A copolymeric quaternary ammonium salt and a method for preparing the same

Abstract

The application discloses a kind of copolymer quaternary ammonium salt and preparation method, belong to surfactant field. Including the following steps: (1) epoxy chloropropane is reacted with tertiary amine to generate epoxy group quaternary ammonium salt;(2) epoxy group quaternary ammonium salt obtained in step (1) is purified by recrystallization with organic solvent, and epoxy group quaternary ammonium salt monomer is obtained after drying, and the epoxy group quaternary ammonium salt monomer is formed into copolymer quaternary ammonium salt by catalytic synthesis in reaction solvent.The bactericidal target of the copolymer quaternary ammonium salt of the application only acts on cell wall, membrane, so it is not easy to produce drug resistance, and there is no co-screening effect.Various bacteria have resistance, even if bacteria are passed through 15 generations, produce drug resistance, and MIC remains stable.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of surfactants, in particular to a copolymer quaternary ammonium salt and a preparation method thereof. BACKGROUND

[0002] Epoxy quaternary ammonium salt is based on the structure of conventional quaternary ammonium salt, and an epoxy group is introduced to improve its own reactivity. The corresponding cationized product can be obtained by the reaction of the epoxy group in the epoxy quaternary ammonium salt with the active groups such as hydroxyl and amino in natural polymers. Therefore, the epoxy quaternary ammonium salt is not only a cationic surfactant, but also a good functional cationic monomer modifier, and has broad application value.

[0003] Bacterial infection related diseases pose a major threat to the health of all mankind, and quaternary ammonium salts are mainly used as bactericides. However, the long-term use of quaternary ammonium salts makes bacteria resistant, so the bactericidal effect of quaternary ammonium salts is reduced. Benzalkonium chloride, for example, can screen out a variety of antibiotic resistance mechanisms, and further promote bacterial resistance to antibiotics.

[0004] The bactericidal effect of polyquaternary ammonium salt is better than that of monomer quaternary ammonium salt. For example, the publication number CN111387186A discloses a quaternary ammonium salt bactericide, a preparation method and an application thereof. The technical solution is obtained by mixing epoxy halogenated alkane and long-chain alkyl tertiary amine, wherein the main bactericidal component is long-chain alkyl tertiary amine monomer. The publication number CN105601913A discloses a preparation and application of a polyquaternary ammonium salt heterotrophic bacteria bactericide. The polyquaternary ammonium salt disclosed in the publication is obtained by the reaction of epoxy chloropropane and ethylenediamine, and the epoxy chloropropane ring-opening reaction obtains a branched or branched polyquaternary ammonium salt. However, the technical solution mainly solves the bactericidal effect, and does not solve the problem of bacterial resistance to quaternary ammonium salts.

[0005] For example, the publication number CN107156167A discloses an oligomeric quaternary ammonium salt bactericide and a preparation method thereof. The oligomeric quaternary ammonium salt bactericide is obtained by the reaction of p-toluenesulfonate-based gemini quaternary ammonium salt, guanidine hydrochloride and sodium ethoxide. The publication number CN110123832A discloses an ophthalmic composition containing a non-drug-resistant bactericide, which includes polyhexamethylene monoguanidine and a bactericidal disinfectant. The bactericidal disinfectant includes a polyquaternary ammonium salt, and the high-polymerization-degree polyhexamethylene monoguanidine is used as an antimicrobial active ingredient to solve the problem of bacterial resistance to antimicrobial ingredients. However, the problem of bacterial resistance to the bactericidal disinfectant itself is not solved.

[0006] For example, the publication number CN1476329A discloses a bactericidal disinfectant, an antibacterial agent and an antibacterial material. The quaternary ammonium salt is polymerized, but the technical solution mainly solves the bactericidal effect of the quaternary ammonium salt on green pyocyanin, and does not solve the problem of drug resistance of the bactericide.

[0007] In summary, the molecular structure of the polyquaternary ammonium salt in the prior art solution is mainly branched or branched structure, and the main technical problem to be solved is the bactericidal effect and broad spectrum of sterilization, and the problem of drug resistance of existing bacteria to polyquaternary ammonium salt is not solved, and the bactericidal effect is reduced. SUMMARY

[0008] In order to solve the above problems, the present application provides a kind of copolymer quaternary ammonium salt, by the polymerization of a plurality of different structures of quaternary ammonium salt, form specific copolymer quaternary ammonium salt structure, adapt to the bactericidal effect of a variety of bacteria, with broad-spectrum bactericidal, while effectively solve the drug resistance of bacteria to bactericide.

[0009] The present application provides a kind of copolymer quaternary ammonium salt preparation method and application.

[0010] In order to achieve the above purpose, the present application is realized by the following technical scheme:

[0011] A kind of copolymer quaternary ammonium salt, structural formula is:

[0012] Wherein, m=1-50 integer, n=1-50 integer, x=1-50 integer.

[0013] Further, R1, R2 and R3 are any one of C8-C14 alkyl, and R1, R2 and R3 include at least two different.

[0014] Further, the R is methyl or any one of C8-C14 alkyl.

[0015] A kind of copolymer quaternary ammonium salt preparation method, comprising the following steps:

[0016] (1) the reaction of epichlorohydrin and tertiary amine to generate epoxy quaternary ammonium salt;

[0017] (2) the epoxy quaternary ammonium salt obtained in step (1) is purified and dried by recrystallization with organic solvent to obtain epoxy quaternary ammonium salt monomer, and the epoxy quaternary ammonium salt monomer is synthesized in a reaction solvent to form a copolymer quaternary ammonium salt.

[0018] Further, the molar ratio of epichlorohydrin to tertiary amine in step (1) is 1-5:1, preferably 3.5-4.5:1.

[0019] Further, the tertiary amine in step (1) is alkyl tertiary amine and / or dialkyl tertiary amine.

[0020] Further, the alkyl group in the alkyl tertiary amine is any one or several of C8-C14, and the dialkyl tertiary amine is any one of C8-C14.

[0021] Further, the alkyl tertiary amine is any one of octyl dimethyl tertiary amine, decyl dimethyl tertiary amine, dodecyl dimethyl tertiary amine, and tetradecyl dimethyl tertiary amine.

[0022] Further, the dialkyl tertiary amine is any one of di-octyl dimethyl tertiary amine, di-decyl dimethyl tertiary amine, di-dodecyl dimethyl tertiary amine, and di-tetradecyl dimethyl tertiary amine.

[0023] Further, the tertiary amine in step (1) is a mixture of 2-3 kinds, and the tertiary amine at least includes dodecyl dimethyl tertiary amine, and the ratio of the dodecyl dimethyl tertiary amine to the rest of any two kinds of tertiary amine is 0.4-1:0.2-0.5:0.2-0.5.

[0024] The copolymerized quaternary ammonium salt and the preparation method have the beneficial effects that:

[0025] (1) The copolymerized quaternary ammonium salt of the present application is synthesized by using long-chain alkyl tertiary amine as raw material, quaternization reaction with epichlorohydrin to synthesize epoxy propyl alkyl ammonium chloride (intermediate), and then polymerization reaction to synthesize copolymerized quaternary ammonium salt. The structure of the copolymerized quaternary ammonium salt of the present application is comb structure, the molecular chain can be extended on the main chain, the comb-shaped branch chain is alkyl tertiary amine group, more sites can be exposed, the surface activity is stronger, the same or different groups can be connected on the alkyl tertiary amine group, and the copolymerized quaternary ammonium salt has bactericidal effect on the same or multiple bacteria, and has broad-spectrum bactericidal property.

[0026] (2) The bactericidal target point of the copolymerized quaternary ammonium salt only acts on the cell wall and membrane, and thus is not easy to produce drug resistance, and has no co-screening effect. The copolymerized quaternary ammonium salt has anti-drug resistance to multiple bacteria, and even if the bacteria are passed through 15 generations, the drug resistance is produced, and the MIC remains stable. DETAILED DESCRIPTION

[0027] In order for those skilled in the art to better understand the present application, the technical solutions will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0028] The copolymerized quaternary ammonium salt of the present application has the following structural formula:

[0029]

[0030] In the formula, m is an integer of 1-50, n is an integer of 1-50, and x is an integer of 1-50. The most preferred m, n and x are 5-35, and the arrangement order of m, n and x segments in the copolymerized quaternary ammonium salt is not limited.

[0031] Wherein, R is methyl or any one of C8-C14 alkyl.

[0032] Wherein, R1, R2 and R3 are C8-C14 alkyl respectively. Specifically, R1, R2 and R3 are any one of C8 alkyl, C10 alkyl, C12 alkyl and C14 alkyl, and at least two of R1, R2 and R3 are different.

[0033] The preparation method of the copolymer quaternary ammonium salt comprises the following steps:

[0034] (1) reacting epichlorohydrin with tertiary amine to form an epoxy quaternary ammonium salt;

[0035] (2) purifying and drying the epoxy quaternary ammonium salt obtained in step (1) by recrystallization with an organic solvent to obtain an epoxy quaternary ammonium salt monomer, and synthesizing the copolymer quaternary ammonium salt by catalysis in a reaction solvent.

[0036] In step (2) of the above preparation method, the organic solvent used in recrystallization is one or more of n-heptane, cyclohexane, tetrahydrofuran, methyl tert-butyl ether, acetone, diethyl ether, dichloromethane, toluene, isopropanol, dimethyl sulfoxide, ethanol and methanol. The most preferred is diethyl ether:dichloromethane 9:1.

[0037] In step (2) of the above preparation method, the epoxy quaternary ammonium salt monomer is vacuum dried, and the temperature of vacuum drying is 20-45℃, and the most preferred is 25℃. Exceeding 45℃ will cause the decomposition of the epoxy quaternary ammonium salt monomer.

[0038] In step (2) of the above preparation method, the reaction solvent for polymerization of the epoxy quaternary ammonium salt monomer is one or more of halogenated hydrocarbons or aromatic hydrocarbons, including dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane and toluene. The most preferred is dichloromethane.

[0039] In step (2) of the above preparation method, the catalyst is boron trifluoride etherate.

[0040] Determination of the epoxy value of the intermediate

[0041] In the preparation method, the epoxy value of the epoxy quaternary ammonium salt needs to be determined, and the specific method is as follows:

[0042] Preparation of HCl-CaCl2 solution: weigh 100g of anhydrous calcium chloride in a 400mL beaker, slowly add 163mL of deionized water to the beaker while stirring, and after the anhydrous calcium chloride is completely dissolved, slowly add 20g of concentrated hydrochloric acid (17mL), cool and filter, and store in a reagent bottle for use.

[0043] Take 1.0 g of the sample and place it in an iodometric flask containing 25 mL of the HCI-CaCl2 solution. Shake for 20 min and then stand for 24 h. After sufficient reaction, add 50 mL of deionized water. Wash the stopper and the bottle mouth and shake well. Add 3 drops of phenolphthalein indicator. Titrate with 0.5 mol / L sodium hydroxide solution until the solution is light red. Shake for 30 s without fading to be the end point. At the same time, titrate 25 mL of the HCI-CaCl2 solution as a blank experiment. Calculate the epoxy value / content (E) of the sample.

[0044]

[0045] In the formula, E is the epoxy value of the product; V1 is the volume of the sodium hydroxide solution consumed by titration of the blank solution, mL; V2 is the volume of the sodium hydroxide solution consumed by titration of the sample solution, mL; C is the concentration of the sodium hydroxide solution, mol / L; M is the relative molecular mass of the measured substance; and m is the mass of the product taken, g.

[0046] Example 1

[0047] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0048] (1) reacting epichlorohydrin with octaalkyl dimethyl tertiary amine and dodecyl dimethyl tertiary amine in a ratio of 3.5:1 to generate epoxy quaternary ammonium salt;

[0049] Specifically, epichlorohydrin is added to a flask, octaalkyl dimethyl tertiary amine is slowly added while stirring, 0.65 w% of potassium iodide catalyst for the reaction raw material is added, the temperature is raised to 30°C, and after the addition is completed, the temperature is kept at 30°C for 12 h. Then, acetone is added to reduce the temperature to 10°C for crystallization. The solid octaalkyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection.

[0050] Epichlorohydrin is added to a flask, dodecyl dimethyl tertiary amine is slowly added while stirring, 0.65 w% of potassium iodide catalyst for the reaction raw material is added, the temperature is raised to 30°C, and after the addition is completed, the temperature is kept at 30°C for 12 h. Then, acetone is added to reduce the temperature to 10°C for crystallization. The solid dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection.

[0051] (2) recrystallizing the solid octaalkyl epoxy propyl dimethyl ammonium chloride monomer and the solid dodecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (1) to obtain high-purity epoxy quaternary ammonium salt monomers; specifically:

[0052] Solid octyl epoxy propyl dimethyl ammonium chloride monomer 30g (content 83.7%) is added into 90g mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25℃, stirred and pulped for 10 hours; cooled to 15℃, centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25℃ for 12 hours; high purity octyl epoxy propyl dimethyl ammonium chloride monomer is obtained, the epoxy value (content) is 99.5%;

[0053] Solid dodecyl epoxy propyl dimethyl ammonium chloride monomer 30g (content 63.9%) is added into 90g mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25℃, stirred and pulped for 10 hours; cooled to 15℃, centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25℃ for 12 hours; high purity dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, the epoxy value (content) is 99.2%;

[0054] (3) The high purity octyl epoxy propyl dimethyl ammonium chloride and dodecyl epoxy propyl dimethyl ammonium chloride monomers obtained in step (2) are mixed in a molar ratio of 1:2, a total of 40g is added into reaction solvent dichloromethane 60g, catalyst boron trifluoride ether 0.4g is added, the reaction temperature is controlled at 20℃, the reaction is monitored by detecting the epoxy value, the reaction is qualified after 8 hours of incubation, and light yellow oily liquid is obtained by vacuum desolventizing, which is the copolymer quaternary ammonium salt of the application.

[0055] Example 2

[0056] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0057] (1) Epoxy chloropropane is reacted with dodecyl dimethyl tertiary amine and tetradecyl dimethyl tertiary amine respectively according to a molar ratio of 3.5:1 to generate epoxy quaternary ammonium salt;

[0058] Epoxy chloropropane is added to a flask, dodecyl dimethyl tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is increased to 30℃, after the dropwise addition is completed, the temperature is incubated at 30℃ for 12h, acetone is added to reduce the temperature to 10℃ for crystallization, and solid dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection;

[0059] Epoxy chloropropane is added to a flask, dodecyl dimethyl tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is increased to 30℃, after the dropwise addition is completed, the temperature is incubated at 30℃ for 12h, acetone is added to reduce the temperature to 10℃ for crystallization, and solid dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection;

[0060] (2) Recrystallize the solid dodecyl epoxy propyl dimethyl ammonium chloride monomer and the solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (1) respectively to obtain high-purity epoxy quaternary ammonium salt monomers; specifically:

[0061] The solid dodecyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 68.3%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25 °C and stirred for 10 hours; cooled to 15 °C and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25 °C for 12 hours; high-purity dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, with an epoxy value (content) of 99.1%;

[0062] The solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 63.6%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25 °C and stirred for 10 hours; cooled to 15 °C and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25 °C for 12 hours; high-purity tetradecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, with an epoxy value (content) of 98.5%;

[0063] (3) Mix the high-purity dodecyl epoxy propyl dimethyl ammonium chloride and tetradecyl epoxy propyl dimethyl ammonium chloride monomers obtained in step (2) according to a molar ratio of 2:1, a total of 40 g, add into reaction solvent dichloromethane 60 g, add catalyst boron trifluoride ether 0.4 g, control the reaction temperature at 20 °C, detect the epoxy value to monitor the reaction, and keep the reaction for 8 hours after the reaction is qualified, and obtain a light yellow oily liquid by vacuum desolventizing, which is the copolymer quaternary ammonium salt of the application.

[0064] Example 3

[0065] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0066] (1) React the epichlorohydrin with dodecyl dimethyl tertiary amine and decyl dimethyl tertiary amine respectively according to a ratio of 3.5:1 to generate an epoxy quaternary ammonium salt;

[0067] Add the epichlorohydrin into a flask, continuously stir and slowly drop the dodecyl dimethyl tertiary amine, add 0.65% w of potassium iodide catalyst of the reaction raw material, at the same time, heat to 30 °C, after the dropping is completed, keep at 30 °C for 12 h, add acetone to cool to 10 °C for crystallization, and filter to obtain the solid dodecyl epoxy propyl dimethyl ammonium chloride monomer under nitrogen protection;

[0068] Epoxy chloropropane is added into a flask, stirring is continuously carried out, and decane dimethyl tertiary amine is slowly added dropwise, 0.65% of potassium iodide catalyst of the reaction raw material is added, the temperature is increased to 30°C, after the dropwise addition is completed, the temperature is kept at 30°C for 12 hours, and acetone is added to reduce the temperature to 10°C for crystallization; the solid decane epoxy propyl dimethyl ammonium chloride monomer is obtained by filtering under the protection of nitrogen;

[0069] (2) The solid dodecyl epoxy propyl dimethyl ammonium chloride monomer and the solid decane epoxy propyl dimethyl ammonium chloride monomer obtained in step (1) are recrystallized, respectively, to obtain high-purity epoxy quaternary ammonium salt monomers; specifically:

[0070] The solid dodecyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 68.2%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, and stirring is carried out for 10 hours; cooling is carried out to 15°C, centrifugation is carried out, the filter cake is rinsed with diethyl ether, and drying is carried out in a vacuum drying box at 25°C for 12 hours; the high-purity dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, and the epoxy value (content) is 99.3%;

[0071] The solid dodecyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 68.2%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, and stirring is carried out for 10 hours; cooling is carried out to 15°C, centrifugation is carried out, the filter cake is rinsed with diethyl ether, and drying is carried out in a vacuum drying box at 25°C for 12 hours; the high-purity dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, and the epoxy value (content) is 99.3%;

[0072] (3) The high-purity dodecyl epoxy propyl dimethyl ammonium chloride and the decane epoxy propyl dimethyl ammonium chloride monomers obtained in step (2) are mixed in a molar ratio of 2:1, a total of 40 g is added into a reaction solvent dichloromethane 60 g, a catalyst boron trifluoride ether 0.4 g is added, the reaction temperature is controlled to be 20°C, the reaction is monitored by detecting the epoxy value, the reaction is kept for 8 hours, and the reaction is qualified; a light yellow oily liquid is obtained by desolventizing under reduced pressure, which is the copolymer quaternary ammonium salt of the application.

[0073] Example 4

[0074] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0075] (1) Epoxy chloropropane is reacted with decane dimethyl tertiary amine, dodecyl dimethyl tertiary amine and tetradecyl dimethyl tertiary amine respectively in a ratio of 3.5:1 to generate an epoxy quaternary ammonium salt; specifically:

[0076] Epoxy chloropropane was added to a flask, stirring constantly and slowly adding decyl dimethyl tertiary amine, adding 0.65w% of potassium iodide catalyst of the reaction raw material, while heating to 30°C, after the dropwise addition was completed, 12h was preserved at 30°C, acetone was added to cool to 10°C crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer was obtained by filtering under nitrogen protection;

[0077] Epoxy chloropropane was added to a flask, stirring constantly and slowly adding decyl dimethyl tertiary amine, adding 0.65w% of potassium iodide catalyst of the reaction raw material, while heating to 30°C, after the dropwise addition was completed, 12h was preserved at 30°C, acetone was added to cool to 10°C crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer was obtained by filtering under nitrogen protection;

[0078] Epoxy chloropropane was added to a flask, stirring constantly and slowly adding decyl dimethyl tertiary amine, adding 0.65w% of potassium iodide catalyst of the reaction raw material, while heating to 30°C, after the dropwise addition was completed, 12h was preserved at 30°C, acetone was added to cool to 10°C crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer was obtained by filtering under nitrogen protection;

[0079] (2) The decyl epoxy propyl dimethyl ammonium chloride monomer, solid dodecyl epoxy propyl dimethyl ammonium chloride monomer and solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (1) were recrystallized respectively to obtain high-purity epoxy quaternary ammonium salt monomer; specifically:

[0080] 30g of solid decyl epoxy propyl dimethyl ammonium chloride monomer (content 75.5%) was added to 90g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, stirring and beating for 10 hours; cooled to 15°C and centrifuged, the filter cake was rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity decyl epoxy propyl dimethyl ammonium chloride monomer was obtained, with an epoxy value (content) of 99.0%;

[0081] 30g of solid decyl epoxy propyl dimethyl ammonium chloride monomer (content 75.5%) was added to 90g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, stirring and beating for 10 hours; cooled to 15°C and centrifuged, the filter cake was rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity decyl epoxy propyl dimethyl ammonium chloride monomer was obtained, with an epoxy value (content) of 99.0%;

[0082] Solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer 30g (content 65.7%) is added to 90g mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25℃ and stirred for 10 hours; cooled to 15℃ and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25℃ for 12 hours; high purity tetradecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, epoxy value (content) 98.9%;

[0083] (3) The high purity decyl epoxy propyl dimethyl ammonium chloride monomer, dodecyl epoxy propyl dimethyl ammonium chloride and tetradecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (2) are mixed in a molar ratio of 0.2:1:0.3, a total of 40g is added to the reaction solvent dichloromethane 60g, the catalyst boron trifluoride ether 0.4g is added, the reaction temperature is controlled at 20℃, the reaction is monitored by detecting the epoxy value, the reaction is qualified after 8 hours of incubation, and a light yellow oily liquid is obtained by vacuum desolventizing, which is the copolymer quaternary ammonium salt of the present application.

[0084] Example 5

[0085] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0086] (1) Epoxy chloropropane is reacted with decyl dimethyl tertiary amine, dodecyl dimethyl tertiary amine and tetradecyl dimethyl tertiary amine respectively in a ratio of 3.5:1 to generate epoxy-based quaternary ammonium salt; specifically:

[0087] Epoxy chloropropane is added to a flask, decyl dimethyl tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is raised to 30℃ at the same time. After the dropwise addition is completed, it is incubated at 30℃ for 12 hours, acetone is added to cool to 10℃ for crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection;

[0088] Epoxy chloropropane is added to a flask, decyl dimethyl tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is raised to 30℃ at the same time. After the dropwise addition is completed, it is incubated at 30℃ for 12 hours, acetone is added to cool to 10℃ for crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection;

[0089] Epoxy chloropropane is added to a flask, decyl dimethyl tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is raised to 30℃ at the same time. After the dropwise addition is completed, it is incubated at 30℃ for 12 hours, acetone is added to cool to 10℃ for crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer is obtained by filtration under nitrogen protection;

[0090] (2) The decyl epoxy propyl dimethyl ammonium chloride monomer, the solid dodecyl epoxy propyl dimethyl ammonium chloride monomer and the solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (1) are recrystallized respectively to obtain high-purity epoxy quaternary ammonium salt monomers; specifically:

[0091] The solid decyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 74.7%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25 ℃, and stirred and pulped for 10 hours; cooled to 15 ℃ and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25 ℃ for 12 hours; high-purity decyl epoxy propyl dimethyl ammonium chloride monomer is obtained, the epoxy value (content) is 99.4%;

[0092] The solid dodecyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 68.6%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25 ℃, and stirred and pulped for 10 hours; cooled to 15 ℃ and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25 ℃ for 12 hours; high-purity dodecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, the epoxy value (content) is 99.2%;

[0093] The solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer 30 g (content 64.2%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25 ℃, and stirred and pulped for 10 hours; cooled to 15 ℃ and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25 ℃ for 12 hours; high-purity tetradecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, the epoxy value (content) is 99.1%;

[0094] (3) The high-purity decyl epoxy propyl dimethyl ammonium chloride monomer, dodecyl epoxy propyl dimethyl ammonium chloride and tetradecyl epoxy propyl dimethyl ammonium chloride monomers obtained in step (2) are mixed in a molar ratio of 0.5:1.0:0.2, and a total of 40 g of monomers are added into 60 g of reaction solvent dichloromethane, 0.4 g of catalyst boron trifluoride ether is added, the reaction temperature is controlled at 20 ℃, the reaction is monitored by detecting the epoxy value, and the reaction is qualified after being incubated for 8 hours. A light yellow oily liquid is obtained by vacuum desolventizing, which is the copolymer quaternary ammonium salt of the application.

[0095] Example 6

[0096] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0097] (1) Epoxy chloropropane is reacted with decyl dimethyl tertiary amine, dodecyl dimethyl tertiary amine and tetradecyl dimethyl tertiary amine respectively in a ratio of 3.5:1 to generate an epoxy quaternary ammonium salt; specifically:

[0098] Epoxy chloropropane was added to a flask, stirring constantly and slowly adding decyl dimethyl tertiary amine, adding 0.65w% of potassium iodide catalyst of the reaction raw material, while heating to 30°C, after the dropwise addition was completed, 12h was preserved at 30°C, acetone was added to cool to 10°C crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer was obtained by filtering under nitrogen protection;

[0099] Epoxy chloropropane was added to a flask, stirring constantly and slowly adding decyl dimethyl tertiary amine, adding 0.65w% of potassium iodide catalyst of the reaction raw material, while heating to 30°C, after the dropwise addition was completed, 12h was preserved at 30°C, acetone was added to cool to 10°C crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer was obtained by filtering under nitrogen protection;

[0100] Epoxy chloropropane was added to a flask, stirring constantly and slowly adding decyl dimethyl tertiary amine, adding 0.65w% of potassium iodide catalyst of the reaction raw material, while heating to 30°C, after the dropwise addition was completed, 12h was preserved at 30°C, acetone was added to cool to 10°C crystallization, and solid decyl epoxy propyl dimethyl ammonium chloride monomer was obtained by filtering under nitrogen protection;

[0101] (2) The decyl epoxy propyl dimethyl ammonium chloride monomer, solid dodecyl epoxy propyl dimethyl ammonium chloride monomer and solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (1) were recrystallized respectively to obtain high-purity epoxy quaternary ammonium salt monomer; specifically:

[0102] Solid decyl epoxy propyl dimethyl ammonium chloride monomer 30g (content 74.3%) was added to 90g mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, stirring and beating for 10 hours; cooled to 15°C and centrifuged, the filter cake was rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity decyl epoxy propyl dimethyl ammonium chloride monomer was obtained, with an epoxy value (content) of 99.3%;

[0103] Solid decyl epoxy propyl dimethyl ammonium chloride monomer 30g (content 74.3%) was added to 90g mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, stirring and beating for 10 hours; cooled to 15°C and centrifuged, the filter cake was rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity decyl epoxy propyl dimethyl ammonium chloride monomer was obtained, with an epoxy value (content) of 99.3%;

[0104] Solid tetradecyl epoxy propyl dimethyl ammonium chloride monomer 30g (content 64.5%) is added to 90g mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25℃ and stirred for 10 hours; cooled to 15℃ and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25℃ for 12 hours; high purity tetradecyl epoxy propyl dimethyl ammonium chloride monomer is obtained, epoxy value (content) 99.2%;

[0105] (3) The high purity decyl epoxy propyl dimethyl ammonium chloride monomer, dodecyl epoxy propyl dimethyl ammonium chloride and tetradecyl epoxy propyl dimethyl ammonium chloride monomer obtained in step (2) are mixed in a molar ratio of 1:2:1, a total of 40g monomer is added to 60g reaction solvent dichloromethane, 0.4g catalyst boron trifluoride ether is added, the reaction temperature is controlled at 20℃, the reaction is monitored by detecting the epoxy value, the reaction is qualified after 8 hours of incubation, and a light yellow oily liquid is obtained by vacuum desolventizing, which is the copolymer quaternary ammonium salt of the present application

[0106] Example 7

[0107] A preparation method of a copolymer quaternary ammonium salt, comprising the following steps:

[0108] (1) Epoxy chloropropane is reacted with bis-deca-tertiary amine, dodecyl dimethyl tertiary amine and bis-dodecyl tertiary amine in a ratio of 3.5:1 to generate epoxy quaternary ammonium salt; specifically:

[0109] Epoxy chloropropane is added to a flask, bis-deca-tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is raised to 30℃, after the dropwise addition is completed, the temperature is incubated at 30℃ for 12 hours, acetone is added to reduce the temperature to 10℃, and the solid bis-deca-epoxy propyl methyl ammonium chloride monomer is obtained by filtering under nitrogen protection;

[0110] Epoxy chloropropane is added to a flask, bis-deca-tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is raised to 30℃, after the dropwise addition is completed, the temperature is incubated at 30℃ for 12 hours, acetone is added to reduce the temperature to 10℃, and the solid bis-deca-epoxy propyl methyl ammonium chloride monomer is obtained by filtering under nitrogen protection;

[0111] Epoxy chloropropane is added to a flask, bis-deca-tertiary amine is continuously stirred and slowly added dropwise, 0.65w% potassium iodide catalyst of the reaction raw material is added, and the temperature is raised to 30℃, after the dropwise addition is completed, the temperature is incubated at 30℃ for 12 hours, acetone is added to reduce the temperature to 10℃, and the solid bis-deca-epoxy propyl methyl ammonium chloride monomer is obtained by filtering under nitrogen protection;

[0112] (2) Recrystallize the ditridecyl epoxide propyl methyl ammonium chloride monomer, the solid dodecyl epoxide propyl dimethyl ammonium chloride monomer and the solid ditridecyl epoxide propyl methyl ammonium chloride monomer obtained in step (1) respectively to obtain high-purity epoxy quaternary ammonium salt monomers; specifically:

[0113] The solid ditridecyl epoxide propyl methyl ammonium chloride monomer 30 g (content 86.6%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, and stirred and pulped for 10 hours; cooled to 15°C and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity dodecyl epoxide propyl dimethyl ammonium chloride monomer is obtained, with an epoxy value (content) of 99.2%;

[0114] The solid dodecyl epoxide propyl dimethyl ammonium chloride monomer 30 g (content 68.3%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, and stirred and pulped for 10 hours; cooled to 15°C and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity dodecyl epoxide propyl dimethyl ammonium chloride monomer is obtained, with an epoxy value (content) of 99.1%;

[0115] The solid ditridecyl epoxide propyl methyl ammonium chloride monomer 30 g (content 72.4%) is added into 90 g of mixed solvent (diethyl ether: dichloromethane 9:1) at room temperature 25°C, and stirred and pulped for 10 hours; cooled to 15°C and centrifuged, the filter cake is rinsed with diethyl ether and dried in a vacuum drying oven at 25°C for 12 hours; high-purity dodecyl epoxide propyl dimethyl ammonium chloride monomer is obtained, with an epoxy value (content) of 99.0%;

[0116] (3) The high-purity ditridecyl epoxide propyl methyl ammonium chloride monomer, dodecyl epoxide propyl dimethyl ammonium chloride and ditridecyl epoxide propyl methyl ammonium chloride monomer obtained in step (2) are mixed in a molar ratio of 1:5:1, and a total of 40 g of monomer is added to 60 g of reaction solvent dichloromethane, 0.4 g of catalyst boron trifluoride ether is added, the reaction temperature is controlled at 20°C, the reaction is monitored by detecting the epoxy value, and the reaction is qualified after 8 hours of incubation, and a light yellow oily liquid is obtained by vacuum desolventizing, which is the copolymer quaternary ammonium salt of the present application.

[0117] Bactericidal effect test

[0118] Control group 1: the bactericide is benzalkonium chloride, with a concentration of 0.005 mol / mL.

[0119] Control group 2: the bactericide is decylmethyl bromide, with a concentration of 0.005 mol / mL.

[0120] The copolymer quaternary ammonium salt obtained by Examples 1-7 is subjected to bactericidal test on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans, with a concentration of 0.005 mol / mL

[0121] The results are shown in Table 1:

[0122] Table 1: Results of 2-hour bactericidal test

[0123]

[0124]

[0125] As can be seen from Table 1, the bactericidal effect of the present application can reach 99.9%, the bactericidal effect is good, and the bactericidal effect on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans can all reach more than 99%, having a broad-spectrum bactericidal effect.

[0126] Antibiotic resistance detection

[0127] Examples 4-7 are taken as examples.

[0128] Control group 1: the bactericide is benzalkonium chloride.

[0129] Control group 2: the bactericide is decylmethyl bromide.

[0130] Control group 3: the bactericide is dodecyl glycidyl dimethyl ammonium chloride.

[0131] Control group 4: the bactericide is oligomeric quaternary ammonium salt I, and the specific preparation method of the oligomeric quaternary ammonium salt is: after the reaction of polyamine and epoxy chloroalkane, polymerization with alkyl tertiary amine is carried out to obtain.

[0132] Control group 5: the bactericide is oligomeric quaternary ammonium salt II, and the specific preparation method of the oligomeric quaternary ammonium salt is: epoxy chloroalkane is polymerized with ethylenediamine to obtain oligomeric quaternary ammonium salt.

[0133] Control group 6: the bactericide is oligomeric quaternary ammonium salt III, and the specific preparation method of the oligomeric quaternary ammonium salt is: after the reaction of hexadecyl dimethyl tertiary amine and epoxy chloropropane, polymerization is carried out to obtain the oligomeric quaternary ammonium salt.

[0134] The specific test method is: standard MIC test is carried out using Escherichia coli ATCC 8099 (0th generation) and Staphylococcus aureus ATCC 6538 (0th generation) to evaluate the MIC before antibacterial treatment. Then, the bacteria are treated with sub-MIC concentration of bactericides of examples 1-4 and control groups 1-6 respectively, and the surviving bacteria are named as 1st generation cells. Then, the 1st generation cells are subjected to MIC test for further culture, and the bacteria with a survival rate of 50% after MIC (1st generation) treatment are called 2nd generation cells. These operations are continuously repeated for 15 times to evaluate the influence of each bactericide on the drug resistance of Escherichia coli ATCC 8099 and Staphylococcus aureus ATCC 6538.

[0135] Bacterial resistance mechanism: quaternary ammonium ion is positively charged in water, positively charged cations adsorb the negatively charged microbial surface, form micelles, and aggregate on the cell wall, resulting in a room block effect, leading to microbial growth inhibition and death; at the same time, its hydrophobic group interacts with the hydrophilic group of microorganisms, changes the permeability of the membrane, and then causes the microbial cell membrane to rupture, destroys the cell structure, the cationic group can also coagulate protein, denature enzymes and structural proteins, inhibit microbial metabolism, and cause cell lysis and death. The bactericidal action mode of single-chain quaternary ammonium salt is to destroy the wall and membrane structure of the cell, inhibit the activity of enzymes or proteins, and affect the metabolic process of the cell. Double-chain quaternary ammonium salt can also interfere with the synthesis of nucleic acids and proteins.

[0136] It is the single-chain quaternary ammonium salt that is easy to cause bacterial resistance by inhibiting the activity of enzymes or proteins, and the double-chain quaternary ammonium salt that is easy to cause bacterial resistance by interfering with the synthesis of nucleic acids and proteins. Taking levofloxacin as an example, its bactericidal mechanism is mainly to inhibit the activity of bacterial DNA gyrase and hinder the replication of bacterial DNA. In the resistance test, only a few generations produced serious drug resistance. Single-chain quaternary ammonium salt and double-chain quaternary ammonium salt have the additional functions of destroying the cell wall and membrane structure, so the generation of drug resistance is slower than that of antibiotics. Because of the activity of inhibiting enzymes or proteins and interfering with the synthesis of nucleic acids and proteins, various antibiotic resistance mechanisms are screened out, and bacteria are promoted to be resistant to antibiotics.

[0137] If the strain produces drug resistance, the MIC will increase significantly, otherwise it will remain stable.

[0138] The results obtained by performing experiments on each control group and experimental group are shown in Tables 2-5:

[0139] Table 2 Influence of each bactericide on the drug resistance of Escherichia coli

[0140]

[0141]

[0142] Table 3 Influence of each bactericide on the drug resistance of Staphylococcus aureus

[0143]

[0144] As can be seen from Tables 2-3, the MIC of the copolymer quaternary ammonium salt obtained by 15 generations of screening in Example 1, Example 2, Example 3 and Example 4 of the present application remains stable and no drug resistance is generated. The MIC of the control group benzalkonium chloride jumps at the 4th and 11th generations, indicating that drug-resistant strains have been generated.

[0145] Reference herein to "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment can be included in at least one embodiment of the application. The appearances of the phrase in various places in the specification are not necessarily all referring to the same embodiment, nor are they necessarily mutually exclusive of one another. As will be apparent to those of ordinary skill in the art, embodiments described herein can be combined with other embodiments.

[0146] Finally, it should be noted that the embodiments disclosed in the present application are only the best ones preferred by the inventor of the present application, and are used to illustrate the technical solutions of the present application, but not to limit the present application; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand; it can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A process for the preparation of a copolymeric quaternary ammonium salt, characterized by: The structural formula of the copolymerized quaternary ammonium salt is: wherein m is an integer of 5-35, n is an integer of 5-35, and x is an integer of 5-35; R1, R2 and R3 are any one of C8-C14 alkyl, and at least two of R1, R2 and R3 are different; and R is methyl or any one of C8-C14 alkyl; The preparation method of the copolymerized quaternary ammonium salt comprises the following steps: (1) reacting epichlorohydrin with tertiary amine to generate an epoxy-based quaternary ammonium salt; (2) purifying and drying the epoxy-based quaternary ammonium salt obtained in step (1) by recrystallization with an organic solvent to obtain an epoxy-based quaternary ammonium salt monomer, and synthesizing the epoxy-based quaternary ammonium salt monomer in a reaction solvent to form a copolymerized quaternary ammonium salt; In step (1), the tertiary amine comprises at least dodecyl dimethyl tertiary amine, and the ratio of the dodecyl dimethyl tertiary amine to the other two tertiary amines is 0.4-1:0.2-0.5:0.2-0.5; the other two tertiary amines are each different from each other and are selected from one of alkyl tertiary amine or dialkyl tertiary amine, and the other two tertiary amines are different from the dodecyl dimethyl tertiary amine.

2. The process for preparing the copolymeric quaternary ammonium salt according to claim 1, characterized in that: In step (1), the molar ratio of epichlorohydrin to tertiary amine is 1-5:

1.

3. The method for preparing the copolymerized quaternary ammonium salt according to claim 1, characterized in that: The alkyl in the alkyl tertiary amine is any one or several of C8-C14, and the alkyl in the dialkyl tertiary amine is any one of C8-C14.

4. The process for preparing the copolymeric quaternary ammonium salt according to claim 3, characterized in that: The alkyl tertiary amine is any one of octyl dimethyl tertiary amine, decyl dimethyl tertiary amine or tetradecyl dimethyl tertiary amine.

5. The method for preparing the copolymerized quaternary ammonium salt according to claim 3, characterized in that: The dialkyl tertiary amine is any one of di-octyl dimethyl tertiary amine, di-decyl dimethyl tertiary amine, di-dodecyl dimethyl tertiary amine or di-tetradecyl dimethyl tertiary amine.

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