CN117887031A - High molecular weight high biosafety sulfonamide polymer and preparation method thereof - Google Patents
High molecular weight high biosafety sulfonamide polymer and preparation method thereof Download PDFInfo
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- CN117887031A CN117887031A CN202410071903.2A CN202410071903A CN117887031A CN 117887031 A CN117887031 A CN 117887031A CN 202410071903 A CN202410071903 A CN 202410071903A CN 117887031 A CN117887031 A CN 117887031A
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- sulfonamide
- polyethylene glycol
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- hexamethylene diisocyanate
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- 229920000642 polymer Polymers 0.000 title claims abstract description 44
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 36
- 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 16
- 229910052797 bismuth Inorganic materials 0.000 claims abstract description 16
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000005057 Hexamethylene diisocyanate Substances 0.000 claims abstract description 12
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 polyethylene Polymers 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000004698 Polyethylene Substances 0.000 claims abstract description 3
- 229920001577 copolymer Polymers 0.000 claims abstract description 3
- 229920000573 polyethylene Polymers 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- NSPSPMKCKIPQBH-UHFFFAOYSA-K bismuth;7,7-dimethyloctanoate Chemical compound [Bi+3].CC(C)(C)CCCCCC([O-])=O.CC(C)(C)CCCCCC([O-])=O.CC(C)(C)CCCCCC([O-])=O NSPSPMKCKIPQBH-UHFFFAOYSA-K 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- KHBQMWCZKVMBLN-IDEBNGHGSA-N benzenesulfonamide Chemical group NS(=O)(=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 KHBQMWCZKVMBLN-IDEBNGHGSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 208000005189 Embolism Diseases 0.000 abstract description 10
- 230000002792 vascular Effects 0.000 abstract description 7
- 231100000053 low toxicity Toxicity 0.000 abstract description 5
- 238000006116 polymerization reaction Methods 0.000 abstract description 3
- 239000012974 tin catalyst Substances 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 229920006158 high molecular weight polymer Polymers 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
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- 230000004044 response Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000003073 embolic effect Effects 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
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- 230000008588 hemolysis Effects 0.000 description 3
- 239000000017 hydrogel Substances 0.000 description 3
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 229940035024 thioglycerol Drugs 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
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- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229960002135 sulfadimidine Drugs 0.000 description 2
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
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- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
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- 239000012975 dibutyltin dilaurate Substances 0.000 description 1
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- 229920001971 elastomer Polymers 0.000 description 1
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- 230000010102 embolization Effects 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
The invention provides a sulfonamide polymer with high molecular weight and high biological safety and a preparation method thereof. The technical scheme for achieving the purpose is as follows: polyethylene glycol and sulfonamides are used as raw materials and are coupled with hexamethylene diisocyanate under the catalysis of a green nontoxic bismuth catalyst, and finally the polyethylene glycol-sulfonamide copolymer is obtained. The polymerization method adopts a novel low-toxicity bismuth catalyst, and overcomes the toxicity problem of the traditional tin catalyst. Meanwhile, the method can prepare high molecular weight polymers, and the strength of the polymers is greatly improved, so that the polymers have a great application prospect in the field of vascular embolism.
Description
Technical Field
The invention relates to the technical field of biomedical polymer technology and interventional embolism, in particular to a preparation method of a novel medical polymer material, which is mainly used for realizing effective vascular interventional embolism.
Background
Vascular embolization is a method of achieving therapeutic objectives by implanting embolic material into a blood vessel and blocking blood flow. The liquid embolism technology mainly uses micro-catheter to inject liquid embolism material into specific position, then the latter generates phase change in blood vessel to block blood flow, so as to achieve specific therapeutic purpose.
Liquid embolic agents can be largely classified into solvent-precipitation type, temperature-responsive type, and pH-responsive type according to the difference in response mechanism. The pH response type liquid embolic agent only contacts with blood, and the phase change of the pH response type liquid embolic agent can be induced after the pH environment is changed, so that the risks of tube blockage, backflow and thrombus error can be avoided.
The sulfanilamide polymer prepared by taking sulfadimidine as a raw material is widely used for pH response hydrogel. When the pH is reduced to below the pKa (7.4) of the compound, the sulfonamide polymer can undergo a deionization process, and macroscopic manifestation is that the hydrogel undergoes a phase change and is solidified. However, this class of polymers generally suffers from several problems: 1) The molecular weight of the polymeric material is too small. Prior studies have shown that the molecular weight of such polymers is generally low (3000-30000). The hydrogel can be insufficient in strength after response, can only be used for developing subcutaneous slow-release preparations, but cannot be used in the field of vascular embolism, in particular in the application fields of arterial blood vessels with larger blood flow and rich blood supply tumors. 2) Cytotoxicity problem. The polymerization reaction mostly adopts dibutyl tin dilaurate as a catalyst, and the catalyst has high toxicity and greatly limits the application of the catalyst in biomedicine.
The bismuth catalyst is a green low-toxicity polyurethane catalyst and is used for catalytic synthesis in the fields of polyurethane resin, adhesive, paint, elastomer and the like. However, to date, no relevant literature has reported the use of bismuth catalysts for the synthesis of sulfadimidine polymers. Therefore, the green low-toxicity bismuth catalyst is of great significance for the synthesis of the polymer.
Disclosure of Invention
In view of the defects of the prior art, the invention provides a preparation method of a high-molecular-weight high-biosafety sulfonamide polymer so as to obtain a novel pH-responsive vascular embolism medical polymer material.
The technical scheme for achieving the purpose is as follows: polyethylene glycol and sulfonamides are used as raw materials and are coupled with hexamethylene diisocyanate under the catalysis of a green nontoxic bismuth catalyst, and finally the polyethylene glycol-sulfonamide copolymer is obtained. The polymerization method adopts a novel low-toxicity bismuth catalyst, and overcomes the toxicity problem of the traditional tin catalyst. Meanwhile, the method can prepare high molecular weight polymers, and the strength of the polymers is greatly improved, so that the polymers have a great application prospect in the field of vascular embolism.
Specifically, polyethylene glycol, a sulfanilamide intermediate and hexamethylene diisocyanate are mixed into a solvent N, N-dimethylformamide (according to the feed liquid ratio of 0.1-1g/ml, namely the ratio of the total mass of the polyethylene glycol, the sulfanilamide intermediate and the hexamethylene diisocyanate to the solvent) according to a certain molar ratio (1:1-7:2-8, and the sum of the molar amounts of hydroxyl groups in the polyethylene glycol and the sulfanilamide intermediate is equal to the molar amount of NCO in the hexamethylene diisocyanate), and a bismuth catalyst with the molar ratio of 0.5-1% (compared with all materials) is added for reaction for 3-6 hours under the anhydrous anaerobic condition at 60-80 ℃; and then purifying by using a tetrahydrofuran/tert-butyl methyl ether mixed system, and drying to obtain the pH-responsive sulfonamide polymer with high molecular weight and high biosafety. In the purification process, tert-butyl methyl ether is adopted to separate out the product, and tetrahydrofuran is adopted to dissolve the product. In certain embodiments of the invention, tetrahydrofuran is 1-5 equivalents of the volume of the reaction solution and t-butyl methyl ether is 1-5 equivalents of the volume of the reaction solution.
The sulfonamide intermediates described herein are a class of compounds having a benzenesulfonamide structure, including, but not limited to, sulfonamide intermediates of the following structural formulas referred to in the examples of the present application:
wherein,
XNH,O
the synthetic route of the polymer is as follows:
for this sulfonamide intermediate, it can be prepared by the following method:
i) Reacting the amino or hydroxyl of the raw material A with the acryloyl chloride to generate C with an amide bond or an ester bond; in the reaction process, the acid binding agent is one of sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, potassium carbonate and sodium bicarbonate, the reaction solvent is DMF, chloroform, tetrahydrofuran, dichloromethane or the mixture of water and acetone, the reaction temperature is-20-10 ℃, and the reaction time is 8-24 hours.
ii) click reaction of the double bond of C with an amide bond or an ester bond with the mercapto group of the raw material D to obtain a sulfonamide intermediate; in the reaction, triethylamine is used as a catalyst, a reaction solvent is DMF, chloroform, tetrahydrofuran or dichloromethane, the reaction temperature is 0-25 ℃, and the reaction time is 8-24h.
The reaction route is as follows:
in the present application, the drying conditions of the purified product are: the temperature of the oven is between room temperature and 40 ℃, and the drying time is between 6 and 24 hours.
Bismuth catalysts employed in the present application include, but are not limited to: bismuth neodecanoate, bismuth isooctanoate.
The polyethylene glycol and sulfonamide intermediates may be subjected to a water removal treatment prior to the catalytic reaction of the present application. The water removal mode includes, but is not limited to, reduced pressure water removal at a certain temperature by a vacuum pump. The water removal temperature is 80-100 ℃ and the water removal time is 0.5-2h.
The invention has the beneficial effects that: the invention adopts the novel low-toxicity bismuth catalyst, and overcomes the toxicity problem of the traditional tin catalyst. The polymer prepared by the invention has the number average molecular weight of 15-20w and the weight average molecular weight of 25-30w, which is far larger than the polymer studied in the prior art. The polymer solution of the invention can not be dispersed in an in vitro embolism simulation test, presents a continuous strip shape, and the clusters are gathered together after shaking, so that the strength is greatly improved [ figure 6]. In conclusion, the polymer prepared by the invention has great application prospect in the field of vascular embolism.
Drawings
FIG. 1 shows a compound E1 prepared in example 1 of the present invention 1 H NMR chart;
FIG. 2 shows the compound E2 prepared in example 2 of the present invention 1 H NMR chart;
FIG. 3 shows a compound C3 prepared in example 3 of the present invention 1 H NMR chart;
FIG. 4 shows a compound E4 prepared in example 4 of the present invention 1 H NMR chart;
FIG. 5 shows the compound H4 prepared in example 7 of the present invention 1 H NMR chart;
FIG. 6 is a photograph showing a solution of Compound H4 prepared in example 7 of the present invention after responding to PBS;
FIG. 7 is a graph showing cytotoxicity results of Polymer H4 of the present invention.
Detailed Description
The invention is further illustrated below with reference to examples.
Example 1
Synthesis of compound C1: into A1L three-necked flask equipped with a stirrer and a thermometer, 100.0g of starting compound A1 and 200mL of THF were charged, stirred, and cooled to 0-5 ℃. 42.5g TEA was added. 38.0g of acryloyl chloride (dissolved in 200 mM DCM) was added dropwise, after 1h. After the dripping is finished, stirring for 15min at 0-5 ℃, removing the ice bath, naturally heating to room temperature, continuing to react for 2h, and stopping the reaction. After filtration on silica gel, concentration gave crude C1, 80.0g.
Synthesis of sulfonamide intermediate E1: into a 1L three-neck flask with a stirrer and a thermometer, 80.0g of sulfonamide intermediate C1 and 300mLDCM were added, stirred, and cooled to 0-5 ℃. 0.26g TEA was added. 328.1g of thioglycerol (dissolved in 100 mM DCM) were added dropwise, after 15 min. After the dripping is finished, stirring for 15min at 0-5 ℃, removing the ice bath, naturally heating to room temperature, continuing to react for 5h, and stopping the reaction. After removal of the solvent by rotary evaporation, column chromatography gave 65.2g of oil.
Example 2
Synthesis of compound C2: into a 250mL three-necked flask equipped with a stirrer and a thermometer, 22.8g of Compound A2,4.4g of NaOH,100mL of water and 50mL of acetone were charged, and the mixture was stirred and cooled to 0-5 ℃. 9.9g of acryloyl chloride (dissolved in 50mL of acetone) was added dropwise, after 30 min. After the dripping is finished, stirring for 15min at 0-5 ℃, removing the ice bath, naturally heating to room temperature, continuing to react for 3h, and stopping the reaction. Concentrated, 100mL of water was added, and the solid was precipitated and filtered. The solid was slurried with ethanol for 3h. Drying to obtain 25g of product.
Synthesis of sulfonamide intermediate E2: into a 250mL three-necked flask equipped with a stirrer and a thermometer, 25.0g of Compound C2 and 100mL of MF were charged, stirred, and cooled to 10 ℃. 0.09g of TEA was added. 10.4g of thioglycerol (dissolved in 20 mM LDMF) was added dropwise, after 15 min. After the dripping is finished, removing the ice bath, naturally heating to room temperature, continuing the reaction for 12 hours, and stopping the reaction. After removal of the solvent by rotary evaporation, column chromatography gave 28.0g of a white solid.
Example 3
Synthesis of compound C3: into a 100mL three-necked flask equipped with a stirrer and a thermometer, 2.5g of Compound A3,1.1g of sodium carbonate, 4mL of water and 15mL of LTHF were charged, and the mixture was stirred and cooled to 0-5 ℃.1g of acryloyl chloride (dissolved in 5ml of THF) was added dropwise, after 5 min. After the dripping is finished, stirring for 15min at 0-5 ℃, removing the ice bath, naturally heating to room temperature, continuing to react for 3h, and stopping the reaction. Concentrated, 10ml of water was added, and the solid was precipitated and filtered. The solid was slurried with water for 3h. 2.5g of product is obtained after drying.
Synthesis of sulfonamide intermediate E3: into a 100mL three-necked flask equipped with a stirrer and a thermometer, 1.0g of Compound C3 and 5mL of MF were added, followed by stirring and cooling to 10 ℃. 0.003g of TEA was added. 0.4g of thioglycerol (dissolved in 5 mM LDMF) was added dropwise, after 1 min. After the dripping is finished, removing the ice bath, naturally heating to room temperature, continuing the reaction for 12 hours, and stopping the reaction. After removal of the solvent by rotary evaporation, column chromatography gave 1.2g of white solid.
Example 4
Synthesis of compound C4: into a 500mL three-necked flask equipped with a stirrer and a thermometer, 27.8g of Compound A4,4.4g of NaOH,150mL of water and 100mL of acetone were charged, and the mixture was stirred and cooled to 0-5 ℃. 9.9g of acryloyl chloride (dissolved in 50mL of acetone) was added dropwise, after 30 min. After the dripping is finished, stirring for 15min at 0-5 ℃, removing the ice bath, naturally heating to room temperature, continuing to react for 3h, and stopping the reaction. Concentrated, 100mL of water was added, and the solid was precipitated and filtered. The aqueous phase was extracted three times with DCM/meoh=10:1 and concentrated to a solid. The solids were combined and dried to give 26.5g of product.
Synthesis of sulfonamide intermediate E4: into a 250mL three-necked flask equipped with a stirrer and a thermometer, 20.0g of C4 and 100mL of MF were charged, stirred, and cooled to 10 ℃. 0.06g of TEA was added. 7.1g of acryloyl chloride (dissolved in 20 mM DCM) was added dropwise, after 15 min. After the dripping is finished, removing the ice bath, naturally heating to room temperature, continuing the reaction for 12 hours, and stopping the reaction. After removal of the solvent by rotary evaporation, column chromatography gave 22.0g of white solid.
Example 5
Preparation of Polymer H1: to a reaction flask with stirring of 100mL was added 1.03g of polyethylene glycol (mn=1500), and the polyethylene glycol was dehydrated with a vacuum oil pump at 80 ℃ for 1h. 1.92g of sulfonamide intermediate E1 was added to the above-mentioned reaction flask under nitrogen protection, and vacuum dehydration was continued for 0.5h at 80 ℃. 10mLN, N-dimethylformamide was added under nitrogen to dissolve the reactant, and 0.111g bismuth isooctanoate catalyst, and 0.90g hexamethylene diisocyanate were added to react at 60℃for 3 hours. The reaction was stopped, cooled to room temperature and the polymer was precipitated with 50ml of t-butyl methyl ether. Then 20mL of tetrahydrofuran was added to dissolve the polymer, and 50mL of t-butyl methyl ether was added dropwise to precipitate the polymer; after purification, 2.4g of a polymer was obtained.
Example 6
Preparation of Polymer H2: to a reaction flask with stirring of 100mL was added 1.03g of polyethylene glycol (mn=1500), and the polyethylene glycol was dehydrated with a vacuum oil pump at 80 ℃ for 1h. 0.26g of sulfonamide intermediate E2 was added to the above reaction flask under nitrogen protection, and vacuum dehydration was continued for 0.5h at 80 ℃. 2.5mL of N-dimethylformamide was added under nitrogen to dissolve the reactant, and 0.028g of bismuth neodecanoate catalyst and 0.224g of hexamethylene diisocyanate were further added to react at 60℃for 3 hours. The reaction was stopped, cooled to room temperature and the polymer was precipitated with 12.5ml of t-butyl methyl ether. Then 12.5mL of tetrahydrofuran was added to dissolve the polymer, and 12.5mL of t-butyl methyl ether was added dropwise to precipitate the polymer; after purification, 2.2g of a polymer was obtained.
Example 7
Preparation of Polymer H4: to a 100mL reaction flask with stirring was added 2.58g polyethylene glycol (mn=1500) and the water was removed in vacuo at 80 ℃ for 1h. 5.14g of sulfonamide intermediate E4 was added under nitrogen protection and water removal was continued for 0.5h at 80 ℃. 25mLN, N-dimethylformamide was added under nitrogen to dissolve the reaction product, and 0.278g bismuth neodecanoate and 2.24g hexamethylene diisocyanate were added to react at 80℃for 6 hours. Cooled to room temperature and the polymer was precipitated with 125ml of t-butyl methyl ether. Then 25mL of tetrahydrofuran was added to dissolve the polymer, and 125mL of t-butyl methyl ether was added dropwise to precipitate the polymer; after purification, 6.2g of a polymer was obtained.
The polymers obtained in examples 5 to 7 were characterized by Gel Permeation Chromatography (GPC) using a narrow distribution polyethylene glycol as a standard, and as shown in Table 1, the molecular weights of the polymers described in examples 5 to 7 were 20w (Mw) or more, which is far higher than those of the polymers in the literature.
TABLE 1 example 6GPC data
| Polymer | Mn | Mw | PDI |
| Example 5 | 14.7w | 21.7w | 1.47 |
| Example 6 | 14.4w | 21.3w | 1.42 |
| Example 7 | 14.1w | 20.9w | 1.33 |
300mg of the sample of example 6 was extracted with 3mL of the medium for 24 hours to obtain an extract. After plating the L929 cells, the extracts were then added to 96-well plates at various concentrations and incubated with the cells for 24h. And then sucking out the culture medium, adding a CCK8 detection kit to detect the cell survival rate, reading the absorbance value at 450nm by using an enzyme-labeled instrument, and calculating to obtain the relative cell survival rate, wherein the result is shown in figure 7, and the survival rate of the cells is above 70% after 0.1g/mL of leaching solution is co-cultured for 24 hours.
10mL of New Zealand rabbit blood was placed in a heparin anticoagulation tube, and diluted with physiological saline for use. The sample of example 6 was subjected to leaching at 0.1g/mL for 24 hours (leaching medium: physiological saline), 10mL of the leaching solution was added to the test tube, 10mL of physiological saline and distilled water were taken as a negative control and a positive control, the sample tube was placed in a thermostatic water bath at 37℃for incubation for 30 minutes, diluted blood was added to the test tube at 0.2mL per 10mL of the test sample, and the mixture was gently shaken, and incubation was continued in the thermostatic water bath at 37℃for 60 minutes. After centrifugation with an 800g centrifuge for 5min, the supernatant was then aspirated to test its absorbance at 545nm and calculated to give the hemolysis ratio. The results showed that the polymer obtained in example 6 had a hemolysis ratio of 1.2% (5% or less), indicating that the material did not cause hemolysis.
Claims (10)
1. A preparation method of a high molecular weight and high biosafety sulfonamide polymer is characterized in that polyethylene glycol and a sulfonamide compound are used as raw materials and are coupled with hexamethylene diisocyanate under the catalysis of a bismuth catalyst to obtain a polyethylene glycol-sulfonamide copolymer.
2. The method according to claim 1, wherein the molar ratio of polyethylene glycol, sulfonamide compound, hexamethylene diisocyanate is 1:1 to 7: 2-8, and the sum of the molar quantity of hydroxyl groups in the polyethylene glycol and the sulfonamide intermediate is equal to the molar quantity of NCO in hexamethylene diisocyanate.
3. The method according to claim 1, wherein the polyethylene glycol, the sulfonamide compound and the hexamethylene diisocyanate are mixed in a solvent N, N-dimethylformamide according to a feed liquid ratio of 0.1-1 g/ml.
4. The method of claim 1, wherein the bismuth catalyst includes, but is not limited to: bismuth neodecanoate, bismuth isooctanoate.
5. The process according to claim 1, wherein the molar content of bismuth catalyst is 0.5-1% of the total amount of reactants.
6. The process according to claim 1, wherein the catalytic reaction is carried out in the absence of water and oxygen at 60-80 ℃ for a period of 3-6 hours.
7. The process according to claim 1, wherein the product obtained after the catalytic reaction is purified by means of a tetrahydrofuran/tert-butyl methyl ether system, in particular by precipitation of the product by means of tert-butyl methyl ether and dissolution of the product by means of tetrahydrofuran.
8. The method according to claim 1, wherein the sulfonamide compound is a compound having a benzenesulfonamide structure.
9. The method according to claim 1, wherein the sulfonamide compound has the structural formula:
wherein,
XNH,O
10. the sulfonamide polymer of claim 1.
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