Carbadox from 2-quinoxaline, carboxaldehyde methyl carbazate

The present invention relates to a process for the production of N¹ , N⁴-methyl nium dioxide. This compound is known to be a urinary tract antiseptic, a systemically acting anti-infection agent, an animal growth promoting agent and an agent for treating chronic respiratory and poultry diseases, and an animal food utilization enhancer [(Australian Vet. J. 48, No. 10, 579, (1972) and Rec. Med. Vet. Ecole alfort 148 No. 3 365 373 (1972)].

The production method of N1, N⁴/ Dioxide / 3 // 2 / quinoxalinylmethylene / methyl carbazate is known from U.S. Patents Nos. 3,371,090 and 3,493,752. The disadvantage of this known process is that light-decomposing intermediates are produced in the early stages of the process. especially quinoxaline di-N-oxide, which results in a reduction in the efficiency of the process already in the intermediate stages. The sensitivity of quinoxaline di-N-oxide to light is a known fact and e.g. in order to prevent the degradation of the biologically active compound in the preparations, the addition of tetracycline derivatives is used.

The method according to the invention avoids these disadvantages of the known process.

By the process of the invention, methyl 3- (2-quinoxalinylmethylene) -carbazate N, bβ-dioxide, i.e. 3- (2-quinoxalinylmethylene) -hydrazinecarboxylic acid N1 -dioxide, is prepared by reacting 3- (2-quinoxalinylmethylene) -carbazane of methyl with at least 2 equivalents of oxidizing agent, carrying out this reaction in an inert solvent at a temperature of 20-100 ° C. Peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, performic acid or trifluoroperacetic acid, or hydrogen peroxide are used as the oxidizing agent.

When hydrogen peroxide is used, it is usual to add a catalyst such as tungsten acid, sodium or potassium tungstate, sodium vanadate, sodium or potassium mole benzoate, vanadium pentoxide, zirconium dioxide, tungsten trioxide or molybdenum trioxide. It is particularly advantageous to use as

858 the catalyst is peracetic acid, and the solvent is acetic acid, as these are relatively inexpensive. The second preferred oxidizing agent is m-chloroperbenzoic acid, chloroform is then suitable as the solvent. In both of these processes, the reaction temperature is preferably less than 50 ° C.

The process according to the invention is carried out in a solvent which is inert under the reaction conditions. For this purpose, any solvent is used which is capable of dissolving the reaction components and does not adversely affect the reaction components and products. Two types of '-solvents are particularly suitable, viz. organic acids, e.g. acetic acid, and halogenated solvents such as chloroform, methylene chloride. In some cases, water can be used as a solvent. However, other solvents meeting the above-mentioned requirements can be used, the choice of the solvent having a great influence on the temperature at which the reaction is carried out. Depending on the type of oxidizing agent used and the temperature, the reaction continues. from a few minutes to 24 hours, with rather long durations being preferred to complete the reaction.

The ratio of oxidizing agent to starting product may vary, but the reaction is particularly advantageous when at least 2 equivalents of oxidizing agent are used per mole of starting carbazate. The product is crystalline and precipitates from the reaction mixture. . The -go is separated and dried in a known manner.

The possibility of carrying out the reaction according to the invention is completely unexpected, since from earlier publications, e.g. from the article by WD Emmons in JACS, 79, p. 5739 (1957), a very high sensitivity of the carbon-nitrogen double bond to oxidation is known.

The compound of the present invention is a valuable anti-urinary agent in animals and humans, and is active against microorganisms, including gram-positive and gram-negative bacteria. Especially valuable is its action against gram-negative bacteria, both in virto and in vito

The compound of the present invention, when administered to ruminant or non-ruminant animals in low doses of about 0.04-10 mg per day per kg of body weight over a longer period of time, especially during most of the active growth period of the animal, also causes increasing growth rate and better utilization of food. The compound is preferably administered to birds, e.g. such as chickens, ducks and turkeys, and animals such as cattle, sheep, - dogs, cats, pigs, rats, mice, horses, goats, mules, rabbits, minks, etc.

The beneficial effect of this compound on the growth and food utilization of animals is much greater and more pronounced when the animals are given whole nutritious food containing all the nutrients, vitamins, minerals and other known substances required for maximum healthy growth of the animal. When using this compound, the animal reaches the desired state faster and saves feed.

Compound feeds containing the compound of the invention give particularly good results in poultry, rats, pigs, lambs, cattle and the like. In some cases, the response to this agent depends on the sex of the animal. The compound according to the invention can be used with one of the feed ingredients or evenly mixed with the whole feed as well as with drinking water, and it can be used with foods containing various ingredients used in nutritional feed.

The starting product used in the process according to the invention is prepared, for example, by 14.0 g (0.0886 mol) of 2-quinoxalinecarboxylaldehyde obtained by the method of Landguist iSilk, J.Chem. Soc. (1956) p. 2052, dissolved in 100 ml of ethanol, added 14.0 g (0.156 mol) of methyl carbazate, refluxed on a steam bath, and left at room temperature for several hours. After the crystalline product is separated off, 14.0 g (69% of theory) of methyl 3- (2-quinoxalinylmethylene) carbazate are obtained, m.p.

242-244 ° C.

Example 1 To a solution of 46 g (0.20 mol) of methyl 3- (2-quinoxaHnylmethylene) carbazate in 200 ml of glacial acetic acid was added dropwise 7.6 g (0.40 mol) of 40% peracetic acid at such a rate as to maintain the temperature of the mixture is less than about 50 ° C. The mixture is allowed to stand for 12 hours, then diluted with water, the precipitated solid product is collected, washed with water and dried to give methyl 3- (2-quinoxahnylmethylene) carbazate dioxide.

Example II. To a solution of 46 g (0.20 mol) of methyl 3- (2-quinoxalinylmethylene) carbazate in 300 ml of chloroform is added a solution of 82 g (0.40 mol) of m-chloroperbenzoic acid in 300 ml of chloroform. The mixture is cooled externally and the rate of addition of the m-chloroperbenzoic acid is controlled

858 so as to keep the temperature of the mixture below 50 ° C. After stirring for 24 hours, the precipitate was filtered off and mixed with excess aqueous sodium bicarbonate to remove residual m-chlorobenzoic acid. The suspension is filtered, washed with water and dried to give N¹ Methyl 3- (2-quinoxalinylmethylene) -carbazate N-dioxide.

Example III. The mixture was 23.0 g (0.1 mol). Methyl 3- (2-quinoxaHnylmethylene) - carbazate,

2.5 g of tungsten acid and 30 ml of the third row. butanol is heated to 60-65 ° C and 30 ml of a 30% aqueous hydrogen peroxide solution are added over a few minutes. After 2 1/2 hours, the mixture is cooled, diluted with 200 ml of water, and the crystalline Ni, N is filtered off.⁴methyl 3- (2-quinoxalinylmethylene) carbazate dioxide, washed with water and dried.

Example IV. To 46 ml of anhydrous methylene chloride containing 6.5 g of phosphorus pentoxide was added with stirring and cooling 10 ml of 40% technical peracetic acid. After. After 15 minutes, 35 ml of the resulting clear solution are withdrawn with a syringe, and 2.3 g (0.01 mol) of methyl 3- (2-quinoxalinylene) carbazate in 10 ml of methylene chloride are slowly added to the suspension. The resulting mixture is kept at 40 ° C for 23 hours; then it is cooled and the resulting precipitate is filtered off.

1.25 g of 3- (2-quinox, 4-nylmethyl) 1,4-dioxide are obtained^rMethyl ester, yellow, melting with decomposition at 240 ° -242 ° C. A sample, purified by silica gel column chromatography using a mixture of chloroform and tetrahydrofuran as eluent, mp 242-243 ° C. The structure of the compound is confirmed by the results of mass spectrum analysis, infrared spectrum and nuclear magnetic resonance spectrum.