Additive based on fluorinated carbamate prepolymer, and preparation and use thereof in preparation of medical fluorinated anticoagulant polyurethane material

Abstract

A type of additive based on a fluorinated carbamate prepolymer, a preparation method therefor, and a use thereof in the preparation of a medical fluorinated anticoagulant polyurethane material. The preparation method of the additive comprises: reacting a polyester / polyether diol, a diisocyanate and a fluorinated small-molecule diol, to obtain a carbamate prepolymer having an isocyanate end group, and then capping with a monohydric alcohol having a fluorinated carbon chain, to obtain an additive based on a fluorinated carbamate prepolymer. The additive has a high fluorine content. After being blended with a polyurethane masterbatch, fluorine atoms having low surface energy can be enriched on the surface of the material, and the fluorine atom content on the surface of the material can be as high as 60%. This effectively reduces the adhesion of plasma proteins, cells and platelets on the surface of the material, providing the medical polyurethane material with an excellent anticoagulant effect. In addition, it maintains the excellent mechanical properties of polyurethane, and is thus widely applicable in the preparation of medical fluorinated anticoagulant polyurethane materials.

Description

A class of additives based on fluorinated urethane prepolymers and their preparation and application in the preparation of medical fluorinated anticoagulant polyurethane materials Technical Field

[0001] The present invention belongs to the technical field of polymer materials, and particularly relates to an additive based on fluorine-containing urethane prepolymer, a preparation method thereof, and an application of the additive in preparing medical fluorine-containing anticoagulant polyurethane materials. Background Art

[0002] Polyurethane is a general term for a class of polymer compounds containing carbamate (-NHCOO-) structural units. Polyurethane has excellent biocompatibility and is used in the manufacture of numerous medical devices, including artificial pacemakers, artificial blood vessels, artificial bones, artificial esophagus, artificial kidneys, and artificial dialysis membranes.

[0003] When medical materials come into contact with blood, plasma proteins rapidly adsorb to the material surface and bind to platelet glycoprotein receptors, leading to platelet activation, coagulation crosslinking, complement activation, and ultimately thrombosis. Because of this, biomedical materials often face the challenge of coagulation. The application value of polyurethane materials in the biomedical field also depends on their anticoagulant properties. Current research on anticoagulant polyurethane materials focuses primarily on surface grafting, heparinization, and NO-releasing polyurethane materials. These methods all achieve anticoagulant properties through chemical modification. For example, Fu Qiang et al. blended a fluorophosphatidylcholine-containing polycarbonate polyurethane with a polyether polyurethane. Experimental results demonstrated that this polyurethane mixture improved the biocompatibility and anticoagulant properties of the polyether polyurethane. While chemical modification can enhance the anticoagulant properties of medical polyurethane materials, the resulting materials are still far from clinical application, as this approach places high demands on the reproducibility, stability, and material and production costs of the polyurethane batch preparation.

[0004] Introducing low-surface-energy fluorocarbon chains into polyurethane materials can significantly reduce the adhesion of proteins, cells, and platelets to the material's surface, ultimately enabling medical polyurethane materials to achieve excellent anticoagulant properties. Currently, there are three main approaches to introducing fluorocarbon chains into polyurethanes: The first involves synthesizing polyurethane materials using fluorinated polyethers or polyester diols as soft segments, but the synthesis of these is complex and costly. The second approach involves synthesizing polyurethane materials using fluorinated small-molecule diols / amines as chain extenders, but the limited availability of commercially available fluorinated small-molecule diols / amines limits the selection. The third approach involves preparing polyurethane prepolymers using fluorinated monoalcohols as end-capping agents, which are then blended with commercially available polyurethane masterbatch to create anticoagulant polyurethane materials. While this approach is simple and relatively inexpensive, the resulting anticoagulant polyurethane materials contain low fluorine content and exhibit limited anticoagulant properties.

[0005] Summary of the Invention

[0006] To overcome the shortcomings and deficiencies of the prior art, the present invention provides a class of additives based on fluorinated urethane prepolymers. These additives are low-molecular-weight polyurethanes with a high fluorine content and contain fluorocarbon chains in both the side chains and the chain ends.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned additive based on fluorine-containing urethane prepolymer.

[0008] The method of the present invention first synthesizes a small molecule diol with a high fluorine content through a simple method. This fluorine-containing diol is then used as a chain extender, and a commercially available fluorine-containing carbon chain monohydric alcohol is used as an end-capping agent to prepare an additive for a high-fluorine-containing urethane prepolymer. The method of the present invention has a simple process, low batch production cost, and can be converted to industrial production to produce a material with stable performance.

[0009] Another object of the present invention is to provide the use of the above-mentioned additive based on fluorine-containing urethane prepolymer in the preparation of medical fluorine-containing anticoagulant polyurethane materials.

[0010] The additive of the present invention is blended with a commercial polyurethane masterbatch to prepare a medical fluorine-containing anticoagulant polyurethane material. The additive of the present invention is a low-molecular-weight polyurethane with a high fluorine content. Both the side chains and the chain ends of the structure contain fluorocarbon chains. When the additive is blended with the commercial polyurethane masterbatch, the fluorine atoms with low surface energy can be enriched on the surface of the prepared medical fluorine-containing anticoagulant polyurethane material, effectively reducing the adhesion of plasma proteins, cells, and platelets to the surface of the medical polyurethane material, thereby imparting an excellent anticoagulant effect to the medical polyurethane material. Moreover, due to the high fluorine content of the additive of the present invention, only a relatively low addition amount (less than 10%) is required to achieve an excellent anticoagulant effect. Furthermore, the relatively low addition amount can effectively reduce the impact on the mechanical properties of the polyurethane material, thereby maintaining the excellent mechanical properties of the polyurethane and meeting medical needs.

[0011] Another object of the present invention is to provide a medical fluorine-containing anticoagulant polyurethane material containing the above additive.

[0012] The purpose of the present invention is achieved through the following solutions:

[0013] A class of additives based on fluorinated urethane prepolymers having the structure shown below:

[0014] Wherein, m is a positive integer, 1≤m≤30; n is 0 or a positive integer, 0≤n≤15.

[0015] Furthermore, m represents the number of structural units containing R0, R1 and R2 groups and urethane bonds; n represents the number of repeating units containing -CF2- groups.

[0016] Furthermore, m is a positive integer, 1≤m≤15; n is a positive integer, 3≤n≤10.

[0017] Furthermore, R0, R1, and R2 are each selected from at least one of the following groups:

[0018] Furthermore, in R2, x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

[0019] Furthermore, in R2, x is 1 or 2; y is a positive integer, 4≤y≤16; z is 0 or 1; and j is a positive integer, 9≤j≤33.

[0020] Furthermore, in R2, x is the number of repeating units containing -CH2-, and y is the number of repeating units in the fluorocarbon chain except the group -(CH2) x -, z is the number of carbon atoms in the fluorocarbon chain excluding the group -(CH2) x - is the number of hydrogen atoms outside the ring, and j is the number of fluorine atoms in the fluorocarbon chain.

[0021] The present invention also provides a method for preparing the above-mentioned additive based on fluorine-containing carbamate prepolymer, comprising reacting polyester / polyether diol, diisocyanate and fluorine-containing small molecule diol A to obtain a carbamate prepolymer with an isocyanate end group, and then capping it with a monohydric alcohol containing a fluorine carbon chain to obtain an additive based on the fluorine-containing carbamate prepolymer.

[0022] Furthermore, the structural formula of the polyester / polyether diol is as follows: HO-RO-OH.

[0023] Furthermore, R0 is selected from at least one of the following groups:

[0024] Furthermore, the molecular weight of the polyester / polyether diol may be 800-30000 g / moL, preferably 1000-5000 g / moL.

[0025] Furthermore, the polyester / polyether diol may include at least one of polypropylene oxide diol (PPO), polytetramethylene glycol (PTMG), polyethylene glycol (PEG), polycaprolactone diol (PCL) and polyadipate diol.

[0026] Furthermore, the diisocyanate may include at least one of toluene diisocyanate (2,4-TDI, 2,6-TDI and mixtures thereof), isophorone diisocyanate (IPDI), hexamethylene diisocyanate (HDI), diphenylmethane diisocyanate (MDI), lysine diisocyanate (LDI) and dicyclohexylmethane diisocyanate (H12MDI).

[0027] Furthermore, the structural formula of the diisocyanate is as follows: OCN-R1-NCO.

[0028] Furthermore, R1 is selected from the following groups:

[0029] Furthermore, the structural formula of the fluorinated small molecule diol is as follows: HO-R2-OH.

[0030] Further,

[0031] Furthermore, in R2, x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

[0032] Furthermore, the end-capping agent is a monohydric alcohol containing a fluorine-containing carbon chain, which contains 2-18 carbon atoms and 3-33 fluorine atoms in its structure, and the structural formula is as follows:

[0033] Furthermore, n is 0 or a positive integer, 0≤n≤15.

[0034] Furthermore, the fluorinated small molecule diol can be prepared by reacting thioglycerol with a fluorinated carbon chain (meth)acrylate through Michael addition reaction B. The reaction formula is as follows:

[0035] Furthermore, the (meth)acrylate containing a fluorine-carbon chain may include at least one of (meth)acrylates having a side chain containing 2 to 30 carbon atoms and 3 to 37 fluorine atoms.

[0036] Furthermore, the structural formula of the fluorine-containing carbon chain (meth)acrylate is as follows:

[0037] Furthermore, x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

[0038] Furthermore, the molar ratio of the fluorine-containing carbon chain (meth)acrylate to thioglycerol is 1:1-1:5, preferably 1:1-1:2.

[0039] Furthermore, the reaction temperature of the Michael addition reaction B may be 0-80° C., preferably 20-30° C.; and the reaction time may be 0-48 h, preferably 4-24 h.

[0040] Furthermore, the Michael addition reaction B is preferably carried out in a solvent environment, such as at least one of ethyl acetate, dichloromethane, chloroform, acetone, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, diethyl ether, methanol, ethanol, isopropanol, etc.

[0041] Furthermore, the Michael addition reaction B is carried out under base catalysis. The molar ratio of the base to thioglycerol is 0.5:1-1.5:1, preferably 1:1-1.2:1. The base used may include at least one of triethylamine, N,N-diisopropylethylamine, potassium (bicarbonate), sodium (bicarbonate), tripotassium (sodium) phosphate, lithium hydroxide, N-methylpiperidine, pyridine, N-methylmorpholine, and the like.

[0042] Furthermore, after the Michael addition reaction B is completed, the reaction mixture can be poured into water to precipitate the product, which can be evenly stirred and then filtered, washed with water, and finally dried in vacuo.

[0043] In the preparation method of the present invention, the molar ratio of -OH of all diols to -NCO of diisocyanate in the reaction system can be 1:1.05-1:4, preferably 1:1.5-1:2.

[0044] Furthermore, the molar ratio of the blocking agent to -NCO in the diisocyanate may be 1:1-1:2.

[0045] Furthermore, the reaction temperature of the reaction A can be 40-120° C., preferably 60-90° C.; the reaction time can be 0-48 h, preferably 4-24 h.

[0046] Furthermore, the reaction A can be carried out in a solvent environment; the solvent can include at least one of acetone, butanone, ethyl acetate, acetonitrile, toluene, N,N-dimethylformamide, N-methylpyrrolidone, etc.; or a solvent-free bulk polymerization method can be adopted without using a solvent.

[0047] Furthermore, the reaction A may be carried out under the catalysis of a catalyst; the catalyst may include stannous octoate or dibutyltin dilaurate, etc.; the catalyst used may be a catalytic amount, such as 0-0.5% of the total reactant mass, preferably 0.05-0.2%.

[0048] Furthermore, in the reaction A, the components can be added to the reaction together, or the diisocyanate and polyester / polyether diol can be mixed and reacted first and then the fluorinated small molecule diol is added to the reaction.

[0049] Furthermore, the end-capping reaction temperature may be 40-100° C., preferably 40-80° C.; and the reaction time may be 0-24 h, preferably 2-12 h.

[0050] Furthermore, the end-capping can be performed in a solvent environment; the solvent can include at least one of acetone, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, etc.

[0051] Furthermore, after the end-capping reaction is completed, the reaction mixture can be dropped into isopropanol, n-butanol, 2-butanol or diethyl ether to precipitate the polymer, stirred evenly and then filtered, washed with isopropanol, n-butanol, 2-butanol or diethyl ether and then vacuum dried.

[0052] Furthermore, the preparation method of the additive based on the fluorinated urethane prepolymer of the present invention comprises the following specific steps:

[0053] (1) reacting thioglycerol with a fluorinated carbon chain-containing (meth)acrylate to prepare a fluorinated small molecule diol;

[0054] (2) utilizing a stepwise addition polymerization reaction between diisocyanate and polyester / polyether diol and a fluorinated small molecule diol that acts as a chain extender to prepare a urethane prepolymer having -NCO groups at both ends;

[0055] (3) The urethane prepolymer with NCO groups at both ends in step (2) is capped with a fluorine-containing carbon chain monohydric alcohol to obtain a fluorine-containing urethane prepolymer.

[0056] In the method of the present invention, polyester / polyether diol is used as a soft segment, diisocyanate is used as a hard segment, and a fluorine-containing small molecule diol is used as a chain extender. A stepwise addition polymerization reaction is performed to obtain a urethane prepolymer with an isocyanate terminal group. The prepolymer is then capped with a fluorine-containing carbon chain monohydric alcohol to obtain an additive based on the fluorine-containing urethane prepolymer with a molecular weight of 3000-100000 g / mol, a molecular weight distribution index of 1.05-5.0, a percentage of fluorine atoms of 0-60%, and a mass percentage of the hard segment of 0-80%.

[0057] Furthermore, the fluorine-containing urethane-based prepolymer of the present invention has a molecular weight of 8,000-40,000 g / mol, a molecular weight distribution index of 1.1-2.5, a fluorine atom percentage of 10-60%, and a hard segment percentage of 30-70%.

[0058] The method of the present invention first synthesizes a small molecule diol with a high fluorine content through a simple method. This fluorine-containing diol is then used as a chain extender, and a commercially available fluorine-containing carbon chain monohydric alcohol is used as an end-capping agent to prepare an additive for a high-fluorine-containing urethane prepolymer. The method of the present invention has a simple process, low batch production cost, and can be converted to industrial production to produce a material with stable performance.

[0059] The additive of the present invention is a low-molecular-weight polyurethane with a high fluorine content. Both the side chains and the chain ends of the structure contain fluorocarbon chains. When the additive is blended with a commercial polyurethane masterbatch, fluorine atoms with low surface energy can be enriched on the surface of the prepared medical fluorine-containing anticoagulant polyurethane material, so that the fluorine atom content on the material surface can be as high as 60%, effectively reducing the adhesion of plasma proteins, cells and platelets on the surface of the medical polyurethane material, thereby giving the medical polyurethane material an excellent anticoagulant effect. Moreover, due to the high fluorine content of the additive of the present invention, only a relatively low addition amount (less than 10%) is required to achieve an excellent anticoagulant effect. Furthermore, the relatively low addition amount can effectively reduce the impact on the mechanical properties of the polyurethane material, thereby maintaining the excellent mechanical properties of the polyurethane. Therefore, the additive of the present invention can be added to the polyurethane masterbatch and is widely used in the preparation of medical fluorine-containing anticoagulant polyurethane materials.

[0060] The present invention also provides a medical fluorine-containing anti-coagulant polyurethane material containing the above-mentioned additive based on fluorine-containing urethane prepolymer of the present invention, wherein the component thereof contains 0-10wt% of the additive based on fluorine-containing urethane prepolymer of the present invention; preferably, the component contains 2.5-8wt% of the additive based on fluorine-containing urethane prepolymer of the present invention.

[0061] The masterbatch of the medical fluorine-containing anticoagulant polyurethane material may include at least one of polyether polyurethane, polyester polyurethane, etc.

[0062] By adding the additive based on the fluorinated urethane prepolymer of the present invention to a commercial polyurethane masterbatch, a medical fluorinated anticoagulant polyurethane material can be prepared in large quantities and at low cost through a simple blending process. The material has broad application prospects in the fields of blood-contact medical devices and implantable medical devices.

[0063] The blending process may include melt blending, solution blending or other conventional polymer blending methods.

[0064] The medical fluorinated anticoagulant polyurethane material of the present invention can achieve excellent anticoagulant effect by adding an additive based on a fluorinated urethane prepolymer in an amount of less than 10 wt %. The surface adsorption rate of bovine serum albumin is 0-10% after 2 hours, the adhesion rate of HUVECs cells is 0-15% after 4 hours, and the platelet adhesion rate is 5×10 3 -1×10 6The additive reduces the number of cells per square centimeter by 15 times, resulting in excellent biocompatibility. Cell viability tests show a survival rate of 80-120% and a hemolysis rate of 0-3%. Furthermore, the small amount added effectively prevents any impact on the mechanical properties of the polyurethane material, ensuring the material possesses comparable performance to meet medical needs. Compared to currently used commercial medical polyurethane masterbatches, the medical fluorinated anticoagulant polyurethane material containing the additive of this invention exhibits improved surface hydrophobicity and resistance to cell, protein, and platelet adhesion, resulting in superior anticoagulant properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0066] FIG1 is a schematic diagram of the chemical structure of a fluorine-containing urethane prepolymer according to the present invention.

[0067] Figure 2 is a graph showing the structure of the fluorinated small molecule diol synthesized in Example 1. 1 H NMR spectrum.

[0068] FIG3 is a graph showing the fluorinated urethane prepolymer synthesized in Example 3. 1 H NMR spectrum.

[0069] FIG4 is a stress-strain curve of the fluorine-containing anticoagulant polyurethane material for traditional Chinese medicine in Example 5.

[0070] FIG5 shows the tensile strength of the fluorine-containing anticoagulant polyurethane material for traditional Chinese medicine in Example 5.

[0071] FIG6 shows the F element content on the upper and bottom surfaces of the fluorine-containing anticoagulant polyurethane material for traditional Chinese medicine in Example 6.

[0072] FIG7 is a static contact angle of the surface of the fluorine-containing anticoagulant polyurethane material for traditional Chinese medicine in Example 6.

[0073] FIG8 shows the adsorption rate of BSA on the surface of the fluorine-containing anticoagulant polyurethane material for traditional Chinese medicine in Example 7.

[0074] FIG9 and FIG10 are adhesion diagrams and adhesion degree analysis of the surface of the traditional Chinese medicine fluorine-containing anticoagulant polyurethane material of Example 7 to HUVECs cells.

[0075] Figures 11 and 12 show the platelet adhesion diagram and adhesion degree analysis on the surface of the medical fluorine-containing anticoagulant polyurethane material in Example 7. Figure 11A shows a commercial polyurethane masterbatch; Figure 11B shows a medical fluorine-containing anticoagulant polyurethane material (containing 5% additives). DETAILED DESCRIPTION

[0076] The present invention will be described in further detail below with reference to the following examples, but the embodiments of the present invention are not limited thereto. Materials used in the following examples are commercially available unless otherwise specified. The methods described are conventional methods unless otherwise specified. The amounts of each component are expressed in parts by weight (g, mL). Figure 1 is a schematic diagram of the chemical structure of the fluorinated urethane prepolymer of the present invention.

[0077] In one embodiment, a type of additive based on a fluorinated urethane prepolymer has a structure shown in the following formula:

[0078] Wherein, m is a positive integer, 1≤m≤30; n is 0 or a positive integer, 0≤n≤15.

[0079] Furthermore, m represents the number of structural units containing R0, R1 and R2 groups and urethane bonds; n represents the number of repeating units containing -CF2- groups.

[0080] Furthermore, m is a positive integer, 1≤m≤15; n is a positive integer, 3≤n≤10.

[0081] In one embodiment, R0, R1, and R2 are each selected from at least one of the following groups:

[0082] In one embodiment, in R2, x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

[0083] In another embodiment, in R2, x is 1 or 2; y is a positive integer, 4≤y≤16; z is 0 or 1; and j is a positive integer, 9≤j≤33.

[0084] In one embodiment, in R2, x is the number of repeating units containing -CH2-, and y is the number of repeating units in the fluorocarbon chain except the group -(CH2) x -, z is the number of carbon atoms in the fluorocarbon chain excluding the group -(CH2) x - is the number of hydrogen atoms outside the ring, and j is the number of fluorine atoms in the fluorocarbon chain.

[0085] In one embodiment, a method for preparing the above-mentioned additive based on fluorinated carbamate prepolymer comprises reacting polyester / polyether diol, diisocyanate and fluorinated small molecule diol A to obtain a carbamate prepolymer having an isocyanate end group, and then capping it with a monohydric alcohol containing a fluorinated carbon chain to obtain an additive based on fluorinated carbamate prepolymer.

[0086] In one embodiment, the polyester / polyether diol has the following structural formula: HO-RO-OH, where R0 is selected from at least one of the following groups:

[0087] In one embodiment, R0 is In another embodiment, R0 is In another embodiment, R0 is

[0088] In one embodiment, the molecular weight of the polyester / polyether diol is 800-30000 g / moL; in another embodiment, the molecular weight of the polyester / polyether diol is 1000-5000 g / moL.

[0089] In one embodiment, the polyester / polyether diol comprises at least one of polypropylene oxide diol (PPO), polytetramethylene glycol (PTMG), polyethylene glycol (PEG), polycaprolactone diol (PCL), and polyadipate diol. In one embodiment, the polyester / polyether diol comprises polypropylene oxide diol; in another embodiment, the polyester / polyether diol comprises polytetramethylene glycol; and in another embodiment, the polyester / polyether diol comprises polycaprolactone diol.

[0090] In one embodiment, the diisocyanate comprises at least one of toluene diisocyanate (2,4-TDI, 2,6-TDI, and mixtures thereof), isophorone diisocyanate (IPDI), hexamethylene diisocyanate (HDI), diphenylmethane diisocyanate (MDI), lysine diisocyanate (LDI), and dicyclohexylmethane diisocyanate (H12MDI). In one embodiment, the diisocyanate comprises toluene diisocyanate; in another embodiment, the diisocyanate comprises isophorone diisocyanate; and in yet another embodiment, the diisocyanate comprises lysine diisocyanate.

[0091] In one embodiment, the structural formula of the fluorinated small molecule diol is as follows: HO-R2-OH,

[0092] In one embodiment, in R2, x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

[0093] In one embodiment, the end-capping agent is a monohydric alcohol containing a fluorine-containing carbon chain, which contains 2-18 carbon atoms and 3-33 fluorine atoms in its structure, and the structural formula is as follows:

[0094] n is 0 or a positive integer, 0≤n≤15.

[0095] In one embodiment, the fluorinated small molecule diol is prepared by reacting thioglycerol with a fluorinated carbon chain (meth)acrylate through Michael addition reaction B. The reaction formula is as follows:

[0096] In one embodiment, the fluorine-containing carbon chain (meth)acrylate includes at least one of (meth)acrylates having 2-30 carbon atoms and 3-37 fluorine atoms in the side chain.

[0097] In one embodiment, the structural formula of the fluorine-containing carbon chain (meth)acrylate is as follows:

[0098] x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

[0099] In one embodiment, the molar ratio of the fluorinated carbon chain-containing (meth)acrylate to thioglycerol is 1:1-1:5; in another embodiment, the molar ratio of the fluorinated carbon chain-containing (meth)acrylate to thioglycerol is 1:1-1:2.

[0100] In one embodiment, the reaction temperature of the Michael addition reaction B is 0-80°C; in another embodiment, the reaction temperature of the Michael addition reaction B is 20-30°C.

[0101] In one embodiment, the reaction time of the Michael addition reaction B is 0-48 hours; in another embodiment, the reaction time of the Michael addition reaction B is 4-24 hours.

[0102] In one embodiment, the Michael addition reaction B is carried out in a solvent environment, such as at least one of ethyl acetate, dichloromethane, chloroform, acetone, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, diethyl ether, methanol, ethanol, isopropanol, and the like. In one embodiment, the reaction B is carried out in ethyl acetate; in another embodiment, the reaction B is carried out in tetrahydrofuran; and in yet another embodiment, the reaction B is carried out in N-methylpyrrolidone.

[0103] In one embodiment, the Michael addition reaction B is carried out under base catalysis.

[0104] In one embodiment, the molar ratio of the base to the thioglycerol is 0.5:1-1.5:1; in another embodiment, the molar ratio of the base to the thioglycerol is 1:1-1.2:1.

[0105] In one embodiment, the base used includes at least one of triethylamine, N,N-diisopropylethylamine, potassium carbonate (bicarbonate), sodium carbonate (bicarbonate), tripotassium (sodium) phosphate, lithium hydroxide, N-methylpiperidine, pyridine, N-methylmorpholine, and the like. In one embodiment, the base used includes triethylamine; in another embodiment, the base used includes N,N-diisopropylethylamine; and in yet another embodiment, the base used includes lithium hydroxide.

[0106] In one embodiment, after the Michael addition reaction B is completed, the reaction mixture is poured into water to precipitate the product, which is then stirred evenly and filtered, washed with water, and finally dried in vacuo.

[0107] In one embodiment, in the preparation method of the present invention, the molar ratio of -OH groups of all diols to -NCO groups of diisocyanates in the reaction system is 1:1.05-1:4. In another embodiment, in the preparation method of the present invention, the molar ratio of -OH groups of all diols to -NCO groups of diisocyanates in the reaction system is 1:1.5-1:2. In one embodiment, the molar ratio is 1:1.5; in another embodiment, the molar ratio is 1:2; and in yet another embodiment, the molar ratio is 1:1.8.

[0108] In one embodiment, the molar ratio of the blocking agent to -NCO in the diisocyanate is 1:1-1:2. In one embodiment, the molar ratio is 1:1; in another embodiment, the molar ratio is 1:2; and in yet another embodiment, the molar ratio is 1:1.5.

[0109] In one embodiment, the reaction temperature of reaction A is 40-120° C.; in another embodiment, the reaction temperature of reaction A is 60-90° C. In one embodiment, the reaction time of reaction A is 0-48 hours; in another embodiment, the reaction time of reaction A is 4-24 hours.

[0110] In one embodiment, the reaction A is carried out in a solvent environment; the solvent includes at least one of acetone, butanone, ethyl acetate, acetonitrile, toluene, N,N-dimethylformamide, N-methylpyrrolidone, etc.

[0111] In one embodiment, the reaction A does not use a solvent, and adopts a solvent-free bulk polymerization method.

[0112] In one embodiment, the reaction A is carried out under the catalysis of a catalyst.

[0113] In one embodiment, the catalyst includes stannous octoate or dibutyltin dilaurate.

[0114] In one embodiment, the catalyst used is in a catalytic amount, such as 0-0.5% by weight of the total reactants, preferably 0.05-0.2%.

[0115] In one embodiment, in the reaction A, all components are added to the reaction together; in another embodiment, in the reaction A, the diisocyanate and polyester / polyether diol are first mixed and reacted before adding the fluorinated small molecule diol to the reaction.

[0116] In one embodiment, the end-capping reaction temperature is 40-100° C.; in another embodiment, the end-capping reaction temperature is 40-80° C. In one embodiment, the end-capping reaction time is 0-24 hours; in another embodiment, the end-capping reaction time is 2-12 hours.

[0117] In one embodiment, the end-capping is performed in a solvent environment; the solvent includes at least one of acetone, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, etc. In one embodiment, the solvent includes acetone; in another embodiment, the solvent includes dimethyl sulfoxide; and in yet another embodiment, the solvent includes N,N-dimethylformamide.

[0118] In one embodiment, after the end-capping reaction is completed, the reaction mixture is added dropwise to isopropanol, n-butanol, 2-butanol or diethyl ether to precipitate the polymer, which is then stirred evenly and filtered, washed with isopropanol, n-butanol, 2-butanol or diethyl ether and then dried in vacuo.

[0119] In one embodiment, a method for preparing an additive based on a fluorinated urethane prepolymer comprises the following specific steps:

[0120] (1) reacting thioglycerol with a fluorinated carbon chain-containing (meth)acrylate to prepare a fluorinated small molecule diol;

[0121] (2) utilizing a stepwise addition polymerization reaction between diisocyanate and polyester / polyether diol and a fluorinated small molecule diol that acts as a chain extender to prepare a urethane prepolymer having -NCO groups at both ends;

[0122] (3) The urethane prepolymer with NCO groups at both ends in step (2) is capped with a fluorine-containing carbon chain monohydric alcohol to obtain a fluorine-containing urethane prepolymer.

[0123] In one embodiment, a medical fluorine-containing anticoagulant polyurethane material containing the above-mentioned additive based on fluorine-containing urethane prepolymer of the present invention contains 0-10 wt% of the additive based on fluorine-containing urethane prepolymer of the present invention.

[0124] In another embodiment, a medical fluorine-containing anticoagulant polyurethane material containing the above-mentioned additive based on fluorine-containing urethane prepolymer of the present invention contains 2.5-8 wt% of the additive based on fluorine-containing urethane prepolymer of the present invention.

[0125] In one embodiment, the added amount is 5 wt %; in another embodiment, the added amount is 8 wt %; and in yet another embodiment, the added amount is 2.5 wt %.

[0126] In one embodiment, a medical fluorinated anticoagulant polyurethane material containing the fluorinated urethane prepolymer-based additive of the present invention can have a surface fluorine atom content of up to 60%. In one embodiment, the surface fluorine atom content of the medical fluorinated anticoagulant polyurethane material is 47.9%; in another embodiment, the surface fluorine atom content of the medical fluorinated anticoagulant polyurethane material is 58.3%; and in yet another embodiment, the surface fluorine atom content of the medical fluorinated anticoagulant polyurethane material is 35.6%.

[0127] The additive of the present invention is a low-molecular-weight polyurethane with a high fluorine content. Both the side chains and the chain ends of the structure contain fluorocarbon chains. When the additive is blended with a commercial polyurethane masterbatch, fluorine atoms with low surface energy can be enriched on the surface of the prepared medical fluorine-containing anticoagulant polyurethane material, so that the fluorine atom content on the material surface can be as high as 60%, effectively reducing the adhesion of plasma proteins, cells and platelets on the surface of the medical polyurethane material, thereby giving the medical polyurethane material an excellent anticoagulant effect. Moreover, due to the high fluorine content of the additive of the present invention, only a relatively low addition amount (less than 10%) is required to achieve an excellent anticoagulant effect. Furthermore, the relatively low addition amount can effectively reduce the impact on the mechanical properties of the polyurethane material, thereby maintaining the excellent mechanical properties of the polyurethane. Therefore, the additive of the present invention can be added to the polyurethane masterbatch and is widely used in the preparation of medical fluorine-containing anticoagulant polyurethane materials.

[0128] In one embodiment, the masterbatch of the medical fluorine-containing anticoagulant polyurethane material may include at least one of polyether polyurethane, polyester polyurethane, etc. In one embodiment, the masterbatch includes polyether polyurethane; in another embodiment, the masterbatch includes polyester polyurethane.

[0129] In one embodiment, the additive based on the fluorinated urethane prepolymer of the present invention is added to a commercial polyurethane masterbatch. Through a simple blending process, medical fluorinated anticoagulant polyurethane materials can be prepared in large quantities and at low cost. The materials have broad application prospects in the fields of blood-contact medical devices and implantable medical devices.

[0130] In one embodiment, the blending process may include melt blending, solution blending, or other conventional polymer blending methods. In one embodiment, the blending process includes melt blending; in another embodiment, the blending process includes solution blending.

[0131] Example 1: Synthesis of Fluorinated Small Molecule Diols

[0132] Mix 2.1 parts by mass of thioglycerol and 5 parts by mass of 1H,1H,2H,2H-perfluorodecyl acrylate, use 1.95 parts by mass of triethylamine as a base catalyst, 30 parts by volume of tetrahydrofuran as a solvent, and continue stirring at 25°C for 6 hours; after the reaction is completed, add the reaction mixture dropwise into 100 parts by volume of water under stirring to precipitate the product, stir for 10 minutes, let it stand and pour out the upper solution. Add the remaining precipitate to 100 parts by volume of water and stir, and repeat the above steps. After filtration (or centrifugation), wash the product with water and dry it in vacuum at 65-70°C overnight with a yield of 83%. The obtained fluorinated small molecule diol 1 H NMR is shown in Figure 2, and its chemical structure is shown below:

[0133] Example 2: Synthesis of Fluorinated Small Molecule Diols

[0134] Mix 10.8 parts by mass of thioglycerol and 51.9 parts by mass of 1H,1H,2H,2H-perfluorooctyl methacrylate, use 10.1 parts by mass of N-methylmorpholine as a base catalyst, and 30 parts by volume of DMF as a solvent. Stir continuously for 6 hours at 25°C. After the reaction is completed, the reaction mixture is added dropwise to 100 parts by volume of water under stirring to precipitate the product. Stir for 15 minutes, let it stand, and pour off the supernatant. The remaining precipitate is added to 100 parts by volume of water, stirred, and the above steps are repeated. After filtration (or centrifugation), the product is washed with water and dried under vacuum at 65-70°C overnight to obtain the corresponding fluorinated small molecule diol with a yield of 87%.

[0135] Example 3: Synthesis of Fluorinated Urethane Prepolymer

[0136] PPG diol (14 parts by mass, Mw = 1000 g / moL) was added to 150 parts by volume of DMF, followed by the addition of hexamethylene diisocyanate (HDI, 4.70 parts by mass), and 0.01 parts by volume of DBTDL was added dropwise to the reaction system. The mixture was stirred and reacted for 4 hours to obtain an HDI-PPG prepolymer. The small molecule fluorinated diol (3.76 parts by mass) synthesized in Example 1 was added to the prepolymer solution for chain extension. The reaction was carried out at 70°C for 5 hours to obtain a chain-extended polyurethane prepolymer. Perfluorohexylethyl alcohol (10 parts by mass) was added to the above reaction system and stirred overnight to obtain a capped fluorinated prepolymer. The mixed solution was cooled to room temperature and added dropwise to 180 parts by volume of water for precipitation. The mixture was filtered and washed with water several times. The prepolymer was transferred to a three-necked flask, isopropyl alcohol was added and heated to dissolve. After cooling to room temperature, the prepolymer was added dropwise to n-hexane to precipitate the prepolymer, and vacuum dried at 60°C overnight. The yield was 64%. The average molecular weight was 13.5 kDa and the molecular weight distribution index was 1.26 as measured by high performance gel permeation chromatography. 1 H NMR is shown in Figure 3, and its chemical structure is shown below:

[0137] Example 4: Synthesis of Fluorinated Urethane Prepolymer

[0138] PCL diol (14 parts by mass, Mw = 2000 g / moL) was added to 180 parts by volume of DMF, and then toluene diisocyanate (TDI, 2.96 parts by mass) was added. 0.015 parts by volume of DBTDL was added dropwise to the reaction system, and the mixture was stirred and reacted for 4 hours to obtain a TDI-PCL prepolymer. At this time, the small molecule fluorinated diol (1.62 parts by mass) synthesized in Example 2 was added to the prepolymer solution for chain extension, and the reaction was carried out at 70°C for 5 hours to obtain a chain-extended polyurethane prepolymer. 1H,1H,2H,2H-tridecafluoro-1-n-octanol (7.43 parts by mass) was added to the above reaction system and stirred overnight to finally obtain a capped fluorinated prepolymer. The mixed solution was cooled to room temperature and added dropwise to 180 parts by volume of water for precipitation. The mixture was then filtered and washed several times with water. The prepolymer was transferred to a three-necked flask, 2-butanol was added and heated to dissolve. After cooling to room temperature, the prepolymer was added dropwise to n-hexane to precipitate the prepolymer, which was then dried overnight under vacuum at 60°C. The yield was 70%. High-performance gel permeation chromatography (HPLC) revealed an average molecular weight of 21.4 kDa and a molecular weight distribution index of 1.58.

[0139] Example 5: Preparation and basic mechanical properties evaluation of medical fluorinated anticoagulant polyurethane materials

[0140] The fluorinated urethane prepolymer additive obtained in Example 3 and a commercial polyurethane masterbatch (Pellethane TPU 2363-90A) were sequentially added to an N,N-dimethylformamide solvent and heated at 70-90°C until completely dissolved. The prepolymer additive accounted for 5% of the total weight of the blend, and the combined weight concentration of the prepolymer additive and commercial polyurethane masterbatch in the DMF solution was 10%. The mixture was poured into a polytetrafluoroethylene mold and the solvent was completely evaporated at 50°C to form dumbbell-shaped specimens (75 mm long × 12.5 mm wide).

[0141] The tensile properties of the specimens were tested using a universal tensile testing machine at a tensile speed of 500 mm / min. All specimens were loaded until rupture to obtain their elongation at break and stress-strain curves. Each specimen was tested five times in parallel. The results are shown in Figures 4 and 5.

[0142] As can be seen from the figure, after the additive of the present invention is added to the commercial polyurethane masterbatch to prepare the medical fluorine-containing anticoagulant polyurethane material, the elongation at break and the tensile strength decrease, but the degree of decrease is not large. The elongation at break decreases from 576% to 521%, a decrease of 9.6%, and the tensile strength decreases from 34 MPa to 20 MPa. However, according to the mechanical performance requirements of medical materials, the elongation at break of 521% and the tensile strength of 20 MPa fully meet the use needs.

[0143] Example 6: Surface structure analysis and hydrophobicity evaluation of medical fluorinated anticoagulant polyurethane materials

[0144] A mixture solution was prepared according to the steps described in Example 5. 2.0 mL of the solution was poured into a transparent glass bottle with a diameter of 12 mm and a height of 35 mm, and the solvent was completely evaporated at 50°C. The cylindrical specimen was taken out, and the F element content on its upper surface and bottom surface was analyzed using X-ray electron spectroscopy (XPS). The test results are shown in Figure 6. As can be seen from the figure, the F element content on the surface of the medical fluorine-containing anticoagulant polyurethane material of the present invention is as high as 47.9%. The additive of the present invention is a low molecular weight polyurethane with a high fluorine content. Both the side chains and the chain ends in the structure contain fluorocarbon chains. When it is blended with a commercial polyurethane masterbatch, the fluorine atoms with low surface energy can be enriched on the surface of the prepared medical fluorine-containing anticoagulant polyurethane material, thereby greatly improving the fluorine content on the surface of the medical fluorine-containing anticoagulant polyurethane material.

[0145] At the same time, the surface water contact angle of the upper surface of the cylindrical spline was measured using a static contact angle meter. The test results are shown in Figure 7. As can be seen from the figure, the surface static contact angle of the medical fluorinated anticoagulant polyurethane material of the present invention is 106°, an increase of 9.3% compared to the masterbatch, indicating that the addition of the fluorinated additive can increase the hydrophobicity of the material surface.

[0146] Example 7: Evaluation of cell, protein and platelet adhesion on the surface of medical fluorinated anticoagulant polyurethane materials

[0147] (1) Surface cell adhesion:

[0148] According to the method described in Example 3, DMF solutions of medical fluorine-containing anticoagulant polyurethane material and commercial polyurethane masterbatch were prepared. The polyurethane DMF solutions were applied to small glass-bottomed dishes with a diameter of 35 mm, and the dishes were placed in a 50°C forced air drying oven for 24 h. After the DMF solvent was fully evaporated, the material formed a thin film on the bottom of the dish. Finally, human umbilical vein endothelial cells (HUVECs) were seeded in the dishes for cell adhesion experiments; the number of cells seeded was 3×10 4 After culturing for 4 hours at 37°C, live cells in the small dishes were stained with Calcein-AM, and cell adhesion to the membrane surface was photographed using a fluorescence microscope. The cell adhesion levels of HUVECs on the surfaces of a commercial polyurethane masterbatch and the medical fluorinated anticoagulant polyurethane material are shown in Figures 9 and 10. As can be seen, the cell density adhered to the surface of the medical fluorinated anticoagulant polyurethane material of the present invention was significantly reduced from 33% to 8%, demonstrating the excellent anti-cell adhesion properties of the medical fluorinated anticoagulant polyurethane material surface of the present invention.

[0149] (2) Surface protein / platelet adhesion:

[0150] Medical fluorine-containing anticoagulant polyurethane material specimens and commercial polyurethane masterbatch specimens were prepared according to the method of Example 3, and the specimens were cut into membrane sheets with a length of 1.0 cm and a width of 1.0 cm to evaluate the adhesion of proteins and platelets on the membrane surface.

[0151] a. Surface Protein Adhesion: Soak the membrane in PBS overnight and place it in a 24-well plate. Add 2 mL of a 1 mg / mL bovine serum albumin (BSA) solution in PBS to each well. Incubate the 24-well plate in a 37°C incubator for 2 hours, then remove the membrane and rinse three times with fresh PBS. Place the membrane in 200 μL of PBS containing 1% SDS and incubate at 37°C for 1 hour. Finally, measure the protein content in the eluate using a BCA assay kit. OD values ​​are read at 562 nm, and the amount of protein adsorbed on the membrane surface is calculated using a BSA standard curve. The results are shown in Figure 8. As shown in the figure, the protein adsorption concentration on the surface of the medical fluorinated anticoagulant polyurethane material of the present invention is 5.0% within 2 hours, which is lower than the 5.5% concentration of the masterbatch membrane, demonstrating that the present material exhibits superior anti-protein adhesion properties.

[0152] b. Surface platelet adhesion: Soak the membrane in PBS overnight and place it in an EP tube. Then add 0.5 mL / tube of freshly prepared platelet-rich plasma (blood was collected from an adult male Dutch rabbit weighing approximately 3 kg). Place the EP tube containing the platelet-rich plasma in a 37°C water bath for 180 minutes, then remove the membrane and rinse the membrane three times with fresh PBS. Soak the rinsed membrane in a PBS solution containing 2.5% glutaraldehyde for 30 minutes to fix the platelets adhered to the sample. Remove the membrane and soak it in 25%, 50%, 75%, and 95% ethanol aqueous solutions and anhydrous ethanol for 20 minutes in sequence for step-by-step dehydration. After drying the membrane, observe the surface platelet adhesion using a scanning electron microscope. The results are shown in Figures 11 and 12. As can be seen from the figure, the platelet adhesion amount on the surface of the medical fluorine-containing anticoagulant polyurethane material of the present invention is 7.1×10 4 / square centimeter, while the platelet adhesion on the surface of the masterbatch membrane is about 1.1×10 6 / cm2, which is 15 times that of the material of the present invention, indicating that the medical fluorine-containing anticoagulant polyurethane material of the present invention has excellent anti-platelet adhesion.

[0153] In summary, the additive of the present invention is a low-molecular-weight polyurethane with a high fluorine content. Both the side chains and the chain ends of the structure contain fluorocarbon chains. When the additive is blended with a commercial polyurethane masterbatch, the fluorine atoms with low surface energy can be enriched on the surface of the prepared medical fluorine-containing anticoagulant polyurethane material, so that the fluorine atom content on the surface of the material can be as high as 60%, effectively reducing the adhesion of the surface of the medical polyurethane material to plasma proteins, cells and platelets, thereby giving the medical polyurethane material an excellent anticoagulant effect.

[0154] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A type of additive based on fluorinated urethane prepolymer, characterized in that It has the structure shown below: Wherein, m is a positive integer, 1≤m≤30; n is 0 or a positive integer, 0≤n≤15; R0, R1, and R2 are each selected from at least one of the following groups: In R2, x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

2. A method for preparing the additive based on fluorinated urethane prepolymer according to claim 1, characterized in that: The invention comprises a reaction A of polyester / polyether diol, diisocyanate and fluorine-containing small molecule diol to obtain a urethane prepolymer with isocyanate as the terminal group, and then end-capping with a monohydric alcohol containing a fluorine carbon chain to obtain an additive based on the fluorine-containing urethane prepolymer.

3. The preparation method according to claim 2, characterized in that: The structural formula of the polyester / polyether diol is as follows: HO-R0-OH; R0 is selected from at least one of the following groups:

4. The preparation method according to claim 2, characterized in that: The diisocyanate includes at least one of toluene diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, diphenylmethane diisocyanate, lysine diisocyanate and dicyclohexylmethane diisocyanate.

5. The preparation method according to claim 2, characterized in that The structural formula of the fluorinated small molecule diol is as follows: HO-R2-OH; x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

6. The preparation method according to claim 2, characterized in that The end-capping agent is a monohydric alcohol containing a fluorine-containing carbon chain, and its structure contains 2-18 carbon atoms and 3-33 fluorine atoms. The structural formula is as follows: n is 0 or a positive integer, 0≤n≤15.

7. The preparation method according to claim 2, characterized in that The fluorine-containing small molecule diol is prepared by Michael addition reaction B using thioglycerol and (meth)acrylate containing a fluorine carbon chain.

8. The preparation method according to claim 7, characterized in that The structural formula of the (meth)acrylate containing fluorine carbon chain is as follows: x is 0 or a positive integer, 0≤x≤2; y is a positive integer, 1≤y≤18; z is 0 or a positive integer, 0≤z≤7; j is a positive integer, 3≤j≤37.

9. Use of the additive based on fluorine-containing urethane prepolymer according to claim 1 in the preparation of medical fluorine-containing anticoagulant polyurethane materials.

10. A medical fluorine-containing anticoagulant polyurethane material, characterized in that The component contains the additive based on fluorine-containing urethane prepolymer as claimed in claim 1.

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