1. A polycarbonate copolymer, characterized in that the polycarbonate copolymer comprises at least the general formula:

wherein R is₁And R₂Independently of each other, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a cycloalkyl group or an aralkyl group having 7 to 10 carbon atoms, preferably a methyl group; m + n is an integer between 90 and 150, preferably 100; m: n is 0.5: 1-2: 1, preferably 1: 1-1.2:1。

2. the polycarbonate copolymer according to claim 1, wherein the polycarbonate copolymer has a weight average molecular weight of 20000 to 40000g/mol, preferably 25000 to 35000 g/mol.

3. The method for preparing a polycarbonate copolymer according to claim 1 or 2, comprising the steps of:

(1) mixing 2- (diethanolamino) sodium ethanesulfonate, bisphenol compound, end capping agent, alkali metal hydroxide and water in certain proportion, and mechanically stirring until clear and transparent solution is obtained;

(2) adding an inert organic solvent into the water phase according to a certain water-oil ratio, and mechanically stirring to form a stable water-oil mixed system;

(3) introducing phosgene into the water-oil system preferably at a rate of 0.2-6g/min, and simultaneously adding a catalyst to react to obtain sulfonic polycarbonate copolymer emulsion;

(4) and (3) post-treatment: and (4) purifying the sulfonic polycarbonate copolymer emulsion prepared in the step (3) to obtain a product.

4. The production method according to claim 3, characterized in that: in step (1), the end-capping reagent is phenol, p-methyl phenol, p-isopropyl phenol or p-tert-butyl phenol, preferably p-tert-butyl phenol;

the bisphenol-type compound is selected from bisphenol A, bisphenol B, bisphenol E, bisphenol F, bisphenol Z or bisphenol TMC, preferably bisphenol A;

the alkali metal hydroxide is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide, preferably sodium hydroxide;

the molar ratio of the two comonomers of 2- (diethanolamino) sodium ethanesulfonate to the bisphenol compound is 0.5: 1-2: 1, preferably 1: 1-1.2: 1; the end capping agent accounts for 1-10% of the mass of the bisphenol compound; the mass ratio of the bisphenol compound to water is 1: 20-2: 25, preferably 3: 50; the mass concentration of the alkali metal hydroxide is 3 to 8 wt%, preferably 5 to 6 wt%.

5. The production method according to claim 3 or 4, characterized in that: in the step (2), the inert organic solvent is selected from one or more of dichloromethane, trichloromethane, dichloroethane and trichloroethane, and is preferably dichloromethane; the weight ratio of water to inert organic solvent is 1: (0.5-1.2), preferably 1 (1-1.05).

6. The production method according to any one of claims 3 to 5, characterized in that: the molar ratio of the total molar weight of the comonomer 2- (diethanolamino) sodium ethanesulfonate and the bisphenol compound to the phosgene is 1: (1-1.15), preferably 1: (1-1.12);

the catalyst is one or more of triethylamine, tetrabutylammonium bromide and tetrabutylammonium chloride, and triethylamine is preferred; the mass ratio of the catalyst to the bisphenol compound is 0.0001 to 0.005:1, preferably 0.0002 to 0.0003: 1.

7. The production method according to any one of claims 3 to 6, characterized in that: the step (4) post-treatment is carried out by conventional methods in the art, such as: the copolymer emulsion is firstly subjected to oil-water separation, and then is sequentially subjected to washing, devolatilization, crushing and drying to obtain powder.

8. The production method according to any one of claims 3 to 7, characterized in that: in the step (3), the pH of the reaction system is maintained at 11 to 12 during the polymerization reaction.

9. The production method according to any one of claims 3 to 8, characterized in that: in the step (3), the reaction temperature is 25-35 ℃, preferably 30-32 ℃; the reaction time is 0.5-4 h.

10. The polycarbonate copolymer according to claim 1 or 2 or the polycarbonate copolymer prepared by the preparation method according to any one of claims 3 to 9 is used for hemodialysis membranes, hemoperfusion adsorption microspheres, and surgical sutures.

Background

At present, many polymer materials have wide applications in the medical field, for example, some materials are used as artificial organs and medical instruments. Among them, various functionalized polymers have been receiving wide attention in the blood contact field. Such as hemodialysis membranes, hemoperfusion adsorbents, etc. applied in vitro; artificial blood vessels, artificial blood vessel stents, etc. implanted in the body. As a blood contact material, in addition to having good blood compatibility such as anticoagulant property, platelet adhesion inhibition property, no inflammation reaction and hemolysis, etc., it is required to have good mechanical properties.

Polycarbonate (PC) is a high molecular polymer containing a carbonate bond in a molecular chain, and can be classified into aliphatic, alicyclic, aliphatic-aromatic, and aromatic polycarbonates, wherein aromatic polycarbonates have excellent mechanical properties, heat resistance, and the like, and are widely used in the fields of automobiles, electronic devices, buildings, office supplies, optical disks, sports equipment, medical care, computers, aerospace, and the like. However, the application of aromatic PC in the field of blood contact materials is narrow, and its blood compatibility needs to be further improved. Secondly, the melt viscosity of PC is high, the fluidity is poor and the processing is not facilitated because the molecular chains have higher rigidity and the entanglement among the molecular chains is serious.

It has been shown that the biocompatibility of polycarbonate is improved by blending with biologically active substances. For example, in patent CN105062029B, polycarbonate, chitin and hydroxypropyl methyl cellulose are blended to prepare the polycarbonate biological purification material. The patent CN108815590A blends corn starch, Arabic gum, mannan, silk fibroin and other components with polyvinyl carbonate and polycarbonate to prepare the polysaccharide-silk fibroin composite anticoagulant biomaterial. However, the method of blending is used to improve the biocompatibility of the polycarbonate, and a small molecule plasticizer is usually added to improve the compatibility among the components. Small molecule plasticizers run the risk of migration and leakage, which can have an adverse effect on the human body.

The method for improving the blood compatibility of the material comprises the following steps: the hydrophilicity of the surface of the material is improved; preparing a surface with negative charges; designing a microphase separation structure; introducing bioactive substances, etc. In recent years, an anticoagulant such as heparin is fixed on the surface of a polymer material, and a method for improving blood compatibility of the material has been attracting much attention. However, heparin is expensive and is easily inactivated during the fixation process. Many researches indicate that the introduction of heparinoid groups, such as carboxyl groups, sulfonic groups and the like, into the material can effectively improve the blood compatibility of the material.

Therefore, there is a need to prepare a novel polycarbonate copolymer which can be widely used in the field of blood contact materials.

Disclosure of Invention

An object of the present invention is to provide a polycarbonate copolymer which has excellent blood compatibility and mechanical properties and can be used as a blood contact material.

In order to achieve the above purpose, the technical scheme of the invention is as follows:

the polycarbonate copolymer is a novel polycarbonate copolymer containing sulfonic acid group aliphatic polycarbonate chain segments and aromatic polycarbonate chain segments in a molecular chain, and the novel polycarbonate copolymer has the following general formula:

wherein R is₁And R₂Independently of each other, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a cycloalkyl group or an aralkyl group having 7 to 10 carbon atoms, preferably a methyl group; m + n is an integer between 90 and 150, preferably 100; m: n is 0.5: 1-2: 1, preferably 1: 1-1.2:1.

The weight-average molecular weight of the polycarbonate copolymer is 20000-40000 g/mol, preferably 25000-35000 g/mol.

Another object of the present invention is to provide a process for producing a polycarbonate copolymer, which has a low reaction temperature, a low energy consumption and a stable product quality. Which comprises the following steps:

(1) mixing 2- (diethanolamino) sodium ethanesulfonate, bisphenol compound, end capping agent, alkali metal hydroxide and ultrapure water according to a certain proportion, and mechanically stirring until a clear and transparent solution is obtained;

(2) adding an inert organic solvent into the water phase according to a certain water-oil ratio, and mechanically stirring to form a stable water-oil mixed system;

(3) introducing phosgene into the water-oil system at a certain speed, adding a catalyst, preferably maintaining the pH value of the system between 11 and 12 and the reaction temperature between 25 and 35 ℃, preferably between 30 and 32 ℃ during the reaction process, and continuously reacting for 0.5 to 4 hours to obtain sulfonic polycarbonate copolymer emulsion;

(4) and (3) post-treatment: and (4) purifying the sulfonic polycarbonate copolymer emulsion prepared in the step (3) to obtain a product.

In the step (1), the end capping agent is phenol, p-methyl phenol, p-isopropyl phenol or p-tert-butyl phenol, preferably p-tert-butyl phenol.

The bisphenol-type compound is selected from bisphenol A, bisphenol B, bisphenol E, bisphenol F, bisphenol Z, bisphenol TMC and the like, and bisphenol A is preferred.

The alkali metal hydroxide is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide or cesium hydroxide, preferably sodium hydroxide.

The molar ratio of the two comonomers of 2- (diethanolamino) sodium ethanesulfonate to the bisphenol compound is 0.5: 1-2: 1, preferably 1: 1-1.2:1, the end capping agent accounts for 1 to 10 percent of the mass of the bisphenol compound; the mass ratio of the bisphenol compound to the pure water is 1: 20-2: 25, preferably 3: 50; the mass concentration of the alkali metal hydroxide is 3 to 8 wt%, preferably 5 to 6 wt%.

In the step (2), the inert organic solvent is selected from dichloromethane, trichloromethane, dichloroethane and trichloroethane, preferably dichloromethane; the weight ratio of pure water to inert organic solvent is selected from 1: (0.5-1.2), preferably 1 (1-1.05); the molar ratio of the comonomer (2- (diethanolamino) sodium ethanesulfonate and bisphenol type compound) to phosgene is 1: (1-1.15), preferably 1: (1-1.12).

In step (3), phosgene is preferably introduced into the above-mentioned oil-in-water system at a rate of 0.2 to 6 g/min.

The catalyst is triethylamine, tetrabutylammonium bromide and tetrabutylammonium chloride, and triethylamine is preferred; the mass ratio of the catalyst to the bisphenol compound is 0.0001 to 0.005:1, preferably 0.0002 to 0.0003: 1.

The comonomers employed in the present invention may optionally be prepared by prior published techniques or by commercial monomer synthesis.

The pH of the reaction system is maintained at 11 to 12 during the polymerization reaction.

In the step (4), the post-treatment can be performed by a conventional method in the art, such as the post-treatment methods disclosed in chinese patents CN202010666164.3 and CN 202010698811.9. For example: the copolymer emulsion is firstly subjected to oil-water separation, and then is sequentially subjected to washing, devolatilization, crushing and drying to obtain powder.

The polycarbonate copolymer of the invention can be used for blood contact products, such as hemodialysis membranes, hemoperfusion adsorption microspheres, surgical sutures and the like.

The invention has the beneficial effects that:

1. according to the invention, on the basis of utilizing the original good mechanical properties of aromatic PC, the polycarbonate copolymer containing sulfonic group is prepared by a copolymerization method, so that the blood compatibility of the polycarbonate material is improved, and meanwhile, the whole flexibility of a molecular chain is improved by introducing the aliphatic polycarbonate chain segment, thereby solving the problems of poor flowability and difficult processing of PC. The novel polycarbonate copolymer prepared by the invention provides a blood contact material with blood compatibility and mechanical property, and has wide application prospect in the field of blood contact materials.

2. The molecular weight and the composition of the copolymer prepared by the invention can be regulated, and the method has simple steps, is convenient for realizing industrialization, and has good industrial application prospect.

Detailed Description

In order to better understand the technical solution of the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.

The analytical evaluation methods referred to in examples or comparative examples are as follows:

(1) the molecular weight is measured by Gel Permeation Chromatography (GPC) method, and is measured by a gel permeation chromatograph with model number Waters 1515, wherein the mobile phase is dichloromethane, and the temperature is 30 ℃;

(2) the infrared test was performed by attenuated total reflectance infrared (ATR-FTIR) spectroscopy using Nicolet 560 from Thermo Fisher, usa;

(3) the nuclear magnetic test adopts a nuclear magnetic resonance spectrometer with the model of AV III HD 400MHz of Burker company for testing;

(4) the tensile property is tested according to the tensile property test standard of the plastic film specified in ISO 1184-1983;

(5) bovine serum fibrinogen (BFG) is selected as a representative protein, and the protein adsorption performance of the prepared polycarbonate copolymer is tested.

The specific experimental steps are as follows: soaking PC film with size of 1cm x 1cm in normal saline overnight, and incubating at 37 deg.C for 1 h; adding 2mL of BFG (fibrinogen) solution of 1mg/mL into a pore plate filled with the pretreated material, and standing and incubating for 1h at 37 ℃; the material was washed three times with each of physiological saline and deionized water, after which it was added to 2mL of a 2 wt% Sodium Dodecyl Sulfate (SDS) solution and shaken at 37 ℃ for 2 h. Finally, the protein concentration eluted by SDS was determined by BCA assay kit.

(6) Coagulation response test Activated Partial Thrombin Time (APTT) and Thrombin Time (TT) were measured using a semi-automatic coagulometer (Sysmex Corporation, Kobe, Japan).

The specific experimental procedure is as follows: firstly, soaking a 1 cm-by-1 cm PC film in normal saline overnight and incubating for 1h at 37 ℃; the saline was then removed and 300. mu.L of fresh Platelet Poor Plasma (PPP) was added to the well plate containing the material and incubated at 37 ℃ for 30 min. For APTT testing, 50 μ L of incubated PPP, 50 μ L of APTT reagent, 50 μ L of 0.025M CaCl were added to a test cup in sequence₂And (3) solution. For testing of TT, 50 μ L of incubated PPP was added first to the test cup, followed by 100 μ L of thrombin reagent.

(7) The test for the hemolysis rate was carried out according to the hemolysis rate test standard for materials specified in ASTM F756-08.

Example 1

117.615g of sodium 2- (diethanolamino) ethanesulfonate, 228.29g of bisphenol A, 6.74g of p-tert-butylphenol, 190.24g of sodium hydroxide and 3804.83g of ultrapure water are added into a reactor protected by nitrogen, mixed by mechanical stirring until the materials are completely dissolved, 3804.83g of dichloromethane is added, and the mixture is mechanically stirred to form a stable water-oil mixed system. 0.046g of triethylamine as catalyst was then added, while 166.32g of phosgene were passed into the system at 1.386 g/min. In the whole reaction process, 32 wt% of sodium hydroxide aqueous solution is used for maintaining the pH value of the system to be 11-12, the reaction temperature is 30 ℃, and the reaction time is 120 min. After the reaction is finished, the product is obtained by alkali washing with 20 wt% NaOH solution, acid washing with 0.5mol/L hydrochloric acid, washing with deionized water, devolatilization (water boiling in a glass kettle at 40 ℃ for powder preparation for 2h), crushing and drying (drying in a blast oven at 120 ℃ for 4 h). The weight average molecular weight of the product was 24200 and the polydispersity index was 1.61 using GPC. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the molar ratio of bisphenol A was 0.47: 1. The result of the attenuated total reflection infrared test shows 1163cm^-1And 1092cm^-1An absorption peak is shown, which is a typical absorption peak of sulfonic acid group, and is at 1611cm^-1、1509cm^-1、1446cm^-1Has obvious absorption peak, which is attributed to skeleton vibration of benzene ring, at 1720cm^-1An absorption peak of carbonyl group was observed, and the infrared test results indicated successful preparation of the sulfonic acid group polycarbonate.

Example 2

235.23g of sodium 2- (diethanolamino) ethanesulfonate, 228.29g of bisphenol A, 9.03g of p-tert-butylphenol, 190.24g of sodium hydroxide and 3804.83g of ultrapure water are added into a reactor protected by nitrogen, mixed by mechanical stirring until the materials are completely dissolved, 3804.83g of dichloromethane is added, and the mixture is mechanically stirred to form a stable water-oil mixed system. 0.046g of the catalyst triethylamine was then added, while 221.76g of phosgene were passed into the system at a rate of 1.848 g/min. In the whole reaction process, 32 wt% of sodium hydroxide aqueous solution is used for maintaining the pH value of the system to be 11-12, the reaction temperature is 30 ℃, and the reaction time is 120 min. After the reaction was completed, the product was obtained by post-treatment (same as example 1). The weight average molecular weight of the product was 23920 and the polydispersity index was 1.48 as measured by GPC. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the molar ratio of bisphenol A is 1.01: 1.

Example 3

470.46g of sodium 2- (diethanolamino) ethanesulfonate, 228.29g of bisphenol A, 13.61g of p-tert-butylphenol, 190.24g of sodium hydroxide and 3804.83g of ultrapure water are added into a reactor protected by nitrogen, mixed by mechanical stirring until the materials are completely dissolved, 3804.83g of dichloromethane is added, and the mixture is mechanically stirred to form a stable water-oil mixed system. 0.046g of triethylamine as catalyst was then added, while 332.64g of phosgene were passed into the system at a rate of 2.772 g/min. In the whole reaction process, 32 wt% of sodium hydroxide aqueous solution is added to maintain the pH of the system to be 11-12, the reaction temperature is 30 ℃, and the reaction time is 120 min. After the reaction was completed, the product was obtained by post-treatment (same as example 1). The weight average molecular weight of the product was 24351 and the polydispersity index was 1.54, as determined by GPC. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the molar ratio of bisphenol A was 1.98: 1.

Example 4

235.23g of sodium 2- (diethanolamino) ethanesulfonate, 268.35g of bisphenol Z, 9.98g of p-tert-butylphenol, 223.63g of sodium hydroxide and 4472.5g of ultrapure water are added into a reactor protected by nitrogen, mixed by mechanical stirring until the materials are completely dissolved, 4472.5g of dichloromethane is added, and the mixture is mechanically stirred to form a stable water-oil mixed system. Thereafter, 0.054g of triethylamine as a catalyst was added, and 221.76g of phosgene were simultaneously passed into the above system at a rate of 1.848 g/min. In the whole reaction process, 32 wt% of sodium hydroxide aqueous solution is used for maintaining the pH value of the system to be 11-12, the reaction temperature is 30 ℃, and the reaction time is 120 min. After the reaction was completed, the product was obtained by post-treatment (same as example 1). The product had a weight average molecular weight of 23875 and a polydispersity index of 1.47 as determined by GPC. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the molar ratio of bisphenol Z is 1.01: 1. Attenuated total reflection infrared spectrum 1163cm^-1And 1092cm^-1An absorption peak is shown, which is a typical absorption peak of sulfonic acid group, and is at 1611cm^-1、1509cm^-1、1446cm^-1Has obvious absorption peak, which is attributed to the skeleton vibration of benzene ring, at 2860cm^-1、2930cm^-1Is the C-H vibration peak on cyclohexane at 1720cm^-1An absorption peak of carbonyl group was observed.

Example 5

This example differs from example 1 in that the amount of the end-capping agent added, p-tert-butylphenol, was 5.15 g. The rest of the operation was the same as in example 1. The weight average molecular weight of the product was 34250 and the polydispersity index was 1.63 by GPC. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the molar ratio of bisphenol A was 0.48: 1.

Example 6

This example differs from example 2 in that the amount of the end-capping agent added, p-tert-butylphenol, was 6.9 g. The rest of the operation was the same as in example 2. The product had a weight average molecular weight of 34122 and a polydispersity index of 1.53 as determined by GPC. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the molar ratio of bisphenol A was 0.98: 1.

Example 7

This example differs from example 3 in that the amount of the end-capping agent added, p-tert-butylphenol, was 10.41 g. The rest of the operation was the same as in example 3. The weight average molecular weight of the product was 34440 by GPC, with a polydispersity index of 1.71. The results of the nuclear magnetic test showed sodium 2- (diethanolamino) ethanesulfonate: the bisphenol A molar ratio was 1.99: 1.

Comparative example 1

228.29g of bisphenol A, 3.96g of p-tert-butylphenol, 190.24g of sodium hydroxide and 3804.83g of ultrapure water are added into a reactor protected by nitrogen for mixing, mechanical stirring is carried out until the bisphenol A, the sodium hydroxide and the ultrapure water are completely dissolved, then 3804.83g of dichloromethane is added, and mechanical stirring is carried out to form a stable water-oil mixed system. 0.046g of triethylamine as catalyst was then added, while 110.88g of phosgene were passed into the system at a rate of 0.924 g/min. In the whole reaction process, 32 wt% of sodium hydroxide aqueous solution is added to maintain the pH of the system to be 11-12, and the reaction temperature is 30 ℃. After the reaction was completed, the product was obtained by post-treatment (same as example 1). The weight average molecular weight of the product was 24220 and the polydispersity index was 1.45 using GPC. Attenuation ofTotal reflection infrared spectrum showed 1611cm^-1、1509cm^-1、1446cm^-1Has a distinct absorption peak at 1720cm^-1An absorption peak of a carbonyl group was observed, and no absorption peak typical of a sulfonic acid group was observed.

Comparative example 2

This comparative example differs from comparative example 1 in that the amount of p-tert-butylphenol as the end-capping agent added was 3.4g, and the rest of the procedure was the same as in comparative example 1.

The performance tests of the above examples and comparative examples are shown in the following table:

the comparison of the data shows that compared with the conventional polycarbonate, the polycarbonate copolymer disclosed by the invention has the advantages that the mechanical property is maintained, the blood compatibility is improved, the protein adsorption amount is reduced, the blood coagulation time is slightly prolonged, the hemolysis rate is obviously reduced, the spiral line length is prolonged, the polycarbonate copolymer has better fluidity, the performance of the polycarbonate is effectively improved, and the application field of the material is widened.

It will be appreciated by those skilled in the art that modifications or adaptations to the invention may be made in light of the teachings of the present specification. Such modifications or adaptations are intended to be within the scope of the present invention as defined in the claims.