ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｃｏ−ＬＡ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Example 1-1]
<The phosphorylcholine group containing polymer whose X is -NHC (O) O- in Formula (23):
Synthesis of poly (Lys (PC) -co-LA) [NHC (O) O]>

Lys (Cbz) + LA → poly (Lys (Cbz) -co-LA)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

The cyclic depsipeptide (Lys (Cbz)) (0.8 g, 2.5 mmol) and lactide (LA) (1.1 g, 7.5 mmol) produced in Production Example 1-1 were added to a two-necked eggplant flask, and argon substitution was performed. went. 1M 2-ethylhexanoic acid tin-dehydrated toluene solution (10 μl, 10 μmol) was added thereto, and the solvent was distilled off under reduced pressure. Subsequently, deaeration and argon substitution were performed several times, and a polymerization reaction was performed at 115 ° C. for 48 hours. After completion of the reaction, the polymer was dissolved in chloroform and reprecipitated using diethyl ether to obtain poly (Lys (Cbz) -co-LA) which is a random copolymer. The composition ratio of Lys (Cbz) and LA was calculated from the proton ratio of the methylene group of Lys (Cbz) and the methyl group of LA by performing ¹ H NMR measurement. Further, the molecular weight was measured by gel permeation chromatography.

  The yield was 38%.

The results of NMR measurement are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.6ppm (m, 7H, -CH 2 - CH 2 - CH 2 -CH 2 -, - CH- CH 3), 1.8-2.0ppm (m _{, 2H, -CH 2 -CH 2 -CH} 2 - CH 2 -CH -), 3.1-3.2ppm (m, 2H, - CH 2 -CH 2 -CH 2 -CH 2 -CH -), 4 _{.2ppm (m, 1H, - CH} -CH 2 -), 4.5-4.7ppm (m, 2H, -CO- CH 2 -O -), 5.0ppm (s, 2H, Ph- CH 2 - _{), 5.2-5.3ppm (m, 2H,} -CH 2 - NH -CO-O -, - CH -CH 3), 7.3-7.4ppm (m, 5H, Ph -CH 2 -) 7.7 ppm (m, 1H, —CH— NH— CO—)

The composition ratio (m: p), number average molecular weight (Mn), and molecular weight distribution (Mw / Mn) of Lys (Cbz) and LA are as follows.
Composition ratio m: p = 8.7: 91.3
Mn = 9100
Mw / Mn = 1.6

ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｃｏ−ＬＡ） → ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＬＡ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。）

poly (Lys (Cbz) -co-LA) → poly (Lys-co-LA)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

To an eggplant flask, 0.5 g of poly (Lys (Cbz) -co-LA), 5 ml of chloroform, and 5 ml of 32% HBr-acetic acid solution were added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was reprecipitated using diethyl ether, and the resulting solid was filtered off. This solid was dissolved in 5 ml of chloroform, 1 ml of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was reprecipitated using a diethyl ether-methanol mixed solvent (diethyl ether / methanol = 9/1 by volume), and the resulting solid was filtered off. This solid was washed with water to obtain a polymer poly (Lys-co-LA) containing a repeating unit described in the formula (51) having an amino group. Confirmation of the production was judged by disappearance of the phenyl peak of the Cbz group by ¹ H NMR measurement.

ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＬＡ） → ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｃｏ−ＬＡ）〔ＮＨＣ（Ｏ）Ｏ〕

poly (Lys-co-LA) → poly (Lys (PC) -co-LA) [NHC (O) O]

Poly (Lys-co-LA) 0.5 g (number of moles of amino group in the copolymer 0.53 mmol) obtained in the eggplant flask, 2-oxo-1,3-dioxolan-4-yl-methylphosphorylcholine ( 0.15 g, 0.53 mmol), and 6.7 g of a chloroform-methanol mixed solvent (chloroform / methanol = 3/1 by volume) were added and stirred at room temperature for 8 hours. After completion of the reaction, reprecipitation is performed using ethanol, whereby a phosphorylcholine group-containing polymer poly (Lys (PC) -co) containing a repeating unit represented by the formula (23) in which X is —NHC (O) O—. -LA) [NHC (O) O] was obtained. The confirmation of the formation was confirmed by confirming that a peak appeared at 0.7-1.1 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, it was number average molecular weight (Mn) 9200 when the molecular weight was measured by the gel permeation chromatography.

  Calculation of the modification rate (Q) of the obtained poly (Lys (PC) -co-LA) [NHC (O) O] was carried out by quantifying phosphorus in the polymer by the molybdenum blue method, and using the formula (A) Calculated. Phosphorus was quantified by measuring the phosphorus element content with a simple total phosphorus meter using a phosphate cell test manufactured by Merck. As a measuring instrument, a reactor (CR3200 type (manufactured by WTW)) and a portable water quality meter (pHoFlex (manufactured by WTW)) were used. As reagents, p-1K: potassium peroxodisulfate 30%, p-2K: sulfuric acid (15.0%), potassium antimonyl tartrate (30%), p-3K: ascorbic acid was used.

  To the reaction cell was added sulfuric acid (15.0%), 5 ml of a poly (Lys (PC) -co-LA) [NHC (O) O] solution prepared to a predetermined concentration (about 0.01 wt%), and p-1K The reagent was added for one measurement and stirred, and then reacted in a 120 ° C. reactor for 30 minutes. After the reaction, the mixture was cooled for 30 minutes, and 5 drops of p-2K reagent was added and stirred. Further, p-3K reagent was added for 1 measurement and allowed to stand for 5 minutes. Thereafter, the phosphorus content (mg / l) was measured from the absorbance at 612 nm using pHoFlex.

  The modification rate (Q) was calculated to be 0.69.

ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＬＡ） → ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｃｏ−ＬＡ）〔ＮＨ〕
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Example 1-2]
<The phosphorylcholine group containing polymer whose X is -NH- in Formula (23):
Synthesis of poly (Lys (PC) -co-LA) [NH]>

poly (Lys-co-LA) → poly (Lys (PC) -co-LA) [NH]
(In the formula, Cbz represents a benzyloxycarbonyl group.)

In a recovery flask, 0.5 g of poly (Lys-co-LA) obtained in Example 1-1 (0.53 mmol of amino groups in the copolymer), formylmethylphosphorylcholine (0.14 g, 0.64 mmol) ), 2-picoline borane (0.1 g, 1.06 mmol), and 6.7 g of a chloroform-methanol mixed solvent (chloroform / methanol = 3/1 by volume) were added and stirred at room temperature for 1 hour. After completion of the reaction, reprecipitation using ethanol is performed so that a phosphorylcholine group-containing polymer poly (Lys (PC) -co-LA) containing a repeating unit represented by the formula (23) in which X is —NH— [ NH] was obtained. The confirmation of the production was judged by confirming that a peak appeared at 0.8-0.9 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, it was number average molecular weight (Mn) 9200 when the molecular weight was measured by the gel permeation chromatography.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.91.

Ａｓｐ（ＯＢｎ） ＋ ＬＡ → ｐｏｌｙ（Ａｓｐ（ＯＢｎ）−ｃｏ−ＬＡ）
→ ｐｏｌｙ（Ａｓｐ−ｃｏ−ＬＡ）
（式中、Ｂｎはベンジル基を表す。） [Example 1-3]
<The phosphorylcholine group containing polymer whose X is -C (O)-in Formula (23):
Synthesis of poly (Asp (PC) -co-LA)>

Asp (OBn) + LA → poly (Asp (OBn) -co-LA)
→ poly (Asp-co-LA)
(In the formula, Bn represents a benzyl group.)

The cyclic depsipeptide (Asp (OBn)) (0.26 g, 1 mmol) and lactide (LA) (1.3 g, 9 mmol) produced in Production Example 1-2 were added to a two-necked eggplant flask, and the reaction temperature was 160 ° C. The polymer poly (Asp) containing the repeating unit of the formula (51) having a carboxyl group via poly (Asp (OBn) -co-LA) is carried out in the same manner as in Example 1-1 except for the above. -Co-LA). The confirmation of the formation was judged by disappearance of the phenyl peak of the Bn group by ¹ H NMR measurement.

  The yield was 40%.

The results of NMR measurement of poly (Asp (OBn) -co-LA) are as follows.
¹ H NMR (CDCl ₃ ): 1.5 ppm (m, 3H, —CH— CH ₃ ), 3.0 ppm (m, 2H, —CH— CH ₂ —CO—), 4.6 to 4.7 ppm (m _{, 3H, - CH -CH 2 -CO} -, - CO- CH 2 -O -), 5.1-5.2ppm (m, 3H, - CH 2 -Ph, - CH -CH 3), 7.2 _{-7.3ppm (m, 5H, -CH 2} - Ph)

The composition ratio (m: p), number average molecular weight (Mn), and molecular weight distribution (Mw / Mn) of Asp (OBn) and LA of poly (Asp (OBn) -co-LA) are as follows. .
Composition ratio m: p = 4.3: 95.7
( ¹ H NMR measurement was performed and calculated from the proton ratio of the methylene group of Asp (OBn) to the methyl group of LA.)
Mn = 10400
Mw / Mn = 1.9

ｐｏｌｙ（Ａｓｐ−ｃｏ−ＬＡ） → ｐｏｌｙ（Ａｓｐ（ＰＣ）−ｃｏ−ＬＡ）

poly (Asp-co-LA) → poly (Asp (PC) -co-LA)

Poly (Asp-co-LA) 0.5 g obtained in an eggplant flask (number of carboxyl groups in the copolymer: 0.28 mmol), 5,6-epoxyhexyl phosphorylcholine (0.10 g, 0.34 mmol), And 6.7 g of a chloroform-methanol mixed solvent (volume ratio of chloroform / methanol = 3/1) was added, and the mixture was stirred at 50 ° C. for 5 hours. After the completion of the reaction, reprecipitation is performed using ethanol, so that a phosphorylcholine group-containing polymer poly (Asp (PC) -co) containing a repeating unit represented by the formula (23) in which X is —C (O) O—. -LA). The confirmation of the production was judged by confirming that a peak appears at 1.1-1.2 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when the molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 10400.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.70.

Ｓｅｒ（Ｏａｌｌｙｌ） ＋ ＬＡ → ｐｏｌｙ（Ｓｅｒ（Ｏａｌｌｙｌ）−ｃｏ−ＬＡ） [Example 1-4]
<The phosphorylcholine group containing polymer whose X is -S- in Formula (23):
Synthesis of poly (Ser (PC) -co-LA)>

Ser (Oallyl) + LA → poly (Ser (Oallyl) -co-LA)

The cyclic depsipeptide (Ser (Oallyl)) (0.09 g, 0.5 mmol) produced in Production Example 1-3 and lactide (LA) (1.4 g, 9.5 mmol) were added to a two-necked eggplant flask, and the reaction temperature was adjusted. The same operation as in Example 1-1 was performed except that the temperature was 150 ° C., to obtain a polymer poly (Ser (Oallyl) -co-LA) containing a repeating unit described in the formula (51) having a vinyl group. ¹ H NMR measurement was performed to confirm generation and calculate the composition ratio.

  The yield was 68%.

The results of NMR measurement of poly (Ser (Olyly) -co-LA) are as follows.
¹ H NMR (CDCl ₃ ): 1.5-1.6 ppm (m, 3H, —CH— CH ₃ ), 3.8-3.9 ppm (m, 2H, —CH— CH ₂ —O—) _{4-4.6ppm (m, 5H, -O- CH} 2 -CH = CH 2, - CH -CH 2 -O -, - CO- CH 2 -O -), 5.2ppm (m, 1H, - CH _{-CH 3), 5.5ppm (m,} 2H, -O-CH 2 -CH = CH 2), 6.1-6.2ppm (m, 1H, -O-CH 2 - CH = CH 2), 7 .6 ppm (s, 1H, —CH— NH— CO—)

In addition, the composition ratio (m: p), number average molecular weight (Mn), and molecular weight distribution (Mw / Mn) of Ser (Olyly) and LA of poly (Ser (Oallyl) -co-LA) are as follows. .
Composition ratio m: p = 1.9: 98.1
( ¹ H NMR measurement was performed and calculated from the proton ratio of the vinyl group of Ser (Olyl) and the methyl group of LA.)
Mn = 18100
Mw / Mn = 2.1

ｐｏｌｙ（Ｓｅｒ（Ｏａｌｌｙｌ）−ｃｏ−ＬＡ） → ｐｏｌｙ（Ｓｅｒ（ＰＣ）−ｃｏ−ＬＡ）

poly (Ser (Olyly) -co-LA) → poly (Ser (PC) -co-LA)

Poly (Ser (Oallyl) -co-LA) 0.5 g obtained in an eggplant flask (number of moles of vinyl group in the copolymer 0.13 mmol), 2-hydroxy-3- produced in Production Example 3-1. (2-mercaptoethylcarbamoyloxy) propyl phosphorylcholine and a mixture of 2-hydroxymethyl-2- (2-mercaptoethylcarbamoyloxy) ethylphosphorylcholine (0.06 g, 0.16 mmol), chloroform-methanol mixed solvent (by volume ratio) 6.7 g of chloroform / methanol = 3/1) and azobis (iso-butyronitrile) (0.03 g, 0.18 mmol) were added, and the mixture was stirred at 60 ° C. for 24 hours. After completion of the reaction, reprecipitation is performed using ethanol, so that a phosphorylcholine group-containing polymer poly (Ser (PC) -co-LA) containing a repeating unit according to the formula (23) in which X is —S— is obtained. Obtained. The confirmation of the production was judged by confirming that a peak appeared at 0.6-1.0 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 18000.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 1.00.

Ｌｙｓ（Ｃｂｚ） ＋ ＧＡ → ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｃｏ−ＧＡ）
→ ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＧＡ）
式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Example 1-5]
<The phosphorylcholine group containing polymer whose X is -NHC (O) O- in Formula (23):
Synthesis of poly (Lys (PC) -co-GA)>

Lys (Cbz) + GA → poly (Lys (Cbz) -co-GA)
→ poly (Lys-co-GA)
In the formula, Cbz represents a benzyloxycarbonyl group. )

The same procedure as in Example 1-1 was carried out except that glycolide (GA) was used instead of lactide (LA), and a compound having an amino group via poly (Lys (Cbz) -co-GA) ( 51) The polymer poly (Lys-co-GA) containing the repeating unit described in 51) was obtained. Confirmation of the production was judged by disappearance of the phenyl peak of the Cbz group by ¹ H NMR measurement.

  The yield was 37%.

The results of NMR measurement of poly (Lys (Cbz) -co-GA) are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.6ppm (m, 4H, -CH 2 - CH 2 - CH 2 -CH 2 -), 1.8-1.9ppm (m, 2H, -CH 2 _{-CH 2 -CH 2 - CH 2 -CH} -), 3.1-3.2ppm (m, 2H, - CH 2 -CH 2 -CH 2 -CH 2 -CH -), 4.2ppm (m, 1H _{, - CH -CH 2 -),} 4.5-4.7ppm (m, 2H, -NH-CO- CH 2 -O -), 5.0-5.1ppm (m, 4H, Ph- CH 2 - _{, -CO- CH 2 -O -),} 5.2-5.3ppm (m, 1H, -CH 2 - NH -CO-O -), 7.3-7.4ppm (m, 5H, Ph -CH _2- ), 7.7 ppm (m, 1H, —CH— NH— CO—)

The composition ratio (m: p), number average molecular weight (Mn), and molecular weight distribution (Mw / Mn) of Lys (Cbz) and GA of poly (Lys (Cbz) -co-GA) are as follows. .
Composition ratio m: p = 9.9: 90.1
( ¹ H NMR measurement was performed and calculated from the proton ratio of the methylene group of Lys (Cbz) to the methylene group of GA.)
Mn = 8400
Mw / Mn = 1.7

ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＧＡ） → ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｃｏ−ＧＡ）

poly (Lys-co-GA) → poly (Lys (PC) -co-GA)

0.5 g of poly (Lys-co-GA) obtained in an eggplant flask (number of moles of amino group in the copolymer: 0.70 mmol), 2-oxo-1,3-dioxolan-4-yl-methylphosphorylcholine ( 0.10 g, 0.35 mmol) and a chloroform-methanol mixed solvent (chloroform / methanol = 3/1 by volume) were added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, reprecipitation is performed using ethanol, whereby a phosphorylcholine group-containing polymer poly (Lys (PC) -co) containing a repeating unit represented by the formula (23) in which X is —NHC (O) O—. -GA). The confirmation of the formation was confirmed by confirming that a peak appeared at 0.7-1.1 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when the molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 8300.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.29.

Ｌｙｓ（Ｃｂｚ） ＋ ＣＬ → ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｃｏ−ＣＬ）
ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＣＬ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Example 1-6]
<The phosphorylcholine group containing polymer whose X is -NHC (O)-in Formula (23):
Synthesis of poly (Lys (PC) -co-CL)>

Lys (Cbz) + CL → poly (Lys (Cbz) -co-CL)
poly (Lys-co-CL)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

  Example 1 except that the cyclic depsipeptide (Lys (Cbz)) (0.3 g, 1 mmol) and ε-caprolactone (CL) (1.0 g, 9 mmol) produced in Production Example 1-1 were added to a 2-neck eggplant flask. The polymer poly (Lys-co-CL) containing the repeating unit according to the formula (51) having an amino group via poly (Lys (Cbz) -co-CL) Got.

  The yield was 43%.

The results of NMR measurement of poly (Lys (Cbz) -co-CL) are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.8ppm (m, 12H, -CH- CH 2 - CH 2 - CH 2 -CH 2 -, - CO-CH 2 - CH 2 - CH 2 - CH 2 _{-CH 2 -O -), 2.3ppm (} m, 2H, -CO- CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -O -), 3.1-3.2ppm (m, 2H, _{-NH- CH 2 -CH 2 -CH 2 -CH} 2 -), 4.2-4.3ppm (m, 3H, -CO- CH -CH 2 -, - CO-CH 2 -CH 2 -CH 2 - _{CH 2 - CH 2 -O -)} , 4.5-4.7ppm (m, 2H, -CO- CH 2 -O -), 5.0ppm (s, 2H, Ph- CH 2 -), 5.2 _{-5.3ppm (m, 1H, -CO- NH} -CH 2 -), 7.3-7.4ppm (m, 5H, P _{-CH 2 -), 7.6ppm (s} , 1H, -CH- NH -CO-)

Also, the ratio (Mw / Mn) of the composition ratio (m: q), number average molecular weight (Mn), and molecular weight distribution (Mn) of Lys (Cbz) and CL of poly (Lys (Cbz) -co-CL) Is as follows.
Composition ratio m: q = 5.1: 94.9
( ¹ H NMR measurement was performed and calculated from the proton ratio of the methylene group of Lys (Cbz) to the methylene group of CL.)
Mn = 16900
Mw / Mn = 2.2

ｐｏｌｙ（Ｌｙｓ−ｃｏ−ＣＬ）
→ ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｃｏ−ＣＬ）

poly (Lys-co-CL)
→ poly (Lys (PC) -co-CL)

0.5 g of poly (Lys-co-CL) obtained in the eggplant flask (0.22 mmol of amino group in the copolymer), 2-oxo-1,3-dioxolan-4-yl-methylphosphorylcholine ( 0.12 g, 0.44 mmol) and 6.7 g of a chloroform-methanol mixed solvent (chloroform / methanol = 3/1 by volume) were added and stirred at room temperature for 8 hours. After completion of the reaction, reprecipitation is performed using ethanol, whereby a phosphorylcholine group-containing polymer poly (Lys (PC) -co) containing a repeating unit represented by the formula (23) in which X is —NHC (O) O—. -CL). The confirmation of the formation was confirmed by confirming that a peak appeared at 0.7-1.1 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 17000.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.96.

Ｌｙｓ（Ｃｂｚ） ＋ Ｓｅｒ（ＯＢｎ） ＋ ＬＡ
→ ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｃｏ−Ｓｅｒ（ＯＢｎ）−ｃｏ−ＬＡ）
→ ｐｏｌｙ（Ｌｙｓ−ｃｏ−Ｓｅｒ−ｃｏ−ＬＡ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を、Ｂｎはベンジル基を表す。） [Example 1-7]
<The phosphorylcholine group containing polymer whose X is -NHC (O)-in Formula (23):
Synthesis of poly (Lys (PC) -co-Ser-co-LA)>

Lys (Cbz) + Ser (OBn) + LA
→ poly (Lys (Cbz) -co-Ser (OBn) -co-LA)
→ poly (Lys-co-Ser-co-LA)
(In the formula, Cbz represents a benzyloxycarbonyl group, and Bn represents a benzyl group.)

  Cyclic depsipeptide (Lys (Cbz)) produced in Production Example 1-1 (0.48 g, 1.5 mmol) in a 2-neck eggplant flask, (Ser (OBn)) produced in Production Example 2-1 (0.24 g, 1 mmol) and lactide (LA) (1.1 g, 7.5 mmol) were added, and the same operation as in Example 1-1 was performed except that the reaction temperature was 150 ° C., and poly (Lys (Cbz) -co— A polymer poly (Lys-co-Ser-co-LA) containing a repeating unit described in the formula (51) having an amino group was obtained via Ser (OBn) -co-LA).

  The yield was 38%.

The results of NMR measurement of poly (Lys (Cbz) -co-Ser (OBn) -co-LA) are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.6ppm (m, 7H, -CH 2 - CH 2 - CH 2 -CH 2 -, - CH- CH 3), 1.8-1.9ppm (m _{, 2H, -CH 2 -CH 2 -CH} 2 - CH 2 -CH -), 3.1-3.2ppm (m, 2H, - CH 2 -CH 2 -CH 2 -CH 2 -CH -), 3 _{.8ppm (m, 2H, -CH- CH} 2 -O-CH 2 -Ph), 4.2ppm (m, 1H, -CH 2 -CH 2 - CH -CO -), 4.5-4.7ppm ( _{m, 5H, -O- CH 2 -CO} -NH- CH -CH 2 -O -, - O- CH 2 -CO-NH-CH-CH 2 -CH 2 -,), 5.0-5.3ppm _{(m, 6H, Ph- CH 2} -O-CO-, Ph- CH 2 -O -, - CH -CH 3, -CO- N _{-CH 2 -), 6.8ppm (m} , 1H, -O-CH 2 -CH- NH -CO -), 7.3-7.4ppm (m, 10H, Ph -CH 2 -O-CH 2 - , Ph— CH ₂ —O—CO—), 7.6 ppm (m, 1H, —CH ₂ —CH ₂ —CH— NH— CO—)

Further, the composition ratio (m: r: p) of Lys (Cbz), Ser (OBn) and LA of poly (Lys (Cbz) -co-Ser (OBn) -co-LA), number average molecular weight (Mn), The molecular weight distribution (Mw / Mn) is as follows.
Composition ratio m: r: p = 6.6: 4.0: 89.4
( ¹ H NMR measurement was performed and calculated from the proton ratio of the methylene group of Lys (Cbz), the methylene group of Ser (OBn), and the methyl group of LA.)
Mn = 9300
Mw / Mn = 2.0

ｐｏｌｙ（Ｌｙｓ−ｃｏ−Ｓｅｒ−ｃｏ−ＬＡ）
→ ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｃｏ−Ｓｅｒ−ｃｏ−ＬＡ）

poly (Lys-co-Ser-co-LA)
→ poly (Lys (PC) -co-Ser-co-LA)

0.5 g of poly (Lys-co-Ser-co-LA) obtained in an eggplant flask (number of moles of amino group in copolymer: 0.40 mmol), 2-oxo-1,3-dioxolan-4-yl -Methyl phosphorylcholine (0.14 g, 0.48 mmol) and 6.7 g of a chloroform-methanol mixed solvent (volume ratio chloroform / methanol = 3/1) were added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, reprecipitation is performed using ethanol, whereby a phosphorylcholine group-containing polymer poly (Lys (PC) -co) containing a repeating unit represented by the formula (23) in which X is —NHC (O) O—. -Ser-co-LA). The confirmation of the formation was confirmed by confirming that a peak appeared at 0.7-1.1 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, it was number average molecular weight (Mn) 9200 when the molecular weight was measured by the gel permeation chromatography.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.82.

Ｓｅｒ（Ｏａｌｌｙｌ） ＬＡ ＋ メトキシＰＥＧ →
→ ｐｏｌｙ［（Ｓｅｒ（Ｏａｌｌｙｌ）−ｃｏ−ＬＡ）−ｂ−ＥＧ］ [Example 1-8]
<The phosphorylcholine group containing polymer whose X is -S- in Formula (23):
Synthesis of poly [(Ser (PC) -co-LA) -b-EG]>

Ser (Oallyl) LA + MethoxyPEG →
→ poly [(Ser (Olylyl) -co-LA) -b-EG]

  Cyclic depsipeptide Ser (Oallyl) (0.09 g, 0.5 mmol), lactide (LA) (0.3 g, 2.0 mmol), SUNBRIGHT MEH-50H (NOF) manufactured in Preparation Example 1-3 in a two-necked eggplant flask Mw = 5000) (methoxy PEG) (1.3 g, 0.25 mmol), 1M 2-ethylhexanoic acid tin-dehydrated toluene solution (25 μl, 25 μmol) was added, and the reaction temperature was 150 ° C. Was the same as in Example 1-1, and a polymer poly [(Ser (Olylyl) -co-LA) -b-EG] containing a repeating unit described in the formula (51) having a vinyl group was obtained. .

  The yield was 50%.

The results of NMR measurement of poly [(Ser (Olylyl) -co-LA) -b-EG] are as follows.
¹ H NMR (CDCl ₃ ): 1.5-1.6 ppm (m, 3H, —CH— CH ₃ ), 3.1-3.2 ppm (m, 3H, —O CH ₃ ) 3.7-3. _{9ppm (m, 6H, -O CH} 2 CH 2 O -, - CH- CH 2 -O-) 4.2-4.6ppm (m, 7H, -OCH 2 CH 2 OCO -, - O- CH 2 - _{CH = CH 2, - CH -CH} 2 -O -, - CO- CH 2 -O -), 5.2ppm (m, 1H, - CH -CH 3), 5.5ppm (m, 2H, -O- _{CH 2 -CH = CH 2),} 6.1-6.2ppm (m, 1H, -O-CH 2 - CH = CH 2), 7.6ppm (s, 1H, -CH- NH -CO-)

In addition, the composition ratio (m: p: s), number average molecular weight (Mn), and molecular weight distribution (Mw) of poly [(Ser (Olylyl) -co-LA) -b-EG]. / Mn) is as follows.
Composition ratio m: p: s = 4.5: 60.1: 35.4
( ¹ H NMR measurement was performed and calculated from the proton ratio of the vinyl group of Ser (Olyl) and the methyl group of LA.)
Mn = 14700
Mw / Mn = 1.7

ｐｏｌｙ［（Ｓｅｒ（ＰＣ）−ｃｏ−ＬＡ）−ｂ−ＥＧ］

poly [(Ser (PC) -co-LA) -b-EG]

Poly [(Ser (Oallyl) -co-LA) -b-EG] 0.5 g (number of moles of vinyl group in the copolymer 0.33 mmol) obtained in the eggplant flask, produced in Production Example 3-1. A mixture of 2-hydroxy-3- (2-mercaptoethylcarbamoyloxy) propyl phosphorylcholine and 2-hydroxymethyl-2- (2-mercaptoethylcarbamoyloxy) ethyl phosphorylcholine (0.14 g, 0.40 mmol), chloroform-methanol 6.7 g of a mixed solvent (chloroform / methanol = 3/1 by volume) and azobis (iso-butyronitrile) (0.08 g, 0.48 mmol) were added, and the mixture was stirred at 60 ° C. for 24 hours. After completion of the reaction, reprecipitation is performed using ethanol, so that X is —S—, and the phosphorylcholine group-containing polymer poly [(Ser (PC) -co-LA) containing the repeating unit according to formula (23) -B-EG] was obtained. The confirmation of the production was judged by confirming that a peak appeared at 0.6-1.0 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when the molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 14800.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 1.00.

Ｌｙｓ（Ｃｂｚ） → ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ））
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Example 2-1]
<The phosphorylcholine group containing polymer (block copolymer) whose X is -NHC (O) O- in Formula (23):
Synthesis of poly (Lys (PC) -b-LA)>

Lys (Cbz) → poly (Lys (Cbz))
(In the formula, Cbz represents a benzyloxycarbonyl group.)

  The polymerization operation was performed in a glove box substituted with argon gas. Ethanol (0.002 g, 50 μmol) and 1 mM potassium naphthalene-THF solution (150 ml, 150 μmol) were added and stirred at room temperature for 10 minutes. To the obtained mixed solution, a 1M THF solution (50 ml, 50 mmol) of Lys (Cbz) produced in Production Example 1-1 was added, and a polymerization reaction was performed at room temperature for 30 minutes. After completion of the reaction, 5 ml of acetic acid was added to stop the polymerization, and reprecipitation was performed using methanol to obtain poly (Lys (Cbz)).

ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）） ＋ ＬＡ → ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｂ−ＬＡ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。）

poly (Lys (Cbz)) + LA → poly (Lys (Cbz) -b-LA)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

To poly (Lys (Cbz)) obtained by reprecipitation, 1 mM potassium naphthalene-THF solution (150 ml, 150 μmol) was added and stirred at room temperature for 10 minutes. A 1M THF solution of lactide (50 ml, 50 mmol) was added to the obtained mixed solution, and a polymerization reaction was performed at room temperature for 30 minutes. After completion of the reaction, 5 ml of acetic acid was added to terminate the polymerization, and reprecipitation was performed using methanol to obtain poly (Lys (Cbz) -b-LA). ¹ H NMR measurement was performed to confirm generation and calculate the composition ratio.

  The total yield was 32%.

The results of NMR measurement of poly (Lys (Cbz) -b-LA) are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.6ppm (m, 7H, -CH 2 - CH 2 - CH 2 -CH 2 -, - CH- CH 3), 1.8-2.0ppm (m _{, 2H, -CH 2 -CH 2 -CH} 2 - CH 2 -CH -), 3.1-3.2ppm (m, 2H, - CH 2 -CH 2 -CH 2 -CH 2 -CH -), 4 _{.2ppm (m, 1H, - CH} -CH 2 -), 4.5-4.7ppm (m, 2H, -CO- CH 2 -O -), 5.0ppm (s, 2H, Ph- CH 2 - _{), 5.2-5.3ppm (m, 2H,} -CH 2 - NH -CO-O -, - CH -CH 3), 7.3-7.4ppm (m, 5H, Ph -CH 2 -) 7.7 ppm (m, 1H, —CH— NH— CO—)

The composition ratio (m: p), number average molecular weight (Mn), and molecular weight distribution (Mw / Mn) of Lys (Cbz) and LA of poly (Lys (Cbz) -b-LA) are as follows. .
Composition ratio m: p = 4.7: 95.3
( ¹ H NMR measurement was performed and calculated from the proton ratio of the methylene group of Lys (Cbz) to the methyl group of LA.)
Mn = 9300
Mw / Mn = 1.8

ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｂ−ＬＡ） → ｐｏｌｙ（Ｌｙｓ−ｂ−ＬＡ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。）

poly (Lys (Cbz) -b-LA) → poly (Lys-b-LA)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

To the eggplant flask, 0.5 g of poly (Lys (Cbz) -b-LA), 5 ml of chloroform, and 5 ml of 32% HBr-acetic acid solution were added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was reprecipitated using diethyl ether, and the resulting solid was filtered off. This solid was dissolved in 5 ml of chloroform, 1 ml of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was reprecipitated using a diethyl ether-methanol mixed solvent (diethyl ether / methanol = 9/1 by volume), and the resulting solid was filtered off. This solid was washed with water to obtain a polymer (block copolymer) poly (Lys-b-LA) containing a repeating unit described in the formula (51) having an amino group. Confirmation of the production was judged by disappearance of the phenyl peak of the Cbz group by ¹ H NMR measurement.

ｐｏｌｙ（Ｌｙｓ−ｂ−ＬＡ）
→ ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｂ−ＬＡ）

poly (Lys-b-LA)
→ poly (Lys (PC) -b-LA)

0.5 g of poly (Lys-b-LA) obtained in an eggplant flask (0.30 mmol of amino groups in the copolymer), 2-oxo-1,3-dioxolan-4-yl-methylphosphorylcholine ( 0.10 g, 0.36 mmol), and 6.7 g of a chloroform-methanol mixed solvent (chloroform / methanol = 3/1 by volume) were added and stirred at room temperature for 8 hours. By performing reprecipitation using ethanol, a phosphorylcholine group-containing polymer (block copolymer) poly (Lys (PC)) containing a repeating unit represented by the formula (23) in which X is —NHC (O) O— -B-LA). The confirmation of the formation was confirmed by confirming that a peak appeared at 0.7-1.1 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when the molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 9400.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.81.

ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）） メトキシＰＥＧ → ｐｏｌｙ（Ｌｙｓ（Ｃｂｚ）−ｂ−ＥＧ）
→ ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｂ−ＥＧ）
（式中、Ｃｂｚはベンジルオキシカルボニル基を表す。） [Example 2-2]
<Synthesis of phosphorylcholine group-containing polymer in which X is —NHC (O) O— in formula (23) (block copolymer): synthesis of poly (Lys (PC) -b-EG)>

poly (Lys (Cbz)) Methoxy PEG → poly (Lys (Cbz) -b-EG)
→ poly (Lys (PC) -b-EG)
(In the formula, Cbz represents a benzyloxycarbonyl group.)

  Cyclic depsipeptide (Lys (Cbz)) (0.8 g, 2.5 mmol) produced in Production Example 1-1 in a 2-neck eggplant flask, SUNBRIGHT MEH-50H (manufactured by NOF Corporation, Mw = 5000) (methoxy) PEG) (1.3 g, 0.25 mmol) 1M2-ethylhexanoic acid-dehydrated toluene solution (25 μl, 25 μmol) was added, except that poly-Lys (Cbz) -B-EG), a polymer (block copolymer) poly (Lys-b-EG) containing a repeating unit described in the formula (51) having an amino group was obtained.

  The yield was 73%.

The results of NMR measurement of poly (Lys (Cbz) -b-EG) are as follows.
_{^{1 H NMR (CDCl 3):}} 1.4-1.6ppm (m, 4H, -CH 2 - CH 2 - CH 2 -CH 2 -), 1.8-2.0ppm (m, 2H, -CH 2 _{-CH 2 -CH 2 - CH 2 -CH} -), 3.1-3.3ppm (m, 5H, - CH 2 -CH 2 -CH 2 -CH 2 -CH -, - O CH 3), 3. _{7 (s, 4H, -O CH} 2 CH 2 O -), 4.2-4.3ppm (m, 3H, -CH 2 - CH -CO -, - OCH 2 CH 2 OCO -), 4.5- _{4.7ppm (m, 2H, -O- CH} 2 -CO -), 5.0ppm (s, 2H, Ph- CH 2 -), 5.2-5.3ppm (m, 1H, -CO- NH - _{CH 2 -), 7.3-7.4ppm (m} , 5H, Ph -CH 2 -), 7.7ppm (m, 1H, -CH- H -CO-)

The composition ratio (m: s), number average molecular weight (Mn), and molecular weight distribution (Mw / Mn) of Lys (Cbz) and EG of poly (Lys (Cbz) -b-EG) are as follows. .
Composition ratio m: s = 7.1: 92.9
( ¹ H NMR measurement was performed and calculated from the proton ratio of the methylene group of Lys (Cbz) to the methylene group of EG.)
Mn = 6500
Mw / Mn = 1.6

ｐｏｌｙ（Ｌｙｓ−ｂ−ＥＧ） → ｐｏｌｙ（Ｌｙｓ（ＰＣ）−ｂ−ＥＧ）

poly (Lys-b-EG) → poly (Lys (PC) -b-EG)

0.5 g of poly (Lys-b-EG) obtained in an eggplant flask (0.66 mmol of amino groups in the copolymer), 2-oxo-1,3-dioxolan-4-yl-methylphosphorylcholine ( 0.22 g, 0.79 mmol) and 6.7 g of a chloroform-methanol mixed solvent (volume ratio of chloroform / methanol = 3/1) were added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, reprecipitation is performed using ethanol, whereby a phosphorylcholine group-containing polymer (block copolymer) poly (X) containing a repeating unit represented by the formula (23) in which X is —NHC (O) O—. Lys (PC) -b-EG) was obtained. The confirmation of the formation was confirmed by confirming that a peak appeared at 0.7-1.1 ppm by ³¹ P NMR measurement of the sample after reprecipitation. Moreover, when the molecular weight was measured by gel permeation chromatography, it was number average molecular weight (Mn) 6600.

  As a result of calculating the modification rate (Q) by the molybdenum blue method, it was 0.77.

[Example 3-1]
<Hydrolysis test>
Phosphorylcholine group-containing polymer poly (Lys (PC) -co-LA) [NHC (O) containing the repeating unit represented by the formula (23) in which X produced in Example 1-1 is —NHC (O) O—. ) O] 30 mg was put into 200 mL of PBS buffer (pH = 7.4), stored at 37 ° C., and subjected to a hydrolysis test. The number average molecular weight of the sample before the test (0 day), 7 days after the test, and 30 days after the test was measured by gel permeation chromatography (eluent: chloroform, standard: polystyrene) to evaluate the hydrolyzability. As a result, it was confirmed that hydrolysis was progressing.

[Example 3-2]
<Hydrolysis test>
Instead of a phosphorylcholine group-containing polymer poly (Lys (PC) -co-LA) [NHC (O) O] containing a repeating unit according to formula (23), wherein X is —NHC (O) O— Except having used the phosphorylcholine group containing polymer poly (Lys (PC) -co-LA) [NH] containing the repeating unit as described in the formula (23) whose X manufactured in Example 1-2 is -NH-, The same operation as in Example 3-1 was performed to evaluate hydrolyzability. As a result, it was confirmed that hydrolysis was progressing.

[Example 3-3]
<Hydrolysis test>
Instead of a phosphorylcholine group-containing polymer poly (Lys (PC) -co-LA) [NHC (O) O] containing a repeating unit according to formula (23), wherein X is —NHC (O) O— The phosphorylcholine group-containing polymer poly [(Ser (PC) -co-LA) -b-EG] containing a repeating unit represented by the formula (23) in which X is —S— produced in Example 1-8 was used. Except for the above, the same operation as in Example 3-1 was performed to evaluate hydrolyzability. The results are summarized in Table 1. As a result, it was confirmed that hydrolysis was progressing.

[Comparative Example 1]
<Hydrolysis test>
Instead of the phosphorylcholine group-containing polymer poly (Lys (PC) -co-LA) [NHC (O) O] containing a repeating unit according to formula (23), wherein X is —NHC (O) O—, LIPIDURE Except that a sample obtained by freeze-drying -B (manufactured by NOF Corporation, aqueous solution of 2-methacryloyloxyethyl phosphorylcholine (MPC) and butyl methacrylate copolymer, Mn = 53000) was used. The same operation as 3-1 was performed, and the hydrolyzability was evaluated. As a result, it was confirmed that hydrolysis did not proceed.

[Hydrolysis test summary]
Table 1 shows the results (number average molecular weight) of hydrolysis tests of Example 3-1, Example 3-2, Example 3-3, and Comparative Example 1. In Example 3-1, Example 3-2, and Example 3-3 according to the present embodiment, hydrolysis was observed and biodegradability was recognized.

  On the other hand, in Comparative Example 1, no hydrolysis was observed and no biodegradability was observed. As described above, it was confirmed that the depsipeptide skeleton of the phosphorylcholine group-containing polymer according to this embodiment contributes to biodegradability.

Claims (5)

A phosphorylcholine group-containing polymer containing a repeating unit represented by the formula (1).

(In the formula, A1 represents a divalent organic group, A2 represents a divalent organic group independent of A1, and X represents —O—, —C (O) O—, —NHCO—, —NHC ( O) represents O-, -S-, or -NH-. The phosphorylcholine group-containing polymer according to claim 1,
A phosphorylcholine group-containing polymer containing at least one type of repeating unit selected from the group of repeating units represented by formulas (2) to (5).

(In the formula, R ¹ represents an organic group represented by — (CH ₂ ) _a —, and a is 3, 4, or 5.)

(In the formula, R ² represents a hydrogen atom or a methyl group.)

(In the formula, R ³ represents a hydrogen atom, a methyl group, a methylol group, a benzyl group, a 2-propyl group, a 2-methylpropyl group, or a 2-butyl group.)
— (R ⁴ —O) — (5)
(In the formula, R ⁴ —O represents an oxyethylene group or an oxypropylene group.) Producing an intermediate polymer comprising a repeating unit represented by formula (6);
A method for producing a phosphorylcholine group-containing polymer, wherein the produced intermediate polymer is reacted with a phosphorylcholine group modifier represented by formula (7).

(In the formula, A3 represents a divalent organic group, and Y represents a carboxyl group, an amino group, or a vinyl group.)

(In the formula, A4 represents a divalent organic group, and Z represents a functional group selected from the group of functional groups represented by formulas (8) to (13).)

-SH (12)

A method for producing a phosphorylcholine group-containing polymer according to claim 3,
The intermediate polymer is a random copolymer. A method for producing a phosphorylcholine group-containing polymer. A method for producing a phosphorylcholine group-containing polymer according to claim 3,
The intermediate polymer is a block copolymer. A method for producing a phosphorylcholine group-containing polymer.