CN117264180A - Polymer with valine and mannose in side chains prepared by utilizing ROMP polymerization and click chemistry and preparation method thereof - Google Patents
Polymer with valine and mannose in side chains prepared by utilizing ROMP polymerization and click chemistry and preparation method thereof Download PDFInfo
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- CN117264180A CN117264180A CN202311391121.9A CN202311391121A CN117264180A CN 117264180 A CN117264180 A CN 117264180A CN 202311391121 A CN202311391121 A CN 202311391121A CN 117264180 A CN117264180 A CN 117264180A
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- 229920000642 polymer Polymers 0.000 title claims abstract description 72
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 title claims abstract description 52
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 239000004474 valine Substances 0.000 title claims abstract description 52
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 title claims abstract description 50
- 238000006116 polymerization reaction Methods 0.000 title claims abstract description 30
- 238000007152 ring opening metathesis polymerisation reaction Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 28
- 238000001311 chemical methods and process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 22
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 5
- LLPXJBWCSUOLNU-XECIQJBQSA-N [N-]=[N+]=[N-].O[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO Chemical compound [N-]=[N+]=[N-].O[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO LLPXJBWCSUOLNU-XECIQJBQSA-N 0.000 claims abstract description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 19
- 230000035484 reaction time Effects 0.000 claims description 18
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 10
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 10
- 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 description 10
- 229960005055 sodium ascorbate Drugs 0.000 claims description 10
- 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 description 10
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 9
- KNDQHSIWLOJIGP-UHFFFAOYSA-N 826-62-0 Chemical compound C1C2C3C(=O)OC(=O)C3C1C=C2 KNDQHSIWLOJIGP-UHFFFAOYSA-N 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 9
- 239000003999 initiator Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- KSRDTSABQYNYMP-PQMKYFCFSA-N (2s,3s,4s,5s,6r)-2-azido-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@H](N=[N+]=[N-])[C@@H](O)[C@@H](O)[C@@H]1O KSRDTSABQYNYMP-PQMKYFCFSA-N 0.000 claims description 6
- 238000006959 Williamson synthesis reaction Methods 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 239000011988 third-generation catalyst Substances 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 8
- 229960004295 valine Drugs 0.000 abstract description 36
- 229940024606 amino acid Drugs 0.000 abstract description 7
- 150000001413 amino acids Chemical class 0.000 abstract description 7
- UGNIYGNGCNXHTR-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical group C1=CC=C2C(COC(=O)N[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UGNIYGNGCNXHTR-SFHVURJKSA-N 0.000 abstract description 5
- -1 alkyne compound Chemical group 0.000 abstract description 5
- 238000005741 Steglich esterification reaction Methods 0.000 abstract description 2
- 150000001345 alkine derivatives Chemical group 0.000 abstract description 2
- 150000001540 azides Chemical group 0.000 abstract description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 238000006266 etherification reaction Methods 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000000843 powder Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000001720 carbohydrates Chemical class 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 102000004856 Lectins Human genes 0.000 description 4
- 108090001090 Lectins Proteins 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002523 lectin Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- SYFZCLMMUNCHNH-UHFFFAOYSA-N 2-(prop-2-ynoxymethyl)oxirane Chemical compound C#CCOCC1CO1 SYFZCLMMUNCHNH-UHFFFAOYSA-N 0.000 description 1
- 101710141544 Allatotropin-related peptide Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000662429 Fenerbahce Species 0.000 description 1
- 229920001231 Polysaccharide peptide Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000010550 living polymerization reaction Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 108010022457 polysaccharide peptide Proteins 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940056729 sodium sulfate anhydrous Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G61/12—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule
- C08G61/122—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides
- C08G61/123—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds
- C08G61/124—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds with a five-membered ring containing one nitrogen atom in the ring
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/10—Definition of the polymer structure
- C08G2261/11—Homopolymers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/30—Monomer units or repeat units incorporating structural elements in the main chain
- C08G2261/32—Monomer units or repeat units incorporating structural elements in the main chain incorporating heteroaromatic structural elements in the main chain
- C08G2261/324—Monomer units or repeat units incorporating structural elements in the main chain incorporating heteroaromatic structural elements in the main chain condensed
- C08G2261/3241—Monomer units or repeat units incorporating structural elements in the main chain incorporating heteroaromatic structural elements in the main chain condensed containing one or more nitrogen atoms as the only heteroatom, e.g. carbazole
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/40—Polymerisation processes
- C08G2261/41—Organometallic coupling reactions
- C08G2261/418—Ring opening metathesis polymerisation [ROMP]
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/70—Post-treatment
- C08G2261/72—Derivatisation
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a polymer with valine and mannose in side chains prepared by utilizing ROMP polymerization and click chemistry and a preparation method thereof. Firstly, utilizing a dihydroxyl compound and propargyl bromide to carry out Williamson etherification reaction to synthesize a monoalkyne compound, then carrying out Steglich esterification reaction between terminal hydroxyl and carboxyl by using the terminal alkyne compound and Fmoc-L-valine, then carrying out CuAAC reaction between terminal alkyne and azide by using alpha-D-mannopyranose azide, preparing a polymer derivative containing valine and mannose through ROMP polymerization, and finally removing the protection of fluorenylmethoxycarbonyl under the alkaline condition of piperidine to obtain the polymer containing valine and mannose on the side chain. Compared with the prior art, the invention innovatively applies high-efficiency and rapid ROMP polymerization and click chemistry reaction to prepare the amino acid and mannose-containing polymer with high biocompatibility, and provides a feasible way for preparing the functionalized amino acid and mannose-containing polymer.
Description
Technical Field
The invention relates to the technical field of synthesis of polymers containing amino acids and saccharides, in particular to a polymer containing valine and mannose at a side chain, which is prepared by utilizing ROMP polymerization and click chemistry, and a preparation method thereof.
Background
Sugar-containing polymers are functional polymeric materials in which sugar units are incorporated into the polymer backbone by chemical synthetic means, which achieve a "sugar cluster effect" comparable to that of natural polysaccharides in the form of sugar chains, imparting the sugar-containing polymers with high affinity for the particular protein. In the life-action and biomedical applications in which sugar-containing polymers are involved, specific molecular recognition of sugar units with lectins plays a critical role. At present, the specific recognition of the sugar-containing polymer and human lectin is utilized to treat various diseases, such as influenza virus (Flu), human Immunodeficiency Virus (HIV) and the like, and the sugar-containing polymer is utilized to be used in a drug delivery system by utilizing the specific recognition effect of the sugar-containing polymer, so that the sugar-containing polymer has guiding significance for treating serious diseases such as HIV and the like. Meanwhile, lectin in human body plays a vital role in the occurrence of diseases, so that the functions and actions of saccharides in the fields of biology, medicine, new materials and the like are explored, the recognition and combination actions of the carbohydrate-containing polymer and human lectin are studied in depth, and the method has important research value for researching the practical application of the carbohydrate-containing polymer and preventing and treating related diseases.
The glycopolypeptide polymers are polymers in which sugar compounds are bonded to side chains or terminal ends of polyamino acids. The skeleton structure of the polyamino acid ensures that the glycopolypeptide macromolecule has good biodegradability and a secondary structure similar to natural protein; the side group or the terminal saccharide compound endows the glycopolypeptide polymer with a plurality of biological activity functions, such as biological molecular recognition, cell adhesion regulation or cell endocytosis mediation, etc., so that the glycopolypeptide polymer is expected to be widely applied to biomedical fields of targeted drug transmission, tissue regeneration induction, etc.
Click chemistry is first proposed by a famous chemist Sharpless in 2001 in the United states, is a subverted synthesis technology after combinatorial chemistry, is widely favored by chemical researchers due to the advantages of simple, quick and efficient reaction, has the advantages of high efficiency, high selectivity, mild reaction conditions, good stereoselectivity and the like, and is widely applied to the fields of material preparation, drug synthesis and the like. At present, ATRP, RAFT, ROMP and other controllable polymerization reactions lay a foundation for preparing various functional sugar-containing polymers. Meanwhile, the combination of controlled living polymerization and click chemistry provides a new way for synthesizing sugar-containing polymers with regular structure, but the preparation process and yield thereof still need to be further studied.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a polymer with valine and mannose in side chains prepared by ROMP polymerization and click chemistry and a preparation method thereof, wherein first, a dihydroxyl compound and propargyl bromide are used for carrying out Williamson etherification reaction to synthesize a monoalkyne compound, then, a terminal alkyne compound and Fmoc-L-valine are subjected to Steglich esterification reaction between terminal hydroxyl and carboxyl, then, the terminal alkyne compound and alpha-D-mannopyranose azide are subjected to CuAAC reaction between terminal alkyne and azide, derivatives of the polymer with valine and mannose are prepared by ROMP polymerization, and finally, protection of fluorenylmethoxycarbonyl groups is removed under alkaline conditions of piperidine to obtain the polymer with valine and mannose in side chains. The invention innovatively applies the efficient and rapid ROMP polymerization and click chemistry reaction to prepare the amino acid and mannose containing polymer with high biocompatibility, and provides a feasible way for preparing the functionalized amino acid and mannose containing polymer.
The aim of the invention can be achieved by the following technical scheme:
the invention provides a polymer with valine and mannose in side chains, wherein the chemical structural formula of the polymer with valine and mannose in the side chains is shown as the formula (I):
in the formula (I), n is a positive integer greater than or equal to 1.
The invention also provides a method for preparing a polymer with valine and mannose in side chains by ROMP polymerization and click chemistry, which comprises the following steps:
(1) Taking 5-norbornene-2, 3-dicarboxylic anhydride and 2-amino-2-methyl-1, 3-propanediol to react, and carrying out post-treatment to obtain a first compound;
(2) Carrying out Williamson ether synthesis reaction on the first compound obtained in the step (1) with propargyl bromide and potassium hydroxide, and carrying out post-treatment to obtain a second compound;
(3) Esterifying the second compound obtained in the step (2) with valine protected by fluorenylmethoxycarbonyl, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and performing post-treatment to obtain a third compound;
(4) Performing CuAAC click chemical reaction on the third compound obtained in the step (3), alpha-D-mannopyranosyl azide, copper sulfate pentahydrate and sodium ascorbate, and performing post-treatment to obtain a fourth compound;
(5) Performing ROMP polymerization reaction on the fourth compound obtained in the step (4) and an initiator, and performing post-treatment to obtain a fifth compound;
(6) Carrying out substitution reaction on the fifth compound obtained in the step (5) and piperidine, and carrying out post-treatment to obtain a polymer with valine and mannose in side chains;
the chemical structural formulas of the polymer with valine and mannose in the side chains, the first compound, the second compound, the third compound, the fourth compound and the fifth compound are respectively shown as the formula (I), the formula (II), the formula (III), the formula (IV), the formula (V) and the formula (VI):
wherein n is a positive integer of 1 or more.
In one embodiment of the present invention, in step (1), the molar ratio of the 5-norbornene-2, 3-dicarboxylic anhydride and the 2-amino-2-methyl-1, 3-propanediol is 1:1 to 1.5;
the reaction temperature is 110-125 ℃ and the reaction time is 18-24 h.
In one embodiment of the present invention, in step (2), the molar ratio of the first compound, propargyl bromide and potassium hydroxide is 1:1.4-1.6:1.5-2.5;
in the Williamson ether synthesis reaction process, the reaction temperature is 0-25 ℃, and the reaction time is 16-18 h.
In one embodiment of the present invention, in step (3), the molar ratio of the second compound, fluorenylmethoxycarbonyl-protected valine, dicyclohexylcarbodiimide, 4-dimethylaminopyridine is 1:1-1.5:1-1.5:0.1-0.3;
in the esterification reaction process, the reaction temperature is 15-30 ℃ and the reaction time is 1-3 h.
In one embodiment of the present invention, in step (4), the molar ratio of the third compound, α -D-mannopyranose azide, copper sulfate pentahydrate, and sodium ascorbate is 1:1.0-1.5:0.4-0.6:0.8-1.2;
the reaction temperature of the CuAAC click chemistry reaction is 15-30 ℃ and the reaction time is 4-8 h.
In one embodiment of the invention, in step (5), the molar ratio of the initiator to the fourth compound is from 12 to 15:1, a step of; the initiator is Grubbs third generation catalyst;
the reaction temperature of the ROMP polymerization reaction is 50-70 ℃ and the reaction time is 12-24 h.
In one embodiment of the invention, in step (6), the fifth compound and piperidine are used in an amount ratio of 0.076mol;
the reaction temperature of the substitution reaction is 25-30 ℃ and the reaction time is 1-2 h.
In one embodiment of the present invention, in step (1) to step (5), the post-treatment comprises washing, drying, and purifying processes.
In one embodiment of the invention, in step (6), the post-treatment is a purification process.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention prepares the glycopolypeptide by combining click reaction and ROMP polymerization to form a small polymer library with complete system and sufficient contrast group data, obtains the physical and chemical characteristics of the small polymer library, and explores a simple and efficient general method for the accurate synthesis of various peptidoglycans.
2. The preparation method has the advantages of simple route, few synthesis steps and high purification efficiency.
3. The invention can prepare the glycopolypeptide polymer with accurate and controllable sequence and structure.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a first compound in example 1;
FIG. 2 is a nuclear magnetic resonance spectrum of the first compound of example 1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the second compound of example 1;
FIG. 4 is a nuclear magnetic resonance spectrum of the second compound of example 1;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the third compound in example 1;
FIG. 6 is a nuclear magnetic resonance spectrum of the third compound in example 1;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of a fourth compound in example 1;
FIG. 8 is a nuclear magnetic resonance spectrum of a fourth compound in example 1;
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of the fifth compound in example 1;
FIG. 10 is a nuclear magnetic resonance spectrum of a polymer containing valine and mannose in example 1.
Detailed Description
The following describes in detail specific embodiments of the present invention by way of examples, which are given as detailed embodiments and specific operation procedures based on the embodiments of the present invention, but the scope of the present invention is not limited to the examples described below.
The invention provides a polymer with valine and mannose in side chains, wherein the chemical structural formula of the polymer with valine and mannose in the side chains is shown as the formula (I):
wherein n is a positive integer of 1 or more.
The invention also provides a preparation method of the polymer with valine and mannose in the side chain, which comprises the following steps:
(1) Reacting 5-norbornene-2, 3-dicarboxylic anhydride with 2-amino-2-methyl-1, 3-propanediol, and performing aftertreatment to obtain a first compound;
(2) The first compound obtained in the step (1) is subjected to Williamson ether synthesis reaction with propargyl bromide and potassium hydroxide, and is subjected to post-treatment to obtain a second compound;
(3) The second compound obtained in the step (2) is subjected to esterification reaction with valine protected by fluorenylmethoxycarbonyl, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and then a third compound is obtained after post-treatment;
(4) The third compound obtained in the step (3), alpha-D-mannopyranosyl azide, copper sulfate pentahydrate and sodium ascorbate undergo CuAAC click chemical reaction, and the fourth compound is obtained after post treatment;
(5) Performing ROMP polymerization reaction on the fourth compound obtained in the step (4) and an initiator, and performing post-treatment to obtain a fifth compound;
(6) Carrying out substitution reaction on the fifth compound obtained in the step (5) and piperidine, and carrying out post-treatment to obtain a polymer with valine and mannose in side chains;
the chemical structural formulas of the polymer with valine and mannose in the side chains, the first compound, the second compound, the third compound, the fourth compound and the fifth compound are respectively shown as the formula (I), the formula (II), the formula (III), the formula (IV), the formula (V) and the formula (VI):
wherein n is a positive integer of 1 or more.
In one embodiment of the present invention, in step (1), the molar ratio of 5-norbornene-2, 3-dicarboxylic anhydride to 2-amino-2-methyl-1, 3-propanediol is 1:1 to 1.5; in the reaction process, the reaction temperature is 110-125 ℃ and the reaction time is 18-24 h.
In one embodiment of the invention, in step (2), the molar ratio of the first compound, propargyl bromide and potassium hydroxide is 1:1.4-1.6:1.5-2.5; in the Williamson ether synthesis reaction process, the reaction temperature is 0-25 ℃ and the reaction time is 16-18 h.
In one embodiment of the present invention, in step (3), the molar ratio of the second compound, fluorene methoxycarbonyl protected valine, dicyclohexylcarbodiimide, 4-dimethylaminopyridine is 1:1-1.5:1-1.5:0.1-0.3; in the esterification reaction process, the reaction temperature is 15-30 ℃ and the reaction time is 1-3 h.
In one embodiment of the invention, in step (4), the molar ratio of the third compound, α -D-mannopyranose azide, copper sulfate pentahydrate, and sodium ascorbate is 1:1.0-1.5:0.4-0.6:0.8-1.2; in the process of CuAAC click chemistry reaction, the reaction temperature is 15-30 ℃ and the reaction time is 4-8 h.
In one embodiment of the invention, in step (5), the molar ratio of initiator to fourth compound is from 12 to 15:1, a step of; the initiator is Grubbs third generation catalyst; in the process of the ROMP polymerization reaction, the reaction temperature is 50-70 ℃ and the reaction time is 12-24 h.
In one embodiment of the invention, in step (6), the ratio of the amount of the fifth compound to the amount of piperidine used is 0.076mol; in the substitution reaction process, the reaction temperature is 25-30 ℃ and the reaction time is 1-2 h.
In one embodiment of the present invention, in step (1) to step (5), the post-treatment comprises washing, drying, and purifying processes.
In one embodiment of the invention, in step (6), the post-treatment is a purification process.
The invention will be further described with reference to the accompanying drawings and specific examples. In the technical scheme, the characteristics such as preparation means, raw material reagents, structures or composition ratios and the like which are not explicitly described are regarded as common technical characteristics disclosed in the prior art.
In the following examples, the sources of reagents used are as follows: alpha-Man-OAc-N 3 According to the literature [1] Synthesizing by a method; n, N-dimethylformamide (i.e., DMF, the same applies hereinafter) (99.8%) and anhydrous tetrahydrofuran (99%) were purchased from Shanghai Micin Biochemical technologies Co., ltd; propargyl bromide>99％)、Sodium ascorbate (99%), 4-lutidine (i.e., DMAP, the same applies below) were purchased from adamas reagent limited, shanghai; potassium hydroxide (95%), copper sulfate pentahydrate (99%), sodium sulfate anhydrous (95%) were purchased from national pharmaceutical group chemical reagent company, inc; ethyl acetate (99%) and tert-butanol%>=99.5%), methanol (99%), dichloromethane (99.5%), etc. and other non-mentioned reagents, all purchased from Shanghai research technologies, inc. Wherein, [1 ]]Herzberger J,Leibig D,Langhanki J,Moers C,Opatz T,Frey H.“Clickable PEG”via anionic copolymerization of ethylene oxide and glycidyl propargyl ether.Polymer Chemistry 2017,8(12)：1882-1887.
In the following examples, the raw material reagents and treatment techniques, unless otherwise specified, are all typical commercially available raw materials or typical treatment techniques in the art.
Example 1
This example provides a method for preparing polymers containing valine and mannose in the side chains using ROMP polymerization and click chemistry.
(1) Preparation of the first Compound
5-norbornene-2, 3-dicarboxylic anhydride (10 g,60.91 mmol) was added to a 1000mL dry reaction flask, 250mL toluene was added for dissolution, followed by 2-amino-2-methyl-1, 3-propanediol (7.685 g,73.09 mmol) and stirring at 110℃for 18h. After the reaction, the solvent was removed by rotary evaporation, ethyl acetate was dissolved, and the mixture was added dropwise to petroleum ether for recrystallization, and 5.8g of a white solid was obtained by filtration, with a yield of 38%.
The nuclear magnetic hydrogen spectrogram and the nuclear magnetic carbon spectrogram of the first compound are shown in fig. 1 and fig. 2 respectively.
The chemical structural formula of the first compound is shown as follows:
the nuclear magnetic data of the first compound are as follows:
1 H NMR(400MHz,CDCl 3 )δ6.14(s,2H),4.15(s,2H),3.64(s,4H),3.39(s,2H),3.22(s,2H),1.69(s,1H),1.52(s,1H),1.17(s,3H).
(2) Preparation of the second Compound
The first compound (10.00 g,39.82 mmol) was dissolved in 150mL of anhydrous DMF and placed in an ice-water bath with stirring, propargyl bromide (5.2 mL,59.73 mmol) was added slowly dropwise to the reaction flask over 30min, and stirring was continued after adding KOH (4.45 g,79.64 mmol) under ice-water bath conditions for a further 30min, and the reaction was continued at 0deg.C for 16h. The mixed solution was extracted three times with ethyl acetate and saturated brine, and after drying over anhydrous sodium sulfate, the product was separated by silica gel column chromatography to give 3.2g of a pale yellow oily substance, which was the second compound, in 28% yield.
The nuclear magnetic hydrogen spectrogram and the nuclear magnetic carbon spectrogram of the second compound are shown in fig. 3 and fig. 4 respectively.
The chemical structural formula of the second compound is shown as the following formula:
the nuclear magnetic data of the second compound are shown below:
1 H NMR(400MHz,CDCl 3 )δ6.15(s,2H),4.19(s,2H),3.65(s,4H),3.40(s,2H),3.23(s,2H),1.70s,1H),1.68(s,2H),1.53(s,1H),1.18(s,3H).
(3) Preparation of the third Compound
The second compound (1.5 g,5.19 mmol) was dissolved in 20mL anhydrous CH 2 Cl 2 Fmoc-L-valine (1.75 g,5.19 mmol) was added thereto and stirring was continued, and DCC (1.07 g,5.19 mmol) and DMAP (0.0637 g, 0.399 mmol) were added thereto to dissolve methylene chloride, and reacted at 15℃for 1 hour. After completion of the reaction, the product was filtered and separated by silica gel column chromatography to give 2.7g of a third compound as a white powder with a yield of 85%.
The nuclear magnetic hydrogen spectrogram and the nuclear magnetic carbon spectrogram of the third compound are shown in fig. 5 and 6 respectively.
The chemical structural formula of the third compound is shown as the following formula:
the nuclear magnetic data of the third compound are as follows:
1 H NMR(501MHz,CDCl 3 )δ7.76(s,2H),7.60(s,2H),7.40(s,2H),7.32(s,2H),6.13(s,2H),5.35(s,1H),4.67s,1H),4.46(s,2H),4.37(s,1H),4.30(s,1H),4.23(s,1H),3.90(s,2H),3.34(s,2H),3.13(s,2H),2.41(s,1H),2.16(s,1H),1.66(s,2H),1.48(s,4H),0.97(s,3H),0.89(s,3H).
(4) Preparation of the fourth Compound
A third compound (0.5 g,0.8 mmol) and α -D-mannopyranosyl azide (0.1848 g,0.9 mmol) were added to a 50mL reaction flask, and a mixed solution of t-butanol and deionized water (t-BuOH: H) was added to 15mL 2 O=1v: 1 v), copper sulfate pentahydrate (0.1 g,0.41 mmol), sodium ascorbate (0.16 g,0.8 mmol) was added after stirring for 30min, and the reaction was carried out at room temperature for 5h. After the completion of the reaction, the reaction mixture was extracted with saturated brine and methylene chloride, dried over anhydrous sodium sulfate, and then the product was separated by silica gel column chromatography to obtain 0.48g of a fourth compound as a white powder, the yield was 72%.
The nuclear magnetic hydrogen spectrogram and the nuclear magnetic carbon spectrogram of the fourth compound are shown in fig. 7 and 8 respectively.
The chemical structural formula of the fourth compound is shown as the following formula:
the nuclear magnetic data of the fourth compound are as follows:
1 H NMR(501MHz,CDCl 3 )δ7.73(s,2H),7.57(s,2H),7.35(s,2H),7.28(s,3H),6.02(s,3H),5.62(s,1H),4.76(s,2H),4.53(s,4H),4.39(s,3H),4.29(s,1H),4.26(s,2H),4.18(s,1H),4.08(s,1H),3.86(s,4H),3.26(s,2H),3.10(s,2H),2.10(s,1H),1.43(s,4H),1.25(s,2H),0.93(s,3H),0.87(s,3H).
(5) Preparation of the fifth Compound
In a nitrogen glove box, a fourth compound (0.1 g,0.12 mmol) was dissolved in 1mL DMF, grubbs' third generation catalyst was added, stirred at 50deg.C for 24h, quencher was added, stirred for 30min, diethyl ether was allowed to settle three times, and then dried under vacuum oven at 40deg.C for 12h to give a pale yellow powder, 0.06g of the fifth compound, in 60% yield.
The nuclear magnetic hydrogen spectrum of the fifth compound is shown in fig. 9.
The chemical structural formula of the fifth compound is shown as the following formula:
the nuclear magnetic data of the fifth compound are as follows:
1 H NMR(501MHz,CDCl 3 )δ8.01(s,1H),7.72(s,3H),7.57(s,2H),7.36(s,3H),7.26(s,2H),5.42(s,3H),4.33(s,12H),3.76(s,3H),3.47(s,1H),3.26(s,1H),3.09(s,1H),2.95(s,1H),2.88(s,1H),2.44(s,3H),2.23(s,1H),2.05(d,J＝50.9,1H),1.62(s,2H),1.42(s,1H),1.28(d,J＝19.2,2H),0.89(d,J＝38.8,6H).
(6) Preparation of polymers containing valine and mannose in side chains
The fifth compound (50 mg,0.06 mmol) was dissolved in DMF 1mL at room temperature, 0.2mL piperidine was added dropwise, the reaction was stirred for 1h at 25℃and then diluted hydrochloric acid was added for neutralization and filtration. The crude product was centrifuged three times with anhydrous diethyl ether. After vacuum drying, 40mg of brown powder, i.e., polymer having valine and mannose in its side chains, was obtained in 80% yield.
The nuclear magnetic resonance spectrum of the polymer with valine and mannose in the side chain is shown in FIG. 10.
The chemical structural formula of the polymer containing valine and mannose at the side chain is shown as the following formula:
the nuclear magnetic data of polymers containing valine and mannose in the side chains are shown below:
1 H NMR(400MHz,DMSO)δ8.17(s,1H),7.29(s,1H),5.89(s,1H),5.32(s,2H),4.46(d,J＝63.8,4H),3.82(s,3H),3.36(s,10H),3.08(s,2H),2.79(d,J＝63.9,2H),2.31(s,1H),1.62(d,J＝133.3,5H),0.74(s,6H).
the side chain valine and mannose containing polymer obtained in this example is a polysaccharide peptide which has been widely used in drug delivery studies, and the incorporation of amino acids and carbohydrates into one polymer not only compensates for the disadvantages of the sugar polymer, but also combines the properties of the two individual components with novel synergistic effects, the unique characteristics of the polypeptide, including chemical diversity, bioactivity and good biocompatibility of the amino acids, makes it have wide biological applications. Chen et al synthesized a galactosylated block polypeptide that effectively carried the DOX drug and formed a nano-drug with a hydrodynamic radius of about 50 nm. The nano-drug has the pH performance of responding to drug release, can be efficiently absorbed by HepG-2 liver cancer cells, and has good tumor cell targeting effect.
Example 2
This example provides a method for preparing polymers containing valine and mannose in the side chains using ROMP polymerization and click chemistry.
(1) Preparation of the first Compound
5-norbornene-2, 3-dicarboxylic anhydride (10 g,60.91 mmol) was added to a 1000mL dry reaction flask, 250mL toluene was added for dissolution, followed by 2-amino-2-methyl-1, 3-propanediol (6.404 g,60.91 mmol) and stirring at 120℃for 20h. After the reaction, the solvent was removed by rotary evaporation, ethyl acetate was dissolved, and the mixture was added dropwise to petroleum ether for recrystallization, and 6.3g of a white solid was obtained by filtration, with a yield of 41%.
(2) Preparation of the second Compound
The first compound (10.00 g,39.82 mmol) was dissolved in 150mL of anhydrous DMF and placed in an ice-water bath with stirring, propargyl bromide (4.8 mL,55.75 mmol) was added slowly dropwise to the reaction flask over 30min, and stirring was continued after adding KOH (3.34 g,59.73 mmol) under ice-water bath conditions for a further 30min, and reacted for 17h at 15 ℃. The mixed solution was extracted three times with ethyl acetate and saturated brine, and after drying over anhydrous sodium sulfate, the product was separated by silica gel column chromatography to give 3.3g of a pale yellow oily substance, which was the second compound, in 29% yield
(3) Preparation of the third Compound
The second compound (1.5 g,5.19 mmol) was dissolved in 20mL anhydrous CH 2 Cl 2 Fmoc-L-valine (2.10 g,6.23 mmol) was added thereto and stirring was continued, and DCC (1.28 g,6.23 mmol) and DMAP (0.1274 g,1.04 mmol) were added thereto to dissolve methylene chloride, followed by reaction at 20℃for 2 hours. After completion of the reaction, the product was filtered and separated by silica gel column chromatography to give 2.76g of a third compound as a white powder with a yield of 87%.
(4) Preparation of the fourth Compound
A third compound (0.5 g,0.8 mmol) and α -D-mannopyranosyl azide (0.2259 g,1.1 mmol) were added to a 50mL reaction flask, and a mixture of t-butanol and deionized water was added to 15mL (t-BuOH: H) 2 O=1v: 1 v), copper sulfate pentahydrate (0.12 g,0.48 mmol), sodium ascorbate (0.192 g,0.96 mmol) was added after stirring for 30min, and the reaction was carried out at room temperature for 5h. After the completion of the reaction, the reaction mixture was extracted with saturated brine and methylene chloride, dried over anhydrous sodium sulfate, and then the product was separated by silica gel column chromatography to obtain 0.48g of a fourth compound as a white powder, the yield was 72%.
(5) Preparation of the fifth Compound
In a nitrogen glove box, a fourth compound (0.1 g,0.12 mmol) was dissolved in 1mL DMF, grubbs' third generation catalyst was added, stirred at 50deg.C for 24h, quencher was added, stirred for 30min, diethyl ether was allowed to settle three times, and then dried under vacuum oven at 50deg.C for 18h to give a pale yellow powder, fifth compound 0.063g, in 63% yield.
(6) Preparation of polymers containing valine and mannose in side chains
The fifth compound (50 mg,0.06 mmol) was dissolved in DMF 1mL at room temperature, 0.2mL piperidine was added dropwise, the reaction was stirred at room temperature for 1.5h, then diluted hydrochloric acid was added for neutralization, and filtration. The crude product was centrifuged three times with anhydrous diethyl ether. After vacuum drying, 40mg of brown powder, i.e., polymer having valine and mannose in its side chains, was obtained in 80% yield.
Example 3
This example provides a method for preparing polymers containing valine and mannose in the side chains using ROMP polymerization and click chemistry.
(1) Preparation of the first Compound
5-norbornene-2, 3-dicarboxylic anhydride (10 g,60.91 mmol) was added to a 1000mL dry reaction flask, 250mL toluene was added to dissolve, followed by 2-amino-2-methyl-1, 3-propanediol (9.606 g,91.365 mmol) and stirred at 125℃for 24h. After the reaction, the solvent was removed by rotary evaporation, ethyl acetate was dissolved, and the mixture was added dropwise to petroleum ether for recrystallization, and 6.6g of a white solid was obtained by filtration, with a yield of 43%.
(2) Preparation of the second Compound
The first compound (10.00 g,39.82 mmol) was dissolved in 150mL of anhydrous DMF and placed in an ice-water bath with stirring, propargyl bromide (5.5 mL,63.71 mmol) was added slowly dropwise to the reaction flask over 30min, and stirring was continued with the addition of KOH (5.57 g,99.55 mmol) after 30min under ice-water conditions at 25℃for 18h. The mixed solution was extracted three times with ethyl acetate and saturated brine, and after drying over anhydrous sodium sulfate, the product was separated by silica gel column chromatography to give 3.4g of a pale yellow oily substance, which was a second compound, in 30% yield
(3) Preparation of the third Compound
The second compound (1.5 g,5.19 mmol) was dissolved in 20mL anhydrous CH 2 Cl 2 Fmoc-L-valine (2.63 g,7.79 mmol) was added thereto, stirring was continued, and DCC (1.61 g,7.79 mmol) and DMAP (0.1911 g,1.56 mmol) were added thereto to dissolve methylene chloride, followed by reaction at 30℃for 3 hours. After completion of the reaction, the product was filtered and separated by silica gel column chromatography to give 2.8g of a third compound as a white powder with a yield of 88%.
(4) Preparation of the fourth Compound
A third compound (0.5 g,0.8 mmol) and α -D-mannopyranosyl azide (0.1540 g,0.75 mmol) were added to a 50mL reaction flask, and 15mL of a mixed solution of t-butanol and deionized water (t-BuOH: H) 2 O=1v: 1 v), copper sulfate pentahydrate (0.08 g,0.32 mmol), sodium ascorbate (0.128 g,0.64 mmol) was added after stirring for 30min, and reacted at room temperature for 5h. After the completion of the reaction, the mixture was extracted with saturated brine and dichloromethane, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatographyThe product was isolated as a white powder, 0.48g of the fourth compound, 72% yield.
(5) Preparation of the fifth Compound
In a nitrogen glove box, a fourth compound (0.1 g,0.12 mmol) was dissolved in 1mL DMF, grubbs' third generation catalyst was added, stirred at 50deg.C for 24h, quencher was added, stirred for 30min, diethyl ether was allowed to settle three times, and then dried under vacuum oven at 60deg.C for 24h to give a pale yellow powder, namely, 0.065g of fifth compound with 65% yield.
(6) Preparation of polymers containing valine and mannose in side chains
The fifth compound (50 mg,0.06 mmol) was dissolved in DMF 1mL at room temperature, 0.2mL piperidine was added dropwise, the reaction was stirred at room temperature for 2h, then diluted hydrochloric acid was added for neutralization, and filtration. The crude product was centrifuged three times with anhydrous diethyl ether. After drying in vacuo, 42mg of a brown powder, i.e., a polymer having valine and mannose in its side chain, was obtained in a yield of 84%.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. A polymer with valine and mannose in side chains, which is characterized in that the chemical structural formula of the polymer with valine and mannose in side chains is shown as the formula (I):
in the formula (I), n is a positive integer greater than or equal to 1.
2. A method for preparing a polymer containing valine and mannose in a side chain by ROMP polymerization and click chemistry, comprising the steps of:
(1) Taking 5-norbornene-2, 3-dicarboxylic anhydride and 2-amino-2-methyl-1, 3-propanediol to react, and carrying out post-treatment to obtain a first compound;
(2) Carrying out Williamson ether synthesis reaction on the first compound obtained in the step (1) with propargyl bromide and potassium hydroxide, and carrying out post-treatment to obtain a second compound;
(3) Esterifying the second compound obtained in the step (2) with valine protected by fluorenylmethoxycarbonyl, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and performing post-treatment to obtain a third compound;
(4) Performing CuAAC click chemical reaction on the third compound obtained in the step (3), alpha-D-mannopyranosyl azide, copper sulfate pentahydrate and sodium ascorbate, and performing post-treatment to obtain a fourth compound;
(5) Performing ROMP polymerization reaction on the fourth compound obtained in the step (4) and an initiator, and performing post-treatment to obtain a fifth compound;
(6) Carrying out substitution reaction on the fifth compound obtained in the step (5) and piperidine, and carrying out post-treatment to obtain a polymer with valine and mannose in side chains;
the chemical structural formulas of the polymer with valine and mannose in the side chains, the first compound, the second compound, the third compound, the fourth compound and the fifth compound are respectively shown as the formula (I), the formula (II), the formula (III), the formula (IV), the formula (V) and the formula (VI):
wherein n is a positive integer of 1 or more.
3. The method for producing a polymer having valine and mannose in side chains by means of ROMP polymerization and click chemistry according to claim 2, wherein in step (1), the molar ratio of 5-norbornene-2, 3-dicarboxylic anhydride and 2-amino-2-methyl-1, 3-propanediol is 1:1 to 1.5;
the reaction temperature is 110-125 ℃ and the reaction time is 18-24 h.
4. The method for producing a polymer having valine and mannose in side chains by means of ROMP polymerization and click chemistry according to claim 2, wherein in step (2), the molar ratio of the first compound, propargyl bromide and potassium hydroxide is 1:1.4-1.6:1.5-2.5;
in the Williamson ether synthesis reaction process, the reaction temperature is 0-25 ℃, and the reaction time is 16-18 h.
5. The method for producing a polymer having valine and mannose in side chains by means of ROMP polymerization and click chemistry according to claim 2, wherein in step (3), the molar ratio of the second compound, fluorenylmethoxycarbonyl-protected valine, dicyclohexylcarbodiimide, 4-dimethylaminopyridine is 1:1-1.5:1-1.5:0.1-0.3;
in the esterification reaction process, the reaction temperature is 15-30 ℃ and the reaction time is 1-3 h.
6. The method for producing a polymer having valine and mannose in side chains by means of ROMP polymerization and click chemistry according to claim 2, wherein in step (4), the molar ratio of the third compound, α -D-mannopyranose azide, copper sulfate pentahydrate, and sodium ascorbate is 1:1.0-1.5:0.4-0.6:0.8-1.2;
the reaction temperature of the CuAAC click chemistry reaction is 15-30 ℃ and the reaction time is 4-8 h.
7. The method for producing a polymer having valine and mannose in side chains by means of ROMP polymerization and click chemistry according to claim 2, wherein in step (5), the molar ratio of the initiator to the fourth compound is 12 to 15:1, a step of; the initiator is Grubbs third generation catalyst;
the reaction temperature of the ROMP polymerization reaction is 50-70 ℃ and the reaction time is 12-24 h.
8. The method for producing a polymer having valine and mannose in side chains by using ROMP polymerization and click chemistry as recited in claim 2, wherein in step (6), the ratio of the fifth compound to piperidine used is 0.076mol;
the reaction temperature of the substitution reaction is 25-30 ℃ and the reaction time is 1-2 h.
9. The method for producing a polymer having valine and mannose in side chains by using ROMP polymerization and click chemistry according to claim 2, wherein the post-treatment comprises washing, drying, and purifying processes in the steps (1) to (5).
10. The method for producing a polymer having valine and mannose in side chains by using ROMP polymerization and click chemistry according to claim 2, wherein in step (6), the post-treatment is a purification process.
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