Synthesis method and application of hexamidine dihydroxyethyl sulfonate

Abstract

The invention belongs to the technical field of synthesis, and particularly relates to a synthetic method and application of hexamidine dihydroxyethyl sulfonate, and the synthetic method comprises the following steps: carrying out reaction on p-cyanophenol and 1, 6-dibromohexane to synthesize 1, 6-(p-cyanophenyl) hexanediether, then sequentially introducing hydrogen chloride into a solvent for reaction and ammonia water-ethanol mixed liquid for reaction to obtain an intermediate product, and finally, carrying out purification to obtain hexamidine dihydroxyethyl sulfonate. And carrying out acid-base regulation treatment on the intermediate product, and carrying out gradient activated carbon suction filtration and cooling crystallization to obtain the hexamidine dihydroxyethyl sulfonate. The problem that the purity of existing hexamidine diisethionate is difficult to improve is solved, the adsorption capacity of impurities in the activated carbon is increased in a gradient activated carbon mode, and the stability of the impurities adsorbed by the activated carbon in the suction filtration process is guaranteed.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis, and in particular relates to a synthesis method of hexamidine dihydroxyethyl sulfonate and application thereof. Background Art

[0002] Hexamidine salt, also known as dihydrochloride and dihydroxyethyl sulfonate, is a cationic substance with broad-spectrum antibacterial and bactericidal properties. It has good bactericidal and antibacterial activity against various Gram-positive bacteria and many fungi. Therefore, hexamidine salt has important and extensive applications in many industries, especially the cosmetics industry.

[0003] The synthesis method of hexamidine generally involves the reaction of p-cyanophenol and 1,6-dibromohexane to synthesize 1,6-(p-cyanophenyl)hexanediether, followed by alcoholysis and aminolysis to obtain hexamidine, i.e., 4-(6-(4-carboxamidinophenoxy)hexyloxy)benzamidine). However, the hexamidine salt obtained by the existing synthesis process can reach 98%, and the highest can barely reach 99.0%, and further improvement is relatively difficult. Summary of the invention

[0004] In view of the problems in the prior art, the present invention provides a method for synthesizing hexamidine dihydroxyethyl sulfonate, which solves the problem that the purity of the existing hexamidine dihydroxyethyl sulfonate is difficult to improve, and uses gradient activated carbon to increase the adsorption capacity of impurities in activated carbon, thereby ensuring the stability of impurities adsorbed by activated carbon during the filtration process.

[0005] In order to achieve the above technical objectives, the technical solution of the present invention is:

[0006] A method for synthesizing hexamidine diisethionate comprises the following steps:

[0007] Step 1, in a reaction kettle, using isopropanol as a solvent, adding 1,6-dibromohexane, p-cyanophenol and sodium methoxide in sequence, heating to reflux and then stirring for 24 hours, then cooling to room temperature and filtering to obtain a solid crude product, finally, the solid crude product is pulped, filtered and dried to obtain 1,6-(p-cyanophenyl)hexanediether, the mass ratio of 1,6-dibromohexane to p-cyanophenol is 1:1-1.1, the concentration of 1,6-dibromohexane in isopropanol is 200-300g / L, the amount of sodium methoxide added is 47-49% of the mass of 1,6-dibromohexane, the heating reflux temperature is 85-90°C, the time is 3-6h, the temperature of the insulation stirring is 30-50°C, the stirring speed is 500-1000r / min, the pulping uses distilled water, and the mass ratio of distilled water to the solid crude product is 3-4:1, and the drying temperature is 70-80°C;

[0008] Step 2, adding 1,6-(p-cyanophenyl) hexanediether to a dichloroethane-ethanol mixture, introducing hydrogen chloride gas under a low temperature environment, stirring at a constant temperature for 16-18 hours after the introduction is completed, then cooling and adding to an ammonia-ethanol mixture and stirring evenly, finally heating and stirring for 2-3 hours, filtering, beating and crystallizing after cooling to obtain an intermediate product, wherein the volume ratio of dichloroethane to ethanol in the dichloroethane-ethanol mixture is 4:1-1.2, the mass ratio of 1,6-(p-cyanophenyl) hexanediether to ethanol is 1:1.8-2, the low temperature environment is not higher than 30°C, and the amount of hydrogen chloride gas added is 1,6-(p-cyanophenyl) hexanediether mass 1:1.8-2. 90-92%, the temperature of constant temperature stirring is 25-35°C, and the temperature of cooling is not higher than 20°C; the mass ratio of ethanol to ammonia water in the ammonia-ethanol mixture is 4:3, and the ammonia content of ammonia water is 25-28%, the temperature of heating and stirring is 50-55°C, and the temperature of suction filtration after cooling is 20-25°C; distilled water is used for pulping, and the mass of distilled water is twice the mass of solids, and the crystallization is that the solid filtered after pulping is mixed with ethanol in a mass ratio of 1:3, heated to dissolve, and then cooled to crystallize, and the intermediate product is obtained by centrifugation after heat preservation and stirring for 1h, and the heating temperature is 60-70°C, and the temperature of cooling and crystallization is 15-25°C;

[0009] Step 3, adding the intermediate product to water to form a mixed solution, and adding sodium hydroxide dropwise to adjust the pH, collecting the solid precipitate after centrifugation, then putting the solid precipitate into ethanol, and adjusting the pH with isethionic acid, adding activated carbon after heating to dissolve, and filtering while hot to obtain a filtrate; finally, cooling the filtrate and stirring for 1 hour, centrifuging and drying at a constant temperature to obtain hexamidine dihydroxyethyl sulfonate, wherein the mass ratio of the intermediate product to water is 1:3, the mass fraction of the sodium hydroxide is 10-20%, the adjusted pH is 7, the mass ratio of the solid precipitate to ethanol is 1:4, the pH after adjustment with isethionic acid is 5-6, the heating temperature for dissolving is 60-80°C, the concentration of the activated carbon is 5-8g / L, the cooling temperature is 0-10°C, and the constant temperature drying temperature is 50-60°C; the hexamidine dihydroxyethyl sulfonate is used in beauty cosmetics.

[0010] The activated carbon adopts gradient activated carbon, which has good adsorption properties and completely adsorbs the impurities of the solid precipitated clear liquid, thereby achieving the removal effect, and the activated carbon forms solid-liquid separation by hot filtration. However, during the filtration process, the impurities are difficult to remove based on the pore structure and filtration pressure of the activated carbon particles, that is, the purity of hexamidine dihydroxyethyl sulfonate is difficult to improve. To solve this problem, the activated carbon adopts gradient activated carbon, and the gradient activated carbon uses the pore structure from large to small in sequence, and improves the adsorption force in the pores by reducing the pore structure, thereby ensuring that the impurities still maintain good adsorption stability during the filtration process, thereby achieving the purity improvement of hexamidine dihydroxyethyl sulfonate. The preparation method of the gradient activated carbon comprises the following steps: a1, putting the activated carbon into ethanol and stirring evenly, spraying hydrochloric acid on the surface after filtering and standing for 1-2 hours, filtering and drying to obtain acidified activated carbon, wherein the mass ratio of the activated carbon to the ethanol is 1:8-10, the stirring speed is 100-300r / min, the pH of the hydrochloric acid is 5-6, and the spraying amount is 4-6% of the mass of the activated carbon, the spraying speed is 10-20mL / min, the standing temperature is 10-20°C, and the drying temperature is 100-120°C. This step utilizes During the stirring process, ethanol wets the activated carbon, and the rapid permeability of ethanol and water is utilized to ensure that hydrogen chloride directly acts on the surface of the activated carbon to achieve a good acidification effect; a2, aluminum isopropoxide and polyvinyl pyrrolidine are added to ethanol and stirred evenly, and then the acidified activated carbon is added and ultrasonically dispersed for 20-30 minutes to obtain a homogeneous suspension; the mass ratio of the aluminum isopropoxide to polyvinyl pyrrolidine is 1-2:1, and the mass ratio of the aluminum isopropoxide to ethanol is 1:3-5, the stirring speed of the stirring evenly is 300-500r / min, and the acidified activated carbon is stirred at a speed of 1:2. The mass of the aluminum isopropoxide is 3-5 times the mass of the aluminum isopropoxide, the ultrasonic frequency of the ultrasonic dispersion is 80-90kHz, and the temperature is 20-30°C; this step utilizes the solubility of aluminum isopropoxide and polyvinyl pyrrolidone in ethanol to ensure that aluminum isopropoxide and polyvinyl pyrrolidone form a homogeneous dispersion and exhibit good flow state; when the acidified activated carbon is added and ultrasonically dispersed, the mixed liquid with good flow state penetrates into the acidified activated carbon to achieve suspension and homogeneity of the acidified activated carbon; a3, after the homogeneous suspension is distilled, it is placed in a mold and pressed at a constant temperature for 2-4 hours to obtain activated carbon pressing The distillation temperature is 70-80°C, the constant temperature pressing temperature is 100-110°C, and the pressing pressure is 0.5-0.7MPa. In this step, ethanol is removed by vacuum distillation to form a ternary mixture of acidified activated carbon, aluminum isopropoxide and polyvinyl pyrrolidone to form a pressed block; a4, the activated carbon pressed block is constant temperature pressed for 20-30min, after cooling, the activated carbon pressed block is wrapped and heated and left to stand for 2-4h, and the prefabricated activated carbon mixed block is cooled to obtain the constant temperature pressing temperature of 130-135°C and the pressure of 0.5-0.7MPa, the temperature of the heating and standing is 140-145°C; in this step, aluminum isopropoxide and polyvinyl pyrrolidine are completely liquefied by constant temperature pressing to form a liquid phase mixed system, and the stable framework structure of the acidified activated carbon is ensured. The activated carbon pressed block after constant temperature pressing is sealed and wrapped, and then heated and stood, polyvinyl pyrrolidine is converted into a liquid state, and aluminum isopropoxide is converted into a gaseous state, forming an upper and lower separation of gaseous and liquid states inside. At the same time, considering the fluidity and viscosity of polyvinyl pyrrolidone itself, the gaseous aluminum isopropoxide will form a phenomenon of gathering more and more upwards, and as the temperature drops, the aluminum isopropoxide is converted into a liquid state or even a solid state, thereby realizing the gradual separation of polyvinyl pyrrolidine and aluminum isopropoxide of the prefabricated activated carbon mixed block. Layering, that is, the prefabricated activated carbon mixed block uses activated carbon as the framework, and the concentration of polyvinyl pyrrolidone is gradually reduced from bottom to top; a5, the prefabricated mixed block is allowed to stand for 20-30 minutes, dried and then sintered to obtain gradient activated carbon; the standing atmosphere is a mixed atmosphere of nitrogen and water vapor, and the volume ratio of nitrogen to water vapor is 10-12:1, the drying temperature is 80-100°C, and the sintering temperature is 220-250°C; this step utilizes the standing method to absorb distilled water into polyvinyl pyrrolidone, and forms a hydrolysis reaction with aluminum isopropoxide. During drying and sintering, aluminum isopropoxide is converted into aluminum hydroxide, and finally activated alumina is formed, and polyvinyl pyrrolidone is directly removed to form a porous structure. The gradient activated carbon prepared by the previous process uses activated carbon as the framework and activated alumina as the dopant to form a gradually dense pore structure from bottom to top; the acidified activated carbon and aluminum isopropoxide form activated alumina to form a stable connection, thereby ensuring the immobilization of alumina; at the same time, activated alumina and activated carbon form a double adsorption, thereby achieving the impurity adsorption effect. .

[0011] It can be seen from the above description that the present invention has the following advantages:

[0012] 1. The present invention solves the problem that the purity of the existing hexamidine dihydroxyethyl sulfonate is difficult to improve, and uses a gradient activated carbon method to increase the adsorption capacity of impurities in the activated carbon, thereby ensuring the stability of the impurities adsorbed by the activated carbon during the filtration process.

[0013] 2. The present invention utilizes the gas-liquid separation of aluminum isopropoxide and polyvinyl pyrrolidone to form natural rise and fall, thereby achieving the natural distribution of aluminum isopropoxide and polyvinyl pyrrolidone in the activated carbon, thereby forming a gradient activated carbon with activated alumina.

[0014] 3. The present invention utilizes gradient activated carbon adsorption filtration to effectively reduce impurities in the filtrate, and simultaneously utilizes cooling and crystallization to form secondary impurity removal, thereby achieving a high concentration of hexamidine dihydroxyethyl sulfonate. DETAILED DESCRIPTION

[0015] The present invention is described in detail with reference to the embodiments, but no limitation is imposed on the claims of the present invention.

[0016] Example 1

[0017] A method for synthesizing hexamidine diisethionate comprises the following steps:

[0018] Pretreatment: The activated carbon adopts a gradient activated carbon preparation method, which includes the following steps: a1, putting the activated carbon into ethanol and stirring evenly, spraying hydrochloric acid on the surface after filtering and standing for 1h, filtering and drying to obtain acidified activated carbon, the mass ratio of the activated carbon to ethanol is 1:8, the stirring speed is 100r / min, the pH of the hydrochloric acid is 5, and the spraying amount is 4% of the mass of the activated carbon, the spraying speed is 10mL / min, the standing temperature is 10°C, and the drying temperature is 100°C; a2, adding aluminum isopropoxide and polyvinyl pyrrolidine to ethanol and stirring evenly, and then adding the acidified activated carbon and ultrasonically dispersing for 20min to obtain a homogeneous suspension; the mass ratio of aluminum isopropoxide to polyvinyl pyrrolidine is 1:1, and the mass ratio of aluminum isopropoxide to ethanol is 1:3-5, the stirring speed for stirring evenly is 300r / min, the mass of the acidified activated carbon is 3 times the mass of aluminum isopropoxide, and the ultrasonic frequency of ultrasonic dispersion is 80 kHz, the temperature is 20℃; a3, the homogeneous suspension is distilled and then placed in a mold for constant temperature pressing for 2h to obtain an activated carbon pressed block, the distillation temperature is 70℃, the constant temperature pressing temperature is 100℃, and the pressing pressure is 0.5MPa; a4, the activated carbon pressed block is constant temperature pressed for 20min, and after cooling, the activated carbon pressed block is wrapped and heated and left to stand for 2h, and the prefabricated activated carbon mixed block is cooled to obtain the constant temperature pressing temperature of 130℃, the pressure is 0.5MPa, and the temperature of the heated standing is 140℃; a5, the prefabricated mixed block is left to stand for 20min, dried and then sintered to obtain a gradient activated carbon; the standing atmosphere is a mixed atmosphere of nitrogen and water vapor, and the volume ratio of nitrogen to water vapor is 10:1, the drying temperature is 80℃, and the sintering temperature is 220℃; the gradient activated carbon uses activated carbon as a framework and activated alumina as a dopant to form a gradually dense pore structure from bottom to top;

[0019] Step 1, in a reactor, using isopropanol as a solvent, adding 1,6-dibromohexane, p-cyanophenol and sodium methoxide in sequence, heating to reflux and then stirring for 24 hours, then cooling to room temperature and filtering to obtain a solid crude product, finally, the solid crude product is pulped, filtered and dried to obtain 1,6-(p-cyanophenyl) hexanediether, the mass ratio of 1,6-dibromohexane to p-cyanophenol is 1:1, the concentration of 1,6-dibromohexane in isopropanol is 200g / L, the amount of sodium methoxide added is 47% of the mass of 1,6-dibromohexane, the heating reflux temperature is 85°C, the time is 3h, the temperature of the insulation stirring is 30°C, the stirring speed is 500r / min, the pulping uses distilled water, and the mass ratio of distilled water to the solid crude product is 3:1, and the drying temperature is 70°C;

[0020] Step 2, adding 1,6-(p-cyanophenyl) hexanediether to a dichloroethane-ethanol mixture, introducing hydrogen chloride gas under a low temperature environment, stirring at a constant temperature for 16 hours after the introduction is completed, then cooling and adding to an ammonia-ethanol mixture and stirring evenly, finally heating and stirring for 2 hours, filtering, beating and crystallizing after cooling to obtain an intermediate product, wherein the volume ratio of dichloroethane to ethanol in the dichloroethane-ethanol mixture is 4:1, the mass ratio of 1,6-(p-cyanophenyl) hexanediether to ethanol is 1:1.8, the low temperature environment is 10°C, and the amount of hydrogen chloride gas added is 1,6-(p-cyanophenyl) 90% of the mass of hexanediol, the temperature of constant temperature stirring is 25°C, and the temperature of cooling is 10°C; the mass ratio of ethanol to ammonia water in the ammonia water and ethanol mixture is 4:3, and the ammonia content of ammonia water is 25%, the temperature of heating and stirring is 50°C, and the temperature of suction filtration after cooling is 20°C; the pulping uses distilled water, and the mass of distilled water is twice the mass of the solid, the crystallization is that the solid filtered after pulping is mixed with ethanol in a mass ratio of 1:3, heated to dissolve and then cooled to crystallize, and the intermediate product is obtained by centrifugation after heat preservation and stirring for 1h, the heating temperature is 60°C, and the temperature of cooling and crystallization is 15°C;

[0021] Step 3, adding the intermediate product to water to form a mixed solution, and adding sodium hydroxide to adjust the pH, collecting after centrifugation to obtain a solid precipitate, then putting the solid precipitate into ethanol, and adjusting the pH with isethionic acid, adding gradient activated carbon after heating and dissolving, and filtering while hot to obtain a filtrate; finally, cooling the filtrate and stirring for 1h, centrifuging and drying at a constant temperature to obtain hexamidine dihydroxyethyl sulfonate, the mass ratio of the intermediate product to water is 1:3, the mass fraction of the sodium hydroxide is 10%, the adjusted pH is 7, the mass ratio of the solid precipitate to ethanol is 1:4, the pH adjusted by isethionic acid is 5, the heating and dissolving temperature is 60°C, the concentration of the gradient activated carbon is 5g / L, the cooling temperature is 0°C, and the constant temperature drying temperature is 50°C. The purity of hexamidine dihydroxyethyl sulfonate prepared by this method is 99.21%.

[0022] Example 2

[0023] A method for synthesizing hexamidine diisethionate comprises the following steps:

[0024] Pretreatment: The activated carbon adopts a gradient activated carbon preparation method, including the following steps: a1, putting the activated carbon into ethanol and stirring evenly, spraying hydrochloric acid on the surface after filtering and standing for 2h, filtering and drying to obtain acidified activated carbon, the mass ratio of the activated carbon to ethanol is 1:10, the stirring speed is 300r / min, the pH of the hydrochloric acid is 6, and the spray amount is 6% of the mass of the activated carbon, the spray speed is 20mL / min, the standing temperature is 20°C, and the drying temperature is 120°C; a2, adding aluminum isopropoxide and polyvinyl pyrrolidine to ethanol and stirring evenly, then adding the acidified activated carbon and ultrasonically dispersing for 30min to obtain a homogeneous suspension; the mass ratio of aluminum isopropoxide to polyvinyl pyrrolidine is 2:1, and the mass ratio of aluminum isopropoxide to ethanol is 1:5, the stirring speed of the uniform stirring is 500r / min, the mass of the acidified activated carbon is 5 times the mass of aluminum isopropoxide, and the ultrasonic frequency of the ultrasonic dispersion is 90k Hz, the temperature is 30℃; a3, the homogeneous suspension is distilled and then placed in a mold for constant temperature pressing for 4h to obtain an activated carbon pressed block, the distillation temperature is 80℃, the constant temperature pressing temperature is 110℃, and the pressing pressure is 0.7MPa; a4, the activated carbon pressed block is constant temperature pressed for 30min, and after cooling, the activated carbon pressed block is wrapped and heated and allowed to stand for 4h, and the prefabricated activated carbon mixed block is obtained by cooling, the constant temperature pressing temperature is 135℃, the pressure is 0.7MPa, and the temperature of the heated standing is 145℃; a5, the prefabricated mixed block is allowed to stand for 30min, dried and then sintered to obtain a gradient activated carbon; the standing atmosphere is a mixed atmosphere of nitrogen and water vapor, and the volume ratio of nitrogen to water vapor is 12:1, the drying temperature is 100℃, and the sintering temperature is 250℃; the gradient activated carbon uses activated carbon as a framework and activated alumina as a dopant to form a gradually dense pore structure from bottom to top;

[0025] Step 1, in a reactor, using isopropanol as a solvent, adding 1,6-dibromohexane, p-cyanophenol and sodium methoxide in sequence, heating to reflux and then stirring for 24 hours, then cooling to room temperature and filtering to obtain a solid crude product, finally, the solid crude product is pulped, filtered and dried to obtain 1,6-(p-cyanophenyl) hexanediether, the mass ratio of 1,6-dibromohexane to p-cyanophenol is 1:1.1, the concentration of 1,6-dibromohexane in isopropanol is 300g / L, the amount of sodium methoxide added is 49% of the mass of 1,6-dibromohexane, the heating reflux temperature is 90°C, the time is 6h, the temperature of the insulation stirring is 50°C, the stirring speed is 1000r / min, the pulping uses distilled water, and the mass ratio of distilled water to the solid crude product is 4:1, and the drying temperature is 80°C;

[0026] Step 2, adding 1,6-(p-cyanophenyl) hexanediether to a dichloroethane-ethanol mixture, introducing hydrogen chloride gas under a low temperature environment, stirring at a constant temperature for 18 hours after the introduction is completed, then cooling and adding to an ammonia-ethanol mixture and stirring evenly, finally heating and stirring for 3 hours, filtering after cooling, beating and crystallizing to obtain an intermediate product, wherein the volume ratio of dichloroethane and ethanol in the dichloroethane-ethanol mixture is 4:1.2, the mass ratio of 1,6-(p-cyanophenyl) hexanediether to ethanol is 1:2, the low temperature environment is 5°C, and the amount of hydrogen chloride gas added is 1,6-(p-cyanophenyl) hexanediether. The mass ratio of ethanol to ammonia water in the ammonia-ethanol mixture is 4:3, and the ammonia content of the ammonia water is 28%. The temperature of the heating and stirring is 55°C, and the temperature of the suction filtration after cooling is 25°C. The pulping uses distilled water, and the mass of the distilled water is twice the mass of the solid. The crystallization is a mixture of the solid filtered after pulping and ethanol in a mass ratio of 1:3, heating to dissolve, cooling to crystallize, and centrifuging to obtain an intermediate after heat preservation and stirring for 1 hour. The heating temperature is 70°C, and the temperature of the cooling and crystallization is 25°C.

[0027] Step 3, adding the intermediate product to water to form a mixed solution, and adding sodium hydroxide to adjust the pH, collecting after centrifugation to obtain a solid precipitate, then putting the solid precipitate into ethanol, and adjusting the pH with isethionic acid, adding gradient activated carbon after heating and dissolving, and filtering while hot to obtain a filtrate; finally, cooling the filtrate and stirring for 1h, centrifuging and drying at a constant temperature to obtain hexamidine dihydroxyethyl sulfonate, the mass ratio of the intermediate product to water is 1:3, the mass fraction of the sodium hydroxide is 20%, the adjusted pH is 7, the mass ratio of the solid precipitate to ethanol is 1:4, the pH adjusted by isethionic acid is 6, the heating and dissolving temperature is 80°C, the concentration of the gradient activated carbon is 5-8g / L, the cooling temperature is 10°C, and the constant temperature drying temperature is 60°C. The purity of hexamidine dihydroxyethyl sulfonate prepared by this method is 99.26%.

[0028] Example 3

[0029] A method for synthesizing hexamidine diisethionate comprises the following steps:

[0030] Pretreatment: The activated carbon adopts a gradient activated carbon preparation method, including the following steps: a1, putting the activated carbon into ethanol and stirring evenly, spraying hydrochloric acid on the surface after filtering and standing for 2h, filtering and drying to obtain acidified activated carbon, the mass ratio of the activated carbon to ethanol is 1:9, the stirring speed is 200r / min, the pH of the hydrochloric acid is 5, and the spray amount is 5% of the mass of the activated carbon, the spray speed is 15mL / min, the standing temperature is 15°C, and the drying temperature is 110°C; a2, adding aluminum isopropoxide and polyvinyl pyrrolidine to ethanol and stirring evenly, then adding the acidified activated carbon and ultrasonically dispersing for 25min to obtain a homogeneous suspension; the mass ratio of aluminum isopropoxide to polyvinyl pyrrolidine is 1:1, and the mass ratio of aluminum isopropoxide to ethanol is 1:4, the stirring speed of the uniform stirring is 400r / min, the mass of the acidified activated carbon is 4 times the mass of aluminum isopropoxide, and the ultrasonic frequency of the ultrasonic dispersion is 85k Hz, the temperature is 25℃; a3, the homogeneous suspension is distilled and placed in a mold for constant temperature pressing for 3h to obtain an activated carbon pressed block, the distillation temperature is 75℃, the constant temperature pressing temperature is 105℃, and the pressing pressure is 0.6MPa; a4, the activated carbon pressed block is constant temperature pressed for 25min, and after cooling, the activated carbon pressed block is wrapped and heated and allowed to stand for 3h, and the prefabricated activated carbon mixed block is obtained by cooling, the constant temperature pressing temperature is 135℃, the pressure is 0.6MPa, and the temperature of the heated standing is 140℃; a5, the prefabricated mixed block is allowed to stand for 25min, dried and then sintered to obtain a gradient activated carbon; the standing atmosphere is a mixed atmosphere of nitrogen and water vapor, and the volume ratio of nitrogen to water vapor is 11:1, the drying temperature is 90℃, and the sintering temperature is 240℃; the gradient activated carbon uses activated carbon as a framework and activated alumina as a dopant to form a gradually dense pore structure from bottom to top;

[0031] Step 1, in a reactor, using isopropanol as a solvent, adding 1,6-dibromohexane, p-cyanophenol and sodium methoxide in sequence, heating to reflux and then stirring for 24 hours, then cooling to room temperature and filtering to obtain a solid crude product, finally, the solid crude product is pulped, filtered and dried to obtain 1,6-(p-cyanophenyl) hexanediether, the mass ratio of 1,6-dibromohexane to p-cyanophenol is 1:1, the concentration of 1,6-dibromohexane in isopropanol is 200g / L, the amount of sodium methoxide added is 49% of the mass of 1,6-dibromohexane, the heating reflux temperature is 85°C, the time is 6h, the temperature of the insulation stirring is 40°C, the stirring speed is 800r / min, the pulping uses distilled water, and the mass ratio of distilled water to the solid crude product is 4:1, and the drying temperature is 75°C;

[0032] Step 2, adding 1,6-(p-cyanophenyl) hexanediether to a dichloroethane-ethanol mixture, introducing hydrogen chloride gas under a low temperature environment, stirring at a constant temperature for 17 hours after the introduction is completed, then cooling and adding to an ammonia-ethanol mixture and stirring evenly, finally heating and stirring for 3 hours, filtering after cooling, beating and crystallizing to obtain an intermediate product, wherein the volume ratio of dichloroethane and ethanol in the dichloroethane-ethanol mixture is 4:1, the mass ratio of 1,6-(p-cyanophenyl) hexanediether to ethanol is 1:2, the low temperature environment is 5°C, and the amount of hydrogen chloride gas added is 1,6-(p-cyanophenyl) hexanediether. The mass ratio of ethanol to ammonia water in the ammonia-ethanol mixture is 4:3, and the ammonia content of the ammonia water is 28%. The temperature of the heating and stirring is 55°C, and the temperature of the suction filtration after cooling is 20°C. The pulping uses distilled water, and the mass of the distilled water is twice the mass of the solid. The crystallization is a mixture of the filtered solid after pulping and ethanol in a mass ratio of 1:3, heated to dissolve, and then cooled to crystallize. After keeping warm and stirring for 1 hour, centrifuge to obtain an intermediate. The heating temperature is 65°C, and the temperature of the cooling and crystallization is 20°C.

[0033] Step 3, adding the intermediate product to water to form a mixed solution, and adding sodium hydroxide dropwise to adjust the pH, collecting after centrifugation to obtain a solid precipitate, then placing the solid precipitate in ethanol, and adjusting the pH with isethionic acid, adding gradient activated carbon after heating to dissolve, and filtering while hot to obtain a filtrate; finally, cooling the filtrate and stirring for 1h, centrifuging and drying at a constant temperature to obtain hexamidine dihydroxyethyl sulfonate, the mass ratio of the intermediate product to water is 1:3, the mass fraction of the sodium hydroxide is 15%, the adjusted pH is 7, the mass ratio of the solid precipitate to ethanol is 1:4, the pH adjusted by isethionic acid is 6, the heating and dissolving temperature is 70°C, the concentration of the gradient activated carbon is 6g / L, the cooling temperature is 5°C, and the constant temperature drying temperature is 55°C. The purity of hexamidine dihydroxyethyl sulfonate prepared by this method is 99.23%.

[0034] Comparative Example 1

[0035] A method for synthesizing hexamidine diisethionate comprises the following steps:

[0036] Step 1, in a reactor, using isopropanol as a solvent, adding 1,6-dibromohexane, p-cyanophenol and sodium methoxide in sequence, heating to reflux and then stirring for 24 hours, then cooling to room temperature and filtering to obtain a solid crude product, finally, the solid crude product is pulped, filtered and dried to obtain 1,6-(p-cyanophenyl) hexanediether, the mass ratio of 1,6-dibromohexane to p-cyanophenol is 1:1, the concentration of 1,6-dibromohexane in isopropanol is 200g / L, the amount of sodium methoxide added is 49% of the mass of 1,6-dibromohexane, the heating reflux temperature is 85°C, the time is 6h, the temperature of the insulation stirring is 40°C, the stirring speed is 800r / min, the pulping uses distilled water, and the mass ratio of distilled water to the solid crude product is 4:1, and the drying temperature is 75°C;

[0037] Step 2, adding 1,6-(p-cyanophenyl) hexanediether to a dichloroethane-ethanol mixture, introducing hydrogen chloride gas under a low temperature environment, stirring at a constant temperature for 17 hours after the introduction is completed, then cooling and adding to an ammonia-ethanol mixture and stirring evenly, finally heating and stirring for 3 hours, filtering after cooling, beating and crystallizing to obtain an intermediate product, wherein the volume ratio of dichloroethane and ethanol in the dichloroethane-ethanol mixture is 4:1, the mass ratio of 1,6-(p-cyanophenyl) hexanediether to ethanol is 1:2, the low temperature environment is 5°C, and the amount of hydrogen chloride gas added is 1,6-(p-cyanophenyl) hexanediether. The mass ratio of ethanol to ammonia water in the ammonia-ethanol mixture is 4:3, and the ammonia content of the ammonia water is 28%. The temperature of the heating and stirring is 55°C, and the temperature of the suction filtration after cooling is 20°C. The pulping uses distilled water, and the mass of the distilled water is twice the mass of the solid. The crystallization is a mixture of the filtered solid after pulping and ethanol in a mass ratio of 1:3, heated to dissolve, and then cooled to crystallize. After keeping warm and stirring for 1 hour, centrifuge to obtain an intermediate. The heating temperature is 65°C, and the temperature of the cooling and crystallization is 20°C.

[0038] Step 3, adding the intermediate product to water to form a mixed solution, and adding sodium hydroxide to adjust the pH, collecting the solid precipitate after centrifugation, then putting the solid precipitate into ethanol, and adjusting the pH with isethionic acid, adding activated carbon after heating and dissolving, and filtering while hot to obtain a filtrate; finally, cooling the filtrate and stirring for 1 hour, centrifuging and drying at a constant temperature to obtain hexamidine dihydroxyethyl sulfonate, the mass ratio of the intermediate product to water is 1:3, the mass fraction of the sodium hydroxide is 15%, the adjusted pH is 7, the mass ratio of the solid precipitate to ethanol is 1:4, the pH after adjustment with isethionic acid is 6, the heating and dissolving temperature is 70°C, the concentration of the activated carbon is 6g / L, the cooling temperature is 5°C, and the constant temperature drying temperature is 55°C. The purity of hexamidine dihydroxyethyl sulfonate prepared by this method is 99.04%

[0039] Comparative Example 2

[0040] Comparative Example 2 uses commercially available hexamidine dihydroxyethyl sulfonate, specifically from Wuhan Biotechnology Co., Ltd., with a purity of 99.02%.

[0041] From the data comparison of the above Examples 1-3 and Comparative Examples 1-2, it can be seen that the use of gradient activated carbon in the present technical solution can effectively improve the purity of hexamidine dihydroxyethyl sulfonate without increasing the number of yields, providing a new idea for high-purity hexamidine dihydroxyethyl sulfonate.

[0042] It is understood that the above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents to achieve the same technical effects; as long as the use requirements are met, they are within the protection scope of the present invention.

Claims

1. A method for synthesizing hexamidine dihydroxyethyl sulfonate, characterized in that: The steps include: Step 1, in a reaction kettle, using isopropanol as a solvent, adding 1,6-dibromohexane, p-cyanophenol and sodium methoxide in sequence, heating to reflux and then stirring for 24 hours, then cooling to room temperature and filtering to obtain a solid crude product, finally, the solid crude product is pulped, filtered and dried to obtain 1,6-(p-cyanophenyl)hexanediether; Step 2, adding 1,6-(p-cyanophenyl)hexanediether to a dichloroethane-ethanol mixture, introducing hydrogen chloride gas under low temperature, stirring at a constant temperature for 16-18 hours after the introduction, then cooling and adding to an ammonia-ethanol mixture and stirring evenly, finally heating and stirring for 2-3 hours, filtering, beating and crystallizing after cooling to obtain an intermediate; Step 3, adding the intermediate product into water to form a mixed solution, and adding sodium hydroxide dropwise to adjust the pH, collecting the solid precipitate after centrifugation, then placing the solid precipitate into ethanol, and adjusting the pH with isethionic acid, adding activated carbon after heating to dissolve, and filtering while hot to obtain a filtrate; finally, cooling the filtrate and stirring for 1 hour, centrifuging and drying at a constant temperature to obtain hexamidine dihydroxyethyl sulfonate, wherein the activated carbon uses gradient activated carbon.

2. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The mass ratio of 1,6-dibromohexane to p-cyanophenol in step 1 is 1:1-1.1, the concentration of 1,6-dibromohexane in isopropanol is 200-300 g / L, and the amount of sodium methoxide added is 47-49% of the mass of 1,6-dibromohexane.

3. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The heating reflux temperature in step 1 is 85-90°C, the time is 3-6h, the insulation stirring temperature is 30-50°C, the stirring speed is 500-1000r / min, the pulping uses distilled water, and the mass ratio of distilled water to solid crude product is 3-4:1, and the drying temperature is 70-80°C.

4. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The volume ratio of ethylene dichloride to ethanol in the ethylene dichloride-ethanol mixed solution in step 2 is 4:1-1.2, the mass ratio of 1,6-(p-cyanophenyl)hexanediether to ethanol is 1:1.8-2, the low temperature environment is not higher than 30° C., the amount of hydrogen chloride gas added is 90-92% of the mass of 1,6-(p-cyanophenyl)hexanediether, the temperature of constant temperature stirring is 25-35° C., and the temperature of cooling is not higher than 20° C.

5. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The mass ratio of ethanol to ammonia water in the ammonia-ethanol mixture in step 2 is 4:3, and the ammonia content of the ammonia water is 25-28%. The temperature of the heating and stirring is 50-55°C, and the temperature of the suction filtration after cooling is 20-25°C.

6. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The beating in step 2 uses distilled water, and the mass of the distilled water is twice the mass of the solid. The crystallization is performed by mixing the solid filtered after beating with ethanol in a mass ratio of 1:3, heating to dissolve and then cooling to crystallize. The intermediate product is obtained by centrifugation after stirring for 1 hour. The heating temperature is 60-70°C, and the cooling temperature for crystallization is 15-25°C.

7. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The mass ratio of the intermediate product to water in step 3 is 1:3, the mass fraction of the sodium hydroxide is 10-20%, and the adjusted pH is 7.

8. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The mass ratio of the solid precipitate to ethanol in step 3 is 1:4, the pH after adjustment with isethionic acid is 5-6, the temperature of heating and dissolving is 60-80°C, the concentration of activated carbon is 5-8g / L, the temperature of cooling is 0-10°C, and the temperature of constant temperature drying is 50-60°C.

9. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The gradient activated carbon in step 3 uses activated carbon as a framework and activated alumina as a dopant to form a pore structure that is gradually denser from bottom to top, and the preparation method of the gradient activated carbon.

10. The method for synthesizing hexamidine diisethionate according to claim 1, characterized in that: The hexamidine diisethionate is used in cosmetics.