CN117164848A - Single molecular weight precise cyclic polyethylene glycol and preparation method thereof - Google Patents
Single molecular weight precise cyclic polyethylene glycol and preparation method thereof Download PDFInfo
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- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 153
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 148
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 14
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 14
- 230000004048 modification Effects 0.000 claims abstract description 10
- 238000012986 modification Methods 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 7
- 239000011630 iodine Substances 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 57
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000005846 sugar alcohols Polymers 0.000 claims description 4
- 125000002355 alkine group Chemical group 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000011161 development Methods 0.000 abstract description 3
- 239000012620 biological material Substances 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 230000003044 adaptive effect Effects 0.000 abstract 1
- 238000001819 mass spectrum Methods 0.000 description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 238000001228 spectrum Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 230000002209 hydrophobic effect Effects 0.000 description 8
- 229920005862 polyol Polymers 0.000 description 8
- 150000003077 polyols Chemical class 0.000 description 8
- 238000012512 characterization method Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000006116 polymerization reaction Methods 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 125000003827 glycol group Chemical group 0.000 description 4
- 150000002334 glycols Chemical class 0.000 description 4
- 229920000151 polyglycol Polymers 0.000 description 4
- 239000010695 polyglycol Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000021164 cell adhesion Effects 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012975 dibutyltin dilaurate Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- 241001089723 Metaphycus omega Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- 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
Landscapes
- Polyethers (AREA)
Abstract
The invention provides single-molecular-weight precise annular polyethylene glycol and a preparation method thereof, belonging to the technical field of chemistry and biological materials. The polyethylene glycol has a structural formula shown in a formula I or a formula II:wherein m and n respectively represent the number of the repeated units of polyethylene glycol, m=1 to 800, and n=1 to 400; c (C) k H l Selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl; r is R 1 、R 2 、R 3 Selected from any one of the following structures:R 4 selected from any one of the following structures:R 5 selected from any one of hydrogen, methyl, bromine and iodine. The structure of the single-molecular-weight precise cyclic polyethylene glycol is the combination of the cyclic polyethylene glycol and the linear polyethylene glycol with hydroxyl at the tail end, and the hydrophilicity and the stronger affinity of the hydroxyl enable the hydroxyl to react with different groups so as to prepare the derivative of the adaptive cyclic polyethylene glycol, thereby realizing the functional modification of the precise cyclic polyethylene glycol and further promoting the development of the precise cyclic polyethylene glycol.
Description
Technical Field
The invention relates to the field of chemistry and biological materials, in particular to single-molecular-weight precise annular polyethylene glycol and a preparation method thereof.
Background
Polyethylene glycol (PEG) is a typical water-soluble polymer, has excellent lubricity, moisture retention, dispersibility and adhesiveness, and is widely applied to industries such as cosmetics, biological medicines, pesticides, food processing and the like. In the biomedical application field, PEG with better biocompatibility is a polymer with lower cellular uptake level in the known synthetic polymer. Meanwhile, the PEG can be introduced into terminal functional groups through chemical modification to form various PEG derivatives, and the molecular weight and the topological structure of the PEG derivatives can be regulated and controlled. These properties make PEG and its derivatives more widely used in the fields of drug covalent conjugation and surface modification of medical instruments.
Compared with the traditional high polymer materials, the PEG raw materials used in the PEGylation drugs at present are mixtures with chain length polydisperse characteristics. Although in the related art, relatively narrow distributions can be synthesized by anionic polymerization meansThe products produced remain as a mixture (the degree of mixing of which comprises 40 to 60).
In the related art, ethylene glycol is taken as a starting material, and PEG with 36 percent (490 mg) of total yield is obtained by a six-step bidirectional growth method 29 The method comprises the steps of carrying out a first treatment on the surface of the Subsequently, related studies have avoided cumbersome protection/deprotection steps using macrocyclic intermediate strategies to synthesize terminal methoxy monodisperse PEG (MeO-PEG) with a degree of polymerization of 64 64 -OH) and cyclic monodisperse PEG, but conventional polymer characterization means such as GPC are not used in the report, and the cyclic monodisperse PEG cannot be functionally modified, so that serious limitation is imposedThe application range is widened. While biomacromolecule-PEG coupling strategies require terminal chemical modification of PEG, the most common coupling strategy involves amide bond (by activating carboxylate) and thioether/disulfide bond formation. The most synthesized monodisperse cyclic PEG is reported to be a crown ether of 81 atoms with a degree of polymerization of 27, but lacks a more stringent characterization means.
In summary, in the related art, monodisperse polyethylene glycol is prepared more, but the polymerization degree is improved compared with that of the polydisperse polyethylene glycol, but the components are not sufficiently accurate, and a more strict characterization means is lacking, so that the monodisperse polyethylene glycol is still in the exploration stage.
Disclosure of Invention
In view of the above, the invention proposes to construct a single molecular weight precise cyclic polyethylene glycol, which can precisely position and prepare polyethylene glycol compounds, and directly associate to the precise structure itself through experimental structure, thereby defining the specific structure, being a single compound with determined molecular weight, and further promoting the development of precise cyclic polyethylene glycol.
The invention aims to provide single-molecular-weight precise cyclic polyethylene glycol.
The invention also aims at providing a preparation method of the single-molecular-weight precise cyclic polyethylene glycol.
The above object of the present invention is achieved by the following means.
According to an embodiment of one aspect of the present invention, there is provided a single molecular weight precise cyclic polyethylene glycol having a structural formula shown in formula I or formula ii:
wherein m and n respectively represent the number of the repeated units of polyethylene glycol, m=1 to 800, and n=1 to 400; c (C) k H l Selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl; r is R 1 、R 2 、R 3 Selected from any one of the following structures:
R 4 selected from any one of the following structures:
r5 is selected from any one of hydrogen, methyl, bromine and iodine.
In some embodiments, the single molecular weight precision cyclic polyethylene glycol has a number average molecular weight of 250 to 50000.
In some embodiments, n is 4 to 200, m=2n_1.
In some embodiments, the single molecular weight precision cyclic polyethylene glycol described above includes formula I 1 To formula I 12 A compound of the structure shown in (a):
according to an embodiment of another aspect of the present invention, there is provided a method for preparing a single molecular weight precise cyclic polyethylene glycol, comprising the steps of: reacting the polyglycerin shown in the formula A with the polyalcohol shown in the formula B to prepare the single-molecular-weight three-arm branched glycol shown in the formula C;
protecting one hydroxyl group in the single-molecular-weight three-arm branched glycol shown in the formula C by using a protecting group T to prepare a compound shown in the formula D;
protecting the other hydroxyl group in the compound shown in the formula D by using p-toluenesulfonyl to obtain a compound shown in the formula E;
cyclizing the obtained compound shown in the formula E to obtain a compound shown in the formula F or the formula G;
deprotection reaction is carried out on the compound shown in the formula F or the formula G to obtain precise cyclic polyethylene glycol with single molecular weight shown in the formula H or the formula I;
i is 1 to 200, n is 1 to 400, m is 1 to 800, and k and l are 0 to 400.
In some embodiments, the protecting group T is selected from the following structural formulas:
R 6 h, C of a shape of H, C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkylene radicals C of (2) 2 ～C 100 Any one of the alkyne groups of (a);
R 7 selected from the following structural formulas:
or C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkenyl, C 2 ～C 100 Any one of the alkynyl groups of (2), u, v and w are each independently 0 to 400.
In some embodiments, the ether forming reaction conditions are: reacting in a first solvent for 4 hours to 3 days at a temperature of 20 to 100 ℃, wherein the first solvent comprises tetrahydrofuran and methanol;
the conditions for radical protection of the single molecular weight three-arm branched glycols of formula C are: reacting in a second solvent at a temperature of-10 to 20 ℃ for 8 hours to 2 days, wherein the second solvent comprises tetrahydrofuran and dichloromethane;
the conditions for preparing the compound of formula D are: reacting for 12-24 h in a third solvent at 0-20 ℃, wherein the third solvent comprises tetrahydrofuran and sodium hydroxide aqueous solution;
the conditions for preparing the precise cyclic polyethylene glycol shown in the formula F or the formula G are as follows: reacting in a fourth solvent at 0-20 ℃ for 12 hours-3 days, wherein the concentration of the compound shown in the formula F or the formula G is 0.1-10 mol/L, and the fourth solvent comprises tetrahydrofuran;
the reaction conditions for obtaining the precise cyclic polyethylene glycol shown in the formula H or the formula I are as follows: reacting in a fifth solvent at 0-20 ℃ for 2-12 h, wherein the fifth solvent comprises methanol.
In some embodiments, the method further comprises the step of carrying out group modification on the terminal hydroxyl of the single-molecular-weight precise cyclic polyethylene glycol shown in the formula H or the formula I to prepare a compound shown in the formula I or the formula II;
wherein m and n respectively represent the number of the repeated units of polyethylene glycol, m=1 to 800, and n=1 to 400;
C k H l selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl;
R 1 、R 2 、R 3 selected from any one of the following structures:
R 4 selected from any one of the following structures:
R 5 selected from any one of hydrogen, methyl, bromine and iodine.
Based on the technical scheme, the single-molecular-weight precise annular polyethylene glycol and the preparation method thereof provided by the invention have one or a part of the following beneficial effects:
in the related art, polydisperse polyethylene glycol (the polymerization degree contains 20-80) or monodisperse polyethylene glycol (the polymerization degree contains 40-60) is used, and compared with polydisperse polyethylene glycol, the monodisperse polymerization degree has smaller relatively span range, the disperse phase variety is relatively single, the particle size is relatively narrow in steps, but the disadvantage is that the components still belong to a mixture and are not accurate enough. The single molecular weight cyclic polyethylene glycol of the invention has only one polymerization degree, can define a specific structure, is a single compound with determined molecular weight, and can directly relate to the precise structure thereof. The intermediate of the structure of the single molecular weight cyclic polyethylene glycol is hydroxyl of polyethylene glycol with one end being cyclic and the other end being linear, or hydroxyl of polyethylene glycol with both ends being linear, and polyethylene glycol with the middle being cyclic, the hydrophilic property and the stronger affinity of the hydroxyl enable the intermediate to react with different groups or motifs to adapt to the prepared derivatives of various cyclic polyethylene glycols, so that the functional modification of the precise cyclic polyethylene glycol is realized, and the development of the precise cyclic polyethylene glycol is further promoted. The structure of the single molecular weight cyclic polyethylene glycol is favorable for further popularization and application in resisting protein adsorption and cell adhesion and enhancing the curative effect of the medicine when the single molecular weight cyclic polyethylene glycol forms subsequent derivatives. Meanwhile, because different groups connected with the main chain and the tail end of the polyethylene glycol have different affinities for the polyethylene glycol antibody, the precise cyclic polyethylene glycol is beneficial to have profound reference significance in the biomedical aspect of polyethylene glycol drugs. In addition, no related research report on the accurate annular polyethylene glycol exists at present, and the invention fills a gap for the system of the accurate annular polyethylene glycol.
Drawings
The present invention is described in further detail below with reference to the accompanying drawings.
FIG. 1 shows the nuclear magnetic resonance hydrogen spectrum and the mass spectrum of single molecular weight end-protected triethylene glycol of product 3 in example 1 of the present invention, wherein a is the nuclear magnetic resonance hydrogen spectrum of product 3 and b is the mass spectrum of product 3;
FIG. 2 shows the NMR hydrogen spectrum and the mass spectrum of single molecular weight triethylene glycol of product 5 in example 1 of the present invention, wherein a is the NMR hydrogen spectrum of product 5 and b is the mass spectrum of product 5;
fig. 3 shows the nmr hydrogen spectrum and the mass spectrum of a single molecular weight precise cyclic polyethylene glycol of molecular weight n=8 in example 1 of the invention, wherein a is the nmr hydrogen spectrum of polyethylene glycol of n=8, and b is the mass spectrum of polyethylene glycol of n=8;
fig. 4 shows the nmr hydrogen spectrum and the mass spectrum of a single molecular weight precise cyclic polyethylene glycol of molecular weight n=16 in example 2 of the invention, where a is the nmr hydrogen spectrum of the polyethylene glycol at n=16 and b is the mass spectrum of the polyethylene glycol at n=16; and
fig. 5 shows a mass spectrum of single molecular weight precision cyclic dihydroxypolyethylene glycol with a molecular weight of n=8 in example 3 of the present invention.
Detailed Description
In the related art, in polyethylene glycol having an average molecular weight of 2000Da (a dispersity of 1.04), the molecular weight distribution of the polyethylene glycol component covers a wide range of 1000 to 3000 Da. However, polyethylene glycols of relatively high purity, e.g. PEG n (n>7-8), there is currently a lack of reliable commercial sources. Whereas PEG of relatively low purity n Is relatively expensive, such as PEG with a purity of 95% 8 Up to 100 euros per gram. In the process of realizing the invention, the invention discovers that after the polyglycol prepared by the ether forming reaction and the single radical protection of the polyglycol, one of the residual hydroxyl groups can be reacted, and then the ring closure reaction is further carried out, thus being beneficial to forming the single molecular weight precise annular polyglycol.
In view of the above, the invention prepares the single molecular weight three-arm branched glycol through ether formation reaction, then carries out selective group protection on one of three hydroxyl groups in the three-arm branched glycol, then reacts one of the remaining two hydroxyl groups, then carries out ring closure reaction, and finally carries out deprotection to obtain the single molecular weight precise annular polyethylene glycol which can be modified functionally, and finally carries out group modification on hydroxyl suitability.
The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent.
According to an embodiment of one aspect of the present invention, there is provided a single molecular weight precision cyclic polyethylene glycol of formula I or formula II,
wherein m and n each represent the number of repeating units of polyethylene glycol, and m=1 to 800, for example, 10. 20, 50, 100, 200, 250, 300, 350, 400, 450, 500, 600, 700; n=1 to 400, for example 10, 20, 50, 100, 200, 250, 300, 350; c (C) k H l Selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl; r is R 1 、R 2 、R 3 Selected from any one of the following structures:
R 4 selected from any one of the following structures:
R 5 selected from any one of hydrogen, methyl, bromine and iodine.
Further preferably, C k H l Selected from C 1 ～C 50 Alkyl, C of (2) 2 ～C 50 At least one of alkenyl or alkynyl.
In some embodiments, a single molecular weight precision cyclic polyethylene glycol as shown in formula I or formula ii, due to having a definite number of single molecular weights, is of definite composition, and the experimental effect exhibited can be directly related to its precision structure itself. The structure of the single molecular weight cyclic polyethylene glycol is polyethylene glycol with one end being cyclic, the other end being the hydroxyl of linear polyethylene glycol, or the two ends being the hydroxyl of linear polyethylene glycol, and the middle being the cyclic polyethylene glycol. The hydroxyl at the end of the modified polyethylene glycol has hydrophilicity and stronger affinity, so that the hydroxyl can react with different groups or motifs to adapt to the prepared derivatives of various cyclic polyethylene glycols, the functional modification of the precise cyclic polyethylene glycol is realized, and the progress of the precise cyclic polyethylene glycol is further promoted. The structure of the single molecular weight cyclic polyethylene glycol is favorable for further popularization and application in resisting protein adsorption and cell adhesion and enhancing the curative effect of the medicine when the single molecular weight cyclic polyethylene glycol forms subsequent derivatives. Meanwhile, because different groups connected with the main chain and the tail end of the polyethylene glycol have different affinities for the polyethylene glycol antibody, the precise cyclic polyethylene glycol is beneficial to have profound reference significance in the biomedical aspect of polyethylene glycol drugs. In addition, no related research report on the accurate annular polyethylene glycol exists at present, and the invention fills a gap for the system of the accurate annular polyethylene glycol.
In some embodiments, the number average molecular weight of the single molecular weight precision cyclic polyethylene glycol is 250-50000, e.g., 1000, 5000, 8000, 10000, 13000, 15000, 18000, 21000, 25000, 30000, 35000, 40000, 45000, 50000, and the like. But are not limited to, the recited values, and other non-recited values within the range of values are equally applicable. The number average molecular weight of polyethylene glycol with single molecular weight directly affects the activity property in organisms, different molecular weights can generate different biological effects and influences, and low molecular weight polymers have stronger toxicity, when the molecular weight is increased, the aggregation degree is reduced, the particle diameter is increased, so that the space size can be increased, and the usability of an active center can be increased. The single-molecular-weight precise annular polyethylene glycol prepared by the embodiment of the invention has the dispersity of 1, and can further widen the molecular weight of the annular polyethylene glycol, so that the annular polyethylene glycol is suitable for wider practical application in biomedical aspects and the like.
In some embodiments, n is 4 to 200, e.g., 10, 20, 40, 60, 80, 100, 150, 180, 200, m=2n_1 or m=2n. When the related pre-experiment of the invention is carried out, the preparation process is relatively simpler when m is the range of the interval, because when three arms of the three-arm branched glycol are equal in length, the equal-length polyethylene glycol can be adopted to react to form an ether chain, and the hydroxy protection and deprotection are not required to be repeatedly carried out, so that the method is simpler and more convenient compared with the polyethylene glycol with different carbon numbers.
In some embodiments, the single molecular weight precision cyclic polyethylene glycol described above includes formula I 1 To formula I 12 A compound of the structure shown in (a):
according to an embodiment of the present invention, there is also provided a method for preparing a single molecular weight precise cyclic polyethylene glycol, including operations S101 to S105:
in operation S101, a polyol represented by formula a and a polyol represented by formula B are reacted to prepare a single molecular weight three-arm branched glycol represented by formula C.
In operation S102, protecting one hydroxyl group in the single-molecular-weight three-arm branched glycol shown in the formula C by using a protecting group T to prepare a compound shown in the formula D;
in operation S103, protecting the other hydroxyl group in the compound represented by formula D with p-toluenesulfonyl to obtain a compound represented by formula E;
in operation S104, cyclizing the obtained compound represented by formula E to obtain a compound represented by formula F or formula G;
in operation S105, performing deprotection reaction on the compound shown in the formula F or the formula G to obtain precise cyclic polyethylene glycol with single molecular weight shown in the formula H or the formula I;
wherein i is 1 to 200, for example 10, 20, 50, 100, 130, 150, 180; n is 1 to 400 and may be, for example, 10, 20, 50, 100, 200, 250, 300, 350, 400; m is 1 to 800, for example 10, 20, 50, 100, 200, 250, 300, 350, 400, 450, 500, 600, 700; k. l is 0 to 400, for example, 10, 20, 50, 100, 200, 250, 300, 350, 400, etc., but is not limited to the recited values, and other non-recited values within the range are equally applicable.
In some embodiments, further reacting the polyglycerin represented by formula a with the polyol represented by formula B is specifically the following steps: performing hydrophobic end capping on one end of the polyglycerin shown in the formula A to obtain a polyglycerin with one end subjected to hydrophobic end capping, and performing condensation reaction on the polyglycerin with one end subjected to hydrophobic end capping and the polyalcohol shown in the formula B to bond the polyalcohol shown in the formula B with the polyglycerin; carrying out hydrolysis reaction on polyol bonded with the polyethylene glycol to remove hydrophobic end-capping groups, so as to obtain three-arm branched ethylene glycol with single molecular weight; the single molecular weight three-arm branched glycol is iterated to form new polyol, and the condensation reaction and the hydrolysis reaction are repeated until the single molecular weight three-arm branched glycol with target molecular weight is obtained.
In some embodiments, further, the structure of the hydrophobically capped polyglycol at one end isWherein TG represents a hydrophobic end capping group, including any one of the following structures:
wherein,p is each independently 0 to 100, for example 10, 20, 30, 40, 50, 60, 70, 80, 90; q is each independently 0 to 201For example 10, 20, 50, 100, 130, 150, 180, 200; r is each independently 0 to 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, etc., but is not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some embodiments, C f H g The same or different are each independently selected from hydrogen, C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkenyl, C 2 ～C 100 Alkynyl of (a); c (C) f H g O e The same or different are each independently selected from hydrogen, hydroxy, C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkenyl, C 2 ～C 100 Alkynyl, C 1 ～C 100 An alkoxy group. C (C) f H g May be C 18 H 37 ，C f H g O e May be C 20 H 41 O。
In some embodiments, C 1 ～C 100 The alkyl group of (C) may be, for example, methyl, ethyl, propyl, isopropyl, n-heptyl, etc., C 2 ～C 100 Alkenyl groups of (C) may be, for example, vinyl, allyl, 3-butenyl, etc 2 ～C 100 The alkynyl group of (C) may be, for example, ethynyl, propargyl, 3-butynyl or the like 1 ～C 100 The alkoxy group may be, for example, methoxy, ethoxy, propoxy, isopropoxy, n-heptyloxy and the like.
In some embodiments, the first condensation reaction of a hydrophobically capped polyol having one end with a polyol of formula B comprises:
diethylene glycol with one end hydrophobically cappedThe resulting compound was +.>Condensation reaction with a polyol represented by formula B. />
In some casesIn embodiments, for ease of illustration of the preparation of single molecular weight three-arm branched glycols of formula C, hydrophobic end capping groups are usedBy way of illustration as a specific example,
one specific embodiment is shown in the following variant:
in some embodiments, where the reaction conditions for obtaining the single molecular weight precise cyclic polyethylene glycol of formula I or formula ii are the same, the details are not repeated herein, except that when preparing the single molecular weight precise cyclic polyethylene glycol of formula I, the concentration of the cyclization reaction solution is controlled to be 0.1-2 mmol/L; when preparing single molecular weight precise cyclic polyethylene glycol of formula II, the concentration of cyclization reaction solution is controlled at 5-10 mmol/L.
In some embodiments, one hydroxyl group in the single molecular weight three-arm branched glycol of formula C is protected with a protecting group T, specifically the following steps: the hydrophobic end-capped compound reacts with single-molecular-weight three-arm branched glycol shown in a formula C under the catalysis of a base catalyst to obtain an intermediate, and then reacts with p-toluenesulfonyl chloride to generate a compound shown in a formula D, one end of which is end-capped by hydrophobic.
In some embodiments, the protecting group T is selected from the following structural formulas:
/>
wherein R is 6 H, C of a shape of H, C 1 ～C 100 Alkoxy, C 2 ～C 100 Alkylene radicals C of (2) 2 ～C 100 Any one of the alkyne groups of (a);
R 7 selected from the following structural formulas:
or C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkenyl, C 2 ～C 100 Any one of the alkynyl groups of (2), u, v and w are each independently 0 to 400.
In some embodiments, the ether forming reaction conditions are: reacting in a first solvent, which may be tetrahydrofuran and methanol, at a temperature of 20 to 100 ℃, for example, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃ for 4 hours to 3 days, for example, 4 hours, 12 hours, 18 hours, 1 day, 32 hours, 40 hours, 2 days, 3 days;
the conditions for radical protection of the single molecular weight three-arm branched glycols of formula C are: reacting in a second solvent, which may be tetrahydrofuran and methylene chloride, at a temperature of-10 to 20 ℃, for example, at-10 ℃, 0 ℃, 10 ℃, 20 ℃ for 8 hours to 2 days, for example, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 36 hours, 2 days;
the conditions for preparing the compound shown in the formula D are that the compound reacts for 12 to 24 hours in a third solvent at the temperature of 0 to 20 ℃, wherein the third solvent comprises tetrahydrofuran and sodium hydroxide aqueous solution;
the conditions for preparing the precise cyclic polyethylene glycol shown in the formula F or the formula G are as follows: reacting in a fourth solvent at 0-20 ℃ for 12 hours-3 days, wherein the concentration of the compound shown in the formula F or the formula G is 0.1-10 mol/L, and the fourth solvent comprises tetrahydrofuran;
the reaction conditions for obtaining the precise cyclic polyethylene glycol shown in the formula H or the formula I are as follows: reacting in a fifth solvent at 0-20 ℃ for 2-12 h, wherein the fifth solvent comprises methanol.
In some embodiments, the method further comprises the step of carrying out group modification on the terminal hydroxyl group of the single-molecular-weight precise cyclic polyethylene glycol shown in the formula (H) or the formula (I) to prepare a compound shown in the formula (I) or the formula (II);
wherein m and n respectively represent the number of the repeated units of polyethylene glycol, m=1 to 800, and n=1 to 400;
C k H l selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl;
R 1 、R 2 、R 3 selected from any one of the following structures:
R 4 selected from any one of the following structures:
R 5 selected from any one of hydrogen, methyl, bromine and iodine.
It should be noted that, the conventional dispersion type cyclic polyethylene glycol often has a limitation in practical application, for example, polyethylene glycol does not have a suitable modification site, which greatly limits the practical application in various aspects of biomedicine and the like. In one aspect of the present invention, the precise cyclic modifiable polyethylene glycol has not been reported in the related research, which fills a gap for the precise cyclic polyethylene glycol system. On the other hand, the biological activity of traditional polydisperse polyethylene glycol and single molecular weight accurate polyethylene glycol is different. Recent researches find that the single molecular weight precise polyethylene glycol has obvious advantages in the aspects of resisting protein adsorption and cell adhesion, enhancing the curative effect of medicines and the like, so that the precise annular polyethylene glycol system has the same advantages. Finally, anti-polyethylene glycol antibodies are of various kinds, and different anti-polyethylene glycol antibodies exhibit different affinities for polyethylene glycol backbone and end groups. Therefore, the system of the precise annular polyethylene glycol has profound reference significance in the biomedical aspect of polyethylene glycol drugs. Therefore, the design and synthesis of the single-molecular-weight precise annular polyethylene glycol capable of being functionally modified have important scientific significance and great practical value.
The invention is further illustrated by the following examples. In the following detailed description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough explanation of the embodiments of the invention. It may be evident, however, that one or more embodiments may be practiced without these specific details. Moreover, the details of the various embodiments below may be arbitrarily combined into other viable embodiments without conflict.
It should be noted that the following examples illustrate the details of the present invention, and tetraethylene glycol was purchased from pichia pastoris and used as such. Sodium hydride was purchased from Alfa Aesar. 4-Methylbenzenesulfonyl chloride, trityl chloride, 1-trimethylolethane, trifluoroacetic acid, triethylsilane were purchased from Anaglycone chemical and used as received. Sodium carbonate (Na) 2 CO 3 ) Dibutyl tin Dilaurate (DBTL), ethyl acetate (EtOAc), tetrahydrofuran (THF), methanol, diethyl ether, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene were purchased from national medicine company, chemical company limited and used as received. The water was Deionized (DI) using a Milli-Q SP reagent water system (Millipore) to achieve a resistivity of 18.4 M.OMEGA.cm. Unless otherwise indicated, all other reagents were purchased from national pharmaceutical group chemical company, ltd, and used as received. Methods such as immunofluorescent staining are well known in the art and may be performed by textbooks or descriptions of related documents, and are not described in detail.
The nuclear magnetic detection of the embodiment of the invention uses a Bruker 400MHz nuclear magnetic instrument, the element analysis is measured by China science and technology center of theory, the molecular weight and the molecular weight distribution are measured by high-temperature GPC, and the mass spectrum is measured by Thermo LTQ Orbitrap XL.
Example 1
Preparation of single molecular weight precision cyclic polyethylene glycol with molecular weight of n=8
The three-arm glycol molecule is prepared by the following synthetic route:
8mmol of the compound represented by formula 1 and 2mmol of the compound represented by formula 2 as described in the above figures were taken and mixed in a 250mL round-bottomed flask, and 100mL of tetrahydrofuran was added thereto and stirred sufficiently to be dissolved uniformly. Then 12mmol of NaH was added to the system in portions and heated to 70℃for reaction at reflux for 12h. Purification by column gave a white solid as shown in product 3 in the above scheme. FIG. 1 shows the nuclear magnetic resonance hydrogen spectrum and the mass spectrum of single molecular weight end-protected triethylene glycol of the product 3 in the embodiment 1 of the invention, wherein a is the nuclear magnetic resonance hydrogen spectrum of the product 3, b is the mass spectrum of the product 3, the specific structure of the compound shown in the product 3 can be clarified through the characterization of the nuclear magnetic resonance hydrogen spectrum and the mass spectrum, and the results are shown in FIGS. 1 a-b.
2mmol of the compound represented by the product 3 was added to a 250mL round-bottomed flask, 50mL of methanol was added thereto for sufficient dissolution, and then 2mmol of the compound represented by the formula 4 was added to the round-bottomed flask for sufficient stirring, and reacted at room temperature of 20℃for 6 hours. Final column purification afforded the three-arm glycol shown in product 5 as a colorless viscous material. FIG. 2 shows the NMR spectrum and the mass spectrum of single molecular weight triethylene glycol of product 5 in example 1 of the invention, wherein a is the NMR spectrum of product 5 and b is the mass spectrum of product 5. The specific structure of the compound shown in this product 5 can be clarified by characterization of nuclear magnetic resonance hydrogen spectra and mass spectra, and the results are shown in fig. 2a to b.
Precursors of closed-loop molecules (i.e., compounds shown in scheme 9 below) were synthesized. The synthetic route is as follows:
1.5mmol of the compound represented by formula 5 was added to a 250mL round-bottomed flask, 50mL of anhydrous dichloromethane was added thereto, and the mixture was sufficiently dissolved, 1.5mmol of the compound represented by formula 6, 3.0mmol of the compound represented by formula 7, and 0.15mmol of the compound represented by formula 8 were added to the round-bottomed flask, and the mixture was reacted at room temperature for 12 hours under protection of inert gas nitrogen. Purifying by column to obtain the compound shown in formula 9 as light yellow sticky substance.
Then 0.5mmol of the compound shown in the formula 9 is added into a 250mL round bottom flask, 100mL of tetrahydrofuran is added, the mixture is fully stirred and dissolved uniformly, the mixture is placed in an ice bath environment at 0 ℃ for fully cooling, 0.5mmol of the compound shown in the formula 10 is dissolved in the tetrahydrofuran, the mixture is dropwise added into a reaction system, and the reaction is carried out for 12 hours at the room temperature of 20 ℃. Purification by column afforded the compound of formula 11 as a pale yellow solid.
The single molecular weight precise cyclic polyethylene glycol is prepared, and the synthetic route is as follows:
0.2mmol of the compound shown in the formula 11 is added into a 250mL round bottom flask, 1000m tetrahydrofuran is added for full and uniform dissolution, the mixture is placed in an ice bath environment at 0 ℃ for full cooling, 0.5mmol of NaH is added into a reaction system, and the reaction is carried out for 72 hours at room temperature of 20 ℃. Purifying with column to obtain compound shown in formula 12 as light yellow sticky substance.
0.1mmol of the compound represented by formula 12 was added to a 250mL round-bottomed flask, 10mL of methanol was added thereto and dissolved sufficiently and uniformly, and 10mL of an aqueous solution of 0.1mmol of NaOH was added to the reaction system to perform reflux reaction for 12 hours. Purification by column afforded product 14 as a white solid. Fig. 3 shows a nuclear magnetic resonance hydrogen spectrum and a mass spectrum of a single molecular weight precise cyclic polyethylene glycol with a molecular weight of n=8 in the embodiment of the invention, wherein a is the nuclear magnetic resonance hydrogen spectrum of the polyethylene glycol with n=8, b is the mass spectrum of the polyethylene glycol with n=8, and the specific structure of the compound shown in the formula 14 can be clarified through the characterization of the nuclear magnetic hydrogen spectrum and the mass spectrum. The results are shown in fig. 3.
Example 2
In a similar manner to example 1, a single molecular weight precise cyclic polyethylene glycol structure corresponding to n=16 was synthesized. Fig. 4 shows the nmr hydrogen spectrum and the mass spectrum of the single molecular weight precise cyclic polyethylene glycol of the molecular weight n=16 in example 2 of the present invention, wherein a is the nmr hydrogen spectrum of the polyethylene glycol of the molecular weight n=16, b is the mass spectrum of the polyethylene glycol of the molecular weight n=16, and the specific structure of the compound can be clarified by the characterization of the nmr hydrogen spectrum and the mass spectrum. The results are shown in fig. 4.
Example 3
In a similar manner to example 1, except that the reaction concentration of the compound represented by formula 11 was controlled to 5 to 10mmol/L, the compound represented by formula 29 was finally obtained.
Fig. 5 shows a mass spectrum of a single molecular weight precision cyclic dihydroxypolyethylene glycol having a molecular weight of n=8 in example 3 of the present invention, and the structure thereof is characterized by mass spectrometry (MALDI-TOF MS) as shown in fig. 5.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the invention thereto, but to limit the invention thereto, and any modifications, equivalents, improvements and equivalents thereof may be made without departing from the spirit and principles of the invention.
Claims (8)
1. A single molecular weight precise cyclic polyethylene glycol, which has a structural formula shown in a formula (I) or a formula (II):
wherein m and n respectively represent the number of the repeated units of polyethylene glycol, m=1 to 800, and n=1 to 400;
C k H l selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl;
R 1 、R 2 、R 3 selected from any one of the following structures:
R 4 selected from any one of the following structures:
R 5 selected from any one of hydrogen, methyl, bromine and iodine.
2. The single molecular weight precision cyclic polyethylene glycol according to claim 1, wherein said single molecular weight precision cyclic polyethylene glycol has a number average molecular weight of 250 to 50000.
3. The single molecular weight precise cyclic polyethylene glycol according to claim 1, wherein n is 4 to 200, m = 2n-1 or m = 2n.
4. The single molecular weight precision cyclic polyethylene glycol according to claim 1, wherein said single molecular weight precision cyclic polyethylene glycol has formula (I 1 ) Of formula (I) 12 ) Any one of the structures shown in:
5. the preparation method of the single-molecular-weight precise cyclic polyethylene glycol comprises the following steps:
reacting the polyglycerin shown in the formula (A) with the polyalcohol shown in the formula (B) to prepare the single-molecular-weight three-arm branched glycol shown in the formula (C);
protecting one hydroxyl group in the single-molecular-weight three-arm branched glycol shown in the formula (C) by using a protecting group T to prepare a compound shown in the formula (D);
protecting the other hydroxyl group in the compound shown in the formula (D) by using p-toluenesulfonyl to obtain a compound shown in the formula (E);
cyclizing the obtained compound shown in the formula (E) to obtain a compound shown in the formula (F) or (G);
deprotection reaction is carried out on the compound shown in the formula (F) or the formula (G) to obtain precise cyclic polyethylene glycol with single molecular weight shown in the formula (H) or the formula (I);
wherein i is 1-200, n is 1-400, m is 1-800, and k and l are 0-400.
6. The process according to claim 5, wherein the protecting group T is selected from the following formulae:
wherein R is 6 H, C of a shape of H, C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkylene radicals C of (2) 2 ～C 100 Any one of the alkyne groups of (a);
R 7 selected from the following structural formulas:
or C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 Alkenyl, C 2 ～C 100 Any one of the alkynyl groups of (2), u, v and w are each independently 0 to 400.
7. The process according to claim 5, wherein the ether-forming reaction conditions are:
reacting in a first solvent for 4 hours to 3 days at a temperature of 20 to 100 ℃, wherein the first solvent comprises tetrahydrofuran and methanol;
the conditions for group protection of the single molecular weight three-arm branched glycol of formula (C) are:
reacting in a second solvent at a temperature of-10 to 20 ℃ for 8 hours to 2 days, wherein the second solvent comprises tetrahydrofuran and dichloromethane;
the conditions for preparing the compound of formula (D) are:
reacting for 12-24 h in a third solvent at 0-20 ℃, wherein the third solvent comprises tetrahydrofuran and sodium hydroxide aqueous solution;
the conditions for preparing the precise cyclic polyethylene glycol represented by the formula (F) or the formula (G) are as follows:
reacting in a fourth solvent for 12 hours to 3 days at a temperature of 0 to 20 ℃, wherein the concentration of the compound shown in the formula (F) or the formula (G) is 0.1 to 10mol/L, and the fourth solvent comprises tetrahydrofuran;
the reaction conditions for obtaining the precise cyclic polyethylene glycol shown in the formula (H) or the formula (I) are as follows:
reacting in a fifth solvent at 0-20 ℃ for 2-12 h, wherein the fifth solvent comprises methanol.
8. The preparation method of claim 5, further comprising the step of carrying out group modification on the terminal hydroxyl group of the single-molecular-weight precise cyclic polyethylene glycol shown in the formula (H) or the formula (I) to prepare the compound shown in the formula (I) or the formula (II);
wherein m and n respectively represent the number of the repeated units of polyethylene glycol, m=1 to 800, and n=1 to 400;
C k H l selected from C 1 ～C 100 Alkyl, C of (2) 2 ～C 100 At least one of alkenyl or alkynyl;
R 1 、R 2 、R 3 selected from any one of the following structures:
R 4 selected from any one of the following structures:
R 5 selected from any one of hydrogen, methyl, bromine and iodine.
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