Preparation method of hexamidine

Abstract

The invention discloses a preparation method of hexamidine, which comprises the following steps of: carrying out alcoholysis reaction on 1, 6-(p-cyanophenyl) hexanediether (I) and alcohol under the catalysis of solid superacid to obtain a compound (II) after the reaction, filtering to remove the solid superacid, and then directly adding ammonia into filtrate to carry out ammonolysis reaction to prepare hexamidine shown as a formula (III). The solid superacid is selected to replace traditional acid and alkali, the solid superacid can be recycled for multiple times, the reaction process is simple, green and environment-friendly, the yield is high, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemical synthesis, and in particular to a method for preparing hexamidine. Background Art

[0002] Hexamidine di(hydroxyethyl sulfonic acid) salt has broad-spectrum antibacterial and bactericidal capabilities. It is a new type of anti-dandruff and antipruritic agent. It is safe and mild, has little irritation to the skin, has excellent compatibility with commonly used raw materials in daily chemical products, and is widely used in the cosmetics industry. Hexamidine is the key intermediate for the synthesis of hexamidine di(hydroxyethyl sulfonic acid) salt.

[0003] The current synthesis process of hexamididine is mainly to react 4-hydroxybenzonitrile with 1,6-dibromohexane to undergo nucleophilic substitution reaction to obtain the intermediate 1,6-(p-cyanophenyl)hexane diether, and then the intermediate undergoes alcoholysis and aminolysis to obtain hexamididine. In the process of synthesizing hexamididine, the first step of nucleophilic substitution and the third step of aminolysis are simple and can be industrialized. The key step is the second step of alcoholysis. Currently, alcoholysis is divided into two catalytic methods. The first is base catalysis, such as Synthetic Chemistry, Vol. 17, No. 5, 2009, p642-644, using sodium alcoholate, lithium amide, etc. This method has a low yield, the strong base used is highly dangerous, and has high requirements for equipment, so it is less used. The second is acid catalysis, which is currently used more frequently. For example, patents CN105566163A, CN105884652A, CN105037206A, and CN118221550A use hydrogen chloride, trifluoroacetic acid, acetic acid, methanesulfonic acid, concentrated sulfuric acid, etc. This method is difficult to operate and will produce a large amount of acidic gas, which will corrode production equipment and produce a large amount of acidic wastewater, causing great environmental pollution. In addition, the obtained product contains a large amount of unreacted acid, and the product needs to be purified. The purification steps are cumbersome and the yield is low. Summary of the invention

[0004] In order to solve the problems existing in the prior art, the present invention provides a method for preparing hexamidine, which has simple process operation, avoids the use of a large amount of acidic and alkaline substances for catalysis, uses a small amount of solvent, has high product purity and high yield.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

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

[0007] Step 1: 1,6-(p-cyanophenyl)hexanediether is added to an alcohol solvent, and a solid superacid is added, and the reaction is continued at 10 to 30° C. for 18 to 24 hours. After the reaction is completed, the solid superacid is filtered out;

[0008] Step 2: Add an ammonia source to the filtrate, react at 15-25°C for 3 hours, reflux until the reaction is complete, and recover the solvent under reduced pressure to obtain a solid of hexamidine.

[0009] According to the above scheme, in step 1, the alcohol is one of methanol, ethanol, isopropanol or n-butanol.

[0010] According to the above scheme, in step 1, the mass ratio of 1,6-(p-cyanophenyl)hexanediether to alcohol is 1:1.6-5.

[0011] According to the above scheme, in step 1, the solid superacid includes SO4 2- / ZrO2,PO4 3- / ZrO2, SO4 2- / TiO2,PO4 3- / TiO2,PO4 3- / Al2O3 or SO4 2- / One of Al2O3.

[0012] According to the above scheme, in step 1, the mass ratio of 1,6-(p-cyanophenyl)hexanediether to the solid superacid is 1:0.2-0.5.

[0013] According to the above scheme, in step 1, the solid superacid filtered out can be reused after being washed with water and dried.

[0014] According to the above scheme, in step 2, the ammonia source is one of ammonia gas, ammonia water, ammonium chloride, urea or hydroxylamine.

[0015] According to the above scheme, in step 2, the molar ratio of 1,6-(p-cyanophenyl)hexanediether to ammonia is 1:2-5.

[0016] Compared with the prior art, the present invention has the following advantages:

[0017] 1) In the alcoholysis reaction of 1,6-(p-cyanophenyl)hexanediol, the present invention adopts solid acid instead of traditional acid and alkali, avoids the use of highly corrosive acid and alkali, overcomes the defects of serious pollution, poor safety, strict equipment anti-corrosion requirements, large amount of waste acid and waste alkali and difficulty in handling, etc.

[0018] 2) The solid superacid used in the present invention is subjected to alcoholysis with alcohol under anhydrous conditions to obtain an intermediate product with high yield, and the next step of ammonia source reaction can be carried out without separation. The solid superacid can be recycled by filtering the solid superacid after the alcoholysis reaction is completed; and since no acid catalyst remains when reacting with the ammonia source after the solid superacid is filtered out, the product does not need to be purified, and not only the steps are simple, but also the purity and yield are significantly improved compared with conventional acid-base catalysts.

[0019] Therefore, the present invention uses the solid superacid in the alcoholysis reaction of hexamidine, obtains unexpected technical effects, is simple to operate, and has high product purity and high yield, and has great industrial application prospects. DETAILED DESCRIPTION

[0020] Some specific examples are provided below to verify the performance of the implementation method of the present invention.

[0021] Example 1

[0022] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous methanol, and solid superacid SO4 were added. 2- / Al2O320.0g, keep warm at 25℃ for 18h, the reaction is completed by liquid spectrum monitoring, filter (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), and then ammonia is passed into the filtered mother liquor at 20℃ to constant weight, react at 20℃ for 3h, slowly heat to reflux, the reaction is completed by liquid spectrum monitoring, the reaction solution is cooled to 0-5℃, filtered, and dried to obtain 105.2g white powder, content 99.55% (HPLC), yield 95.0%. 1 H-NMR (500MHz, d6-DMSO) δ9.13 (s, 4H), 8.90 (s, 4H), 7.78 (d, J = 8.5Hz, 4H), 7. 11(d,J=9.0Hz,4H), 4.18(t,J=6.5Hz,4H), 1.70(t,J=6.0Hz,4H), 1.45(m,4H).

[0023] Example 2

[0024] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid SO4 were added. 2- / Al2O320.0g, keep warm at 25℃ and react for 22h. After the reaction is completed by liquid spectrum monitoring, filter (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), then ammonia is passed into the filtered mother liquor at 20℃ to constant weight, react at 20℃ for 3h, slowly heat to reflux, after the reaction is completed by liquid spectrum monitoring, cool the reaction solution to 0-5℃, filter and dry to obtain 105.1g white powder with a content of 99.54% (HPLC) and a yield of 94.9%.

[0025] Example 3

[0026] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid SO4 were added. 2- / Al2O350.0g, keep warm at 25℃ and react for 19h. After the reaction is completed by liquid spectrum monitoring, filter (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), then ammonia is introduced into the filtered mother liquor at 20℃ to constant weight, react at 20℃ for 3h, slowly heat to reflux, after the reaction is completed by liquid spectrum monitoring, cool the reaction solution to 0-5℃, filter and dry to obtain 105.4g white powder with a content of 99.60% (HPLC) and a yield of 95.2%.

[0027] Example 4

[0028] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid PO4 were added. 3- / Al2O320.0g, keep warm at 25℃ and react for 23h. After the reaction is completed by liquid spectrum monitoring, filter (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), then ammonia is passed into the filtered mother liquor at 20℃ to constant weight, react at 20℃ for 3h, slowly heat to reflux, after the reaction is completed by liquid spectrum monitoring, cool the reaction solution to 0-5℃, filter and dry to obtain 100.9g white powder with a content of 99.42% (HPLC) and a yield of 91.1%.

[0029] Example 5

[0030] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid SO4 were added. 2- / Al2O310.0g,PO4 3- / Al2O310.0g, keep warm at 25℃ and react for 21h. After the reaction is completed as monitored by liquid spectrum, filter (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), then ammonia is passed into the filtered mother liquor at 20℃ to constant weight, react at 20℃ for 3h, slowly heat to reflux, after the reaction is completed as monitored by liquid spectrum, the reaction solution is cooled to 0-5℃, filtered, and dried to obtain 103.0g white powder with a content of 99.49% (HPLC) and a yield of 93.0%.

[0031] Example 6

[0032] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and the recovered solid superacid SO4 were added. 2- / Al2O320.0g, keep warm at 25℃ and react for 22h. After the reaction is completed by liquid spectrum monitoring, filter (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), then ammonia is passed into the filtered mother liquor at 20℃ to constant weight, react at 20℃ for 3h, slowly heat to reflux, after the reaction is completed by liquid spectrum monitoring, cool the reaction solution to 0-5℃, filter and dry to obtain 104.6g white powder with a content of 99.53% (HPLC) and a yield of 94.5%.

[0033] Example 7

[0034] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid SO4 were added. 2- / Al2O320.0g, keep warm at 25℃ and react for 22h. The reaction is completed by liquid spectrum monitoring, and filtered (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), and then 83.6g ammonium chloride (1.56mol) is added to the filtered mother liquor at 20℃, and the reaction is carried out for 3h at 20℃. The temperature is slowly raised to reflux. The reaction is completed by liquid spectrum monitoring, and the reaction solution is cooled to 0-5℃, filtered, and dried to obtain 103.7g white powder with a content of 99.51% (HPLC) and a yield of 93.7%.

[0035] Example 8

[0036] In a 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and the recovered solid superacid SO4 were added. 2- / Al2O320.0g, keep warm at 25℃ for 22h, the reaction is completed by liquid spectrum monitoring, filtered (the filtered solid super acid is rinsed once with 100.0g ethanol, then rinsed once with 100.0g water, and dried for use), and then 93.8g urea (1.56mol) is added to the filtered mother liquor at 20℃, and the reaction is carried out for 3h at 20℃. The temperature is slowly raised to reflux, the reaction is completed by liquid spectrum monitoring, the reaction solution is cooled to 0-5℃, filtered, and dried to obtain 103.1g white powder with a content of 99.48% (HPLC) and a yield of 93.1%.

[0037] Comparative Example 1

[0038] To a 500mL four-necked flask equipped with a stirring device, a thermometer and connected to a tail gas absorption device, 100.0g (0.31mol) of 1,6-(p-cyanophenyl)hexanediether and 215.0mL of anhydrous ethanol were added, the internal temperature was maintained at 25°C, dry hydrogen chloride gas was introduced into the reaction system until saturation, ventilation was stopped, and then the reaction was kept at 25°C for 40h. The reaction was completed by liquid spectrum monitoring, filtered, and the filter cake was put into a 500mL four-necked flask again, and 215mL of methanol was added. Then, ammonia gas was introduced into the reaction solution at 20°C to constant weight, and the reaction was carried out at 20°C for 3h. The temperature was slowly raised to reflux. The reaction was completed by liquid spectrum monitoring, the reaction solution was cooled to 0-5°C, filtered, recrystallized from methanol, and dried to obtain 57.1g of white powder with a content of 99.21% (HPLC) and a yield of 51.6%.

[0039] The above contents are only basic descriptions of the concept of the present invention, and any changes made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for preparing hexamidine, characterized in that, The steps include: 1,6-(p-cyanophenyl)hexanediether (I) is added to an alcohol solvent, and a solid superacid is added. The reaction is continued at 10-30°C for 18-24 hours. After the reaction is completed, compound (II) is obtained. The solid superacid is removed by filtration, and an ammonia source is directly added to the filtrate. The reaction is carried out at 15-25°C for 2-4 hours, and then refluxed until the reaction is completed. The solvent is recovered under reduced pressure, and the obtained solid is hexamidine (III):

2. The preparation method according to claim 1, characterized in that: The alcohol is one of methanol, ethanol, isopropanol or n-butanol.

3. The preparation method according to claim 1, characterized in that: The mass ratio of 1,6-(p-cyanophenyl)hexanediether to alcohol is 1:1.6-5.

4. The preparation method according to claim 1, characterized in that: The solid superacid includes SO4 2- / ZrO2,PO4 3- / ZrO2, SO4 2- / TiO2,PO4 3- / TiO2,PO4 3- / Al2O3 or SO4 2- / Al2O3 or a mixture of two or more.

5. The preparation method according to claim 1, characterized in that: The mass ratio of 1,6-(p-cyanophenyl)hexanediether to the solid superacid is 1:0.2-0.

5.

6. The preparation method according to claim 1, characterized in that: The ammonia source is one of ammonia gas, ammonia water, ammonium chloride, urea or hydroxylamine.

7. The preparation method according to claim 1, characterized in that: The molar ratio of 1,6-(p-cyanophenyl)hexanediether to the ammonia source is 1:2-6.

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