JP7414250B2 - Diene monomers, polymers obtained therefrom, antithrombotic materials containing the polymers - Google Patents
Diene monomers, polymers obtained therefrom, antithrombotic materials containing the polymers Download PDFInfo
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- JP7414250B2 JP7414250B2 JP2019187569A JP2019187569A JP7414250B2 JP 7414250 B2 JP7414250 B2 JP 7414250B2 JP 2019187569 A JP2019187569 A JP 2019187569A JP 2019187569 A JP2019187569 A JP 2019187569A JP 7414250 B2 JP7414250 B2 JP 7414250B2
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- hydrocarbon group
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- 229920000642 polymer Polymers 0.000 title claims description 92
- 239000000463 material Substances 0.000 title claims description 63
- 230000002785 anti-thrombosis Effects 0.000 title claims description 51
- 239000003146 anticoagulant agent Substances 0.000 title claims description 50
- 239000000178 monomer Substances 0.000 title claims description 27
- 150000001993 dienes Chemical class 0.000 title claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 210000004369 blood Anatomy 0.000 claims description 26
- 239000008280 blood Substances 0.000 claims description 26
- -1 tert-amyl Chemical group 0.000 claims description 25
- 239000012528 membrane Substances 0.000 claims description 22
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 239000000470 constituent Substances 0.000 claims description 8
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000002473 artificial blood Substances 0.000 claims description 7
- 210000004204 blood vessel Anatomy 0.000 claims description 7
- 210000003734 kidney Anatomy 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 5
- 230000000379 polymerizing effect Effects 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 15
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 150000002430 hydrocarbons Chemical group 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 239000002954 polymerization reaction product Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006116 polymerization reaction Methods 0.000 description 9
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 8
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 229920000139 polyethylene terephthalate Polymers 0.000 description 7
- 239000005020 polyethylene terephthalate Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000012790 confirmation Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000005227 gel permeation chromatography Methods 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 208000007536 Thrombosis Diseases 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000007865 diluting Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000012567 medical material Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 210000004623 platelet-rich plasma Anatomy 0.000 description 5
- 229920002587 poly(1,3-butadiene) polymer Polymers 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 4
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XOAUXFIKYVGQHT-UHFFFAOYSA-N 3-bromocyclooctene Chemical compound BrC1CCCCCC=C1 XOAUXFIKYVGQHT-UHFFFAOYSA-N 0.000 description 3
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- YACLQRRMGMJLJV-UHFFFAOYSA-N chloroprene Chemical compound ClC(=C)C=C YACLQRRMGMJLJV-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 230000002528 anti-freeze Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000498 cooling water Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000005548 dental material Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940078552 o-xylene Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003505 polymerization initiator Substances 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- UBKCMQCDHVYUAF-UHFFFAOYSA-N (2,2-dichloro-3-diphenylphosphanylpropyl)-diphenylphosphane Chemical compound ClC(CP(C1=CC=CC=C1)C1=CC=CC=C1)(CP(C1=CC=CC=C1)C1=CC=CC=C1)Cl UBKCMQCDHVYUAF-UHFFFAOYSA-N 0.000 description 1
- IRUCBBFNLDIMIK-FPLPWBNLSA-N (z)-oct-4-ene Chemical compound CCC\C=C/CCC IRUCBBFNLDIMIK-FPLPWBNLSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 1
- DZFGVGDQHQHOKZ-UHFFFAOYSA-N 2-dodecylsulfanylcarbothioylsulfanyl-2-methylpropanoic acid Chemical compound CCCCCCCCCCCCSC(=S)SC(C)(C)C(O)=O DZFGVGDQHQHOKZ-UHFFFAOYSA-N 0.000 description 1
- XVEASTGLHPVZNA-UHFFFAOYSA-N 3,4-dichlorobut-1-ene Chemical compound ClCC(Cl)C=C XVEASTGLHPVZNA-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920000049 Carbon (fiber) Polymers 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N Tetrahydropalmatine Natural products C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 238000012662 bulk polymerization Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000004917 carbon fiber Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000012986 chain transfer agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011256 inorganic filler Substances 0.000 description 1
- 229910003475 inorganic filler Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006082 mold release agent Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Materials For Medical Uses (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Description
本発明は、新規なジエン系モノマー並びにそれを用いたポリマー及び該ポリマーの製造方法に関する。より詳しくは、新規なジエン系モノマーを原料に用いたポリマーを含む抗血栓性材料及びそれを用いた医療用器具に関する。 The present invention relates to a novel diene monomer, a polymer using the same, and a method for producing the polymer. More specifically, the present invention relates to an antithrombotic material containing a polymer using a novel diene monomer as a raw material and a medical device using the same.
近年、各種の高分子材料を利用した医療用材料の検討が進められており、人工腎臓用膜、血漿分離用膜、カテーテル、ステント、人工肺用膜および人工血管等への利用が期待されている。生体にとって異物である合成材料を生体内組織や血液と接触させて使用することとなるため、医療用材料が生体適合性を有していることが要求される。医療用材料を血液と接触する材料として使用する場合、血小板の粘着および活性化の抑制が生体適合性として重要な項目となる。 In recent years, medical materials using various polymeric materials have been studied, and they are expected to be used in artificial kidney membranes, plasma separation membranes, catheters, stents, oxygenator membranes, artificial blood vessels, etc. There is. Since synthetic materials that are foreign to living bodies are used in contact with in-vivo tissues and blood, medical materials are required to have biocompatibility. When a medical material is used as a material that comes into contact with blood, inhibition of platelet adhesion and activation is an important aspect of biocompatibility.
また、生体適合性を示す物質は「中間水」と呼ばれる状態の水分子を含有可能であることが明らかにされている（特許文献１参照）。中間水とは、示差走査型熱量測定（ＤＳＣ）において－１００℃からの昇温過程で水の低温結晶化に基づくコールドクリスタリゼーション（以下、「ＣＣ」と略す）に由来する発熱ピークが－６０℃以上０℃未満の温度範囲で観測される状態の水のことを言う。この低温結晶化は、生体適合性を示す物質と水との相互作用により、水が通常とは異なる凍結の挙動を示しているものと考えられており、高分子鎖と特定の相互作用により組織化された水であると考えられている。 Furthermore, it has been revealed that substances exhibiting biocompatibility can contain water molecules in a state called "intermediate water" (see Patent Document 1). Intermediate water refers to the exothermic peak derived from cold crystallization (hereinafter abbreviated as "CC") based on low-temperature crystallization of water during the heating process from -100°C in differential scanning calorimetry (DSC). Water in a state observed in a temperature range of 60°C or higher and lower than 0°C. This low-temperature crystallization is thought to be caused by water exhibiting unusual freezing behavior due to the interaction between biocompatible substances and water, and by specific interactions with polymer chains. It is considered to be water that has been converted into water.
水酸基を有するビニル重合性化合物、例えば第一級水酸基を有するメタクリル酸２－ヒドロキシエチルは医療用材料として用いられているが、高い飽和含水率のため、膨潤する性質を有しており、ポリマー剥離の観点から改善が求められている。一方、第三級水酸基を有するビニル重合性化合物は、適度な反応性と親水性を有することが知られている（特許文献２参照）。この特性により、塗料、医療用材料等種々の用途が考えられている。 Vinyl polymerizable compounds having a hydroxyl group, such as 2-hydroxyethyl methacrylate having a primary hydroxyl group, are used as medical materials, but due to their high saturated water content, they have the property of swelling, and polymer exfoliation. Improvements are required from this perspective. On the other hand, vinyl polymerizable compounds having a tertiary hydroxyl group are known to have appropriate reactivity and hydrophilicity (see Patent Document 2). Due to this property, various uses such as paints and medical materials are being considered.
このような状況において、新規な抗血栓性材料が求められている。 Under these circumstances, new antithrombotic materials are needed.
本発明者らは、特定構造を有するモノマーから得られたポリマーが血小板の粘着を抑制し、抗血栓性を有していることを見出し、本発明に至った。即ち、本発明は以下の通りである。
＜１＞ 下記式（１）で表されるジエン系モノマーである。
＜２＞ Ｒ１が、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ（ＣＨ３）-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ）（ＣＨ３）ＣＨ２-、-ＣＨ（ＣＨ３）ＣＨ（ＣＨ３）-、-ＣＨ２（ＣＨ２）３ＣＨ２-、-ＣＨ２（ＣＨ２）２Ｃ（ＣＨ３）２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-からなる群より選択される２価の飽和炭化水素基である、上記＜１＞に記載のジエン系モノマーである。
＜３＞ Ｒ２が、エーテル結合を有していてもよい、メチル、エチル、ｎ-プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、tert-ブチル、ｎ-ペンチル、ネオペンチル、イソアミル、tert-アミル、ｎ-ヘキシル、及びｉ-ヘキシルからなる群より選択される炭化水素基である、上記＜１＞または＜２＞に記載のジエン系モノマーである。
＜４＞ 下記構造式で表される、上記＜１＞に記載のジエン系モノマーである。
＜６＞ Ｒ１が、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ（ＣＨ３）-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ）（ＣＨ３）ＣＨ２-、-ＣＨ（ＣＨ３）ＣＨ（ＣＨ３）-、-ＣＨ２（ＣＨ２）３ＣＨ２-、-ＣＨ２（ＣＨ２）２Ｃ（ＣＨ３）２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-からなる群より選択される２価の飽和炭化水素基である、上記＜５＞に記載のポリマーである。
＜７＞ Ｒ２が、エーテル結合を有していてもよい、メチル、エチル、プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、tert-ブチル、ｎ-ペンチル、ネオペンチル、イソアミル、tert-アミル、ｎ-ヘキシル、及びｉ-ヘキシルからなる群より選択される炭化水素基である、上記＜５＞または＜６＞に記載のポリマーである。
＜８＞ 下記式（３）で表される繰り返し単位を含むポリマーである。
＜９＞ Ｒ１が、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ（ＣＨ３）-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ）（ＣＨ３）ＣＨ２-、-ＣＨ（ＣＨ３）ＣＨ（ＣＨ３）-、-ＣＨ２（ＣＨ２）３ＣＨ２-、-ＣＨ２（ＣＨ２）２Ｃ（ＣＨ３）２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-からなる群より選択される炭化水素基である、上記＜８＞に記載のポリマーである。
＜１０＞ Ｒ２が、エーテル結合を有していてもよい、メチル、エチル、プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、tert-ブチル、ｎ-ペンチル、ネオペンチル、イソアミル、tert-アミル、ｎ-ヘキシル、及びｉ-ヘキシルからなる群より選択される炭化水素基である、上記＜８＞または＜９＞に記載のポリマーである。
＜１１＞ 下記式（１）で表されるジエン系モノマーを重合する工程を含む、下記式（２）で表される繰り返し単位を含むポリマーの製造方法である。
＜１２＞ 下記式（２）で表される繰り返し単位を含むポリマーを水素添加する工程を含む、下記式（３）で表される繰り返し単位を含むポリマーの製造方法である。
＜１３＞ 上記＜５＞から＜１０＞のいずれかに記載のポリマーを含み、血液と接触する部材の構成材料として用いられる抗血栓性材料である。
＜１４＞ 上記＜１３＞に記載の抗血栓性材料を血液と接触する表面に用いた医療用器具である。
＜１５＞ 前記医療用器具が、人工腎臓用膜、血漿分離用膜、カテーテル、人工肺用膜、または人工血管である、上記＜１４＞に記載の医療用器具である。
The present inventors have discovered that a polymer obtained from a monomer having a specific structure suppresses the adhesion of platelets and has antithrombotic properties, leading to the present invention. That is, the present invention is as follows.
<1> A diene monomer represented by the following formula (1).
<2> R 1 is -CH2- , -CH2CH2- , -CH ( CH3 ) -, -CH2CH2CH2- , -CH2 ( CH2 ) 2CH2- , -CH 2 (CH)( CH3 ) CH2- , -CH( CH3 )CH( CH3 )-, -CH2 ( CH2 ) 3CH2- , -CH2(CH2 ) 2C ( CH3 ) The diene monomer described in <1> above is a divalent saturated hydrocarbon group selected from the group consisting of 2 -, and -CH 2 (CH 2 ) 4 CH 2 -.
<3> R 2 may have an ether bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, neopentyl, isoamyl, tert The diene monomer according to <1> or <2> above, which is a hydrocarbon group selected from the group consisting of -amyl, n-hexyl, and i-hexyl.
<4> The diene monomer described in <1> above, which is represented by the following structural formula.
<6> R 1 is -CH2- , -CH2CH2- , -CH ( CH3 ) -, -CH2CH2CH2- , -CH2 ( CH2 ) 2CH2- , -CH 2 (CH)( CH3 ) CH2- , -CH( CH3 )CH( CH3 )-, -CH2 ( CH2 ) 3CH2- , -CH2(CH2 ) 2C ( CH3 ) The polymer according to <5> above is a divalent saturated hydrocarbon group selected from the group consisting of 2- , and -CH2 ( CH2 ) 4CH2- .
<7> R 2 may have an ether bond, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, neopentyl, isoamyl, tert-amyl , n-hexyl, and i-hexyl, the polymer according to <5> or <6> above.
<8> A polymer containing a repeating unit represented by the following formula (3).
<9> R 1 is -CH2- , -CH2CH2- , -CH ( CH3 )-, -CH2CH2CH2- , -CH2 ( CH2 ) 2CH2- , -CH 2 (CH)( CH3 ) CH2- , -CH( CH3 )CH( CH3 )-, -CH2 ( CH2 ) 3CH2- , -CH2(CH2 ) 2C ( CH3 ) The polymer according to <8> above is a hydrocarbon group selected from the group consisting of 2- , and -CH2 ( CH2 ) 4CH2- .
<10> R 2 may have an ether bond, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, neopentyl, isoamyl, tert-amyl , n-hexyl, and i-hexyl, the polymer according to <8> or <9> above.
<11> A method for producing a polymer containing a repeating unit represented by the following formula (2), including a step of polymerizing a diene monomer represented by the following formula (1).
<12> A method for producing a polymer containing a repeating unit represented by the following formula (3), which includes a step of hydrogenating a polymer containing a repeating unit represented by the following formula (2).
<13> An antithrombotic material containing the polymer according to any one of <5> to <10> above and used as a constituent material of a member that comes into contact with blood.
<14> A medical device using the antithrombotic material according to <13> above on a surface that comes into contact with blood.
<15> The medical device according to <14> above, wherein the medical device is an artificial kidney membrane, a plasma separation membrane, a catheter, an artificial lung membrane, or an artificial blood vessel.
本発明の一態様の好適な抗血栓性材料を血液と接触する表面の部材として用いると、血液と接触した際に、中間水の存在により、血小板の粘着および活性化を抑制することができる。従って、本発明の一態様の好適な抗血栓性材料は、人工腎臓用膜、血漿分離用膜、カテーテル、人工肺用膜および人工血管等の医療用器具の材料として極めて有用である。 When a suitable antithrombotic material according to one embodiment of the present invention is used as a surface member that comes into contact with blood, adhesion and activation of platelets can be suppressed due to the presence of intermediate water upon contact with blood. Therefore, the preferred antithrombotic material of one embodiment of the present invention is extremely useful as a material for medical devices such as membranes for artificial kidneys, membranes for plasma separation, catheters, membranes for artificial lungs, and artificial blood vessels.
以下、本発明の実施の形態について説明する。なお、以下に説明する材料、構成等は本発明を限定するものではなく、本発明の趣旨の範囲内で種々改変することができるものである。 Embodiments of the present invention will be described below. Note that the materials, configurations, etc. described below do not limit the present invention, and can be variously modified within the scope of the spirit of the present invention.
〔抗血栓性材料〕
本発明の抗血栓性材料は、下記式（２）で表される繰り返し単位を含むポリマー、または下記式（３）で表される繰り返し単位を含むポリマーを含み、血液と接触する部材の構成材料として用いられるものである。
なお、「エーテル結合を有してもよい炭化水素基」とは、炭化水素基を構成する２つの炭素原子がエーテル結合（－Ｏ－）を介して結合してもよい旨を規定している。
例えば、エチル基（－ＣＨ２－ＣＨ３）であれば、－ＣＨ２－Ｏ－ＣＨ３で表される基であってもよいことを意味する。また、エーテル結合（－Ｏ－）は複数有していてもよく、例えば、ｎ－ブチル基（－ＣＨ２－ＣＨ２－ＣＨ２－ＣＨ３）であれば、－ＣＨ２－Ｏ－ＣＨ２－Ｏ－ＣＨ２－Ｏ－ＣＨ３で表される基であってもよい。
式（２）及び式（３）において、Ｒ１の好ましい具体例としては、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ（ＣＨ３）-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ）（ＣＨ３）ＣＨ２-、-ＣＨ（ＣＨ３）ＣＨ（ＣＨ３）-、-ＣＨ２（ＣＨ２）３ＣＨ２-、-ＣＨ２（ＣＨ２）２Ｃ（ＣＨ３）２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-からなる群より選択される２価の飽和炭化水素基が挙げられ、より好ましくは、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ２）３ＣＨ２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-が挙げられる。
式（２）及び式（３）において、Ｒ２の好ましい具体例としては、エーテル結合を有していてもよい、メチル、エチル、プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、tert-ブチル、ｎ-ペンチル、ネオペンチル、イソアミル、tert-アミル、ｎ-ヘキシル、及びｉ-ヘキシルからなる群より選択される炭化水素基が挙げられ、より好ましくは、メチル、エチル、プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、及びtert-ブチルが挙げられる。
[Antithrombotic material]
The antithrombotic material of the present invention includes a polymer containing a repeating unit represented by the following formula (2) or a polymer containing a repeating unit represented by the following formula (3), and is a constituent material of a member that comes into contact with blood. It is used as a.
Note that the term "hydrocarbon group that may have an ether bond" specifies that two carbon atoms constituting the hydrocarbon group may be bonded via an ether bond (-O-). .
For example, if it is an ethyl group (-CH 2 -CH 3 ), it means that a group represented by -CH 2 -O-CH 3 may be used. Furthermore, there may be a plurality of ether bonds (-O-); for example, in the case of n-butyl group (-CH 2 -CH 2 -CH 2 -CH 3 ), -CH 2 -O-CH 2 It may also be a group represented by -O-CH 2 -O-CH 3 .
In formula (2) and formula (3), preferred specific examples of R 1 include -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, - CH2 ( CH2 ) 2CH2- , -CH2 (CH)(CH3) CH2- , -CH( CH3 )CH( CH3 )-, -CH2 ( CH2 ) 3CH2- , Divalent saturated hydrocarbon groups selected from the group consisting of -CH 2 (CH 2 ) 2 C(CH 3 ) 2 - and -CH 2 (CH 2 ) 4 CH 2 -, more preferably, -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH2 ( CH2 ) 2CH2- , -CH2 ( CH2 ) 3CH2- , and -CH2 ( CH2 ) 4CH2- is mentioned.
In formulas (2) and (3), preferred specific examples of R2 include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, and tert-butyl, which may have an ether bond. Examples include hydrocarbon groups selected from the group consisting of butyl, n-pentyl, neopentyl, isoamyl, tert-amyl, n-hexyl, and i-hexyl, more preferably methyl, ethyl, propyl, i-propyl, Mention may be made of n-butyl, i-butyl, and tert-butyl.
上記式（２）または式（３）で表される繰り返し単位を含むポリマーは、「示差走査熱量計測定において、－６０℃以上０℃未満の温度範囲で発熱ピークを有する」なる要件（以下、「要件（Ｉ）」と呼ぶ）を満たすものである。この要件（Ｉ）は、本発明の抗血栓性材料に含まれる前記ポリマーが、「中間水」と呼ばれる状態の水を含水していることを意味する。
一般的に、ポリマーを含む抗血栓性材料を、水と接触し得る環境下で使用した場合に、抗血栓性材料の表面近傍では、抗血栓性材料に含まれるポリマーからの相互作用を受けて抗血栓性材料の表面に水が吸着される。ポリマーからの相互作用を受けない水は、通常０℃で凍結又は融解するが、この吸着された水は、ポリマーからの相互作用により、－６０℃でも凍結しないため「不凍水」とも呼ばれている。
一方で、上記の「中間水」は、抗血栓性材料の表面近傍に吸着している不凍水よりも、抗血栓性材料の表面からわずかに離れた範囲に存在している。そのため、この「中間水」は、抗血栓性材料に含まれるポリマーの相互作用を受けるため、０℃では凍結又は融解しないが、その相互作用の力は不凍水よりは小さく、－６０℃以上０℃未満の範囲で凍結又は融解する性質を有する。
つまり、前記ポリマーは、上記要件（Ｉ）を満たすため、上述の「中間水」を含水したものであり、本発明の抗血栓性材料は、このような「中間水」を含水したポリマーを含むものである。
A polymer containing a repeating unit represented by the above formula (2) or formula (3) must meet the requirement (hereinafter referred to as (referred to as "requirement (I)"). This requirement (I) means that the polymer contained in the antithrombotic material of the present invention contains water in a state called "intermediate water."
In general, when an antithrombotic material containing a polymer is used in an environment where it may come into contact with water, the surface of the antithrombotic material is subject to interaction from the polymer contained in the antithrombotic material. Water is adsorbed on the surface of the antithrombotic material. Water that does not interact with polymers usually freezes or thaws at 0°C, but this adsorbed water does not freeze even at -60°C due to interactions with polymers, so it is also called "unfreezing water." ing.
On the other hand, the above-mentioned "intermediate water" exists in a range slightly farther from the surface of the antithrombotic material than the antifreeze water adsorbed near the surface of the antithrombotic material. Therefore, this "intermediate water" undergoes interaction with the polymer contained in the antithrombotic material, so it does not freeze or melt at 0°C, but the force of this interaction is smaller than that of antifreeze water, and at -60°C or higher. It has the property of freezing or thawing at temperatures below 0°C.
In other words, the polymer contains the above-mentioned "intermediate water" in order to satisfy the above requirement (I), and the antithrombotic material of the present invention contains a polymer containing such "intermediate water". It is something that
上述の「中間水」を含水したポリマーを含む抗血栓性材料は、血栓の発生を効果的に抑制し得、優れた生体適合性を有することが、様々な検討の中で分かった。そのような効果を奏する理由としては、以下のように考えられる。
血液中に含まれる最大成分は水であり、一般的な抗血栓性材料に血液を接触させた場合には、血液中の水が、抗血栓性材料に含まれるポリマーの相互作用により、抗血栓性材料の表面近傍に吸着されるという現象が起こり易い。そして、その吸着された水が、さらに血液中のタンパク質と接触した場合に、タンパク質が表面近傍の水に吸着されることで血栓が生じるのではないかと考えられる。
一方で、本発明の抗血栓性材料に含まれるポリマーは、上述の「中間水」を含水しているため、当該抗血栓性材料を血液と接触させた際、血液中のタンパク質は、抗血栓性材料の表面近傍に接触する前に、中間水と接触するため、抗血栓性材料の表面に生じ得る血栓を抑制し得ると推測される。
つまり、本発明の抗血栓性材料に含まれるポリマーは、上記要件（Ｉ）を満たし、上述の「中間水」を含水したものであるため、当該抗血栓性材料を血液と接触する部材の構成材料として用いた場合においても、血栓の発生を効果的に抑制し得る。そのため、本発明の抗血栓性材料は、優れた生体適合性を有するものである。
Through various studies, it has been found that an antithrombotic material containing a polymer containing the above-mentioned "intermediate water" can effectively suppress the occurrence of blood clots and has excellent biocompatibility. The reason for such an effect can be considered as follows.
The largest component contained in blood is water, and when blood comes into contact with general antithrombotic materials, the water in the blood becomes antithrombotic due to the interaction of the polymers contained in the antithrombotic materials. The phenomenon of being adsorbed near the surface of a flexible material is likely to occur. It is thought that when the adsorbed water further comes into contact with proteins in the blood, the proteins are adsorbed to the water near the surface, resulting in thrombus formation.
On the other hand, since the polymer contained in the anti-thrombotic material of the present invention contains the above-mentioned "intermediate water", when the anti-thrombotic material is brought into contact with blood, the proteins in the blood become anti-thrombotic. It is presumed that since it comes into contact with intermediate water before contacting the vicinity of the surface of the antithrombotic material, it is possible to suppress blood clots that may occur on the surface of the antithrombotic material.
In other words, since the polymer contained in the antithrombotic material of the present invention satisfies the above requirement (I) and contains the above-mentioned "intermediate water," the structure of the member that contacts the antithrombotic material with blood Even when used as a material, the generation of blood clots can be effectively suppressed. Therefore, the antithrombotic material of the present invention has excellent biocompatibility.
なお、上記要件（Ｉ）で規定する前記発熱ピークの発熱量は、好ましくは１Ｊ／ｇ以上、より好ましくは１．５Ｊ／ｇ以上であり、また、好ましくは、２０Ｊ／ｇ以下である。
本明細書において、上記要件（Ｉ）における示差走査熱量計（ＤＳＣ）測定の測定条件は、後述の実施例に記載されたとおりである。
The calorific value of the exothermic peak defined by the above requirement (I) is preferably 1 J/g or more, more preferably 1.5 J/g or more, and preferably 20 J/g or less.
In this specification, the measurement conditions for the differential scanning calorimeter (DSC) measurement in the above requirement (I) are as described in the Examples below.
＜ポリマーの構成及び製造方法＞
下記式（２）で表される繰り返し単位を含むポリマーは、下記式（１）で表されるジエン系モノマーを重合する工程を含む製造方法によって得ることができる。
式（１）において、Ｒ１の好ましい具体例としては、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ（ＣＨ３）-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ）（ＣＨ３）ＣＨ２-、-ＣＨ（ＣＨ３）ＣＨ（ＣＨ３）-、-ＣＨ２（ＣＨ２）３ＣＨ２-、-ＣＨ２（ＣＨ２）２Ｃ（ＣＨ３）２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-からなる群より選択される２価の飽和炭化水素基が挙げられ、より好ましくは、-ＣＨ２-、-ＣＨ２ＣＨ２-、-ＣＨ２ＣＨ２ＣＨ２-、-ＣＨ２（ＣＨ２）２ＣＨ２-、-ＣＨ２（ＣＨ２）３ＣＨ２-、及び-ＣＨ２（ＣＨ２）４ＣＨ２-が挙げられる。
式（１）において、Ｒ２の好ましい具体例としては、エーテル結合を有していてもよい、メチル、エチル、プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、tert-ブチル、ｎ-ペンチル、ネオペンチル、イソアミル、tert-アミル、ｎ-ヘキシル、及びｉ-ヘキシルからなる群より選択される炭化水素基が挙げられ、より好ましくはメチル、エチル、プロピル、ｉ-プロピル、ｎ-ブチル、ｉ-ブチル、及びtert-ブチルが挙げられる。
<Polymer composition and manufacturing method>
A polymer containing a repeating unit represented by the following formula (2) can be obtained by a manufacturing method including a step of polymerizing a diene monomer represented by the following formula (1).
In formula (1), preferred specific examples of R 1 include -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -CH 2 (CH 2 ) 2 CH 2 -, -CH 2 (CH) (CH 3 ) CH 2 -, -CH (CH 3 ) CH (CH 3 ) -, -CH 2 (CH 2 ) 3 CH 2 -, -CH 2 (CH 2 ) Divalent saturated hydrocarbon groups selected from the group consisting of 2C( CH3 ) 2- , and -CH2 ( CH2 ) 4CH2- , more preferably -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH2 ( CH2 ) 2CH2- , -CH2 ( CH2 ) 3CH2- , and -CH2 ( CH2 ) 4CH 2 - is mentioned.
In formula (1), preferred specific examples of R2 include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, which may have an ether bond. , neopentyl, isoamyl, tert-amyl, n-hexyl, and i-hexyl, more preferably methyl, ethyl, propyl, i-propyl, n-butyl, i- butyl and tert-butyl.
上記式（１）で表されるジエン系モノマーは、特に、下記構造式で表されるジエン系モノマーであることが好ましい。
下記式（３）で表される繰り返し単位を含むポリマーは、下記式（２）で表される繰り返し単位を含むポリマーを水素添加する工程を含む製造方法によって得ることができる。
上記式（２）で表される繰り返し単位を含むポリマーは、上記式（１）で表されるジエン系モノマーに由来する構成単位のみを有する単独重合体であってもよく、その他のモノマーに由来する構成単位を有する共重合体であってもよい。 The polymer containing repeating units represented by the above formula (2) may be a homopolymer having only constitutional units derived from the diene monomer represented by the above formula (1), or may be derived from other monomers. It may also be a copolymer having a structural unit.
上記式（１）で表されるジエン系モノマーに由来する構成単位の含有量は、上記要件（Ｉ）を満たすように調製する観点から、上記式（２）または式（３）で表される繰り返し単位を含むポリマーの構成単位の全量（１００質量％）に対して、好ましくは１０～１００質量％、より好ましくは３０～１００質量％、更に好ましくは５０～１００質量％、より更に好ましくは７０～１００質量％、特に好ましくは９０～１００質量％である。 From the viewpoint of preparation to satisfy the above requirement (I), the content of the structural unit derived from the diene monomer represented by the above formula (1) is expressed by the above formula (2) or (3). Preferably 10 to 100% by mass, more preferably 30 to 100% by mass, even more preferably 50 to 100% by mass, even more preferably 70% by mass, based on the total amount (100% by mass) of the polymer constituent units including repeating units. ~100% by weight, particularly preferably 90-100% by weight.
本発明の一態様において、上記式（２）または式（３）で表される繰り返し単位を含むポリマーの数平均分子量（Ｍｎ）は、上記要件（Ｉ）を満たすように調製する観点から、好ましくは５，０００～８００，０００、より好ましくは１０，０００～５００，０００、特に好ましくは２０，０００～１００，０００である。 In one aspect of the present invention, the number average molecular weight (Mn) of the polymer containing the repeating unit represented by the above formula (2) or formula (3) is preferably from the viewpoint of preparation to satisfy the above requirement (I). is 5,000 to 800,000, more preferably 10,000 to 500,000, particularly preferably 20,000 to 100,000.
また、本発明の一態様において、上記式（２）または式（３）で表される繰り返し単位を含むポリマーの分子量分布（Ｍｗ／Ｍｎ）は、上記と同様の観点から、好ましくは３以下、より好ましくは２以下であり、また、好ましくは１．０１以上である。
なお、Ｍｗ及びＭｎは、それぞれ、当該ポリマーの重量平均分子量及び数平均分子量である。
また、本明細書において、ポリマーの重量平均分子量（Ｍｗ）及び数平均分子量（Ｍｎ）は、実施例に記載の方法に基づいて測定された値を意味する。
Further, in one embodiment of the present invention, the molecular weight distribution (Mw/Mn) of the polymer containing the repeating unit represented by the above formula (2) or formula (3) is preferably 3 or less, from the same viewpoint as above, It is more preferably 2 or less, and preferably 1.01 or more.
Note that Mw and Mn are the weight average molecular weight and number average molecular weight of the polymer, respectively.
Moreover, in this specification, the weight average molecular weight (Mw) and number average molecular weight (Mn) of a polymer mean values measured based on the method described in Examples.
＜他の成分＞
本発明の一態様の抗血栓性材料は、本発明の効果を損なわない範囲で、前記ポリマー以外の他の有効成分を含有していてもよい。
本明細書において、「有効成分」とは、抗血栓性材料に含まれる希釈溶媒を除いた成分を意味する。
前記ポリマー以外の他の有効成分としては、例えば、抗酸化剤、紫外線吸収剤、滑剤、流動性調節剤、離型剤、帯電防止剤、光拡散剤等の添加剤や、ガラス繊維、炭素繊維、粘土化合物等の無機フィラー等が挙げられる。
<Other ingredients>
The antithrombotic material according to one embodiment of the present invention may contain other active ingredients other than the above-mentioned polymer to the extent that the effects of the present invention are not impaired.
As used herein, the term "active ingredient" refers to the components contained in the antithrombotic material excluding the diluent solvent.
Examples of active ingredients other than the polymer include additives such as antioxidants, ultraviolet absorbers, lubricants, fluidity regulators, mold release agents, antistatic agents, and light diffusing agents, as well as glass fibers and carbon fibers. , inorganic fillers such as clay compounds, and the like.
本発明の一態様の抗血栓性材料において、他の有効成分の含有量としては、当該抗血栓性材料に含まれる前記ポリマー１００質量部に対して、好ましくは０～５０質量部、より好ましくは０～２５質量部、更に好ましくは０～１０質量部、より更に好ましくは０～２質量部である。 In the antithrombotic material according to one aspect of the present invention, the content of other active ingredients is preferably 0 to 50 parts by mass, more preferably 0 to 50 parts by mass, based on 100 parts by mass of the polymer contained in the antithrombotic material. The amount is 0 to 25 parts by weight, more preferably 0 to 10 parts by weight, even more preferably 0 to 2 parts by weight.
また、本発明の一態様の抗血栓性材料の形態は、特に限定されず、前記ポリマーと共に希釈溶媒を含む溶液の形態であってもよく、当該溶媒を基材等の表面に塗布してなる塗膜の形態であってもよく、当該塗膜を乾燥してなるシート状物の形態であってもよい。 Further, the form of the antithrombotic material according to one embodiment of the present invention is not particularly limited, and may be in the form of a solution containing a diluent solvent together with the polymer, and the antithrombotic material may be formed by applying the solvent to the surface of a base material or the like. It may be in the form of a coating film, or it may be in the form of a sheet-like product obtained by drying the coating film.
なお、本発明の一態様の抗血栓性材料が上記溶液の形態である場合、当該溶液中の前記ポリマーの含有量（ポリマー濃度）としては、当該溶液の全量（１００質量％）に対して、好ましくは０．００１～６０質量％、より好ましくは０．０１～４５質量％、更に好ましくは０．０３～３０質量％、より更に好ましくは０．０５～１０質量％である。 Note that when the antithrombotic material of one embodiment of the present invention is in the form of the above solution, the content (polymer concentration) of the polymer in the solution is as follows with respect to the total amount (100% by mass) of the solution: Preferably 0.001 to 60% by weight, more preferably 0.01 to 45% by weight, even more preferably 0.03 to 30% by weight, even more preferably 0.05 to 10% by weight.
また、本発明の一態様の抗血栓性材料が上記溶液の形態である場合、希釈溶媒としては、前記ポリマーを溶解し得る溶媒であればよく、例えば、水や、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、メチルエチルケトン、アセトン、酢酸エチル、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド、ジオキサン、シクロヘキサン、ｎ－ヘキサン、トルエン、キシレン等の有機溶媒が挙げられる。
これらの希釈溶媒は、単独で用いてもよく、２種以上を併用した混合溶媒であってもよい。
Further, when the antithrombotic material of one embodiment of the present invention is in the form of the above solution, the diluting solvent may be any solvent that can dissolve the polymer, such as water, methanol, ethanol, n-propanol, etc. , isopropanol, methyl ethyl ketone, acetone, ethyl acetate, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide, dioxane, cyclohexane, n-hexane, toluene, xylene, and other organic solvents.
These diluting solvents may be used alone or as a mixed solvent in which two or more of them are used in combination.
〔抗血栓性材料の製造方法〕
本発明の一態様の抗血栓性材料の製造方法としては、特に限定されないが、例えば、以下の工程（１）及び（３）あるいは工程（１）～（３）を有する方法であることが好ましい。
・工程（１）：少なくとも上記式（１）で表されるジエン系モノマーを含む原料モノマーを重合させて、上記式（２）で表される繰り返し単位を含む重合反応物を得る工程。
・工程（２）：工程（１）で得た重合反応物を水素添加させ、上記式（３）で表される繰り返し単位を含むポリマーを得る工程。
・工程（３）：工程（１）で得た重合反応物もしくは工程（２）で得たポリマーを水に接触させ、中間水を含有するポリマーを得る工程。
[Method for producing antithrombotic material]
The method for producing the antithrombotic material according to one embodiment of the present invention is not particularly limited, but preferably includes the following steps (1) and (3) or steps (1) to (3). .
- Step (1): A step of polymerizing a raw material monomer containing at least a diene monomer represented by the above formula (1) to obtain a polymerization reaction product containing a repeating unit represented by the above formula (2).
- Step (2): A step of hydrogenating the polymerization reaction product obtained in step (1) to obtain a polymer containing a repeating unit represented by the above formula (3).
- Step (3): A step of bringing the polymerization reaction product obtained in step (1) or the polymer obtained in step (2) into contact with water to obtain a polymer containing intermediate water.
工程（１）での重合体の重合方法としては、特に制限は無く、例えば、前記原料モノマーと重合開始剤のみを用いた塊状重合による方法であってもよく、重合開始剤及び溶媒を用いた溶液重合、懸濁重合、及び乳化重合等による方法であってもよい。また、これらの重合方法において、必要に応じて、連鎖移動剤を用いてもよい。
用いる溶媒としては、例えば、メタノール、エタノール、イソプロパノール等のアルコール類や、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド、ジオキサン、トルエン、アセトン等の有機溶媒が挙げられ、また、水であってもよい。
これらの溶媒は、単独で用いてもよく、２種以上を併用した混合溶媒であってもよい。
The method of polymerizing the polymer in step (1) is not particularly limited, and may be, for example, a bulk polymerization method using only the raw material monomer and a polymerization initiator, or a method using a polymerization initiator and a solvent. Methods such as solution polymerization, suspension polymerization, and emulsion polymerization may also be used. Furthermore, in these polymerization methods, a chain transfer agent may be used as necessary.
Examples of the solvent used include alcohols such as methanol, ethanol, and isopropanol, and organic solvents such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide, dioxane, toluene, and acetone. , or water.
These solvents may be used alone or as a mixed solvent in which two or more of them are used in combination.
工程（１）で得た重合反応物は、その重合過程で、水を取り込んでいる場合には、上記要件（１）を満たすポリマーとなっている場合もある。
ただし、工程（３）によって、重合反応物から、上記要件（１）を満たすポリマーに容易に調製することができる。
If the polymerization reaction product obtained in step (1) incorporates water during the polymerization process, it may become a polymer that satisfies the above requirement (1).
However, by step (3), a polymer that satisfies the above requirement (1) can be easily prepared from the polymerization reaction product.
工程（３）における、前記重合反応物を水に接触させる方法としては、水を構成成分とする液体に接触させる方法であれば特に制限は無いが、好ましくはリン酸緩衝食塩水、もしくは生理食塩水、あるいは水、特に好ましくは血液中に含まれる水と接触させる方法が挙げられる。
このようにして、前記重合反応物を水に接触させて、上述の「中間水」を含水させることで、上記要件（１）を満たすポリマーを調製できる。
The method of bringing the polymerization reaction product into contact with water in step (3) is not particularly limited as long as it is a method of bringing the polymerization reaction product into contact with a liquid containing water as a constituent, but preferably phosphate buffered saline or physiological saline is used. Examples include a method of contacting with water or water, particularly preferably water contained in blood.
In this way, by bringing the polymerization reaction product into contact with water and impregnating it with the above-mentioned "intermediate water," a polymer that satisfies the above requirement (1) can be prepared.
なお、工程（３）は、工程（１）で重合反応物を得た後に、他の工程を経ずに行ってもよく、その場合には、工程（３）で得た前記ポリマーに、必要に応じて、上述の他の有効成分や、希釈溶媒を加えて、抗血栓性材料を調製することができる。 Note that step (3) may be carried out after obtaining the polymerization reaction product in step (1) without going through any other steps. In that case, the polymer obtained in step (3) may contain the necessary materials. Depending on the situation, antithrombotic materials can be prepared by adding other active ingredients or diluting solvents as described above.
また、工程（１）で重合反応物を得た後、工程（３）を経ずに、重合反応物に、必要に応じて、上述の他の有効成分や希釈溶媒を加えて組成物を調製し、当該組成物からシート状物等の成形品を製造し、この成形品を使用しながら、同時に工程（３）を経てもよい。つまり、使用時に、この成形品を水と接触させて、成形品に含まれる重合反応物に「中間水」を含水させて前記ポリマーとすることもできる。 Alternatively, after obtaining the polymerization reaction product in step (1), without going through step (3), the above-mentioned other active ingredients and diluting solvent may be added to the polymerization reaction product as necessary to prepare a composition. However, a molded article such as a sheet-like article may be produced from the composition, and step (3) may be performed at the same time as this molded article is used. That is, at the time of use, the molded article can be brought into contact with water to impregnate the polymerization reaction product contained in the molded article with "intermediate water" to form the polymer.
工程（２）において工程（１）で得た重合反応物を水素添加させる方法としては、当業者に公知の手段を用いることができ、例えばｐ－トルエンスルホン酸ヒドラジド等のヒドラジド化合物と反応させることで行うことができる。また、パラジウム担持活性炭素等を触媒として、その存在下で水素ガスと反応させる等によって生じさせることができる。 In step (2), methods known to those skilled in the art can be used to hydrogenate the polymerization reaction product obtained in step (1), such as reacting with a hydrazide compound such as p-toluenesulfonic acid hydrazide. It can be done with Alternatively, it can be produced by reacting with hydrogen gas in the presence of palladium-supported activated carbon or the like as a catalyst.
水素添加の際に用いられる溶媒は、反応に対して不活性であり、水素添加される重合反応物に対して溶解性がある溶媒であれば特に制限されない。使用されうる溶媒の例としては、ＴＨＦ、ＴＨＰ、ベンゼン、トルエン、キシレン等が挙げられるが、これらに限定されない。 The solvent used during hydrogenation is not particularly limited as long as it is inert to the reaction and soluble in the polymerization reaction product to be hydrogenated. Examples of solvents that may be used include, but are not limited to, THF, THP, benzene, toluene, xylene, and the like.
水素添加によって上記式（２）で示されるようなポリマー組成物中の不飽和結合が還元される水素添加率は、好ましくは９０％以上、より好ましくは９５％以上、最も好ましくは９９％以上とされることが望ましい。水素添加率は、例えば１ＨＮＭＲを用いて、不飽和結合の水素に由来するシグナルを観測することによって求めることができる。 The hydrogenation rate at which the unsaturated bonds in the polymer composition represented by the above formula (2) are reduced by hydrogenation is preferably 90% or more, more preferably 95% or more, and most preferably 99% or more. It is desirable that The hydrogenation rate can be determined by observing signals derived from hydrogen in unsaturated bonds using, for example, 1 HNMR.
また、上記式（２）で示されるような不飽和結合を有するポリマー組成物に対しては、水素添加の他にも、二重結合に対して反応性を示す試薬と反応させる等により、水素以外の官能基を導入することも可能である。不飽和結合に対して置換基を導入する反応として、例えばハロゲン化水素の付加、ハロゲン化、ハイドロボレーション、syn-ジヒドロキシル化等が挙げられ、得られるポリマー組成物の用途等に応じて適宜決定することができる。 Additionally, for polymer compositions having unsaturated bonds as shown in formula (2) above, in addition to hydrogenation, hydrogen It is also possible to introduce functional groups other than the above. Reactions for introducing substituents into unsaturated bonds include, for example, addition of hydrogen halide, halogenation, hydroboration, syn-dihydroxylation, etc., and may be carried out as appropriate depending on the use of the resulting polymer composition. can be determined.
〔抗血栓性材料の用途〕
本発明の抗血栓性材料は、血栓の発生を効果的に抑制し得、優れた生体適合性を有する。そのため、本発明の抗血栓性材料は、血液と接触する部材の構成材料として用いられることが好ましく、具体的には、血液浄化膜、人工腎臓用膜、血漿分離用膜、人工肺用膜、人工血管、カテーテル、歯科材料、細胞シート等の構成材料として好適に使用し得る。
また、本発明の抗血栓性材料を、医療用器具の血液と接触する表面の少なくとも一部に導入すると、凝固系、補体系、血小板系の活性化等を抑制することが可能であり、優れた生体適合性を付与することができる。
[Applications of antithrombotic materials]
The antithrombotic material of the present invention can effectively suppress the occurrence of thrombus and has excellent biocompatibility. Therefore, the antithrombotic material of the present invention is preferably used as a constituent material of a member that comes into contact with blood, and specifically, it can be used as a constituent material of a member that comes into contact with blood, and specifically, a blood purification membrane, an artificial kidney membrane, a plasma separation membrane, an artificial lung membrane, It can be suitably used as a constituent material for artificial blood vessels, catheters, dental materials, cell sheets, etc.
Furthermore, when the antithrombotic material of the present invention is introduced into at least a portion of the surface of a medical device that comes into contact with blood, it is possible to suppress activation of the coagulation system, complement system, platelet system, etc. It can provide biocompatibility.
また、本発明は、下記［１］及び［２］も提供し得る。
［１］上述の抗血栓性材料を血液と接触する表面に用いた医療用器具。
［２］上述の抗血栓性材料を用いて形成された部材を血液と接触させる、抗血栓性材料の使用方法。
上記［１］に記載の前記医療用器具としては、血液浄化膜、人工腎臓用膜、血漿分離用膜、人工肺用膜、人工血管、カテーテル、歯科材料、細胞シート等が挙げられるが、人工腎臓用膜、血漿分離用膜、カテーテル、人工肺用膜、または人工血管であることが好ましい。
Moreover, the present invention can also provide the following [1] and [2].
[1] A medical device using the above-mentioned antithrombotic material on the surface that comes into contact with blood.
[2] A method of using an antithrombotic material, which comprises bringing a member formed using the above antithrombotic material into contact with blood.
Examples of the medical device described in [1] above include blood purification membranes, membranes for artificial kidneys, membranes for plasma separation, membranes for oxygenator lungs, artificial blood vessels, catheters, dental materials, cell sheets, etc. Preferably, it is a kidney membrane, a plasma separation membrane, a catheter, an oxygenator membrane, or an artificial blood vessel.
以下、実施例により本発明を詳細に説明するが、本発明はこれら実施例によって限定されるものではない。なお、以下の例で用いた試薬は、とくに断りの無い場合は市販品をそのまま用いた。以下の例において、実施例１及び比較例１～２で得られた生成物（中間化合物、最終化合物）の構造の確認、重合の進行度、各実施例で得られた重合体の数平均分子量及び分子量分布の測定、ＮＭＲ測定による構造の確認、中間水の有無の確認は以下のようにして行った。 EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples. In addition, the reagents used in the following examples were commercially available products as they were, unless otherwise specified. In the following examples, confirmation of the structures of the products (intermediate compounds, final compounds) obtained in Example 1 and Comparative Examples 1 and 2, the degree of polymerization progress, and the number average molecular weight of the polymers obtained in each example. Measurement of the molecular weight distribution, confirmation of the structure by NMR measurement, and confirmation of the presence or absence of intermediate water were performed as follows.
（１）数平均分子量（［Ｍｎ］、単位：ｇ/mol）
ピーク分子量が既知の標準ポリスチレンを用い、該標準ポリスチレンで校正したゲル浸透クロマトグラフィー（ＧＰＣ）（島津製作所社製「Ｐｒｏｍｉｎｅｎｃｅ」、カラム構成：ＴｏｓｏｈＴＳＫｇｅｌ ｇｕａｒｄｃｏｌｕｍｎ ＨＨＲ－Ｈ、Ｇ５０００ＨＨＲ、Ｇ４０００ＨＨＲ、Ｇ３０００ＨＨＲ）を使用して、重合体の数平均分子量（Ｍｎ）及び重量平均分子量（Ｍｗ）を測定した。（溶媒：テトラヒドロフラン、温度：４０℃、流量：１．０ｍＬ／ｍｉｎ）。
(1) Number average molecular weight ([Mn], unit: g/mol)
Gel permeation chromatography (GPC) using a standard polystyrene with a known peak molecular weight and calibrating with the standard polystyrene ("Prominence" manufactured by Shimadzu Corporation, column configuration: TosohTSKgel guardcolumn H HR -H, G5000H HR , G4000H HR , G3000H HR ) was used to measure the number average molecular weight (Mn) and weight average molecular weight (Mw) of the polymer. (Solvent: tetrahydrofuran, temperature: 40°C, flow rate: 1.0 mL/min).
（２）分子量分布（［Ｍｗ／Ｍｎ］）
上記（１）の方法で求めた重量平均分子量（Ｍｗ）と数平均分子量（Ｍｎ）の値を用い、その比（Ｍｗ／Ｍｎ）として求めた。
(2) Molecular weight distribution ([Mw/Mn])
Using the values of weight average molecular weight (Mw) and number average molecular weight (Mn) determined by the method (1) above, it was determined as the ratio (Mw/Mn).
（３）ＮＭＲ測定
モノマー及びポリマーの構造解析については、ＮＭＲ測定装置（ブルカー社製、ＡＶＡＮＣＥ ＩＩＩ ４００ＭＨｚ）を用い、１Ｈ ＮＭＲ測定及び１３Ｃ ＮＭＲ測定を行った。なお、ケミカルシフトは１Ｈ ＮＭＲの場合にはテトラメチルシラン（０．００ｐｐｍ）を基準とし、１３Ｃ ＮＭＲの場合にはＣＤＣｌ３（７７．１ｐｐｍ）を基準とした。
(3) NMR Measurement For structural analysis of monomers and polymers, 1 H NMR measurement and 13 C NMR measurement were performed using an NMR measuring device (manufactured by Bruker, AVANCE III 400 MHz). In addition, the chemical shift was based on tetramethylsilane (0.00 ppm) in the case of 1 H NMR, and was based on CDCl 3 (77.1 ppm) in the case of 13 C NMR.
（４）中間水の有無の確認
ＤＳＣ装置（エスアイアイ・ナノテクノロジーズ株式会社、「ＥＸＳＴＡＲＸ-ＤＳＣ７０００」）を用い、窒素流量５０ｍＬ／ｍｉｎ、５．０℃／ｍｉｎの条件で測定を行った。温度プログラムは、（ｉ）３０℃から－１００℃まで冷却、（ｉｉ）－１００℃で５分間保持、（ｉｉｉ）－１００℃から３０℃まで加熱を行った。リン酸緩衝食塩水に３日以上浸漬させた含水高分子を用いて測定を行い、上記（ｉ）において－４０℃における水の低温結晶化に起因する発熱ピークの有無によって中間水の有無を確認した。
(4) Confirmation of presence or absence of intermediate water Measurement was performed using a DSC device ("EXSTARX-DSC7000", manufactured by SII Nanotechnologies Co., Ltd.) under conditions of a nitrogen flow rate of 50 mL/min and 5.0° C./min. The temperature program was (i) cooling from 30°C to -100°C, (ii) holding at -100°C for 5 minutes, and (iii) heating from -100°C to 30°C. Measurement is performed using a water-containing polymer immersed in phosphate buffered saline for 3 days or more, and the presence or absence of intermediate water is confirmed by the presence or absence of an exothermic peak caused by low-temperature crystallization of water at -40°C in (i) above. did.
（実施例１）
２－（３－メトキシプロピル）－１，３－ブタジエン（式（１）で表されるジエン系モノマー）の製造
（１）クロロプレンの調製
５００ｍＬの三口フラスコに水酸化ナトリウム５２ｇ（１．３ｍｏｌ）、水２１０ｍＬ、テトラブチルアンモニウムブロミド１４ｇ（４３．４ｍｍｏｌ）を加え、ディーンスターク装置および冷却管を立てて冷却水を流し、オイルバスで６５℃に加熱しながら３，４－ジクロロ－１－ブテン８１．３ｇ（６５０ｍｍｏｌ）を滴下した。生成するクロロプレンをディーンスターク装置にて回収しながら７０℃で２時間攪拌を続け、加熱を止めて反応を停止した。回収した溶液を硫酸マグネシウム（無水）で乾燥し、濾過した後、水素化カルシウム存在下で蒸留（常圧、５７℃）することで目的物を得た（収量３０．９ｇ、収率５４％）。
１Ｈ ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝６．４２（１Ｈ），５．６７（１Ｈ），５．４４-５．３６（ｍ，２Ｈ），５．３２（１Ｈ）．
(Example 1)
Production of 2-(3-methoxypropyl)-1,3-butadiene (diene monomer represented by formula (1)) (1) Preparation of chloroprene In a 500 mL three-necked flask, 52 g (1.3 mol) of sodium hydroxide, Add 210 mL of water and 14 g (43.4 mmol) of tetrabutylammonium bromide, set up the Dean-Stark apparatus and cooling pipe, let the cooling water flow, and while heating to 65°C in an oil bath, 3,4-dichloro-1-butene 81. 3 g (650 mmol) was added dropwise. Stirring was continued at 70° C. for 2 hours while the produced chloroprene was collected using a Dean-Stark apparatus, and then heating was stopped to terminate the reaction. The collected solution was dried with magnesium sulfate (anhydrous), filtered, and then distilled in the presence of calcium hydride (normal pressure, 57°C) to obtain the target product (yield: 30.9 g, yield 54%). .
The signals detected by 1 H NMR measurement were as follows.
1H NMR (400MHz, CDCl3 ) δ=6.42 (1H), 5.67 (1H), 5.44-5.36 (m, 2H), 5.32 (1H).
（２）２－（３－メトキシプロピル）－１，３－ブタジエンの製造
１Ｌの三口フラスコに上記で得られたクロロプレン１４．１ｇ（１６０ｍｍｏｌ）とジクロロ［１，３－ビス（ジフェニルホスフィノ）プロパン］ニッケル（ＩＩ）０．８７ｇ（１．６ｍｍｏｌ）、乾燥ＴＨＦ７０ｍＬを加え、氷浴で冷やしながら攪拌した。そこに、調製したグリニャール試薬を滴下し、カップリング反応を行った。滴下後室温で１２時間攪拌を続け、水１００ ｍＬの入った１Ｌビーカー中に反応溶液を流しいれて反応を停止させた。２Ｎ ＨＣｌを加えて中和し、分液漏斗を用いて有機層と水層を分離した。水層に対してエーテルによる抽出操作を３回行い、有機層に加えた。回収した有機層を硫酸マグネシウム（無水）で乾燥し、濾過後ジブチルヒドロキシトルエン５ｍｇを加え、エバポレータで濃縮した。
続いて、ヘキサン：エーテル＝９：１の混合溶媒を展開溶媒としてシリカゲルカラムクロマトグラフィ―による精製を行った。得られた粗生成物を水素化カルシウム存在下で減圧蒸留し、目的とする２－（３－メトキシプロピル）－１，３－ブタジエン（沸点４０℃／１０ｍｍＨｇ）目的物を収量３．５８ｇ、収率１８％で得た。ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝６．３６（１Ｈ），５．２３（１Ｈ），５．１０-４．９５（ｍ，３Ｈ），３．３９（２Ｈ），３．３３（ｓ，３Ｈ），２．３４-２．２２（ｍ，２Ｈ），１．８３-１．７０（ｍ，２Ｈ）．
１３Ｃ ＮＭＲ（１０１ＭＨｚ，ＣＤＣｌ３）δ＝１４５．９７，１３８．８９，１１５．９４，１１３．４１，７２．４５，５８．６６，２８．２０，２７．８６．
(2) Production of 2-(3-methoxypropyl)-1,3-butadiene In a 1 L three-necked flask, 14.1 g (160 mmol) of the chloroprene obtained above and dichloro[1,3-bis(diphenylphosphino)propane ] 0.87 g (1.6 mmol) of nickel (II) and 70 mL of dry THF were added, and the mixture was stirred while cooling in an ice bath. The prepared Grignard reagent was added dropwise thereto to perform a coupling reaction. After the dropwise addition, stirring was continued at room temperature for 12 hours, and the reaction solution was poured into a 1 L beaker containing 100 mL of water to stop the reaction. 2N HCl was added to neutralize, and the organic and aqueous layers were separated using a separatory funnel. The aqueous layer was extracted with ether three times and added to the organic layer. The collected organic layer was dried over magnesium sulfate (anhydrous), filtered, added with 5 mg of dibutylhydroxytoluene, and concentrated using an evaporator.
Subsequently, purification was performed by silica gel column chromatography using a mixed solvent of hexane:ether=9:1 as a developing solvent. The obtained crude product was distilled under reduced pressure in the presence of calcium hydride to obtain 2-(3-methoxypropyl)-1,3-butadiene (boiling point 40°C/10 mmHg) in a yield of 3.58 g. The yield was 18%. The signals detected by NMR measurement were as follows.
1H NMR (400MHz, CDCl3 ) δ = 6.36 (1H), 5.23 (1H), 5.10-4.95 (m, 3H), 3.39 (2H), 3.33 (s , 3H), 2.34-2.22 (m, 2H), 1.83-1.70 (m, 2H).
13C NMR (101 MHz, CDCl3 ) δ=145.97, 138.89, 115.94, 113.41, 72.45, 58.66, 28.20, 27.86.
（３）２－（３－メトキシプロピル）－１，３－ブタジエン重合体（式（２）で表される繰り返し単位を含むポリマー）の製造
シュレンク管に上記で得られた２－（３－メトキシプロピル）－１，３－ブタジエン３．００ｇ（２３．８ｍｍｏｌ）、２－（ドデシルチオカルボノチオイルチオ）－２－メチルプロパン酸１７．４ｍｇ（０．０４７６ｍｍｏｌ）、アゾビスイソブチロニトリル３．９１ｍｇ（０．０２３８ｍｍｏｌ）を加え、フリーズポンプソウによる脱気操作を３回行い、アルゴン雰囲気下、常圧、７５℃で重合を行った。２４、３６、５４時間後に随時反応容器を開放して少量の重合溶液をサンプリングし、１Ｈ ＮＭＲで重合の進行度を確認した。確認のたびに同量のアゾビスイソブチロニトリルを添加して重合を継続し、目的の重合度に達するまで反応を続けた。
重合後は室温に冷却することで反応を停止した。ＴＨＦ／ＭｅＯＨ系での沈殿精製操作を３回行い、得られた高分子を大過剰の純水中で一晩撹拌することで水に可溶な成分の除去を行った（以下、この操作を「水精製」という）。上澄みの水を取り除き、少量のジブチルヒドロキシトルエンを加えたＴＨＦで高分子を回収し、真空オーブンを用いて室温で２４時間乾燥させ、粘稠体の目的物である２－（３－メトキシプロピル）－１，３－ブタジエン重合体を得た。収量は０．９７４ｇ（モノマーユニット換算で７．７３ｍｍｏｌ）、収率３２％であった。ＧＰＣを用いて分子量を測定した結果、Ｍｎは２２ｋｇ／ｍｏｌ、Ｍｗ／Ｍｎは１．３であった。ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝５．２１－５．０４（ｍ，１Ｈ），４．８４－４．６９（ｍ，２Ｈ），３．３９－３．２７（ｍ，５Ｈ），２．１５－１．９１（ｍ，６Ｈ），１．７５－１．５６（ｍ，２Ｈ）．
１３Ｃ ＮＭＲ（１０１ＭＨｚ，ＣＤＣｌ３）δ＝１３８．７７，１２４．９５，７２．５２，５８．４７，３７．２１，３３．３３，２８．１７，２６．６３．
(3) Production of 2-(3-methoxypropyl)-1,3-butadiene polymer (polymer containing repeating units represented by formula (2)) propyl)-1,3-butadiene 3.00 g (23.8 mmol), 2-(dodecylthiocarbonothioylthio)-2-methylpropanoic acid 17.4 mg (0.0476 mmol), azobisisobutyronitrile 3. 91 mg (0.0238 mmol) was added, deaeration was performed three times using a freeze pump saw, and polymerization was carried out at normal pressure and 75° C. under an argon atmosphere. After 24, 36, and 54 hours, the reaction vessel was opened at any time to sample a small amount of the polymerization solution, and the degree of polymerization was confirmed by 1 H NMR. Polymerization was continued by adding the same amount of azobisisobutyronitrile each time the confirmation was made, and the reaction was continued until the desired degree of polymerization was reached.
After polymerization, the reaction was stopped by cooling to room temperature. A precipitation purification operation using a THF/MeOH system was performed three times, and the resulting polymer was stirred overnight in a large excess of pure water to remove water-soluble components (hereinafter, this operation was (referred to as "water purification"). The supernatant water was removed, the polymer was recovered with THF to which a small amount of dibutylhydroxytoluene was added, and the polymer was dried in a vacuum oven at room temperature for 24 hours to obtain a viscous target product, 2-(3-methoxypropyl). A -1,3-butadiene polymer was obtained. The yield was 0.974 g (7.73 mmol in terms of monomer unit), and the yield was 32%. As a result of measuring the molecular weight using GPC, Mn was 22 kg/mol and Mw/Mn was 1.3. The signals detected by NMR measurement were as follows.
1 H NMR (400 MHz, CDCl 3 ) δ = 5.21-5.04 (m, 1H), 4.84-4.69 (m, 2H), 3.39-3.27 (m, 5H), 2.15-1.91 (m, 6H), 1.75-1.56 (m, 2H).
13C NMR (101 MHz, CDCl3 ) δ=138.77, 124.95, 72.52, 58.47, 37.21, 33.33, 28.17, 26.63.
（４）水素添加２－（３－メトキシプロピル）－１，３－ブタジエン重合体（式（３）で表される繰り返し単位を含むポリマー）の製造
上記で得られた２－（３－メトキシプロピル）－１，３－ブタジエン重合体０．８６ｇ（６．８ｍｍｏｌ）、ｏ－キシレン２０ｍＬ、ｐ－トルエンスルホニルヒドラジド６．３３ｇ（３４ｍｍｏｌ）、トリブチルアミン７．０４ｇ（３８ｍｍｏｌ）、ジブチルヒドロキシトルエン５ｍｇを加え、１００℃で６時間加熱攪拌した。同様の操作を再度行ったのち、１Ｈ ＮＭＲで二重結合のシグナルの消失を確認し、加熱を止め反応を停止させた。ＴＨＦ／ＭｅＯＨ系での沈殿精製を３回と水精製を行った。上澄みの水を取り除き、少量のＴＨＦで沈殿物を回収した後、エバポレータでＴＨＦを留去し、真空オーブンを用いて１２時間室温で乾燥することで無色粘稠体の目的物を得た。収量０．７５８ｇ（モノマーユニット換算で５．９２ｍｍｏｌ）、収率８７％であった。ＧＰＣを用いて分子量を測定した結果、Ｍｎは３３ｋｇ／ｍｏｌ、Ｍｗ／Ｍｎは１．４であった。ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝３．４０－３．２７（ｍ，５Ｈ），２．１５－０．９２（ｍ，１１Ｈ）．
１３Ｃ ＮＭＲ（１０１ＭＨｚ，ＣＤＣｌ３）δ＝７３．５７，５８．６３，３７．５４，３４．３６，２９．９４，２６．９４．
ここで、得られた水素添加２－（３－メトキシプロピル）－１，３－ブタジエン重合体について、上記「（４）中間水の有無の確認」を行ったところ、－４０℃における水の低温結晶化に起因する発熱ピークによって中間水の存在を確認した。
(4) Production of hydrogenated 2-(3-methoxypropyl)-1,3-butadiene polymer (polymer containing repeating units represented by formula (3)) 2-(3-methoxypropyl) obtained above )-1,3-butadiene polymer 0.86 g (6.8 mmol), o-xylene 20 mL, p-toluenesulfonyl hydrazide 6.33 g (34 mmol), tributylamine 7.04 g (38 mmol), and dibutylhydroxytoluene 5 mg were added. The mixture was heated and stirred at 100° C. for 6 hours. After performing the same operation again, disappearance of the double bond signal was confirmed by 1 H NMR, and heating was stopped to terminate the reaction. Precipitation purification using a THF/MeOH system was performed three times and water purification was performed. After removing the supernatant water and recovering the precipitate with a small amount of THF, the THF was distilled off using an evaporator, and the product was dried at room temperature for 12 hours using a vacuum oven to obtain the desired product as a colorless viscous substance. The yield was 0.758 g (5.92 mmol in terms of monomer unit), and the yield was 87%. As a result of measuring the molecular weight using GPC, Mn was 33 kg/mol and Mw/Mn was 1.4. The signals detected by NMR measurement were as follows.
1 H NMR (400 MHz, CDCl 3 ) δ=3.40-3.27 (m, 5H), 2.15-0.92 (m, 11H).
13C NMR (101 MHz, CDCl3 ) δ=73.57, 58.63, 37.54, 34.36, 29.94, 26.94.
Here, when the hydrogenated 2-(3-methoxypropyl)-1,3-butadiene polymer obtained was subjected to the above "(4) Confirmation of the presence or absence of intermediate water", it was found that the low temperature of water at -40°C. The presence of intermediate water was confirmed by the exothermic peak due to crystallization.
（比較例１）
ＰＥＴ（ポリエチレンテレフタレート）フィルム（三菱樹脂株式会社、ダイアホイル カタログ番号Ｔ１００Ｅ１２５）をそのまま用いた。実施例１と同様に、含水させたポリマーについて発熱ピークを測定したところ、－４０℃で発熱ピークを示さなかった。
(Comparative example 1)
A PET (polyethylene terephthalate) film (Mitsubishi Plastics Co., Ltd., Diafoil catalog number T100E125) was used as it was. As in Example 1, when the exothermic peak of the hydrated polymer was measured, no exothermic peak was observed at -40°C.
（比較例２）
水素添加ポリ（３－（３－メトキシプロピル）－１－シクロオクテン）の製造
（１）３－ブロモ－１－シクロオクテンの調製
１Ｌの三口フラスコにｃｉｓ－シクロオクテン６６．１ｇ（６００ｍｍｏｌ）、四塩化炭素３５０ｍＬ、Ｎ－ブロモスクシンイミド（ＮＢＳ）７７．０ｇ（４３０ｍｍｏｌ）、アゾビスイソブチロニトリル（ＡＩＢＮ）７０．６ｍｇ（０．４３ｍｍｏｌ）を加え、系内を撹拌しながら窒素バブリングを２０分間行った。その後、窒素を流しながら９０℃で２時間還流を行ったのち、加熱を止め室温まで冷却した。反応溶液を吸引ろ過しスクシンイミドを取り除いた後、エバポレータを用いて余分な溶媒を取り除き、ヘキサンを展開溶媒とするシリカゲルカラムクロマトグラフィにより精製を行った。その後、エバポレータを用いてヘキサンを取り除き、水素化カルシウム存在下で減圧蒸留を行い、３４℃／０．０８ｍｍＨｇの沸点で無色透明の液体である３－ブロモ－１－シクロオクテンを収量５１．３ｇ（２７１ｍｍｏｌ）、収率６３％で得た。１Ｈ ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝５．７９（１Ｈ），５．６０（１Ｈ），４．９５（１Ｈ），２．３２-２．００（ｍ，４Ｈ），１．７６－１．２４（ｍ，６Ｈ）．
(Comparative example 2)
Production of hydrogenated poly(3-(3-methoxypropyl)-1-cyclooctene) (1) Preparation of 3-bromo-1-cyclooctene 66.1 g (600 mmol) of cis-cyclooctene, 4 Add 350 mL of carbon chloride, 77.0 g (430 mmol) of N-bromosuccinimide (NBS), and 70.6 mg (0.43 mmol) of azobisisobutyronitrile (AIBN), and perform nitrogen bubbling for 20 minutes while stirring the system. Ta. Thereafter, the mixture was refluxed at 90° C. for 2 hours while flowing nitrogen, and then the heating was stopped and the mixture was cooled to room temperature. After the reaction solution was suction-filtered to remove succinimide, excess solvent was removed using an evaporator, and purification was performed by silica gel column chromatography using hexane as a developing solvent. Thereafter, hexane was removed using an evaporator, and vacuum distillation was performed in the presence of calcium hydride to yield 51.3 g of 3-bromo-1-cyclooctene, a colorless and transparent liquid with a boiling point of 34°C/0.08 mmHg. 271 mmol) in a yield of 63%. The signals detected by 1 H NMR measurement were as follows.
1 H NMR (400 MHz, CDCl 3 ) δ = 5.79 (1H), 5.60 (1H), 4.95 (1H), 2.32-2.00 (m, 4H), 1.76-1 .24 (m, 6H).
（２）３－（３－メトキシプロピル）－１－シクロオクテンの調製
（ｉ）３００ｍＬの三口フラスコにマグネシウム（削り状）４．８６ｇ（２００ｍｍｏｌ）とスターラーチップを入れ、冷却管およびＴ字管、塩化カルシウム管をつなぎ、冷却水を流しつつ系内をアルゴンガスで満たした。乾燥ジエチルエーテル２０ｍＬとジブロモエタン０．１ｍＬを加え、攪拌することでマグネシウムの活性化を促した。その後、３－ブロモ－１－メトキシプロパン２２．８ｇ（１４９ｍｍｏｌ）を乾燥ジエチルエーテル１５０ｍＬで希釈した溶液を０℃で３０分かけてゆっくり滴下した。滴下終了後、室温で３時間攪拌したものをグリニャール試薬としてカップリング反応に使用した。
(2) Preparation of 3-(3-methoxypropyl)-1-cyclooctene (i) Put 4.86 g (200 mmol) of magnesium (shavings) and a stirrer tip into a 300 mL three-necked flask, add a cooling tube and a T-tube, A calcium chloride pipe was connected, and the system was filled with argon gas while cooling water was flowing. 20 mL of dry diethyl ether and 0.1 mL of dibromoethane were added and stirred to promote activation of magnesium. Thereafter, a solution of 22.8 g (149 mmol) of 3-bromo-1-methoxypropane diluted with 150 mL of dry diethyl ether was slowly added dropwise at 0° C. over 30 minutes. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours and used as a Grignard reagent in the coupling reaction.
（ｉｉ）５００ｍＬの三口フラスコに上記で得られた３－ブロモ－１－シクロオクテン２２．４ｇ（１１８ｍｍｏｌ）とヨウ化銅（Ｉ）５４０ｍｇ（２．８４ｍｍｏｌ）、乾燥ＴＨＦ１００ｍＬを加え、攪拌した。そこに、上記で調製したグリニャール試薬を０℃で３０分かけて滴下し、室温で２時間攪拌を続けた。水１００ｍＬの入った１Ｌビーカー中に反応溶液を流しいれ、反応を停止させた。２規定塩酸を加えて中和し、分液漏斗を用いて有機層と水層を分離した。水層に対してエーテルによる抽出操作を３回行い、有機層に加えた。回収した有機層をチオ硫酸ナトリウム水溶液で洗浄後、炭酸カリウム（無水）で乾燥し、濾過した溶液をエバポレータで濃縮することにより粗生成物を得た。これを水素化カルシウム存在下で減圧蒸留することによって精製し、目的とする３－（３－メトキシプロピル）－１－シクロオクテン（ｂ．ｐ．＝５２．０～５４．５℃／０．０８ｍｍＨｇ）を収量１４．６ｇ、収率６８％で得た。ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝５．６３（１Ｈ），５．１９（１Ｈ），３．３５（ｔ，２Ｈ），３．３２（ｓ，３Ｈ），２．５０－２．３７（ｍ，１Ｈ），２．２７－１．９５（ｍ，２Ｈ），１．７３－１．０６（ｍ，１２Ｈ）．
１３Ｃ ＮＭＲ（１０１ＭＨｚ，ＣＤＣｌ３）δ＝１３５．４４，１２９．６５，７３．１５， ５８．６３，３６．７１，３５．８４，３３．２４，２９．７７，２８．０６，２７．０６，２６．８９，２５．９７．
(ii) 22.4 g (118 mmol) of 3-bromo-1-cyclooctene obtained above, 540 mg (2.84 mmol) of copper(I) iodide, and 100 mL of dry THF were added to a 500 mL three-necked flask and stirred. The Grignard reagent prepared above was added dropwise thereto at 0° C. over 30 minutes, and stirring was continued at room temperature for 2 hours. The reaction solution was poured into a 1 L beaker containing 100 mL of water to stop the reaction. The mixture was neutralized by adding 2N hydrochloric acid, and the organic layer and aqueous layer were separated using a separatory funnel. The aqueous layer was extracted with ether three times and added to the organic layer. The collected organic layer was washed with an aqueous sodium thiosulfate solution, dried over potassium carbonate (anhydrous), and the filtered solution was concentrated using an evaporator to obtain a crude product. This was purified by distillation under reduced pressure in the presence of calcium hydride to obtain the desired 3-(3-methoxypropyl)-1-cyclooctene (b.p.=52.0-54.5℃/0.08mmHg). ) was obtained in a yield of 14.6 g and 68%. The signals detected by NMR measurement were as follows.
1 H NMR (400 MHz, CDCl 3 ) δ = 5.63 (1H), 5.19 (1H), 3.35 (t, 2H), 3.32 (s, 3H), 2.50-2.37 (m, 1H), 2.27-1.95 (m, 2H), 1.73-1.06 (m, 12H).
13C NMR (101MHz, CDCl3 ) δ = 135.44, 129.65, 73.15, 58.63, 36.71, 35.84, 33.24, 29.77, 28.06, 27.06 , 26.89, 25.97.
（３）３－（３－メトキシプロピル）－１－シクロオクテン重合体の製造
上記で得られた３－（３－メトキシプロピル）－シクロオクテン８．０ｇ（４４．０ｍｍｏｌ）、ｃｉｓ－４－オクテン１４．８ｇ（０．１３ｍｍｏｌ）、第二世代グラブス触媒７４．７ｍｇ（０．０９ｍｍｏｌ）、乾燥ＣＨＣｌ３を１５ｍＬ加え、反応溶液を調製した。攪拌２０時間後に転化率が９８％であることを確認し、少量のＣＨＣｌ３とエチルビニルエーテルを加えて室温で１時間撹拌することで反応を停止させた。使用した触媒の量に対して２０当量の金属スカベンジャーを加え、室温で一晩撹拌することで触媒を吸着させた。ガラスフィルター、０．４５μｍテフロンフィルター、０．１μｍテフロンフィルターを用いて段階的に金属スカベンジャーを濾別した。２Ｌのビーカーを用いてＴＨＦ／ＭｅＯＨ系での沈殿精製を３回行った後、得られた高分子を大過剰の純水中で一晩撹拌することで水に可溶な成分の除去を行った（以下、この操作を「水精製」という）。上澄みの水を取り除き、少量のＴＨＦに溶解させて高分子を回収した後、エバポレータでＴＨＦを留去し、真空オーブンを用いて１２時間室温で乾燥することで目的物である３－（３－メトキシプロピル）－１－シクロオクテン重合体を得た。精製操作の後、粘稠体の目的物を収量６．８４ｇ（３７．６ｍｍｏｌ）、収率８６％で得た。ＧＰＣを用いて分子量を測定した結果、Ｍｎは９０ｋｇ／ｍｏｌ、Ｍｗ／Ｍｎは１．７であった。ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝５．３０（１Ｈ），５．０５（１Ｈ），３．３９-３．２７（ｍ，５Ｈ），２．０１－１．９０（ｍ，２Ｈ），１．８９－１．７８（ｍ，１Ｈ），１．６５－１．０６（ｍ，１２Ｈ）．
１３Ｃ ＮＭＲ（１０１ＭＨｚ，ＣＤＣｌ３）δ＝１３４．５２，１３０．４７，７３．１２，５８．４８，４２．７４，３５．５９，３２．６２，３１．８４，２９．７３，２９．３２，２７．４６，２７．０８．
(3) Production of 3-(3-methoxypropyl)-1-cyclooctene polymer 8.0 g (44.0 mmol) of 3-(3-methoxypropyl)-cyclooctene obtained above, cis-4-octene A reaction solution was prepared by adding 14.8 g (0.13 mmol), 74.7 mg (0.09 mmol) of second generation Grubbs catalyst, and 15 mL of dry CHCl 3 . After 20 hours of stirring, it was confirmed that the conversion rate was 98%, and a small amount of CHCl 3 and ethyl vinyl ether were added and the reaction was stopped by stirring at room temperature for 1 hour. 20 equivalents of metal scavenger was added to the amount of catalyst used, and the catalyst was adsorbed by stirring overnight at room temperature. The metal scavenger was filtered out stepwise using a glass filter, a 0.45 μm Teflon filter, and a 0.1 μm Teflon filter. After performing precipitation purification in a THF/MeOH system three times using a 2L beaker, water-soluble components were removed by stirring the resulting polymer overnight in a large excess of pure water. (Hereinafter, this operation will be referred to as "water purification"). After removing the supernatant water and recovering the polymer by dissolving it in a small amount of THF, the THF was distilled off using an evaporator, and the target product 3-(3- A methoxypropyl)-1-cyclooctene polymer was obtained. After the purification operation, a viscous target product was obtained in an amount of 6.84 g (37.6 mmol) and a yield of 86%. As a result of measuring the molecular weight using GPC, M n was 90 kg/mol and M w /M n was 1.7. The signals detected by NMR measurement were as follows.
1H NMR (400MHz, CDCl 3 ) δ = 5.30 (1H), 5.05 (1H), 3.39-3.27 (m, 5H), 2.01-1.90 (m, 2H) , 1.89-1.78 (m, 1H), 1.65-1.06 (m, 12H).
13C NMR (101MHz, CDCl3 ) δ=134.52, 130.47, 73.12, 58.48, 42.74, 35.59, 32.62, 31.84, 29.73, 29.32 , 27.46, 27.08.
（４）水素添加３－（３－メトキシプロピル）－１－シクロオクテン重合体の製造
冷却塔を接続した三口フラスコに上記で得られた３－（３－メトキシプロピル）－シクロオクテン重合体４．００ｇ（モノマーユニット換算で２１．７ｍｍｏｌに相当）、ｏ－キシレン９０ｍＬ、ｐ－トルエンスルホニルヒドラジド２０．５ｇ（１１０ｍｍｏｌ）、トリブチルアミン２１．３ｇ（１１５ｍｍｏｌ）、ジブチルヒドロキシトルエン５ｍｇを加え、１００℃で３時間加熱攪拌した。１Ｈ ＮＭＲで二重結合のシグナルの消失を確認した後、加熱を止め反応を停止させた。反応溶液を室温まで冷却し、ＴＨＦ／ＭｅＯＨ系での沈殿精製を３回と水精製を行った。上澄みの水を取り除き、少量のＴＨＦで沈殿物を回収した後、エバポレータでＴＨＦを留去し、真空オーブンを用いて１２時間室温で乾燥することで無色粘稠体の目的物を収量３．９６ｇ（２１．５ｍｍｏｌ）、収率９９％で得た。ＧＰＣを用いて分子量を測定した結果、Ｍｎは９６ｋｇ／ｍｏｌ、Ｍｗ／Ｍｎは１．９であった。ＮＭＲ測定によって検出されたシグナルは以下の通りであった。
１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ＝３．３８－３．３０（ｍ，５Ｈ），１．５８－１．４７（ｍ，２Ｈ），１．３３－１．１４（ｍ，１７Ｈ）．
１３Ｃ ＮＭＲ（１０１ＭＨｚ，ＣＤＣｌ３）δ＝７３．６１，５８．６５，３７．４８，３３．８２，３０．３６，３０．０６，２９．９３，２６．９６，２６．８８．
ここで、得られた水素添加３－（３－メトキシプロピル）－１－シクロオクテン重合体について、実施例１と同様に、含水させたポリマーについて発熱ピークを測定したところ、－４０℃での発熱ピークは非常に小さかった。
(4) Production of hydrogenated 3-(3-methoxypropyl)-1-cyclooctene polymer The 3-(3-methoxypropyl)-cyclooctene polymer obtained above was placed in a three-necked flask connected to a cooling tower. 00 g (equivalent to 21.7 mmol in terms of monomer unit), 90 mL of o-xylene, 20.5 g (110 mmol) of p-toluenesulfonyl hydrazide, 21.3 g (115 mmol) of tributylamine, and 5 mg of dibutylhydroxytoluene were added, and the mixture was heated at 100°C. The mixture was heated and stirred for hours. After confirming the disappearance of the double bond signal by 1 H NMR, heating was stopped to terminate the reaction. The reaction solution was cooled to room temperature, and subjected to precipitation purification using a THF/MeOH system three times and water purification. After removing the supernatant water and collecting the precipitate with a small amount of THF, the THF was distilled off using an evaporator and dried at room temperature for 12 hours using a vacuum oven, yielding 3.96 g of the target product as a colorless viscous substance. (21.5 mmol) with a yield of 99%. As a result of measuring the molecular weight using GPC, M n was 96 kg/mol and M w /M n was 1.9. The signals detected by NMR measurement were as follows.
1 H NMR (400 MHz, CDCl 3 ) δ=3.38-3.30 (m, 5H), 1.58-1.47 (m, 2H), 1.33-1.14 (m, 17H).
13C NMR (101 MHz, CDCl3 ) δ=73.61, 58.65, 37.48, 33.82, 30.36, 30.06, 29.93, 26.96, 26.88.
Here, for the obtained hydrogenated 3-(3-methoxypropyl)-1-cyclooctene polymer, the exothermic peak of the hydrated polymer was measured in the same manner as in Example 1. The peak was very small.
（血小板粘着試験）
（１）試験用基板の調製
実施例１および比較例２で得られた水素添加ポリマーをそれぞれメタノール１０ｍＬに対して０．０２ｇになるように投入して全量を溶解させた。得られた溶液を用いて比較例１のＰＥＴ（ポリエチレンテレフタレート）板上にスピンコートし、コート被膜を形成させた。得られたコート基板から８ｍｍ角に切り出したものを走査型電子顕微鏡（ＳＥＭ）用試料台に固定した。それらの材料表面にリン酸緩衝生理食塩水（ｐｈｏｓｐｈａｔｅ ｂｕｆｆｅｒｅｄ ｓａｌｉｎｅ：ＰＢＳ）２００μＬを接触させ、３７℃、1時間インキュベートした。
(Platelet adhesion test)
(1) Preparation of test substrate The hydrogenated polymers obtained in Example 1 and Comparative Example 2 were each added in an amount of 0.02 g per 10 mL of methanol, and the entire amount was dissolved. The obtained solution was spin-coated on the PET (polyethylene terephthalate) plate of Comparative Example 1 to form a coating film. An 8 mm square piece was cut out from the obtained coated substrate and fixed on a sample stage for a scanning electron microscope (SEM). The surfaces of these materials were brought into contact with 200 μL of phosphate buffered saline (PBS) and incubated at 37° C. for 1 hour.
（２）血小板懸濁液の調製
クエン酸ナトリウムで抗凝固したヒト新鮮血液を１５００ｒｐｍで５分間遠心分離し、上澄みを多血小板血漿（ｐｌａｔｅｌｅｔ ｒｉｃｈ ｐｌａｓｍａ：ＰＲＰ）として回収した。残りの血液をさらに４０００ｒｐｍで１０分間遠心分離した上澄みを乏血小板血漿（ｐｌａｔｅｌｅｔ ｐｏｏｒ ｐｌａｓｍａ：ＰＰＰ）として回収した。回収したＰＲＰをＰＢＳを用いて８００倍に希釈したのち、血球計算板を用いてＰＲＰ中の血小板濃度の確認を行った。血小板濃度が既知の上記ＰＲＰを、回収したＰＰＰを用いて希釈し、血小板濃度が４×１０７ｃｅｌｌｓ／ｍＬの血小板懸濁液を調製した。
(2) Preparation of platelet suspension Fresh human blood anticoagulated with sodium citrate was centrifuged at 1500 rpm for 5 minutes, and the supernatant was collected as platelet rich plasma (PRP). The remaining blood was further centrifuged at 4000 rpm for 10 minutes, and the supernatant was collected as platelet poor plasma (PPP). After diluting the recovered PRP 800 times with PBS, the platelet concentration in the PRP was confirmed using a hemocytometer. The PRP whose platelet concentration was known was diluted with the collected PPP to prepare a platelet suspension having a platelet concentration of 4×10 7 cells/mL.
（３）血小板粘着試験
この血小板懸濁液を各試料上に２００μＬ滴下し、３７℃にて１時間インキュベートした。その後、各試料をＰＢＳにて２回洗浄した後、１質量％のグルタルアルデヒド溶液に浸漬し、３７℃にて２時間固定した。固定化した試料はＰＢＳに１０分間、ＰＢＳ：水＝１：１の混合液に８分間、水に８分間、さらに別に用意した水にもう一度８分間浸漬させて洗浄し、室温で風乾した。コーティングをしていないＰＥＴ基板（比較例１）についても同様の処理により血小板を粘着した。粘着した血小板を電子顕微鏡で観察し、単位面積あたりの血小板数を測定して、ＰＥＴ基板への粘着数に対する各試験サンプルの粘着数の比〔試験サンプルの粘着数／ＰＥＴ基板の粘着数〕を算出し、血小板の粘着性を評価した。結果を表１に示す。
(3) Platelet adhesion test 200 μL of this platelet suspension was dropped onto each sample and incubated at 37° C. for 1 hour. Thereafter, each sample was washed twice with PBS, then immersed in a 1% by mass glutaraldehyde solution and fixed at 37°C for 2 hours. The fixed sample was washed by immersing it in PBS for 10 minutes, in a mixture of PBS:water = 1:1 for 8 minutes, in water for 8 minutes, and again in separately prepared water for 8 minutes, and air-dried at room temperature. Platelets were attached to an uncoated PET substrate (Comparative Example 1) in the same manner. Observe the adhered platelets with an electron microscope, measure the number of platelets per unit area, and calculate the ratio of the number of adhesion of each test sample to the number of adhesion to the PET substrate [number of adhesion of test sample / number of adhesion of PET substrate]. was calculated to evaluate the stickiness of platelets. The results are shown in Table 1.
表１に示すように、比較例１及び２と比べ、実施例１で得られた水素添加ポリマーは、血小板の粘着を著しく抑制していることが分かった。
As shown in Table 1, compared with Comparative Examples 1 and 2, it was found that the hydrogenated polymer obtained in Example 1 significantly suppressed the adhesion of platelets.
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