Method to manufacture benzyldimethyl[3-(myristoilamino)propyl]ammoinium chloride monohydrate - С26Н47cln2o·Н2o

FIELD: chemistry.

SUBSTANCE: method to manufacture benzyldimethyl[3-(myristoilamino)propyl]ammonium chloride monohydrate-С26Н47ClN2О·Н2О implies two stages, which are reacting myristic acid followed by the end product formation at the second stage. 3-dimethylaminopropylamide is obtained at the first stage by direct reaction of myristic acid with 3-dimethylaminopropylamine in aromatic hydrocarbons, while end product is obtained at the second stage by direct benzylation in alcohols or ketones.

EFFECT: improved purity of end product and process safety.

3 dwg, 1 ex

 

The technical field

The present invention relates to methods of producing drugs, and more exactly, to antiseptic remedies, destroying pathogenic microflora on the body and wounds, without causing harmful side effects. This property distinguishes the drug, made by the proposed method, currently used antiseptics.

The most effective present invention can be used in medicine for treatment of open wounds, burn skin, and other significant skin injury as a disinfectant and antiseptic.

In addition, the present invention can be used in pharmaceutical industry as a method of obtaining a highly pure substance for the manufacture of medicinal and cosmetic preparations and creams with an antiseptic effect.

Prior art

The known Quaternary ammonium compounds (see, for example, U.S. patent 2362760, published in 1943). Its chemical structural formula is expressed as follows:

In this formula R represents an aliphatic hydrocarbon radical containing at least seven carbon atoms; R1and R 2are alkyl groups of low molecular weight, such as methyl, ethyl and the like, R3is a member of the group consisting of alkyl, aralkyl and unsaturated aliphatic hydrocarbon radicals, and X represents an anion, such as halide, acid sulfate, etc.

The products of this group are partially crystalline substances, and partly dense liquids or viscous substances, soluble in water and form stable aqueous solutions. From the point of view of their dispersion and disinfectant properties they are good as wetting and emulsifiers funds.

All the products described above chemical formula, practically odourless and non-toxic to human.

It is also known chemical compound of this class is described in U.S. patent No. 2459062 published 11.01.1949, which is the prototype of the present invention. This chemical compound in U.S. patent No. 2459062 called "ministeriopoliticaterritorial.svg". Now this name is deprecated and not used, and instead used the name benzyldimethyl[3-(myristoylation)propyl]ammoniacal, monohydrate. It has the chemical formula C26H47ClN2O·N2O. Its structural formula expressing substances is the most powerful aseptic properties has the following form:

where the above R, R1, R2represent alkyl groups. In the prototype of the present invention alkylating agent in the synthesis is benzylchloride. As a result, the chemical reaction producing the ammonium salt of the above structure.

The method of obtaining this compound is as follows. In 545 parts of 25%aqueous solution of dimethylamine, cooled with ice and water added from a dropping funnel 170 parts of Acrylonitrile. The speed of addition of the nitrile is adjusted so that the temperature in the reaction vessel remained below 20°C. After exposure to the cold reaction mixture for 1 hour, poured into her 0,35 l of 10%aqueous sodium hydroxide solution, collect the oily layer and an aqueous layer extracted with ether. The combined ether extract and the oily layer is dried with sodium sulfate, and then dispersed. When the temperature 73-74°collect 218 parts of 3-dimethylaminopropionitrile.

Then 207 parts of 3-dimethylaminopropionitrile hydronaut in an autoclave at a pressure of 90 atmospheres at 100°in the presence of 72.4 parts of anhydrous ammonia, using as catalyst a Nickel. The product is dried with solid potassium hydroxide and distilled in vacuum. At atmospheric pressure and 134°collect 204,5 parts of N,N-di is ethylpropylamine.

Then, 38 parts of myristoylated added dropwise into a solution of 15.5 parts of N,N-dimethylpropanediamine in 160 parts of benzene. After 1 hour stirring the benzene solution washed with 10%aqueous sodium hydroxide. The benzene layer is then washed once with water and the solvent is removed by distillation in vacuum. The residue is distilled at 200°and get a solid gamma miristildimetilaminoksid.

A solution of 6.2 parts of gamma-miristildimetilaminoksid and 3.4 parts of benzylchloride in 30 parts of benzene is refluxed for 4 hours. The benzene is removed in vacuo and get light-colored amorphous substance, semi-solid at room temperature, which melts at temperatures above 54°in liquid straw color. The resulting product is a Quaternary ammonium salt - gamma miristildimetilaminoksid. This compound is soluble in water and is a good antibacterial agent.

The above method are in industrial scale benzyldimethyl[3-(myristoylation)propyl]ammoniacal, monohydrate and use it in medicine and pharmacy as an effective antiseptic, destroys pathogens and normal flora and do not have unwanted side effects on the body in the treatment of wounds and burns on the body is the ne.

In medical and pharmaceutical practice, this drug is widely known under the trade name "Miramistin" and is used in the form of a solution in distilled water at a ratio of 1:10000.

However, the described method for the production of Miramistin has significant shortcomings.

First, Miramistin, obtained as described in U.S. patent No. 2459062, 1949, traditional technology, contains a significant amount (up to 1.15%) impurities, which reduces its effectiveness. Secondly, the traditional method of obtaining Miramistin associated with the use of a long and manipulation of extremely harmful chemicals, namely with the acid chloride myristic acid, which has an extremely harmful effect on the human respiratory system. In addition, this substance causes corrosion of the equipment. Way connected with the use of benzene, with pronounced carcinogenic activity. With benzene have to deal with during the entire production process Miramistin from its beginning to end. Protective equipment that is necessary to apply, not effective and do not protect pharmacists from the harmful effects of these reagents. As practice shows production Miramistin, despite all efforts to implement the permanent and the temporary protection of the operators, organization it is difficult for a variety of reasons, including by negligence of the staff.

It would be desirable to find a method of manufacturing benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate, free from the above disadvantages.

Disclosure of inventions

The present of the invention is to provide a method of manufacturing benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate, free from the above disadvantages, i.e. it is desirable to have the target product impurities less than half that obtained using the conventional technology and to exclude when making use of particularly harmful to human health reagents.

This object is achieved in that in the method of manufacturing benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate performed in two stages by the reaction of myristic acid with 3-dimethylaminopropylamine with 3-dimethylaminopropylamine myristic acid and then bringing it into the second stage to the target product, characterized in that the obtaining 3-dimethylaminopropylamine myristic acid is performed in the first stage, the direct interaction of myristic acid with 3-dimethylaminopropylamine, and the formation of the target product in W is Roy stage is direct benzylalkonium.

Carrying out such chemical reactions can reduce the number of impurities in the target product to 0.58% and exclude work with particularly hazardous chemicals.

The method is characterized also by the fact that the interaction of myristic acid with 3-dimethylaminopropylamine produced in the environment of aromatic hydrocarbons. This difference helps to reduce the amount of impurities in the target product.

The method is characterized also by the fact that direct benzylidene produce alcohols. This difference allows you to refuse the use of particularly hazardous chemicals.

The method is characterized also by the fact that direct benzilirovaniya produce in the simplest ketone. It also allows you to refuse the use of particularly hazardous chemicals.

The list of graphical materials

For a better understanding of the invention, its description with a graphical materials, where

- figure 1 shows graphs of the IR spectra benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate, obtained by traditional ( trade name "Miramistin") and the same drug that Miramistin, but obtained as described in the present application of new technology, for which we proposed trade name "Antisept-With",

- figure 2 and 3 shows graphs of the results of HPLC "Miramistin"received traditional the way and benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate, obtained as described in the present application of the new technology.

An example of obtaining benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate according to the new proposed technology.

1. The first stage of the process consists of obtaining the 3-dimethylaminopropylamine myristic acid.

To do this, weigh the sample, equal to 45.6 g (0.2 mol)of myristic acid and implement its recrystallization traditional way. Specified recrystallized sample myristic acid is placed in a flask with a capacity of 500 ml, equipped with a nozzle Dean-stark exactly at the volume of 10 ml. of This system purge with argon.

Next, in a flask with myristic acid, add 180 ml of m-xylene. Previously distilled over sodium 3-dimethylaminopropylamine, measure its 30 ml (24.3 g, 0,24 mol) and added to the flask.

Then carry out the distillation of the xylene azeotrope-water-Amin, continuing to achieve in the nozzle Dean-stark volume lower (aqueous-amine) layer, equal to 3.6 ml of This process (distillation of the xylene azeotrope-water-Amin) usually lasts about 2 hours.

Then to the reaction mixture additionally add 6 ml (a 4.86 g, 0.05 m) 3-dimethylaminopropylamine and continue the distillation of the xylene azeotrope-water-Amin to achieve the volume of the lower (aqueous-amine) layer of 4.8 ml This is the process lasts about 4 hours.

Next, the reaction mixture is distilled off on a rotary evaporator m-xylene and the remaining part of the reaction mixture are added 60 ml of toluene. Then again the solvent is distilled off.

After performing these operations is obtained (remains) parafinalia mass. This mass is dried in a vacuum desiccator over paraffin, and then on the air.

As a result of the above reactions get from 59,6 to 60.5 g (95-98%) 3-dimethylaminopropylamine myristic acid. Next comes the second stage of the process.

2. The second stage of the process is directly obtain the target product.

In a flask with a capacity of 500 ml was placed 62,05 g (0.2 mole) of 3-dimethylaminopropylamine myristic acid, obtained in the first stage of the process, and purge the system with argon. After purging with argon specified in the flask, add 200 ml of absolute ethanol and then there was placed 30 ml (33 g, of 0.26 mole) of benzylchloride.

The reaction mixture is boiled for 3.5 hours in a stream of argon. The resulting solution is filtered through a folded filter. Then the solvent is distilled off. The oily residue is dissolved in 100 ml of toluene and again the solvent is distilled off to remove excess benzylchloride. Then the oil obtained is heated to 50°and dissolve it in 300 g of acetone. The resulting solution is filtered. After filtering in the specified R is the target add a few (5-10, depending on their size) crystals of ammonium salt and place this solution in a refrigerator. In the refrigerator, this solution is aged for a short time (10-30 min) before the formation of a small number of small crystals. After this, the solution is removed from the fridge and leave it for a day at room temperature (18-22°).

Then aged at room temperature the solution together with the resulting crystalline precipitate is placed in the refrigerator for 2 hours. While the bulk of the product zakristallizuetsya.

After that, the product is filtered, and then dried in a stream of air filter. Then do the final drying of the product in a vacuum desiccator. In the above steps get 68,4-70,3 g of the target product - benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate the formulas above.

Target product melts unclear, since 52°C and ending at 95°C.

A thorough analysis with the help of modern instruments with absolute certainty demonstrated that the substance obtained in a traditional way, as described in U.S. patent No. 2459062, 1949, and the substance obtained is described in this application method, it is one and the same substance, obtained by different methods, which is confirmed by the graphs (see figure 1). Full match of the absorption bands And in the spectra of these drugs confirms their identity. In addition, the comparison of the results of HPLC (see figure 2 and 3) shows that the substance prepared according to the proposed technology has a higher degree of purity, since the total amount of impurities in it does not exceed 0,58%, which is almost 2 times less than in the substance prepared according to the conventional technology.

Industrial utility

Previously it was stated that the product obtained is known and proposed by the present invention method, it is one and the same substance, so medical application is the same. However, the substance obtained in a new way, has fewer impurities and therefore more safe to use. This substance is used in a 0.01% solution in distilled water. The solution is prepared under sterile conditions, and bottling in bottles in the cabinets (zones) with a laminar flow of sterile air and observing all the rules of asepsis. The preparation method is simple, ordinary dissolution benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate, in distilled water, the amount of which are selected so as to achieve a 0.01%solution.

"Miramistin" and "Solution Miramistin 0,01%" and approved for medical use, and registered by the Ministry of health of the Russian Federation under registration numbers 91-146/1 and 91-146/2. With pharmacopaeia article numbers FS 42-3498-98 (Miramis is in) and the Solution Miramistin 0,01% - FS 42-3255-95 and Fund - 42-0414-2768-02.

The solution Antisept With a 0.01%Solution Miramistin of 0.01% is intended for topical application. After standard treatment of wounds and burns them covered with a gauze bandage soaked in the solution. Festering wounds loose plugging tampons soaked in 0.01% solution of the drug. Such as tampons can be entered into fistulous passages. In the treatment of purulent wounds in patients with thrombosis after suturing is used irrigation solution through the drain two to three times per day.

When peritonitis internal reorganization is carried out according to the method of Gould. Operating the wound should be washed with a solution of not less than three times a day, with at least 50 ml / 3-4 drainage. Usually treatment is 5-7 days, but if necessary it can be extended and further.

Prevention of puerperal infection with OPG-gestosis solution used in the form of vaginal irrigation while in the hospital with disorders of pregnancy (5-7 days), during childbirth, after each vaginal examination in the postpartum period, 50 ml of the drug in the form of a tampon with an exposure time of 2 hours for 5 days.

During delivery women with OPG-gestosis by Caesarean section, except prenatal prevention mentioned above, in the operating room immediately before surgery process vagina. During operationresult cavity, where is the uterus and cut it using about 100 ml of the drug. In the postoperative period used tampons soaked in 50 ml of introducing them into the vagina with an exposure time of 2 hours within 7 days.

For the prevention of sexually transmitted diseases, the solution is extremely effective if it is used not later than 2 hours after intercourse. The solution is injected into the urethra: a man 2-3 ml, woman 1-2 ml into the urethra and an additional 5-10 ml of the vagina. One should keep the drug at the point of entry for 2-3 minutes Then you should treat the skin of the inner thighs, pubic area and genitals. After this procedure, it is recommended not to urinate for 2 hours.

In dermatology for the treatment of mycosis of the skin and mucous places, mycoses and large folds affected area and cover with a gauze bandage soaked in a solution 3-4 times a day.

The solution is very effective in the treatment of connecting using a solution of 0.01% with receiving oral antifungal drugs for 5-6 weeks.

In urology for the treatment of acute and chronic urethritis and retroprosthetic the solution is used in treatment of these diseases in the form of daily injections into the urethra and bladder. Also in th the operational period after prostatotomy and operations on the urinary bladder apply the injection of the solution into the cavity of the bladder.

The method of manufacturing benzyldimethyl[3-(myristoylation)propyl]ameriglide, monohydrate26H47ClN2O·N2O performed in two stages by the reaction of myristic acid with subsequent education in the second stage of the target product, wherein obtaining 3-dimethylaminopropylamine myristic acid is carried out in a first stage, the direct interaction of myristic acid with 3-dimethylaminopropylamine in the environment of aromatic hydrocarbons and the formation of the target product is performed in the second stage direct benzylalkonium in alcohols or ketones.



 

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