Preparation method of amidine-type compounds dihydroxyethyl sulfonate and their intermediates

Abstract

This invention discloses a method for preparing dihydroxyethyl sulfonate of amidine compounds and its intermediates. Specifically, this invention provides a method for preparing dihydroxyethyl sulfonate of amidine compounds, comprising the following steps: (1) in a solvent, in the presence of tungstic acid, cyanophenol as shown in Formula I undergoes an addition reaction with an ammonium salt to obtain hydroxylated benzamide as shown in Formula II; (2) in a solvent, under alkaline conditions, hydroxylated benzamide as shown in Formula II undergoes a condensation reaction with Br(CH2)nBr to obtain an amidine compound as shown in Formula III; (3) in a solvent, the amidine compound as shown in Formula III undergoes a salt formation reaction with hydroxyethyl sulfonic acid to obtain dihydroxyethyl sulfonate of amidine compounds as shown in Formula IV. The reagents used in this invention are mild, green, and easy to store. Furthermore, the reaction is simple to operate, has a short reaction time, and a high yield.

Description

Technical Field

[0001] This invention relates to a method for preparing amidoside dihydroxyethyl sulfonate and its intermediates, which belong to the field of daily chemical products. Background Technology

[0002] Hexamididine diisocyanate, also known as hexamididine dihydroxyethyl sulfonate, is a water-soluble cationic substance with broad-spectrum antibacterial and bactericidal properties. It has particularly high bactericidal and bacteriostatic properties against Gram-positive and Gram-negative bacteria, as well as various molds and yeasts.

[0003] In cosmetics, hexamidine dihydroxyethyl sulfonate is used as a bactericide at a mass fraction of 0.03%–0.1%. Studies have shown that hexamidine dihydroxyethyl sulfonate is poorly absorbed by the skin of live mice and is not stored in any tissue. As a highly effective broad-spectrum antibacterial agent, hexamidine dihydroxyethyl sulfonate is very safe and mild, with minimal skin irritation, and exhibits excellent compatibility with commonly used raw materials in daily chemical products, thus possessing unique applications in the cosmetic industry.

[0004] Hexamidine dihydroxyethyl sulfonate is a novel anti-dandruff and antipruritic agent. Due to its unique structure, it possesses a very strong killing effect on Malassezia (Malassezia ovalis), the fungus that causes dandruff. In particular, its cationic nature and adsorption to hair enhance and prolong its anti-dandruff effect, a characteristic not found in other anti-dandruff agents. Clinical dermatological studies have shown that shampoos containing 0.1% hexamidine dihydroxyethyl sulfonate significantly reduce Malassezia per unit area of ​​the scalp compared to control shampoos, and with the reduction in Malassezia density, the severity of dandruff also significantly improves.

[0005] Hexamidine dihydroxyethyl sulfonate is particularly suitable for acne treatment products, with an addition level of 0.08%–0.1%. For open acne, the bactericide alone is effective; for closed acne, combining it with exfoliating and penetrating ingredients further enhances its rapid bactericidal effect. Furthermore, hexamidine dihydroxyethyl sulfonate also inhibits the lipase of Propionibacterium acnes, making it particularly suitable for oily skin prone to acne.

[0006] Hexamidine dihydroxyethyl sulfonate has been widely used in the international cosmetics industry due to its outstanding advantages of high bactericidal activity, non-irritation, and high safety.

[0007] Currently, the synthesis method for hexamidine dihydroxyethyl sulfonate disclosed in CN105884652A has the following problems: high raw material prices, stringent feeding requirements, difficult operation, and long reaction time. Furthermore, the production process requires the use of large amounts of hydrogen chloride gas and ammonia gas (chemical reaction equations shown below), which not only corrodes production equipment, reducing its service life and increasing replacement and maintenance costs, but also pollutes the surrounding environment.

[0008] Summary of the Invention

[0009] The purpose of this invention is to provide a novel method for preparing amidine-type compounds, dihydroxyethyl sulfonate and its intermediates. The advantages are simple operation, few steps, green reagents, high product purity, and high yield.

[0010] The present invention solves the above-mentioned technical problems through the following solution.

[0011] This invention provides a method for preparing hydroxylated benzamide, comprising the following steps: in a solvent, in the presence of tungstic acid, a cyanophenol as shown in Formula I is reacted with an ammonium salt by an addition reaction to obtain hydroxylated benzamide as shown in Formula II.

[0012]

[0013] In some embodiments, the solvent in the addition reaction may be of the type conventional for such reactions in the art. Preferably, the solvent is selected from one or more of nitrogen-containing compound solvents, sulfur-containing compound solvents, hydrocarbon solvents, and ether solvents. For example, the solvent is selected from one or more of DMF, dimethyl sulfoxide, toluene, and 1,4-dioxane, and is preferably N,N-dimethylformamide.

[0014] In some embodiments, the amount of solvent used in the addition reaction can be conventional for such reactions in the art. Preferably, the mass-to-volume ratio of the cyanophenol as shown in Formula I to the solvent is 0.005-0.03 g / mL, and more preferably 0.012-0.02 g / mL.

[0015] In some embodiments, in the addition reaction, the molar ratio of the cyanophenol as shown in Formula I to the tungstic acid is (8-20):1; preferably (10-12):1.

[0016] In some embodiments, in the addition reaction, the ammonium salt is one or more of ammonium oxalate, ammonium sulfate, ammonium chloride, and ammonium acetate, preferably ammonium acetate.

[0017] In some embodiments, in the addition reaction, the molar ratio of the cyanophenol as shown in Formula I to the ammonium salt is 1:(4-10), preferably 1:(5-7).

[0018] In some embodiments, the reaction temperature in the addition reaction is a conventional reaction temperature for such reactions in the art, for example, a reaction temperature of 100-150°C, preferably 110-130°C.

[0019] In some embodiments, the progress of the addition reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), generally with the disappearance of p-cyanophenol or the cessation of the reaction as the reaction endpoint. For example, the reaction time is 10-24 hours, preferably 16 hours.

[0020] In some embodiments, the addition reaction further includes post-processing steps, such as filtration, concentration, and recrystallization.

[0021] In some embodiments, the cyanophenol represented by Formula I is p-cyanophenol, and correspondingly, the hydroxy-substituted benzamide represented by Formula II is p-hydroxybenzamide.

[0022] This invention also provides a method for preparing amidine compounds, comprising the following steps:

[0023] (1) In a solvent, in the presence of tungstic acid, cyanophenol as shown in Formula I is added to an ammonium salt to obtain hydroxylated benzamide as shown in Formula II;

[0024]

[0025] (2) In a solvent, under alkaline conditions, the hydroxy-substituted benzamide shown in Formula II undergoes a condensation reaction with Br(CH2)nBr to obtain the amidine compound shown in Formula III.

[0026]

[0027] Where n is 1, 2, 3, 4, 5, 6, 7 or 8.

[0028] In the preparation method of the amidotropic compounds, the conditions and operations of the addition reaction in step (1) are as described in any one of the present invention.

[0029] In the preparation method of the amidine compounds, the conditions and operation of the condensation reaction in step (2) can be conventional for such reactions in the art, and the present invention particularly prefers the following:

[0030] In some embodiments, in the condensation reaction, the solvent is selected from one or more of water and alcohol solvents. Preferably, the solvent is a mixed solution of water and alcohol solvents, and more preferably, the solvent is a mixed solution of water and ethanol.

[0031] In some embodiments, the volume ratio of ethanol to water in the condensation reaction is 1:(0.5-3), preferably 1:(0.8-2).

[0032] In some embodiments, in the condensation reaction, the mass-to-volume ratio of the hydroxylated benzamide as shown in Formula II to the solvent is 0.01-0.1 g / mL, preferably 0.02-0.07 g / mL.

[0033] In some embodiments, in the condensation reaction, the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate, preferably sodium hydroxide.

[0034] In some embodiments, the molar ratio of the hydroxylated benzamide as shown in Formula II to the base in the condensation reaction is 1:(0.2-1), preferably 1:(0.3-0.7).

[0035] In some embodiments, in the condensation reaction, the molar ratio of the hydroxylated benzamide as shown in Formula II to the Br(CH2)nBr is 1:(1-4), preferably 1:(2-3).

[0036] In some embodiments, the condensation reaction is carried out at a reaction temperature that is conventional for such reactions in the art, such as a reflux temperature.

[0037] In some embodiments, the progress of the condensation reaction can be detected using methods conventional in the art (e.g., TLC, GC, HPLC, or NMR). The reaction endpoint is generally defined as the disappearance of the hydroxylated benzamide as shown in Formula II or the cessation of the increase of the amidine-like compounds as shown in Formula III, detected by HPLC. For example, the reaction time is 4-10 hours, preferably 6 hours.

[0038] In some embodiments, the condensation reaction further includes post-processing steps, such as crystallization, filtration, and drying.

[0039] In some embodiments, the hydroxylated benzamide as shown in Formula II is p-hydroxybenzoamide.

[0040] In some embodiments, n is 6 in Br(CH2)nBr, and correspondingly, the amidoside compound as shown in Formula III is hexamidoside.

[0041] This invention also provides a method for preparing an amidotropic compound, dihydroxyethyl sulfonate, comprising the following steps:

[0042] (1) In a solvent, in the presence of tungstic acid, cyanophenol as shown in Formula I is added to an ammonium salt to obtain hydroxylated benzamide as shown in Formula II;

[0043]

[0044] (2) In a solvent, under alkaline conditions, the hydroxy-substituted benzamide shown in Formula II undergoes a condensation reaction with Br(CH2)nBr to obtain the amidine compound shown in Formula III.

[0045]

[0046] Where n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0047] (3) In a solvent, the amidoside compound shown in Formula III reacts with hydroxyethyl sulfonic acid to form a salt, thereby obtaining the amidoside compound dihydroxyethyl sulfonate shown in Formula IV.

[0048]

[0049] In the preparation method of the amidotropic compound dihydroxyethyl sulfonate, the conditions and operations of the addition reaction in step (1) and the condensation reaction in step (2) are independently as described in any one of the present invention.

[0050] In the preparation method of the amidoside dihydroxyethyl sulfonate compound, the conditions and operation of the salt formation reaction in step (3) can be conventional for such reactions in the art, and the present invention particularly prefers the following:

[0051] In some embodiments, the solvent in the salt-forming reaction is a nitrile solvent, preferably acetonitrile.

[0052] In some embodiments, during the salt-forming reaction, the mass-to-volume ratio of the amidine compound as shown in Formula III to the solvent is 0.01-0.1 g / mL, preferably 0.02-0.07 g / mL.

[0053] In some embodiments, in the salt-forming reaction, the molar ratio of the amidine compound as shown in Formula III to the hydroxyethylsulfonic acid is 1:(0.1-1), preferably 1:(0.3-0.5).

[0054] In some embodiments, the salt-forming reaction is carried out at a temperature that is conventional for such reactions in the art, for example, a reaction temperature of 80-100°C, preferably 90-95°C.

[0055] In some embodiments, the progress of the salt formation reaction can be detected using methods conventional in the art (e.g., TLC, GC, HPLC, or NMR). The reaction endpoint is generally defined as the disappearance of the amidotropic compound shown in Formula III or the cessation of increase in the amidotropic compound dihydroxyethyl sulfonate shown in Formula IV, as detected by HPLC. For example, the reaction time is 6-40 hours, preferably 20-30 hours.

[0056] In some embodiments, the salt-forming reaction further includes post-processing steps, such as crystallization, filtration, washing, and drying.

[0057] In some embodiments, the amidoside compound dihydroxyethyl sulfonate as shown in Formula IV is hexamidine dihydroxyethyl sulfonate.

[0058] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0059] The reagents and raw materials used in this invention are all commercially available.

[0060] The positive and progressive effects of this invention are as follows: the amidoside dihydroxyethyl sulfonate and its intermediates obtained by this invention use mild, green and easy-to-store reagents. Compared with the traditional reaction using dry hydrogen chloride gas and ammonia, this invention greatly improves the safety of the reaction and effectively reduces the emission of waste gas, wastewater, and solid waste during the reaction process. At the same time, the reaction is simple to operate, has a short reaction time and a high yield. Detailed Implementation

[0061] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0062] Example 1: Preparation of the catalyst tungstic acid:

[0063] Add 89g of sodium tungstate (dihydrate) to 100mL of water and stir to dissolve. Slowly add the solution dropwise to 67.5mL of boiling concentrated hydrochloric acid (at a temperature not lower than 48℃). During the addition, a yellow precipitate will gradually form. Ensure the temperature of the mixed solution does not drop below 48℃. Complete the addition within 60 minutes. After the addition is complete, continue heating the reaction for another 60 minutes. After the reaction is complete, cool and allow the reaction solution to stand. Filter the solution using a vacuum filtration flask. Wash the solid several times with 5% ammonium nitrate solution and test the filtrate with AgNO3 until the filtrate is neutral (indicating the absence of chloride ions). Dry the filtered solid at 120℃ for 2 hours to obtain 102g of tungstic acid catalyst.

[0064] Example 2: Preparation of p-hydroxybenzomidine

[0065]

[0066] In a 500 mL three-necked flask, a mechanical stirrer, thermometer, and reflux condenser were installed. Tungstic acid (2.1 g, 7.15 mmol), ammonium acetate (43 g, 557.86 mmol), p-cyanophenol (10 g, 83.95 mmol), and N,N-dimethylformamide (220 mL) were added sequentially. After thorough mixing, the mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain crude p-hydroxybenzoic acid, which was recrystallized from ethanol to give 9.8 g of pure p-hydroxybenzoic acid, yield 86% (purity: 93%), ESI m / z: 137.0 (M+H). + . 1 H NMR (400MHz, DMSOd6) δ (ppm) 9.66 (s, 1H), 7.20-7.14 (m, 3H), 6.95 (s, 2H), 6.85-6.82 (m, 2H).

[0067] Example 3: Preparation of hexamidine

[0068]

[0069] In a 250 mL round-bottom flask, sodium hydroxide (2.9 g, 73.5 mmol) was added to a solution of ethanol (60 mL) and water (60 mL) containing p-hydroxybenzoic acid (5.0 g, 36.8 mmol). 1,6-Dibromohexane (3.6 g, 14.7 mmol) was slowly added dropwise to the mixture over 10 minutes. The reaction was carried out under reflux for 6 hours. After the reaction was complete, the temperature was lowered to below 5 °C, and stirring was continued for 1 hour. The mixture was filtered, and the filter cake was dried to obtain 4.9 g of a white powder, with a yield of 94% (purity: 99%), ESI m / z: 355.2 (M+H). + . 1 H NMR (400MHz, DMSOd6) δ (ppm) 7.95-7.87 (m, 4H), 6.85-6.82 (m, 4H), 4.31-4.26 (m, 4H), 1.72-1.69 (m, 4H), 1.56-1.50 (m, 4H).

[0070] Example 4: Preparation of hexamidine dihydroxyethyl sulfonate

[0071]

[0072] In a 100 mL round-bottom flask, hexamididine (5.0 g, 14.1 mmol) was dissolved in acetonitrile (120 mL), followed by the addition of hydroxyethyl sulfonic acid (4.5 g, 35.3 mmol). The reaction mixture was reacted at 90 °C for 24 hours. After the reaction was complete, the temperature was lowered to approximately 5 °C, and stirring was continued for 1 hour. A white needle-like solid precipitated, which was filtered, washed, and dried to give 7.87 g of a white product, with a yield of 92% (purity: 99%) and an ESI m / z of 355.2 (M+H). + . 1 H NMR (400MHz, D2O) δ (ppm) 7.95-7.87 (m, 4H), 6.85-6.82 (m, 4H), 4.31-4.06 (m, 8H), 3.65-3.58 (m, 4H), 1.72-1.69 (m, 4H), 1.56-1.50 (m, 4H).

[0073] Comparative Example 1

[0074] (1) Preparation of 20wt% tungstate sulfate

[0075] In a 500 mL three-necked flask, a mechanical stirrer and thermometer were installed, and the temperature was maintained at approximately 0 °C using an ice bath. Chlorosulfonic acid (46.4 g) was added to dichloromethane (280 mL), followed by the addition of 66.0 g of anhydrous sodium tungstate in batches over ten minutes, with stirring continuing for one hour. A large amount of pale yellow solid was produced during the reaction. The solid was filtered using a vacuum filtration flask, and the solid was washed multiple times with deionized water. The filtrate was tested with AgNO3 until it was neutral (indicating the absence of chloride ions). The filtered solid was then freeze-dried to obtain 65 g of tungstate sulfate.

[0076] (2) Preparation of p-hydroxybenzomid

[0077]

[0078] In a 500 mL three-necked flask, a mechanical stirrer, thermometer, and reflux condenser were installed. Tungrotungstate sulfate (1.0 g, 20 wt%), ammonium acetate (43 g), p-cyanophenol (10 g), and N,N-dimethylformamide (220 mL) were added sequentially. After thorough mixing, the mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain crude p-hydroxybenzoic acid, which was recrystallized from ethanol to give 6.5 g of pure p-hydroxybenzoic acid, yield 57% (purity: 90%), ESI m / z: 137.0 (M+H). + . 1H NMR (400MHz, DMSOd6) δ (ppm) 9.66 (s, 1H), 7.20-7.14 (m, 3H), 6.95 (s, 2H), 6.85-6.82 (m, 2H).

[0079] Comparative Example 2

[0080] (1) Preparation of 30 wt% tungstate sulfate:

[0081] In a 500 mL three-necked flask, a mechanical stirrer and thermometer were installed, and the temperature was maintained at approximately 0 °C using an ice bath. 79.0 g of chlorosulfonic acid was added to 280 mL of dichloromethane, followed by the addition of 66.0 g of anhydrous sodium tungstate in batches over ten minutes, with stirring continuing for one hour. A large amount of pale yellow solid was produced during the reaction. The solid was filtered using a vacuum filtration flask, washed repeatedly with deionized water, and the filtrate was tested with AgNO3 until it was neutral (indicating the absence of chloride ions). The filtered solid was then freeze-dried to obtain 75 g of tungstate sulfate.

[0082] (2) Preparation of p-hydroxybenzomid

[0083]

[0084] In a 500 mL three-necked flask, a mechanical stirrer, thermometer, and reflux condenser were installed. Tungrotungstate sulfate (1.0 g, 30 wt%), ammonium acetate (43 g), p-cyanophenol (10 g), and N,N-dimethylformamide (220 mL) were added sequentially. After thorough mixing, the mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to obtain crude p-hydroxybenzoic acid, which was recrystallized from ethanol to give 8.0 g of pure p-hydroxybenzoic acid, yield 70% (purity: 90%), ESI m / z: 137.0 (M+H). + . 1 H NMR (400MHz, D2O) δ (ppm) 7.18-7.14 (m, 2H), 6.85-6.82 (m, 2H).

Claims

1. A method for preparing hydroxylated benzamide, characterized in that, The process includes the following steps: In a solvent, in the presence of tungstic acid, cyanophenol as shown in Formula I undergoes an addition reaction with an ammonium salt to obtain hydroxylated benzamide as shown in Formula II. 。 2. The method for preparing hydroxylated benzamide according to claim 1, characterized in that, The method for preparing the hydroxylated benzamide satisfies one or more of the following conditions: ① In the addition reaction, the solvent is selected from one or more of nitrogen-containing compound solvents, sulfur-containing compound solvents, hydrocarbon solvents, and ether solvents; ② In the addition reaction, the mass-to-volume ratio of the cyanophenol as shown in Formula I to the solvent is 0.005-0.03 g / mL; ③ In the addition reaction, the molar ratio of the cyanophenol as shown in Formula I to the tungstic acid is (8-20):1; ④ In the addition reaction, the ammonium salt is one or more of ammonium oxalate, ammonium sulfate, ammonium chloride, and ammonium acetate; ⑤ In the addition reaction, the molar ratio of the cyanophenol as shown in Formula I to the ammonium salt is 1:(4-10). ⑥ In the addition reaction, the reaction temperature is 100-150℃; ⑦ In the addition reaction, the reaction time is 10-24 hours; The addition reaction described in ⑧ also includes a post-processing step.

3. The method for preparing hydroxylated benzamide according to claim 2, characterized in that, The post-processing steps are filtration, concentration, and recrystallization.

4. The method for preparing hydroxylated benzamide according to claim 2, characterized in that, The method for preparing the hydroxylated benzamide satisfies one or more of the following conditions: ①The solvent is selected from one or more of DMF, dimethyl sulfoxide, toluene, and 1,4-dioxane; ② The mass-to-volume ratio of the cyanophenol as shown in Formula I to the solvent is 0.012-0.02 g / mL; ③ The molar ratio of the cyanophenol as shown in Formula I to the tungstic acid is (10-12):1; ④ The ammonium salt is ammonium acetate; ⑤ The molar ratio of the cyanophenol as shown in Formula I to the ammonium salt is 1:(5-7); ⑥ The reaction temperature is 110-130℃; The reaction time for ⑦ is 16 hours.

5. The method for preparing hydroxylated benzamide according to claim 4, characterized in that, The solvent is DMF.

6. The method for preparing hydroxylated benzamide according to any one of claims 1-5, characterized in that, The cyanophenol shown in Formula I is p-cyanophenol, and the hydroxy-substituted benzamide shown in Formula II is p-hydroxybenzamide.

7. A method for preparing an amidotropic compound, characterized in that, Includes the following steps: (1) In a solvent, in the presence of tungstic acid, cyanophenol as shown in Formula I is added to an ammonium salt to obtain hydroxylated benzamide as shown in Formula II; ； (2) In a solvent, under alkaline conditions, hydroxylated benzamide as shown in Formula II undergoes a condensation reaction with Br(CH2)nBr to obtain amidine compounds as shown in Formula III. ； Where n is 1, 2, 3, 4, 5, 6, 7 or 8.

8. The method for preparing the amidine-type compounds according to claim 7, characterized in that, The reaction conditions and operation of the addition reaction in step (1) are as described in any one of claims 2-5.

9. The method for preparing the amidine-type compounds according to claim 7, characterized in that, The preparation method of the amidotropic compounds satisfies one or more of the following conditions: ① In the condensation reaction, the solvent is selected from one or more of water and alcohol solvents; ② In the condensation reaction, the mass-to-volume ratio of the hydroxylated benzamide as shown in Formula II to the solvent is 0.01-0.1 g / mL; ③ In the condensation reaction, the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; ④ In the condensation reaction, the molar ratio of the hydroxylated benzamide as shown in Formula II to the base is 1:(0.2-1). ⑤ In the condensation reaction, the molar ratio of the hydroxylated benzamide as shown in Formula II to the Br(CH2)nBr is 1:(1-4). ⑥ In the condensation reaction, the reaction temperature is the reflux temperature; ⑦ In the condensation reaction, the reaction time is 4-10 hours; The condensation reaction described in ⑧ also includes a post-processing step.

10. The method for preparing the amidine-type compounds according to claim 9, characterized in that, The preparation method of the amidotropic compounds satisfies one or more of the following conditions: ① In the condensation reaction, the solvent is a mixed solution of water and alcohol; ② In the condensation reaction, the mass-to-volume ratio of the hydroxylated benzamide as shown in Formula II to the solvent is 0.02-0.07 g / mL; ③ In the condensation reaction, the base is sodium hydroxide; ④ In the condensation reaction, the molar ratio of the hydroxylated benzamide as shown in Formula II to the base is 1:(0.3-0.7). ⑤ In the condensation reaction, the molar ratio of the hydroxylated benzamide as shown in Formula II to the Br(CH2)nBr is 1:(2-3). ⑥ In the condensation reaction, the reaction time is 6 hours; In the condensation reaction described in ⑦, the post-processing steps are crystallization, filtration, and drying.

11. The method for preparing the amidine-type compounds according to claim 10, characterized in that, It meets one or two of the following conditions: ①In the condensation reaction, the solvent is a mixed solution of water and ethanol; In the condensation reaction described in ②, the volume ratio of the alcohol solvent to water is 1:(0.5-3).

12. The method for preparing the amidine-type compounds according to claim 11, characterized in that, In the condensation reaction, the volume ratio of the alcohol solvent to water is 1:(0.8-2).

13. The method for preparing the amidine-type compounds according to claim 7, characterized in that, The cyanophenol shown in Formula I is p-cyanophenol, the hydroxy-substituted benzidine shown in Formula II is p-hydroxybenzidine, n is 6, and the amidine compound shown in Formula III is hexamididine.

14. A method for preparing a amidoside compound dihydroxyethyl sulfonate, characterized in that, Includes the following steps: (1) In a solvent, in the presence of tungstic acid, cyanophenol as shown in Formula I is added to an ammonium salt to obtain hydroxylated benzamide as shown in Formula II; ； (2) In a solvent, under alkaline conditions, hydroxylated benzamide as shown in Formula II undergoes a condensation reaction with Br(CH2)nBr to obtain amidine compounds as shown in Formula III. ； (3) In a solvent, the amidoside compound shown in Formula III reacts with hydroxyethyl sulfonic acid to form a salt, yielding the amidoside compound dihydroxyethyl sulfonate shown in Formula IV; ； Where n is 1, 2, 3, 4, 5, 6, 7 or 8.

15. The method for preparing the amidoside dihydroxyethyl sulfonate compound according to claim 14, characterized in that, The reaction conditions and operation of the addition reaction in step (1) are as described in any one of claims 2-5; the reaction conditions and operation of the condensation reaction in step (2) are as described in any one of claims 9-12.

16. The method for preparing the amidoside dihydroxyethyl sulfonate compound according to claim 14, characterized in that, The preparation method of the amidotropic compound dihydroxyethyl sulfonate satisfies one or more of the following conditions: ① In the salt-forming reaction, the solvent is a nitrile solvent; ② In the salt-forming reaction, the mass-to-volume ratio of the amidine compound as shown in Formula III to the solvent is 0.01-0.1 g / mL; ③ In the salt-forming reaction, the molar ratio of the amidine compound as shown in Formula III to the hydroxyethyl sulfonic acid is 1:(0.1-1). ④ In the salt formation reaction, the reaction temperature is 80-100℃; ⑤ In the salt formation reaction, the reaction time is 6-40 hours; The salt-forming reaction described in section ⑥ also includes a post-processing step.

17. The method for preparing the amidoside dihydroxyethyl sulfonate compound according to claim 16, characterized in that, The preparation method of the amidotropic compound dihydroxyethyl sulfonate satisfies one or more of the following conditions: ①In the salt-forming reaction, the solvent is acetonitrile; ② In the salt-forming reaction, the mass-to-volume ratio of the amidine compound as shown in Formula III to the solvent is 0.02-0.07 g / mL; ③ In the salt-forming reaction, the molar ratio of the amidine compound as shown in Formula III to the hydroxyethyl sulfonic acid is 1:(0.3-0.5). ④ In the salt formation reaction, the reaction temperature is 90-95℃; ⑤ In the salt formation reaction, the reaction time is 20-30 hours; In the salt formation reaction described in ⑥, the post-processing steps are crystallization, filtration, washing, and drying.

18. The method for preparing the amidoside dihydroxyethyl sulfonate compound according to claim 14, characterized in that, The cyanophenol shown in Formula I is p-cyanophenol, the hydroxy-substituted benzamide shown in Formula II is p-hydroxybenzamide, n is 6, the amidine compound shown in Formula III is hexamidine, and the amidine compound dihydroxyethyl sulfonate shown in Formula IV is hexamidine dihydroxyethyl sulfonate.

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