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Synthesis method and application of a kind of methacrylamide orthoester monomer and acid-sensitive amphiphilic block copolymer thereof

A technology of methacrylamide ortho acid and amphiphilic block, which is applied in the directions of organic chemistry, emulsion delivery, etc., can solve the problems of reducing human immunity, delayed treatment, slow release, etc., and achieves good application prospects and good acidity. effect of sensitivity

Active Publication Date: 2016-05-04
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For the treatment of tumors, most of the current anti-tumor drugs have obvious deficiencies: the targeting is not obvious, and the treatment process often causes irreversible damage to the normal tissues of the body, which reduces the body's immunity and delays treatment.
pH-responsive polymer micelles are mainly prepared by the self-assembly of amphiphilic block copolymers to form micelles. The copolymers contain chemical bonds that are rapidly hydrolyzed under acidic conditions, such as hydrazone bonds, glyoxal bonds, and amide bonds. Ester bonds, etc., wherein polymers with orthoester bonds as sensitive groups can now be obtained through fewer steps and simple reactions (Chinese patent CN103588752 Chinese patent CN101880265A), but these polymers degrade slowly in acidic environments, Slow drug release after embedding, resulting in reduced drug efficacy

Method used

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  • Synthesis method and application of a kind of methacrylamide orthoester monomer and acid-sensitive amphiphilic block copolymer thereof
  • Synthesis method and application of a kind of methacrylamide orthoester monomer and acid-sensitive amphiphilic block copolymer thereof
  • Synthesis method and application of a kind of methacrylamide orthoester monomer and acid-sensitive amphiphilic block copolymer thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] N-{2-[2-Methoxy-[1,3]dioxolane-4-(2-methoxy-[1,3]dioxolane-4-methyleneoxy)]- The synthetic method of ethyl}-2-methacrylamide monomer is realized through the following steps:

[0040] (1) 2,2,2-Trifluoro-N-{2-methoxy-[1,3]dioxolane-2-[4-(2-methoxy-[1,3]dioxo Preparation of pentane-4-methyleneoxy)]-ethyl}-acetamide:

[0041] Under the action of pyridine-p-toluenesulfonate, 4,4'-dimethyloxy-bis-(2-methoxy-1,3-dioxolane) and N-(2-hydroxyethyl ) trifluoroacetamide reaction, the molar ratio of which is 1:1-1.2, reacted at 130°C for 6h; the reaction system was dissolved in ethyl acetate, washed with 10% sodium carbonate solution, and dried to obtain pure compound 2,2,2- Trifluoro-N-{2-methoxy-[1,3]dioxolane-2-[4-(2-methoxy-[1,3]dioxolane-4-methyleneoxy )]-ethyl}-acetamide, directly used in the next step reaction. 1 HNMR (400MHz, CDCl 3 ,δ,ppm):2.0-2.18(m,NH 2 -CH 2 )3.27-3.28 (m,3H,O-CH 3 ),3.43-3.710(m,6H,CH—

[0042] CH 2 -CH,N-CH 2 -CH 2 ),3.68-4.13(m,4H,O-CH 2...

Embodiment 2

[0048] 1.00g (2.88mmoL) N-{2-[2-methoxy-[1,3]dioxolane-4-(2-methoxy-[1,3]dioxolane-4- Methylene oxide)]-ethyl}-2-methacrylamide, polyethylene glycol macroinitiator 0.52g (0.096mmoL), 2,2-azobisisobutylcyanide 3.15mg (0.0192mmoL) is accurate Weigh it into a dry and clean glass polymerization tube, then add N,N-dimethylformamide (2.5mL), degas the polymerization system with nitrogen for 30 minutes, seal the tube, and put the polymerization reaction tube in an oil bath at 70°C Heating and polymerizing, after 24 hours of reaction, the reaction mixture was dissolved in N,N-dimethylformamide, then added dropwise into glacial ether, the sediment was collected, rinsed with a small amount of glacial ether, and the product was vacuum-dried to constant weight to obtain The target copolymer P1, the properties of the polymer are shown in Table 1.

Embodiment 3

[0050] 1g (2.88mmoL) N-{2-[2-methoxy-[1,3]dioxolane-4-(2-methoxy-[1,3]dioxolane-4- Methyl oxygen)]-ethyl}-2-methacrylamide, polyethylene glycol macroinitiator 0.26g (0.048mmoL), 2,2-azobisisobutyrocyanide 1.58mg (9.6×10 -3 mmoL) was accurately weighed into a dry and clean glass polymerization tube, then N,N-dimethylformamide (2.5mL) was added, the polymerization system was degassed with nitrogen for 30 minutes, and then the tube was sealed, and the polymerization reaction tube was placed at 70°C Heated and polymerized in an oil bath. After 24 hours of reaction, the reaction mixture was dissolved in N,N-dimethylformamide, then added dropwise into glacial ether, the sediment was collected, rinsed with a small amount of glacial ether, and the product was vacuum-dried to The target copolymer P2 was obtained by constant weight, and the properties of the polymer are shown in Table 1.

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Abstract

The invention discloses a new methacrylamide orthoester monomer as well as a synthetic method and an application of an acid-sensitive amphiphilic block polymer of the new methacrylamide orthoester monomer, and belongs to the technical field of polymer carriers and sustained-release materials. The new methacrylamide orthoester monomer is as shown in a chemical formula I; and the structure of the acid-sensitive amphiphilic block polymer which is synthesized through the new methacrylamide orthoester monomer and contains two orthoester five-membered rings in a lateral chain is as shown in a chemical formula II. Drugs (such as anti-tumor paclitaxel) which are difficultly dissolved in water can be delivered in vivo by utilizing a micelle formed through self-assembly in a water solution of the acid-sensitive amphiphilic block polymer with the lateral chain containing the two orthoester five-membered rings. The acid-sensitive amphiphilic block polymer with the lateral chain containing the two orthoester five-membered rings has good acid sensibility, biocompatibility and biodegradability and has a good application prospect in the field of targeted therapy.

Description

technical field [0001] The invention relates to a synthesis method and application of a novel methacrylamide orthoester monomer and an acid-sensitive amphiphilic block copolymer thereof, and belongs to the technical field of polymer carriers and slow-release materials. Background technique [0002] Cancer seriously endangers human life and health, and has been listed as the second killer of human beings. For the treatment of tumors, most of the current anti-tumor drugs have obvious deficiencies: the targeting is not obvious, and the treatment process often causes irreversible damage to the normal tissues of the body, reducing the body's immune ability, thereby delaying treatment. Therefore, choosing an appropriate drug carrier has become the key to improving the efficacy of antitumor drugs. [0003] The use of polymeric micelles to deliver anticancer drugs to improve the tumor targeting properties of drugs and overcome drug resistance of tumor cells has aroused extensive re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/34C08F293/00A61K47/34A61K9/107
CPCA61K9/1075A61K47/34C07D317/34C08F293/005
Inventor 唐汝培曹志鹏周晓晶
Owner ANHUI UNIVERSITY
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