CN114479044B

CN114479044B - Preparation and application of biodegradable functional hyperbranched polycarbonate compound

Info

Publication number: CN114479044B
Application number: CN202210183152.4A
Authority: CN
Inventors: 陈维; 吕梦桐; 赵昌顺; 潘井芳; 黄德春; 钟伊南
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2022-02-24
Filing date: 2022-02-24
Publication date: 2023-05-23
Anticipated expiration: 2042-02-24
Also published as: CN114479044A

Abstract

The invention discloses preparation and application of a biodegradable functional hyperbranched polycarbonate compound. The functional hyperbranched polycarbonate is prepared by reacting a cyclic carbonate monomer with a mercapto alcohol compound to obtain a hydroxylated cyclic carbonate, and then ring-opening polymerizing the hydroxylated cyclic carbonate with a functional group-containing cyclic carbonate. The invention rapidly and simply obtains the functional polycarbonate through a one-pot method, has high drug loading rate, highly branched three-dimensional topological structure, good biocompatibility and simple synthetic route, and is a method for preparing the functional polycarbonate more conveniently and effectively.

Description

Preparation and application of biodegradable functional hyperbranched polycarbonate compound

Technical Field

The invention relates to a preparation method and application of a high molecular material, in particular to a preparation method and application of a biodegradable functional hyperbranched polycarbonate compound.

Background

Hyperbranched polymers (HBPs) are a highly branched three-dimensional network of molecules that have received widespread attention over the past decades. The novel hyperbranched high molecular polymer has been widely used in the field of drug delivery due to its highly branched three-dimensional topology structure with many excellent properties such as monodispersity, multiple reaction sites on the periphery, controllable size, good repeatability, etc. However, preparation of hyperbranched polymers requires tedious multi-step synthesis steps, and common hyperbranched polymer carriers such as hyperbranched polyethyleneimine, hyperbranched polyamide-amine and the like generally have the defects of high cytotoxicity, biodegradation difficulty and the like.

In order to overcome the above drawbacks, more and more researchers have been working on developing biodegradable hyperbranched polymers. Furthermore, the functionalization of the polymer is also an important aspect, which is of great importance for the subsequent chemical modification of the polymer and for meeting the demands of drug carrier versatility. For example, chen Xuesai et al synthesized lactide and carbonate copolymer microspheres containing alkynyl groups, which were subjected to surface "Click" reaction with azide-modified calf serum albumin to give polymer microspheres having BSA grafted on the surface. However, the synthesis of functional polycarbonates always involves protection and deprotection of functional groups, resulting in complex synthetic routes and low yields. Thus, developing a more convenient and efficient method for preparing functional polycarbonates remains an active area of research.

Disclosure of Invention

The invention aims to: the invention aims to provide a preparation method of biodegradable functional hyperbranched polycarbonate.

The technical scheme is as follows: the invention generates hydroxyl cyclic carbonate through the reaction of cyclic carbonate monomer and mercapto alcohol compound, and then obtains functional hyperbranched polycarbonate through ring-opening polymerization with cyclic carbonate with functional group.

Further, the cyclic carbonate monomer is selected from compounds having the following structures:

wherein R is ₁ Selected from H or CH ₃ ，R ₂ Selected from N ₃ Alkynyl, ONO ₂ Br, etc.

Further, the mercapto alcohol compound is selected from the compounds having the structures shown below:

wherein R is ₃ Selected from C2-C4 alkyl or C4-C8 aryl.

Further, the ring-opening polymerization catalyst is selected from: 1, 8-diazabicyclo undec-7-ene (DBU), stannous octoate (Sn (Oct) ₂ ) 4-Dimethylaminopyridine (DMAP) or Zinc bis (bistrimethylsilyl) amine (Zinc).

The preparation method of the biodegradable functional hyperbranched polycarbonate takes preferable process conditions as an example and comprises the following steps:

(1) And (3) reacting the cyclic carbonate monomer with a mercapto alcohol compound with a certain proportion by using methylene dichloride as a solvent for 2-6h to obtain an intermediate product of hydroxylated cyclic carbonate.

(2) And (3) continuously adding cyclic carbonate with other functional groups and a catalyst into the reaction mixed solution to initiate ring-opening polymerization, and reacting to obtain the functional hyperbranched polycarbonate.

The beneficial effects are that: compared with the prior art, the invention has the following advantages:

the hyperbranched polycarbonate with functional groups can be directly obtained through one-pot synthesis, the synthesis process is simple and convenient, the drug loading rate is high, the hyperbranched polycarbonate has a highly branched three-dimensional topological structure, the biocompatibility is good, and the metabolites are harmless to human bodies. The functional polycarbonate can further carry out corresponding chemical reaction with other compounds with functional groups, so that the functional polycarbonate has great application prospect in the aspects of drug delivery and tumor treatment.

Drawings

FIG. 1 shows the azido polycarbonate of example 1 ^H P (HAC-co-AEC), hydrogen nuclear magnetic spectrum of HAC: AEC 2:1);

FIG. 2 shows the azido polycarbonate of example 1 ^H P (HAC-co-AEC), infrared spectrum of HAC: AEC 2:1);

FIG. 3 shows the azido polycarbonate of example 2 ^H P (HAC-co-AEC), hydrogen nuclear magnetic spectrum of HAC: AEC 1:1);

FIG. 4 is a schematic diagram of example 3Azidated polycarbonate [ ] ^H Hydrogen nuclear magnetic spectrum of P (HAC-co-AEC), HAC: AEC 1:2).

Detailed Description

EXAMPLE 1 Synthesis of hyperbranched polycarbonates containing azide groups dPC (HAC: AEC 2:1)

One-pot method for synthesizing hyperbranched polycarbonate

Hyperbranched ^H Synthesis of P (HAC-co-AEC): in a glove box, AC (1 g,5 mmol) monomer was dissolved in 10mL dichloromethane, charged into a closed reactor, and then mercaptoethanol ME (l 97.27mg,2.525 mmol) and catalytic amount of triethylamine were added to react for 4h at normal temperature. After the reaction time was over, AEC monomer (427.9 mg,2.5 mmol) solution in 4mL dichloromethane was added, then catalyst DBU was added directly to the reaction solution, the reactor was sealed, transferred out of the glove box, placed in an oil bath at 50℃for 48h, after the reaction was completed, 2 drops of glacial acetic acid were used to terminate the reaction, precipitation was performed in glacial diethyl ether, the supernatant was discarded, and the oily viscous liquid with a transparent bottom was collected and dried in vacuo to obtain the product. The nuclear magnetic results indicate that the ratio of HAC units to AEC units in the hyperbranched polymer is 10:1. The infrared spectrum is shown in FIG. 2, at 2100cm ^-1 The absorption peak at this point is a characteristic peak of the azide group.

EXAMPLE 2 Synthesis of hyperbranched polycarbonates containing azide groups dPC (HAC: AEC 1:1)

Hyperbranched ^H Synthesis of P (HAC-co-AEC): in a glove box, AC (500 mg,2.5 mmol) monomer was dissolved in 8mL dichloromethane, charged into a closed reactor, then mercaptoethanol ME (394.5 mg,5.05 mmol) and catalytic amount of triethylamine were added and reacted at room temperature for 4h. After the reaction time was completed, AEC monomer (427.9 mg,2.5 mmol) solution in 4mL of methylene chloride was added, then 1, 8-diazabicyclo undec-7-ene (DBU) catalyst was directly added to the reaction solution, the reactor was sealed, transferred out of the glove box, placed in an oil bath at 50℃for 48 hours, and after the reaction was completed, the reaction was terminated with 2 drops of glacial acetic acidPrecipitating in glacial ethyl ether, removing supernatant, collecting oily viscous liquid with transparent bottom, and vacuum drying to obtain product ^H P (HAC-co-AEC). The nuclear magnetic results indicate that the ratio of HAC units to AEC units in the hyperbranched polymer is 5:2.

EXAMPLE 3 Synthesis of hyperbranched polycarbonate dPC with azide groups (HAC: AEC 1:2)

Hyperbranched ^H Synthesis of P (HAC-co-AEC): in a glove box, AC (500 mg,2.5 mmol) monomer was dissolved in 8mL dichloromethane, charged into a closed reactor, then mercaptoethanol ME (394.5 mg,5.05 mmol) and catalytic amount of triethylamine were added and reacted at room temperature for 4h. After the reaction time is over, AEC monomer (855.8 mg,5 mmol) solution dissolved in 8mL of dichloromethane is added, then catalyst 1, 8-diazabicyclo undec-7-ene (DBU) is directly added into the reaction solution, then the reactor is sealed, transferred out of the glove box, placed into 50 ℃ oil bath for reaction for 48 hours, after the reaction is over, 2 drops of glacial acetic acid are used for stopping the reaction, precipitation is carried out in glacial diethyl ether, the supernatant is discarded, the oily viscous liquid with transparent bottom is collected, and the product is obtained by vacuum drying ^H P (HAC-co-AEC). The nuclear magnetic results indicate that the ratio of HAC units to AEC units in the hyperbranched polymer is 5:4.

EXAMPLE 4 Synthesis of hyperbranched polycarbonate dPC containing nitrate groups

Hyperbranched ^H Synthesis of P (HAC-co-NTC): in a glove box, AC (500 mg,2.5 mmol) monomer was dissolved in 8mL dichloromethane, charged into a closed reactor, then mercaptoethanol ME (394.5 mg,5.05 mmol) and catalytic amount of triethylamine were added and reacted at room temperature for 4h. After the reaction time is over, adding NTC monomer (955 mg,5 mmol) solution dissolved in 10mL of dichloromethane, then directly adding catalyst 1, 8-diazabicyclo undec-7-ene (DBU) into the reaction solution, sealing the reactor, transferring out of the glove box, placing into an oil bath at 50 ℃ for reaction for 48h, stopping the reaction with 2 drops of glacial acetic acid after the reaction is over, precipitating in glacial diethyl ether, discarding the supernatant, collecting oily viscous liquid with transparent bottom, and vacuum drying to obtain the product ^H P(HAC-co-NTC)。

EXAMPLE 5 Synthesis of hyperbranched polycarbonate dPC containing bromine functional groups

Hyperbranched ^H Synthesis of P (HAC-co-BTC): in a glove box, AC (500 mg,2.5 mmol) monomer was dissolved in 8mL dichloromethane, charged into a closed reactor, then mercaptoethanol ME (394.5 mg,5.05 mmol) and catalytic amount of triethylamine were added and reacted at room temperature for 4h. After the reaction time is over, adding BTC monomer (1.045 g,5 mmol) solution dissolved in 10mL of dichloromethane, then directly adding catalyst 1, 8-diazabicyclo undec-7-ene (DBU) into the reaction solution, sealing the reactor, transferring out of the glove box, placing into 50 ℃ oil bath for reaction for 48h, stopping the reaction with 2 drops of glacial acetic acid after the reaction is over, precipitating in glacial diethyl ether, discarding supernatant, collecting oily viscous liquid with transparent bottom, and vacuum drying to obtain the product ^H P(HAC-co-BTC)。

Claims

1. A method for preparing a biodegradable functional hyperbranched polycarbonate compound, which is characterized by comprising the following steps: the method comprises the steps of reacting a cyclic carbonate monomer with a mercapto alcohol compound to obtain hydroxylated cyclic carbonate, and then performing ring-opening polymerization on the hydroxylated cyclic carbonate and the cyclic carbonate with a functional group to obtain a functional hyperbranched polycarbonate compound;

the structural formula of the cyclic carbonate monomer is as follows:

，

wherein R is ₁ Selected from H or CH _3；

The structural formula of the cyclic carbonate with the functional group is as follows:

，

wherein R is ₂ Selected from N ₃ 、ONO ₂ Alkynyl or Br functional groups.

2. The method for preparing a biodegradable functional hyperbranched polycarbonate compound according to claim 1, characterized in that: the mercapto alcohol compound is selected from compounds with the following structures:

，

wherein R is ₃ Selected from C2-C4 alkyl or C4-C8 aryl.

3. The method for preparing a biodegradable functional hyperbranched polycarbonate compound according to claim 1, characterized in that: the ring-opening polymerization catalyst is selected from: 1, 8-diazabicyclo undec-7-ene, stannous octoate, 4-dimethylaminopyridine or zinc bis (bistrimethylsilyl) amine.

4. Use of a biodegradable functional hyperbranched polycarbonate compound prepared according to any one of claims 1-3 for the preparation of a drug controlled release carrier.