Synthesis process of hexamidine dihydroxyethyl sulfonate

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a novel synthesis process of hexamidine dihydroxyethyl sulfonic acid. The synthesis method comprises the following steps: (1) adsorbing ammonia gas by using the MOFs material; (2) carrying out condensation reaction to prepare an SN1 intermediate; (3) carrying out addition reaction to prepare an SN2 intermediate; and (4) sulfonating and salifying to prepare a final product. The synthesis process provided by the invention is simple to operate, high in safety and less in three wastes, the catalyst can be recycled, the yield of the prepared hexamidine dihydroxyethyl sulfonic acid is greatly improved, the total yield of the product can reach 90% or above, and the purity reaches 99.0% or above.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis process of hexamidine diisethionate. BACKGROUND

[0002] Hexamidine diisethionate is a broad-spectrum antibacterial agent, mainly used in cosmetics and skin care products, and has multiple effects such as dandruff removal, itching relief and antibacterial effect. It is disclosed in the literature that the synthesis process of hexamidine diisethionate is: etherification of p-cyanophenol and 1,6-dibromohexane, esterification by passing anhydrous hydrogen chloride gas, and then ammonolysis into salt by dry ammonia gas. Even if liquid acid and ammonia solution are used to replace gas, the safety performance is also limited, and the above method requires higher equipment, the overall solvent usage is increased, and the waste liquid is greatly increased, thereby increasing the difficulty of waste liquid treatment.

[0003] Overall, the current synthesis process of hexamidine diisethionate has the following disadvantages: (1) dangerous gas is used in the preparation process, and the process is complex and the steps are long; (2) the reaction process is violent, ammonia gas is released during the reaction, which is harmful to the operating environment, resulting in low production safety and high operating requirements; (3) the existing process has a low reaction yield, only about 80%; (4) special equipment such as tail gas absorption device needs to be installed to treat corrosive gas, and the cost of gas raw material transportation and storage is high.

[0004] Therefore, it is urgent to invent a synthesis process of hexamidine diisethionate which has mild reaction conditions, safe operation, can be repeatedly used, has low equipment requirements, reduces cost, has high yield, and is environmentally friendly and reliable. SUMMARY

[0005] In order to solve the above technical problems of high equipment requirements, large solvent usage and increased waste liquid, the present application provides a synthesis process of hexamidine diisethionate. In the first step, SN1 intermediate is prepared by condensation reaction, then SN2 intermediate is prepared by continuous addition and ammonolysis reaction, and then hexamidine diisethionate is prepared by sulfonating SN2 intermediate into salt.

[0006] The synthesis process of hexamidine diisethionate in the present application comprises the following steps: (1) adsorbing ammonia gas with MOFs material: MOFs material is fixed on a high-pressure gas adsorption instrument, ammonia gas is slowly introduced, the pressure is controlled at 1.2-1.5 bar, the maintenance time is 2-3 h, ammonia gas is turned off, nitrogen gas is slowly introduced, pressure is supplemented, pressure is supplemented for 2-3 h, vacuum is extracted, pressure is released, and the adsorbed material is taken out for standby; (2) Preparation of SN1 intermediate: Using p-cyanophenol and 1,6-dibromohexane as raw materials, add an organic solvent with a mass of 3 to 4 times that of p-cyanophenol, add a strong base ion exchange resin with a mass of 0.05 to 0.1 times that of p-cyanophenol, control the reaction temperature at 70 to 90°C, reflux for 16 to 20 h, and prepare SN1 intermediate by condensation reaction. After the reaction is completed, cool down to 10 to 20°C, filter, wash the solid with 50% methanol water, and dry to obtain SN1 intermediate; (3) Preparation of SN2 intermediate: Add 2 to 3 times the mass of the SN1 intermediate to the solvent, control the temperature at 5 to 10℃, then add 40% of cold hydrogen chloride methanol solution, stir for 1 to 2 hours, raise the temperature to 25 to 35℃, keep it at the temperature for 5 to 8 hours, test, and after passing the test, lower the temperature to -5 to 0℃, slowly add the MOF material for adsorbing ammonia into the system, control the temperature below 20℃ during the addition of the adsorbent material, keep it at 10 to 30℃ for 1 to 3 hours, raise the temperature to 70 to 80℃ and reflux for 8 to 10 hours, test, and after passing the test, lower the temperature to 20 to 30℃, stir for 1 to 2 hours, filter, and obtain the SN2 intermediate; (4) Preparation of hexamidine dihydroxyethyl sulfonate: The SN2 intermediate was alkali-hydrolyzed with 10% sodium hydroxide solution. After alkali hydrolysis, the solid was filtered, and hydroxyethyl sulfonic acid and water were added to raise the temperature to 85~95℃ and kept at the temperature for 1.5~3h. After hot filtration, the filtrate was cooled and crystallized. The crude product was obtained by filtration and recrystallization to obtain the finished product hexamidine dihydroxyethyl sulfonate.

[0007] Preferably, in step (1), the MOF material is one of Uio-66, MOF-808, and MFM-303.

[0008] More preferably, in step (1), the MOF material is MFM-303.

[0009] Preferably, in step (1), the mass ratio of the MOFs material to ammonia is 10~12:1, and the absorption pressure is controlled at 1.2~1.5 bar.

[0010] Preferably, in step (2), the organic solvent is one of methanol, ethanol, isopropanol, dichloroethane, toluene, and xylene, and the solvent is 3 to 4 times the mass of cyanophenol.

[0011] More preferably, in step (2), the organic solvent is one of methanol and ethanol.

[0012] Preferably, in step (2), the strong basic ion exchange resin is one of PA-308, D201, IRA900, and MP-500, and the strong basic ion exchange resin is 0.05 to 0.1 times the mass of p-cyanophenol.

[0013] More preferably, in step (2), the strong basic ion resin is D201.

[0014] Preferably, in step (2), the molar ratio of p-cyanophenol to 1,6-dibromohexane is 1.5-2.0:1.

[0015] Preferably, in step (3), the solvent is one of methanol, ethanol, toluene, xylene, etc.; and the amount of solvent added is 2-3 times the mass of the intermediate.

[0016] More preferably, in step (3), the solvent is one of methanol and ethanol.

[0017] Preferably, in step (3), the mass ratio of intermediate SN1 to hydrogen chloride methanol solution is 1:3.5-4, and the mass ratio of intermediate to MOFs material is 1:5.5-7.5.

[0018] Preferably, in step (4), the mass ratio of intermediate SN2 to 10% sodium hydroxide solution is 1:3-4; the mass ratio of intermediate SN2 to isethionic acid is 1:1.5-2, and the amount of water added is 1.5-2 times the mass of intermediate SN2.

[0019] The beneficial effects of the present application are: (1) Compared with the existing synthesis process, the yield and yield of the product prepared by the synthesis method of the present application are greatly improved, and the total yield of the product is more than 90% and the purity is more than 99.0%.

[0020] (2) The content of by-products in each step of the present application is low, and the operation is simple, which is more suitable for industrialized production.

[0021] (3) In the entire synthesis process of the present application, there is no high pressure and high temperature, the catalyst and solvent in the process are conventional reagents, which are safe and have high operability, and the reaction can be carried out in a conventional reaction kettle.

[0022] (4) In the overall reaction process, the amount of three wastes is reduced compared with the existing synthesis process, and there is no need to consider the leakage of hydrogen chloride and ammonia gas and the problem of tail gas absorption. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The liquid chromatogram of the target product after purification of Example 1 is shown in the figure; Figure 2 The liquid chromatogram of the target product after purification of Example 5 is shown in the figure; Figure 3 The liquid chromatogram of the target product after purification of Comparative Example 1 is shown in the figure; Figure 4 The liquid chromatogram of the target product after purification of Comparative Example 7 is shown in the figure; Figure 5Liquid chromatogram of the target product produced according to the traditional process for Comparative Example 15. DETAILED DESCRIPTION

[0024] In order to enable those skilled in the art to better understand the present application, the present application will be further described in conjunction with specific embodiments.

[0025] Example 1 A synthesis process of hexamidine diisethionate includes the following steps: (1) Fix 600 g of MOFs material (MFM-303) on a high-pressure gas adsorption instrument, slowly pass in 75 mL of ammonia gas, control the pressure at 1.2 bar, maintain for 2.5 h, close the ammonia gas, slowly pass in nitrogen, perform pressure compensation, compensate for 2.5 h, vacuumize, and unload the pressure, and take out the material after adsorption for standby use.

[0026] (2) Prepare the SN1 intermediate: take 12.16 g of p-cyanophenol and 11.9 g of 1,6-dibromohexane as raw materials, add methanol with a mass of 3 times that of the p-cyanophenol, add strong basic ion resin D201 with a mass of 0.1 times that of the p-cyanophenol, control the reaction temperature at 70°C, and reflux for 16 h to prepare the SN1 intermediate by condensation reaction. After the reaction is completed, cool to 20°C, filter, wash the solid with 50% methanol water, and dry to obtain the SN1 intermediate.

[0027] (3) Prepare the SN2 intermediate: add the SN1 intermediate to 3 times the mass of a solvent, control the temperature at 5-10°C, then add 3.5 times the mass of a cold 40% hydrogen chloride methanol solution dropwise, stir for 1-2 h, warm to 35°C, and incubate for 8 h. After detection, if qualified, cool to 0°C, slowly add 600 g of MOFs material adsorbed with ammonia into the system, control the temperature below 20°C during the addition of the adsorbed material, and after the addition is completed, incubate at 30°C for 2 h, warm to 80°C, and reflux for 10 h. After detection, if qualified, cool to 20°C, stir for 2 h, filter, and obtain the SN2 intermediate.

[0028] (4) Prepare hexamidine diisethionate: alkali hydrolyze the SN2 intermediate with 3 times the mass of a 10% sodium hydroxide solution. After alkali hydrolysis, filter, add hydroxyethyl sulfonic acid and 1.5 times the mass of water to the solid, warm to 95°C, and incubate for 1.5-3 h. Hot filter, cool the filtrate to precipitate crystals, filter to obtain a crude product, recrystallize the crude product, and obtain the finished product. The yield of the finished product is 92%, and the purity is 99.5%.

[0029] Example 2 The difference from Example 1 is that in step (1), other conditions remain unchanged, and the MOFs material type is changed to Uio-66. The amount of Uio-66 required to absorb the same mass of ammonia is increased, and 1200g of Uio-66 is required. The product yield is 90%, and the purity is 99.3%.

[0030] Example 3 The difference from Example 1 is that in step (1), other conditions remain unchanged, and the MOFs material type is changed to MOF-808. The amount of MOF-808 required to absorb the same mass of ammonia is increased, and 1000g of MOF-808 is required. The product yield is 91%, and the purity is 99.4%.

[0031] Example 4 The difference from Example 1 is that in step (1), the MOFs material used is subjected to repeated tests for verification, and the specific test results are shown in the table below.

[0032] Table 2 Comparison data of various MOFs materials Materials Amount of material to absorb the same mass of ammonia gas Number of cycles Uio-66 1200g 5 MOF-808 1000g 8 MFM-303 600g 10 Through the comparison of test data and results of Examples 1-4, the best MOFs material is MFM-303. Compared with other materials, MFM-303 has high ammonia absorption efficiency and high recycling times, and can be recycled for ten times.

[0033] Example 5 The difference from Example 1 is that in step (2), other conditions remain unchanged, and the type of strong basic ion exchange resin is changed to PA-308. The product yield is 65%, and the purity is 96.0%.

[0034] Example 6 The difference from Example 1 is that in step (2), other conditions remain unchanged, and the type of strong basic ion exchange resin is changed to IRA900. The product yield is 69%, and the purity is 97.2%.

[0035] Example 7 The difference from Example 1 is that in step (2), other conditions remain unchanged, and the type of strong basic ion exchange resin is changed to MP-500. The product yield is 72%, and the purity is 96.9%.

[0036] Example 8 The difference from Example 1 is that in step (2), various types of strong basic ion exchange resins are subjected to repeated tests, and the specific experimental data are shown in the table below.

[0037] Table 3 Comparison data of various types of strong basic ion exchange resins Strong base ion resin type Yield of finished product Number of cycles D201 92% More than 10 times PA-308 65% 8 times IRA900 69% 10 times MP-500 72% More than 10 times Example 9 In Examples 9-10, the effect of reaction temperature in Step (2) on product yield was investigated. When the reaction temperature was less than 70°C, the condensation reaction time increased. When the reaction temperature was greater than 90°C, side reactions occurred, resulting in an increase in the content of by-products. When the reaction time was less than 16 h, the amount of raw material residue was large. When the reaction time was greater than 20 h, the reaction efficiency was basically the same as that of 20 h, with no significant change. Therefore, the reaction temperature in Step (1) is preferably 70-90°C, and the reaction time is preferably 16-20 h.

[0038] The difference from Example 1 is that in Step (2), the other conditions are unchanged, and the reaction temperature is reduced to 65°C. The yield of the finished product is 75%, and the purity is 97.2%.

[0039] Example 10 The difference from Example 1 is that in Step (2), the other conditions are unchanged, and the reaction temperature is reduced to 95°C. The yield of the finished product is 85%, and the purity is 98.3%.

[0040] Example 11 In Examples 11-12, the effect of holding temperature in Step (3) on product yield was investigated.

[0041] In Step (3), when the reaction temperature after adding hydrogen chloride methanol solution is less than 25°C, the reaction time increases. When the reaction temperature after adding hydrogen chloride methanol solution exceeds 35°C, the side reactions increase. When the reaction holding time is less than 5 h, the reaction is not fully reacted. When the reaction holding time is more than 8 h, side reactions occur. When the reflux temperature during the addition of the adsorption material is less than 70°C, the reaction is not fully reacted. When the reflux temperature during the addition of the adsorption material is more than 80°C, side reactions occur. When the reflux time is less than 8 h, the reaction efficiency decreases. When the reflux time exceeds 10 h, the reaction efficiency is basically unchanged.

[0042] The difference from Example 1 is that in Step (3), the other conditions are unchanged, and the holding temperature is set to 20°C for holding. The yield of the finished product is 82%, and the purity is 99.2%.

[0043] Example 12 The difference from Example 1 is that in Step (3), the other conditions are unchanged, and the holding temperature is set to 40°C for holding. The yield of the finished product is 83%, and the purity is 99.3%.

[0044] Example 13 The effect of reaction temperature in step (4) on product yield was investigated in Examples 13-14. When the reaction temperature was lower than 85°C, the reaction efficiency was low. When the reaction temperature was higher than 95°C, the reaction efficiency was basically unchanged. When the holding time was lower than 1.5h, the reaction was incomplete. When the holding time was higher than 3h, the reaction efficiency was basically unchanged.

[0045] The difference from Example 1 was that, in step (4), the reaction temperature was 80°C. The yield of the finished product was 86%, and the purity was 99.1%.

[0046] Example 14 The difference from Example 1 was that, in step (4), the reaction temperature was 100°C. The yield of the finished product was 83%, and the purity was 99.0%.

[0047] Comparative Example 1 When the nitrogen gas was supplemented for less than 2h in step (1), there was still a small amount of ammonia gas in the system. When the supplementing time was more than 3h, the amount of ammonia gas in the system was consistent with that in the system for 3h, and there was almost no change.

[0048] The synthesis method was the same as in Example 1, except that the ammonia gas was passed for 1.5h in step (1). The gas was not completely absorbed, the yield of the finished product was 60%, and the purity was 94.3%.

[0049] Comparative Example 2 The synthesis method was the same as in Example 1, except that the gas was passed for 3.5h in step (1). The gas was completely absorbed, and the effect was consistent with that for 3h. The yield of the finished product was 91%, and the purity was 99.4%.

[0050] Comparative Example 3 The synthesis method was the same as in Example 1, except that the gas was passed for 1.1bar in step (1). The gas was not completely absorbed, the yield of the finished product was 84%, and the purity was 98.1%.

[0051] Comparative Example 4 The effect of the gas passing pressure in step (1) on product yield was investigated. When the pressure was lower than 1.2bar, the amount of ammonia gas attached to the MOFs material was small, and the amount of MOFs material needed to be increased in the subsequent reaction. When the pressure was higher than 1.5bar, the amount of ammonia gas attached to the MOFs was basically consistent with that when the pressure was 1.5bar, and there was no need to increase the pressure. When the reaction time was less than 2h, the amount of ammonia gas attached was insufficient, and the amount of MOFs material needed to be increased in the subsequent reaction. When the reaction time was more than 3h, the amount of ammonia gas attached was basically consistent. The synthesis method was the same as in Example 1, except that the gas was passed for 1.6bar in step (1). The gas absorption efficiency was consistent with that when the pressure was 1.5bar, the yield of the finished product was 91%, and the purity was 99.0%.

[0052] Comparative Example 5 The present invention further investigated the amount used in each step and found that: in step (2), when the mass of the strong base ion exchange resin and p-cyanophenol is less than 0.05 times, the raw materials are not completely reacted and 5% of the raw materials remain. When the mass of the strong base ion exchange resin and p-cyanophenol is greater than 0.1 times, the reaction efficiency is basically unchanged and 0.1% of the raw materials remain. The content of intermediates is 95%.

[0053] The synthesis method was the same as in Example 1, except that in step (2), other conditions remained unchanged, and the molar ratio of p-cyanophenol to 1,6-dibromohexane was 1.4:1. The yield of the finished product was 76%, and the purity was 98.4%.

[0054] Comparative Example 6 The synthesis method was the same as in Example 1, except that in step (2), other conditions remained unchanged, and the molar ratio of p-cyanophenol to 1,6-dibromohexane was 2.1:1. The yield of the finished product was 87%, and the purity was 98.6%.

[0055] Comparative Example 7 The synthesis method was the same as in Example 1, except that in step (3), other conditions remained unchanged, and the mass ratio of intermediate SN1 to hydrogen chloride methanol solution was 1:3. The yield of the finished product was 77%, and the purity was 97.9%. Comparative Example 8 The synthesis method is the same as in Example 1, except that in step (3), other conditions remain unchanged, the mass ratio of intermediate SN1 to hydrogen chloride methanol solution is 1:4.5, the yield of the finished product is 80%, and the purity is 97.5%.

[0056] Comparative Example 9 In step (3), when the mass ratio of the SN1 intermediate to the hydrogen chloride methanol solution is less than 1:3.5, the reaction is incomplete, and too much intermediate remains. When the mass ratio of the SN1 intermediate to the hydrogen chloride methanol solution exceeds 1:4, side reactions increase, and the amount of alkali used in subsequent reactions increases. When the mass ratio of the SN1 intermediate to the MOFs material is less than 1:5.5, the reaction efficiency decreases, and the reaction is incomplete. When the mass ratio of the SN1 intermediate to the MOFs material exceeds 1:7.5, the reaction conversion rate decreases, and side reactions increase.

[0057] The synthesis method is the same as in Example 1, except that in step (3), other conditions remain unchanged, the mass ratio of intermediate SN1 to MOFs material is 1:5.4, the yield of finished product is 86%, and the purity is 99.1%.

[0058] Comparative Example 10 The synthesis method is the same as that of Example 1, except that in step (3), the mass ratio of intermediate SN1 to MOFs material is 1:7.6, the yield of the finished product is 88%, and the purity is 99.3%.

[0059] Comparative Example 11 The synthesis method is the same as that of Example 1, except that in step (4), the mass ratio of intermediate SN2 to 10% sodium hydroxide solution is 1:2.9, the yield of the finished product is 87%, and the purity is 98.7%.

[0060] Comparative Example 12 The synthesis method is the same as that of Example 1, except that in step (4), the mass ratio of intermediate SN2 to 10% sodium hydroxide solution is 1:4.1, the yield of the finished product is 86%, and the purity is 98.1%.

[0061] Comparative Example 13 The synthesis method is the same as that of Example 1, except that in step (4), the mass ratio of intermediate SN2 to hydroxyethyl sulfonic acid is 1:1.4, the yield of the finished product is 88%, and the purity is 99.0%.

[0062] Comparative Example 14 The synthesis method is the same as that of Example 1, except that in step (4), the mass ratio of intermediate SN2 to hydroxyethyl sulfonic acid is 1:2.1, and the effect is basically the same as that of the mass ratio 1:2, the yield of the finished product is 90%, and the purity is 99.1%.

[0063] Comparative Example 15 According to the conventional method, first prepare intermediate SN1, then prepare intermediate SN2, and then treat intermediate SN2 to prepare hexamidine dihydroxyethyl sulfonate. The specific synthesis method is as follows: Step one: add 35.7g of ethanol to a three-necked flask, add 12.16g of p-cyanophenol under stirring, dissolve under stirring, slowly add sodium methoxide powder, pay attention to the control of reaction temperature during the addition of sodium methoxide powder, the internal temperature will rise sharply, stir for 20min (internal temperature 80℃), heat to reflux for 2h, then slowly drop 1,6-dibromohexane 11.9g, drop for about 1h. Heat to reflux for 16h, control the liquid phase, after the raw material is basically completely reacted, cool to 10~20℃, filter and dry the solid to obtain intermediate SN1.

[0064] Step two: assemble the device, check the gas generating device, drying device, reaction device, tail gas device, etc., and check the airtightness of the whole device.

[0065] At room temperature, the reaction bottle was added with SN1 intermediate 10 g, toluene 30 g, stirring, cooling to 5-10 °C, then dropwise added with cold hydrogen chloride methanol solution 35 g (42%) into the system, 5-10 °C, stirring for 1 h. The temperature was increased to 35 °C, and kept for 6 h, and sample detection was performed until the raw material was completely reacted. High vacuum degassing, cooling to-5 °C, and slowly passing ammonia gas into the system, the temperature was increased faster in the early stage, and the system temperature was controlled below 20 °C. After the ammonia gas was passed in, the temperature was kept at 20 °C for 1 h, and then increased to reflux for more than 8 h, and sample detection was performed until the raw material was completely reacted. The temperature was cooled to 20 °C, and stirred for 1 h, then filtered, and the wet material was added with sodium hydroxide solution (10%) 33 g, filtered, and the wet material was added with hydroxyethyl sulfonic acid 15 g, pure water 20 g, the temperature was increased to 90 °C, and kept for 2 h, then hot filtered, and the filtrate was slowly crystallized, and filtered to obtain the product. The product yield was 70%, and the purity was 99.5%.

[0066] Compared with the traditional process, the yield of the process of the present application is improved, and the three wastes are reduced, which is safer and easier to operate. The strong alkaline ion resin used in the reaction process can be repeatedly used, and the MOFs adsorption material can also be repeatedly used.

[0067] The total yield and purity of the products prepared in Examples 1-3, 5-7, 9-14 and Comparative Examples 1-15 are shown in Table 4.

[0068] Table 4 Total yield and purity of hexamidine dihydroxyethyl sulfonate under different conditions Item Total yield Purity Example 1 92% 99.5% Example 2 90% 99.3% Example 3 91% 99.4% Example 5 65% 96.0% Example 6 69% 97.2% Example 7 72% 96.9% Example 9 75% 97.2% Example 10 85% 98.3% Example 11 82% 99.2% Example 12 83% 99.3% Example 13 86% 99.1% Example 14 83% 99.0% Comparative Example 1 60% 94.3% Comparative Example 2 91% 99.4% Comparative Example 3 84% 98.1% Comparative Example 4 91% 99.0% Comparative Example 5 76% 98.4% Comparative Example 6 87% 98.6% Comparative Example 7 77% 97.9% Comparative Example 8 80% 97.5% Comparative Example 9 86% 99.1% Comparative Example 10 88% 99.3% Comparative Example 11 87% 98.7% Comparative Example 12 86% 98.1% Comparative Example 13 88% 99.0% Comparative Example 14 90% 99.1% Comparative Example 15 70% 99.5% As shown in Table 4, the hexamidine dihydroxyethyl sulfonate prepared in Example 1 has higher yield and higher purity compared with the product prepared by using the traditional method. The molar ratio between the solvents and raw materials, and the reaction time, temperature and time will have a great influence on the final total yield, that is, the highest total yield and purity of the product can be obtained within the limited range of temperature, time and molar ratio in the present application.

Claims

1. A process for synthesizing hexamidine dihydroxyethyl sulfonate, characterized in that, Includes the following steps: (1) Adsorption of ammonia using MOF materials MOFs material was fixed on a high-pressure gas adsorption instrument, ammonia gas was slowly introduced, the pressure was controlled at 1.2~1.5 bar, and maintained for 2~3 hours. The ammonia gas was then turned off. Nitrogen gas was slowly introduced to replenish the pressure for 2~3 hours, a vacuum was drawn, and the pressure was released to obtain MOFs material that adsorbed ammonia gas. (2) Preparation of SN1 intermediate Using p-cyanophenol and 1,6-dibromohexane as raw materials, an organic solvent was added, followed by the addition of a strong basic ion exchange resin. The reaction temperature was controlled at 70-90℃, and the mixture was refluxed for 16-20 hours to induce a condensation reaction and prepare an SN1 intermediate. After the reaction was completed, the temperature was lowered to 10-20℃, the mixture was filtered, and the solid was washed with 50% methanol-water solution and dried to obtain the SN1 intermediate. (3) Preparation of SN2 intermediate Add an organic solvent to the SN1 intermediate obtained in (2), control the temperature at 5~10℃, then add a 5℃ hydrogen chloride methanol solution, stir for 1~2h, raise the temperature to 25~35℃, keep it warm for 5~8h, and check until the content of the intermediate SN1 in the reaction system is less than 1%, then lower the temperature to -5~0℃, slowly add the MOFs material that adsorbs ammonia obtained in (1) to the reaction system, control the temperature below 20℃ during this process, after the addition is completed, keep it warm at 10~30℃ for 1~3h, raise the temperature to 70~80℃, reflux for 8~10h, check until the content of the SN2 intermediate is greater than or equal to 95%, then lower the temperature to 20~30℃, stir for 1~2h, filter, and obtain the SN2 intermediate; (4) Preparation of hexamidine dihydroxyethyl sulfonate The SN2 intermediate obtained in (3) was subjected to alkaline hydrolysis with sodium hydroxide solution, then filtered. The resulting solid was then added to hydroxyethyl sulfonic acid and water and heated to 85~95℃. The temperature was maintained for 1.5~3h, and the mixture was hot filtered. The filtrate was cooled and crystallized. The crude product was obtained by filtration again and recrystallization was performed to obtain the finished product.

2. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, In (1), the MOFs material is selected from one of Uio-66, MOF-808, and MFM-303.

3. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, (1) The mass ratio of the MOFs material to ammonia is 10~12:1; nitrogen is continuously introduced at 1.2~1.5 bar.

4. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, (2) The molar ratio of p-cyanophenol to 1,6-dibromohexane is 1.5~2.0∶1; the organic solvent is selected from any one of methanol, ethanol, isopropanol, dichloroethane, toluene, and xylene; the amount of organic solvent added is 3~4 times the mass of p-cyanophenol.

5. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, (2) The strong basic ion exchange resin is selected from any one of PA-308, D201, IRA900, and MP-500; its addition amount is 5% to 10% of p-cyanophenol.

6. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, In (3), the organic solvent added to the SN1 intermediate obtained in (2) is any one of methanol, ethanol, toluene, or xylene; the mass of the added solvent is 2 to 3 times that of the SN1 intermediate.

7. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, In (3), the mass ratio of SN1 intermediate to the added hydrogen chloride methanol solution is 1:3.5~4; the mass concentration of the hydrogen chloride methanol solution is 40%; and the mass ratio of SN1 intermediate to the MOFs material that adsorbs ammonia is 1:5.5~7.

5.

8. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, In (4), the mass ratio of the added SN2 intermediate to the sodium hydroxide solution is 1:3~4; the mass concentration of the sodium hydroxide solution is 10%.

9. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, In (4), the mass ratio of SN2 intermediate to hydroxyethyl sulfonic acid is 1:1.5~2, and the amount of water added is 1.5~2 times the mass of SN2 intermediate.

10. The synthesis process of hexamidine dihydroxyethyl sulfonate as described in claim 1, characterized in that, Includes the following steps: (1) Fix 600g of MOFs material on a high-pressure gas adsorption instrument, slowly introduce 75mL of ammonia gas, control the pressure at 1.2~1.5bar, maintain for 2~3h, turn off the ammonia gas, slowly introduce nitrogen gas to replenish the pressure, replenish the pressure for 2~3h, evacuate the vacuum, release the pressure, and take out the adsorbed material for later use. (2) Preparation of SN1 intermediate: Using 12.16g of p-cyanophenol and 11.9g of 1,6-dibromohexane as raw materials, methanol with a mass of 3 times that of p-cyanophenol was added, and strong basic ion exchange resin D201 with a mass of 0.1 times that of p-cyanophenol was added. The reaction temperature was controlled at 70℃, and the reaction was refluxed for 16h to prepare SN1 intermediate by condensation reaction. After the reaction was completed, the temperature was lowered to 20℃, filtered, and the solid was washed with 50% methanol water and dried to obtain SN1 intermediate; (3) Preparation of SN2 intermediate: Add 3 times the mass of the SN1 intermediate to the solvent, control the temperature at 5~10℃, then add 3.5 times the mass of the cold 40% hydrogen chloride methanol solution, stir for 1~2h, raise the temperature to 35℃, keep it at the temperature for 8h, test, and after passing the test, cool down to 0℃, slowly add 600g of MOFs material for ammonia adsorption into the system, control the temperature below 20℃ during the addition of adsorption material, keep it at 30℃ for 2h after the addition, raise the temperature to 80℃ and reflux for 10h, test, after passing the test, cool down to 20℃, stir for 2h, filter, and obtain SN2 intermediate; (4) Preparation of hexamididine dihydroxyethyl sulfonate: The SN2 intermediate was alkali-hydrolyzed with 3 times the mass of 10% sodium hydroxide solution. After alkali hydrolysis, the solid was filtered, and hydroxyethyl sulfonic acid and 1.5 times the mass of water were added to raise the temperature to 95°C and keep it at that temperature for 1.5~3h. After hot filtration, the filtrate was cooled and crystallized. The crude product was obtained by filtration and recrystallization to obtain the finished product.

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