RU2501797C1 - Method of producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: starting substances used are thiosemicarbazide, acetic anhydride, sodium hydroxide, monochloroacetic acid; the liquid medium used is 95% ethanol and purified water, wherein the thiosemicarbazide is dissolved in the purified water, the reaction mass is cooled to 0°C±0.5°C and while mixing, acetic anhydride is added at such a rate that temperature of the reaction mass does not rise above 4°C; after adding all the acetic anhydride, the mass is mixed for another 20-30 minutes at temperature not higher than 1°C±1°C; the precipitate is filtered, washed with cooled water (2-4°C), pressed and the purified water and the obtained moist precipitate are then placed in a round-bottom flask with a mixer; while stirring for 0.5-1 hours, sodium hydroxide solution is added to the reaction mass and then boiled for 1 hour; the monochloroacetic acid is then added to water, stirred for 30 minutes and boiled for 1 hour, cooled to 2-4°C; the precipitate is filtered, washed with cold water thrice and twice with cold 95% ethanol; the obtained moist precipitate is transferred into the round-bottom flask with a mixer; 95% ethanol is added, stirred and while stirring, morpholine solution is added to 95% ethanol, boiled while stirring for 30 minutes and then cooled to 85-90°; activated carbon is added, boiled for 10-20 minutes; the carbon is filtered, the filtrate is cooled to 4-5°C, the precipitate of the end product is filtered, washed with 95% ethanol and dried at 50-70°C.EFFECT: high output of the end product, high quality of said product, cheap production and faster process.1 cl, 1 ex

Description

The invention relates to pharmacy, and in particular, to a technology for the production of heterocyclic compounds, in particular, to a technology for the production of 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium, which is known as the thiotriazolin drug.

Thiotriazolin is a highly effective metabolitotropic cardioprotector that has antioxidant, antiapoptotic, anti-inflammatory, antiviral, immunomodulatory, membrane-stabilizing, wound healing and cytoprotective effects. In clinical practice, thiotriazolin is widely used as a cardioprotective agent in the complex treatment of patients with myocardial infarction, angina pectoris, arrhythmias, heart failure, cardiosclerosis, myocarditis and arterial hypertension. Thiotriazolin, thanks to a wide range of biological effects, is also used in gastroenterology, surgery, ophthalmology, combustiology, neurology, gynecology, and in the treatment of infectious and viral pathologies. Currently, the drug is widely used in Ukraine and the interest of doctors is increasing every year [Thiotriazolin: pharmacological aspects and clinical use / [Mazur I.A., Voloshin N.A., Chekman I.S. and etc.]. - Zaporozhye, Lviv, 2005 .-- 146 p .; Thiotriazoline, thiocetam, thiodarone in the practice of a doctor / N.A. Voloshin, V.A. Vizir, I.N. Voloshin. - Zaporozhye: ZSMU, 2008. - 220 p.].

The high compatibility of the substance of thiotriazoline made it possible to create complex agents. Due to the action of the substance thiotriazolin, the activity of drug components increases significantly, and side reactions of complex drugs are also reduced. So, on the basis of thiotriazolin, new complex highly effective Ukrainian drugs were developed - Tiocetam, Tiodaron, Indotril and others.

Thiotriazolin in various dosage forms and complex preparations based on it are registered in the CIS countries: the Russian Federation, Belarus, Kazakhstan, Uzbekistan, Tajikistan, Azerbaijan, Georgia, and Moldova.

The use of the domestic substance thiotriazoline makes it possible to achieve a high economic and social effect due to the fact that drugs based on thiotriazolin are affordable for a wide range of people, while they are highly effective, demonstrate a wide spectrum of action and there are practically no side effects in these drugs. The demand for medicines containing thiotriazolin as an active substance increases every year, therefore, the development of a more effective method for its preparation, which will ensure a high yield of the target product, increase its quality, reduce the cost of production, accelerate and simplify the process, is relevant.

A known method of producing thiotriazoline according to the patent of Ukraine No. 1988 ("Morpholine 3-methyl-1,2,4-triazolyl-5-thioacetate, some hepatosis, wound-up and anti-inflammatory activity", IPC (2006) C07D 413/12 (2007.01) A61K 31/4196 A61K 31/535 A61P 17/02 (2007.01) A61P 31/12 (2007.01), publ. 12/20/1994), which consists in the fact that 3-methyl-1,2,4-triazolyl-5- thioacetic acid is loaded into the reactor, poured with alcohol (homogeneous medium), the mass is stirred, heated to 60 ° C, morpholine is added, brought to a boil and kept at boiling point for one hour. Then the mass is cooled to the cessation of boiling, activated carbon is added, boiled for 15-20 minutes, the hot solution is filtered, cooled, the resulting precipitate is filtered off, washed and dried. In this case, technical thiotriazoline (morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate) is obtained. Then, from technical thiotriazolin by recrystallization from alcohol, thiotriazoline (morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate) is obtained with a quality that corresponds to the pharmacopeia article.

The disadvantage of this method is the low yield of the target product and high production costs for its preparation.

Closest to the claimed method is a method for producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate (Ukrainian patent No. 57476, IPC 7: C07D 413/12. Method for eliminating morpholined 3-methyl-1,2,4 -triazolyl-5-thioacetate. - published on June 16, 2003. - Bull.6), which includes the reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in a liquid medium, filtration, washing and drying the resulting precipitate. As the liquid medium, methylene chloride is used. In this case, morpholine is added to methylene chloride, stirred and 3-methyl-1,2,4-triazolyl-5-thioacetic acid is added to the resulting mixture, stirred until the reaction is completed, then the resulting precipitate is filtered off, washed with methylene chloride and dried. To ensure the quality of the target product in accordance with the pharmacopeia article, 3-methyl-1,2,4-triazolyl-5-thioacetic acid and morpholine are used in the reaction in the ratios of 1: (1.0 ± 0.1) moles. We take this method as a prototype.

Common essential features of the method taken as a prototype, and the present invention are the following:

- carrying out reactions of starting materials and morpholine in a liquid medium, filtering, washing and drying the precipitate obtained.

The disadvantages of the prototype method is that methylene chloride is used as a liquid medium. Methylene chloride is an organic solvent with a sufficiently low boiling point (40 ° C), which complicates its industrial use due to its high volatility. In addition, methylene chloride is very toxic, irritates the skin, mucous membranes of the eyes and respiratory tract, has narcotic properties.

The basis of the invention is the task of improving the method for producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate by using 95% ethanol as a liquid medium, using other starting materials and changing reaction parameters and their sequence, which will provide a high yield target product, improving its quality, reducing the cost of production and accelerating the process.

The problem is solved in that in the method for producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate by carrying out reactions of the starting materials and morpholine in a liquid medium, filtering, washing and drying the precipitate obtained, it is new that starting materials use thiosemicarbazide, acetic anhydride, sodium hydroxide, monochloracetic acid and purified water, and 95% ethanol is used as a liquid medium. In this case, thiosemicarbazide is dissolved in purified water, the reaction mass is cooled to 0 ° C ± 0.5 ° C, and acetic anhydride is added with stirring so that the temperature of the reaction mass does not rise above 4 ° C. After adding all the acetic anhydride, the reaction mass is stirred for another 20-30 minutes at a temperature not exceeding 1 ° C ± 1 ° C, the precipitate is filtered off, washed 2 times with chilled (2-4 ° C) water, and squeezed thoroughly. The purified water and the obtained wet precipitate are placed in a round bottom flask with a mechanical stirrer, a solution of sodium hydroxide in water is added to the reaction mass as a suspension with stirring for 0.5-1 hours, after which the reaction mass is boiled for 1 hour, then a solution of monochloracetic acid is added in water, the reaction mass is stirred for 30 minutes and boiled for 1 hour, cooled to 2-4 ° C, the precipitate is filtered off, washed with cold water 3 times and 2 times with cold 95% ethanol. The resulting wet cake was transferred to a round bottom flask with a stirrer, 95% ethanol was added, stirred well and a solution of morpholine in 95% ethanol was added with stirring. The reaction mass is boiled with stirring for 30 minutes, then cooled to a temperature of 85-90 °, activated carbon is added, boiled for 10-20 minutes, the carbon is filtered off, the filtrate is cooled to 4-5 ° C. The precipitate of the target product is filtered off, washed with 95% ethanol and dried at a temperature of 50-70 ° C.

A causal relationship between the totality of the claimed features and the technical result is as follows.

We propose a method during the implementation of which certain conditions are strictly adhered to, which are not obvious to the specialist. It:

- a sequence of steps in the process of obtaining the target product,

- temperature conditions for each stage of the process,

- time of the chemical process.

The ratio of the components that take part in the reactions is unknown to specialists, as well as their mass, method and sequence of addition.

The above parameters were determined experimentally and are not obvious.

A very important point in obtaining the target product was the order of addition of the reagents, that is, in our case, exactly the same as that specified in the claims.

An unobvious result was also that acetic anhydride must be added at such a rate that the temperature of the reaction mass does not rise above 4 ° C.

In general, just such a combination of the substances used to obtain thiotriazolin, the sequence of stages of the reactions, the concentration and volume of the substances used, the time of the reactions allowed us to obtain a result — an increase in the yield of the target product and an increase in its quality.

The advantage of the proposed method is that it uses only one organic solvent - 95% ethanol. This significantly reduces the possibility of solvent contamination of the final product and simplifies the purification of the drug and its analysis, which is a very important advantage for the industrial production of the substance.

To date, the chemical-pharmaceutical industry does not produce 3-methyl-1,2,4-triazolyl-5-thioacetic acid, which was used to produce thiotriazoline, which creates certain problems in its industrial production.

We propose a method in the implementation process of which other starting materials are used to obtain thiotriazoline.

The method does not provide for the isolation of intermediate products in a dry state, they are immediately used in a wet form, which makes it possible to accelerate the process of obtaining the target product with its high quality.

Thus, we believe that our application for an invention can be recognized as one that meets the condition of "inventive step", since although certain steps of the production process are known, their selection, choice of components, reaction parameters, and their sequence are not based on known recommendations were not previously known and are not described in the literature.

The method of producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate (thiotriazoline) is as follows.

Example

91.14 g (1 mol) of thiosemicarbazide is placed in a two-necked flask with an anchor stirrer, dissolved in 800 ml of purified water. The reaction mass is cooled to 0 ° C ± 0.5 ° C and 117.3 g (1.15 mol) of acetic anhydride are slowly added with stirring. The rate of addition is controlled so that the temperature of the reaction mass does not rise above 4 ° C. After adding all the acetic anhydride, the reaction mass is stirred for another 20-30 minutes at a temperature not exceeding 1 ° C ± 1 ° C. The precipitate is filtered off, washed 2 times with 50 ml of chilled (2-4 ° C) water, squeezed thoroughly.

300 ml of purified water and wet acetylthiosemicarbazide are placed in a round bottom flask with a mechanical stirrer. A solution of 46.0 g (1.15 mol) of sodium hydroxide in 300 ml of water is added to the reaction mass in the form of a suspension with stirring for 0.5-1 hours from a separatory funnel, after which the reaction mass is boiled for 1 hour, then solution 103 is added 95 g (1.1 mol) of monochloracetic acid in 150 ml of water. The reaction mass is stirred for 30 minutes and boiled for 1 hour, cooled to 2-4 ° C, the precipitate is filtered off, washed with cold water 3 times 40 ml and 2 times 50 ml with cold 95% ethanol. The resulting wet cake was transferred to a round bottom flask with a stirrer, 350 ml of 95% ethanol were added, stirred well and a solution of 95.7 g (1.1 mol) of morpholine in 50 ml of 95% ethanol was added with stirring. The reaction mass is boiled with stirring for 30 minutes, then cooled to a temperature of 85-90 °, 5-10 g of activated carbon are added, boiled for 10-20 minutes, the carbon is filtered off, the filtrate is cooled to 4-5 ° C. The precipitate of the target product (morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate) is filtered off, washed with 40-50 ml of 95% ethanol and dried at a temperature of 50-70 ° C. The yield of the target product is 156 g (87.6% of theory in terms of the first starting product thiosemicarbazide). The obtained target product is a white crystalline powder, readily soluble in water, soluble in alcohol, insoluble in ether. The melting point is 149-150 ° C.

Found,%: C 41.6; H 6.1; N, 21.6; S 12.0.

C ₉ H ₁₀ N ₄ O ₃ S.

Calculated,%: C 41.5, H 6.2; N, 21.5; S 12.3.

IR, cm ^-1 : 3300 (NH); 1630 (COO); 2500 ( ⁺ NH ₂ ).

Obtained by the proposed method, the target product meets the requirements that apply to medicinal substances.

Thus, the method is affordable, highly effective, while the target product does not contain impurities and corresponds to pharmacopoeial quality.

Claims (1)

A method of producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate by carrying out reactions of the starting materials and morpholine in a liquid medium, filtering, washing and drying the precipitate obtained, characterized in that the starting materials use thiosemicarbazide, acetic anhydride, sodium hydroxide, monochloracetic acid, as liquid medium use 95% ethanol and purified water, while thiosemicarbazide is dissolved in purified water, the reaction mass is cooled to 0 ° C ± 0.5 ° C and acetic anhydride is added with stirring so that the temperature of the reaction mixture did not rise above 4 ° C, then after adding all the acetic anhydride, the reaction mixture was stirred for another 20-30 minutes at a temperature not exceeding 1 ° C ± 1 ° C, the precipitate was filtered off, washed 2 times with chilled (2-4 ° C) water is carefully squeezed and then purified water and the obtained wet precipitate are placed in a round bottom flask with a mechanical stirrer, a solution of sodium hydroxide in water is added to the reaction mass in the form of a suspension with stirring for 0.5-1 hours, after which the reaction mass is boiled for 1 hour then add the rust a monochloracetic acid thief in water, the reaction mass is stirred for 30 minutes and boiled for 1 hour, cooled to 2-4 ° C, the precipitate is filtered off, washed with cold water 3 times and 2 times with cold 95% ethanol, the resulting wet precipitate is transferred to a round bottom flask with a stirrer, 95% ethanol is added, stir well and a solution of morpholine in 95% ethanol is added with stirring, the reaction mass is boiled with stirring for 30 minutes, then cooled to a temperature of 85-90 °, activated carbon is added, boiled for 10-20 minutes, the carbon is filtered off, the filtrate is cooled before 4-5 ° C, the precipitate of the target product is filtered off, washed with 95% ethanol and dried at a temperature of 50-70 ° C.