FI59405C - PROCEDURE FOR FRAMSTATION OF METHYL-3- (2-QUINOXALYNYLMETHYLENE CARBACATE-N1, N4-DIOXIDE - Google Patents

Description

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* 4ΒΤα W (11) utläccnincsskrift 5 9405 • S-SNg C (4¾ Patent myonneity 10 08 1931

Patent meddelat ¢ ,, ** W c 07 D 241/52 FINLAND — FINLAND (*) * - «--- 978 / 7¾ (22) Hakambpliv · —Anaeknlngadtl 29.03-7¾ (FI) (23) Atkwfltvl — CiMftieodag 29- 03-7¾ (41) TuHet ΙμΗιΙμΜ - BHvH offsnclig 11-10-7¾

Patent * and the National Board of Registration (44) Nthtivtksipanon Ja kiMiL (expired * «m date - .. Q_,

Patent and refinery AnUMt »« hi <eeh «ijknfue ρ« μιμ «<30.0k.öl (32) (31) () 1) IffhRr« niIhn> 4i | MprMnt 10.0¾.73 USA (US) 3¾9805 (71) Pfizer Inc-, 235 East nd2nd Street, New York, New York 17, USA (72) Herman Faubl, Mystic, Connecticut, Banavara Lakshmana Mylari,

Waterford, Connecticut, USA (US) (7¾) Oy Kolster Ab (5¾) Process for the preparation of methyl 3- (2-quinoxalinylmethylene) -carbazate N, N-dioxide - For the preparation of methyl 3- (2-quinoxalinylmethylene) The present invention relates to a process for the preparation of methyl 3- (2-quinoxalinylmethylene) carbazate N1, N-dioxide, of the formula I,

T

N CH = NNHC00CH3 x f o in which process of formula II,

Okainen 0

T

aK ^ --- CHl® + -o "

R II

M-S-J

o 59405 2 wherein R is lower alkyl, preferably methyl, is reacted with at least an equimolar amount of methyl carbazate in a reaction inert solvent in the presence of a strong acid catalyst such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or trifluoroacetic acid: temperature.

The compound to be prepared according to the new method to be presented is well known as a urinary antiseptic, a systemic anti-infective agent, an animal growth promoter, a poultry respiratory disease agent and an animal appetite enhancer. (Australian Vet. J. U8, No.

10,579, (1972) and Rec. Med. Vet. Ecole Alfort 1Π8, No. 3 365-73 (1972).

It is known from Finnish application 1 βί + Τ / 69 to prepare methyl 3- (2-quinoxalinylmethylene) carbazate N * ', N-dioxide from acetal and carbazate, and from English patent 1,058 0 ^ 7 it is known to use an aldehyde or carbateate. as starting material.

The process according to the invention differs from the current state of the art in that a special starting material, nitron, reacts quite satisfactorily with carbazate to form the desired end products. The nitrone can be prepared by a simple method from benzofuroxane, eliminating the need for expensive methyl glyoxal acetal. It is also not necessary in the process of the present invention to prepare the aldehyde intermediate required in the prior art processes. The aldehyde intermediate is a volatile compound and must therefore be handled with care. The process according to the invention can thus be carried out under less "subtle" conditions.

The novel reaction of the present invention is carried out in a reaction-inert solvent. Suitable solvents for the inert solvent are any solvent in which the reactants are soluble and which do not adversely affect the starting materials or the products under the conditions used. Two preferred groups are organic acids such as acetic acid and lower alcohols and esters such as ethanol and ethyl acetate. An acid catalyst concentration of about 2 to 10% by weight of the total reaction mixture is sufficient. (If a strong acid, e.g. trifluoroacetic acid, is used as the reaction solvent, an acid catalyst is unnecessary). Often a small amount of water in the reaction mixture is desirable, in which case acids such as concentrated hydrochloric acid or hydrobromic acid containing water may be used as the acid catalyst. However, any solvent that meets the above requirements is satisfactory. The optimum temperature depends for the most part on the reaction components selected. Higher temperature ranges may require the use of an autoclave or other high pressure vessel.

Depending on the particular reagents and temperature, the reaction time may vary from a few minutes to 2 hours. In general, long reaction times are recommended for complete conversion of starting materials. Optimal reaction conditions 3 59405 are easily determined experimentally.

The ratio of quinoxaline derivative to carbazate can vary widely, but efficient conversion requires at least about one equivalent of carbazate per mole of quinoxaline derivative and it is recommended to use a 50-100% mole excess of carbazate.

The nitrones used as starting materials are prepared by H.K. According to the procedure set forth by Kim in U.S. Patent 3,6hh 363. Methyl carbazate and its derivatives are obtained by the method of N. Rabjohn and H.D. In Barnstorff, J.Am. Chem. Soc., 75, 2259 (1953).

The product is isolated by diluting the reaction mixture with water, cooling and then filtering. The solid thus obtained is washed with water and dried to give the desired methyl 3- (2-quinoxalinylmethylene) carbazate N-N dioxide.

The valuable product of this invention has a systemic anti-urinary tract inflammatory effect in animals, including humans, by acting against a large number of microorganisms, including gram-positive and gram-negative bacteria. It is particularly effective against inflammation caused by gram-negative bacteria both in vitro and in vivo.

In addition, when a small amount of the Schiff base disclosed herein is added to the diet of animals, both ruminants and non-ruminants, so that the animals receive the product over a prolonged period of about 0.0-10 mg / kg body weight daily, especially during the major part of their active growing season. and food utilization is improved. These two categories of animals include poultry (chickens, ducks, turkeys), cattle, sheep, dogs, cats, rats, pigs, mice, horses, goats, mules, rabbits, minks, etc. The beneficial effects on growth rate and food utilization are greater than those normally achieved with complete diets that include all the nutrients, vitamins, minerals, and other factors known to be necessary for the maximum healthy growth of these animals. Animals thus reach market size faster and with less food.

These nutrient compositions have been found to be particularly valuable and important for the following animal species: poultry, rats, pigs, sheep, cattle, and the like. In some cases, efficacy can vary according to sex of the animal. The products can, of course, be dispensed as a single ingredient in the food or they can be mixed evenly throughout the food mixture; alternatively, as mentioned above, they may be administered in an equivalent amount to the water doses of the animals. It should be noted that a variety of nutrients can be used in nutritionally balanced foods.

11 59405

The following examples illustrate the invention:

Example 1

To a solution of 1 + 3.8 g (0.20 moles) of N-methyl-c (- (quinoxalinylmethylene) nitron-N 2, N 2 -dioxide and methyl carbazate (27 g, 0.30 moles) in acetic acid ( 1 + 00 mg), concentrated sulfuric acid (20 ml) is added and the resulting mixture is heated at about 90-100 ° C for about 20-2l + hours.After cooling and diluting with water (1200 ml), the precipitated solid is collected and dried. to give methyl 3- (2-quinoxalinylmethylene) carbazate N, N-dioxide.

Example 2

To acetic acid (20 mL) is added N-methyl- (t- (quinoxalinylmethylene)) -1+ nitrone N, N-dioxide (2.19 g, 0.01 mol), methyl carbazate (1.35 g, 0.015 mol) and concentrated sulfuric acid (1 ml). The mixture is heated at 90-100 ° C for 20 hours, then cooled and diluted with 60 ml of water and filtered to give methyl 3- (2-quinoxalinemethylene) 11 * carbazate-M, H-dioxide ( 2.2 g, 8U%) as a pale yellow solid, m.p. 2-8-250 ° (decomposes). The structure of the compound is confirmed by mass spectral, NMR and IR analysis.

Claims (1)

59405 Claim: A process for the preparation of methyl 3- (2-quinoxalinylmethylene) -carbat-1U of the formula I. . . for the preparation of N, N-dioxide, characterized in that the N-lower alkyl-c (- (quinoxalinylmethylene) nitron-N 2, N 2 -dioxide of the formula II N JCH = N-O nr * o wherein R is lower alkyl, preferably methyl, is reacted with at least an equimolar amount of methyl carbazate in a reaction inert solvent in the presence of a strong acid catalyst such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or p-toluenesulfonic acid at.