Diphosphonic acid double salt containing acryloyloxy and quaternary ammonium cation

Abstract

The invention provides a diphosphonate with a molecular structure containing a single acryloyloxy group and a single quaternary ammonium cation, the diphosphonate is used as a functional acrylate monomer and a functional acrylate cross-linking agent, and the functional acrylate monomer is expected to be mixed into MMA (Methyl Methacrylate) for a copolymerization reaction to prepare the copolymerization modified PMMA-based bone cement. Meanwhile, the antibacterial and bacteriostatic performance of the PMMA powder, the medical efficiency of the bisphosphonate and the water absorption expansion performance in a medium are improved, the elastic modulus is reduced, the tensile strength is improved, the curing heat effect is low, the biocompatibility is improved, and optimization or improvement of multiple technical indexes of the PMMA-based bone cement is achieved.

Description

Technical Field

[0001] The present invention relates to a functional acrylate and a preparation method thereof, in particular to a bisphosphonic acid double salt containing a single acryloxy group and a single quaternary ammonium cation in its molecular structure, which can be used for copolymer modification of methacrylate and belongs to the field of functional polymer materials. Technical Background

[0002] Polymethyl methacrylate (PMMA) is an artificially synthesized biocompatible polymer material, which has the characteristics of low density, good processability and plasticity compared with metal materials and inorganic materials. As a bone cement for replacing bone, it does not cause a host reaction when implanted in the body, can remain biochemically stable when staying in the body for a long time, and has no cytotoxicity and no degradation. Compared with titanium metal, ceramics and other polymer-based bone replacement materials (such as polyethylene, polyaryletherketone and polyetheretherketone), PMMA-based bone cement has good fluidity and cures at room temperature, ensuring that it can be made into a geometric shape that perfectly fits the bone defect site during the operation, so it plays an important role in the field of bone tissue repair. PMMA bone cement is composed of a powder component and a liquid component. The powder component is composed of 80-89% by mass of PMMA or modified PMMA, plus a radiopaque agent, an initiator, an antibiotic, a modifier, etc.; the liquid component is composed of 90-98% by mass of methyl methacrylate (MMA), plus an accelerator, a stabilizer, a modifier, etc. Whether using the powder component of modified PMMA or adding a modifier to the powder component and the liquid component respectively, the purpose is to eliminate the defects of PMMA-based bone cement.

[0003] The main defects revealed by PMMA-based bone cement used for more than half a century include: ① There is a significant difference between the elastic modulus of PMMA-based bone cement and the host bone around its filling position. The elastic modulus of PMMA-based bone cement is 2552 MPa, which is much higher than the elastic modulus of trabecular bone (100-700 MPa). This difference will produce a stress shielding effect and a change in stress load transfer, resulting in an increased risk of adjacent vertebral fractures. ② The heat released by the addition polymerization reaction of 1 g of MMA monomer in the liquid component of PMMA-based bone cement at room temperature is as high as 560 joules, causing a significant increase in the temperature of the bone cement. The highest temperature of PMMA-based bone cement can reach 80-120 °C, which can cause necrosis of bone cells and bone tissue near the bone cement. ③ During the curing process of PMMA-based bone cement, the low-density MMA monomer (ρ = 0.94 g / cm 3 ) in the liquid component is polymerized into a higher-density PMMA polymer (ρ = 1.19 g / cm 3) This results in volume shrinkage after therapeutic filling, which is an important issue that must be paid attention to in clinical applications. ④ As an in-vivo implantable bio-inert polymer material, PMMA-based bone cement cannot be biodegraded in the body, and its PMMA bone cement cannot induce the growth of bone cells and bone tissue, resulting in a low bone interface bonding force between it and the host. Therefore, the bone cement is prone to loosening after being implanted at the surgical site for a period of time, ultimately causing the failure of bone repair. ⑤ Introducing antibiotics into PMMA-based bone cement is of great significance for preventing and treating acute and chronic osteoarticular infections after surgeries such as osteomyelitis, bone replacement, and fractures. ⑥ Incorporating some bisphosphonates with bone resorption inhibitory effects into PMMA-based bone cement has a positive effect on promoting the differentiation of osteoblasts and inhibiting the generation of osteoclasts.

[0004] Regarding the raw material types, preparation techniques, and usage methods of the above-mentioned PMMA-based bone cement, relevant scientific researchers, scholars, and medical workers have conducted comprehensive experimental studies and technical improvements on the defects of PMMA-based bone cement and achieved remarkable results. For example, inorganic materials are filled and blended in the powder component of PMMA-based bone cement, including hydroxyapatite, bioactive glass, bentonite, TiO 2 nanofibers, halloysite nanotubes, carbon nanotubes, graphene oxide, etc., and using γ-methacryloxypropyltrimethoxysilane to surface-modify hydroxyapatite, bioactive glass, bentonite, etc., can all reduce the elastic modulus and heat of curing release of PMMA-based bone cement, enhance its tensile strength and flexural strength, and improve the bioactivity of PMMA-based bone cement. However, blending inorganic materials in the powder component will also cause some problems. For example, after the PMMA-grade bone cement is cured, the residual amount of MMA will gradually increase with the increase in the blending amount of inorganic materials, indicating that the inorganic material powder blocks the chain reaction of the free radical polymerization process. There are also cases where some functional monomers are added to MMA during the preparation of PMMA powder, including acrylic acid, hydroxyethyl methacrylate, butyl methacrylate, 2-ethylhexyl acrylate, methacrylate quaternary ammonium salt, 5-nitrofurfuryl methacrylate, methacryloyl betaine, γ-methacryloxypropyltrimethoxysilane, etc. for polymerization modification, obtaining the effects of reducing the elastic modulus and curing volume shrinkage of the copolymer-modified PMMA-based bone cement and improving its bioactivity and antibacterial properties. In short, so far, most of the modifications of PMMA-based bone cement by blending methods or copolymerization techniques are aimed at single properties or functions, and it is relatively rare to have multiple modification effects taken into account.

[0005] Based on the performance, functions, and usage requirements of PMMA-based bone cement, aiming at the defects and deficiencies of existing modification technologies and methods, to ensure the safe and stable applicability of PMMA-based bone cement, according to the chemical principle of molecular design, the present invention has created a bisphosphonic acid double salt containing a single acryloxy group and a single quaternary ammonium cation in its molecular structure as a functional acrylate monomer for copolymer modification in MMA, expecting to improve and enhance the antibacterial and bacteriostatic properties, medical efficacy of bisphosphonates, water absorption and swelling properties in the medium, as well as reduce the elastic modulus, increase the tensile strength, have a low curing heat effect, and possess biocompatible properties, so as to optimize many technical indicators of PMMA-based bone cement. Summary of the Invention

[0006] The present invention provides a bisphosphonic acid double salt containing an acryloxy group and a quaternary ammonium cation, which is characterized by having the structure shown in general formula (Ⅰ):

[0007]

[0008] Among them, R in general formula (Ⅰ) is selected from H or CH 3 , R 1 is selected from C 1 ~C 18 hydrocarbon group, M n+ is selected from Na + , K + , NH 4 + , Ag + , Ca 2+ , Co 2+ , Cu 2+ , Fe 2+ , Mg 2+ , Mn 2+ , Zn 2+ , Sr 2+ , Al 3+ , Bi 3+ , Cr 3+ , Fe 3+ , Sn 4+ , Ti 4+ , Zr 4+ , N-benzyl-N,N,N-trimethylammonium cation, N-benzyl-N,N,N-triethylammonium cation, N-benzyl-N,N,N-tributylammonium cation, N,N,N,N-tetrabutylammonium cation, N-dodecyl-N,N-dimethyl-N-benzylammonium cation, N-dodecyl-N,N-diethyl-N-benzylammonium cation, N-tetradecyl-N,N-dimethyl-N-benzylammonium cation or N-tetradecyl-N,N-diethyl-N-benzylammonium cation, and among them, n is selected from one of 1, 2, 3, or 4, X - is selected from Cl- , Br - or NO 3 - One of the following

[0009] The preparation method of the bisphosphonic acid double salt containing acryloyloxy group and quaternary ammonium cation of general formula (I) is realized through the following preparation steps: Step 1, preparation of N-(2-hydroxyethyl)-N-alkyl-N,N-bis(ethyl-2-phosphonic acid) ammonium of general formula (II)

[0010] Put the solvent and vinyl phosphonate into the reaction kettle, control the temperature of the materials in the reaction kettle between 5 and 25 °C, slowly add ethanolamine, after the addition of ethanolamine is completed, raise the temperature to 50 - 60 °C and stir for 8 - 12 hours, then add the alkylating agent, raise the temperature of the materials in the reaction kettle to 20 - 120 °C, continue to stir for 2 - 12 hours, lower the temperature of the materials in the reaction kettle to room temperature, and filter out the solid intermediate product ①; dissolve the solid intermediate product ① in an aqueous acid solution with a molar concentration of 3 - 15 M, control the temperature at 80 - 120 °C and stir for hydrolysis reaction for 12 - 24 hours, cool down and filter out the solid intermediate product ②; dissolve the solid intermediate product ② in deionized water to prepare an aqueous solution, use an alkali to adjust the pH value of the aqueous solution of the solid intermediate product ② to 3.0 - 6.0, and after rotary evaporation concentration, filtration, recrystallization, and drying to constant weight, prepare N-(2-hydroxyethyl)-N-alkyl-N,N-bis(ethyl-2-phosphonic acid) ammonium with the structure shown in general formula (II):

[0011]

[0012] Among them, R in general formula (II) 1 selects C 1 ~C 18 alkyl

[0013] The solid intermediate product ① and the solid intermediate product ② respectively have the structures shown in general formula ① and general formula ②:[[]]

[0014]

[0015] Among them, R in general formula ① and general formula ② 1 selects C 1 ~C 18 alkyl, R 2 and R 3 respectively select one of methyl, ethyl or propyl.

[0016] The dosage of the vinyl phosphonate is 2.0 - 2.5 times the molar amount of ethanolamine, the dosage of the alkylating agent is 1.0 - 2.5 times the molar amount of ethanolamine, the dosage of the aqueous acid solution is 0.5 - 5.0 times the mass of ethanolamine, and the dosage of deionized water is 1 - 10 times the mass of ethanolamine.

[0017] The vinyl phosphonate refers to one of dimethyl vinylphosphonate, diethyl vinylphosphonate or dipropyl vinylphosphonate.

[0018] The alkylating agent has the structure shown in the general formula (Ⅲ):

[0019] R 1 -X

[0020] General formula (Ⅲ)

[0021] Wherein R in the general formula (Ⅲ) 1 selects C 1 ~C 18 hydrocarbyl, and X selects Cl or Br.

[0022] The aqueous acid solution refers to one of an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution.

[0023] The base refers to one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or ammonia water with a mass percentage concentration of 18-30%.

[0024] The solvent refers to one or more of tetrahydrofuran, 1,4-dioxane, cyclohexane, decalin, acetonitrile, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0025] Step 2. Preparation of the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cation of general formula (Ⅰ)

[0026] Weigh in sequence the solvent, N-(2-hydroxyethyl)-N-hydrocarbyl-N,N-bis(ethyl-2-phosphonic acid) ammonium and the inhibitor, put them into the reaction kettle and stir evenly. Control the temperature of the materials in the reaction kettle between 5-25 °C. After purging with nitrogen to remove oxygen, add acryloyl chloride or methacryloyl chloride to the reaction kettle. After the feeding of acryloyl chloride or methacryloyl chloride is completed, raise the temperature of the materials in the reaction kettle to 50-60 °C and stir for 2-6 hours. Lower the temperature of the materials in the reaction kettle to room temperature, use the base to adjust the pH value of the materials in the reaction kettle to 7.0-9.0, then add a saline solution with a mass percentage concentration of 5-50%, and quickly stir for 0.5-5.0 hours to complete the metathesis reaction. Then, concentrate by rotary evaporation, filter, wash, recrystallize, and dry to constant weight to obtain the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cation with the structure shown in the general formula (Ⅰ):

[0027]

[0028] Wherein R in the general formula (Ⅰ) selects H or CH 3 , R 1 selects C1 ~C 18 hydrocarbyl, M n+ Select Na + , K + , NH 4 + , Ag + , Ca 2+ , Co 2+ , Cu 2+ , Fe 2+ , Mg 2+ , Mn 2+ , Zn 2+ , Sr 2+ , Al 3+ , Bi 3+ , Cr 3+ , Fe 3+ , Sn 4+ , Ti 4+ , Zr 4+ , one of N-benzyl-N,N,N-trimethylammonium cation, N-benzyl-N,N,N-triethylammonium cation, N-benzyl-N,N,N-tributylammonium cation, N,N,N,N-tetrabutylammonium cation, N-dodecyl-N,N-dimethyl-N-benzylammonium cation, N-dodecyl-N,N-diethyl-N-benzylammonium cation, N-tetradecyl-N,N-dimethyl-N-benzylammonium cation or N-tetradecyl-N,N-diethyl-N-benzylammonium cation, wherein n is selected from one of 1, 2, 3 or 4, X - is selected from Cl - , Br - or NO 3 - one of them.

[0029] The amount of the solvent used is 0.5 to 5.0 times the mass of the N-(2-hydroxyethyl)-N-hydrocarbyl-N,N-bis(ethyl-2-phosphonic acid) ammonium, the amount of acryloyl chloride or methacryloyl chloride used is 1.0 to 1.2 times the molar amount of the N-(2-hydroxyethyl)-N-hydrocarbyl-N,N-bis(ethyl-2-phosphonic acid) ammonium, the amount of the polymerization inhibitor used is 0.013 to 0.05 times the mass of acryloyl chloride or methacryloyl chloride, and the amount of the salt used is 0.25 to 1.5 times the molar amount of the N-(2-hydroxyethyl)-N-hydrocarbyl-N,N-bis(ethyl-2-phosphonic acid) ammonium.

[0030] The polymerization inhibitor refers to one or more of hydroquinone, p-methoxyphenol, tert-butylhydroquinone, 2,6-dibutylhydroquinone, 2,6-di-tert-butyl-p-cresol or 2,4,6-tri-tert-butylphenol.

[0031] The solvent refers to one or more of tetrahydrofuran, 1,4-dioxane, cyclohexane, decalin, acetonitrile, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0032] The salt refers to one or more of sodium chloride, potassium chloride, ammonium chloride, sodium bromide, potassium bromide, ammonium bromide, sodium nitrate, potassium nitrate, ammonium nitrate, silver nitrate, calcium chloride, cobalt chloride hexahydrate, cobalt nitrate hexahydrate, copper chloride, basic copper chloride, ferrous chloride, magnesium hydroxide, zinc chloride, manganese nitrate, strontium dichloride, aluminum nitrate, aluminum chloride hexahydrate, basic bismuth nitrate, chromium chloride, ferric chloride, tin tetrachloride pentahydrate, titanium nitrate, zirconium nitrate, zirconium oxychloride octahydrate, N-benzyl-N,N,N-trimethylammonium chloride, N-benzyl-N,N,N-triethylammonium chloride, N-benzyl-N,N,N-tributylammonium chloride, N,N,N,N-tetrabutylammonium chloride, N-dodecyl-N,N-dimethyl-N-benzylammonium chloride, N-dodecyl-N,N-diethyl-N-benzylammonium chloride, N-tetradecyl-N,N-dimethyl-N-benzylammonium chloride, N-tetradecyl-N,N-diethyl-N-benzylammonium chloride, N-benzyl-N,N,N-trimethylammonium bromide, N-benzyl-N,N,N-triethylammonium bromide, N-benzyl-N,N,N-tributylammonium bromide, N,N,N,N-tetrabutylammonium bromide, N-dodecyl-N,N-dimethyl-N-benzylammonium bromide, N-dodecyl-N,N-diethyl-N-benzylammonium bromide, N-tetradecyl-N,N-dimethyl-N-benzylammonium bromide, or N-tetradecyl-N,N-diethyl-N-benzylammonium bromide.

[0033] The beneficial effects of the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cations of the present invention are as follows:

[0034] The raw materials for preparing the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cations of the present invention are all commercially available products. The product yields in each step of the preparation process are high, the purification technology is simple and reliable, and the process is easy to implement.

[0035] The molecular structure of the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cations of the present invention contains quaternary ammonium cations, bisphosphonates, or phosphocholine units. If through the copolymerization reaction after mixing it with methacrylate, it is theoretically predicted that the resulting copolymer-modified PMMA will have antibacterial and bacteriostatic properties, the medical efficacy of bisphosphonates, the water absorption and swelling properties in the medium, improve the tensile strength of PMMA, improve the biocompatibility of PMMA, and reduce the elastic modulus and MMA curing heat effect of PMMA, etc. Detailed implementation mode

[0036] To further understand the present invention, the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cations is specifically described through examples, aiming to better understand the content of the present invention. Therefore, the bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cations and its preparation method not listed in the examples should not be regarded as a limitation to the protection scope of the present invention.

[0037] Example 1 Preparation of N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium

[0038] Put 36 g of ethanolamine and 80 g of 1,4-dioxane into the reaction kettle, control the temperature of the materials in the reaction kettle at 20-25 °C, and slowly put 102 g of diethyl vinylphosphonate. After the feeding of diethyl vinylphosphonate is completed, raise the temperature to 50 °C and stir for 12 hours. Then put 93 g of benzyl chloride, raise the temperature of the materials in the reaction kettle to 80-90 °C, continue to stir for 12 hours, lower the temperature of the materials in the reaction kettle to room temperature, filter to obtain 338.4 g of crude product. After sampling and analysis, 87.3% of the crude product is N-(2-hydroxyethyl)-N-benzyl-N,N-bis(2-(diethoxyphosphoryl)ethyl) ammonium chloride. From this, the yield of N-(2-hydroxyethyl)-N-benzyl-N,N-bis(2-(diethyloxyphosphoryl)ethyl) ammonium chloride calculated based on ethanolamine is 94.8%; dissolve 338.4 g of the crude product in 305 g of hydrochloric acid with a molar concentration of 5.5 M, control the temperature at 90-100 °C and stir for hydrolysis reaction for 12 hours, lower the temperature of the hydrolysis reaction product to room temperature, filter to obtain 300.7 g of crude N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium chloride; dissolve 300.7 g of the crude N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium chloride in 250 g of deionized water, use a 30% sodium hydroxide aqueous solution with a mass percentage concentration to adjust the pH value of the materials in the reaction kettle to 4.5, rotary evaporate and concentrate until solid substances precipitate, cool and let stand to precipitate solid products, filter, recrystallize with absolute ethanol, and vacuum dry at 40-50 °C to constant weight to obtain 191.5 g of white crystal-like products. The elemental analysis (%) of the white crystal-like products: C 42.32, H 6.23, N 3.78, P 16.48, which is basically consistent with the calculated values of C 13 H 23 NO 7 P 2 Calculated values C 42.51, H 6.31, N 3.81, P 16.87; its IR (KBr tablet, cm -1): 3453, 3346, 3021, 2923, 2873, 1638, 1546, 1445, 1362, 1256, 1108, 1037, 974, 926 are respectively attributed to the characteristic vibration absorption peaks of P-O-H, C-O-H, C=C-H, H-C-H, C=C, C-N, P=O, C-O, and P-O. 1 H-NMR (using TMS as the internal standard, CD 3 OD, δ): 1.82 (t, 2H), 2.03 (s, 3H), 3.37 (t, 4H), 3.45 (t, 2H), 3.98 (t, 4H), 4.49 (t, 2H), 5.02 (s, 1H), 7.04 - 7.58 (m, 5H). From the spectral analysis results of elemental analysis, IR, and 1 H-NMR, it is confirmed that the white crystal product has the structural characteristics of N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium of formula (Ⅱ-1):

[0039]

[0040] Example 2 Preparation of N-(2-hydroxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium

[0041] According to the method and steps of Example 1, replacing benzyl chloride in Example 1 with 1-bromododecane, a beige solid product is obtained. Using the same instrumental analysis and characterization method as in Example 1, it is confirmed that the beige solid product has the structural characteristics of N-(2-hydroxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium of formula (Ⅱ-2):

[0042]

[0043] Example 3 Preparation of silver N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium nitrate

[0044] At room temperature, 45 g of N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium of formula (II-1) prepared in Example 1 and 0.32 g of 2,6-di-tert-butylhydroquinone were dissolved in 105 g of 1,4-dioxane in a reaction kettle. After purging with nitrogen to remove oxygen, 20.2 g of methacryloyl chloride was added. After stirring for 2 hours, the reaction temperature was raised to 50-60 °C and stirring was continued for 6 hours. The pH of the reaction product system was adjusted to 7.5 with an aqueous sodium hydroxide solution with a mass percentage concentration of 30%. After cooling and standing to remove the water-insoluble substances, 158 g of an aqueous silver nitrate solution with a mass percentage concentration of 25% was slowly added to the obtained organic phase. Under light-shielded conditions, rapid stirring reaction was carried out for 2 hours. After rotary evaporation concentration, filtration, ethanol washing, and vacuum drying, an off-white solid product was obtained. Reaction formula-1 shows the whole process of preparing silver N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium tetrahydrate of formula (I-1) using ethanolamine, diethyl vinylphosphonate, benzyl chloride, hydrochloric acid, methacryloyl chloride, and silver nitrate as the main raw materials:

[0045]

[0046] The elemental analysis results (%) of the off-white solid product: C 24.56, H 4.53, N 3.36, P 6.63, which are basically in agreement with the calculated values of C 17 H 34 Ag 2 N 2 O 15 P 2 24.89, H 4.67, N 3.42, P 7.55; Its IR (KBr tablet, cm -1 ): 3742, 3435, 3019, 3017, 2924, 2867, 1723, 1637, 1544, 1438, 1259, 1163, 1036, 974 are respectively attributed to the characteristic vibration absorption peaks of P-O-H, C-O-H, C═C-H, C-H, C═O, C═C, C-N, P═O, C-O, P-O. 1 H-NMR (using TMS as the internal standard, D 2 2O, δ): 1.78 (m, 2H), 1.87 (s, 3H), 3.21 (m, 4H), 3.52 (t, 2H), 3.98 (t, 4H), 4.51 (s, 2H), 5.39-5.63 (m, 2H), 7.06-7.61 (m, 5H). Based on the comprehensive inference and judgment of its elemental analysis, IR and 1 H-NMR analysis results, it is confirmed that the white solid product has the structural characteristics of silver N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium tetrahydrate of formula (I-1):

[0047]

[0048] Preparation of Zinc Ammonium N-(2-Methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) Chloride in Example 4

[0049] According to the method and steps of Example 3, replacing silver nitrate in Example 3 with zinc chloride, a white powdery product can be obtained. Using the same analytical characterization method as in Example 3, it is confirmed that the white powdery product has the structural characteristics of zinc ammonium N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) chloride tetrahydrate of formula (Ⅰ-2):

[0050]

[0051] Preparation of Chromium Ammonium N-(2-Methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) Chloride in Example 5

[0052] According to the method and steps of Example 3, replacing silver nitrate in Example 3 with chromium(III) chloride hexahydrate, a dark purple crystalline product can be obtained. Using the same analytical characterization method as in Example 3, it is confirmed that the dark purple crystalline product has the structural characteristics of chromium ammonium N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) chloride dodecahydrate of formula (Ⅰ-3):

[0053]

[0054] Preparation of N’,N’,N’,N’-Tetrabutylammonium-N-(2-Methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) Ammonium Bromide in Example 6

[0055] According to the method and steps of Example 3, replacing silver nitrate in Example 3 with tetrabutylammonium bromide, a white crystalline product can be obtained. Using the same analytical characterization method as in Example 3, it is confirmed that the white crystalline product has the structural characteristics of N’,N’,N’,N’-tetrabutylammonium-N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium bromide of formula (Ⅰ-4):

[0056]

[0057] Preparation of Calcium Ammonium N-(2-Methacryloyloxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) Chloride in Example 7

[0058] According to the method and steps of Example 3, replace N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium in Example 3 with N-(2-hydroxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium, and replace silver nitrate with calcium chloride, then a white powdery product can be obtained. According to the analysis and characterization method of Example 3, it is confirmed that this white powdery product has the structure of calcium N-(2-methacryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium dihydrate of formula (I-5):

[0059]

[0060] Example 8 Preparation of Zinc N-(2-acryloyloxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium chloride

[0061] According to the method and steps of Example 3, replace N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium in Example 3 with N-(2-hydroxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium, replace methacryloyl chloride with acryloyl chloride, and replace silver nitrate with zinc chloride, then a white powdery product can be obtained. By using an analysis and characterization method similar to that of Example 3, it is confirmed that this white powdery product has the structural characteristics of zinc N-(2-acryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium tetrahydrate of formula (I-2):

[0062]

[0063] Example 9 Preparation of Chromium N-(2-acryloyloxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium chloride

[0064] According to the method and steps of Example 3, replace N-(2-hydroxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium in Example 3 with N-(2-hydroxyethyl)-N-dodecyl-N,N-bis(ethyl-2-phosphonic acid) ammonium, replace methacryloyl chloride with acryloyl chloride, and replace silver nitrate with chromium(III) chloride hexahydrate, then a purple-blue crystalline product can be obtained. By using an analysis and characterization method similar to that of Example 3, it is confirmed that this purple-blue crystalline product has the structural characteristics of chromium N-(2-acryloyloxyethyl)-N-benzyl-N,N-bis(ethyl-2-phosphonic acid) ammonium dodecahydrate of formula (I-2):

[0065]

[0066] Example 10 Dissolution Characteristics of Bisphosphonic Acid Double Salts Containing Acryloyloxy and Quaternary Ammonium Cations in Examples 3 to 9

[0067] In a certain amount of deionized water, ethanol, ethyl acetate, acetonitrile, and toluene, the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts in Examples 3 to 9 were respectively added, and the temperature was controlled and oscillated for dissolution for 24 hours. The dissolution of the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts was observed, and the results are shown in Table 1.

[0068] Table 1 Solubility of the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts in Examples 3 to 7 *

[0069]

[0070] * Note: "Soluble" means that the room temperature dissolution amount of the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts in Examples 3 to 7 in 100 g of solvent is greater than 10 g; "Thermosoluble" means that at a temperature of 60 °C, the dissolution amount of the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts in Examples 3 to 7 in 100 g of solvent is greater than 10 g; "Thermally soluble" means that at a temperature of 60 °C, the dissolution amount of the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts in Examples 3 to 7 in 100 g of solvent is less than 10 g; "Thermally slightly soluble" means that at a temperature of 60 °C, the dissolution amount of the acryloyloxy- and quaternary ammonium cation-containing bisphosphonic acid double salts in Examples 3 to 7 in 100 g of solvent is less than 2 g.

Claims

1. A bisphosphonic acid double salt containing an acryloyloxy group and a quaternary ammonium cation, characterized in that It has the structure shown in the general formula (Ⅰ): Wherein R in the general formula (I) is selected from H or CH3, and R1 is selected from C1~C 18 Hydrocarbon, M n+ Select Na + , K + NH4 + 、Ag + , Ca 2+ 、Co 2+ , Cu 2+ , Fe 2+ Mg 2+ , Mn 2+ 、Zn 2+ , Sr 2+ 、Al 3+ 、Bi 3+ Cr 3+ , Fe 3+ Sn 4+ 、Ti 4+ 、Zr 4+ , N-benzyl-N,N,N-trimethylammonium cation, N-benzyl-N,N,N-triethylammonium cation, N-benzyl-N,N,N-tributylammonium cation, N,N,N,N-tetrabutylammonium cation, N-dodecyl-N,N-dimethyl-N-benzylammonium cation, N-dodecyl-N,N-diethyl-N-benzylammonium cation, N-tetradecyl-N,N-dimethyl-N-benzylammonium cation or N-tetradecyl-N,N-diethyl-N-benzylammonium cation, wherein n is selected from one of 1, 2, 3 or 4, and X - Selected from Cl - Br - or NO3 - One of them.

2. A bisphosphonic acid double salt containing an acryloyloxy group and a quaternary ammonium cation according to claim 1, characterized in that The method for preparing the bisphosphonic acid double salt containing acryloxy and quaternary ammonium cation is achieved by taking the following steps: Step 1: Preparation of N-(2-hydroxyethyl)-N-alkyl-N,N-di(ethyl-2-phosphonic acid) ammonium salt of general formula (II) Add a solvent and vinyl phosphonate into a reaction kettle, control the temperature of the materials in the reaction kettle between 5 and 25° C., slowly add ethanolamine, and after the addition of ethanolamine is completed, heat the temperature to 50 to 60° C. and stir for reaction for 8 to 12 hours, then add an alkylating agent, increase the temperature of the materials in the reaction kettle to 20 to 120° C., continue stirring for reaction for 2 to 12 hours, lower the temperature of the materials in the reaction kettle to room temperature, and filter out a solid intermediate product ①; dissolve the solid intermediate product ① in an acid aqueous solution with a molar concentration of 3 to 15M, control the temperature to 80 to 120° C. and stir for hydrolysis reaction for 12 to 24 hours, and filter out a solid intermediate product ② after cooling; dissolve the solid intermediate product ② in deionized water to prepare an aqueous solution, use a base to adjust the pH value of the aqueous solution of the solid intermediate product ② to 3.0 to 6.0, concentrate by rotary evaporation, filter, recrystallize, and dry to constant weight to obtain N-(2-hydroxyethyl)-N-alkyl-N,N-di(ethyl-2-phosphonic acid)ammonium with a structure shown in general formula (II): Wherein R1 in the general formula (II) is selected from C1~C 18 Hydrocarbon; The amount of the vinylphosphonic acid used is 1.85 to 2.15 times the molar amount of ethanolamine, the amount of the alkylating agent used is 1.0 to 2.5 times the molar amount of ethanolamine, the amount of the acid aqueous solution used is 0.5 to 5.0 times the mass of ethanolamine, and the amount of deionized water used is 1 to 10 times the mass of ethanolamine; The vinyl phosphonate refers to one of dimethyl vinyl phosphonate, diethyl vinyl phosphonate or dipropyl vinyl phosphonate. The alkylating agent has a structure shown in the general formula (III): R1-X General formula (III) Wherein R1 in the general formula (III) is selected from C1~C 18 Hydrocarbyl, X is Cl or Br; The solid intermediate product ① and the solid intermediate product ② have structures shown in general formula ① and general formula ② respectively: In the general formula ① and ②, R1 is selected from C1 to C 18 The hydrocarbon group, R2 and R3 are each selected from one of methyl, ethyl or propyl. Step 2: Preparation of a bisphosphonic acid double salt containing acryloyloxy and quaternary ammonium cation of general formula (I) The solvent, N-(2-hydroxyethyl)-N-alkyl-N,N-di(ethyl-2-phosphonic acid) ammonium and the polymerization inhibitor are weighed in sequence and put into a reactor and stirred evenly, the temperature of the material in the reactor is controlled between 5 and 25° C., acryloyl chloride or methacryloyl chloride is added to the reactor after nitrogen filling and deoxygenation, and after the acryloyl chloride or methacryloyl chloride is added, the temperature of the material in the reactor is increased to 50 to 60° C. and stirred for reaction for 2 to 6 hours, the temperature of the material in the reactor is lowered to room temperature, the pH value of the material in the reactor is adjusted to 7.0 to 9.0 with alkali, and then a saline solution with a mass percentage concentration of 5 to 50% is added, and the reaction is rapidly stirred for 0.5 to 5.0 hours to complete the double decomposition reaction, and then concentrated by rotary evaporation, filtered, washed, recrystallized, and dried to constant weight to obtain a diphosphonic acid complex salt containing acryloyloxy and quaternary ammonium cation with a structure represented by the general formula (I); The amount of the solvent is 0.5 to 5.0 times the mass of the N-(2-hydroxyethyl)-N-alkyl-N,N-di(ethyl-2-phosphonic acid)ammonium, the amount of acryloyl chloride or methacryloyl chloride is 1.0 to 1.2 times the molar amount of the N-(2-hydroxyethyl)-N-alkyl-N,N-di(ethyl-2-phosphonic acid)ammonium, the amount of the inhibitor is 0.013 to 0.03 times the mass of acryloyl chloride or methacryloyl chloride, and the amount of the salt is 0.25 to 1.5 times the molar amount of the N-(2-hydroxyethyl)-N-alkyl-N,N-di(ethyl-2-phosphonic acid)ammonium; The salt refers to sodium chloride, potassium chloride, ammonium chloride, sodium bromide, potassium bromide, ammonium bromide, sodium nitrate, potassium nitrate, ammonium nitrate, silver nitrate, calcium chloride, cobalt chloride hexahydrate, cobalt nitrate hexahydrate, cupric chloride, basic cupric chloride, ferrous chloride, magnesium hydroxide, zinc chloride, manganese nitrate, strontium dichloride, aluminum nitrate, hydrated aluminum chloride, basic bismuth nitrate, chromium chloride, ferric chloride, tin tetrachloride pentahydrate, titanium nitrate, zirconium nitrate, basic zirconium chloride octahydrate, N-benzyl-N,N,N-trimethylammonium chloride, N-benzyl-N,N,N-triethylammonium chloride, N-benzyl-N,N,N-tributylammonium chloride, N,N,N,N-tetrabutylammonium chloride, N-dodecyl-N,N-dimethyl-N-benzylammonium chloride, One or more of N-dodecyl-N,N-diethyl-N-benzylammonium chloride, N-tetradecyl-N,N-dimethyl-N-benzylammonium chloride, N-tetradecyl-N,N-diethyl-N-benzylammonium chloride, N-benzyl-N,N,N-trimethylammonium bromide, N-benzyl-N,N,N-triethylammonium bromide, N-benzyl-N,N,N-tributylammonium bromide, N,N,N,N-tetrabutylammonium bromide, N-dodecyl-N,N-dimethyl-N-benzylammonium bromide, N-dodecyl-N,N-diethyl-N-benzylammonium bromide, N-tetradecyl-N,N-dimethyl-N-benzylammonium bromide, or N-tetradecyl-N,N-diethyl-N-benzylammonium bromide.

3. A bisphosphonic acid double salt containing an acryloyloxy group and a quaternary ammonium cation according to claim 2, characterized in that The alkali refers to sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or one of ammonia water with a mass percentage concentration of 18-30%.

4. A phosphonate containing an acryloyloxy group and a quaternary ammonium cation according to claim 2, characterized in that The acid aqueous solution refers to one of a hydrogen chloride aqueous solution or a sulfuric acid aqueous solution.

5. A bisphosphonic acid double salt containing an acryloyloxy group and a quaternary ammonium cation according to claim 1, characterized in that The solvent refers to one or more of tetrahydrofuran, 1,4-dioxane, cyclohexane, decahydronaphthalene, acetonitrile, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, chlorobenzene, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

6. A bisphosphonic acid double salt containing an acryloyloxy group and a quaternary ammonium cation according to claim 1, characterized in that The polymerization inhibitor refers to one or more of hydroquinone, p-methoxyphenol, tert-butylhydroquinone, 2,6-dibutylhydroquinone, 2,6-di-tert-butyl-p-cresol or 2,4,6-tri-tert-butylphenol.

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