HU201016B - Process for producing 3,6-diaminoacridine (proflavin) - Google Patents

Abstract

3,6-Di:amino-acridine (proflavin) is prepd. from m-phenylene-di:amine and formic acid; m-phenylene-di:amine reacts in the presence of mineral, pref. sulphuric-acid at a 1:1.0-1.2 mol. ratio, or m-phenylene-di:amine mono-hydrogen-chloride or a mixt. of mono- and mono-hydrogen-chlorides of m-phenylene-di:amine representing, based on di:amine a mol. ratio of 1.1.0-1.2 of hydrochloric acid entering the reaction with anhydrous formic acid, in a medium of 2-4C glycol. The cooled reaction mix is diluted with a 1-4C alcohol, pref. ethanol and the obtd. proflavin salt is filtered, converted with an alkaline into free base and recrystallised from glycol.

Description

The present invention relates to a process for the economical industrial production of 3,6-diaminoacridine (proflavin), characterized in that either m-phenylenediamine in the presence of 1: 1.0-1.2 molar sulfuric acid or m-phenylenediamine is used. monohydrochloride, or a mixture of m-Phenylenediamine mono- or dihydrochloride, which is reacted with anhydrous formic acid at a molar ratio of hydrochloric acid to salts of m-Phenylenediamine 1: 1, ΟΙ, 2- glycol. The reaction mixture is cooled and diluted with C 1-4 aliphatic alcohol, the precipitated proflavin salt is filtered off, dissolved in water, the base is liberated with sodium hydroxide solution, filtered again and recrystallized from ethylene glycol.

Proflavin is a valuable drug substance with antiseptic activity, which is used in compositions for the treatment of, inter alia, various ulcerative and inflammatory diseases. In addition, it can be used as a starting material for organic syntheses.

A. Albert investigated and summarized the possibility of its production and the most favorable way of industrial production (A. Albert: The Acridines London E. Arnold Publ. Ltd. 1966). According to Albert, m-phenylene diamine is reacted on glycerol with 90% formic acid in the presence of concentrated hydrochloric acid at 155 ° C for 75 minutes. After cooling to 100 ° C, the reaction mixture is diluted with water and added to an aqueous solution of sodium hydroxide. The precipitated proflavin base is filtered off, dissolved in dilute acetic acid, the solution is neutralized with sodium hydroxide, and the precipitate is filtered off, then the clear solution is made alkaline and the proflavin is filtered. The product thus obtained is purified by recrystallization. For recrystallization, 55 times ethyl alcohol or 400 times water are recommended. Thus, proflavin is obtained in a yield of 60%.

Albert's reproduction experiments have shown that the final product thus obtained is of poor purity. Recrystallization was required to obtain proflavin uniform by TLC, which reduced the yield to 50%.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for preparing proflavin simply and economically, in a better yield and purer form than previously known methods.

The present invention is based on the realization that by minimizing or completely eliminating the water added to the reaction mixture, it is possible to create substantially more favorable conditions for the reaction, in particular by improving the quality and ease of purification of the crude product. This simplifies the production process, increases production and makes production more economical. The beneficial effect is due to the fact that in the presence of water, the optimum reaction temperature (155 ° C) cannot be achieved until the added water is removed from the reaction mixture. This means that depending on the starting amount of the reaction partners, at least one hour is needed to reach the appropriate temperature since the internal temperature fluctuates between 130-140 ° C as long as water is present in the reaction mixture.

Since proflavin formation is only very low below 145 ° C, due to the increase in side effects, the contamination of the crude product is significantly increased.

According to the process according to the invention, the reaction partners are selected so that practically no or only minimal amount of water is introduced into the system. To this end, anhydrous formic acid is used and the reaction partner is m-phenylene diamine monohydrochloride or a mixture of the mono- and dihydrochloride salts of m-phenylene diamine such that the molar ratio of hydrochloric acid to the reaction mixture is m-femylene diamine. 1: 1.0 to 1.2.

If only m-Phenylenediamine is to be used, the reaction may be carried out in the presence of concentrated sulfuric acid, which also has a molar ratio of m-Phenylenediamine of from 1: 1.0 to 1.2. An important advantage of using sulfuric acid is that industrial production can be carried out in a simple autoclave of stainless steel, in contrast to the very aggressive hydrochloric acid which requires the use of a much more expensive enameled autoclave.

A further advantage is that when sulfuric acid is used, the production is simplified, since it is not necessary to form a salt from m-phenylenediamine in a separate reaction step, as is the case with hydrochloric acid.

It has been found that glyceryl is preferably a C2-C4 glycol, preferably ethylene glycol, because of its highly absorbent nature, as the reaction medium.

By eliminating or minimizing water, it is possible to raise the temperature of the reaction mixture to 155 ° C in 25-30 minutes. In this way, side reactions can be suppressed and product contamination is greatly reduced.

It is further recognized that when the reaction mixture is diluted with aliphatic C 1-4 aliphatic alcohol, preferably ethyl alcohol, rather than water, the impurities remain in the glycolic mother liquor and the filtered pro-valin salt can be obtained in a substantially better quality.

Thus, according to the invention, m-Phenylenediamine is used in the presence of sulfuric acid in a molar ratio of 1: 1.0 to 1.2, or m-Phenylenediamine monohydrochloride or m-Phenylenediamine mono- and a mixture of dihydrochloride with a molar ratio of hydrochloric acid to salts of m-Phenylenediamine of from 1: 1.0 to 1.2, in ethylene glycol, the mixture is cooled, diluted with ethyl alcohol and the precipitated crude product is filtered off. .

The purification of the product poses a major problem in the practical implementation of industrial scale production of proflavin because of the high volume requirement of the operation due to the low solubility of proflavin.

An important part of the process is the recognition that proflavin is highly soluble in ethylene glycol at 95-100 ° C, but poorly soluble at 20-25'C. Another advantage of ethylene glycol is that it removes the impurities accompanying proflavin well at room temperature.

The solvent requirement of the purification step may vary depending on the degree of impurity in the crude product, but in any case requires a smaller volume than recrystallization from water or ethyl alcohol used hitherto. In our experience, 5-8 times ethylene glycol, based on the dry weight of the crude product, is sufficient for recrystallization.

The invention is illustrated by the following examples, without limiting our claims.

Example 1

35.7 g (0.66 mole) of 85% formic acid and 129.8 g (1.2 mole) of m-phenylenediamine were charged into 388 g of ethylene glycol. Concentrated hydrochloric acid solution (48.1 g, 1.32 mol) was added with stirring. The solution was heated to an internal temperature of 155 ° C. At this temperature, the reaction was stirred for 75 minutes with vigorous stirring. Ethyl alcohol (360 g) was added to the reaction mixture, which was cooled to 80 ° C, cooled to 10 ° C, the precipitated proflavin hydrochloride was filtered off, washed in several portions with a total of 360 g ethyl alcohol and dissolved in 500 g water. With stirring, make alkaline with about 220 g of 20% sodium hydroxide solution until the phenolphthalein indicator is indicated. The proflavin is filtered off and washed with water to make it alkaline. The proflavin is filtered off and washed with water to make it alkaline. The crude product was dissolved in 58x ethylene glycol based on dry matter at 95100C with stirring. After stirring for 10 minutes with 10% dry solids, the charcoal is filtered off. The carbon-free filtrate was slowly cooled to 20 ° C with stirring and stirred for 60 minutes. The crystallized pro -lavin was filtered off, washed with ethyl alcohol and dried at 50 ° C in vacuo. The quality of the crystalline proflavin was examined by thin layer chromatography (acetonrammonium hydroxide 8: 2; Kieselgel 60, aluminum foil; Rf: 0.80-0.85).

Yield: 62.8-69.1 g (50-55%).

Mp: 276-77'C.

Example 2

Water from a mixture of the reaction partners measured in Example 1 is distilled under vacuum with nitrogen inlet at an internal temperature not exceeding 60 ° C. The reaction mixture was then heated to 155 ° C for 30-35 minutes. Hereinafter referred to as

Example 1 was followed.

Yield: 79.1 g (63%).

M.p .: 276-77'C.

Example 3

To 388 g of ethylene glycol was added 30.4 g (0.66 mole) of anhydrous formic acid in 156.2 g (1.08 mole) of m-phenylene diamine monohydrochloride and 21.7 g (0.12 mole) of m-phenylene. diamine dihydrochloride. The reaction mixture was heated to 155 ° C over 25-30 minutes. In the following, the procedure of Example 1 is followed.

Yield: 85.4 g (68%).

M.p .: 276-77'C.

Example 4

To 388 g of ethylene glycol was added 30.4 g (0.66 mol) of anhydrous formic acid and 129 (1.2 mol) of m-phenylenediamine. 122.6 g (1.2 mol) of 196% sulfuric acid were added with stirring, and the reaction mixture was heated to 155 ° C over 30-35 minutes and stirred at this temperature for 75 minutes. The reaction mixture was then cooled to 50 ° C and poured into 2000 g of 6% sodium hydroxide solution with vigorous stirring under a thin stream. The crude proflavin was filtered off, washed with water to make it alkaline, filtered and recrystallized from ethylene glycol.

Yield: 89.1 g (71%).

M.p .: 276-77'C.

Claims (3)

PATIENT INDIVIDUAL POINTS A process for the preparation of 3,6-diaminoacridine (proflavine) by reaction of m-phenylenediamine and formic acid by purification of the crude product by recrystallization, characterized in that or m-phenylenediamine in the presence of a mineral acid, preferably sulfuric acid, in a molar ratio of 1: 1.0 to 1.2, - either m-phenylenediamine monohydrochloride or a mixture of m-phenylenediamine mono- and dihydrochloride, with which the molar ratio of hydrochloric acid added to the reaction mixture is calculated from 1: 1.0 to 1.2 per m-phenylenediamine with anhydrous formic acid in C2-C4 glycol, then the reaction mixture is cooled and diluted with C1-C4 aliphatic alcohol, preferably ethyl alcohol, the proflavine salt is filtered, the base is liberated with aqueous sodium hydroxide and recrystallized from ethylene glycol. A process according to claim 1, wherein the reaction is carried out in ethylene glycol. Method according to claims 1 and 2, characterized in that the reaction temperature is maintained at 155160 'C.