IL44434A - Process for producing methyl 3-(2-quinoxalinylmethylene)carbazate n1,n4-dioxide - Google Patents

Abstract

1462424 Methyl 3-(2-quinoxalinylmethylene)- carbazate-N<SP>1</SP>,N<SP>4</SP>-dioxide PFIZER Inc 15 March 1974 [10 April 1973] 11706/74 Heading C2C The title compound is prepared by reacting a nitrone, acetal, oxime, semicarbazone or thiosemicarbazone derivative of 2-formylquinoxaline-1,4-dioxide with NH 2 NHCO 2 Me or a hydrazone derived therefrom, provided that only said hydrazone may be used for reaction with an acetyl. Reference has been directed by the Comptroller to Specification 1,058,047. [GB1462424A]

Description

44434/2 4 Process for productin methyl 3-(q inoxaliiayl-methylene )carbazate I ,N2-di6xide PFIZER INC.

This invention relates to a novel synthetic procedure and more particularly to a novel method for the-preparation, of methyl 3- (2-quinoxalinylmethylene) carbazai^ 1 4 N ,N -dioxide. The compound prepared by the novel subject process is well known as a. systemic anti-infective, animal growth promotant, as an agent for the control of chronic respiratory diseases in poultry and improvement of feed efficiency in animals.

[Australian Vet. J. 4_8, No. 10* 579, (1972) and Rec. Med.

Vet. ecole Alfort 148 No. 3 365-73 (1972) ] .

A process for the production of methyl 3- 1 4 (2-quinoxalinylmethylene) carbazate N ,N -dioxide by 1 4 · reaction of 2-quinoxalinecarboxaldehyde N ,N -dioxide acetal with methyl carbazate is described in Israeli Patent No. 32243. Such a route, however , requires the use of an expensive reagent in methy.lglyoxalacetal which is used to prepare the acetal which is reacted with the methyl carbazate and also requires the formation of the intermediate aldehyde during the production of the final product. We have now found a route to the production of methyl 3- (2-quinoxalinylmethylene) carbazate ,N4 -dioxide which avoids the problems by employing as the starting material the nitrone of 2-quinoxalinecarboxaldehyde dioxide which can itself be prepared simply from acetone.

Accordingly, the present invention discloses a process for the preparation of methyl 3- (quinoxalinyl-methylene) carbazate ,N4-dioxide which . comprises con- tacting a 2-quinoxalinecarboxaldehyde N ,N -dioxide nitrone derivative with at least about an equimolar proportion of methyl carbazate in reaction-inert solvent in the presence of strong acid catalyst at a temperature of from about 30 to 200 °C. until reaction is substantially complete.

The new reaction of the present invention is carried out in a reaction-inert solvent. An inert solvent" for purposes of this invention contemplates any solvent which allows solubilization of the reactants and is free of adverse effect on the reagents and products under the con-ditions employed. Two preferred types include organic acids, such as acetic acid, and lower alcohols and esters such as ethanol and ethyl acetate. The novel reaction of the present invention requires the presence of a strong acid catalyst. Examples of such acids suitable for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p_-toluenesulfonic acid and tri-fluoroacetic acid. It is usually satisfactory to employ from about 2-10$ by weight of the total reaction mixture of the acid catalyst. (If a strong acid e.g., trifluoro-acetic acid is used for a reaction solvent,. an acid catalyst is unnecessary.) Often the presence of a small quantity of water in the reaction mixture is desirable and this may be conveniently introduced by employing as an acid catalyst such acids as concentrated hydrochloric or hydrobromic acid which contain water. However, any solvent possessing the qualities set forth above will be satisfactory. The temperature at which the reaction is performed may vary from 30°C. to about 200°C. and for the most part the optimum temperature will vary with the choice of re-agents. The higher temperature ranges may require the use of an autoclave or other high-pressure vessel.

Depending upon the particular reagents and temperature, the reaction time can vary from a few minutes, to as long as 24 hours. Generally, to ensure complete re-action the relatively long time periods are preferred.

Optimum reaction conditions are readily determined by ^ experiment.

• The proportion of quinoxaline nitrone derivative relative to the methyl carbazate may vary widely but for efficient conversion at least about one equivalent of methyl carbazate per mole of quinoxaline nitrone derivative is necessary and a molar excess of 50-100% of the methyl carbazate is preferred.

The starting materials for the process of the present invention are readily prepared by well known standard organic chemical techniques. For example, the quinoxaline nitrones are prepared via the route described by H.K. Kim. United States Patent 3 , 6 4 , 363 - The methyl carbazate and its derivatives are available through the sequence described by N. Rabjohn and H.D. Barnstorff, J. Am. Chem. Soc . , 75 , 2259 ( 1953 ) .

The product is isolated by dilution of the reaction mixture with water, cooling and subsequent filtration.

The solid thus collected is washed with; water and dried to v provide the desired methyl-3- ( 2-quino;xalinylmethylene ) carbazate N1,N1,-dioxlde.

The valuable product of this invention exhibits activity as urinary tract systemic anti-infective in animals, including man, against a wide variety of microorganisms including Gram-positive and Gram-negative bacteria. It is especially valuable against Gram-negative infections both in vitro and in vivo .

Further, the addition of a low level of the herein described Schiff base to the diet of animals, both ruminant and non-ruminant, such that these animals receive the product over an extended period of time, at a level of from about 0.04 mg/kg. to about 10 mg./kg. of body weight per day, especially over a major portion of their active growth period, results in an acceleration of the rate of growth and improved feed efficiency. Included in these two classes of animals are poultry (chickens, ducks, turkeys), cattle, sheep, dogs, cats, rats, swine, mice, horses, goats, mules, rabbits, mink, etc. The beneficial effects in growth rate and feed efficiency are over and above what is normally obtained with complete nutritious diets containing all the nutrients, vitamins, minerals and other factors known to be required for the maximum healthy growth of such animals.

The animals, thus attain market size sooner and on less feed.

These feed compositions have been found to be particularly valuable and outstanding in the case of such animals as poultry, rats, hogs, swine, lambs, cattle, and the like. In some instances the degree of response may vary with respect to the sex of the animals. The products, may, of course, be administered in one component of the feed or they may be blended uniformly throughout a mixed feed; alternatively, as noted above, they may be administered in an equivalent amount via the animal's water ration. It 44434/2 should be noted that a variety of feed components may be of use in the nutritionally balanced feeds.

The following examples are merely illustrative and in no way limit the scope of the appended claims; EXAMPLE I CH»NNHCO-CH To acetic acid (20 ml) was added N-methyl÷2- (2- 1 4 quinoxaline-N :,IS -dioxide) -nitrone (2.19 g, 0.01 mol) , methyl carbazate (1.35 g, 0.015 mol) and cone, sulfuric acid (1 ml).

The mixture was heated at 90-100°C for 20 hrs. then cooled and diluted with 60 ml of water and filtered to give methyl 3-(2-quinoxalinylmethylene)carbazate-N 1 ,N4-dioxide (2.2 g, 84%) as a light yellow solid mp. 248-250· (d) . Mass spec, NMR and IR consistent with assigned structure.

EXAMPLE II 3 44434/2 A mixture of acetic acid (19 ml), cone. HCl (0.7 ml) and N- (p-dimethylamlnophenyl) -2- (2-quinoxalinyl-N 1,N4-dioxide)-nitrone (2.85 g, 0.0088 mol) was stirred at room temperature for 30 min. and then filtered. To the filtrate, was added methyl carbazate (1.23 g, 0.0131 mol) and the reaction heated at 55° for 2 hrs. and then stirred at room temperature overnight. The mixture filtered, washed with water and methanol, dried to give methyl 3- (2-quinoxalinylmethylene)carbazate- 1 Ν ,Ν' -dioxide (1.79 g, 78%) as a dark solid (tan+yellow) mp 242° (d) IR, NMR and mass spec are consistent with assigned structure.

Claims (4)

44434/2 CLAIMS: Jf'

1. A process for the preparation of methyl 3- (2- 1 4 quinoxalinylmethylene) carbazate N ,N -dioxide , which 1 comprises contacting a 2-quinoxalinecarboxaldehyde N ,N -dioxide nitrone derivative with at least about an equimolar proportion of methyl carbazate in reaction-inert solvent in the presence of strong acid catalyst, at a temperature of from about 30 to 200eC. until reaction is substantially complete.

2. The process of Claim 1, wherein said nitrone derivative is selected from N-lower alkyl, -hydroxy-lower alk l, -phenyl and -benzyl nit ones.

3. A process for preparing methyl 3- (2-quinoxalinyl-methylene) carbazate N^N^-dioxide, substantially as described. 1 4

4. Methyl 3- (2-quinoxalinylmethylene) carbazate N ,N -dioxide whenever prepared by the, process substantially as described.