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WO2024130673A1 - Polymère et son procédé de préparation - Google Patents

Polymère et son procédé de préparation Download PDF

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Publication number
WO2024130673A1
WO2024130673A1 PCT/CN2022/141241 CN2022141241W WO2024130673A1 WO 2024130673 A1 WO2024130673 A1 WO 2024130673A1 CN 2022141241 W CN2022141241 W CN 2022141241W WO 2024130673 A1 WO2024130673 A1 WO 2024130673A1
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Prior art keywords
formula
solvent
polymer
reaction
mol
Prior art date
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Ceased
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PCT/CN2022/141241
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English (en)
Chinese (zh)
Inventor
洪良智
魏来
魏宏鑫
王照辉
王盛文
黎宇翔
董宇亮
云全新
曾涛
章文蔚
徐讯
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BGI Shenzhen Co Ltd
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BGI Shenzhen Co Ltd
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Priority to PCT/CN2022/141241 priority Critical patent/WO2024130673A1/fr
Priority to CN202280102611.XA priority patent/CN120344593A/zh
Publication of WO2024130673A1 publication Critical patent/WO2024130673A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/42—Block-or graft-polymers containing polysiloxane sequences
    • C08G77/442—Block-or graft-polymers containing polysiloxane sequences containing vinyl polymer sequences
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/42—Block-or graft-polymers containing polysiloxane sequences
    • C08G77/452—Block-or graft-polymers containing polysiloxane sequences containing nitrogen-containing sequences

Definitions

  • the invention relates to a polymer and a preparation method thereof, and belongs to the field of polymers.
  • Self-assembly at the nanoscale is a key property that nature relies on to generate biological membranes.
  • These membranes build a functionalized molecular framework by embedding a combination of channels, receptors, and molecular pumps in the microenvironment and functional framework. Using hydrophobic-hydrophilic interactions, these membranes self-assemble into bilayers and other structures such as vesicles.
  • Self-assembled membranes are a key component if one wishes to mimic the principles of natural nanostructures.
  • a range of polymer systems have been used for drug delivery, biopharmaceutical coatings, virus-assisted gene delivery, and nanoreactors through their self-assembly. These are amphiphilic diblock or triblock copolymers that self-assemble in suitable solvents into micelles, worm-like micelles, tubular structures, membranes, or vesicles.
  • ABA triblock copolymers Although there are many different types of block copolymer structures, ABA triblock copolymers have received particular attention in recent years due to their inherent ability to form vesicular structures by self-assembly despite being highly hydrophobic and hydrophilic. From a biomedical perspective, polyoxazolines are particularly attractive because they provide a pseudopolypeptide architecture and were chosen as the hydrophilic block A.
  • Polymethylsiloxane (PDMS) exhibits a very low glass transition temperature and is mostly liquid at room temperature due to the ionic nature of the Si- CH3 bond.
  • poly(siloxanes) have very low surface energy and are extremely hydrophobic; therefore, they were chosen as the hydrophobic block B. This type of ABA triblock copolymer system has been extensively studied and has been shown to have interesting biomedical and self-assembly properties.
  • the existing synthesis method constructs a series of ABA triblock backbone structure polymers through a core-first synthesis strategy, but it has the disadvantages of many synthesis steps, low yield, high polymer dispersibility, poor repeatability, and difficulty in modifying the molecular structure.
  • the existing technology provides a small amount of triblock polymer preparation schemes, such as the following preparation method, which realizes the preparation of single hydroxyl-terminated triblock polymer PMOXA-PDMS-PMOXA through 4-5 steps.
  • the process steps are too long, and it involves metal lithium reagents with poor stability and pyridine with high toxicity, which seriously pollutes the environment and is not conducive to industrial large-scale production.
  • the technical problem to be solved by the present invention is that the existing method for synthesizing block copolymers has many synthesis steps, involves metal lithium reagents with poor stability, pyridine and other reagents with high toxicity, low yield, high polymer dispersibility, poor repeatability, and difficult molecular structure modification.
  • the present invention provides a polymer and a preparation method thereof.
  • the present invention provides a polymer represented by formula V:
  • the R is -ORt1 , -NRt2Rt3 , -COOMe , -( CH2 ) n1SH , a 5-10 membered heteroaryl substituted by 1, 2 or 3 oxo groups, -O( CH2 ) n2OH , -OP(O)(OMe), -OP(O)(OMe)(O( CH2 ) n3N + (Et) 3 ,
  • R t1 , R t2 , and R t3 are independently H, Ts, C 1 -C 6 alkyl or -(CH 2 ) n4 SH;
  • n1, n3 and n4 are independently 0, 1, 2, 3, 4, 5 or 6;
  • n2 is 2, 3, 4, 5, 6, 7, 8 or 9;
  • the L is a
  • R c is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CN or -NO 2 ;
  • n 1, 2, 3, 4, 5 or 6;
  • n 3, 4, 5, 6, 7, 8 or 9;
  • Ra is ( CH2 ) n , n is 3, 4 or 5, and said Rb is hydrogen, C1 - C6 alkyl or acetyl;
  • poly-2-methyloxazoline polyphospholipid, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, polymethyl methacrylate, poly(N,N-dimethylacrylamide), polyacylalkylene imine, polyhydroxyalkyl acrylate, poly-2-methyloxazoline polyethylene glycol or poly-2-methyloxazoline polyphospholipid;
  • the p is 20-50;
  • the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from one or more of N, O and S.
  • each R 2 is independently a C 1 -C 3 alkyl group, preferably a methyl group; each m is independently any value from 1 to 22; preferably any value from 1 to 6; more preferably 1, 1.1, 1.3, 3.6, 3.8 or 5.4; further preferably 1, 1.1, 1.3 or 3.6; each w is independently any value from 1 to 22; preferably any value from 1 to 6; more preferably 3.
  • the R 1 is preferably a C 1 -C 6 alkyl group, more preferably a methyl group.
  • the R 1' is preferably a C 1 -C 6 alkyl group, more preferably a methyl group.
  • Y is preferably a C 1 -C 6 alkyl group, more preferably a methyl group.
  • the R is preferably hydroxyl, methoxy, TsO- or More preferably, hydroxyl or
  • L is preferably or -CH 2 -.
  • the p is preferably any value between 20 and 47, and more preferably 20 or 35.
  • the R 1 is preferably methyl; the R 1' is preferably methyl;
  • the R2 is preferably a methyl group; the R is preferably a hydroxyl group; the Y is preferably a methyl group; the L is preferably The m is preferably 3.6; the p is preferably 35.
  • the R 1 is preferably methyl; the R 1' is preferably methyl;
  • the R 2 is preferably methyl;
  • the R is preferably
  • the Y is preferably a methyl group;
  • the L is preferably -CH 2 -;
  • the m is preferably 3.6; and
  • the p is preferably 35.
  • the R 1 is preferably methyl; the R 1' is preferably methyl;
  • the R 2 is preferably a methyl group; the R is preferably a hydroxyl group; the Y is preferably a methyl group; the L is preferably -CH 2 -; the m is preferably 1; the w is preferably 3; and the p is preferably 30.
  • the R 1 is preferably methyl; the R 1' is preferably methyl;
  • the R2 is preferably a methyl group; the R is preferably a hydroxyl group; the Y is preferably a methyl group; the L is preferably The m is preferably 1.1; the w is preferably 3; and the p is preferably 20.
  • the R 1 is preferably methyl; the R 1' is preferably methyl;
  • the R2 is preferably a methyl group; the R is preferably a hydroxyl group; the Y is preferably a methyl group; the L is preferably The m is preferably 1.3; the w is preferably 3; and the p is preferably 20.
  • the polymer represented by formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention provides a method for preparing a polymer represented by formula V, which comprises the following steps: in a solvent and in an inert atmosphere, subjecting a polymer represented by formula Z8 and a polymer represented by formula S4 to an addition reaction as shown below under the action of a catalyst to obtain a polymer represented by formula V, that is,
  • R, L, R 1 , R 1′ , Y and p are as defined above.
  • the catalyst in the method for preparing the polymer represented by formula V, may be conventional in the art for such reactions, preferably H 2 PtCl 2 or a platinum (0)-1,3-diethylene-1,1,3,3-tetramethyldisiloxane complex solution.
  • the catalyst is more preferably a platinum (0)-1,3-diethylene-1,1,3,3-tetramethyldisiloxane complex solution.
  • the solvent in the method for preparing the polymer of formula V, may be a commonly used solvent for such reactions in the art.
  • the solvent is preferably one or more of chlorinated hydrocarbon solvents, ether solvents, ester solvents, aromatic hydrocarbon solvents and nitrile solvents.
  • the chlorinated hydrocarbon solvent is preferably one or more of chloroform and dichloroethane.
  • the ether solvent is preferably tetrahydrofuran.
  • the ester solvent is preferably ethyl acetate.
  • the aromatic hydrocarbon solvent is preferably toluene.
  • the nitrile solvent is preferably one or more of benzonitrile and acetonitrile.
  • the solvent is preferably a mixed solvent of aromatic hydrocarbon solvents and nitrile solvents, more preferably a mixed solvent of toluene and acetonitrile.
  • the volume ratio of the aromatic hydrocarbon solvent to the nitrile solvent is preferably 1:0.01-1:3; more preferably 1:1.
  • the molar ratio of Z8 to S4 can be conventional in this field for such reactions, preferably 2.5-3, and more preferably 2.5.
  • the molar volume ratio of Z8 to the catalyst can be conventional in this field for such reactions, preferably 15-30 mol/L.
  • the platinum content in the catalyst may be conventional for such reactions in the art, preferably 1-4%, and more preferably 2%.
  • the molar volume ratio of Z8 to the solvent may be conventional in the art for such reactions, preferably 0.05-0.2 mol/L, and more preferably 0.125 mol/L.
  • the reaction temperature may be conventional in the art for such reactions, preferably 60 to 80°C, more preferably 60°C or 80°C.
  • the reaction time of the reaction may be conventional for such reactions in the art, preferably 24 to 48 hours, more preferably 24 hours or 48 hours.
  • the inert atmosphere may be conventional for such reactions in the art, preferably nitrogen atmosphere and argon atmosphere.
  • the reaction may further include post-treatment.
  • the post-treatment step may be conventional for such reactions in the art.
  • ethanol and regenerated cellulose membranes are used for diafiltration purification.
  • regenerated cellulose membranes are used for diafiltration purification.
  • the molar volume ratio of the compound represented by formula Z8 to ethanol can be conventional in this field for such reactions, preferably 1:40 mol/L.
  • the order of adding materials for the reaction can be conventional in the art for such reactions.
  • Z8 is first dissolved in a solvent, S4 is added, and then a catalyst is added.
  • the order of adding materials for the reaction is more preferably to first dissolve Z8 in a solvent, add S4 after it is completely dissolved or mostly dissolved, and then add a catalyst after it is completely dissolved.
  • the specific operation of the reaction can be conventional in the art.
  • a) Z8 is first dissolved in a solvent and stirred thoroughly until it is completely dissolved or mostly dissolved; b) S4 is added, and after it is dissolved, it is stirred thoroughly for 5 minutes; c) a catalyst is added and stirred thoroughly for 5-10 minutes; d) the temperature is raised and stirred.
  • the polymer represented by formula Z8 is The polymer represented by formula S4 is The polymer represented by formula V is
  • the catalyst is a platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane complex solution;
  • the solvent is a mixed solvent of toluene and acetonitrile; the volume ratio of toluene and acetonitrile is 1:1;
  • the inert atmosphere is an argon atmosphere;
  • the molar ratio of Z8 to S4 is preferably 2.5;
  • the molar volume ratio of Z8 to the catalyst is preferably 125:6 mol/L;
  • the platinum content in the catalyst is preferably 2%;
  • the molar volume ratio of Z8 to the solvent is preferably 0.125 mol/L;
  • the reaction temperature is 80°C; and the reaction time is 24h.
  • the polymer represented by formula Z8 is The polymer represented by formula S4 is The polymer represented by formula V is
  • the catalyst is a platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane complex solution;
  • the solvent is a mixed solvent of toluene and acetonitrile; the volume ratio of toluene and acetonitrile is 1:1;
  • the inert atmosphere is argon;
  • the molar ratio of Z8 to S4 is preferably 2.5;
  • the molar volume ratio of Z8 to the catalyst is preferably 125:6 mol/L;
  • the platinum content in the catalyst is preferably 2%;
  • the molar volume ratio of Z8 to the solvent is preferably 0.125 mol/L;
  • the reaction temperature is 80°C; and the reaction time is 48h.
  • the polymer represented by formula Z8 is The polymer represented by formula S4 is The polymer represented by formula V is
  • the catalyst is a platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane complex solution;
  • the solvent is a mixed solvent of toluene and acetonitrile; the volume ratio of toluene and acetonitrile is 1:1;
  • the inert atmosphere is argon;
  • the molar ratio of Z8 to S4 is preferably 2.5;
  • the molar volume ratio of Z8 to the catalyst is preferably 125:6 mol/L;
  • the platinum content in the catalyst is preferably 2%;
  • the molar volume ratio of Z8 to the solvent is preferably 0.125 mol/L;
  • the reaction temperature is 80°C; and the reaction time is 48h.
  • the polymer represented by formula Z8 is The polymer represented by formula S4 is The polymer represented by formula V is
  • the catalyst is a platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane complex solution;
  • the solvent is a mixed solvent of toluene and acetonitrile; the volume ratio of toluene and acetonitrile is 1:1;
  • the inert atmosphere is an argon atmosphere;
  • the molar ratio of Z8 to S4 is preferably 2.5;
  • the molar volume ratio of Z8 to the catalyst is preferably 125:6 mol/L;
  • the platinum content in the catalyst is preferably 2%;
  • the molar volume ratio of Z8 to the solvent is preferably 0.125 mol/L;
  • the reaction temperature is 80°C; and the reaction time is 48h.
  • the polymer represented by formula Z8 is The polymer represented by formula S4 is The polymer represented by formula V is
  • the catalyst is a platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane complex solution;
  • the solvent is a mixed solvent of toluene and acetonitrile; the volume ratio of toluene and acetonitrile is 1:1;
  • the inert atmosphere is an argon atmosphere;
  • the molar ratio of Z8 to S4 is preferably 2.5;
  • the molar volume ratio of Z8 to the catalyst is preferably 125:6 mol/L;
  • the platinum content in the catalyst is preferably 2%;
  • the molar volume ratio of Z8 to the solvent is preferably 0.125 mol/L;
  • the reaction temperature is 80°C; and the reaction time is 48h.
  • the method for preparing the polymer of formula V also includes a method for preparing the polymer of formula Z8, which comprises the following steps: in a solvent, in an inert atmosphere, reacting the compound of formula S5, the compound of formula Z6 and the quenching agent S7 as shown below to obtain the polymer of formula Z8, that is,
  • R, L and The definitions are the same as above;
  • Said X is halogen, OTf or OTs
  • the quenching reagent S7 is an inorganic base (such as KOH) or RH, and R is defined as above;
  • the solvent in the method for preparing the polymer represented by formula Z8, may be a commonly used solvent for such reactions in the art.
  • the solvent is preferably a nitrile solvent.
  • the solvent is more preferably acetonitrile.
  • L is preferably or -CH 2 -, and the 1 end is connected to X.
  • the 2-Methyloxazoline is preferred.
  • X is preferably Br, Cl or OTs.
  • X is preferably Br.
  • X is preferably Cl.
  • X is preferably OTs.
  • the quenching reagent S7 is preferably a methanol solution of potassium hydroxide
  • the quenching reagent S7 is preferably a methanol solution of potassium hydroxide, more preferably a methanol solution with a potassium hydroxide concentration of 0.5M.
  • the quenching reagent S7 is preferably
  • the quenching reagent S7 is preferably
  • the molar ratio of the compound represented by formula S5 to the compound represented by formula Z6 can be conventional in the art for such reactions, preferably 2:1-1:8, more preferably 1:1 or 1:4.
  • the molar volume ratio of the compound represented by formula S5 to the quenching agent S7 can be conventional in the art for such reactions, preferably 5-20 mol/L, and more preferably 10 mol/L.
  • the quenching reagent S7 when the quenching reagent S7 is When the molar ratio of the compound represented by formula S5 to the quenching agent S7 can be conventional in the art for such reactions, preferably 1:2-2:1, and more preferably 1:1.
  • the quenching reagent S7 when the quenching reagent S7 is When the molar ratio of the compound represented by formula S5 to the quenching agent S7 can be conventional in the art for such reactions, preferably 1:2-2:1, and more preferably 1:1.
  • the molar volume ratio of the compound represented by formula S5 to the solvent can be conventional in the art for such reactions, preferably 1:1.5 mol/L-1:3 mol/L, and more preferably 50:120 mol/L.
  • the reaction temperature may be conventional for such reactions in the art, preferably 40-120°C, more preferably 80°C.
  • the reaction time may be conventional for such reactions in the art, preferably 12-48 hours, and more preferably 24 hours.
  • the inert atmosphere may be conventional in the art for such reactions, preferably a nitrogen atmosphere or an argon atmosphere.
  • the timing of adding the quenching reagent S7 can be conventional in the art for such reactions. Preferably, it is added after the reaction is cooled to room temperature. More preferably, it is added after the reaction is cooled to room temperature and stirred for 3 hours.
  • the reaction may further include post-treatment.
  • the post-treatment step may be conventional for such reactions in the art.
  • ethanol and regenerated cellulose membranes are used for diafiltration purification.
  • regenerated cellulose membranes are used for diafiltration purification.
  • the molar volume ratio of the compound represented by formula S5 to ethanol can be conventional in the art for such reactions, preferably 5:70 mol/L.
  • the solvent is acetonitrile; the compound represented by S5 is The quenching reagent S7 is a methanol solution with a potassium hydroxide concentration of 0.5M; the polymer represented by the formula Z8 is The compound represented by Z6 is 2-methyloxazoline; the compound represented by formula S5 and the compound represented by formula Z6
  • the molar ratio of the compound represented by formula S5 to the quenching reagent S7 is 1:4; the molar volume ratio of the compound represented by formula S5 to the quenching reagent S7 is 10 mol/L; the molar volume ratio of the compound represented by formula S5 to the solvent is 50:120 mol/L; the reaction is carried out at a reaction temperature of 80°C; the reaction time is 24 hours; the inert atmosphere is argon; the quenching reagent S7 is added after the reaction is cooled to room temperature and stirred for 3 hours after addition.
  • the solvent is acetonitrile; the compound represented by S5 is The quenching reagent S7 is The polymer represented by formula Z8 is The compound represented by Z6 is 2-methyloxazoline; the compound represented by formula S5 and the compound represented by formula Z6
  • the molar ratio of the compound represented by formula S5 to the quenching reagent S7 is 1:4; the molar ratio of the compound represented by formula S5 to the quenching reagent S7 is 1:1; the molar volume ratio of the compound represented by formula S5 to the solvent is 50:120 mol/L; the reaction is carried out at a reaction temperature of 80°C; the reaction time is 24 hours; the inert atmosphere is argon; the quenching reagent S7 is added after the reaction is cooled to room temperature and stirred for 3 hours after addition.
  • the solvent is acetonitrile; the compound represented by S5 is The quenching reagent S7 is The polymer represented by formula Z8 is The compound represented by Z6 is 2-methyloxazoline; the compound represented by formula S5 and the compound represented by formula Z6
  • the molar ratio of the compound represented by formula S5 to the quenching reagent S7 is 1:4; the molar ratio of the compound represented by formula S5 to the quenching reagent S7 is 1:1; the molar volume ratio of the compound represented by formula S5 to the solvent is 50:120 mol/L; the reaction is carried out at a reaction temperature of 80°C; the reaction time is 24 hours; the inert atmosphere is argon; the quenching reagent S7 is added after the reaction is cooled to room temperature and stirred for 3 hours after addition.
  • the solvent is acetonitrile; the compound represented by S5 is The quenching reagent S7 is The polymer represented by formula Z8 is The compound represented by Z6 is 2-methyloxazoline; the compound represented by formula S5 and the compound represented by formula Z6 The molar ratio of the compound represented by formula S5 to the quenching reagent S7 is 1:1; the molar volume ratio of the compound represented by formula S5 to the solvent is 50:120 mol/L; the reaction is carried out at a reaction temperature of 80°C; the reaction time is 24 hours; the inert atmosphere is argon; the quenching reagent S7 is added after the reaction is cooled to room temperature and stirred for 3 hours after addition.
  • the solvent is acetonitrile;
  • the compound represented by S5 is The quenching reagent S7 is a methanol solution with a potassium hydroxide concentration of 0.5M;
  • the polymer represented by the formula Z8 is The compound represented by Z6 is 2-methyloxazoline;
  • the compound represented by formula S5 and formula Z6 The molar ratio of the compounds shown is 1:1; the molar volume ratio of the compound shown in formula S5 and the quenching reagent S7 is 2.5 mol/L; the molar volume ratio of the compound shown in formula S5 and the solvent is 12.5:120 mol/L;
  • the reaction is carried out at a reaction temperature of 80°C;
  • the reaction time is 24 hours;
  • the inert atmosphere is argon;
  • the quenching reagent S7 is added after the reaction is cooled to room temperature and stirred for 3 hours after addition.
  • the present invention provides a polymer represented by formula Z8:
  • R, L and The definitions are the same as above.
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the polymer represented by formula Z8 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention provides a method for preparing a polymer represented by formula Z8, which comprises the following steps: in a solvent and in an inert atmosphere, reacting a compound represented by formula S5, a compound represented by formula Z6 and a quenching agent S7 as shown below to obtain a polymer represented by formula Z8, that is,
  • R, X, quenching reagent S7, L and The definitions and reaction conditions such as reaction temperature, reaction time, molar ratio of each reactant, reaction operation and the like are the same as described above.
  • a "-" at the end of a group means that the group is attached to the rest of the molecule through that site.
  • -CN refers to a cyano group.
  • alkyl refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms.
  • C1 - C6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.
  • alkoxy refers to the group R X -O-, where R X is defined as the term “alkyl”. Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • alkylthio refers to the group R X -S-, where R X is defined as the term "alkyl”.
  • Alkylthio includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like.
  • aryl refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of carbon atoms (e.g., C 6 -C 10 ), which is a single ring or multiple rings (e.g., 2 or 3). When it is a multiple ring, the single rings share two atoms and a bond, and at least one ring is aromatic.
  • the aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, wait.
  • heteroaryl refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is a single ring or multiple rings, with two atoms and a bond shared between the single rings, and at least one ring being aromatic.
  • a heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; a heteroaryl group is attached to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties.
  • Heteroaryl groups include, but are not limited to: wait.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive progress of the present invention is that the polymer of the present invention can self-assemble into a vesicle structure in a solution, and the vesicle has good stability.
  • the preparation method of the present invention has the advantages of fewer synthesis steps, mild reaction conditions, high yield, low polymer dispersibility, good repeatability, and accurate molecular weight control and diversified modification of the end-capping group and the connecting group between the hydrophobic block and the hydrophilic block of the polymer.
  • the synthetic route of triblock polymer P1 is as follows:
  • Step 1 synthesis of prepolymer S4-1: add 21 mL S1 (0.956 g/mL, 296.62 g/mol, 67.68 mmol) to the schlenk bottle with a pipette under nitrogen protection, seal the top with a rubber stopper, and then add 1.5 mL of 1,1,3,3-tetramethyldisiloxane S2 (0.76 g/mL, 134.33 g/mol, 8.49 mmol) with a syringe.
  • the molar ratio of S1 to S2 is 8:1.
  • S1 can be slightly excessive, and argon gas is used for deoxygenation three times.
  • Step 2 synthesis of prepolymer Z8-1: dry vinyl compound S5-1 (7.6 g, 152.62 g/mol, 50 mmol) and reaction raw material Z6-1 (17 g, 85.1 g/mol, 200 mmol) were mixed and dissolved in dry acetonitrile (120 mL) in argon. React at 80 ° C for 24 h. The reaction was completed by nuclear magnetic hydrogen spectrum. After the reaction was complete, the mixture was cooled to room temperature, and then 5 ml of 0.5 M methanol solution containing potassium hydroxide S7-1 (0.48 g) was added to the mixture to terminate the reaction, and stirred for 3 hours.
  • Step 3 synthesis of triblock P1: In argon, the reaction raw material S4-1 (3.2 g, 3200 g/mol, 1 mmol) and the dry reaction raw material Z8-1 (1.1 g, 440 g/mol, 2.5 mmol) were dissolved in 20 ml of dry toluene acetonitrile mixed solvent (1/1). After sufficient dissolution, 120 uL Karstedt Catalyst (in xylene, Pt ⁇ 2%) was added, and then the temperature was raised to 80°C and stirred at 80°C for 24 h. After the reaction was complete, the mixture was cooled to room temperature and filtered.
  • the synthetic route of triblock polymer P2 is as follows:
  • Step 1 synthesis of prepolymer S4-1: add 21 mL S1 (0.956 g/mL, 296.62 g/mol, 67.68 mmol) to the schlenk bottle with a pipette under nitrogen protection, seal the top with a rubber stopper, and then add 1.5 mL of 1,1,3,3-tetramethyldisiloxane S2 (0.76 g/mL, 134.33 g/mol, 8.49 mmol) with a syringe.
  • the molar ratio of S1 to S2 is 8:1.
  • S1 can be slightly excessive and deoxygenated three times.
  • Step 2 synthesis of prepolymer Z8-2: dry vinyl compound S5-2 (50mmol) (6.1g, 120.99g/mol, 50mmol) and reaction raw material Z6-1 (17g, 85.1g/mol, 200mmol) were mixed and dissolved in dry acetonitrile (120mL) in argon. React at 80°C for 24h. The reaction was completed by H NMR. After the reaction was complete, the mixture was cooled to room temperature, and then the reaction was terminated by adding S7-2 (14.7g, 147.1g/mol, 50mmol) and stirred for 3 hours. After removing the solvent under reduced pressure, the product was dissolved in 100ml of deionized water and the residual S7-2 was removed by filtration.
  • Step 3 synthesis of triblock P2: In argon, the reaction raw material S4-1 (3.2 g, 3200 g/mol, 1 mmol) and the dry reaction raw material Z8-2 (1.2 g, 493 g/mol, 2.5 mmol) were dissolved in 20 ml of dry toluene/acetonitrile mixed solvent (1/1). After the raw materials were fully dissolved at room temperature, 120 uL Karstedt catalyst (in xylene, Pt ⁇ 2%) was added, the temperature was raised to 80°C, and stirred at 80°C for 48 h. After the reaction was complete, the mixture was cooled to room temperature and filtered.
  • the reaction raw material S4-1 3.2 g, 3200 g/mol, 1 mmol
  • the dry reaction raw material Z8-2 1.2 g, 493 g/mol, 2.5 mmol
  • the synthetic route of the pentablock polymer P3 is as follows:
  • Step 1 synthesis of prepolymer S4-2: add 21 mL S1 (0.956 g/mL, 296.62 g/mol, 67.68 mmol) to the schlenk bottle with a pipette under nitrogen protection, seal the top with a rubber stopper, and then add 1.7 mL 1,1,3,3-tetramethyldisiloxane S2 (0.76 g/mL, 134.33 g/mol, 9.67 mmol) with a syringe.
  • the molar ratio of S1 to S2 is 7:1.
  • S1 can be slightly excessive, and argon gas is used for deoxygenation three times.
  • Step 2 Synthesis of prepolymer Z8-3: Mix the dried vinyl compound S5-2 (6.1 g, 120.99 g/mol, 50 mmol) and the reaction raw material Z6-1 (17 g, 85.1 g/mol, 200 mmol) in dry acetonitrile (120 mL) in argon. React at 80°C for 24 h. The nuclear magnetic hydrogen spectrum confirms that the reaction is complete. After the reaction is complete, the mixture is cooled to room temperature, and then the reaction is terminated by adding S7-3 (7.5 g, 150.2 g/mol, 50 mmol) and stirred for 3 hours.
  • S7-3 7.5 g, 150.2 g/mol, 50 mmol
  • Step 3 synthesis of triblock P3: In argon, the reaction raw material S4-2 (2.3 g, 2354 g/mol, 1 mmol) and the dry reaction raw material Z8-3 (0.7 g, 289 g/mol, 2.5 mmol)) were dissolved in 20 ml of dry toluene/acetonitrile mixed solvent (1/1). After the raw materials were fully dissolved at room temperature, 120 uL of Karstedt catalyst (in xylene, Pt ⁇ 2%) was added, the temperature was raised to 80°C, and stirred at 80°C for 48 h. After the reaction was complete, the mixture was cooled to room temperature and filtered.
  • Karstedt catalyst in xylene, Pt ⁇ 2%
  • the synthetic route of the pentablock polymer P4 is as follows:
  • Step 1 synthesis of prepolymer S4-3: add 21 mL S1 (0.956 g/mL, 296.62 g/mol, 67.68 mmol) to the schlenk bottle with a pipette under nitrogen protection, seal the top with a rubber stopper, and then add 2.4 mL 1,1,3,3-tetramethyldisiloxane S2 (0.76 g/mL, 134.33 g/mol, 13.54 mmol) with a syringe.
  • the molar ratio of S1 to S2 is 5:1.
  • S1 can be slightly excessive, and argon gas is used for deoxygenation three times.
  • Step 2 synthesis of prepolymer Z8-4: dry vinyl compound S5-1 (7.6g, 152.62g/mol, 50mmol) and reaction raw material Z6-1 (4.3g, 85.1g/mol, 50mmol) were mixed and dissolved in dry acetonitrile (120mL) in argon. React at 80°C for 24h. The reaction was completed by H NMR spectrum. After the reaction was complete, the mixture was cooled to room temperature, and then the reaction was terminated by adding S7-3 (7.5g, 150.2g/mol, 50mmol) and stirred for 3 hours. After the solvent was removed under reduced pressure, the product was dissolved in 100ml of dichloromethane, and the residual inorganic salts and excess potassium hydroxide were filtered out. The solvent was removed under reduced pressure, and the resulting polymer was dried under vacuum to obtain vinyl-terminated PMOXA prepolymer Z8-4 (16.1g, yield 88%). Its structure and degree of polymerization were determined by H NMR spectrum integration.
  • Step 3 synthesis of triblock P4: In argon, the reaction raw material S4-3 (1.6 g, 1628 g/mol, 1 mmol) and the dry reaction raw material Z8-4 (0.92 g, 366 g/mol, 2.5 mmol) were dissolved in 20 ml of dry toluene/acetonitrile mixed solvent (1/1). After the raw materials were fully dissolved at room temperature, 120 uL of Karstedt catalyst (in xylene, Pt ⁇ 2%) was added, the temperature was raised to 80°C, and stirred at 80°C for 48 h. After the reaction was complete, the mixture was cooled to room temperature and filtered.
  • Karstedt catalyst in xylene, Pt ⁇ 2%
  • the synthetic route of the pentablock polymer P5 is as follows:
  • Step 1 synthesis of prepolymer S4-3: add 21 mL S1 (0.956 g/mL, 296.62 g/mol, 67.68 mmol) to the schlenk bottle with a pipette under nitrogen protection, seal the top with a rubber stopper, and then add 2.4 mL 1,1,3,3-tetramethyldisiloxane S2 (0.76 g/mL, 134.33 g/mol, 13.54 mmol) with a syringe.
  • the molar ratio of S1 to S2 is 5:1.
  • S1 can be slightly excessive, and argon gas is used for deoxygenation three times.
  • Step 2 Synthesis of prepolymer Z8-9-1: In a nitrogen atmosphere, the dried vinyl compound S5-1 (7.6 g, 152.62 g/mol, 50 mmol)) and the reaction raw material S7-3 (15.0 g, 150.2 g/mol, 100 mmol) were mixed and dissolved in dry 1,4-dioxane (120 mL). Solid potassium hydroxide (5.6 g, 56.10 g/mol, 100 mmol) was added and reacted at 50°C for 48 h. The nuclear magnetic hydrogen spectrum confirmed that the reaction was complete.
  • Step 3 Synthesis of prepolymer Z8-5-3: In a nitrogen atmosphere, the dried vinyl compound Z8-9-1 (7.9 g, 270 g/mol, 29.2 mmol)) and the reaction raw material S11 triethylamine (3.5 g, 101.2 g/mol, 35.0 mmol) were mixed and dissolved in dry dichloromethane (120 mL), and cooled and stirred in an ice bath for 15 minutes. The reaction raw material S10 p-toluenesulfonyl chloride (5.4 g, 154.6 g/mol, 35.0 mmol) was added in 3 portions. The temperature was restored to 25 ° C and stirred for 24 hours.
  • Step 4 synthesis of prepolymer Z8-5: dry vinyl compound Z8-5-3 (5.3 g, 420.5 g/mol, 12.5 mmol) and reaction raw material Z6-1 (1.1 g, 85.1 g/mol, 12.5 mmol) were mixed and dissolved in dry acetonitrile (120 mL) in argon. React at 80 ° C for 24 h. The reaction was completed by nuclear magnetic hydrogen spectrum. After the reaction was complete, the mixture was cooled to room temperature, and then 5 ml of 0.5 M methanol solution containing potassium hydroxide S7-1 (0.48 g) was added to the mixture to terminate the reaction, and stirred for 3 hours.
  • Step 5 synthesis of triblock P5:
  • the reaction raw material S4-3 (1.6 g, 1628 g/mol, 1 mmol) and the dry reaction raw material Z8-5 (0.96 g, 385 g/mol, 2.5 mmol) were dissolved in 20 ml of dry toluene/acetonitrile mixed solvent (1/1).
  • 120 uL of Karstedt catalyst (in xylene, Pt ⁇ 2%) was added, the temperature was raised to 80°C, and stirred at 80°C for 48 h. After the reaction was complete, the mixture was cooled to room temperature and filtered.
  • the droplets of the polymer P5 of the present application can exist stably for more than 30 minutes, have good uniformity, and there is no obvious fusion between the droplets.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

La présente invention concerne un polymère et son procédé de préparation. Est divulgué dans la présente invention un polymère représenté par la formule V, lequel polymère a une bonne stabilité des gouttelettes. Est divulgué en outre dans la présente invention un procédé de préparation du polymère représenté par la formule V, lequel procédé comprenant les étapes suivantes consistant à : dans un solvant, soumettre un polymère représenté par la formule Z8 et un polymère représenté par la formule S4 à une réaction d'addition telle que représentée ci-dessous dans une atmosphère inerte sous l'action d'un catalyseur pour obtenir un polymère représenté par la formule V. Lorsque le polymère représenté par la formule V est préparé à l'aide du procédé, il y a peu d'étapes de synthèse, les conditions de réaction sont douces, le rendement est élevé, la dispersion de polymère est faible, la répétabilité est bonne, et des groupes de contrôle de poids moléculaire et de coiffage d'extrémité précis sont obtenus.
PCT/CN2022/141241 2022-12-23 2022-12-23 Polymère et son procédé de préparation Ceased WO2024130673A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02182724A (ja) * 1989-01-10 1990-07-17 Kao Corp ポリ（ｎ―アシルアルキレンイミン）系共重合体及びその用途
US20080305149A1 (en) * 2007-06-11 2008-12-11 Thomas Hirt Mucoadhesive vesicles for drug delivery
CN102066986A (zh) * 2008-03-17 2011-05-18 博士伦公司 包括两性多嵌段共聚物的透镜
CN106232686A (zh) * 2014-03-26 2016-12-14 应用仿生学有限公司 新型聚合物及制造膜的方法
CN106459410A (zh) * 2014-05-01 2017-02-22 博通分离膜技术（北京）有限公司 嵌段共聚物的合成方法及用途
CN106687508A (zh) * 2014-07-23 2017-05-17 道康宁公司 有机硅乳液

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02182724A (ja) * 1989-01-10 1990-07-17 Kao Corp ポリ（ｎ―アシルアルキレンイミン）系共重合体及びその用途
US20080305149A1 (en) * 2007-06-11 2008-12-11 Thomas Hirt Mucoadhesive vesicles for drug delivery
CN102066986A (zh) * 2008-03-17 2011-05-18 博士伦公司 包括两性多嵌段共聚物的透镜
CN106232686A (zh) * 2014-03-26 2016-12-14 应用仿生学有限公司 新型聚合物及制造膜的方法
CN106459410A (zh) * 2014-05-01 2017-02-22 博通分离膜技术（北京）有限公司 嵌段共聚物的合成方法及用途
CN106687508A (zh) * 2014-07-23 2017-05-17 道康宁公司 有机硅乳液

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