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The synthetic method of hexamidine

A synthesis method and a technology of hexamidine are applied in the field of organic synthesis, and can solve the problems of large amount of waste acid, low yield of intermediate II, low industrial value, etc., and achieve the acceleration of cyano addition reaction, the provision of production safety, Avoid volatile effects

Active Publication Date: 2016-08-17
XIAN WONDER SCI & TECH
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  • Summary
  • Abstract
  • Description
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Problems solved by technology

[0005] In the catalyzed reaction of sodium methoxide and acetic acid reported in the literature in the second step of synthesis, the yield of intermediate II is very low, and even the product cannot be obtained, and the industrial value is small; the method that can obtain the expected result at present is still the catalyzed reaction of anhydrous hydrogen chloride, There are obvious defects in this method: firstly, hydrogen chloride gas is a highly corrosive gas, which is difficult to purchase in the market, and the industry produces hydrogen chloride gas by itself, causing serious pollution, poor safety, strict anti-corrosion requirements for equipment, and a large amount of waste acid that is difficult to handle; secondly, This method needs to use diethyl ether to precipitate solids, and diethyl ether is highly volatile and is a flammable dangerous product, which has potential safety hazards
In short, this method is not suitable for large-scale industrial production

Method used

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  • The synthetic method of hexamidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Synthesis of 1,6-(p-cyanophenyl) hexylene diether (intermediate Ⅰ):

[0033] In a 2L three-necked flask equipped with stirring, a thermometer, a dropping funnel, and a reflux condenser, add 23.3g (0.56mol) of sodium hydroxide and 240ml of water in sequence, stir to dissolve completely, and then cool to room temperature; dropwise add Contain 66.7g (0.56mol) of 4-cyanophenol in 267ml of ethanol solution, control the rate of addition, and keep the temperature at 25-30°C; after the dropwise addition, slowly increase the temperature, react at 80°C for 2 hours, and cool to room temperature; dropwise add 65.3g (0.27mol) 1,6-dibromohexane, reflux (80-85°C) for 8-10h, cool to 0°C, stir for 2-3h, and filter with suction to obtain 98g of intermediate Ⅰ white solid product, add the wet product to In 417ml of ethanol, heated and stirred to 75°C for reflux reaction for 2-3h, cooled, filtered at about 50°C, dried the filter cake, weighed to obtain 70.01g, yield 81%.

[0034] (2) Sy...

Embodiment 2

[0040] (1) Synthesis of 1,6-(p-cyanophenyl) hexylene diether (intermediate I): same as Example 1(1)

[0041] (2) Synthesis of 1,6-(p-iminocarbamate ethylphenyl) hexamethylene diether (intermediate II):

[0042] Add 70g (0.22mol) of intermediate I product, 400ml ethanol, and 1260ml toluene to the reaction flask, add 67g methanesulfonic acid (4.8% of the total amount of the reaction system) under stirring under 10°C, and heat up at 39°C for 43h. It was detected by TLC that the raw material of intermediate I had completely disappeared. After the reaction was completed, it was cooled to below 10°C, filtered, and dried to obtain 86.4 g of crude product. Yield 95.2%. The product is identified as the expected structure by proton nuclear magnetic spectrum, and the proton spectrum data are the same as those in Example 1 (2).

[0043] (3) Synthesis of hexamidine (4-(6-(4-formamidinephenoxy)hexyloxy)benzamidine):

[0044] With embodiment 1 (3). The total yield of the above-mentioned ...

Embodiment 3

[0046] (1) Synthesis of 1,6-(p-cyanophenyl) hexylene diether (intermediate I): same as Example 1(1)

[0047] (2) Synthesis of 1,6-(p-iminocarbamate ethylphenyl) hexamethylene diether (intermediate II):

[0048] Add 70g (0.22mol) of intermediate I product, 400ml of ethanol, and 1260ml of toluene to the reaction flask, add 164g of trifluoroacetic acid (10% of the total amount of the reaction system) under stirring under 10°C, raise the temperature at 40°C for 43h, TLC It was detected that the raw material of intermediate I had completely disappeared, and the reaction was completed, cooled to below 10°C, filtered, and dried to obtain 88.9 g of crude product. Yield 98%. The product is identified as the expected structure by proton nuclear magnetic spectrum, and the proton spectrum data are the same as those in Example 1 (2).

[0049] (3) Synthesis of hexamidine (4-(6-(4-formamidinephenoxy)hexyloxy)benzamidine):

[0050] With embodiment 1 (3). The total yield of the above-menti...

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Abstract

The invention discloses a synthetic method of hexamidine. Hexamidine is a key raw material for producing antibiotic medicines hexamidine salts (such as dihydrochloride and dihydroxyethyl sulfonate). The synthetic method of hexamidine comprises the following steps: 1, reacting p-cyanophenol with 1,6-dibromohexane in an ethanol-water solution of sodium hydroxide to prepare 1,6-(p-cyanophenyl)hexyl diether (an intermediate I); 2, carrying out alcoholysis on the intermediate I in ethanol-toluene under the catalysis of trifluoroacetic acid or methanesulfonic acid to prepare 1,6-(p-ethyl iminoformate phenyl)hexyl diether (an intermediate II); and 3, carrying out aminolysis on the intermediate II in a methanol-ammonia solution to prepare hexamidine. The total yield of three-step synthesis is greater than 72%, and a nuclear magnetism identification result shows that the above obtained product is a preconceived structure product. The method is suitable for large-scale industrial production.

Description

【Technical field】 [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of hexamidine. 【Background technique】 [0002] Hexamidine salts (such as dihydrochloride and diisethionate) are cationic substances with broad-spectrum antibacterial and bactericidal properties against various Gram-negative and Gram-positive bacteria and many fungi All have good bactericidal and antibacterial activities. It has important and extensive applications in many industries, especially the cosmetics industry. Among them, hexamidine is an important intermediate in its synthesis. [0003] The synthesis of hexamidine is generally the following three steps: (1) synthesis of 1,6-(p-cyanophenyl) hexamidine (intermediate I) by reaction of p-cyanophenol and 1,6-dibromohexane, (2) Alcoholyze intermediate I to obtain 1,6-(ethylimidoylphenyl) hexamidine (intermediate II), (3) Ammonolyze intermediate II to obtain hexamidine, namely 4- (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C257/18A61P31/10A61P31/04
Inventor 刘立强周鹏辉王武强孟文斌麻纪斌翟帆李宗霖舒泉湧尹航曲秦
Owner XIAN WONDER SCI & TECH
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