RU2333905C2 - Method of purification of tiosemicarbazone guanylhydrbazone 1,4-benzohinon (ambazone) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method of purification of tiosemicarbazone guanylhydrazone 1,4-benzochinon(ambazone), according to which subjected to purification is non-purified ambazone, includes stage of sulfur extraction, present in non-purified ambazone with non-polar solvents, such as benzole, n-hexane, toluol or xylol, with ratio ambazone:solvent equal to 1:(1-5) (weight/vol.) at temperatures within the range of 20-60°C, filtration and further second stage of purification with addition of solvent mixture, which consists of N,N-dimethylformamide and lower aliphatic alcohols (C₁-C₄) with ratio ambazone : N,N-dimethylformamide : lower aliphatic alkohol equal to 1:(1-3):(2-5) (weight/vol/vol)) at temperatures within the range of 50-80°C, with obtaining pure product. Ambazone is used as active start for obtaining medication FARINGOSEPT.

EFFECT: obtaining product of high quality directly from non-purified ambazone without sulfur.

3 ex

Description

The present invention relates to a method for the purification of 1,4-benzoquinone (ambazone) guanylhydrazone of formula I to produce a substance with pharmaceutical quality. Ambazon is used as an active pharmaceutical principle for the preparation of the medicinal product FARINGOSEPT ^® .

Several impurities resulting from chemical synthesis have been identified in the crude ambazon. These impurities are intermediate synthesis compounds, secondary synthesis products and decomposition products.

The impurities present in the ambazon are isolated and characterized by modern physicochemical methods (NMR spectra, mass spectra, IR spectra, UV-visible spectra).

The following impurities are present in the ambazon product:

a) guanylhydrazone 1,4-benzoquinone (II);

b) 1,4-benzoquinone (III) bis-guanylhydrazone;

c) 1,4-benzoquinone (IV) guanylsemicarbazone;

d) elemental sulfur.

The proposed technical solution is a method for cleaning the crude ambazon obtained by chemical synthesis in two stages.

In the first step, the crude ambazon is macerated with a non-polar solvent (benzene, n-hexane, toluene or xylene) to remove sulfur.

In the second step ambazone is recrystallized from N, N-dimethylformamide and lower aliphatic alcohols (C ₁ -C ₄₎ at temperatures in the range of 50-80 ° C to remove the impurities (II), (III) and (IV).

Methods from the literature indicate methods for purification of crude ambazon by dissolving in N, N-dimethylformamide and then precipitating with water [1], respectively, by dissolving ambazon nitrate in N, N-dimethylformamide and water, followed by neutralization of the salt with ammonia solution [2, 3].

These purification methods have the disadvantage that they do not remove sulfur from the product, and impurities (II), (III) and (IV) are present in high concentrations. This creates problems when using the obtained ambazon in the manufacture of a medicine.

In the proposed method for the removal of sulfur from the ambazon, maceration of the ambazon in non-polar solvents (benzene, n-hexane, toluene or xylene) is used. It uses the ratio of ambazon: solvent = 1: (1-5) (wt./about.) And temperatures in the range of 20-60 ° C. A ratio of 1: 3 and a temperature of 40 ° C. are preferably used.

At the stage of recrystallization of ambazon (I), the ratio ambazon: N, N-dimethylformamide: lower alcohols (C ₁ -C ₄ ) = 1: (1-3): (2-5) (w / v / v) is used and temperatures in the range of 55-60 ° C. It is preferable to use a ratio of 1: 2: 4 and temperatures of 55-60 ° C.

Analytical determination of sulfur content in the range is carried out gravimetrically by extraction of sulfur with n-hexane followed by evaporation of the solvent in a water bath.

Analysis of ambazon (I) and impurities from ambazon is determined by high performance liquid chromatography (HPLC).

Some examples of the invention are presented below:

Example 1

22 g of crude ambazon macerated with stirring in 66 ml of toluene for one hour at 40 ° C and filtered. Allocate 20 g of ambazon. The resulting ambazon is dissolved in 40 ml of N, N-dimethylformamide, reheated at 60 ° C and 80 ml of methanol are added to it. The temperature of the solution should not be lower than 55 ° C during the addition of methanol. A solution of ambazon in a mixture of N, N-dimethylformamide: methanol is cooled and maintained for two hours at 5-10 ° C. Allocate 17 g of pure ambazon with a minimum content by HPLC analysis equal to 99.5%.

Example 2

22 g of crude ambazon macerated with stirring with 66 ml of toluene for one hour at 45 ° C. Ambazon isolated by filtration (20.1 g) was dissolved at 60-65 ° C in 40 ml of N, N-dimethylformamide, and then 80 ml of ethanol was slowly added. After cooling and holding for two hours at 5-10 ° C, 16.8 g of ambazon are obtained as a result with a minimum content by HPLC analysis of 99.5%.

Example 3

30 g of crude ambazon macerated with 90 ml of toluene for one hour at 40 ° C, and 55 ml of N, N-dimethylformamide and 110 ml of methanol were added to the ambazon separated by filtration and then heated with stirring at 60 -65 ° C. After exposure for approximately 15 minutes at this temperature, it is cooled and incubated for two hours at 5-10 ° C. The result is 25 g of ambazon with a minimum content by HPLC analysis of 99.5%.

Bibliography

1. RO81168 (1983), Appl. RO19800103016, December 30, 1980.

2. GB 77494 (1957), Appl. DE 195300774794, June 16, 1953.

3. DE 965723 (1957), Appl. 195300010975, January 31, 1953.

Claims (1)

The method of purification of thiosemicarbazone of guanylhydrazone 1,4-benzoquinone (ambazon) using an organic solvent and a filtration step, characterized in that the crude impurity is directly purified, including the step of extracting sulfur present in the crude ambazone with non-polar solvents such as benzene, n- hexane, toluene or xylene, with a ratio of ambazon: solvent 1: (1-5) (wt./about.) at temperatures in the range of 20-60 ° C, filtering and the subsequent second stage of purification by adding a mixture of solvents, consisting of N, N-dimethylformamide and lower aliphatic alcohols (C ₁ -C ₄ ) with a ratio of ambazon: N, N-dimethylformamide: lower aliphatic alcohol 1: (1-3) :( 2-5) (w / v / about)) at temperatures in the range of 50-80 ° C to obtain a pure product.