CS212276B2 - Method of making the methyl-3-(2-chinoxalinylmethylene) -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.

Description

The present invention relates to a novel process for the preparation of methyl 3- ( ^2- quinoxalinylmethylene) carbazate-N ^1, N ⁴ -dioxide. The product obtainable by the novel process of this invention is a well known antiseptic agent for urinary is systemically active against infections of the intestinal tract, promotes the growth of animals, and is an effective remedy for chronic respiratory disease in ^straight routine or increasing in ^y already ^APPLICATION fo ^y animals .fAustalian. Vet. ^J. .48, δ. ^10,579 (1972) and RecMed. Vet. ecole Alfort 148 No. 3,365-73 (1972)].

British Patent Specification No. 1,202,770 discloses a process for the preparation of this compound starting from the relatively expensive methylglyoxalacetal reacted with benzofuroxane to give acetalo carboxaldehyde, which is converted to the volatile 2-quinoxaline carboxaldehyde reported in reaction with methylcarbazate. This is a complicated and costly method of manufacturing the resulting substance and efforts have been made to improve it.

The present invention provides a process for producing methyl 3- (2-quinoxalinylmethylene) carbazate N ^ ^N ^ -d ^ u ^{and oxide,} characterized in, ^that the mouth is ^B i on derivatives ^and t 2 c ^h ar inocalin ^{to b} benzaldehyde oxalate ^d N j ^{N 1} -D ⁱ ox u ^id, at ^ semiterbazon oxide, nitrone not dimethylhexyl ^{b y} the acetal are ales he ^p e ^k vimoléirním amount of methyl carbazate.

Starting from benzofuroxane, which is reacted with acetone to give a stable intermediate which can be converted directly to the nitron, which is the starting material in the process of the invention.

^{PU bp} compliance with the climb ^{Y is N,} thus unwinding the gain ^{and or} outgoing n ^d n ^e la ^{area, d} and ^l-one eco Saim thereby. in a cheaper way than before.

The new reaction according to the invention is carried out in a solvent which is inert to the reaction mixture. It is any solvent that allows dissolution of all components and has no adverse effect nor does it adversely affect the reaction products under the conditions employed. Two preferred types of solvents are organic acids such as acetic acid and lower alcohols and esters such as ethanol and ethyl acetate. The novel reaction of the invention requires the presence of a strong acid catalyst.

Examples of such acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, or trifluoroacetic acid. The acid, which is the catalyst, is usually used in a proportion of 2 to 10% by weight of the total reaction mixture. In case the solvent for the reaction include a strong acid such as trifluoroacetic acid, 'not at all necessary to use acidulous fcatal ^y Zátor. Often it is ^also desirable ^Pr I ^t omnost ^SMALL quantity of water in the reaction mixture may be accomplished, by such an acid which is used to catalyze the reaction of concentrated hydrochloric acid or hydrobromic acid with a water content.

Otherwise, however, any solvent that satisfies the above conditions is suitable. Lota Te ^{p p} s reaction with ^p oh ^Yb U is in the range of ^{d 30} to ¹⁰⁰ DEG C in ^{an ODL} e ^lb y rea ect ^to folders. ^The higher the temperature, the more likely it is to use an autoclave or pressure reaction vessel;

Depending on the reactants used and the temperature selected, the reaction time varies within a few minutes. up to 24 hours. Usually a long period of time is required to complete the reaction. Optimum reaction conditions are usually determined experimentally.

The ratio of the quinoxaline derivative to the carbazate can vary within a wide range for ^efficient conversion. However, a least one of e ^{and k} in ^{Valent b} ar to ^A to 1 mol of the cMnoxaMnového derivative being preferred to employ from 50 to 100% excess carbazate.

The carbazate used is most often methyl carbazate, although other carbazates, such as methyl 3-isopropylene carbazate, may also be used.

The starting materials for carrying out the process according to the invention can be: easily prepared by known standard organic chemistry procedures. For example, quinoxaline dioxide acetals can be prepared by the method of Issidorides and Haddadi, British Patent Specification No. 12158.5. Semicarbazone can be prepared according to J. D. Johnston, United States Patent No. 3,493,572. Thiosemicarbazone and oxime are prepared in a similar manner using thiosemicarbazide hydrochloride or hydroxylamine hydrochloride.

Nitrons can be made according to Η. K. Kim, U.S. Patent No. 3,644,363. Methyl carbazate and derivatives thereof can be prepared according to the method of N. Rabjohn, and HD Barnstorff, J. Am. Chem. ^S oc ·, ⁷ 5>, 2,259 ⁽¹⁹⁵³⁾ ·

The product is isolated by diluting the reaction with water, cooling and filtering. The solid so separated was washed with water and dried to give the desired methyl 3- (2-chinoxalinylmetlh / linen) ^for arbazát- ^N '^ dioxide.

The product produced by the novel process of the invention is effective as a systemic antiinfective of the urinary tract in animals, including humans, against a wide range of microorganisms including gram-positive and gram-negative bacteria. The compounds of the invention are particularly active against both gram-negative microorganisms in vitro and in vivo.

In addition, it is possible to accelerate the growth of animals and improve food utilization by adding a small amount of these compounds to the feed, both ruminants and non-ruminants, for extended periods of time at doses of 0.04 mg / kg to 10 mg / kg animal weight per day; especially during the growth period of the animals. These include, for example, poultry such as chickens, ducks and turkeys, cattle, sheep, dogs, cats, rats, pigs, mice, horses, goats, mules, rabbits, minkes, etc. containing all necessary nutrients, mineral salt vitamins and other factors known to be important for the growth of the animals. The animals fed in this way reach the carcass weight earlier, using less feed.

A feed additive according to the invention is particularly valuable in poultry, rats, pigs, pigs, lambs, with ^the apo ol ^{d. Some of manufacture} p pa ^d ec ^h is ^dp OVE ^{at least} rilzná indigent ^p oh ^l avi animals. ^{Lou No} enyne ^y according to the invention can be administered as a component of feed or it can be mixed into the mixed feed, optionally administered together with drinking water.

The invention will be illustrated by the following examples.

Example 1

Thawed ^to 4 ^{1, 0 g, 0. 20} mol of 2-chloro ^about noxae ^lo nkarboxaideh ^{an ID} and ^a 'j ^ - ^ oxidoximu and 27 ^{g, 0.} 30 moles of methyl carbazate in 400 ml of trifluoroacetic acid is heated to boiling with reflux 20 to 24 hours. The mixture is cooled and diluted with 1200 ml of water. The resulting solid precipitate was collected and dried to give the desired methyl 3- (2-quinoxalonynymethylene) carbazate- ^N , N-oxoxi-4.

Example 2

4

To a solution of 49.4 · g, 0.2 mole of 2-ch0noxal0nkarboxaliehyi- N, -i0ox0isem0kanbazonu and 39 g, 0.30 mole of methyl 3-isopnopyl0ienkarbazátu · in 400 ml of acetic acid was added 20 mL concentrated to ^{y i} n sel ^y saline. ^MES looks at ⁸⁰ and ¹ °° C ^{16-1 8} it ^ n. ^P oz ^ČHL Azen ^í mixture was diluted with 1200 ml water and the precipitate formed was separated and washed with water to give, after usu ^S en ^s ear to mod ^d ZTE ^{ka Appl} Aný 3- ⁽² -ch ^by noxae ^l0 nylmeth ^{yl en) to} an ^b aza ^t - ^N1, N ^z- .

Example 3 '1 4

To a solution of 43.8 ^g 0 0 ² mol of 2-quinoxaline carboxaldehyde N, N -dioxidnitronu ⁴ and 27 g, 0.30 mole of methyl carbazate in 400 ml of acetic acid was added 20 ml of concentrated sulfuric acid. The resulting mixture was zahfoje 9 ^0-100 ° C at ^20-2 4 ^d in it. After cooling to ^R e ^d ENI 1200 ml vody.se precipitated solid is collected and dried Símž to give methyl 3- (2-chinoxarinyhneUxylen) ^for a R ^b N-Azati.

He attaches

To a solution of 4 ^6, 8 ^g, 0.2 mol ⁰ 2- ^{(1, 3-di} oxolan-2-yl) quinoxaline-ы '] N ^ - du ^di-dioxide and ^20.7 g 0.23 mole of methyl carbazate in 500 ml of acetic acid is added 20 ml of concentrated hydrochloric acid. The resulting mixture is heated on a steam bath for about 30 to 60 minutes and then stirred at room temperature for 24 hours. The resulting precipitate was collected and dried to give the title compound ^{by methylation} of L-3- ^(2-Chloro ^ ^{i h} noxalinylmet ^{only) for} R ^b and the ^{AT 1} N j ^ -dlioxidl.

SUBJECT OF THE INVENTION

Claims (1)

Among ^{the para} uso ^{b methylthiophenyl} production of L-3- ^(2-c inoxal ^{h i} n ^{g t} Hylen ^{LME) for} R ^b aza ^t N N? -Dloxl chloride, ^^ ci characterized in that for ^p Úsobí a 2-quinoxaline ^hi c ^to r ^b e ^d oxalate ^hdyd N ^1, N ^ -C ^ ox ^and id ^ u, and ^t on to the oxime sei rt ^^ ^ o ^ nitro- not dimethylhexyl ^b ^ of ^ ace tal ales elkvimolirním ^P on the amount ^^ me ^th yl ^for r ^b and the ^aT on.