A process for the preparation of hexamidines

Abstract

The application discloses a preparation method of hexamidine. The preparation method is as follows: 1,6-(p-cyanophenyl) hexane diether (I) is subjected to alcoholysis reaction with alcohol under the catalysis of a solid superacid, and after the reaction, compound (II) is obtained; the solid superacid is removed through filtration, then ammonia is directly added into the filtrate to generate aminolysis reaction, and hexamidine shown in formula (III) is prepared. 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 present application relates to the technical field of fine chemical synthesis, in particular to a preparation method of hexamidine. BACKGROUND

[0002] Hexamidine diisethionate has broad-spectrum antibacterial and bactericidal ability, is a new type of anti-dandruff and itching agent, is safe and mild, has small skin irritation, has good compatibility with common raw materials in daily chemical products, and is widely used in the cosmetic industry. Hexamidine is a key intermediate for synthesizing hexamidine diisethionate.

[0003] The current synthesis process of hexamidine mainly includes the following steps: 4-hydroxybenzonitrile and 1,6-dibromohexane undergo nucleophilic substitution reaction to obtain an intermediate 1,6-(p-cyanophenyl) hexanediol ether, and then the intermediate undergoes alcoholysis and ammonolysis to obtain hexamidine. In the synthesis of hexamidine, the first step of nucleophilic substitution and the third step of ammonolysis are simple and can be industrialized, and the key step is the second step of alcoholysis. At present, alcoholysis is divided into two kinds of catalytic ways, the first kind is base catalysis, for example, synthetic chemistry, 2009, vol. 17, No. 5, p642-644, sodium alcoholate, lithium amide and the like are used, the yield of this method is low, the strong base used is high-risk, the equipment requirement is high, and the application is less. The second kind is the currently used acid catalysis, for example, patents CN105566163A, CN105884652A, CN105037206A and CN118221550A use hydrogen chloride, trifluoroacetic acid, acetic acid, methane sulfonic acid and concentrated sulfuric acid, this method is difficult to operate, a large amount of acid gas is generated, the production equipment is corroded, a large amount of acid wastewater is generated, the environment is polluted, and the product obtained contains a large amount of unreacted acid, the product needs to be purified, the purification step is complicated, and the yield is low. SUMMARY

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

[0005] In order to achieve the above purpose, the following technical scheme is adopted in the present application:

[0006] A preparation method of hexamidine, comprising the following steps:

[0007] Step 1: 1,6-(p-cyanophenyl) hexanediol ether is added to an alcohol solvent, solid superacid is added, and continuous reaction is carried out at 10-30℃ for 18-24h, and after the reaction is completed, the solid superacid is filtered out;

[0008] Step 2: add ammonia source to the filtrate, react for 3h at 15-25℃, reflux until the reaction is completed, recover the solvent under reduced pressure, and the obtained solid is 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) hexanediol ether to alcohol is 1:1.6-5.

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

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

[0013] According to the above scheme, in step 1, the filtered solid super acid is washed with water and dried, and can be reused.

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

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

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

[0017] 1) In the alcoholysis reaction of 1,6-(p-cyanophenyl) hexanediol ether, the present application uses solid acid instead of traditional acid and base, avoiding the use of strong corrosive acid and base, overcoming the defects of serious pollution, poor safety, strict equipment corrosion requirement, large amount of waste acid and base and difficult treatment.

[0018] 2) The solid super acid used in the present application is subjected to alcoholysis with alcohol under anhydrous conditions, and the yield of the obtained intermediate product is high, which can be subjected to the next ammonia source reaction without separation. After the alcoholysis reaction is completed, the solid super acid is filtered, and the solid super acid can be recycled. Moreover, after the solid super acid is filtered, there is no residual acid catalyst in the reaction with the ammonia source, so that the product does not need to be purified, not only the step is simple, but also the purity and yield are significantly improved compared with conventional acid and base catalysts.

[0019] Therefore, the application uses the solid super acid in the alcoholysis reaction of hexamethylene diamine, and unexpected technical effects are obtained, the operation is simple, the product has high purity and high yield, and the application prospect is very high. DETAILED DESCRIPTION

[0020] The following provides some specific examples to verify the performance of the method for implementing the application.

[0021] Example 1

[0022] A 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel was charged with 1,6-(p-cyanophenyl) hexane diether 100.0 g (0.31 mol), anhydrous methanol 215.0 mL, solid super acid SO4 2- / Al2O3 20.0 g, and the reaction was carried out at 25 ℃ for 18 h, and the reaction was monitored by liquid spectrum. After the reaction was completed, filtration was performed (the filtered solid super acid was washed once with 100.0 g of ethanol and once with 100.0 g of water, and was dried for standby use), ammonia gas was introduced into the filtered mother liquor at 20 ℃ until the weight was constant, the reaction was carried out at 20 ℃ for 3 h, and the reaction liquid was slowly warmed to reflux. The reaction was monitored by liquid spectrum, and after the reaction was completed, the reaction liquid was cooled to 0-5 ℃, filtration was performed, and drying was performed, to obtain 105.2 g of white powder, with a content of 99.55% (HPLC) and a yield of 95.0%. 1 H-NMR (500 MHz, d6-DMSO) δ 9.13 (s, 4H), 8.90 (s, 4H), 7.78 (d, J = 8.5 Hz, 4H), 7.11 (d, J = 9.0 Hz, 4H), 4.18 (t, J = 6.5 Hz, 4H), 1.70 (t, J = 6.0 Hz, 4H), 1.45 (m, 4H).

[0023] Example 2

[0024] A 500 mL four-necked flask equipped with a stirring device, a thermometer, and a constant pressure dropping funnel was charged with 1,6-(p-cyanophenyl) hexane diether 100.0 g (0.31 mol), anhydrous methanol 215.0 mL, solid super acid SO4 2- / Al2O3 20.0 g, and the reaction was carried out at 25 ℃ for 18 h, and the reaction was monitored by liquid spectrum. After the reaction was completed, filtration was performed (the filtered solid super acid was washed once with 100.0 g of ethanol and once with 100.0 g of water, and was dried for standby use), ammonia gas was introduced into the filtered mother liquor at 20 ℃ until the weight was constant, the reaction was carried out at 20 ℃ for 3 h, and the reaction liquid was slowly warmed to reflux. The reaction was monitored by liquid spectrum, and after the reaction was completed, the reaction liquid was cooled to 0-5 ℃, filtration was performed, and drying was performed, to obtain 105.2 g of white powder, with a content of 99.55% (HPLC) and a yield of 95.0%.

[0025] Example 3

[0026] Add 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid SO4 to a 500 mL four-necked flask equipped with a stirrer, thermometer, and constant-pressure dropping funnel. 2- 50.0 g of Al₂O₃ was reacted at 25°C for 19 h. The reaction was monitored by liquid chromatography until completion. The mixture was then filtered (the filtered solid superacid was washed once with 100.0 g of ethanol, then once with 100.0 g of water, and dried for later use). Ammonia gas was then introduced into the mother liquor at 20°C until constant weight was achieved. The mixture was reacted at 20°C for 3 h, and the temperature was slowly increased to reflux. The reaction was monitored by liquid chromatography until completion. The reaction solution was cooled to 0–5°C, filtered, and dried to obtain 105.4 g of white powder with a purity of 99.60% (HPLC) and a yield of 95.2%.

[0027] Example 4

[0028] Add 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid PO4 to a 500 mL four-necked flask equipped with a stirrer, thermometer, and constant-pressure dropping funnel. 3- 20.0 g of Al₂O₃ was reacted at 25°C for 23 h. The reaction was monitored by liquid chromatography until completion. The mixture was then filtered (the filtered solid superacid was washed once with 100.0 g of ethanol, then once with 100.0 g of water, and dried for later use). Ammonia gas was then introduced into the mother liquor at 20°C until constant weight was achieved. The mixture was reacted at 20°C for 3 h, and the temperature was slowly increased to reflux. The reaction was monitored by liquid chromatography until completion. The reaction solution was cooled to 0–5°C, filtered, and dried to obtain 100.9 g of white powder with a purity of 99.42% (HPLC) and a yield of 91.1%.

[0029] Example 5

[0030] Add 100.0 g (0.31 mol) of 1,6-(p-cyanophenyl)hexanediether, 215.0 mL of anhydrous ethanol, and solid superacid SO4 to a 500 mL four-necked flask equipped with a stirrer, thermometer, and constant-pressure dropping funnel. 2- / Al2O3 10.0g, PO4 3- 10.0 g of Al₂O₃ was reacted at 25°C for 21 h. The reaction was monitored by liquid chromatography until completion. The mixture was then filtered (the filtered solid superacid was washed once with 100.0 g of ethanol, then once with 100.0 g of water, and dried for later use). Ammonia gas was then introduced into the mother liquor at 20°C until constant weight was reached. The mixture was reacted at 20°C for 3 h. The temperature was then slowly increased to reflux. The reaction was monitored by liquid chromatography until completion. The reaction solution was cooled to 0–5°C, filtered, and dried to obtain 103.0 g of white powder with a purity of 99.49% (HPLC) and a yield of 93.0%.

[0031] Example 6

[0032] Into a 500ml four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, 100.0g (0.31mol) of 1,6-(p-cyanophenyl) hexanediether, 215.0ml of anhydrous ethanol and 20.0g of solid superacid SO4 2- / Al2O3 20.0g were charged. The reaction was carried out at 25°C for 22h. The reaction was monitored by liquid spectrum. After the reaction was completed, the solid superacid was filtered (the filtered solid superacid was washed once with 100.0g of ethanol and once with 100.0g of water, and dried for use). Then, 83.6g of ammonium chloride (1.56mol) was added to the filtered mother liquor at 20°C. The reaction was carried out at 20°C for 3h. The reaction was monitored by liquid spectrum. After the reaction was completed, the reaction solution was cooled to 0-5°C and filtered. The white powder was dried to obtain 103.7g of white powder with a content of 99.51% (HPLC) and a yield of 93.7%.

[0033] Example 7

[0034] Into a 500ml four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, 100.0g (0.31mol) of 1,6-(p-cyanophenyl) hexanediether, 215.0ml of anhydrous ethanol and 20.0g of solid superacid SO4 2- / Al2O3 20.0g were charged. The reaction was carried out at 25°C for 22h. The reaction was monitored by liquid spectrum. After the reaction was completed, the solid superacid was filtered (the filtered solid superacid was washed once with 100.0g of ethanol and once with 100.0g of water, and dried for use). Then, 83.6g of ammonium chloride (1.56mol) was added to the filtered mother liquor at 20°C. The reaction was carried out at 20°C for 3h. The reaction was monitored by liquid spectrum. After the reaction was completed, the reaction solution was cooled to 0-5°C and filtered. The white powder was dried to obtain 103.7g of white powder with a content of 99.51% (HPLC) and a yield of 93.7%.

[0035] Example 8

[0036] Into a 500ml four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, 100.0g (0.31mol) of 1,6-(p-cyanophenyl) hexanediether, 215.0ml of anhydrous ethanol and 20.0g of solid superacid SO4 2- / Al2O3 20.0g were charged. The reaction was carried out at 25°C for 22h. The reaction was monitored by liquid spectrum. After the reaction was completed, the solid superacid was filtered (the filtered solid superacid was washed once with 100.0g of ethanol and once with 100.0g of water, and dried for use). Then, 83.6g of ammonium chloride (1.56mol) was added to the filtered mother liquor at 20°C. The reaction was carried out at 20°C for 3h. The reaction was monitored by liquid spectrum. After the reaction was completed, the reaction solution was cooled to 0-5°C and filtered. The white powder was dried to obtain 103.7g of white powder with a content of 99.51% (HPLC) and a yield of 93.7%.

[0037] Comparative Example 1

[0038] Into a 500ml four-necked flask equipped with a stirrer, thermometer and connected with a tail gas absorption device, 100.0g of 1,6-(p-cyanophenyl) hexane diether (0.31mol) and 215.0ml of anhydrous ethanol were added, the internal temperature was kept at 25°C, dry hydrogen chloride gas was bubbled into the reaction system until saturation, the bubbling was stopped, and then the reaction was kept at 25°C for 40h. The reaction was monitored by liquid chromatography. After filtration, the filter cake was again put into a 500ml four-necked flask, 215ml of methanol was added, then ammonia gas was bubbled into the reaction liquid until the constant weight at 20°C, the reaction was carried out at 20°C for 3h, and then the temperature was slowly increased to reflux. The reaction was monitored by liquid chromatography. After the reaction was completed, the reaction liquid was cooled to 0-5°C, filtered, recrystallized with methanol, dried, and 57.1g of white powder was obtained, with a content of 99.21%(HPLC) and a yield of 51.6%.

[0039] The above description is only a basic description of the inventive concept, and any transformation of the technical solution according to the present application shall belong to the protection scope of the present application.

Claims

1. A process for the preparation of hexamidines, characterized in that, It comprises the following steps: 1,6-(p-cyanophenyl) hexane diether (I) is added into an alcohol solvent, solid super acid is added, continuous reaction is carried out at 10-30℃ for 18-24h, after the reaction is completed, compound (II) is obtained, the solid super acid is removed by filtration, an ammonia source is directly added into the filtrate, reaction is carried out at 15-25℃ for 2-4h, then reflux is carried out until the reaction is completed, the solvent is recovered under reduced pressure, and the obtained solid is hexamidine (III): ， The solid super acid is SO4 2- / ZrO2, PO4 3- / ZrO2, SO4 2- / TiO2, PO4 3- / TiO2, PO4 3- / Al2O3 or SO4 2- / Al2O3 or a mixture of one or more of the above.

2. The production method according to claim 1, characterized by, The alcohol is one of methanol, ethanol, isopropanol and n-butanol.

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

4. The production method according to claim 1, characterized by, The mass ratio of 1,6-(p-cyanophenyl) hexane diether to solid super acid is 1:0.2-0.

5.

5. The method of claim 1, wherein, The ammonia source is one of ammonia gas, ammonia water, ammonium chloride, urea and hydroxylamine.

6. The method of claim 1, wherein, The molar ratio of 1,6-(p-cyanophenyl) hexane diether to ammonia source is 1:2-6.

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