CN116715704A - 基于点击化学的软骨素寡糖及其制备方法 - Google Patents
基于点击化学的软骨素寡糖及其制备方法 Download PDFInfo
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- CN116715704A CN116715704A CN202310615772.5A CN202310615772A CN116715704A CN 116715704 A CN116715704 A CN 116715704A CN 202310615772 A CN202310615772 A CN 202310615772A CN 116715704 A CN116715704 A CN 116715704A
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- chondroitin
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- 229920001542 oligosaccharide Polymers 0.000 title claims abstract description 44
- -1 Chondroitin oligosaccharide Chemical class 0.000 title claims abstract description 40
- 229920002567 Chondroitin Polymers 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000001311 chemical methods and process Methods 0.000 title description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 72
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 20
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims abstract description 14
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims abstract description 9
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 7
- 229910000365 copper sulfate Inorganic materials 0.000 claims abstract description 7
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 7
- 239000011347 resin Substances 0.000 claims abstract description 7
- 229920005989 resin Polymers 0.000 claims abstract description 7
- 235000010378 sodium ascorbate Nutrition 0.000 claims abstract description 7
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims abstract description 7
- 229960005055 sodium ascorbate Drugs 0.000 claims abstract description 7
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims abstract description 7
- UGUUDTWORXNLAK-UHFFFAOYSA-N azidoalcohol Chemical compound ON=[N+]=[N-] UGUUDTWORXNLAK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229960003280 cupric chloride Drugs 0.000 claims abstract description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 230000021736 acetylation Effects 0.000 claims abstract description 3
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 3
- 230000012447 hatching Effects 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 13
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 claims description 4
- GOQJMMHTSOQIEI-UHFFFAOYSA-N hex-5-yn-1-ol Chemical compound OCCCCC#C GOQJMMHTSOQIEI-UHFFFAOYSA-N 0.000 claims description 4
- WHYHCPIPOSTZRU-UHFFFAOYSA-N 6-azidohexan-1-ol Chemical compound OCCCCCCN=[N+]=[N-] WHYHCPIPOSTZRU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012345 acetylating agent Substances 0.000 claims description 2
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 claims description 2
- USAVSXJFTZUOGV-UHFFFAOYSA-N 4-azidobutan-1-ol Chemical compound OCCCCN=[N+]=[N-] USAVSXJFTZUOGV-UHFFFAOYSA-N 0.000 claims 1
- DZCFSFWVMHRCHN-UHFFFAOYSA-N 5-azidopentan-1-ol Chemical compound OCCCCCN=[N+]=[N-] DZCFSFWVMHRCHN-UHFFFAOYSA-N 0.000 claims 1
- 150000002482 oligosaccharides Chemical class 0.000 abstract description 10
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 11
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 11
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 235000000346 sugar Nutrition 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229920001287 Chondroitin sulfate Polymers 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 229940059329 chondroitin sulfate Drugs 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 238000012650 click reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003848 cartilage regeneration Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000021310 complex sugar Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及基于点击化学的软骨素寡糖及其制备方法,属于寡糖技术领域。本发明的制备方法包括以下步骤,S1、将寡糖化合物、甲醇和乙酰氯混合,孵化反应得到化合物a;S2、将化合物a、乙酰化试剂乙酸酐溶于吡啶,反应得到化合物b;S3、将化合物b、三甲基溴硅烷、三氟化硼***和2,4,6‑三甲基吡啶溶于1,2‑二氯乙烷,反应得到化合物c;S4、将化合物c、叠氮醇和氯化铜溶于氯仿,60℃‑70℃反应8h‑18h,得到化合物d;将化合物c、炔基醇和氯化铜溶于氯仿,55℃‑65℃反应8h‑12h,得到化合物e;S5、将化合物d、化合物e、抗坏血酸钠和硫酸铜溶于甲醇溶液,反应后脱保护并经树脂处理,得到基于点击化学的软骨素寡糖。为铜催化的叠氮‑炔环加成反应,易于执行且具有优异的产率。
Description
技术领域
本发明属于寡糖技术领域,尤其涉及基于点击化学的软骨素寡糖及其制备方法。
背景技术
硫酸软骨素是细胞外基质中的主要成分之一,参与调节神经***的功能,对神经可塑性、迁移和神经干细胞分化具有重要作用,同时也参与软骨再生、炎症反应等多种生理过程。硫酸软骨素糖链是由N-乙酰半乳糖胺和葡萄糖醛酸组成的二糖重复单元,其生物活性与糖链长度和硫酸化修饰紧密相关,多糖因其分子量大、糖链结构复杂等因素,难以与细胞的受体结合。因此,具有明确结构和分子量的硫酸软骨素寡糖是非常适合解决上述挑战的分子。
目前主流的合成硫酸软骨素寡糖的方法,是将葡萄糖和氨基半乳糖作为合成起始原料,通过常规的保护基保护和糖基化操作来进行寡糖的组装。这样的合成策略在合成特定糖单元数的寡糖时路线冗长,步骤多,需分别对糖供体和糖受体做不同的保护处理而导致整条路线的总收率偏低,亟需更为方便快捷的合成手段,对于促进寡糖的药化研究具有重要意义。
发明内容
为解决上述技术问题,本发明提供了一种基于点击化学的软骨素寡糖及其制备方法。
本发明的第一个目的是提供一种基于点击化学的软骨素寡糖的制备方法,包括以下步骤,
S1、将寡糖化合物、甲醇和乙酰氯混合,孵化反应得到化合物a;
S2、将化合物a、乙酰化试剂乙酸酐溶于吡啶,反应得到化合物b;
S3、将化合物b、三甲基溴硅烷、三氟化硼***和2,4,6-三甲基吡啶溶于1,2-二氯乙烷,反应得到化合物c;
S4、将化合物c、叠氮醇和氯化铜溶于氯仿,60℃-70℃反应8h-18h,得到化合物d;
将化合物c、炔基醇和氯化铜溶于氯仿,55℃-65℃反应8h-12h,得到化合物e;
S5、将化合物d、化合物e、抗坏血酸钠和硫酸铜溶于甲醇溶液,反应后脱保护并经树脂处理,得到所述的基于点击化学的软骨素寡糖。
在本发明的一个实施例中,在S1中,所述寡糖化合物的结构如下:
其中,n为0-3的整数。
在本发明的一个实施例中,在S1中,所述甲醇有两个作用,一是溶剂,二是反应物。
在本发明的一个实施例中,在S1和S2中,所述寡糖化合物、乙酰氯、乙酰化试剂乙酸酐的摩尔比为1:40-60:90-110。
在本发明的一个实施例中,在S3中,所述化合物b、三甲基溴硅烷TMSBr、三氟化硼***和2,4,6-三甲基吡啶的摩尔比为1:5-8:5-8:5-8。
在本发明的一个实施例中,在S4中,所述叠氮醇选自1-叠氮-6-己醇、1-叠氮-5-戊醇和1-叠氮-4-丁醇中的一种或多种。
在本发明的一个实施例中,在S4中,所述化合物c、叠氮醇和氯化铜的摩尔比为1:5-9:1-2。
在本发明的一个实施例中,在S4中,所述炔基醇选自3-丁炔-1-醇、4-戊炔-1-醇和5-己炔-1-醇中的一种或多种。
在本发明的一个实施例中,在S4中,将化合物c、炔基醇和氯化铜的摩尔比为1:5-9:1-2。
在本发明的一个实施例中,在S5中,所述化合物d、化合物e、抗坏血酸钠和硫酸铜的摩尔比为1:1-1.2:5-7:1-1.2。
在本发明的一个实施例中,在S5中,所述树脂处理是通过树脂进行中和和离子交换处理。
在本发明的一个实施例中,合成路线如下:
本发明的第二个目的是提供一种所述的方法制备的基于点击化学的软骨素寡糖。
本发明的技术方案相比现有技术具有以下优点:
(1)本发明所述的制备方法构建块的天然糖苷键由铜催化的点击化学形成的1,2,3-***取代,在温和的条件下提供了优异的区域选择性,几乎不生成副产物,对其他官能团具有高耐受性。
(2)本发明所述的制备方法叠氮醇和炔基醇均取代的是寡糖还原端的羟基,从而通过Click反应形成加倍数目糖单元的软骨素寡糖,末端取代对寡糖的生物活性作用区域影响较小。
(3)本发明所述的制备方法为铜催化的叠氮-炔环加成反应,易于执行且具有优异的产率,几乎没有副产品。通过简单的基于单一寡糖的Click反应将单一寡糖两两链接,形成糖单元数加倍的软骨素寡糖,从而比已有的合成方法减少了原料损失,避免了糖受体复杂、冗长的保护过程,并且在糖单元的还原性末端接枝碳臂,没有对寡糖的活性结构区域产生明显破坏。
(4)本发明所述的制备方法成本较低,减少了对昂贵或剧毒的糖基化偶联试剂的需求,对以快速、经济高效的方式设计并合成软骨素寡糖。
附图说明
为了使本发明的内容更容易被清楚地理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细的说明,其中:
图1-5为本发明实施例1中化合物b-化合物f的核磁氢谱图。
图6-10为本发明实施例1中化合物b-化合物f的MALDI-TOF谱图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
本发明的基于点击化学的软骨素寡糖及其制备方法,具体包括以下步骤:
S1、将硫酸软骨素四糖(9.6g,含有三羟甲基氨基甲烷和氯化钠杂质)加入三颈瓶中,用氮气回填后,注射器加入1.2L预冷的无水甲醇和10mL乙酰氯。轻轻摇动溶液,在冰箱的4℃中孵化6天,在此期间,溶液颜色由淡黄色变为深红色。用碳酸钠溶液中和溶液,过滤,然后减压浓缩干燥,得到红色的化合物a,将红色粉末置于真空干燥箱中干燥过夜。
S2、将红色粉末放入三颈瓶中,氮气回填后,注射器加入40mL吡啶,将三颈瓶在冰上冷却至0℃,在0.5h内滴加25mL乙酸酐。将混合物恢复至室温并搅拌反应24h。TLC显示反应完成后,将容器冷却至0℃并用10mL甲醇淬灭。减压浓缩,用150mL乙酸乙酯稀释搅拌20min后,硅藻土过滤除去不溶性沉淀。减压浓缩后得到深棕色糖浆,用石油醚/乙酸乙酯=3/1的混合溶剂固化,得到深棕色固体。在硅胶上通过色谱法纯化(二氯甲烷:乙酸乙酯:甲醇=1:1.1:0.2,Rf=0.6)得到化合物b(3.2g),产率为40%。1HNMR(400MHz,CDCl3)δ:6.09(s,1H,GlcNAcⅢ-NHAc),5.81(d,J=8.6Hz,1H,GlcNAcⅠ-NHAc),5.60(d,J=9.6Hz,1H,GlcNAcⅠ-H-1),5.31–5.11(m,7H),4.93–4.58(m,5H),4.34(d,J=4.4Hz,1H),4.28(d,J=2.9Hz,1H),4.18(d,J=7.5Hz,1H),4.05–4.00(m,2H),3.96–3.93(m,2H),3.84(d,J=3.4Hz,3H,-COOCH3),3.66(d,J=15.3Hz,3H,-COOCH3),3.28-3.38(m,3H)2.20-1.92(m,J=44.5Hz,33H,-COCH3)(图1)。
MALDI-TOF:[M+2H]2+计算值584.180,实测值[M+2H]2+:584.224(图6)。
S3、将化合物b(900mg)放入预先120℃干燥过夜的50mL三颈瓶中,氮气回填后,加入20mL干燥的1,2-二氯乙烷并充分溶解,依次加入570μL三甲基溴硅烷、550μL三氟化硼***和550μL 2,4,6-三甲基吡啶。将混合物在常温下搅拌36h后,用饱和碳酸氢钠溶液淬灭反应,除去水层,减压浓缩至干燥后用40mL二氯甲烷稀释搅拌20min,在无水硫酸钠上过滤,减压浓缩后通过色谱法(二氯甲烷:乙酸乙酯:甲醇=1:1:0.2)纯化得到化合物c(540mg),产率为64%。1HNMR(600MHz,CDCl3)δ:6.03(s,1H,GlcNAcⅢ-NHAc),5.93(s,1H,GlcNAcⅠ-H-1),5.41-5.21(m,5H),5.07-4.75(m,3H),4.62(d,J=5.1Hz,1H),4.51-4.41(dd,J=15.4Hz,3H),4.26–4.04(m,9H,GlcNAcⅠ-H-2,GlcNAcⅠ-H-3),3.82–3.73(m,3H,-COOCH3),3.60(d,J=14.1Hz,3H,-COOCH3),3.49(s,1H),2.12–1.93(m,30H,-COCH3和-N=CCH3)(图2)。
MALDI-TOF:[M+2K]2+计算值591.665,实测值[M+2K]2+:591.506(图7)。
S4、将化合物c(1g)放入预先120℃过夜干燥的25mL三颈瓶中,加入700mg1-叠氮-6-己醇和126mg无水氯化铜,氮气回填后加入9mL氯仿,65℃油浴搅拌回流,反应12h后将溶液恢复至室温,用24mL乙酸乙酯稀释并加入饱和碳酸氢钠溶液淬灭。硅藻土过滤,继续加入30mL乙酸乙酯稀释,用10mL饱和碳酸氢钠溶液和10mL饱和氯化钠溶液萃取,将水相合并后用40mL乙酸乙酯萃取。有机相经无水硫酸钠过滤,减压浓缩。将残余物在石油醚/***=5/1的混合溶剂中剧烈搅拌1h,使残余物充分沉淀。倾去混合溶剂后置于真空干燥箱干燥过夜,得到黑色固体化合物d(800mg),产率为65%。1HNMR(600MHz,CDCl3)δ:6.08(m,1H,GlcNAcⅢ-NHAc),5.83(d,J=21.7Hz,1H,GlcNAcⅠ-NHAc),5.46–4.58(m,11H),4.53–4.44(m,1H),4.27(dd,J=32.5,20.5Hz,2H),4.13–3.96(m,4H),3.87–3.60(m,4H,-COOCH3,-OCH2a(CH2)5N3),3.59-3.49(d,J=8.9Hz,3H),3.46(dt,1H,-OCH2b(CH2)5N3),3.33–3.18(t,2H,-O(CH2)5CH2N3)),3.00–2.75(m,2H,GlcNAcⅠ-H-2),2.07–1.96(m,33H,-COCH3),1.57(s,4H,-OCH2(CH2)4CH2N3),1.40(d,J=13.6Hz,4H,-OCH2(CH2)4CH2N3)(图3)。
MALDI-TOF:[M+2Na]2+计算值647.220,实测值[M+2Na]2+:647.569(图8)。
S5、将化合物c(1.17g)放入25mL三颈瓶中,氮气回填,然后加入600μL 3-丁炔-1-醇、10.5mL氯仿和150mg无水氯化铜粉末。反应物60℃油浴搅拌10h后,恢复至室温,加入饱和碳酸氢钠溶液淬灭反应。加入200mL二氯甲烷稀释,分液漏斗除去水层,用饱和氯化钠溶液洗涤,在无水硫酸钠上过滤并减压浓缩,通过色谱(二氯甲烷:乙酸乙酯:甲醇=1:1:0.2,Rf=0.55)纯化得到黑色固体化合物e(1.03g),产率为84%。1H NMR(600MHz,CDCl3)δ:6.04(2H),5.46–4.58(m,8H),4.53–4.44(m,4H),4.28–4.05(m,8H),3.92–3.51(m,6H),2.96(m,3H,GlcNAcⅠ-H-2,-C≡CH),2.24(s,2H),2.12–1.96(m,33H,-COCH3)(图4)。
MALDI-TOF:[M+2Na]2+计算值610.185,实测值[M+2Na]2+:610.290(图9)。
S6、将250mg化合物e溶于7mL甲醇溶剂中,依次加入7mL含235mg化合物d的甲醇溶液、2mL 0.1M硫酸铜水溶液、1mL 1M抗坏血酸钠溶液。反应在N2环境、室温下进行36h。减压浓缩,用甲醇从Sephadex LH-20柱上洗脱,得到黑色固体(417.3mg),产率为94%。之后在0℃下,之后将产物溶于15mL THF/H2O(3:1)中配置成基质溶液,加入新制备的过氧化氢(30重量%的水溶液)和LiOH(1M)的混合溶液处理,并在0℃下搅拌该混合物1h,升至室温继续搅拌15h,然后冷却至0℃。加入4mL甲醇和10mLNaOH(4M),将混合物在室温下搅拌10h,然后用Amberlite IR-120[H+]树脂将pH调节至7,过滤、浓缩、干燥,然后用水从Sephadex LH-20柱上洗脱,得到终产物。1H NMR(600MHz,Deuterium Oxide)δ7.93(s,1H),6.13–5.04(m,14H),4.46–4.11(m,12H),4.04(s,2H),3.89–3.57(m,38H),3.34(s,2H),3.16(dd,J=16.3,9.1Hz,4H),2.59(s,1H),2.17(s,2H),2.04(s,14H),1.30(s,4H),1.21(s,2H)(图5)。
MALDI-TOF:[M+4Na]4+计算值446.895,实测值[M+4Na]4+:447.151(图10)。
实施例2
本发明的基于点击化学的软骨素寡糖及其制备方法,具体包括以下步骤:
S1、将八糖(4.6g,含有三羟甲基氨基甲烷和醋酸钠杂质)加入三颈瓶中,用氮气回填后,注射器加入287mL预冷的无水甲醇和2.5mL乙酰氯。轻轻摇动溶液,在冰箱的4℃中孵化6天,在此期间,溶液颜色由淡黄色变为深红色。用碳酸钠溶液中和溶液,过滤,然后减压浓缩干燥,得到红色的化合物a,将红色粉末置于真空干燥箱中干燥过夜。
S2、将红色粉末放入三颈瓶中,氮气回填后,注射器加入15mL吡啶,将三颈瓶在冰上冷却至0℃,在0.5h内滴加6mL乙酸酐。将混合物恢复至室温并搅拌反应24h。TLC显示反应完成后,将容器冷却至0℃并用3mL甲醇淬灭。减压浓缩,用60mL乙酸乙酯稀释搅拌20min后,硅藻土过滤除去不溶性沉淀。减压浓缩后得到深棕色糖浆,用石油醚/乙酸乙酯=3/1的混合溶剂固化,得到黄色固体。在硅胶上通过色谱法纯化(二氯甲烷:乙酸乙酯:甲醇=1:1.1:0.2)得到淡黄色固体化合物b(4.1g),产率为56%。
S3、将化合物b(1g)放入预先120℃干燥过夜的50mL三颈瓶中,氮气回填后,加入20mL干燥的1,2-二氯乙烷并充分溶解,依次加入500μL三甲基溴硅烷、477μL三氟化硼***和477μL 2,4,6-三甲基吡啶。将混合物在常温下搅拌36h后,用饱和碳酸氢钠溶液淬灭反应,除去水层后,有机层减压浓缩至干燥后用40mL二氯甲烷稀释搅拌20min,在无水硫酸钠上过滤,减压浓缩后通过色谱法(二氯甲烷:乙酸乙酯:甲醇=1:1:0.2)纯化得到橙色化合物c(640mg),产率为67%。
S4、将化合物c(1g)放入预先120℃过夜干燥的25mL三颈瓶中,加入470mg1-叠氮-6-己醇和80mg无水氯化铜,氮气回填后加入9mL氯仿,65℃油浴搅拌回流,反应12h后将溶液恢复至室温,用24mL乙酸乙酯稀释并加入饱和碳酸氢钠溶液淬灭。硅藻土过滤,继续加入30mL乙酸乙酯稀释,用10mL饱和碳酸氢钠溶液和10mL饱和氯化钠溶液萃取,将水相合并后用40mL乙酸乙酯萃取。有机相经无水硫酸钠过滤,减压浓缩。将残余物在石油醚/***=5/1的混合溶剂中剧烈搅拌1h,使残余物充分沉淀。倾去混合溶剂后置于真空干燥箱干燥过夜,得到褐色固体化合物d(830mg),产率为73%。
S5、将化合物c(730mg)放入25mL三颈瓶中,然后加入210μL 3-丁炔-1-醇、4.5mL氯仿和65mg无水氯化铜粉末。氮气环境下加入,反应物60℃油浴搅拌10h后,恢复至室温,加入饱和碳酸氢钠溶液淬灭反应。加入125mL二氯甲烷稀释,分液漏斗除去水层,用饱和氯化钠溶液洗涤,在无水硫酸钠上过滤并减压浓缩,通过色谱(二氯甲烷:乙酸乙酯:甲醇=1:1:0.2)纯化得到黑色固体化合物e(570mg),产率为78%。
S6、将235mg化合物d和228mg化合物e分别溶于3mL甲醇并混合,依次加入1mL 0.1M的硫酸铜水溶液和0.55mL 1M的抗坏血酸钠水溶液。反应在N2保护、室温下进行36h。减压浓缩,用甲醇从Sephadex LH-20柱上洗脱,得到白色固体(411.3mg),产率为88%。在0℃下,用新制备的过氧化氢(30重量%的水溶液)和LiOH(1M)的混合物处理THF/H2O(3:1)中的基质溶液,并在0℃下搅拌该混合物1h,在室温下搅拌15h,然后冷却至0℃。加入3mL甲醇和6mLNaOH(4M)溶液,将混合物在室温下搅拌10h,然后用Amberlite IR-120[H+]树脂将pH调节至7,过滤、浓缩、干燥,然后用水从Sephadex LH-20柱上洗脱,得到终产物。
显然,上述实施例仅仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种基于点击化学的软骨素寡糖的制备方法,其特征在于,包括以下步骤,
S1、将寡糖化合物、甲醇和乙酰氯混合,孵化反应得到化合物a;
S2、将化合物a、乙酰化试剂乙酸酐溶于吡啶,反应得到化合物b;
S3、将化合物b、三甲基溴硅烷、三氟化硼***和2,4,6-三甲基吡啶溶于1,2-二氯乙烷,反应得到化合物c;
S4、将化合物c、叠氮醇和氯化铜溶于氯仿,60℃-70℃反应8h-18h,得到化合物d;
将化合物c、炔基醇和氯化铜溶于氯仿,55℃-65℃反应8h-12h,得到化合物e;
S5、将化合物d、化合物e、抗坏血酸钠和硫酸铜溶于甲醇溶液,反应后脱保护并经树脂处理,得到所述的基于点击化学的软骨素寡糖。
2.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S1中,所述寡糖化合物的结构如下:
其中,n为0-3的整数。
3.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S1和S2中,所述寡糖化合物、乙酰氯、乙酰化试剂乙酸酐的摩尔比为1:40-60:90-110。
4.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S3中,所述化合物b、三甲基溴硅烷TMSBr、三氟化硼***和2,4,6-三甲基吡啶的摩尔比为1:5-8:5-8:5-8。
5.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S4中,所述叠氮醇选自1-叠氮-6-己醇、1-叠氮-5-戊醇和1-叠氮-4-丁醇中的一种或多种。
6.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S4中,所述化合物c、叠氮醇和氯化铜的摩尔比为1:5-9:1-2。
7.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S4中,所述炔基醇选自3-丁炔-1-醇、4-戊炔-1-醇和5-己炔-1-醇中的一种或多种。
8.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S4中,将化合物c、炔基醇和氯化铜的摩尔比为1:5-9:1-2。
9.根据权利要求1所述的基于点击化学的软骨素寡糖的制备方法,其特征在于,在S5中,所述化合物d、化合物e、抗坏血酸钠和硫酸铜的摩尔比为1:1-1.2:5-7:1-1.2。
10.权利要求1-9任一项所述的方法制备的基于点击化学的软骨素寡糖。
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