JP2011162522A - Phosphorylcholine group-containing diol compound, and the group-containing polymer - Google Patents

Abstract

［式中、Ｘは単結合、酸素原子、−COO−、−CONH−、−OOC−または−CH2O−で示される基を表し、Ｙは単結合、炭素数１〜６のアルキレン基、またはオリゴオキシアルキレン基を表し、ｍおよびｎはそれぞれ１〜６の整数を表す。］
【選択図】なしDisclosed is a phosphorylcholine group-containing diol compound, and a high-molecular-weight polymer having excellent biocompatibility, processability, mechanical strength, water resistance, and heat resistance using the phosphorylcholine group-containing diol compound as one of starting materials. provide.
A specific diol compound having a phosphorylcholine group represented by the following formula (I) and a residue obtained by removing a hydrogen atom from a hydroxyl group of the diol compound as a structural unit is contained at least 1 mol%, and a weight average molecular weight Is a polymer having a ≥ 5,000.

[Wherein X represents a single bond, oxygen atom, —COO—, —CONH—, —OOC— or —CH 2 O—, and Y represents a single bond, an alkylene group having 1 to 6 carbon atoms, or an oligo group. Represents an oxyalkylene group, and m and n each represents an integer of 1 to 6; ]
[Selection figure] None

Description

  The present invention relates to a diol compound having a phosphorylcholine group and a polymer having a phosphorylcholine group in a side chain, which is obtained by polymerization using the compound as a raw material.

  Conventionally, it has been known that when an artificial organ or a medical device is used in contact with a living body, significant effects on the living body such as blood coagulation, inflammation, and encapsulation appear due to the self-defense reaction of the living body. This is the result of a series of bioactivation reactions starting from the protein adsorption phenomenon to the materials constituting the artificial organs and medical devices. Therefore, in the case of performing treatment using such an artificial organ or a medical device, it is necessary to use a drug such as an anticoagulant such as heparin or an immunosuppressant together.

However, it has been pointed out that the effects of these drugs appear as side effects as the treatment period is long and the patient ages.
In order to solve such problems, a series of medical materials called biocompatible materials have been developed. Among these, as materials showing particularly remarkable biocompatibility, focusing on the structure of the surface of biological membranes, phosphorous materials have been developed. A polymer containing a structural unit derived from 2-methacryloyloxyethyl phosphorylcholine (MPC), which is a polymer carrying a phosphorylcholine group, which is a lipid polar group, has been developed (hereinafter also simply referred to as “MPC polymer”). (Refer nonpatent literature 1).

  MPC is a methacrylic acid ester, its homopolymer is water-soluble, but has a structure suitable for treating medical device surfaces by copolymerization with various vinyl monomers, water-insoluble MPC polymer Can be manufactured. By coating this water-insoluble MPC polymer on the surface of the material, blood coagulation can be suppressed even when no anticoagulant is used, and it is also known that it exhibits extremely high biocompatibility even in subcutaneous implantation tests. (See Non-Patent Document 2). Taking advantage of this feature, water-insoluble MPC polymers have been used in Europe and the United States as surface coating agents for medical devices that have already been clinically applied, and devices have been approved in Japan. It is expected that this will dramatically improve the effectiveness of the patient and further improve the quality of life of patients.

  However, the MPC itself is hydrophilic, and even when it is a copolymer of MPC and a vinyl monomer as described above, there is an influence of a flexible main chain structure, which contributes to mechanical strength, water resistance and autoclave sterilization. The appearance of materials with improved mechanical strength, water resistance, and heat resistance while maintaining the excellent biocompatibility and processability of the above-mentioned MPC polymer is still not perfect in terms of heat resistance that can be tolerated. It was.

  The present inventors have previously described a specific diamine compound having a phosphorylcholine group and a polymer excellent in water resistance, heat resistance and biocompatibility obtained by conducting a polymerization reaction using the diamine compound as one of raw materials. Reported (see Patent Documents 1 and 2). On the other hand, a diol compound having a phosphorylcholine group and a polymer thereof have also been reported (see Patent Documents 3 and 4).

International Publication No. 2004/074298 Pamphlet International Publication 2008/029744 Pamphlet JP 63-54383 A Japanese Patent Laid-Open No. 10-287687

Ishihara et al., Polymer Journal, 22, 355, 1990 Ishihara, Iwasaki, Polymer Advanced Technology, 11, 626, 2000

  However, although the above diamine compound can be polymerized to obtain polyurethane-urea (see Nagase et al., Polymer Journal, 40, 1149, 2008), the resulting phosphorylcholine group-containing polyurethane-urea is derived from a diamine compound. It has been found that since the urea bond is included in the main chain structure, mechanical properties peculiar to polyurethane, that is, flexibility are slightly impaired. In addition, known phosphorylcholine group-containing diol compounds mainly consist of aliphatic groups and have extremely high hygroscopicity, so that it is difficult to dry and purify during polymerization.

  From the above problems, the present invention uses a novel phosphorylcholine group-containing diol compound as a starting material, and has a high molecular weight that maintains the excellent biocompatibility of the above MPC polymer and the mechanical properties, flexibility, and processability unique to polyurethane. It is an object of the present invention to provide a phosphorylcholine group-containing polyurethane material.

  In view of such circumstances, the present inventors have intensively studied to solve the above problems, and as a result, synthesized a phosphorylcholine group-containing diol compound having an aromatic group in part, and the purification of the monomer is easy, By conducting a polymerization reaction using a compound as one of the raw materials, it was found that a phosphorylcholine group-containing polymer having excellent biocompatibility and mechanical properties peculiar to polyurethane was obtained, and the present invention was completed.

That is, the present invention includes the following matters.
[1] A diol compound having a phosphorylcholine group represented by the following formula (I);

（式（I）中、Ｘは単結合、酸素原子、−COO−、−CONH−、−OOC−または−CH₂O−で示される基を表し、Ｙは単結合、炭素数１〜６のアルキレン基、またはオリゴオキシアルキレン基を表し、ｍおよびｎはそれぞれ１〜６の整数を表す。）

(In formula (I), X represents a single bond, an oxygen atom, —COO—, —CONH—, —OOC— or —CH ₂ O—, and Y represents a single bond, having 1 to 6 carbon atoms. Represents an alkylene group or an oligooxyalkylene group, and m and n each represents an integer of 1 to 6.)

  [2] A polymer having a phosphorylcholine group-containing structural unit represented by the following formula (II) and having a weight average molecular weight of 5,000 or more;

（式（II）中、Ｘは単結合、酸素原子、−COO−、−CONH−、−OOC−または−CH₂O−で示される基を表し、Ｙは単結合、炭素数１〜６のアルキレン基または炭素数１〜６のオリゴオキシアルキレン基を表し、ｍおよびｎはそれぞれ１〜６の整数を表す。）

(In the formula (II), X represents a single bond, oxygen atom, —COO—, —CONH—, —OOC— or —CH ₂ O—, and Y represents a single bond, having 1 to 6 carbon atoms. Represents an alkylene group or an oligooxyalkylene group having 1 to 6 carbon atoms, and m and n each represents an integer of 1 to 6)

  [3] The polymer according to [2], wherein the polymer has a urethane bond in its main chain skeleton.

Since the diol compound of the present invention exhibits high polymerization reactivity, a high molecular weight polymer having a phosphorylcholine group in the side chain can be easily synthesized.
The polymer of the present invention has excellent antithrombogenicity and is useful as a biocompatible material with low adsorption of biological components such as proteins. Moreover, since it has favorable moldability and excellent mechanical properties, it becomes possible to produce artificial organs such as artificial blood vessels and various medical devices by using the above polymer.

  Hereinafter, the diol compound having a phosphorylcholine group of the present invention (hereinafter also simply referred to as “diol compound”) and a polymer will be described in detail.

[Diol compound having phosphorylcholine group]
The diol compound of the present invention is represented by the following formula (I).

式（I）中、Ｘは単結合、酸素原子、−COO−、−CONH−、−OOC−または−CH₂O−で示される基である。これらの基のうち、合成の簡便さから−COO−、−CONH−または−CH₂O−が好ましく、−COO−がより好ましい。

In the formula (I), X is a single bond, an oxygen atom, -COO -, - CONH -, - OOC- or a group represented -CH ₂ O-in. Of these groups, —COO—, —CONH— or —CH ₂ O— is preferable, and —COO— is more preferable because of ease of synthesis.

Y is a single bond, an alkylene group having 1 to 6 carbon atoms, or an oligooxyalkylene group. Here, the alkylene group having 1 to 6 carbon _{atoms, - (CH 2) x- (} x is an integer from 1 to 6) a group represented by the oligo oxyalkylene group, having 2 to 12 carbon atoms And an oxyalkylene group having 1 to 3 oxygen atoms, preferably-(CH ₂ CH ₂ O) y-,-(CH ₂ CH ₂ CH ₂ O) y- or-(CH ₂ CH ₂ CH ₂ CH ₂ O ) y- (wherein y is an integer of 1 to 3).

Among these groups, a single bond, a group represented by — (CH ₂ ) x — (x is an integer of 1 to 3), or — (CH ₂ CH ₂ O) y — (y is an integer of 1 to 2) ) Is preferred, and a single bond is more preferred.
m is an integer of 1-6, preferably an integer of 2-4, more preferably 2.
n is an integer of 1 to 6, preferably an integer of 2 to 4, more preferably 2.

<Method for producing diol compound>
The diol compound is synthesized, for example, according to the method shown below.

  That is, a compound represented by the following formula (III) (hereinafter referred to as “compound (III)”) and 2-chloro-2-oxo-1,3,2-dioxaphosphorane (COP) are reacted, A compound having a phosphoryl group represented by the following formula (IV) (hereinafter referred to as “compound (IV)”) was synthesized, and this compound (IV) was further reacted with trimethylamine (TMA). By synthesizing a compound having a phosphorylcholine group (hereinafter referred to as “compound (V)”), and then substituting the substituent Q of the compound (V) with a hydrogen atom, a diol compound having a phosphorylcholine group is obtained. Can be synthesized.

ここで、上記化合物（III）は、後述する実施例１に示す方法などにより、市販の化合物から公知の反応を用いて容易に合成することができる。

Here, the compound (III) can be easily synthesized from a commercially available compound using a known reaction by the method shown in Example 1 described later.

  The reaction between the compound (III) and COP is carried out so that the compound (III): COP is in a molar ratio of 1: 1 to 1: 5, and hydrogen chloride generated in the presence of a tertiary amine such as triethylamine is generated. It is preferable to carry out the process while trapping or to carry out while removing an inert gas into the reaction system and removing hydrogen chloride from the system.

In the ring-opening addition reaction between the compound (IV) and TMA, it is preferable to charge the compound (IV): TMA in a molar ratio of 1: 1 to 1: 5.
In the above formulas (III) to (V), the substituent Q is a hydroxyl-protecting group. As the substituent Q, any reaction can be used as long as it does not impair the binding site other than the phosphorylcholine group other than the substituent Q in the reaction of substituting the substituent Q in the compound (V) with a hydrogen atom, that is, the deprotection reaction. Specifically, the methoxybenzyl and nitrobenzyl groups described on pages 17-200 of TW Greene, PGM Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Third Edition, John Wiley & Sons, Inc. (1999) And substituted or unsubstituted benzyl groups such as cyanobenzyl group, halobenzyl group and benzyl group, and trialkylsilyl groups such as trimethylsilyl group, dimethylisopropylsilyl group and t-butyldimethylsilyl group. Regarding the deprotection reaction of the substituent Q, various methods according to the type of Q are described in detail in pages 17 to 200 of the same document.

X, Y, m and n are the same as X, Y, m and n in the formula (I) described above.
In addition, the said method shows an example of the manufacturing method of the diol compound of this invention, It can manufacture using not only the said method but various well-known methods.

(Polymer)
As shown in the following formula (II), the polymer of the present invention contains at least 1 mol% of a structural unit having a phosphorylcholine group, and has a weight average molecular weight (Mw) of 5,000 or more.

式（II）中、Ｘ、Ｙ、ｍおよびｎは、上述した式（Ｉ）中のＸ、Ｙ、ｍおよびｎと同じである。

In formula (II), X, Y, m and n are the same as X, Y, m and n in formula (I) described above.

  The polymer preferably contains at least 1 mol% of a structural unit having a phosphorylcholine group in order to develop good biocompatibility. % Or more, preferably 10 mol% or more. The content of the structural unit having a phosphorylcholine group can be easily controlled by adjusting the charging ratio (molar ratio to other raw materials) of the diol compound used as the raw material monomer in the polymer production method described later.

  The weight average molecular weight (Mw) of the polymer is usually 5,000 or more, preferably 10,000 or more, more preferably 10,000 to 500,000 from the viewpoint of mechanical strength, processability, heat resistance and stability. The weight average molecular weight (Mw) is measured by gel permeation chromatography (GPC) or light scattering method using monodisperse polystyrene as a standard substance.

  The polymer preferably has a urethane bond in its main chain skeleton. By having a urethane bond, the polymer can be given flexibility, which is a mechanical property unique to polyurethane.

<Method for producing polymer>
The polymer of the present invention can be prepared by subjecting the diol compound as a raw material monomer to a conventional polycondensation or polyaddition reaction with another polymerizable monomer, or with a diol compound and a functional group terminal-containing prepolymer capable of reacting therewith. It can be produced by reacting the coalescence. In the present specification, the “other polymerizable monomer” means a monomer other than the diol compound and capable of being polymerized with the diol compound.

  In the above polycondensation or polyaddition reaction, if dicarboxylic acid and its derivative are used as other polymerizable monomers, a polyester having an ester bond in the main chain skeleton can be obtained, and if a diisocyanate compound is used, the main chain skeleton can be obtained. A polyurethane having a urethane bond is obtained.

  This polycondensation or polyaddition reaction is carried out in the presence of a known diol compound (hereinafter also referred to as “other diol compound”), preferably a diol compound having no phosphorylcholine group, in addition to the diol compound. From the viewpoint of enhancing the mechanical strength, water resistance and heat resistance of the resulting polymer.

  Examples of the other diol compounds include hydroquinone, 1,3-phenylene diol, 1,4-xylylene diol, 1,3-xylylene diol, 2,4-toluylene diol, and 2,5-toluylene diol. 4,4′-biphenylenediol, 4,4′-diphenyl ether diol, 4,4′-diphenylmethanediol, bisphenol A, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, heptamethylene glycol, Octamethylene glycol, polyethylene glycol, polypropylene glycol, polytetraethylene oxide, polycarbonate diol, α, ω-bis (hydroxypropyl) polydimethylsiloxane and α, ω-bis (H Etc. b ethoxy propyl) polydimethyl siloxane. These can be used individually by 1 type or in mixture of 2 or more types. When other diol compounds are used, the amount of the diol compound of the present invention is 1 mol% or more, preferably 5 mol in the total of 100 mol% of the diol compound and other diol compounds from the viewpoint of expressing the biocompatibility of the polymer. It mixes so that it may become more than mol%, More preferably, it is 10-90 mol%.

  The dicarboxylic acid and derivatives thereof used as the other polymerizable monomer are compounds represented by the following formula (VI).

式（VI）中、Ｘ¹は水酸基、ハロゲン原子またはアルコキシ基を表し、Ｙ¹は２価の有機基、好ましくはジカルボン酸残基である２価の有機基を表す。

In the formula (VI), X ¹ represents a hydroxyl group, a halogen atom or an alkoxy group, and Y ¹ represents a divalent organic group, preferably a divalent organic group which is a dicarboxylic acid residue.

  Therefore, the repeating unit of the obtained polyester, that is, the structural unit having a phosphorylcholine group represented by the above formula (II) in the polymer of the present invention is a repeating unit represented by the following formula (VII).

式（VII）中、Ｙ¹は２価の有機基、好ましくはジカルボン酸残基である２価の有機基を表し、Ｘ、Ｙ、ｍおよびｎは上記式（II）中のＸ、Ｙ、ｍおよびｎと同じである。

In formula (VII), Y ¹ represents a divalent organic group, preferably a divalent organic group that is a dicarboxylic acid residue, and X, Y, m, and n represent X, Y, Same as m and n.

  Examples of the dicarboxylic acid and derivatives thereof include phthalic acid, terephthalic acid, isophthalic acid, 2,6-naphthalenedicarboxylic acid, 1,6-naphthalenedicarboxylic acid, 2,6-anthracene dicarboxylic acid, and 1,6-anthracene dicarboxylic acid. 4,4′-biphenyldicarboxylic acid, 4,4′-diphenylmethanedicarboxylic acid, 4,4′-diphenyletherdicarboxylic acid, 2,2-bis (4-carboxylphenyl) propane, 2,2-bis [4- ( 4-carboxyphenylphenoxy) phenyl] propane, oxalic acid, fumaric acid, maleic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1,9-nonanedicarboxylic acid Dicarboxylic acids such as 1,10-decanedicarboxylic acid and their acid halos Genated products and alkyl esterified products are exemplified. These can be used individually by 1 type or in mixture of 2 or more types.

  The diisocyanate compound used as the other polymerizable monomer is a compound represented by the following formula (VIII).

式（VIII）中、Ｙ²は２価の有機基、好ましくはジイソシアナート化合物残基である２価の有機基を表す。

In formula (VIII), Y ² represents a divalent organic group, preferably a divalent organic group which is a diisocyanate compound residue.

  Therefore, the repeating unit of the obtained polyurethane, that is, the repeating unit containing the structural unit represented by the formula (II) in the polymer of the present invention is the repeating unit represented by the following formula (IX).

式（IX）中、Ｙ²は２価の有機基、好ましくはジイソシアナート化合物残基である２価の有機基を表し、Ｘ、Ｙ、ｍ、ｎの定義は式（II）と同じである。

In formula (IX), Y ² represents a divalent organic group, preferably a divalent organic group that is a diisocyanate compound residue, and the definitions of X, Y, m, and n are the same as in formula (II). is there.

  Examples of the diisocyanate compound represented by the above formula (IX) include 1,4-phenylene diisocyanate, 1,3-phenylene diisocyanate, 1,4-xylylene diisocyanate, and 1,3-xylylene diene. Isocyanate, 2,4-toluylene diisocyanate, 2,5-toluylene diisocyanate, 4,4'-biphenylene diisocyanate, 4,4'-diphenyl ether diisocyanate, 4,4'-diphenylmethane diisocyanate 4,4 '-(2,2-diphenylpropane) diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, heptamethylene diisocyanate and octamethylene diisocyanate It is done. These can be used individually by 1 type or in mixture of 2 or more types.

  The polycondensation or polyaddition reaction using a diol compound having a phosphorylcholine group represented by the above formula (I) and another polymerizable monomer can be performed by a method known in the literature (for example, JA Moore, "Macromolecular Synthesis", John Wiley & Sons, New York, 1997, SR Sandler, W. Karo, "Polymer Syntheses", Academic Press, Inc., Boston, 1992, The Society of Polymer Science, New Polymer Experiments, Volume 3, Polymers (2) -Synthesis of condensation polymers, see Kyoritsu Shuppan, 1996, etc.).

  Further, as another means for obtaining a polymer having improved mechanical strength, water resistance and heat resistance, there is a method of reacting the diol compound with a functional group terminal-containing prepolymer capable of reacting therewith. . Here, the “functional group terminal-containing prepolymer” means a prepolymer having a functional group capable of reacting with the diol compound, particularly a functional group capable of reacting with the hydroxyl group at the main chain terminal or the side chain terminal or both. Means.

  As said functional group terminal containing prepolymer, the isocyanate group terminal containing urethane prepolymer obtained by making an excessive amount of diisocyanate compounds and a diol compound react by a well-known method is mentioned, for example. More specifically, after an excess amount of a diisocyanate compound and another diol compound are polymerized to obtain a urethane prepolymer having an isocyanate group at the terminal, the diol compound of the present invention is added and reacted. By doing so, it is possible to produce a polyurethane having a formylcholine group in the side chain and a urethane bond in the main chain skeleton.

EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example and a comparative example, this invention is not limited to these Examples and a comparative example.
The molecular weights of the polymers obtained in Examples and Comparative Examples were measured by GPC measurement according to the following measurement conditions.

<GPC measurement conditions>
measuring device:
Liquid feed pump: CCPD made by Tosoh
Column oven: Tosoh CO-8010
Separation column: Tosoh TSKgel Multipore H _XL -M 5 in-line detector: Tosoh RI-8010 (differential refractometer)
Measurement condition:
Column temperature: 45 ° C
Mobile phase: Dimethylformamide Migration rate: 1.0 mL / min Sample concentration: 0.5 wt%
Sample injection volume: 100 μL
Standard material: monodisperse polystyrene

  [Example 1] Synthesis of diol compound

<Synthesis of Compound (1)>
Under an argon atmosphere, p-toluenesulfonyl chloride (15.0 g, 78.9 mmol) and dehydrated tetrahydrofuran (79.0 mL) were placed in a dropping funnel, and 2- (benzyloxy) ethanol (10.0 g, 65.7 mmol) and dehydrated tetrahydrofuran ( 66 mL) and dehydrated triethylamine (19.0 mL) were added to prepare respective solutions, and the solution in the dropping funnel was slowly added dropwise in an ice-water bath. After completion of the addition, the mixture was reacted at room temperature for 20 hours. After completion of the reaction, the reaction solution was poured into excess water and extracted with chloroform. After recovering the organic layer, it was dehydrated using sodium sulfate, and the solvent was distilled off by an evaporator. Then, it was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1: 10 (volume ratio)) to obtain 2- (benzyloxy) ethyl p-toluenesulfonate (1) as a transparent liquid (yield) : 16.7 g, yield: 83.8%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 2.42 (3H, s), 3.61 (2H, t, J = 4.4 Hz), 4.17 (2H, t, J = 2.9 Hz), 4.43 (2H, s), 7.23-7.34 (5H, m), 7.42 (2H, d, J = 7.8 Hz), 7.78 (2H, d, J = 7.8 Hz).

<Synthesis of Compound (2)>
2- (Benzyloxy) ethyl p-toluenesulfonate (1) (16.9 g, 55.1 mmol) and methyl 3,5-dihydroxybenzoate (4.41 g, 26.3 mmol) were 2-butanone in an eggplant flask under an argon atmosphere. (137 mL), potassium carbonate (7.62 g, 55.1 mmol) was added, and the mixture was refluxed for 20 hours. After completion of the reaction, the reaction mixture was poured into excess water and extracted with ethyl acetate. After recovering the organic layer, it was dehydrated using sodium sulfate, and the solvent was distilled off with an evaporator. Then, it is purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 3: 5 (volume ratio)), and methyl 3,5-bis (2- (benzyloxy) ethoxy) benzoate (2) Obtained as a yellow liquid (yield: 10.5 g, yield: 91.5%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 3.79 (4H, t, J = 4.4 Hz), 3.84 (3H, s), 4.17 (4H, t, J = 4.4 Hz), 4.57 (4H, s), 6.79 (1H, s), 7.10 (2H, d, J = 2.0 Hz), 7.23-7.34 (10H, m).

<Synthesis of Compound (3)>
Under argon atmosphere, methyl 3,5-bis (2- (benzyloxy) ethoxy) benzoate (2) (8.29 g, 19.0 mmol) was dissolved in tetrahydrofuran (25.0 mL) in an eggplant flask, and sodium hydroxide (0.960 g, 24.0 mmol) and methanol (25.0 mL) were added and refluxed for 18 hours. Thereafter, the mixture was cooled to room temperature, acidified with hydrochloric acid, and the precipitated solid was suction filtered. The recovered solid was extracted with ethyl acetate and washed with water. The organic layer was dehydrated with sodium sulfate, the solvent was distilled off with an evaporator, and 3,5-bis (2- (benzyloxy) ethoxy) benzoic acid (3) Was obtained as a white solid (yield: 6.83 g, yield: 85.1%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 3.77 (4H, t, J = 4.4 Hz), 4.18 (4H, t, J = 4.4 Hz), 4.56 (4H, s), 6.80 (1H, s), 7.07 (2H, d, J = 2.4), 7.26-7.37 (10H, m), 12.93 (1H, bs).

<Synthesis of Compound (4)>
Under an argon atmosphere, 3,5-bis (2- (benzyloxy) ethoxy) benzoic acid (3) (6.83 g, 16.2 mmol) was dissolved in 2-butanone (57.0 mL), and 2-bromoethanol (3.03 g, 24.3 mmol) and potassium carbonate (2.23 g, 16.2 mmol) were added and refluxed for 21 hours. After completion of the reaction, the reaction mixture was poured into excess water and extracted with ethyl acetate. After dehydrating the organic layer with sodium sulfate, the solvent was distilled off with an evaporator and purified by silica gel column chromatography (developing solvent; ethyl acetate / hexane = 1: 1 (volume ratio)), and 2- (3,5 -Bis (2- (benzyloxy) ethoxy) benzoyloxy) ethanol (4) was obtained as a pale yellow liquid (yield: 4.03 g, yield: 53.5%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 3.70 (2H, bt), 3.77 (4H, t, J = 4.4 Hz), 4.18 (4H, t, J = 4.4 Hz), 4.26 (2H, t, J = 4.9 Hz), 4.56 (4H, s), 4.99 (1H, bs), 6.88 (1H, t, J = 2.4 Hz), 7.14 (2H, d, J = 2.4 Hz), 7.24 -7.39 (10H, m).

<Synthesis of Compound (5)>
2- (3,5-bis (2- (benzyloxy) ethoxy) benzoyloxy) ethanol (4) (4.03 g, 8.65 mmol) was dehydrated in tetrahydrofuran (52.0 mL) and dehydrated in a three-necked flask under an argon atmosphere. Dissolved in triethylamine (2.40 mL). Subsequently, 2-chloro-2-oxo-1,3,2-dioxaphosphorane (2.47 g, 17.3 mmol) was added dropwise from a syringe in an ice-water bath, and the reaction was allowed to proceed at room temperature for 90 minutes. . After completion of the reaction, the produced salt was removed by suction filtration, and the solvent in the filtrate was distilled off with an evaporator. The residue was dissolved in chloroform and washed with water. After collecting the organic layer, dehydration with sodium sulfate, the solvent was distilled off with an evaporator, and 2- (2- (3,5-bis (2- (benzyloxy) ethoxy) benzoyloxy) ethoxy) 2-oxo -1,3,2-Dioxaphosphorane (5) was obtained as a yellow viscous liquid (yield: 4.95 g, yield: 100%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 3.69 (4H + 2H, m), 4.19 (4H, t, J = 4.4 Hz), 4.33-4.44 (6H, m), 4.56 ( 4H, s), 6.85 (1H, d, J = 2.4 Hz), 7.16 (2H, d, J = 2.4 Hz), 7.26-7.39 (10H, m).

<Synthesis of Compound (6)>
In an eggplant flask, 2- (2- (3,5-bis (2- (benzyloxy) ethoxy) benzoyloxy) ethoxy) 2-oxo-1,3,2-dioxaphosphorane (5) (4.95 g, 8.65 mmol) was dissolved in acetonitrile (86.5 mL), and trimethylamine (2.56 g, 43.3 mmol) was added and sealed in an ice-water bath. Thereafter, the reaction was carried out at 60 ° C. for 13 hours. After completion of the reaction, trimethylamine and acetonitrile were distilled off with an evaporator and vacuum-dried to give 2- (3,5-bis (2- (benzyloxy) ethoxy) benzoyloxy. ) Ethyl phosphorylcholine (6) was obtained as a yellow viscous liquid (yield: 5.06 g, yield: 92.6%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 3.10 (9H, s), 3.51 (2H, bs), 3.77 (4H, t, J = 4.4 Hz), 3.98 (2H, bt) , 4.07 (2H, bt), 4.19 (4H, t, J = 4.4 Hz), 4.36 (2H, t, J = 4.4 Hz), 4.56 (4H, s), 6.85 (1H, t, J = 2.4 Hz) , 7.12 (2H, d, J = 2.4 Hz), 7.26-7.38 (10H, m).

<Synthesis of Compound (7)>
In an eggplant flask, 2- (3,5-bis (2- (benzyloxy) ethoxy) benzoyloxy) ethyl phosphorylcholine (5.06 g, 8.01 mmol) was dissolved in methanol (80 mL), and 5% palladium carbon (0.340 g , Pd: 0.160 mmol). Thereafter, the container was cooled to −78 ° C., and the system was replaced with hydrogen, and reacted at room temperature for 70 hours. After completion of the reaction, palladium carbon was filtered off with celite, and the solvent was distilled off with an evaporator to obtain 2- (3,5-bis (2-hydroxyethoxy) benzoyloxy) ethyl phosphorylcholine (7) as a white solid. (Yield: 2.56 g, Yield: 70.9%). The structure of this compound was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 3.12 (9H, s), 3.51 (2H, t, J = 4.4 Hz), 3.70 (4H, t, J = 3.4 Hz), 3.96 (2H, bt), 3.99-4.05 (4H + 2H, m), 4.33 (2H, t, J = 4.4 Hz), 5.10 (2H, bs), 6.73 (1H, d, J = 2.4 Hz), 7.13 ( (2H, d, J = 2.4 Hz).

  [Example 2] Synthesis of polymer

アルゴン雰囲気下、ナシ型フラスコ中にて4,4'-ジフェニルメタンジイソシアナート（2.52 g、10.0 mmol）をN-メチルピロリジノン（NMP）（10.0 mL）に溶解させ、2-（3,5-ビス（2-ヒドロキシエトキシ）ベンゾイルオキシ）エチルホスホリルコリン（７）（1.35 g、3.00 mmol）をN-メチルピロリジノン（10.0 mL）に溶解させた。続いて、ポリカーボネートジオール（旭化成ケミカルズ製，Duranol RT5651）（7.00 g、7.00 mmol）を三ツ口フラスコに入れ70℃に加熱した後、上記の4,4'-ジフェニルメタンジイソシアナートの溶液を約1 mL/minの速さで加え1時間反応させた。その後、さらに化合物（７）の溶液を約1 mL/minの速さで加え7分反応させ、反応溶液を過剰のメタノールに注ぎ込み、析出した沈殿物を吸引ろ過後、熱真空乾燥し、PC基含有セグメント化ポリ（カーボネート-ウレタン）（SPCU-PC）を乳白色固体として得た(収量：10.5 g、収率：96.9 %)。なお、得られた重合体の構造は下記の¹H-NMRスペクトルから確認した。また、¹H-NMRスペクトルのピーク強度比から算出したホスホリルコリン基を含む繰り返し単位の含有率は27.3mol%であった。
¹H-NMR, d (400 MHz, DMSO-d₆, ppm)：1.30 (-CH₂-, bs), 1.57 (-CH₂-, bs), 1.90 (-OC(=O)OCH₂-CH₂-, quin, J= 7.8 Hz), 2.18 (-OC(=O)OCH₂-CH₂-, t, J= 7.8 Hz), 3.08 (-N⁺(CH₃)₃, s), 3.77 (-Ph-CH₂-Ph-, s), 4.03 (-CH₂-, bs), 4.10-4.40 (-NHCOOCH₂CH₂O- + -OCH₂CH₂OP(=O)(-O^-)OCH₂CH₂N⁺, m), 6.86 (-O-Ph-O-, bs), 7.07 (-CH₂-Ph-NHCOO-, d, J= 7.8 Hz) , 7.13 (-O-Ph-O-, bs), 7.34 (-CH₂-Ph-NHCOO-, d, J= 7.8 Hz), 9.34 (-NHCOO-, bs).

Under an argon atmosphere, 4,4'-diphenylmethane diisocyanate (2.52 g, 10.0 mmol) was dissolved in N-methylpyrrolidinone (NMP) (10.0 mL) in a pear-shaped flask, and 2- (3,5-bis (2-Hydroxyethoxy) benzoyloxy) ethyl phosphorylcholine (7) (1.35 g, 3.00 mmol) was dissolved in N-methylpyrrolidinone (10.0 mL). Subsequently, polycarbonate diol (Asahi Kasei Chemicals, Duranol RT5651) (7.00 g, 7.00 mmol) was placed in a three-necked flask and heated to 70 ° C., and then the above 4,4′-diphenylmethane diisocyanate solution was added at about 1 mL / It was added at a speed of min and allowed to react for 1 hour. Then, a solution of compound (7) is further added at a rate of about 1 mL / min and reacted for 7 minutes. The reaction solution is poured into excess methanol, and the deposited precipitate is suction filtered and dried in a hot vacuum, and then PC group Containing segmented poly (carbonate-urethane) (SPCU-PC) was obtained as a milky white solid (yield: 10.5 g, yield: 96.9%). The structure of the obtained polymer was confirmed from the following ¹ H-NMR spectrum. The content of the repeating unit containing a phosphorylcholine group calculated from the peak intensity ratio of the ¹ H-NMR spectrum was 27.3 mol%.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 1.30 (-CH _2- , bs), 1.57 (-CH _2- , bs), 1.90 (-OC (= O) OCH ₂ -CH _2- , quin, J = 7.8 Hz), 2.18 (-OC (= O) OCH ₂ -CH _2- , t, J = 7.8 Hz), 3.08 (-N ⁺ (CH ₃ ) ₃ , s), 3.77 ( _{-Ph-CH 2 -Ph-, s)} , 4.03 (-CH 2 -, bs), 4.10-4.40 (-NHCOOCH 2 CH 2 O- + -OCH 2 CH 2 OP (= O) (- O -) OCH ₂ CH ₂ N ⁺ , m), 6.86 (-O-Ph-O-, bs), 7.07 (-CH ₂ -Ph-NHCOO-, d, J = 7.8 Hz), 7.13 (-O-Ph-O- , bs), 7.34 (-CH ₂ -Ph-NHCOO-, d, J = 7.8 Hz), 9.34 (-NHCOO-, bs).

When the molecular weight of SPCU-PC was measured according to the above conditions, the number average molecular weight (Mn) and the weight average molecular weight (Mw) were 2.33 × 10 ⁴ and 4.50 × 10 ⁴ respectively. The molecular weight was confirmed. Moreover, the glass transition temperature (softening temperature) of SPCU-PC obtained by differential scanning calorimetry (DSC) was not observed in the range of 0 to 200 ° C., and showed sufficient heat resistance.

  Further, the obtained polymer SPCU-PC was soluble in chloroform, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, and insoluble in water, methanol, ethanol, isopropanol and acetone. Such solubility of SPCU-PC is advantageous when performing molding for materialization such as coating and hollow fiber because it is soluble in a specific solvent, and insoluble in many other solvents. Therefore, it is advantageous in that it can be a device having excellent durability after being made into a material.

  Furthermore, when SPCU-PC was dissolved in N-methylpyrrolidinone, the solution was cast on a Teflon (registered trademark) substrate, and the solvent was evaporated at 100 ° C., the film was flexible and tough with a film thickness of about 200 mm. A film could be produced.

  [Comparative Example 1] Synthesis of polyurethane having no phosphorylcholine group

アルゴン雰囲気下、ナシ型フラスコ中にて4,4'-ジフェニルメタンジイソシアナート（2.52 g、10.0 mmol）をN-メチルピロリジノン（10.0 mL）に溶解させ、3,5-ビス（2-ヒドロキシエトキシ）ベンゼン（0.594 g、3.00 mmol）をN-メチルピロリジノン（10.0 mL）に溶解させた。続いて、ポリカーボネートジオール（旭化成ケミカルズ製、Duranol RT5651）（7.00 g、7.00 mmol）を三ツ口フラスコに入れ70℃に加熱した後、上記の4,4'-ジフェニルメタンジイソシアナートの溶液を約1 mL/minの速さで加え1時間反応させた。その後、さらに3,5-ビス（2-ヒドロキシエトキシ）ベンゼンの溶液を約1mL/minの速さで加え25分反応させ、反応溶液を過剰のメタノールに注ぎ込み、析出した沈殿物を吸引ろ過後、熱真空乾燥し、セグメント化ポリ（カーボネート-ウレタン）（SPCU）を白色固体として得た(収量：10.1 g、収率：100 %)。なお、得られた重合体の構造は下記の¹H-NMRスペクトルから確認した。
¹H-NMR, d (400 MHz, DMSO-d₆, ppm)：1.23 (-CH₂-, bs), 1.58 (-CH₂-, bs), 1.90 (-OC(=O)OCH₂-CH₂-, quin, J= 7.8 Hz), 2.18 (-OC(=O)OCH₂-CH₂-, t, J= 7.8 Hz), 3.77 (-Ph-CH₂-Ph-, s), 4.04 (-CH₂-, bs), 4.19 (-NHCOO-CH₂-CH₂-O-, bs), 4.37 (-NHCOO-CH₂-CH₂-O-, bs), 6.54 (-O-Ph-O-, bt), 7.07 (-CH₂-Ph-NHCOO-, d, J= 7.8 Hz) , 7.17 (-O-Ph-O-, bs), 7.34 (-CH₂-Ph-NHCOO-, d, J= 7.8 Hz), 9.50 (-NHCOO-, s).

Under argon atmosphere, 4,4'-diphenylmethane diisocyanate (2.52 g, 10.0 mmol) was dissolved in N-methylpyrrolidinone (10.0 mL) in a pear-shaped flask and 3,5-bis (2-hydroxyethoxy) Benzene (0.594 g, 3.00 mmol) was dissolved in N-methylpyrrolidinone (10.0 mL). Subsequently, polycarbonate diol (Duranol RT5651 manufactured by Asahi Kasei Chemicals) (7.00 g, 7.00 mmol) (7.00 g, 7.00 mmol) was placed in a three-necked flask and heated to 70 ° C. It was added at a speed of min and allowed to react for 1 hour. Thereafter, a solution of 3,5-bis (2-hydroxyethoxy) benzene was further added at a rate of about 1 mL / min, reacted for 25 minutes, the reaction solution was poured into excess methanol, and the deposited precipitate was suction filtered, Hot vacuum drying gave segmented poly (carbonate-urethane) (SPCU) as a white solid (yield: 10.1 g, yield: 100%). The structure of the obtained polymer was confirmed from the following ¹ H-NMR spectrum.
¹ H-NMR, d (400 MHz, DMSO-d ₆ , ppm): 1.23 (-CH _2- , bs), 1.58 (-CH _2- , bs), 1.90 (-OC (= O) OCH ₂ -CH _2- , quin, J = 7.8 Hz), 2.18 (-OC (= O) OCH ₂ -CH _2- , t, J = 7.8 Hz), 3.77 (-Ph-CH ₂ -Ph-, s), 4.04 ( -CH _2- , bs), 4.19 (-NHCOO-CH ₂ -CH ₂ -O-, bs), 4.37 (-NHCOO-CH ₂ -CH ₂ -O-, bs), 6.54 (-O-Ph-O -, bt), 7.07 (-CH ₂ -Ph-NHCOO-, d, J = 7.8 Hz), 7.17 (-O-Ph-O-, bs), 7.34 (-CH ₂ -Ph-NHCOO-, d, J = 7.8 Hz), 9.50 (-NHCOO-, s).

When the molecular weight of SPCU was measured by GPC according to the above-described conditions, the number average molecular weight (Mn) and the weight average molecular weight (Mw) were 3.15 × 10 ⁴ and 6.30 × 10 ⁴ , respectively. Moreover, the glass transition temperature (softening temperature) of SPCU calculated | required from the differential scanning calorimetry (DSC) was not observed in the range of 0 degreeC-200 degreeC.

  Further, the obtained polymer SPCU was soluble in chloroform, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, and insoluble in water, methanol, ethanol, isopropanol and acetone.

  Furthermore, when SPCU was dissolved in N-methylpyrrolidinone, the solution was cast on a Teflon (registered trademark) substrate and the solvent was evaporated at 100 ° C., the same film thickness as in SPCU-PC was obtained. A 200 mm film could be produced.

[Test Example 1] Protein adsorption test of polymer film The SPCU-PC and SPCU films obtained in Example 2 and Comparative Example 1 were sufficiently dried in a vacuum dryer, and then circular (diameter: 14 mm, thickness) : 0.2 mm) to obtain each test piece. Each polymer film thus prepared was immersed in an aqueous solution (1000 mL) of 1% fibrinogen (derived from bovine plasma, manufactured by Wako Pure Chemical Industries, Ltd.) at 37 ° C. for 3 hours. Thereafter, the membrane surface was washed with a phosphate buffer and immersed in a 1% aqueous sodium dodecyl sulfate solution (1000 mL) for 1 hour to elute fibrinogen adsorbed on the membrane surface membrane. Sodium dodecyl sulfate solution (150 mL) containing fibrinogen and Micro BCA? (Thermo Fisher Scientific) solution (150 mL) was mixed in a microplate, allowed to stand at 35 ° C. for 2 hours, returned to room temperature, and then subjected to absorbance measurement with a microplate reader (550 nm). The amount of fibrinogen adsorbed on the membrane surface was calculated from the value.

As a result, the amounts of fibrinogen adsorbed on the film surfaces of SPCU-PC and SPCU were 4.45 mg / cm ² and 14.2 mg / cm ² , respectively. Therefore, it has been clarified that polyurethane containing a phosphorylcholine group can significantly reduce the amount of protein adsorbed on the film surface as compared with a polyurethane having a similar structure not having a phosphorylcholine group.

Furthermore, for comparison, a similar test was performed on MPC polymer (polymer of 2-methacryloylethylphosphorylcholine / butyl methacrylate (molar ratio 3/7), manufactured by NOF Corporation), and the amount of fibrinogen adsorbed was 4.02. mg / cm ² was obtained. Therefore, it was confirmed that the protein adsorption property of SPCU-PC was similar to that of MPC polymer.

[Test Example 2] Tensile test of polymer film The SPCU-PC and SPCU films obtained in Example 2 and Comparative Example 1 were sufficiently dried in a vacuum dryer, and then rectangular (length: 50 mm, width: 15). mm, thickness: 0.2 mm) to obtain respective test pieces. Each of these test pieces was mounted on an LSC-1 / 300-SS-120S-L type tensile tester manufactured by Tokyo Test Machine, and stretched at a tensile speed of 12 mm / min to obtain a stress-strain curve.

  The tensile modulus of SPCU-PC and SPCU calculated from the obtained stress-strain curve is 2.40 MPa and 11.4 MPa, the breaking strength is 6.65 MPa and 2.57 MPa, respectively, and the maximum elongation is 747% and It was 730%. Therefore, it was confirmed that SPCU-PC has flexible and tough mechanical properties unique to polyurethane.

Claims (3)

A diol compound having a phosphorylcholine group represented by the following formula (I);

(In formula (I), X represents a single bond, an oxygen atom, —COO—, —CONH—, —OOC— or —CH ₂ O—, and Y represents a single bond, having 1 to 6 carbon atoms. Represents an alkylene group or an oligooxyalkylene group, and m and n each represents an integer of 1 to 6.) A polymer represented by the following formula (II) containing at least 1 mol% of a structural unit having a phosphorylcholine group and having a weight average molecular weight of 5,000 or more;

(In the formula (II), X represents a single bond, oxygen atom, —COO—, —CONH—, —OOC— or —CH ₂ O—, and Y represents a single bond, having 1 to 6 carbon atoms. Represents an alkylene group or an oligooxyalkylene group having 1 to 6 carbon atoms, and m and n each represents an integer of 1 to 6)   The polymer according to claim 2, wherein the polymer has a urethane bond in its main chain skeleton.