CN106397669B - The alpha-cyanoacrylate ester material of fluorescence can be generated - Google Patents
The alpha-cyanoacrylate ester material of fluorescence can be generated Download PDFInfo
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- CN106397669B CN106397669B CN201610789001.8A CN201610789001A CN106397669B CN 106397669 B CN106397669 B CN 106397669B CN 201610789001 A CN201610789001 A CN 201610789001A CN 106397669 B CN106397669 B CN 106397669B
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- alkylene
- polymer
- alkynylene
- alkenylene
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- -1 alpha-cyanoacrylate ester Chemical class 0.000 title claims abstract description 112
- 239000000463 material Substances 0.000 title claims abstract description 18
- 229920000642 polymer Polymers 0.000 claims abstract description 112
- 229920001651 Cyanoacrylate Polymers 0.000 claims abstract description 52
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 41
- 230000001070 adhesive effect Effects 0.000 claims abstract description 30
- 239000000853 adhesive Substances 0.000 claims abstract description 28
- 239000000178 monomer Substances 0.000 claims abstract description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 40
- 229920001223 polyethylene glycol Polymers 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000007850 fluorescent dye Substances 0.000 claims description 19
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229940125782 compound 2 Drugs 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 229950010048 enbucrilate Drugs 0.000 claims description 11
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 10
- ACNUVXZPCIABEX-UHFFFAOYSA-N 3',6'-diaminospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(N)C=C1OC1=CC(N)=CC=C21 ACNUVXZPCIABEX-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- 125000005577 anthracene group Chemical group 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 4
- JJJFUHOGVZWXNQ-UHFFFAOYSA-N enbucrilate Chemical compound CCCCOC(=O)C(=C)C#N JJJFUHOGVZWXNQ-UHFFFAOYSA-N 0.000 claims description 4
- FGBJXOREULPLGL-UHFFFAOYSA-N ethyl cyanoacrylate Chemical compound CCOC(=O)C(=C)C#N FGBJXOREULPLGL-UHFFFAOYSA-N 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 4
- 239000004614 Process Aid Substances 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000004744 fabric Substances 0.000 claims description 3
- 239000006260 foam Substances 0.000 claims description 3
- PGIKFFJPONMRNO-UHFFFAOYSA-N 6-methylheptan-2-yl 2-cyanoprop-2-enoate Chemical compound C(#N)C(C(=O)OC(C)CCCC(C)C)=C PGIKFFJPONMRNO-UHFFFAOYSA-N 0.000 claims description 2
- 229940053009 ethyl cyanoacrylate Drugs 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- RPQUGMLCZLGZTG-UHFFFAOYSA-N octyl cyanoacrylate Chemical compound CCCCCCCCOC(=O)C(=C)C#N RPQUGMLCZLGZTG-UHFFFAOYSA-N 0.000 claims description 2
- 230000000379 polymerizing effect Effects 0.000 claims description 2
- ZTYMNUBYYQNBFP-UHFFFAOYSA-N propyl 2-cyanoprop-2-enoate Chemical compound CCCOC(=O)C(=C)C#N ZTYMNUBYYQNBFP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 40
- 125000000732 arylene group Chemical group 0.000 claims 40
- 125000004419 alkynylene group Chemical group 0.000 claims 23
- 125000002993 cycloalkylene group Chemical group 0.000 claims 23
- 125000004450 alkenylene group Chemical group 0.000 claims 16
- 125000005275 alkylenearyl group Chemical group 0.000 claims 16
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims 8
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 4
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 claims 3
- CZWUESRDTYLNDE-UHFFFAOYSA-N (2z)-2-[(2e,4e,6e)-7-[1-(5-carboxypentyl)-3,3-dimethyl-5-sulfoindol-1-ium-2-yl]hepta-2,4,6-trienylidene]-1-ethyl-3,3-dimethylindole-5-sulfonate Chemical compound CC1(C)C2=CC(S([O-])(=O)=O)=CC=C2N(CC)\C1=C/C=C/C=C/C=C/C1=[N+](CCCCCC(O)=O)C2=CC=C(S(O)(=O)=O)C=C2C1(C)C CZWUESRDTYLNDE-UHFFFAOYSA-N 0.000 claims 2
- 150000007513 acids Chemical class 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 description 40
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 8
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 229920001577 copolymer Polymers 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 5
- 238000011503 in vivo imaging Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 238000001215 fluorescent labelling Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)C(C)(CC(O*N*)=O)*(C)C Chemical compound CC(C)C(C)(CC(O*N*)=O)*(C)C 0.000 description 3
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 description 2
- DPEOTCPCYHSVTC-UHFFFAOYSA-N 2-aminohexan-1-ol Chemical compound CCCCC(N)CO DPEOTCPCYHSVTC-UHFFFAOYSA-N 0.000 description 2
- IJVRPNIWWODHHA-UHFFFAOYSA-N 2-cyanoprop-2-enoic acid Chemical compound OC(=O)C(=C)C#N IJVRPNIWWODHHA-UHFFFAOYSA-N 0.000 description 2
- SUTWPJHCRAITLU-UHFFFAOYSA-N 6-aminohexan-1-ol Chemical compound NCCCCCCO SUTWPJHCRAITLU-UHFFFAOYSA-N 0.000 description 2
- BZTDTCNHAFUJOG-UHFFFAOYSA-N 6-carboxyfluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(C(=O)O)C=C21 BZTDTCNHAFUJOG-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- STWMCWQBGPDSCY-UHFFFAOYSA-N anthracene;2-cyanoprop-2-enoic acid Chemical compound OC(=O)C(=C)C#N.C1=CC=CC2=CC3=CC=CC=C3C=C21 STWMCWQBGPDSCY-UHFFFAOYSA-N 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 125000006364 carbonyl oxy methylene group Chemical group [H]C([H])([*:2])OC([*:1])=O 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 239000003063 flame retardant Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000004937 luminal membrane Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000012745 toughening agent Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- RNFJDJUURJAICM-UHFFFAOYSA-N 2,2,4,4,6,6-hexaphenoxy-1,3,5-triaza-2$l^{5},4$l^{5},6$l^{5}-triphosphacyclohexa-1,3,5-triene Chemical compound N=1P(OC=2C=CC=CC=2)(OC=2C=CC=CC=2)=NP(OC=2C=CC=CC=2)(OC=2C=CC=CC=2)=NP=1(OC=1C=CC=CC=1)OC1=CC=CC=C1 RNFJDJUURJAICM-UHFFFAOYSA-N 0.000 description 1
- KGJYXDQXRQOEML-UHFFFAOYSA-N 3-anthracen-1-yl-2-cyanoprop-2-enoic acid Chemical compound C1=CC=C2C=C3C(C=C(C(=O)O)C#N)=CC=CC3=CC2=C1 KGJYXDQXRQOEML-UHFFFAOYSA-N 0.000 description 1
- COCMHKNAGZHBDZ-UHFFFAOYSA-N 4-carboxy-3-[3-(dimethylamino)-6-dimethylazaniumylidenexanthen-9-yl]benzoate Chemical compound C=12C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C2C=1C1=CC(C([O-])=O)=CC=C1C(O)=O COCMHKNAGZHBDZ-UHFFFAOYSA-N 0.000 description 1
- YMZMTOFQCVHHFB-UHFFFAOYSA-N 5-carboxytetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=C(C(O)=O)C=C1C([O-])=O YMZMTOFQCVHHFB-UHFFFAOYSA-N 0.000 description 1
- 239000004970 Chain extender Substances 0.000 description 1
- DJXIADRXORLNJX-UHFFFAOYSA-N Nc(cc1)cc(O2)c1C=C(C=C1)C2=CC1=N Chemical compound Nc(cc1)cc(O2)c1C=C(C=C1)C2=CC1=N DJXIADRXORLNJX-UHFFFAOYSA-N 0.000 description 1
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- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
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- 239000000945 filler Substances 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
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- 229960002317 succinimide Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000013008 thixotropic agent Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F222/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof
- C08F222/30—Nitriles
- C08F222/32—Alpha-cyano-acrylic acid; Esters thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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Abstract
The present invention relates to a kind of alpha-cyanoacrylate ester materials that can generate fluorescence, and in particular to a method of the cyanoacrylate polymer with fluorophor is prepared, the method is carried out according to route as follows:
Description
Technical Field
The invention relates to the field of biomedicine and materials, in particular to a method for preparing cyanoacrylate polymers with fluorescent groups, compounds and polymers related to the method, adhesives containing the compounds or the polymers, dressings containing the compounds, the polymers or the adhesives, and application of the compounds or the polymers in preparation of cyanoacrylate polymers with fluorescent groups.
Background
Cyanoacrylate compounds were first synthesized by german scientists in 1949. The compound is colorless transparent liquid at room temperature, and can be used in nucleophilic reagent (such as NH)2 -、OH-) Cyanoacrylate compounds show good adhesive capacity to materials such as plastics, ceramics, wood, glass and the like, and human or animal tissues such as skin, blood vessels, muscles, mucous membranes and the like, for example, the main component of 502 glue which is common in daily life is α -ethyl cyanoacrylate.
Due to the colorless and transparent nature of cyanoacrylate polymers, such materials can be difficult to observe and identify with the naked eye after use. Furthermore, while the FDA currently only approved the use of such materials on the body surface, studies have involved the use of cyanoacrylate materials in animals, where it is difficult to directly observe the condition of the material after use by the naked eye. For example, when cyanoacrylate material is applied to the adhesion of intestinal tissues of animals, the abdominal cavity of a tested animal needs to be opened after a surgery, otherwise, the adhesion effect of the material on the tissues and whether the material falls off or is displaced cannot be effectively observed. Thus, in medical applications and research, there is a need for cyanoacrylate materials that produce fluorescence to facilitate viewing of the materials by a user.
Disclosure of Invention
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. Also, the laboratory procedures referred to herein are all conventional procedures widely used in the corresponding field. Meanwhile, in order to better understand the present invention, the definitions and explanations of related terms are provided below.
As used herein, the term "fluorescent compound" refers to a substance capable of absorbing ultraviolet light and emitting visible light, or a substance capable of absorbing visible light of a shorter wavelength and emitting visible light of a longer wavelength, such as FITC (fluorescein isothiocyanate), FAM (carboxyfluorescein), Cy2, Cy3, Cy5, Cy7, TAMRA, and Rhodamin (rhodamine). The term "fluorophore" refers to a chromophore in a fluorescent compound, i.e., a group that is capable of generating fluorescence. In the context of the present invention, the fluorescent compounds carry groups which can react with amino groups, for example — N ═ C ═ S, -COOH, alkyl ester groups and/or succinimide ester groups.
As used herein, compounds FITC (fluorescein isothiocyanate), FAM (carboxyfluorescein), Cy2, Cy3, Cy5 and Cy7 respectively have the structures shown below (X in the structural formula is halogen):
as used herein, the compounds TAMRA (carboxytetramethylrhodamine) include 5-TAMRA and 6-TAMRA, both having the structures shown below, respectively:
as used herein, the compound Rhodamin (rhodamine) includes Rhodamin6G, Rhodamin b, and Rhodamin123, each of which has the structure shown below:
as used herein, the term "adjuvant" refers to an auxiliary raw material during the production and/or use of an adhesive. Adhesive aids include, but are not limited to: synthesis aids, reactive aids, functional aids, process aids and stabilizing aids.
As used herein, the term "synthesis aid" mainly includes emulsifiers, initiators, polymerization inhibitors, catalysts, solvents, oxidants, dispersants, chain extenders, regulators, neutralizers, terminators, and the like, which are used during the synthesis and/or formulation of the adhesive.
As used herein, the term "reactive auxiliary agent" refers to a compound having a reactive group, which is capable of reacting with the matrix polymer in the adhesive to form a network or cross-linked structure, and mainly includes a toughening agent, a curing agent, a cross-linking agent, a photoinitiator, an accelerator, a reactive flame retardant, and the like.
As used herein, the term "functional adjuvant" also referred to as "modification adjuvant" refers to an adjuvant capable of improving the original performance of an adhesive or imparting a new function thereto, and mainly includes plasticizers, coupling agents, tackifiers, foaming agents, colorants, reinforcing agents, fillers, flame retardants, softeners, antistatic agents, odor-masking agents, toughening agents, accelerators, chelating agents, and the like.
As used herein, the term "process aid" refers to an aid used for the convenience of formulation and use of the adhesive and to ensure its intended properties, and mainly includes thickeners, defoamers, antifreeze, antiblocking agents, diluents, thixotropic agents, scorch retarders, and the like.
As used herein, the term "stabilizing additive" refers to an additive capable of preventing aging and deterioration of an adhesive during synthetic preparation, storage and transportation, and use, prolonging the service life, and/or improving the storage stability, and mainly includes an antioxidant, a heat stabilizer, a light stabilizer, a bactericide, a preservative, a metal ion deactivator, and the like.
As used herein, the term "dressing" refers to a material used in medical treatment to wrap or cover sores, wounds, and other lesions. The dressing may comprise a substrate such as paper, fabric, nonwoven, film material, gel and/or foam, for example, an adhesive comprising a compound or polymer of the invention may be coated onto the substrate to form the dressing; alternatively, the dressing may not comprise a substrate.
As used herein, the term "room temperature" refers to 25 ℃ ± 5 ℃.
As used herein, the term "weak acid" refers to an acid having an ionization constant of less than 0.0001, including but not limited to acetic acid.
The present inventors have obtained a method for preparing a cyanoacrylate polymer capable of generating fluorescence by ingenious conception and inventive work, thereby providing the following inventions:
in one aspect, the present application provides a method for preparing a cyanoacrylate polymer with a fluorescent group, the method following the route shown below:
wherein R is1Is a hydrogen atom or C1-10Alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-octyl, or 2-isooctyl);
R2is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl 6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
z is a protecting group for an amino group, such as benzyloxycarbonyl (-Cbz), t-butoxycarbonyl (-Boc), fluorenylmethyloxycarbonyl (-Fmoc), allyloxycarbonyl (-Alloc), trimethylsiloxyetharbonyl (-Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (-Pht), p-toluenesulfonyl (-Tos), trifluoroacetyl (-Tfa), trityl (-Trt), 2, 4-dimethoxybenzyl (-Dmb), p-methoxybenzyl (-PMB), benzyl (-Bn) or 4, 4' -dimethoxytrityl (-DMT);
R3is a hydrogen atom, C1-10Alkyl (e.g. methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl) or cyanoacrylate C1-10An alkyl group;
n is an integer greater than or equal to 2, such as 2 to 1000, 2 to 10000, or 2 to 100000;
m is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), p is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), and the sum of m and p is greater than or equal to 2 (e.g., 2-1000, 2-10000, or 2-100000).
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (-Fmoc) or 4, 4' -dimethoxytrityl (-DMT).
The method comprises the following steps:
step 1: reacting compound 1 with compound Z-NH-R2-OH reaction to giveA compound 2;
step 2: removing the anthracene protecting group on the compound 2 to obtain a monomer 1;
and step 3: polymerizing the monomer 1 to obtain a polymer 1; or copolymerizing a monomer 1 and a monomer 2 to obtain a polymer 1', wherein the monomer 2 is cyanoacrylate or cyanoacrylate C1-10Alkyl esters (e.g., methyl cyanoacrylate, ethyl cyanoacrylate, n-propyl cyanoacrylate, n-butyl cyanoacrylate, n-octyl cyanoacrylate, or 2-isooctyl cyanoacrylate);
and 4, step 4: removing the Z group on the polymer 1 to obtain a polymer 2; or removing the Z group on the polymer 1 'to obtain a polymer 2';
and 5: reacting the polymer 2 with a fluorescent compound to obtain a polymer 3, or reacting the polymer 2 'with a fluorescent compound to obtain a polymer 3'; preferably, the fluorescent compound is selected from one or more of FITC, FAM, TAMRA, Rhodamin, Cy2, Cy3, Cy5 and Cy 7.
In a preferred embodiment, the reaction of step 1 is carried out in the presence of 4-Dimethylaminopyridine (DMAP) and N, N-Diisopropylcarbodiimide (DIC).
In a preferred embodiment, the reaction of step 1 is carried out at room temperature.
In a preferred embodiment, the step 1 further comprises: isolating and/or purifying compound 2.
In a preferred embodiment, the reaction of step 2 is carried out in the presence of maleic anhydride.
In a preferred embodiment, said step 2 comprises: the compound 2 and maleic anhydride are stirred at room temperature, and then stirred at 40-60 ℃.
In a preferred embodiment, said step 2 comprises: the compound 2 and maleic anhydride are stirred at room temperature for 3-7 hours, and then stirred at 40-60 ℃ for 1-5 hours.
In a preferred embodiment, the reaction of step 2 is carried out in a solvent (e.g., xylene).
In a preferred embodiment, said step 2 comprises: after the reaction, the solvent was removed by distillation under reduced pressure.
In a preferred embodiment, the reaction of step 3 is carried out in the presence of liquid water or water vapor.
In a preferred embodiment, the reaction of step 4 is carried out in an aqueous solution of a weak acid (e.g., acetic acid).
In a preferred embodiment, said step 5 comprises stirring polymer 2 with the fluorescent compound at room temperature, or stirring polymer 2' with the fluorescent compound at room temperature.
In a preferred embodiment, in step 5, the fluorescent compound is present in a fluorescent labeling kit, and step 5 is performed according to the instructions of the fluorescent labeling kit.
In certain embodiments, the fluorescent labeling kit comprises other reagents (e.g., buffer solutions) in addition to the fluorescent compound.
In one aspect, the present application provides compounds having a structure as shown in formula (I):
wherein R is2Is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
z is a protecting group for an amino group, such as benzyloxycarbonyl (-Cbz), t-butoxycarbonyl (-Boc), fluorenylmethyloxycarbonyl (-Fmoc), allyloxycarbonyl (-Alloc), trimethylsiloxyetharbonyl (-Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (-Pht), p-toluenesulfonyl (-Tos), trifluoroacetyl (-Tfa), trityl (-Trt), 2, 4-dimethoxybenzyl (-Dmb), p-methoxybenzyl (-PMB), benzyl (-Bn) or 4, 4' -dimethoxytrityl (-DMT).
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (-Fmoc) or 4, 4' -dimethoxytrityl (-DMT).
In one aspect, the present application provides a polymer having a structure as shown in formula (II):
wherein R is2Is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
z is a protecting group for an amino group, such as benzyloxycarbonyl (-Cbz), t-butoxycarbonyl (-Boc), fluorenylmethyloxycarbonyl (-Fmoc), allyloxycarbonyl (-Alloc), trimethylsiloxyetharbonyl (-Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (-Pht), p-toluenesulfonyl (-Tos), trifluoroacetyl (-Tfa), trityl (-Trt), 2, 4-dimethoxybenzyl (-Dmb), p-methoxybenzyl (-PMB), benzyl (-Bn) or 4, 4' -dimethoxytrityl (-DMT);
n is an integer greater than or equal to 2 (e.g., 2-1000, 2-10000, or 2-100000).
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (-Fmoc) or 4, 4' -dimethoxytrityl (-DMT).
In one aspect, the present application provides a polymer having a structure as shown in formula (III):
wherein R is2Is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
n is an integer greater than or equal to 2, for example from 2 to 1000, from 2 to 10000 or from 2 to 100000.
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In one aspect, the present application provides a polymer having a structure as shown in formula (II'):
wherein R is2Is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
z is a protecting group for an amino group, such as benzyloxycarbonyl (-Cbz), t-butoxycarbonyl (-Boc), fluorenylmethyloxycarbonyl (-Fmoc), allyloxycarbonyl (-Alloc), trimethylsiloxyetharbonyl (-Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (-Pht), p-toluenesulfonyl (-Tos), trifluoroacetyl (-Tfa), trityl (-Trt), 2, 4-dimethoxybenzyl (-Dmb), p-methoxybenzyl (-PMB), benzyl (-Bn) or 4, 4' -dimethoxytrityl (-DMT);
R3is a hydrogen atom, C1-10Alkyl (e.g. methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl) or cyanoacrylate C1-10An alkyl group;
m is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), p is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), and the sum of m and p is greater than or equal to 2 (e.g., 2-1000, 2-10000, or 2-100000).
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In a preferred embodiment, Z is fluorenylmethyloxycarbonyl (-Fmoc) or 4, 4' -dimethoxytrityl (-DMT).
In one aspect, the present application provides a polymer having a structure as shown in formula (III'):
wherein,R2is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
R3is a hydrogen atom, C1-10Alkyl (e.g. methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl) or cyanoacrylate C1-10An alkyl group;
m is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), p is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), and the sum of m and p is greater than or equal to 2 (e.g., 2-1000, 2-10000, or 2-100000).
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In one aspect, the present application provides an adhesive comprising a compound or polymer of the present invention.
In a preferred embodiment, the adhesive also contains auxiliaries, such as synthesis auxiliaries, reactive auxiliaries, functional auxiliaries, process auxiliaries and/or stabilizing auxiliaries.
In one aspect, the present application provides a dressing comprising a compound, polymer or adhesive of the present invention.
In a preferred embodiment, the dressing further comprises a substrate.
In a preferred embodiment, the compound, polymer or adhesive of the present invention is coated on a substrate in the dressing.
In a preferred embodiment, the substrate is selected from the group consisting of paper, fabric, nonwoven, film material, gel, and foam.
The dressing provided by the application can generate an adhesive effect on the used part through the compound, the polymer or the adhesive, so that the relative stability of the position of the dressing is kept; alternatively, the present invention provides dressings that contain other substances that produce adhesive action, either with the aid of an adhesive-acting article (e.g., tape), or with other securing articles and means (e.g., bandaging) to maintain the relative stability of the position of the dressing.
In one aspect, the present application provides the use of a compound or polymer of the present invention for the preparation of a fluorescent cyanoacrylate polymer having the structure of formula (IV):
wherein R is2Is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g. of5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or a polyethylene glycol segment (e.g., a polyethylene glycol segment having a number average molecular mass of 100-;
n is an integer greater than or equal to 2 (e.g., 2-1000, 2-10000, or 2-100000);
in a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In a preferred embodiment, the fluorophore is a chromophore selected from one or more of FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and Rhodamin.
In one aspect, the present application provides the use of a compound or polymer of the present invention for the preparation of a fluorescent cyanoacrylate polymer having the structure of formula (IV'):
wherein R is2Is C1-30Alkyl (e.g. C)1-6Alkyl radical, C1-10Alkyl radical, C10-20Alkyl or C20-30Alkyl), optionally, said C1-30The alkyl is substituted by one or more of acyloxy, haloalkyl, alkoxy, a halogen atom and cyano; c1-30Alkenyl (e.g. C)1-6Alkenyl radical, C1-10Alkenyl radical, C10-20Alkenyl or C20-30Alkenyl); c1-30Alkynyl (e.g. C)1-6Alkynyl, C1-10Alkynyl, C10-20Alkynyl or C20-30Alkynyl groups); cycloalkyl (e.g., 5-10 membered cycloalkyl); aralkyl (e.g. 6-14 membered aryl-C)1-10Alkyl groups); alkylaryl (e.g. C)1-10Alkyl-6-14 membered aryl); aryl (e.g., 6-14 membered aryl); or polyEthylene glycol segments (e.g., polyethylene glycol segments having a number average molecular mass of 100-;
R3is a hydrogen atom, C1-10Alkyl (e.g. methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl) or cyanoacrylate C1-10An alkyl group;
m is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), p is an integer greater than or equal to 1 (e.g., 1-1000, 1-10000, or 1-100000), and the sum of m and p is greater than or equal to 2 (e.g., 2-1000, 2-10000, or 2-100000).
In a preferred embodiment, R2Is C1-6Alkyl radicals, such as the n-butyl, n-octyl, n-hexyl, isobutyl, isooctyl or isohexyl radical.
In a preferred embodiment, the fluorophore is a chromophore selected from one or more of FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and Rhodamin.
In one aspect, the present invention provides a process for preparing a compound having a structure as shown in formula (I), the process being carried out according to the route shown below:
wherein R is1Is a hydrogen atom or C1-10Alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-octyl, or 2-isooctyl);
R2and Z is as defined for formula (I);
the method comprises the following steps:
step 1: reacting compound 1 with compound Z-NH-R2-OH reaction to give compound 2; and
step 2: and (3) removing the anthracene protecting group on the compound 2 to obtain the compound with the structure shown in the formula (I).
In a preferred embodiment, the reaction of step 1 is carried out in the presence of 4-Dimethylaminopyridine (DMAP) and N, N-Diisopropylcarbodiimide (DIC).
In a preferred embodiment, the reaction of step 1 is carried out at room temperature.
In a preferred embodiment, the step 1 further comprises: isolating and/or purifying compound 2.
In a preferred embodiment, the reaction of step 2 is carried out in the presence of maleic anhydride.
In a preferred embodiment, said step 2 comprises: the compound 2 and maleic anhydride are stirred at room temperature, and then stirred at 40-60 ℃.
In a preferred embodiment, said step 2 comprises: the compound 2 and maleic anhydride are stirred at room temperature for 3-7 hours, and then stirred at 40-60 ℃ for 1-5 hours.
In a preferred embodiment, the reaction of step 2 is carried out in a solvent (e.g., xylene).
In a preferred embodiment, said step 2 comprises: after the reaction, the solvent was removed by distillation under reduced pressure.
Advantageous effects
The invention provides a preparation method of cyanoacrylate polymer capable of generating fluorescence. The cyanoacrylate polymer prepared by the method can be used as an adhesive or a dressing, and fluorescence generated by the polymer can effectively play a role in auxiliary observation in vision. For example, after the adhesive or dressing containing the polymer is applied to an internal body part, the falling, degradation, retention and the like of the adhesive or dressing can be conveniently monitored and observed by means of fluorescence in vivo imaging. The polymer is prepared into nano microspheres, and the metabolic condition of the nano microspheres after entering the animal body can be observed and detected by an intuitive fluorescence imaging method.
The preparation method of the invention has the advantages of less operation related to purification and separation of small molecules, less raw material loss, and deprotection (step 4) and fluorescence labeling (step 5) after the polymer is obtained in step 3. In step 4 and step 5, after the polymer is reacted, unreacted reagents can be removed by a simple operation such as washing or centrifugation of the polymer. The method of the invention is simple and flexible in operation, and a user can select a fluorescent compound capable of reacting with amino for marking according to actual requirements after obtaining the cyanoacrylate polymer with amino.
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and are not intended to limit the scope of the present invention. Various objects and advantageous aspects of the present invention will become apparent to those skilled in the art from the following detailed description of the preferred embodiments.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to the drawings and examples, but those skilled in the art will understand that the following drawings and examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. Those not indicated in the drawings and examples were carried out under the conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. The anhydrous solvents used are all commercially available.
Drawings
FIG. 1 shows the results of fluorescence in vivo imaging of mice in example 4, in which blocks labeled with FITC were embedded in the mice. FIGS. 1A-C show the imaging results on the day of embedment, 7 days later and 14 days later, respectively. As shown in the figure, significant fluorescence was observed at the embedded portion of the gel block (as indicated by the arrow in the figure), and no significant interference was observed at other portions of the mouse. After 14 days of embedment, fluorescence was still detected at the embedment site.
FIG. 2 shows the results of fluorescence live body imaging of mice on the day of embedding in mice in which the gel masses labeled with Cy2 were embedded in the mice in example 5. As shown in the figure, significant fluorescence was observed at the embedded portion of the gel block (as indicated by the arrow in the figure), and no significant interference was observed at other portions of the mouse.
Preparation example 1 Synthesis of Anthracene cyano acrylic acid
Referring to the method of patent US4012402, α -ethyl cyanoacrylate is subjected to addition reaction with anthracene to obtain ethyl anthracenylcyanoacrylate, which is then hydrolyzed in an alkaline solution to obtain anthracenylcyanoacrylate.
Preparation example 2.4, 4' -Dimethoxytrityl-aminohexanol (DMT-aminohexanol) Synthesis
Placing 6-aminohexanol (5g,0.043mol) in a 250mL three-necked flask, adding 50mL pyridine, stirring to dissolve, dropwise adding trimethylchlorosilane (13.9g,0.128mol) under ice bath conditions, reacting for 4h, adding 4, 4' -dimethoxytrityl chloride (DMT-Cl,17.3g,0.051mol), and reacting for 12h at room temperature; distilling under reduced pressure to remove pyridine, adjusting pH of the reaction solution to neutrality, extracting, and dissolving the organic phase with 100mL saturated NaHCO3The solution was washed 2 times with 100mL of saturated NaCl solution and then with anhydrous Na2SO4Dry overnight. The product was purified and separated by column chromatography using a petroleum ether-ethyl acetate mixture (volume ratio 4:1) as eluent, and the solvent was removed under reduced pressure to give 9.71g of a pale yellow viscous liquid, i.e., 4' -dimethoxytrityl-aminohexanol (DMT-aminohexanol), with a yield of 53.9%.
1H NMR(CDCl3,400MHz),δ:1.25～1.62[m,8H,(CH2)4],2.72(d,2H,CH2CH2NH),3.80(s,6H,Ph-OCH3),4.22(s,1H,CH2OH),6.83～7.48(m,13H,Ph-H),8.29(s,1H,CH2NH).MS,m/z:420[M-H+].
Preparation example 3 Synthesis of Fmoc-aminohexanol
2.65g of Na2CO3Dissolved in 25ml H22.9g of 6-aminohexanol and 25ml of dioxane were added into O, the mixture was cooled in an ice bath, and then Fmoc-Cl/dioxane (6.5g/25ml) solution was slowly added dropwise, and after completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Drying dioxane, dissolving in dichloromethane, washing with 10% citric acid and saturated NaCl, mixing organic phases, and adding anhydrous Na2SO4Dry overnight. The next day, it was recrystallized from methylene chloride/petroleum ether to give 5.9g of white crystals, i.e., fluorenylmethoxycarbonyl-aminohexanol, in a yield of 72.5%.
1H NMR(CDCl3,400MHz),δ:1.29～1.53[m,9H,(CH2)4],3.2(t,2H,CH2NH),3.51(t,2H,CH2OH),3.89(s,1H,CH2OH),4.5[t,1H,CH2CH(Ph)2],4.73(d,2H,OCH2CH),7.23～7.78(m,8H,Ph-H)，8.02(s,1H,CH2NHCOO).MS,m/z:340[M-H+].
EXAMPLE 1 preparation of a copolymer of Cyanoacrylic acid (FITC-aminohexanol) ester-n-butyl Cyanoacrylate
The following scheme and procedure was followed to prepare cyanoacrylate (FITC-aminohexanol) ester-n-butyl cyanoacrylate copolymer.
Step 1: anthracene cyanoacrylic acid (12.7g,0.046mol) was added to 50mL of dichloromethane, DMAP (0.56g,4.60mmol) and DIC (5.8g,0.046mol) were sequentially added, stirred at room temperature until completely dissolved, and then DMT-aminohexanol (i.e., Z-NH-R) was added2-OH, Z is-DMT, R2Is n-hexylalkyl) (19.3g,0.046mol) at room temperatureReacting for 6 h; filtering, and taking saturated NaHCO as filtrate3The solution and the saturated NaCl solution were washed 3 times with anhydrous Na2SO4Drying; the product was purified and separated by column chromatography using a petroleum ether-ethyl acetate-triethylamine mixture (volume ratio 5:1:0.2) as eluent, and the solvent was removed by distillation under reduced pressure to give 21g of a yellow oily liquid, i.e., anthracyanoacrylate (DMT-aminohexanol) ester, in 67.5% yield.
1H NMR(CDCl3,400MHz),δ:1.25～1.62[m,8H,(CH2)4],2.20(dd,2H,CCH2CH),2.72(d,2H,CH2CH2NH),2.77(dd,2H,CCH2CH),3.80(s,6H,Ph-OCH3),4.05(t,2H,COOCH2),4.43(t,1H,Ph-CH-Ph),4.86(s,1H,CCH-Ph),6.83～7.48(m,21H,Ph-H),8.29(s,1H,CH2NH).MS,m/z:677.5[M-H+],698.9[M-Na+].
Step 2: 0.5g of anthracenecyanoacrylic acid (DMT-aminohexanol) ester, 0.2g of maleic anhydride, and 10mL of xylene were put in a reaction flask, stirred at room temperature for 5 hours, heated to 50 ℃ to react for 2 hours, and the xylene was distilled off under reduced pressure. After distillation under reduced pressure, an anthracene compound and maleic anhydride were precipitated. Filtering to obtain viscous liquid with adhesive force, namely, the cyanoacrylate (DMT-aminohexanol) ester.
And step 3: the block copolymer (gum block 1a) was obtained by mixing (DMT-aminohexanol) cyanoacrylate with n-butyl cyanoacrylate in a mass ratio of 10:90 and copolymerizing the two monomers in air at normal temperature and pressure.
And 4, step 4: the block 1a was placed in a 5% acetic acid aqueous solution for 5 minutes to remove DMT groups, and then washed twice with distilled water to obtain a block 1b containing an aminocaproyl cyanoacrylate-n-butyl cyanoacrylate copolymer.
And 5: the gel block 1b was placed in Na at pH 92CO3/NaHCO3In the buffer, the buffer solution contained FITC at a concentration of 1 mg/ml. The gel 1b was labeled with FITC and aminocaproyl cyanoacrylate-cyanoacrylateThe amino group of the n-butyl enoate copolymer was reacted to give a block 1c containing cyanoacrylate (FITC-aminohexanol) ester-n-butyl cyanoacrylate copolymer.
The gel patch 1c was detected using a non-invasive three-dimensional (3D) imaging quantification system (IVIS spectra, Caliper usa) and significant fluorescence was detected at 488nm excitation and 525nm emission, indicating that FITC has been successfully labeled on cyanoacrylate polymer.
EXAMPLE 2 preparation of a copolymer of Cyanoacrylic acid (FITC-aminohexanol) ester-n-butyl Cyanoacrylate
Polycyanoacrylic acid (FITC-aminohexanol) ester was prepared as follows.
Step 1: anthracenocyanoacrylic acid (Fmoc-aminohexanol) ester was prepared by reacting anthracyanoacrylic acid with Fmoc-aminohexanol.
Adding 7.1g Fmoc-aminohexanol and 5.76g anthracenecyanoacrylic acid into 150ml dichloromethane, stirring for dissolving, sequentially adding DMAP and DIC, stirring at normal temperature for 6h, vacuum filtering, collecting filtrate, sequentially adding saturated NaHCO into the filtrate3The solution, 1N hydrochloric acid and saturated NaCl solution were washed once each, and the organic phases were combined with anhydrous Na2SO4And (5) drying. The product was purified and separated by column chromatography using petroleum ether-ethyl acetate mixture (volume ratio 3:1) as eluent, and the solvent was removed under reduced pressure to give 9.5g of a pale yellow viscous liquid, i.e., anthracenecyanoacrylate (Fmoc-aminohexanol) ester, with a yield of 76.1%.
1H NMR(CDCl3,400MHz),δ:1.26～1.68[m,8H,(CH2)4],2.21～2.8[dd,2H,CCH2CH(Ph)2],3.22(t,2H,CH2NH),4.08(t,2H,COOCH2),4.23[t,1H,CH2CH(Ph)2],4.41[d,2H,OCH2CH(Ph)2],4.87[s,1H,CCH(Ph)2],7.12～7.8(m,16H,Ph-H),8.1(s,1H,NH).MS,m/z:597[M-H+],619[M-Na+].
Step 2: referring to the procedure of example 1, anthracene group was removed from anthracenecyanoacrylate (Fmoc-aminohexanol) ester to obtain a viscous liquid having adhesive strength, i.e., cyanoacrylate (Fmoc-aminohexanol) ester having the following structure:
and step 3: the two monomers were copolymerized in air at normal temperature and pressure by mixing Fmoc-aminohexanol cyanoacrylate with n-butyl cyanoacrylate in a mass ratio of 10:90 to obtain a block copolymer (block 2 a).
And 4, step 4: referring to the procedure of example 1, Fmoc group was removed to obtain a block 2b containing aminohexanol cyanoacrylate-n-butyl cyanoacrylate copolymer.
And 5: referring to the procedure in example 1, the block 2b was labeled with FITC to obtain a block 2c containing cyanoacrylate (FITC-aminohexanol) ester-n-butyl cyanoacrylate copolymer.
Fluorescence detection is carried out on the gel block 2c, and obvious fluorescence can be detected under the conditions of 488nm of exciting light and 525nm of emitting light, which indicates that FITC is successfully marked on the cyanoacrylate polymer.
EXAMPLE 3 preparation of Cy 2-Aminohexanol ester-n-butyl cyanoacrylate copolymer
Referring to the operations of example 1, Steps 1-4, a block 3b containing an aminocaproyl cyanoacrylate-n-butyl cyanoacrylate copolymer was prepared.
Using Na with cy2 and pH 92CO3/NaHCO3Buffer solution, labeling the gel block 3b to obtain gel block 3c containing cyanopropylA copolymer of olefine acid (Cy 2-aminohexanol) ester-n-butyl cyanoacrylate, having the following structure:
the gel block 3c can detect obvious fluorescence under the conditions of 492nm excitation light and 510nm emission light, which indicates that Cy2 has been successfully labeled on the cyanoacrylate polymer.
Example 4 fluorescence Observation experiment of FITC-labeled gel Block in animals
After the SD mouse was anesthetized, the back hair was removed, a 0.5 cm-long incision was made with a scalpel to a depth of the luminal membrane, and a mass of FITC-labeled polymer gel prepared in example 1, which had a size of about 0.3cm and a thickness of about 1mm, was placed between the muscle layer and the luminal membrane, and the wound was then adhered with ordinary 504 gel.
The fluorescence in vivo imaging results of mice were observed using a non-invasive three-dimensional (3D) imaging quantification system (IVIS SPECTRUM, Caliper, USA) under the detection conditions of 488nm excitation light and 525nm emission light. FIGS. 1A-C are fluorescence in vivo imaging results on the day of embedment, 7 days later, and 14 days later, respectively. As shown in the figure, significant fluorescence was observed at the embedded portion of the gel block (as indicated by the arrow in the figure), and no significant interference was observed at other portions of the mouse. The fluorescence intensity on the day of embedment was 6.8. + -. 3.73X 109p/sec/cm2And/sr, after 14 days of embedment, fluorescence can still be detected at the embedment part.
Example 5 fluorescence Observation experiment of Cy 2-labeled gel masses in animals
Referring to the experimental procedure of example 4, the Cy 2-labeled polymer gel block prepared in example 3 was embedded in the mouse. The fluorescence live body imaging result of the mouse was observed under the conditions of excitation light 492nm and emission light 510 nm. FIG. 2 shows fluorescence in vivo imaging results on the day of embedment. As shown in the figure, significant fluorescence was observed at the embedded portion of the gel block (as indicated by the arrow in the figure), and no significant interference was observed at other portions of the mouse.
While specific embodiments of the invention have been described in detail, those skilled in the art will understand that: various modifications and changes in detail can be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (83)
1. A process for the preparation of cyanoacrylate polymers bearing fluorescent groups, said process following the route indicated below:
wherein R is1Is a hydrogen atom or C1-10An alkyl group;
R2is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30Alkynylene, aryleneAn alkyl, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
z is a protecting group of amino;
R3is a hydrogen atom, C1-10Alkyl or cyanoacrylate C1-10An alkyl group;
n is an integer greater than or equal to 2;
m is an integer greater than or equal to 1, p is an integer greater than or equal to 1, and the sum of m and p is greater than or equal to 2;
the method comprises the following steps:
step 1: reacting compound 1 with compound Z-NH-R2-OH reaction to give compound 2;
step 2: removing the anthracene protecting group on the compound 2 to obtain a monomer 1;
and step 3: polymerizing the monomer 1 to obtain a polymer 1; or copolymerizing a monomer 1 and a monomer 2 to obtain a polymer 1', wherein the monomer 2 is cyanoacrylate or cyanoacrylate C1-10Alkyl esters or biscyanoacrylic acids C1-10An alkyl ester;
and 4, step 4: removing the Z group on the polymer 1 to obtain a polymer 2; or removing the Z group on the polymer 1 'to obtain a polymer 2';
and 5: polymer 2 is reacted with a fluorescent compound to give polymer 3, or polymer 2 'is reacted with a fluorescent compound to give polymer 3'.
2. The method of claim 1, having one or more of the following features:
(1)R1is methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl;
(2) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(3) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(4) said C is1-30Alkynylene isC1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(5) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(6) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(7) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(8) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
3. The method of claim 1, having one or more of the following features:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
4. The method of claim 1, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
5. The process of claim 1 wherein Z is benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl or 4, 4' -dimethoxytrityl.
6. The method of claim 1, wherein R3Is methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl.
7. The method of claim 1, having one or more of the following features:
(1) n is 2 to 100000;
(2) m is 1 to 100000;
(3) p is 1 to 100000;
(4) the sum of m and p is 2-100000.
8. The method of claim 1, wherein R2Is C1-6An alkylene group.
9. The method of claim 1, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
10. The process of claim 1 wherein Z is fluorenylmethyloxycarbonyl or 4, 4' -dimethoxytrityl.
11. The process of claim 1, said cyanoacrylate C1-10The alkyl ester is methyl cyanoacrylate, ethyl cyanoacrylate, n-propyl cyanoacrylate, n-butyl cyanoacrylate, n-octyl cyanoacrylate or 2-isooctyl cyanoacrylate.
12. The method of claim 1, the fluorescent compound is selected from one or more of FITC, FAM, TAMRA, Rhodamin, Cy2, Cy3, Cy5, and Cy 7.
13. The method of claim 1, having one or more of the following features:
(1) the reaction of the step 1 is carried out in the presence of 4-dimethylaminopyridine and N, N-diisopropylcarbodiimide;
(2) the step 1 further comprises: isolating and/or purifying compound 2;
(3) the reaction of step 2 is carried out in the presence of maleic anhydride;
(4) the reaction of the step 3 is carried out in the presence of liquid water or water vapor;
(5) the reaction of step 4 is carried out in an aqueous solution of a weak acid;
(6) step 5 comprises stirring polymer 2 with the fluorescent compound at room temperature, or stirring polymer 2' with the fluorescent compound at room temperature.
14. The method of claim 13, said weak acid being acetic acid.
15. A compound having the structure shown in formula (I):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
z is a protecting group of amino.
16. The compound of claim 15, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
17. The compound of claim 15, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
18. The compound of claim 15, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
19. The compound of claim 15, wherein Z is benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl or 4, 4' -dimethoxytrityl.
20. The compound of claim 15, wherein R2Is C1-6An alkylene group.
21. The compound of claim 15, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
22. The compound of claim 15, wherein Z is fluorenylmethyloxycarbonyl or 4, 4' -dimethoxytrityl.
23. A polymer having a structure according to formula (II):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
z is a protecting group of amino;
n is an integer greater than or equal to 2.
24. The polymer of claim 23, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
25. The polymer of claim 23, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
26. The polymer of claim 23, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
27. The polymer of claim 23, wherein Z is benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl or 4, 4' -dimethoxytrityl.
28. The polymer of claim 23, wherein n is 2 to 100000.
29. The polymer of claim 23, wherein R2Is C1-6An alkylene group.
30. The polymer of claim 23, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
31. The polymer of claim 23 wherein Z is fluorenylmethyloxycarbonyl or 4, 4' -dimethoxytrityl.
32. A polymer having a structure according to formula (III):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
n is an integer greater than or equal to 2.
33. The polymer of claim 32, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
34. The polymer of claim 32, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
35. The polymer of claim 32, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
36. The polymer of claim 32, wherein n is 2 to 100000.
37. The polymer of claim 32, wherein R2Is C1-6An alkylene group.
38. The polymer of claim 32, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
39. A polymer having a structure according to formula (II'):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
z is a protecting group of amino;
R3is a hydrogen atom, C1-10Alkyl or cyanoacrylate C1-10An alkyl group;
m is an integer greater than or equal to 1, p is an integer greater than or equal to 1, and the sum of m and p is greater than or equal to 2.
40. The polymer of claim 39, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
41. The polymer of claim 39, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
42. The polymer of claim 39, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
43. The polymer of claim 39, wherein Z is benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl or 4, 4' -dimethoxytrityl.
44. The polymer of claim 39, wherein R3Is methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl.
45. The polymer of claim 39, which has one or more of the following characteristics:
(1) m is 1 to 100000;
(2) p is 1 to 100000;
(3) the sum of m and p is 2-100000.
46. The polymer of claim 39, wherein R2Is C1-6An alkylene group.
47. The polymer of claim 39, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
48. The polymer of claim 39, wherein Z is fluorenylmethyloxycarbonyl or 4, 4' -dimethoxytrityl.
49. A polymer having a structure according to formula (III'):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
R3is a hydrogen atom, C1-10Alkyl or cyanoacrylate C1-10An alkyl group;
m is an integer greater than or equal to 1, p is an integer greater than or equal to 1, and the sum of m and p is greater than or equal to 2.
50. The polymer of claim 49, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
51. The polymer of claim 49, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
52. The polymer of claim 49, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
53. The polymer of claim 49, wherein R3Is methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl.
54. The polymer of claim 49, having one or more of the following characteristics:
(1) m is 1 to 100000;
(2) p is 1 to 100000;
(3) the sum of m and p is 2-100000.
55. The polymer of claim 49, wherein R2Is C1-6An alkylene group.
56. The polymer of claim 49, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
57. An adhesive comprising a compound according to any one of claims 15 to 22 or a polymer according to any one of claims 23 to 56.
58. The adhesive of claim 57 further comprising an adjuvant.
59. The adhesive of claim 57 further comprising synthesis aids, reactive aids, functional aids, process aids and/or stabilizing aids.
60. A dressing comprising a compound according to any one of claims 15 to 22, a polymer according to any one of claims 23 to 56 or an adhesive according to any one of claims 57 to 59.
61. The dressing of claim 60, further comprising a substrate.
62. A dressing according to claim 61, wherein the compound according to any one of claims 15 to 22, the polymer according to any one of claims 23 to 56 or the adhesive according to any one of claims 57 to 59 is coated on the substrate.
63. The dressing of claim 61, wherein said substrate is selected from the group consisting of paper, fabric, nonwoven, film material, gel, and foam.
64. Use of a compound according to any one of claims 15 to 22 or a polymer according to any one of claims 23 to 38 for the preparation of a fluorescent cyanoacrylate polymer having the structure of formula (IV):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
n is an integer greater than or equal to 2.
65. The use of claim 64, which has one or more of the following features:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
66. The use of claim 64, which has one or more of the following features:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
67. The use of claim 64, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
68. The use of claim 64, wherein n is 2-100000.
69. The use of claim 64, wherein R2Is C1-6An alkylene group.
70. The use of claim 64, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
71. The use of claim 64, wherein the fluorophore is a chromophore selected from one or more of FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA and Rhodamin.
72. Use of a compound according to any one of claims 15 to 22 or a polymer according to any one of claims 39 to 56 for the preparation of a fluorescent cyanoacrylate polymer having the structure of formula (IV):
wherein R is2Is C1-30Alkylene radical, C1-30Alkenylene radical, C1-30An alkynylene, cycloalkylene, aralkylene, alkylenearyl, arylene, or polyethylene glycol segment;
R3is a hydrogen atom, C1-10Alkyl or cyanoacrylate C1-10An alkyl group;
m is an integer greater than or equal to 1, p is an integer greater than or equal to 1, and the sum of m and p is greater than or equal to 2.
73. The use of claim 72, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-10Alkylene radical, C10-20Alkylene or C20-30An alkylene group;
(2) said C is1-30Alkenylene radical being C1-10Alkenylene radical, C10-20Alkenylene or C20-30An alkenylene group;
(3) said C is1-30Alkynylene is C1-10Alkynylene, C10-20Alkynylene or C20-30An alkynylene group;
(4) the cycloalkylene group is a 5-to 10-membered cycloalkylene group;
(5) the aralkylene is 6-14 membered arylene C1-10An alkylene group;
(6) said alkylene aryl group is C1-10Alkylene 6-14 membered arylene;
(7) the polyethylene glycol segment is a polyethylene glycol segment with the number average molecular mass of 100-5000-.
74. The use of claim 72, having one or more of the following characteristics:
(1) said C is1-30Alkylene being C1-6An alkylene group;
(2) said C is1-30Alkenylene radical being C1-6An alkenylene group;
(3) said C is1-30Alkynylene is C1-6An alkynylene group;
(4) the arylene group is a 6-to 14-membered arylene group.
75. The use of claim 72, said C1-30The alkylene group is substituted with one or more of an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom and a cyano group.
76. The use of claim 72, wherein R3Is methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl.
77. The use of claim 72, having one or more of the following characteristics:
(1) m is 1 to 100000;
(2) p is 1 to 100000;
(3) the sum of m and p is 2-100000.
78. The use of claim 72, wherein R2Is C1-6An alkylene group.
79. The use of claim 72, wherein R2Is n-butylene, n-octylene, n-hexylene, isobutylene, isooctylene or isohexylene.
80. The use of claim 72, wherein the fluorophore is a chromophore selected from one or more of FITC, FAM, Cy2, Cy3, Cy5, Cy7, TAMRA, and Rhodamin.
81. A process for the preparation of a compound according to any one of claims 15 to 22 having a structure as shown in formula (I) according to the following route:
wherein R is1Is a hydrogen atom or C1-10An alkyl group;
R2and Z is as defined for formula (I) in any one of claims 15 to 22;
the method comprises the following steps:
step 1: reacting compound 1 with compound Z-NH-R2-OH reaction to give compound 2; and
step 2: and (3) removing the anthracene protecting group on the compound 2 to obtain the compound with the structure shown in the formula (I).
82. The method of claim 81, wherein R1Is methyl, ethyl, n-propyl, n-butyl, n-octyl or 2-isooctyl.
83. The method of claim 81, having one or more of the following features:
(1) the reaction of the step 1 is carried out in the presence of 4-dimethylaminopyridine and N, N-diisopropylcarbodiimide;
(2) the step 1 further comprises: isolating and/or purifying compound 2;
(3) the reaction of step 2 is carried out in the presence of maleic anhydride.
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