Method of producing n-(beta-hydroxyethyl)4,6-dimethyldihydropyrimidone-2

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2, known in medicine as Xymedon, involving recrystallisation of hydrochloride, N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 from ethanol and then treated with a sodium hydroxide solution in ethanol. The sodium chloride formed is removed by filtering. Crude N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 is separated by evaporating ethanol and purified by double recrystallisation from chemically pure isopropyl alcohol in the presence of aluminium oxide and activated carbon.

EFFECT: method enables to obtain a highly pure product.

3 ex

 

The invention relates to the field of chemistry and technology of heterocyclic compounds, pyrimidine series, namely N-(β-hydroxyethyl)-4,6-dimethylpyrimidine-2, which is called Ksimedon recommended for use in medicine as a burn-drug immune actions [Segizbayev, Gasimov, Mavergames, Usernick. Ksimedon in clinical practice, ed. NGMI, Nizhny Novgorod, 2001] and in veterinary medicine for the prevention and treatment of gastrointestinal diseases in calves [RF Patents №2086240 and No. 2179846].

A known method of producing Ximena [RF Patent №2044730] hydrochloride Ximena obtained by the interaction of ethanolgasoline with acetylacetone in the environment of isopropyl alcohol in the presence of concentrated hydrochloric acid by treating it with an alkaline reagent (sodium hydroxide, sodium carbonate, sodium bicarbonate, aqueous ammonia) in water or in aqueous chloroform to obtain a solution Ximena with the subsequent removal of water and the partial removal of the chloroform and planting of Ximena from a concentrated solution in chloroform with acetone.

The above method is adopted as the closest equivalent.

Validation of this method in the experimental conditions showed that the resulting ksimedon does not match in appearance pharmacopoeial article [the Fund 42-0037-4764-03, as the product has orange or even red color. To bring the product to the Pharmacopoeia purity had to miss the solution Ximena in chloroform to distillation parts of chloroform through a chromatographic column filled with alumina [Begaliev, Gahaysuddin, Sgharifov, Vpoloborota, Inc, Sielecki, Spodarev, Vpoly. "Himiko-pharmaceutical journal, volume 42, issue 4, p.43-45, 2008].

The disadvantages are the counterpart:

- the use of inefficient column chromatography;

- use of toxic substances, chloroform and ammonia;

- the inability to regenerate formed by the planting of Ximena mixture of chloroform and acetone, as their solutions are practically not separated by rectification.

The technical object of the present invention is to develop a method of producing Ximena devoid of the above disadvantages.

The technical result is achieved by the fact that pre-hydrochloride Ximena recrystallized from ethanol to remove impurities that cause coloration in the processing of alkaline reagents, purified hydrochloride Ximena treated with sodium hydroxide solution in ethanol medium, the precipitated sodium chloride is removed by filtration and the resulting solution Ximena in ethanol concentrate. Fallen ksimedon raw soda is containing up to 4% of sodium chloride, filtered and purified by double recrystallization from isopropyl alcohol brand "chemically pure" in the presence of aluminum oxide and activated carbon.

The developed method allows to obtain ksimedon with a purity of more than 99% (according to HPLC), satisfying the Fund.

Distinctive features of the proposed method are:

the exception is the use of column chromatography for the purification of Ximena;

- exclusion from toxic chemicals - ammonia, chloroform and mixtures thereof with acetone, processing which is virtually impossible with conventional methods, and burning it uneconomical and unsafe for the environment due to the formation of phosgene.

The method of producing Ximena is illustrated by the following examples.

Example 1. Crystallization of the hydrochloride Ximena.

Hydrochloride Ximena in the amount of 348 g dissolved under stirring at 80-90°C in a mixture of 300 ml of water and 1200 ml of ethanol. Then the resulting solution was yellow-brown color is cooled to 10-15°C and maintained at this temperature and stirring for 30-40 minutes the precipitation of the hydrochloride Ximena filtered off, washed on the funnel 100-140 ml) cooled to 10-15°C ethanol. Receive 250 g (71,8% of theory) of the pure hydrochloride Ximena white with a little white shade BL is Stasi crystals with TPL 240-241°C.

Example 2. Getting Ximena raw.

Sodium hydroxide (205,2 g, 5,13 moles) is dissolved with stirring and the temperature of 20-32°C in 3.0 liters of ethanol. To the resulting sodium hydroxide solution add 1.0 kg (4.8 moles) of recrystallized hydrochloride Ximena and stirred for 60 minutes Then the reaction mass was filtered to separate from the separated sodium chloride. The sodium chloride on the funnel was washed with 200 ml of ethanol. From the mother liquor is distilled 2.5...3.0 liters of ethanol, the residue is cooled to 10-15°C, kept at this temperature for ~30 min and filtered. Ksimedon raw washed over 300-500 ml of acetone and dried at ~80°C for 2-3 hours, get 735 g (73.5%) of Ximena raw with TPL 138°C with the content of the basic substance is 95.2%. The resulting ksimedon raw contains up to 4% of sodium chloride.

Example 3. Getting Pharmacopoeia Ximena.

Ksimedon raw (95,5 g) is dissolved at a temperature of 75...80°C 350...400 ml of isopropyl alcohol brand "chemically pure" with the addition of 50 g of aluminum oxide and 10 g of activated charcoal. Then a hot solution is filtered from aluminum oxide, activated carbon and sodium chloride. The precipitate on a vacuum funnel washed with 50 ml of hot isopropyl alcohol and combine the wash with isopropyl alcohol with the main filtrate containing ksimedon. The solution Ximena in isopropyl alcohol, cooled to 10-15°C and maintained at p and the temperature 30-40 minutes Fallen ksimedon filtered off, washed it over 100 ml of acetone and dried at 80°C for 3...4 hours. Get 69,78 g (73% per ksimedon raw) Ximena, appropriate for all indicators of the Fund, except for chloride (0,03 0,04...% instead of 0.02%).

The resulting ksimedon from the first crystallization repeatedly recrystallized from isopropyl alcohol with the aforementioned method. Get 49,54 g (71% per ksimedon from the first recrystallization) Ximena, appropriate for all indicators of the Fund 42-0037-4764-03.

The total yield of Ximena from two precrystallization is 51,83% of theory.

The method of obtaining N-(β-hydroxyethyl)-4,6-dimethylpyrimidine-2 by neutralizing its hydrochloride, characterized in that the hydrochloride of N-(β-hydroxyethyl)-4,6-dimethylpyrimidine-2 pre recrystallized from ethanol, then treated with sodium hydroxide solution in ethanol, to remove the formed sodium chloride by filtration, N-(β-hydroxyethyl)-4,6-dimethylpyrimidin-2 raw produce partial evaporation of ethanol and purified by double recrystallization from isopropyl alcohol brand "chemically pure" in the presence of aluminum oxide and activated carbon.



 

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