FI61888B - FREQUENCY REQUIREMENT FOR QUINOXALIN-1,4-DIOXIDE DERIVATIVES - Google Patents

Description

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National Board of Patents and Registration / 44) Date of entry into force - 30.06. 82

Patents and registers 'AmOkm utiacd och uti. «Kriftwi pubiicsnd (32) (33) (31) Pyy * 1 · 11)'« tuolkuu * —B «gtrd prlorlt« t 11-03-75

Hungary-Hungary (HU) EE-2315 (Tl) EGYT Gyogyszervegyeszeti Gyär, 30, Kereszturi ut, Budapest X,

Hungary-Hungary (HU) (72) Pal Benko, Budapest, Ildiko Ratz nee Simonek, Budapest, Laszlo Pallös, Budapest, Karoly Magyar, Budapest, Jenö Kova.cs, Budapest, Albert Balogh, Szentendre, Hungary-Hungary (HU) ( The present invention relates to a new process for the preparation of known quinoxaline-1/4-dioxide derivatives. with the general formula q

T .CH = N - Q O

wherein Q represents an -NH-COO-R2 group in which R2 represents a C1-2q alkyl group, or a group of the formula -NH-CX-NH2 in which X represents an oxygen or sulfur atom, or in the formula -NH-C- (NH) -NH A group of the formula -R 1 in which R 1 represents a hydrogen atom, an unsubstituted phenyl group, or a phenyl substituted by an alkyl or nitro group or a halogen atom, or a group of the formula -NH-R 1 in which R 4 represents a C 1-6 alkyl group, phenyl, benzyl or a C 2-4 hydroxyalkyl radical, or a group -NH-CO-R 5 in which R 1 represents a C 1-2 alkyl, an unsubstituted phenyl group, by up to three identical or different hydroxy, amino, a phenyl group substituted by a nitro, alkoxy group or a chlorine or bromine atom, a substituted naphthyl group, an aralkyl group having up to three carbon atoms in the alkyl chain, pyridyl, piperidyl, pyrazinyl, furyl, nitrofuryl or α, a, α- a diphenylhydroxymethyl group, or an -O-Rg group in which Rg represents a hydrogen atom or a C1-4 group. g of an alkyl group.

The compounds of general formula I are excellent antibacterial agents and have a weight-increasing effect in animals.

In known syntheses of compounds of general formula I, 2-formyl-quinoxaline-1,4-dioxides or their acetals are reacted with compounds containing a suitable primary amine group and the products are generally formed within a few hours (GB Patent Nos. 1,058,047 and 1,202,770 and DE-A-1,202,770). 1,927,337).

The present invention relates to a process for the preparation of the compounds of the general formula I in an economically very pure form suitable for therapeutic use, saving labor and equipment and in advantageous high yields.

The invention is based on the findings of studies on the reactions of quinoxaline-type compounds having an azomethine structure. Namely, during these experiments, it has been found that 2-formyl-quinoxaline-1,4-dioxide as a heteroaromatic aldehyde is able to remove the aldehyde components of the azomethines formed in the reaction of various aldehydes and amines and hydrazines from these compounds.

This specific reactivity of 2-formyl-quinoxaline-1,4-dioxides is surprising since only the following properties of azomethine-type compounds have been described in the literature (S. Patai: The Chemistry of the Carbon-Nitrogen Double Bond; Int. Pub., New York, 1970; Chapter 6). In the exchange reaction between Schiff's base and aromatic aldehyde, the reactivity of the hydroxybenzaldehydes and benzaldehyde studied can be evaluated. The addition of Schiff's base and 3 61888 aldehyde is also mentioned (Bull.Soc. Chim. Fr. 7, 481/1940 /). It is noted that 2-formyl-quinoxiline-1,4-dioxide cannot be classified in this group because it releases almost quantitatively all aldehydes and (aliphatic, cycloaliphatic, aromatic and heteroaromatic) ketones with their Schiff bases and thus does not participate in any addition.

This high reactivity observed is of considerable importance. In support of this contention, it should be noted that, according to our studies, 2-formyl-k ± noxalin-1,4-dioxide-dimethylacetal decomposes to a significant extent in e.g. acetic acid and even methanol; this can be seen from the thin layer chromatogram and the ultraviolet and infrared spectra. In this decomposition reaction, disadvantageous by-products of as yet unknown structure are formed, which apparently also contaminate the final products formed from the above-mentioned compound. In contrast, the absence of side reactions of the pure reaction components is of particular importance in this synthesis because most of the final products of general formula I are almost insoluble in various solvents. Thus, their final recrystallization from dimethylformamide can only be performed in poor yields while partially decomposing. It is clear that these types of reactions cannot be carried out on an industrial scale.

Thus, the particular importance of the above-mentioned high reactivity is based on the fact that 2-formyl-quinoxaline-1,4-dioxide reacts much faster with the azomethines used in the reaction according to the invention than in the reaction with 2-formyl-quinoxaline-1,4-dioxide and amines, respectively. between hydrazines, as is known in the literature.

It is known that 2-formyl-quinoxaline-1,4-dioxide reacts in any solvent (either polar, apolar, protic or aprotic) at almost the same rate and quantitatively with aldazine or ketazine or even with an animal or ketimine reaction. . As a result, it is obviously most advantageous to work using an aqueous solution, especially when the resulting reaction product is insoluble in water. The reactivity of 2-formyl-quinoxaline-1,4-dioxide in exchange reactions is so high that it reacts even in the heterogeneous phase at a reaction rate of the order of 4 61888 corresponding to the reaction rate in the homogeneous phase.

The azomethines used as reaction components are very different in nature. They are generally compounds known from the literature, although new derivatives exist among them. It is clear to the expert that this reaction is very common due to its nature? thus, only a few examples of the composition of the azepine reaction components need be mentioned here. These derivatives may be azomethines formed from aldehydes or ketones with amine or hydrazine derivatives. Our research on these aldehydes and ketones has unequivocally shown that these reactions occur in the same manner and rapidly regardless of whether aliphatic reagents such as acetaldehyde or diethyl ketone, cycloaliphatic reagents such as cyclopentanone, cyclohexanone, cyclohexanone or cyclohexanone, cyclohexanone or and benzaldehyde, or heteroaromatic reagents such as pyridine aldehyde, imidazolidone and furfural to react to form compounds of general formula I.

Since the above-mentioned reaction conditions and reaction components vary widely, a very rational method of synthesis can be used in a few cases. Thus, for example, a reaction component of the aldazine or ketazine type can be reacted with 2-formyl-cloxoxaline-1,4-dioxide in the same reaction mixture in which it is formed, without isolating it.

By using this advantageous way of working, considerable labor and equipment savings can be achieved.

The process of the invention has additional advantages in selecting an azomethine reagent whose aldehyde or ketone component is liquid. In this case, namely, the aldehyde or ketone released during the reaction of 2-formyl-quinoxaline-1,4-dioxide in the reaction mixture of the azomethine reagent is in turn suitable for the formation of azomethine and subsequently for the repeated reaction with 2-formyl-quinoxaline-1,4-dioxide. Repeating this series of operations arbitrarily several times in a row shortens the reaction times, saves a lot of work and energy, and eliminates the need to install new special equipment.

618 8 8 5 This method, in which only a single device is required, is particularly valuable when the equilibrium reaction can be advantageously influenced by the formation of azomethine, after which the aldazine or ketazine formed in this almost theoretical yield is reacted with 2-formyl-quinoxaline-1,4- with dioxide as mentioned above.

Certain compounds of general formula I, which are generally obtained in excellent yields (about 96-98%) in reactions in an aqueous medium in the same apparatus, are generally formed in less than an hour. It is obvious that there is no need to explain in detail the most characteristic examples of this procedure, since it follows from the nature of the reaction containing the basic idea of the invention that it is only necessary to adjust the optimism parameters to obtain the highest yields of all compounds of general formula I.

The starting materials can be prepared according to known methods described in the literature. Thus, 2-formyl-quinoxaline-1,4-dioxide or its acetal can be prepared according to GB Patents 1,308,370, 1,215,815 and 1,305,138 and also DT Application 1,927,337 while azomethines can be prepared as described in Chemistry of the Carbon-Nitrogen Double B "(Int. Pub. New York, 1970).

Accordingly, according to the invention, quinoxaline dioxide derivatives of the general formula are prepared

O

= n "q if x k A. 1 *

O

wherein Q is as defined above, by reacting an azomethine derivative of the general formula

R

\

C = N - Q II

/ R1 wherein Q is as defined above, R represents an alkyl or phenyl group, a phenyl, pyridyl or furyl radical substituted by a halogen atom, or a nitro, methyl or hydroxy group, and represents a hydrogen atom or an alkyl group, 6 61888 wherein R and together with the carbon atom to which they are attached may also represent a C 1-7 cycloalkylidene or 1,5-diazacyclopentylidene-2 group, to react with 2-formyl-quinoxaline-1,4-dioxide of the formula

O

= 0! m 4- 0

In summary, the advantages of the process according to the invention are that 2-formyl-quinoxaline-1,4-dioxide reacts more rapidly in exchange reactions with azomethines according to the invention than in previously known reactions with amine or hydrazine derivatives and thus achieves considerable equipment, energy and labor savings. .

When applying the conditions of the invention, any solvent or solvent mixture which has previously proved ineffective can be used and thus cleaner products can be obtained.

In some cases, it is possible to carry out the exchange reaction with 2-formyl-quinoxaline-1,4-dioxide as a single-reaction reaction, efficiently in the same reaction mixture in which the azomethines are formed without separating them from the mixture. This continues to result in savings in equipment, labor, time and energy.

The method according to the invention is illustrated by the following examples.

Example 1:

To a solution of 21.2 g (0.2 moles) of benzaldehyde in 200 ml of water containing 2 ml of concentrated hydrochloric acid is added dropwise at room temperature a solution of 18.0 g (0.2 moles) of methyl carbazate in 50 ml: in water. This gives a white suspension in 10 minutes. After a further 10 minutes, a solution of 38.0 g (0.2 mol) of 2-formyl-quinoxaline-1,4-dioxide in 400 ml of hot water is added dropwise, after which the reaction mixture is kept at 95-100 ° C. for 20 minutes. In a water bath of C. The separated yellow 7 61883 crystals are filtered off while hot and washed with a small amount of ethanol.

Yield: 45.0 g (85.8%) of methyl (2-quinoxalinyl-methylene) -carbat-14 oxide N, N-dioxide.

Mp 258-259 ° C (decomposes).

Example 2: 5.7 g / 0.11 mol) of 98% hydrazine hydrate are added dropwise to a solution of 9.9 g (0.11 mol) of dimethyl carbonate in 25 ml of methanol. The reaction mixture is stirred for 2 hours at room temperature, after which methanol and small amounts of unreacted hydrazine are distilled off. The residue is treated with a solution of 12.2 g (0.1 mol) of salicylaldehyde in 30 ml of ethanol and stirred for about 1 hour using 0.5 ml of acetic acid. The resulting azomethine derivative melts at 169-171 ° C. The product is stirred for about an hour with 19 g (0.1 mol) of 2-formyl-quinoxaline-1,4-dioxide in water acidified with hydrochloric acid. The resulting yellow methyl (2-quinoxalinyl-methylene) -carbazate N, N-dioxide is filtered off and washed.

Yield: 16.8 g (73.8%).

Mp 260-261 ° C (decomposes).

Example 3:

An azomethine derivative prepared from 10.8 g (0.1 mol) of pyridine-2-aldehyde as described in Example 2 is reacted with 2-formyl-quinoxaline-1,4-dioxide as described in Example 2. This gives methyl (2-quinoxalinyl-14-methylene) -carbazate N, N-dioxide in 80% yield. Mp 257-259 ° C (decomposes).

Example 4:

As described in Example 2, the azomethine derivative obtained from 8.6 g (0.1 mol) of imidazolidone-2 is reacted with 19 g (0.1 mol) of 2-formyl-quinoxaline-1,4-dioxide to give the desired methyl (2-quinoxalinylmethylene) carbazate N1, N-dioxide in 93% yield, m.p. 260-260 ° C (decomposes).

Example 5:

A solution of 19 g (0.1 mol) of 2-formyl-quinoxaline-1,4-dioxide in 250 ml of 1% aqueous hydrochloric acid is added dropwise hot to a solution of 10.1 g (0.1 mol) ) acetaldehyde semicarbazone in 70 ml ethanol. The mixture is boiled for 8 61888 hours after which time the yellow precipitate is filtered hot and washed with ethanol to give 22 g (80%) of quinoxaline- (2-aldehyde) -14 ° semicarbazone N, N-dioxide, m.p. 288-290 C.

Example 6:

As described in Example 5, 5.9 g (0.1 mol) of acetaldehyde oxime and 19 g (0.1 mol) of 2-formyl-quinoxaline-1,4-dioxide are obtained from 2-quinoxalinyl-aldoxime. 1,4-dioxide in 91% yield, m.p. 248-249 ° C.

Example 7: Starting from 13.1 g (0.1 mol) of glyoxylic acid semicarbazone, working as described in Example 5, quinoxaline-2-aldehyde semicarbazone N, N-dioxide is obtained in 94% yield, m.p. p. 2 89-291 ° C.

Example 8: Starting from 16.2 g (0.1 mol) of benzaldehyde aminoguanidine and then working as described in Example 5, 90% of (2-quinoxalinylmethylene) aminoguanidine N, N-dioxide is obtained. as a yield, m.p. 286 ° C.

Example 9: Starting from 18.8 g (0.1 mol) of cyclohexanone-phenylhydrazone and working as described in Example 5, 14 (2-quinoxalinyl-methylene) -phenylhydrazine-N, N-dioxide is obtained 82% as a yield, m.p. 247 ° C.

Example 10; 22.6 g (0.1 mol) of trimethoxybenzoic acid hydrazide are added to a solution of 10.6 g (0.1 mol) of benzaldehyde in 200 ml of water containing 8 ml of concentrated hydrochloric acid. The mixture is stirred for 15 minutes at room temperature, after which the azomethine derivative formed is reacted with 19 g (0.1 mol) of 2-formyl-quinoxaline-1,4-dioxide. The reaction mixture is stirred for 30 minutes in a water bath at 95-100 ° C. The orange-yellow 2- (3 ', 4', 5'-trimethoxybenzoyl) -hydrazonoformyl-quinoxaline-1,4-dioxide formed is filtered hot and washed with ethanol. Yield 38.8 g (97.4%) of product melting at 255 ° C.

Example 11:

By reacting an azomethine derivative formed from 10.6 g (0.1 mole) of benzaldehyde and 21.4 g (0.1 mole) of lauric 9,61883 nitric acid hydrazide as described in Example 10 with 19 g (0, 1 mole) of 2-formyl-quinoxaline-1,4-dioxide 33.2 g (88.7%) of 2-laurinoyl-hydrazonoformyl-quinoxaline-1,4-dioxide are obtained, melting at 233 ° C.

Example 12:

The azomethine derivative obtained by reacting 10.6 g (0.1 mol) of benzaldehyde and 15.0 g (0.1 mol) of phenylacetic acid hydrazide with 19 g (0.1 mol) of 2-formylquinoxaline 1,4-dioxide and following the same procedure as described in Example 10, 31.8 g (98.4%) of 2- (phenylacetyl) -hydrazonoformyl-quinoxaline-1,4-dioxide are obtained, melting at 256 ° C: in. Example 13:

The azomethine derivative obtained by reacting 20.0 g (0.1 mol) of 1-naphthylacetic acid hydrazide and 10.6 g (0.1 mol) of benzaldehyde with 19 g (0.1 mol) of 2 -formyl-quinoxaline-1,4-dioxide as described in Example 10, 33.4 g (89.9%) of 2- (1'-naphthylacetyl) -hydrazono-formyl-quinoxaline-1,4-dioxide are obtained. melting at 247 ° C.

Example 14:

By reacting a Schiff's base prepared from 10.6 g (0.1 mol) of benzaldehyde and 15.2 g (0.1 mol) of p-hydroxy-benzoic acid hydrazide, 2-formyl-quinoxaline-1,4- with carbon dioxide as described in Example 10, 30.8 g (93%) of 2- (p-hydroxybenzoyl) -hydrazonoformyl-quinoxaline-1,4-dioxide with a melting point of 308 ° C are obtained.

Example 15:

By introducing Schiff's base prepared from 15.1 g (0.1 mol) of p-amino-benzoic acid hydrazide and 10.6 g (0.1 mol) of benzaldehyde with 19 g (0.1 mol) 2-formyl-quinoxaline-1,4-dioxide as described in Example 10, 28.5 g (88.2%) of 2- (p-aminobenzoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide are obtained, which melting at 291-292 ° C.

Example 16: Starting from 22.2 g (0.1 mol) of benzaldehyde-nicotinoylhydrazone and working as described in Example 10, 26.4 g (85.4%) of 2- (nicotinoyl) -hydrazonoformyl-quinoxa are obtained. -lin-1,4-dioxide with a melting point of 270 ° C.

10 61 888

Example 17: Starting from 22.2 g (0.1 mol) of benzaldehyde-isonicotinoyl-hydrazone and working as described in Example 10, 29.0 g (93.8%) of 2- (isonicotinoyl) -hydrazono-formyl are obtained. -quinoxaline-1,4-dioxide with a melting point of 268 ° C.

Example 18: Starting from 19.6 g (0.1 mol) of acetaldehyde- (p-chlorobenzoyl) hydrazone and working as described in Example 10, 32.2 g (94%) of 2- (p-chlorobenzoyl) are obtained. -hydrazono-formyl-quinoxaline-1,4-dioxide, m.p. is 273-274 ° C.

Example 19; Starting from 29.2 g (0.1 mol) of decanealdehyde-furan-2-carbonylhydrazone and proceeding as described in Example 10, 2- (2'-furanoyl) -hydrazonoformyl-quinoxaline-1,4-dioxide is obtained, melting at 261 ° C: in 94% yield.

Example 20: Starting from 26.6 g (0.1 mol) of benzaldehyde- (3-nitrobenzoyl) hydrazone is reacted as described in Example 10, 32.6 g (92%) of 2- (31-nitrobenzoyl) are obtained. -hydrazono-formyl-quinoxaline-1,4-dioxide, m.p. 289-290 ° C.

Example 21: Starting from 25.6 g (0.1 mol) of benzaldehyde- (5-nitrofuranoyl-2) -hydrazone and proceeding as described in Example 10, 2- (5'-nitro-2'-furanoyl) is obtained. -hydrazono-formyl-quinoxaline-1,4-dioxide in 84% yield, m.p. 265 ° C.

Example 22: Starting from 17.8 g (0.1 mol) of acetaldehyde- (o-hydroxy-benzoyl) -hydrazone and proceeding as described in Example 10, 2- (salisoloyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained. . Yield: 83%. Mp 280 ° C.

Example 23: Starting from 27.1 g (0.1 mol) of benzaldehyde-caprinoylhydrazone and proceeding as described in Example 10, 2- (caprinoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained. Yield 88%. Mp 237-238 ° C.

Example 24: Starting from 22.1 g (0.1 mol) of acetone- (p-nitrobenzoyl) -hydrazone and proceeding as described in Example 10, 2- (p-nitrobenzoyl) -hydrazono-formyl-quinoxaline-1.4 - 61888 1 1 dioxide. Yield 91.8%. Mp 275-176 ° C.

Example 25: Starting from benzaldehyde-8-phenylpropionylhydrazone and proceeding as described in Example 10, 2- (β-phenylpropionyl) -hydrazonoformyl-quinoxaline-1,4-dioxide is obtained in 91% yield, m.p. 241 ° C.

Example 26: Starting from benzaldehyde-stearinoyl hydrazone and proceeding as described in Example 10, 2- (stearinoyl) -hyrazonoformyl-quinoxaline-1,4-dioxide is obtained in 76% yield, m.p. 233 ° C.

Example 27: Starting from benzaldehyde-anisoylhydrazone and proceeding as described in Example 10, 2- (anisoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained in 80.3% yield, m.p. 260 ° C. Example 28: Starting from cyclopentanone-piperidine-4-carbonylhydrazone and proceeding as described in Example 10, 2- (piperidine-4-carbonyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained in 76% yield, m.p. p. 185-188 ° C.

Example 29; Starting from benzaldehyde- (2-hydroxy-3-naphthoyl) -hydrazone and proceeding as described in Example 10, 97% of 2- (2'-hydroxy-3-naphthoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained. as a yield, m.p. 260 ° C.

Example 30: Starting from benzaldehyde-benzoyl-hydrazone and proceeding as described in Example 10, 2- (benzoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained in 84.62% yield, m.p. 278 ° C. Example 31: Starting from benzaldehyde-heptanoylhydrazone and proceeding as described in Example 10, 2- (heptanoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained in 87.2% yield, m.p. 241 ° C. Example 32: Starting from benzaldehyde-benzoylhydrazone and proceeding as described in Example 10, 2- (benzoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide is obtained in 89% yield, m.p.

2 6 7 ° C.

Claims (1)

A process for the preparation of a quinoxaline-1,4-dioxide derivative of the general formula 0 T = N "Q 1 CX, J 0 wherein Q represents a group of the formula -NH-COO-R2, wherein R2 represents C2-Q- an alkyl group, or a group of the formula -NH-CX-NH 2 in which X represents an oxygen or sulfur atom, or a group of the formula -NH-C (NH) -NH-R 2 in which R 1 represents a hydrogen atom, an unsubstituted phenyl group or alkyl - or phenyl substituted by a nitro group or a halogen atom, or a group of the formula -NH-R 1 in which R 1 represents a C 1-6 alkyl group, a phenyl, benzyl or C 2 -C 6 hydroxyalkyl radical, or a -NH-CO-R 4 group , wherein R 2 represents a C 1 -C 2 3 3 - (N) / unsubstituted phenyl group, a phenyl group substituted by up to three identical or different hydroxy, amino, nitro, alkoxy groups, or a chlorine or bromine atom, a substituted naphthyl group, an aralkyl group having the alkyl chain has up to three carbon atoms, pyridyl7, pipe a radyl, pyrazinyl, furyl, nitrofuryl or α, α, α-diphenylhydroxymethyl group, or an -O-Rg group in which Rg represents a hydrogen atom or a C1-6 alkyl group, characterized in that the azomethine derivative of the general formula is R = N - Q II wherein R is the same as above, R is an alkyl or phenyl group, or a phenyl, pyridyl or furyl group substituted by a halogen atom or a nitro, methyl or hydroxy group, and R represents a hydrogen atom or an alkyl group, and R and R 1 together with the carbon atom to which they are attached also represent a cycloalkylidene or 1,5-diazacyclopentylidene-2 group are reacted with 2-formyl-quinoxalin-1, With 4-dioxide, 618 8 8 1 3 having the formula 0 T ai CH = 0 III N 'o For the preparation of quinoxaline-1,4-dioxide derivatives with the formula 0 "N' Q if IX i 0 i vilken Q is a -NH-COO-R2 group, and R2 is a C1-C20-alkyl group, or the group of the formula -NH-CX-NH2, and the group X is a substituent or a substituent, or the group of the formula -NH-C (NH) -NH-R2, a group of the formula R1 is a substituent and is not substituted on the phenyl radical , or a phenyl radical substituted with an alkyl or a nitro group or a halogen atom, or a group of the formula -NH-R 2, and then a R 1-6 alkyl group, C 1-6 alkyl, phenyl or benzyl or a C2-6-hydroxy-alkyl radical, or an -NH-CO-R8 group, and then a R1-alkyl group with a ci_20 "a · * · ^!" en is substituted by a phenyl group, and the phenyl group is substituted by an identical or identical ol-hydroxyl group. , amino, nitro, C 1-3 alkoxy, or chloro or bromatomer, unsubstituted naphthyl, and aralkyl, alkyl having the same thio, not pyridyl, piperidyl, pyrizanyl, furyl -, in which nitrofuryl- or in α, α, α-diphenylhydroxymethyl group or in -O-Rg group, in which Rg is a bond or a hydrogen atom in C ^ _g-