RU2248353C2 - Method for preparing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium - Google Patents

Abstract

FIELD: organic chemistry or heterocyclic compounds, chemical technology.

SUBSTANCE: invention relates to technology for manufacturing heterocyclic compounds, in particular, to technology for manufacturing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that is known as a substance for pharmaceutical designation "thiotriazoline". Invention describes a method for preparing 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium that involves reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in liquid medium wherein methylene chloride is used as a liquid medium. Method provides significant elevating the yield percent of the end product, enhances its quality and significant reducing industrial consumptions.

EFFECT: improved preparing method.

4 cl, 1 tbl, 4 ex

Description

The invention relates 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, known as the pharmaceutical substance thiotriazoline, registered by the Ministry of Health of Ukraine on May 31, 1994, certificate No. 94/85/1.

A known method for producing a heterocyclic compound is morpholinium 3-methyl-1,2,4-triazolyl-5-α-thiobutyric acid according to Ukrainian patent No. 2436, C 07 D 249/12, according to which 3-methyl-1,2,4- triazolyl-5-α-thiobutyric acid is dissolved in boiling ethanol. Morpholine was added to the resulting solution, and the solution was evaporated in a boiling water bath. The isolated desired product is crystallized from butanol. The yield of the target product 79%.

The disadvantages of this method are the increased complexity of production and a low percentage of yield of the target product.

A known method of producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate according to the patent of Ukraine No. 1988, C 07 D 413/12 in accordance with the technological regulations TP-64-00205096-011-99 (state enterprise “Plant chemical reagents ”NTK“ Institute of single crystals ”, Kharkov and NPO“ Farmatron ”, Zaporizhia).

In accordance with the specified regulations, 3-methyl-1,2,4-triazolyl-5-thioacetic acid is charged into the reactor, poured with alcohol (homogeneous medium), the mass is stirred, heated to 60 ° C, morpholine is added, brought to a boil and maintained at boiling temperature for 1 hour, then the mass is cooled to the end of boiling, activated carbon is added, boiled for 15-20 minutes, the hot solution is filtered, cooled, the precipitate formed is filtered off, washed and dried to obtain technological thiotriazoline (morpholinium 3-methyl-1,2,4 triazolyl-5-thioacetate).

From technical thiotriazoline, then, through recrystallization from alcohol, thiotriazoline (morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate) of pharmacopoeial quality is obtained.

By the identity of the obtained target product, this method is taken as a prototype.

The disadvantages of the prototype are: low yield of the target product and increased production costs for its production in two stages with the use of alcohol.

The basis of the invention is the task to develop a method for obtaining the target product of pharmacopoeial quality with an increased percentage of its output, quality and reduced production costs.

The solution of this problem provides a method for producing morpholinium-3-methyl-1,2,4-triazolyl-5-thioacetate, including the reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in a liquid medium, filtration, washing and drying the precipitate formed, due to the fact that methylene chloride is used as a liquid medium, morpholine is added to methylene chloride, stirred and 3-methyl-1,2,4-triazolyl-5-thioacetic acid is added to the resulting mixture, stirring until the end of the reaction, then the precipitate formed is filtered off, washed with meth ylena chloride and dried.

To ensure the pharmacopoeial quality of the target product in the reaction, 3-methyl-1,2,4-triazolyl-5-thioacetic acid and morpholine are used in a ratio of 1: (0.9-1.1) moles.

Technical and economic effect when using the proposed method:

- a significant increase in the percentage of the yield of the target product (thiotriazolin) due to the exclusion of its losses in the solution of the waste medium and the quality of the product corresponding to the pharmacopeia article;

- reduction of production costs due to the replacement of alcohol with methylene chloride, which is cheaper than alcohol, and also due to the exclusion of technological operations for the production of technological thiotriazoline: purification of sludge using activated carbon, the use of energy to heat the reactive medium in the process of its reaction and reprocessing of the technological thiotriazoline to thiotriazolin pharmacopoeial quality.

The invention is illustrated by the following description of the proposed method, a chemical-technological scheme, examples and a table of results for experiments in determining the optimal ratios of the reactants involved in the reaction to obtain 3-methyl-1,2,4-triazolyl-5-thioacetate by the proposed method.

The whole process is carried out according to scheme 1.

Scheme 1

In accordance with the proposed method, morpholine is mixed with methylene chloride, then 3-methyl-1,2,4-triazolyl-5-thioacetic acid is added to the resulting mixture, where it is insoluble. Under the action of morpholine mixed with methylene chloride (heterogeneous medium), the precipitate of 3-methyl-1,2,4-triazolyl-5-thioacetic acid is transformed to form morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate ( target product), which is also insoluble in methylene chloride, and the excess of morpholine remains in solution and is easily removed with it.

From the moment morpholine with methylene chloride, 3-methyl-1,2,4-triazolyl-5-thioacetic acid is added to the mixture, the mixture is thoroughly mixed until the reaction is complete, then the precipitate formed is filtered off, washed with methylene chloride, dried and packaged.

The influence of the quantitative ratio of the reagents participating in the reaction on the yield percentage and the quality of the target product are reflected in the following experiment examples and table 1.

Example 1

34.6 g (0.2 mol) of 3-methyl-1,2,4-triazolyl-5-thioacetic acid is mixed with 20 ml of methylene chloride containing 15.7 g (0.18 mol) of morpholine, mixed thoroughly for 15 minutes, the precipitate formed is filtered off, washed on the filter with 10 ml of methylene chloride, dried in air. The substance contains an admixture of unreacted 3-methyl-1,2,4-triazolyl-5-thioacetic acid. The impurity content is determined by thin-layer chromatography according to VFS 42U-38-94. After recrystallization from ethanol, the yield of pure product is 40.56 g (78%).

Example 2

34.6 g (0.2 mol) of 3-methyl-1,2,4-triazolyl-5-thioacetic acid is mixed with 20 ml of methylene chloride containing 17.4 g (0.2 mol) of morpholine, mixed thoroughly for 15 minutes, the precipitate formed is filtered off, washed on the filter with 10 ml of methylene chloride, dried in air. The yield of the target product is 49.4 g (95%). The substance corresponds to pharmacopoeial quality.

Example 3

34.6 g (0.2 mol) of 3-methyl-1,2,4-triazolyl-5-thioacetic acid is mixed with 20 ml of methylene chloride containing 19.2 g (0.22 mol) of morpholine, mixed thoroughly for 15 minutes, the precipitate formed is filtered off, washed on the filter with 10 ml of methylene chloride, dried in air. The yield of the target product is 49.9 g (96%). The substance contains an admixture of morpholine, as determined by thin-layer chromatography.

Table 1 Example No. Reagents Yield of 3-methyl-1,2,4-triazolyl-5-thioacetate morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetic acid Morpholine gram mole gram mole gram % 1. 34.6 0.2 15.7 0.18 40.56 78 2. 34.6 0.2 17.4 0.2 49.4 95 3. 34.6 0.2 19.2 0.22 49.9 96

As can be seen from table 1 and descriptions of examples, the ratio in moles of reagents involved in the reaction of 1: 1 in the second example is optimal in yield and quality of the target product.

When reducing the amount of morpholine (example 1), the target product contains an admixture of unreacted 3-methyl-1,2,4-triazolyl-5-thioacetic acid. With an increased amount of morpholine (example 3), the yield of the target product is 96%, but it contains an admixture of morpholine.

According to the second example, the yield of the target product is 95%, it has no impurities and corresponds to pharmacopoeial quality, therefore, this option is optimal for the yield and quality of the target product.

Example 4

To obtain 10 kg of morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate of pharmacopeia quality, using the proposed method in industrial production, 3 kg of 480 g of morpholine and 3950 ml of methylene chloride are poured into the reactor, mixed thoroughly, and the resulting solution is charged 6 kg 800 g of 3-methyl-1,2,4-triazolyl-5-thioacetic acid, include a stirrer and the whole mixture is stirred for 15-20 minutes until the end of the reagent reaction process.

The precipitate formed is filtered off, washed with 2000 ml of methylene chloride, dried, and the obtained pharmacopoeial quality 3-methyl-1,2,4-triazolyl-5-thioacetate (thiotriazoline) morpholinium is packaged in sealed containers.

Claims (4)

1. The method of producing morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetate, comprising the reaction of 3-methyl-1,2,4-triazolyl-5-thioacetic acid with morpholine in a liquid medium, characterized in that Methylene chloride is used as a liquid medium. 2. The method according to claim 1, characterized in that morpholine is added to methylene chloride, stirred and 3-methyl-1,2,4-triazolyl-5-thioacetic acid is added and mixed to the resulting mixture. 3. The method according to claims 1 to 2, characterized in that the mixture is stirred until the reaction is completed, after which the precipitate formed is filtered off, washed with methylene chloride and dried. 4. The method according to claims 1 to 3, characterized in that 3-methyl-1,2,4-triazolyl-5-thioacetic acid and morpholine are used in the reaction in a ratio of 1: (0.9-1.1) moles.