阅读说明：本技术 一种环己双胍盐酸盐及其制备方法 (Cyclohexylbiguanide hydrochloride and preparation method thereof ) 是由 张科良 吴亚 徐玉乔 成钰 谢娟 于 2021-02-01 设计创作，主要内容包括：一种环己双胍盐酸盐及其制备方法,其结构通式为：制备方法如下：在三口烧瓶中加入氯化铵4.5g-7.5g、脂肪胺10mL-12.5mL、有机溶剂20mL-90mL,通入冷凝水,通氮气流量在20mL-50mL/min,搅拌下升温至70-80℃,反应0.5h-1.5h,后升温至135-150℃反应2.5h-5.5h；后冷却至60℃-75℃,加入双氰胺7.5g-10.5g,加热至135℃-145℃继续反应3.5h-6.5h；后冷却至70℃-85℃,加入25mL-55mL的蒸馏水,升温至90-100℃恒温持续搅拌0.5h-1.0h,产品进入水相；收集水相,水相旋转浓缩析出粗产品,粗产品中加入含80％-90％体积的乙醇的水55mL-80mL,加热溶解后加入0.5g-1.2g活性炭,回流0.5h-1.0h,趁热过滤除去不溶物,滤液冷却至5℃析出产品,干燥；本发明所需原料易得,制备方法简便,可望用于工业生产。(A cyclohexbiguanide hydrochloride and a preparation method thereof, the structural general formula of which is:)

1. The hexamethylene biguanide hydrochloride is characterized in that the structural general formula is as follows:

2. the method for preparing the cyclohexbiguanide hydrochloride according to claim 1, comprising the steps of:

adding 4.5-7.5 g of ammonium chloride, 10-12.5 mL of aliphatic amine and 20-90 mL of organic solvent into a three-neck flask, introducing condensed water, introducing nitrogen flow of 20-50 mL/min, heating to 70-80 ℃ under stirring, reacting for 0.5-1.5 h, and then heating to 135-150 ℃ for reacting for 2.5-5.5 h; then cooling to 60-75 ℃, adding 7.5-10.5 g of dicyandiamide, heating to 135-145 ℃, and continuing to react for 3.5-6.5 h; then cooling to 70-85 ℃, adding 25-55 mL of distilled water, heating to 90-100 ℃, keeping stirring for 0.5-1.0 h at constant temperature, and enabling the product to enter a water phase; collecting the water phase, carrying out rotary concentration on the water phase to separate out a crude product, adding 55mL-80mL of water containing 80% -90% by volume of ethanol into the crude product, heating to dissolve the water phase, adding 0.5g-1.2g of activated carbon, refluxing for 0.5h-1.0h, filtering to remove insoluble substances while the solution is hot, cooling the filtrate to 5 ℃ to separate out a product, and drying.

3. The method of claim 2, wherein the organic solvent is an alcohol selected from n-pentanol, isopentanol, and n-hexanol.

4. The method of claim 2, wherein the aliphatic amine comprises cyclohexylamine.

Technical Field

The invention relates to the technical field of biguanide hydrochloride preparation, and in particular relates to hexamethylene biguanide hydrochloride and a preparation method thereof.

Background

Currently, metformin hydrochloride used for the treatment of type 2 diabetes is found to have inhibitory ability on the proliferation of TPC-1 human papilloma thyroid cancer cells, Eca-109 human esophageal cancer cells, SHSY5Y human neuroblastoma cells, PC-3 human prostate cancer cells, HT-29 human colon cancer cells and HCT-8 human colon cancer cells, revealing that metformin may have a broad antitumor effect (in jing, korea, leiming zhi, etc.. the effect of metformin on the proliferation ability of some malignant tumor cells [ J ]. the university of eastern science (medical edition), 2019,01, 20). Therefore, it is important to develop a novel biguanide derivative and systematically study its pharmacological effects.

Generally, the route for the preparation of the biguanide hydrochloride depends on the structure of the organic amine. For the preparation of the aromatic biguanide hydrochloride, the aromatic biguanide hydrochloride can be obtained by controlling proper pH value reaction of aromatic amine and dicyandiamide in a hydrochloric acid aqueous solution medium or an organic solvent-hydrochloric acid mixed solution medium.

For the preparation of biguanide hydrochloride of fatty amine, the fatty amine and dicyandiamide react to obtain a complex of fatty biguanide and copper sulfate in the presence of copper sulfate; and introducing hydrogen sulfide gas to remove copper ions, and finally obtaining the fatty biguanide sulfate. This step of conversion is required for the preparation of the fatty biguanide hydrochloride. The disadvantage of this route is that the process must use highly toxic hydrogen sulfide gas. In addition, the sulfate salt must be converted to the hydrochloride salt by a conversion process. Obviously, the steps for preparing the fatty biguanide hydrochloride are relatively cumbersome. In addition, as for the production of the aliphatic biguanide hydrochloride, the production method by means of the metformin hydrochloride can be classified into a dry method and a wet method (solvent method). Dimethylamine hydrochloride and dicyandiamide can react in the presence of an organic solvent to prepare metformin, and the method is called as a solvent method; if the reaction is carried out without solvent after the two raw materials are mixed, the method is called dry method. In general, the wet method has the characteristics of easy control of reaction, good reaction reproducibility and the like. However, dimethylamine hydrochloride was prepared first, both by the dry method and the wet method.

Patent CN1171398A proposes a method for preparing morpholine hydrochloride by reacting morpholine with ammonium chloride in xylene solvent at 120 ℃ for 1.5-3h (luohhai, a method for preparing morpholine hydrochloride, a morpholine biguanide hydrochloride precursor, CN1171398A, 1998,1, 28). However, xylene has some toxicity; in addition, xylene p-dicyandiamide has a disadvantage of poor solubility.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the hexamethylene biguanide hydrochloride and the preparation method thereof, which adopt a one-pot preparation process, and in a reaction kettle, fatty amine and ammonium chloride react in a specially selected polar hydroxyl-containing solvent at a certain temperature to obtain the hydrochloride of the fatty amine; and adding dicyandiamide, and reacting the dicyandiamide and the dicyandiamide in the solvent at a set temperature to obtain the target product of the cyclohexanediguanidine hydrochloride.

In order to achieve the purpose, the technical scheme of the invention is realized as follows:

the cyclohexbiguanide hydrochloride has a structural general formula as follows:

the preparation method of the cyclohexbiguanide hydrochloride comprises the following steps:

adding 4.5-7.5 g of ammonium chloride, 10-12.5 mL of aliphatic amine and 20-90 mL of organic solvent into a three-neck flask, introducing condensed water, introducing nitrogen flow of 20-50 mL/min, heating to 70-80 ℃ under stirring, reacting for 0.5-1.5 h, and then heating to 135-150 ℃ for reacting for 2.5-5.5 h; then cooling to 60-75 ℃, adding 7.5-10.5 g of dicyandiamide, heating to 135-145 ℃, and continuing to react for 3.5-6.5 h; then cooling to 70-85 ℃, adding 25-55 mL of distilled water, heating to 90-100 ℃, keeping stirring for 0.5-1.0 h at constant temperature, and enabling the product to enter a water phase; collecting the water phase, carrying out rotary concentration on the water phase to separate out a crude product, adding 55mL-80mL of water containing 80% -90% by volume of ethanol into the crude product, heating to dissolve the water phase, adding 0.5g-1.2g of activated carbon, refluxing for 0.5h-1.0h, filtering to remove insoluble substances while the solution is hot, cooling the filtrate to 5 ℃ to separate out a product, and drying.

The organic solvent is alcohol, including n-amyl alcohol, isoamyl alcohol or n-hexyl alcohol which is not mutually soluble with water.

The aliphatic amine includes cyclohexylamine.

The invention has the advantages that:

1. the one-pot preparation process is adopted, the reaction can be continuously carried out, and the intermediate fatty amine hydrochloride does not need to be separated and refined.

2. Depending on the physical and chemical properties of the organic amine, the solvent type and reaction temperature may be preferred.

3. The purpose of introducing nitrogen is to bring out ammonia gas generated by decomposing ammonium chloride, so that the organic amine hydrochloride is smoothly generated; on the other hand, the ammonium chloride is promoted to be completely decomposed, the residue of the ammonium chloride is reduced, and the occurrence of subsequent side reactions is further avoided.

Drawings

FIG. 1 is an infrared spectrum of dicyandiamide (1) and cyclohexbiguanide hydrochloride (2).

Figure 2 is a hydrogen spectrum of cyclohexbiguanide hydrochloride.

Figure 3 is a carbon spectrum of cyclohexbiguanide hydrochloride.

Detailed Description

The present invention will be described in detail with reference to the accompanying drawings and examples.

The experimental principle of preparation is as follows:

the first embodiment is as follows:

the embodiment comprises the following steps:

a100 mL three-necked flask was equipped with a mechanical stirrer, a reflux condenser, and a thermometer. Firstly adding 6.9g of ammonium chloride and 50mL of n-amyl alcohol, adding 11.5mL of cyclohexylamine at one time under stirring, introducing condensed water, heating to 70-80 ℃, preserving the temperature for 30 minutes, and then quickly heating to 135-145 ℃ for reaction for 4.5 hours. Then the temperature is reduced to 80 ℃, 10g of dicyandiamide is added, and then the temperature is raised to 136 ℃ and 145 ℃ for reaction for 5.5 hours. Then cooling to 90 ℃, adding 55mL of distilled water into the reaction mixture, heating to 90-95 ℃, keeping the temperature and stirring for 50 minutes, and enabling the product to enter a water phase; collecting the water phase, and performing rotary concentration on the water phase to separate out a crude product. 65mL of 85% ethanol-water is used as a recrystallization solvent in the crude product, 1g of activated carbon is added after heating and dissolving, reflux is carried out for 0.5h, insoluble substances are removed by filtration while the solution is hot, and the filtrate is cooled to 5 ℃ to separate out the product. The yield is 79.9 percent and is between 216 and 218 ℃.

Example two:

the embodiment comprises the following steps:

a100 mL three-necked flask was equipped with a mechanical stirrer, a reflux condenser, and a thermometer. Firstly adding 6.5g of ammonium chloride and 40mL of isoamyl alcohol, adding 10.4mL of cyclohexylamine at one time under stirring, introducing condensed water, heating to 70-80 ℃, preserving the temperature for 60 minutes, and then rapidly heating to 145 ℃ of 135 ℃ for reaction for 3.5 hours. Then the temperature is reduced to 75 ℃, 9.2g of dicyandiamide is added, and then the temperature is increased to 136 ℃ and 145 ℃ for reaction for 4.5 hours. Then, the temperature is reduced to 85 ℃, 50mL of distilled water is added into the reaction mixture, the temperature is raised to 95-100 ℃, the constant temperature is kept for stirring for 40 minutes, and the product enters a water phase; collecting the water phase, and performing rotary concentration on the water phase to separate out a crude product. The crude product is heated and dissolved by using 55mL of 80 percent ethanol-water as a recrystallization solvent, 0.8g of activated carbon is added, the mixture is refluxed for 0.5h, insoluble substances are removed by filtration when the mixture is hot, and the filtrate is cooled to 5 ℃ to separate out the product. The yield is 81.5 percent and the temperature is 216-218 ℃.

Example three:

the embodiment comprises the following steps:

a100 mL three-necked flask was equipped with a mechanical stirrer, a reflux condenser, and a thermometer. Firstly adding 6.45g of ammonium chloride and 36mL of n-hexanol, adding 11.0mL of cyclohexylamine once under stirring, introducing condensed water, heating to 70-80 ℃, keeping the temperature for 50 minutes, and then quickly heating to 135-145 ℃ for reaction for 4 hours. Then the temperature is reduced to 80 ℃, 8.4g of dicyandiamide is added, and then the temperature is increased to 136 ℃ and 150 ℃ for reaction for 2.5 hours. Then the temperature is reduced to 90 ℃, 45mL of distilled water is added through the upper part of a condenser, the temperature is raised to 95-100 ℃, the constant temperature is kept for stirring for 45 minutes, and the product enters a water phase; collecting the water phase, and performing rotary concentration on the water phase to separate out a crude product. Pouring the crude product into a clean 250mL beaker again, using 60mL of 95% ethanol-water as a recrystallization solvent, heating to dissolve, adding 0.7g of activated carbon, decolorizing at 85-90 ℃ for 20 minutes, filtering while hot, collecting filtrate, placing in a freezer, cooling to 5 ℃ and crystallizing. The yield is 75.5 percent, and the temperature is 216-218 ℃.

Referring to fig. 1, the ir spectrum of cyclohexbiguanide hydrochloride indicates: 2144cm of the product prepared^-1,2205cm^-1The infrared absorption of (a) has disappeared, indicating that the starting dicyandiamide has been completely converted.

Referring to fig. 2 and 3, the hydrogen nuclear magnetic resonance and carbon spectrum of the cyclohexbiguanide hydrochloride show that: the product produced corresponds to the desired structure.