CN108239278B - Process for preparing amide-linked polymers - Google Patents

Process for preparing amide-linked polymers Download PDF

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CN108239278B
CN108239278B CN201810100807.0A CN201810100807A CN108239278B CN 108239278 B CN108239278 B CN 108239278B CN 201810100807 A CN201810100807 A CN 201810100807A CN 108239278 B CN108239278 B CN 108239278B
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carboxyl
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azide group
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CN108239278A (en
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张伟
赵肖宁
朱秀林
潘向强
周年琛
张正彪
朱健
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Suzhou University
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    • C08G65/32—Polymers modified by chemical after-treatment
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Abstract

The invention relates to a preparation method of an amido bond connected polymer, which comprises the following steps: mixing polymer with one end of azide group, carboxyl-containing compound, and catalyst dipyridyl diselenide (PySeSePy), and adding trimethylphosphine (Me) at 0-5 deg.C3P), reacting the organic solution, and reacting at 25-40 ℃ for 2-24h to obtain an amide bond-connected polymer when no bubble is generated in the reaction, wherein the carboxyl-containing compound is dicarboxylic acid, polycarboxylic acid, a polymer with one end being carboxyl or a polymer with two ends being carboxyl; the molar ratio of the polymer with one end of azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 0.9-2.2:1-2:1-2: 20-40. According to the invention, the Staudingers-Vilarrasa reaction catalyzed by dipyridyl diselenide is used for the connection between polymers, and through the reaction between a carboxyl-containing compound and a polymer with one end being an azide group, an amido bond is formed, so that the polymer connected by the amido bond is prepared.

Description

Process for preparing amide-linked polymers
Technical Field
The invention relates to the field of high-molecular chemistry, in particular to a preparation method of an amido bond connected polymer.
Background
The block polymer has a good application prospect in the fields of nano devices, biological medicines and the like, and more researchers are dedicated to the synthesis of the block polymer. With the development of controllable free radical polymerization such as ATRP and high-efficiency reaction such as click chemistry, more and more types of block polymers, such as block polymers responding to temperature, light, pH and magnetism, can be prepared.
The existing block polymer synthesis method mainly comprises the combination of living anion polymerization, living radical polymerization, efficient click reaction and controllable radical polymerization such as ATRP, RAFT and the like. Among them, the anionic polymerization system is simple, but the reaction conditions are very harsh, and the system is sensitive to water and oxygen, and usually operated under high vacuum, so that the application thereof is limited to a certain extent. And controllable free radical methods such as ATRP, RAFT and the like have the advantages of simple polymerization system, wide monomer application range and strong molecular design capability, but still have certain limitation on the types of the monomers. And click chemistry reaction such as CuAAC and ATRP are combined, so that the limitation of the reaction can be broken, and block polymers with different compositions, structures and performances can be synthesized. The main idea is to synthesize a polymer with alkynyl at the tail end by using an initiator containing alkynyl, synthesize a polymer with chlorine or bromine at the tail end by using a common initiator, nitridize the tail end of the polymer by reacting with sodium azide, and finally connect the polymer with the alkynyl at the tail end and the nitridized polymer by carrying out CuAAC reaction, thereby synthesizing various block polymers.
The reaction of carboxylic acid compounds with organic azides is known as the Staudinger-Vilarrasa reaction, S-V for short. The S-V reaction catalyzed at present is mainly used for synthesizing polypeptide and natural macromolecule reaction containing amido bond.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a preparation method of an amide bond-linked polymer, which uses the bipyridyl diselenide catalyzed Staudingers-Vilarrasa reaction for linking polymers, and forms an amide bond through the reaction between a carboxyl-containing compound and a polymer with one end being an azide group, thereby preparing the amide bond-linked polymer.
The preparation method of the amide bond connected polymer comprises the following steps:
mixing polymer with one end of azide group, carboxyl-containing compound, and catalyst dipyridyl diselenide (PySeSePy), and adding trimethylphosphine (Me) at 0-5 deg.C3P) is reacted, when no bubble is generated in the reaction, the reaction is carried out for 2 to 24 hours at the temperature of between 25 and 40 ℃ to obtain the amide bond connected polymer,
wherein, the carboxyl-containing compound is dicarboxylic acid, polycarboxylic acid, a polymer with one end being carboxyl or a polymer with two ends being carboxyl;
the molar ratio of the polymer with one end of azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 0.9-2.2:1-2:1-2: 20-40.
Preferably, trimethylphosphine (Me) is added at 0 ℃3P) is reacted, and then reacted at 40 ℃ when no bubbles are generated.
When the carboxyl-containing compound is a dicarboxylic acid, the above reaction is routed as follows:
Figure BDA0001566271980000021
in the formula, Polymer-N3Represents a polymer having an azide group at one end, and HOOC-R-COOH represents a dicarboxylic acid.
When the carboxyl-containing compound is a polycarboxylic acid, the above reaction route is as follows (taking a tricarboxylic acid as an example):
Figure BDA0001566271980000022
in the formula, Polymer-N3A polymer having an azide group at one end is shown.
When the carboxyl-containing compound is a polymer having a carboxyl group at one end, the above reaction route is as follows:
Figure BDA0001566271980000023
in the formula, Polymer-N3Denotes a Polymer having an azide group at one end, Polymer1-COOH represents a compound containing a carboxyl group at one end.
When the carboxyl-containing compound is a polymer with carboxyl groups at both ends, the route of the above reaction is as follows:
Figure BDA0001566271980000024
in the formula, Polymer-N3Represents a Polymer having an azide group at one end, HOOC-Polymer2-COOH represents a compound having carboxyl groups at both ends.
Further, the polymer in the polymer with one end of the azide group is polyethylene glycol monomethyl ether, poly (tert-butyl acrylate), polystyrene and the like.
Specifically, the polymer with one end of azide group respectively corresponds to the following molecular formulas:
Figure BDA0001566271980000031
(polyethylene glycol monomethyl azide),
Figure BDA0001566271980000032
(t-butyl polyacrylate azide),
Figure BDA0001566271980000033
(Azide polystyrene). Wherein n represents the degree of polymerization.
The preparation method of the azido polyethylene glycol monomethyl ether comprises the following steps:
uniformly mixing polyethylene glycol monomethyl ether, triethylamine and a solvent, dropwise adding p-toluenesulfonyl chloride under an ice bath condition, and reacting at room temperature for 24 hours to obtain the p-toluenesulfonyl chloride-terminated polyethylene glycol monomethyl ether. The solvent is preferably dichloromethane.
Uniformly mixing the p-toluenesulfonylchloride-terminated polyethylene glycol monomethyl ether, sodium azide and a solvent, and reacting at 80 ℃ for 48 hours to obtain azido polyethylene glycol monomethyl ether, wherein the molar ratio of the p-toluenesulfonylchloride-terminated polyethylene glycol monomethyl ether to the sodium azide is 1: 20. The solvent is preferably N, N-dimethylformamide.
The preparation method of the tert-butyl azide polyacrylate comprises the following steps:
uniformly mixing poly (tert-butyl acrylate), sodium azide and a solvent, and reacting at 60 ℃ for 24 hours to obtain poly (tert-butyl acrylate) azide, wherein the molar ratio of poly (tert-butyl acrylate) to sodium azide is 1: 10; the solvent is preferably N, N-dimethylformamide.
The ATRP method is adopted in the process of preparing the polymer with the azide group at one end, the polymer with the hydroxyl group at the tail end reacts with the paratoluensulfonyl chloride, and finally the nucleophilic reaction with the sodium azide is carried out, so that the method is simple and convenient, and has wide range suitable for the polymer.
Further, the molecular weight of the polymer having an azide group at one end was 2000-5200 Da.
Further, the carboxyl-containing compound is dicarboxylic acid or polycarboxylic acid, the molar ratio of the polymer with one end of azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 1.9-2.2:2:1: 20-40.
Further, the carboxyl group-containing compound is terephthalic acid, tetradecanedioic acid, trimesic acid, or the like.
Further, the carboxyl-containing compound is a polymer with one end being carboxyl or a polymer with two ends being carboxyl, and the molar ratio of the polymer with one end being azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 0.9-1.3:1:2: 20-40.
Further, the polymer of the polymer having a carboxyl group at one end or the polymer having a carboxyl group at both ends is polyethylene glycol, polyethylene glycol monomethyl ether, or the like.
Specifically, a polymer with a carboxyl group at one end corresponds to the following formula:
Figure BDA0001566271980000041
wherein n represents the degree of polymerization.
Specifically, the polymer having carboxyl groups at both ends corresponds to the following molecular formula:
Figure BDA0001566271980000042
wherein n represents the degree of polymerization.
Further, when the carboxyl-containing compound is a polymer having a carboxyl group at one end or a polymer having carboxyl groups at both ends, the preparation method thereof is as follows:
uniformly mixing a polymer with a hydroxyl end, succinic anhydride, 4-dimethylaminopyridine, triethylamine and a solvent, and stirring and reacting for 24-48h at 25 ℃ in a ventilation state to obtain a polymer with a carboxyl end, wherein the molar ratio of the polymer with the hydroxyl end, succinic anhydride, 4-dimethylaminopyridine and triethylamine is 1:1.5-3:1.5-3: 1.5-3.
Further, the organic solvent in the organic solution of trimethylphosphine is toluene. Toluene is used as a solvent, and the reaction efficiency is highest.
Further, the concentration of the organic solution of trimethylphosphine was 1 mol/L.
Further, the reaction is carried out under the protection of inert gas. Specifically, an inert gas is introduced into the reaction solution.
Further, the inert gas is any one of nitrogen, helium or neon, preferably nitrogen.
Further, the preparation method of the catalyst dipyridyl diselenide is as follows:
dissolving sodium hydroxide, selenium powder and hydrazine hydrate in an organic solvent, reacting for 2h at 25 ℃, adding 2-bromopyridine, and reacting for 24h at 120 ℃ to obtain a catalyst dipyridyl diselenide.
Further, the molar ratio of sodium hydroxide, selenium powder, hydrazine hydrate and 2-bromopyridine is 1.5:1:1: 1.
Further, the organic solvent is N, N' -dimethylformamide.
Further, the concentration of hydrazine hydrate was 85%.
In the preparation method, after an organic solution of trimethylphosphine is added, the polymer subjected to terminal azide is quickly reacted with the trimethylphosphine to generate phosphazene, all azide groups can be quickly converted into phosphazene due to the excessive trimethylphosphine and the reaction for generating the phosphazene can be completed within a few minutes, meanwhile, bipyridyl diselenide is reacted with a part of carboxyl-containing compounds to generate active esters, the phosphazene is quickly reacted with the active esters to generate intermediates, the molar ratio of the bipyridyl diselenide to the carboxyl-containing compounds is 1-2:1-2, the bipyridyl diselenide can only activate a part of the carboxyl-containing compounds, the rest of the carboxyl-containing compounds are reacted with the intermediates to obtain target products and the active esters, and the reaction is repeated until the substrate is completely reacted. Taking dicarboxylic acid as an example, the reaction principle is as follows:
Figure BDA0001566271980000051
by the scheme, the invention at least has the following advantages:
(1) the invention combines ATRP and Staudinger-Vilarras reaction catalyzed by dipyridyl diselenide for the first time, selects the polymer with one end of azide group prepared by ATRP and nucleophilic substitution reaction, and then utilizes S-V reaction to connect carboxyl-containing compound and the polymer by amido bond, thereby providing a new method for the mutual connection of the polymers.
(2) The preparation method adopts the Staudinger-Vilarrasa reaction catalyzed by dipyridyl diselenide during amidation, has the obvious characteristics of wide application range, high reaction rate, high yield, few byproducts, easy treatment and the like, and is an efficient method for connecting polymers.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Drawings
FIG. 1 is a NMR spectrum of dipyridyl diselenide prepared in example 1;
FIG. 2 is a NMR selenium spectrum of the diselenide dipyridyl prepared in example 1;
FIG. 3 shows PEG1900-N prepared in example 13Hydrogen spectrum of Nuclear Magnetic Resonance (NMR);
FIG. 4 shows PEG1900-N prepared in example 13The macromolecular mass spectrum of (4);
FIG. 5 shows PEG1900-N in example 13And the nuclear magnetic resonance hydrogen spectrum of the product after the product is connected with terephthalic acid;
FIG. 6 shows PEG1900-N in example 13And the GPC elution curve of the product after it has been linked to terephthalic acid;
FIG. 7 shows PEG1900-N in example 23Nuclear magnetic resonance hydrogen spectrum of the product after connecting with trimesic acid;
FIG. 8 shows PEG1900-N in example 23GPC outflow curve of the product after ligation with trimesic acid;
FIG. 9 shows PtBA-N prepared in example 33GPC outflow graph of (a);
FIG. 10 shows PtBA-N prepared in example 33Hydrogen spectrum of Nuclear Magnetic Resonance (NMR);
FIG. 11 is a NMR hydrogen spectrum of PEG1900-COOH prepared in example 3;
FIG. 12 is an infrared spectrum of PEG1900-COOH prepared in example 3 and PEG1900-OH as a raw material;
FIG. 13 is a macromolecular mass spectrum of PEG1900-COOH prepared in example 3;
FIG. 14 shows PEG1900-COOH, PtBA-N in example 33GPC outflow graph of PEG-b-PtBA;
FIG. 15 is a NMR hydrogen spectrum of HOOC-PEG2050-COOH prepared in example 4;
FIG. 16 is a macromolecular mass spectrum of HOOC-PEG2050-COOH prepared in example 4;
FIG. 17 is a NMR spectrum of PtBA-b-PEG-b-PtBA prepared in example 4;
FIG. 18 shows PtBA-N in example 43GPC outflow graph of PtBA-b-PEG-b-PtBA.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The following test instruments and conditions were used in the following examples of the invention:
gel Permeation Chromatography (GPC): the molecular weight of the column was 100-500000Da using differential refractometer (RI2414), HR1, HR2 and HR4, THF as mobile phase at a flow rate of 1.0mL/min, as determined by Waters1515 gel chromatography, and the polymer molecular weight was calibrated with polystyrene or polymethyl acrylate standards at 30 ℃;
nuclear magnetic resonance hydrogen spectrum (1H-NMR): using a Bruker 300MHz NMR spectrometer in CDCl3Measuring (deuterated chloroform) as a solvent and TMS (tetramethylsilane) as an internal standard at room temperature;
nuclear magnetic resonance selenium spectrum (77Se-NMR): using a Bruker 600MHz NMR spectrometer with CDCl3The TMS is an internal standard, and the TMS is measured at room temperature;
matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF): using Bruker Ultraflex-IIIMS spectrophotometer mass spectrometer with DCTB as matrix;
elemental Analysis (EA): measuring by using an EA1110-CHNO-S microanalyzer;
infrared spectroscopy (FT-IR) was performed using a Bruker TENSOR-27 infrared spectrometer, KBr pellet.
Example 1
(1) 6.1g (152mmol) of sodium hydroxide, 7.9g (100mmol) of selenium powder and 250mL of N, N' -dimethylformamide solvent were charged into a 500mL three-necked flask, stirred under aeration, and then 4.9g of hydrazine hydrate was added slowly to the system, followed by reaction at room temperature for 2 hours. Then 15.8g (100mmol) of 2-bromopyridine is slowly added into the reaction bottle dropwise, and then the temperature is raised to 120 ℃ for reaction for 24 hours, and the reaction is stopped and then the temperature is returned to the room temperature. Suction filtration is carried out, and the filtrate is extracted by a large amount of ethyl acetate. Washing the organic phase with saturated ammonium chloride solution and deionized water saturated saline solution, respectively, stirring and drying with anhydrous sodium sulfate for 2 hr, concentrating to obtain crude product, and purifying with column chromatography. 9.7g of the final product PySePy are obtained in 62% yield. The route of the above reaction is as follows:
Figure BDA0001566271980000071
and performing nuclear magnetic resonance hydrogen spectrum (figure 1), nuclear magnetic resonance selenium spectrum (figure 2) and element analysis test (table 1) on the product respectively, wherein each peak in figure 1 can find out attribution and has correct integral, figure 2 is a single peak, which indicates that the synthesized product is the mono-selenoether or the diselenoether, and the result of element analysis in table 1 is combined to indicate that the dipyridyl diselenide PySePy is successfully synthesized.
TABLE 1 elemental analysis test results for PySeSePy
Figure BDA0001566271980000072
(2) 15g (7.8947mmol) of polyethylene glycol monomethyl ether (named as PEG1900-OH and with the molecular weight of 1900Da), 15.9774g (0.1579mmol) of triethylamine and 200mL of dichloromethane are added into a 500mL round-bottom flask, the reaction system is placed into an ice salt bath and stirred, 30.10g (157.9mmol) of p-toluenesulfonyl chloride is dissolved by 150mL of dichloromethane, then the solution of the p-toluenesulfonyl chloride is dropwise added into the reaction system by using a constant pressure dropping funnel, after the dropwise addition is finished, the ice bath is removed, and the reaction is stirred at room temperature for 24 hours. After the reaction is stopped, removing the generated salt by suction filtration, concentrating the filtrate, then precipitating in cold anhydrous ether, standing, suction filtering, and drying in vacuum to finally obtain 14g of p-toluenesulfonyl chloride-terminated polyethylene glycol monomethyl ether (named PEG 1900-OTs). 14g (7.0mmol) of PEG1900-OTs, 4.55g (70mmol) of sodium azide and 60mL of N, N-dimethylformamide were added to a 100mL round-bottomed flask, reacted at 80 ℃ for 24 hours, then various sodium salts were removed by a neutral alumina column, precipitated in cold anhydrous ether, filtered with suction, dried in vacuo to give 6.9g of terminally azidated polyethylene glycol monomethyl ether (named PEG 1900-N)3). The reaction route is as follows:
Figure BDA0001566271980000073
FIG. 3 is PEG1900-N3Hydrogen spectrum of Nuclear Magnetic Resonance (NMR), number average molecular weight M calculated from nuclear magnetismnAt 2400Da, each peak was able to find the corresponding attribution and the integration was correct. FIG. 4 is PEG1900-N3The macromolecular mass spectrum of (1) shows three groups of peaks, wherein the first group of peaks is attributed to [ PEG-N ]3+Na]+(experimental value 1841.01 corresponds to theoretical value 1841.21, and n-39). While the other two groups of peaks are attributed to [ PEG-N + Na]+(experimental value 1857.08 agrees with theoretical value 1857.24, N40) and metastable ion (experimental value 1860.11), both due to N released from the terminal azide group of the polymer during mass spectrometry testing of macromolecules2And (4) forming. The number average molecular weight M was determined by gel permeation chromatography GPCn2600Da, molecular weight distribution PDI 1.14 (curve a in fig. 6).
(3) In a 50mL reaction tube, 0.4800g (0.24mmol) of polyethylene glycol monomethyl ether PEG1900-N with azide at the end30.0754g (0.024mmol) of diselenide pysepy and 0.0202g (0.12mmol) of terephthalic acid were stirred and passed through an inert gas, 4.0mL of a toluene solution of trimethylphosphine at 0 ℃ was slowly injected into the system, and when no gas was generated in the system, the temperature of the system was raised to 40 ℃ and the reaction was continued for 24 hours under aeration. After the reaction is stopped, adding a proper amount of tetrahydrofuran for dilution, then dropwise adding the tetrahydrofuran into cold anhydrous ether for precipitation, standing, performing suction filtration, and drying in a vacuum box to finally obtain 0.4370g of polyethylene glycol monomethyl ether (PEG-PEG) coupled together by terephthalic acid, wherein the yield is 89.3%. The reaction route is as follows:
Figure BDA0001566271980000081
FIG. 5 shows terephthalic acid and polyethylene glycol monomethyl ether PEG1900-N with azidated ends3The nuclear magnetic hydrogen spectrum after the coupling shows that the characteristic peak of proton hydrogen (d) on the benzene ring of the terephthalic acid appears at 7.86-7.89ppm compared with that before the couplingIndicating the success of the coupling reaction, the coupling efficiency can be calculated to be 93.9% from the characteristic peak (d) and the characteristic peak (b) in fig. 5. FIG. 6 shows the GPC elution curve (curve b) of polyethylene glycol monomethyl ether before ligation (curve a) and after coupling with terephthalic acid, in which curve b the peak number-average molecular weight of number 2 is Mn5100Da, molecular weight distribution PDI 1.02, number 1 peak number average molecular weight MnThe molecular weight distribution PDI was 1.03 at 2500Da, where the peak numbered 2 is the peak of the coupled product (PEG-PEG), and the ratio of coupled product was calculated to be 91.5% by gaussian function. The test results show that terephthalic acid successfully nitrifies the tail end of polyethylene glycol monomethyl ether PEG1900-N3And (4) coupling.
As can be seen from the above analysis, the reaction mixture of terephthalic acid and polyethylene glycol monomethyl ether PEG1900-N3In the coupling reaction, the coupling efficiency of the catalytic Staudinger-Vilarras reaction can reach 93.9%.
Example 2
(1) In a 50mL reaction tube, 0.3840g (0.192mmol) of the terminal-azido polyethylene glycol monomethyl ether PEG1900-N prepared in example 1 were added30.0565g (0.18mmol) of dipyridyl diselenide PySePy and 0.0128g (0.06mmol) of trimesic acid, stirring and introducing inert gas, slowly injecting 2.8mL of trimethyl phosphine solution in toluene at 0 ℃, raising the temperature of the system to 40 ℃ when no gas is generated in the system, and continuing the reaction for 24 hours in an aeration state. After the reaction is stopped, adding a proper amount of tetrahydrofuran for dilution, dropwise adding the tetrahydrofuran into cold anhydrous ether for precipitation, standing, performing suction filtration, and drying in a vacuum box to finally obtain 0.3875g of the three-arm polymer formed by coupling trimesic acid with end-azido polyethylene glycol monomethyl ether, wherein the yield is 99.0%. The reaction route is as follows:
Figure BDA0001566271980000091
FIG. 7 shows polyethylene glycol monomethyl ether PEG1900-N with trimesic acid and terminal azide3The nuclear magnetic hydrogen spectrum after coupling is compared with that before coupling,the characteristic peak of proton hydrogen (a) on benzene ring of trimesic acid appears at 8.48-8.50ppm, which shows success of reaction, and the coupling efficiency can be calculated to reach 94.9% from the characteristic peak (a) and the characteristic peak (c) in figure 7. FIG. 8 shows a polyethylene glycol monomethyl ether before the reaction (curve a) and a GPC outflow curve after the reaction with trimesic acid (curve b), in which curve b, the number average molecular weight of the peak numbered 2 is Mn7200Da, molecular weight distribution PDI 1.02, Peak number average molecular weight M number 2n2600Da, the molecular weight distribution PDI is 1.02, where the peak numbered 2 is the peak of the reaction product and the proportion of coupled product can be calculated as 95.0% by gaussian function. The test result shows that the trimesic acid successfully nitrifies the tail end of polyethylene glycol monomethyl ether PEG1900-N3The three-arm star polymer is formed by the joining.
As a result of the above analysis, it was found that polyethylene glycol monomethyl ether PEG1900-N azide was formed between trimesic acid and the terminal3In the reaction, the connection efficiency of the catalytic Staudinger-Vilarras reaction can reach 95.0%.
Example 3
(1) 18.88g (147.3mmol) of tert-butyl acrylate, 0.3175g (2.2130mmol) of CuBr, 0.0247g (0.1106mmol) of CuBr20.4026g (2.3230mmol) of PMDETA (N, N, N ', N ', N ' -pentamethyldiethylenetriamine), 0.7391g (4.4260mmol) of methyl 2-bromopropionate (MBrP) and 20mL of dimethyl sulfoxide were charged into a 50mL Schlenk flask, which was then placed in an oil bath pan at 60 ℃ for reaction for 3h with 3 puffs. After the reaction is quenched, the product is dissolved by tetrahydrofuran, copper salt is removed by a neutral alumina column, the precipitate is precipitated in a mixed solvent of methanol and water, the filtration and the drying are carried out in a vacuum box for 24 hours, and finally 11.5g of poly (tert-butyl acrylate) (named PtBA-Br) is obtained, the yield is 58.6 percent, and the number average molecular weight M is measured by gel permeation chromatography GPCn5000Da, and the molecular weight distribution PDI is 1.17.
(2) 6g (1.2mmol) of PtBA-Br, 1.5602g (24mmol) of NaN3And 30mL of DMF was added to a 50mL round bottom flask and the reaction stirred in a 60 ℃ oil bath for 24 h. Stopping reaction, returning to room temperature, dissolving in tetrahydrofuran, and adding neutral oxygenRemoving various sodium salts with aluminum column, precipitating in methanol and water, standing, vacuum filtering, and vacuum drying overnight to obtain 4.16g white powdery tert-butyl azide polyacrylate (PtBA-N)3) The yield was 69.3%, and the number average molecular weight M was determined by gel permeation chromatography GPCn5200Da, and 1.15, and the GPC outflow curve is shown in FIG. 9. FIG. 10 shows the NMR spectrum of the molecular weight M obtained by nuclear magnetic calculationn4600Da, corresponding attribution can be found in each peak in the figure, and the integral is correct, so that the azide product PtBA-N is known3And (4) successfully synthesizing. The synthetic routes of the steps (1) to (2) are as follows:
Figure BDA0001566271980000101
(3) 10g (5.2632mmol) of polyethylene glycol monomethyl ether PEG1900-OH (molecular weight of 1900), 0.7900g (7.8947mmol) of succinic anhydride SA, 0.9645g (7.8947mmol) of 4-Dimethylaminopyridine (DMAP), 0.7989g (7.8947mmol) of triethylamine and 400mL of 1, 4-dioxane were introduced into a 500mL three-necked flask, stirred and aerated, and reacted at 25 ℃ for 24 hours. After the reaction is stopped, the precipitated salt is removed by suction filtration, the filtrate is concentrated, and is deposited into cold anhydrous ether, the mixture is kept stand, suction filtered and put into a vacuum box for drying, and finally 9g of polyethylene glycol monomethyl ether (named as PEG1900-COOH) with the yield of 90 percent is obtained. The reaction route is as follows:
Figure BDA0001566271980000102
FIG. 11 shows the NMR spectrum of PEG1900-COOH, in which all the peaks found corresponding assignments and the integral was correct, and the molecular weight M was calculated by nuclear magnetism n2300 Da. FIG. 12 is an infrared spectrum before and after the esterification reaction, in which the curve a represents the product PEG1900-COOH, the curve b represents the raw material PEG1900-OH, and it can be seen that 1732cm of the curve a after the reaction-1The occurrence of a characteristic peak for the carbonyl group indicates the success of the esterification reaction. FIG. 13 is a schematic representation of synthetic PEG1900-COOH macroThe molecular mass spectrogram has two groups of peak distributions, wherein the first group of peaks is assigned to [ PEG-COOH + H ]]+(experimental value 2070.24 corresponds to theoretical value 2070.36, n-43) this ion fragment. Another group of peaks is attributed to [ PEG-COOH + Na]+(the experimental value of 2092.32 is consistent with the theoretical value of 2092.35, and n is 43), that is, each peak can find the corresponding attribution, and the error between the experimental value and the theoretical value is within the allowable range. The successful synthesis of terminally carboxylated polyethylene glycol monomethyl ether PEG1900-COOH is well demonstrated in FIGS. 11, 12 and 13.
(4) In a 50mL reaction tube, 0.2080g (0.04mmol) of PtBA-N was added30.0800g (0.04mmol) of PEG1900-COOH and 0.0126g (0.04mmol) of dipyridyl diselenide PySePy, stirring and introducing inert gas, slowly injecting 1.5mL of trimethyl phosphine toluene solution with the temperature of 0 ℃ into the system, raising the temperature of the system to 40 ℃ when no gas is generated in the system, and continuing the reaction for 24 hours in an aeration state. After the reaction is stopped, adding a proper amount of tetrahydrofuran for dilution, dropwise adding the tetrahydrofuran into cold anhydrous ether for precipitation, standing, performing suction filtration, and drying in a vacuum box to finally obtain 0.2359g of diblock polymer PEG-b-PtBA with the yield of 82.4%. The reaction route is as follows:
Figure BDA0001566271980000111
FIG. 14 is a GPC elution curve before and after ligation, wherein the a-curve represents PEG1900-COOH (number average molecular weight M)n2200Da, molecular weight distribution PDI 1.07), curve b represents PtBA-N3(number average molecular weight Mn5200Da, molecular weight distribution PDI 1.15), and curve c represents the block polymer PEG-b-PtBA (number average molecular weight M)n7500Da, molecular weight distribution PDI 1.17). The test result shows that the end of the polyethylene glycol monomethyl ether PEG1900-COOH is carboxylated and the end of the poly tert-butyl acrylate PtBA-N is nitrified3The efficiency of connection can reach 100 percent when the connection is successfully carried out.
Example 4
(1) 10g (4.8780mmol) of polyethylene glycol HO-PEG2050-OH (molecular weight: 2050), 1.4644g (14.63mmol) of succinic anhydride SA, 1.7873g (14.63mmol) of 4-Dimethylaminopyridine (DMAP), 1.4804g (14.63mmol) of triethylamine and 400mL of 1, 4-dioxane were added to a 500mL three-necked flask, stirred and aerated, and reacted at 25 ℃ for 24 hours. After the reaction was stopped, the precipitated salts were removed by suction filtration, the filtrate was concentrated, and then precipitated into cold anhydrous ether, and the mixture was allowed to stand, suction-filtered, and dried in a vacuum oven to obtain 8.8g of polyethylene glycol HOOC-PEG2050-COOH carboxylated at the end, with a yield of 88.0%. The reaction route is as follows:
Figure BDA0001566271980000112
FIG. 15 shows the NMR spectrum of HOOC-PEG2050-COOH, in which all peaks found corresponding attribution and integrated correctly, and the molecular weight M obtained by NMR calculation n2300 Da. FIG. 16 is the mass spectrum of synthesized HOOC-PEG2050-COOH macromolecule, which has only one group of peaks attributed to [ HOOC-PEG-COOH + Na ]]+The error between the experimental value (2310.32) and the theoretical value (2310.44, n-45) is within the experimentally allowable range. The successful synthesis of terminally carboxylated polyethylene glycol HOOC-PEG2050-COOH is well demonstrated in both FIG. 15 and FIG. 16.
(2) In a 50mL reaction tube, 0.2600g (0.05mmol) of PtBA-N prepared in example 2 was added30.0575g (0.025mmol) of HOOC-PEG2050-COOH and 0.0157g (0.05mmol) of dipyridyl diselenide PySePy, stirring and introducing inert gas, slowly injecting 1.5mL of trimethyl phosphine toluene solution with the temperature of 0 ℃ into the system, raising the temperature of the system to 40 ℃ when no gas is generated in the system, and continuing the reaction for 24 hours in an aeration state. After the reaction is stopped, adding a proper amount of tetrahydrofuran for dilution, then dropwise adding the tetrahydrofuran into cold anhydrous ether for precipitation, standing, performing suction filtration, and drying in a vacuum box to finally obtain 0.2661g of triblock polymer PtBA-b-PEG-b-PtBA with the yield of 85.0%. The reaction route is as follows:
Figure BDA0001566271980000121
FIG. 17 is a NMR chart of the triblock polymer PtBA-b-PEG-b-PtBA after ligation, molecular weight M calculated from nuclear magnetismn14200 Da. FIG. 18 is a GPC outflow curve before and after ligation, wherein the a-curve represents PtBA-N3(number average molecular weight Mn5200Da, molecular weight distribution PDI 1.15), and b-curve represents PtBA-b-PEG-b-PtBA (number average molecular weight M)n14400Da and PDI 1.11). The test results show that the polyethylene glycol HOOC-PEG2050-COOH with carboxyl at the tail end and the polyacrylic acid tert-butyl ester PtBA-N with azide at the tail end3Successfully linked to form the triblock polymer PtBA-b-PEG-b-PtBA.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (7)

1. A method for preparing an amide bond linked polymer, comprising the steps of:
uniformly mixing a polymer with one end being an azide group, a carboxyl-containing compound and a catalyst dipyridyl diselenide, adding an organic solution of trimethylphosphine at 0-5 ℃ for reaction, and reacting at 25-40 ℃ for 2-24h when no bubble is generated in the reaction to obtain the polymer connected by the amide bond, wherein the polymer with one end being the azide group is prepared by adopting an ATRP method; the polymer in the polymer with one end being azide group is poly (tert-butyl acrylate) or polystyrene; the molecular weight of the polymer with one end of the azide group is 2000-5200 Da;
wherein the carboxyl-containing compound is tricarboxylic acid, a polymer with one end being carboxyl or a polymer with two ends being carboxyl; the polymer with one end being carboxyl or the polymer with two ends being carboxyl is polyethylene glycol or polyethylene glycol monomethyl ether;
the molar ratio of the polymer with one end being the azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 0.9-2.2:1-2:1-2: 20-40.
2. The method for producing an amide bond-linked polymer according to claim 1, characterized in that: the carboxyl-containing compound is tricarboxylic acid, and the molar ratio of the polymer with one end being an azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 1.9-2.2:2:1: 20-40.
3. The method for producing an amide bond-linked polymer according to claim 2, characterized in that: the carboxyl-containing compound is trimesic acid.
4. The method for producing an amide bond-linked polymer according to claim 1, characterized in that: the carboxyl-containing compound is a polymer with one end being carboxyl or a polymer with two ends being carboxyl, and the molar ratio of the polymer with one end being azide group, the dipyridyl diselenide, the carboxyl-containing compound and the trimethylphosphine is 0.9-1.3:1:2: 20-40.
5. The method for producing an amide bond-linked polymer according to claim 1, characterized in that: the organic solvent in the organic solution of trimethylphosphine is toluene.
6. The method for producing an amide bond-linked polymer according to claim 1, characterized in that: the concentration of the organic solution of trimethylphosphine is 1 mol/L.
7. The method for producing an amide bond-linked polymer according to claim 1, characterized in that: the reaction is carried out under the protection of inert gas.
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Publication number Priority date Publication date Assignee Title
CN102050953A (en) * 2010-10-18 2011-05-11 武汉理工大学 Method for preparing reducible and degradable supermolecule hydrogel
CN104558427A (en) * 2015-01-13 2015-04-29 苏州大学 Preparation method of ring brush polymer containing polystyrene main chain
CN106317415A (en) * 2015-06-23 2017-01-11 中国科学院化学研究所 Janus nano-particles based on block copolymer and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102050953A (en) * 2010-10-18 2011-05-11 武汉理工大学 Method for preparing reducible and degradable supermolecule hydrogel
CN104558427A (en) * 2015-01-13 2015-04-29 苏州大学 Preparation method of ring brush polymer containing polystyrene main chain
CN106317415A (en) * 2015-06-23 2017-01-11 中国科学院化学研究所 Janus nano-particles based on block copolymer and preparation method thereof

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