CS208707B2 - A process for the preparation of quinoxaline-1,4-dioxide derivatives - Google Patents

Description

(54) A method for producing quinoxaline-1,4-dioxide derivatives

The invention relates to a novel process for the preparation of the known quinosaline-1,4-dioxide derivatives of the general formula I,

in which

Q represents a hydroxyl group, -NH-COOCH3, -NH-CO-NHg or -NH-C (= NH) -NHg, or a group of the formula -NH-R ^ in which R ^ is phenyl, or The formula of formula -NH-CO-R 6, wherein R 6 represents a C 1-6 alkyl group, a phenyl group optionally substituted by 1 to 3 methoxy, hydroxyl, aryloxy, halogen, naphthylmethyl, hydroxynaphthyl, pyridyl, furyl, nitrofuryl, piperidyl, benzyl, phenethyl or N, α-diphenylhydroxymethyl groups.

The compounds of formula I are excellent antibacterial agents and affect the increase in body weight of animals.

According to known syntheses of the compounds of formula (I), 2-formyl-quinoxaline-1,4-dioxides or their acetals are reacted with compounds with the appropriate amino group and the products are formed usually within a few hours (British Pat. No. 1,058,047; No. 1,202,777 and German Pat. No. 1,927,337).

2CB7C

208707 '

The purpose of the present invention is to provide compounds of formula I of high purity, suitable for therapeutic application, in an economic, labor and equipment-saving manner and with high yields.

The invention is based on the finding made during the investigation of reactions of quinoxaline-type compounds with an azomethine structure. Indeed, it has been found during these experiments that 2-formylquinoxaline-1,4-dioxide, a heteroaromatic aldehyde, is capable of displacing the aldehyde components of the azomethinil formed by the reaction of various aldehydes and amines and hydrazines or their compounds.

This specific reactivity of 2-formylquinoxaline-1,4-dioxide is surprising since only the following behavior of azomethine-type compounds (S. Patai) is known from the literature:

The Chemistry of the Carbon-Nitrogen Double Bond; Int. Publ., New York, 1970; Chapter 6),

In the exchange reaction of Schiff's base and aromatic aldehyde, the reactivity of the hydroxybenzaldehyde and benzaldehyde tested can be classified. The addition of Schiff's base and aldehyde is disclosed in Bull. Soo. Chim. Fr. 1, 481 (1940). It can be argued that 2-formylquinoxaline-1,4-dioxide cannot be assigned to this group because it releases virtually quantitatively all aldehydes (aliphatic, cycloaliphatic, aromatic and heteroaromatic) or ketones from their Schiff bases and does not undergo any addition reactions with Schiff bases .

This high reactivity found is of significant importance. To support this finding, we report that 2-formylquinoxaline-1,4-dioxide decomposes to a considerable degree, for example, in acetic acid and methanol, in our experiments; this can be demonstrated by thin layer chromatography and ultraviolet and infrared spectra.

This decomposition leads to undesirable byproducts of a hitherto unknown structure, which apparently also contaminate the end products formed from the above compound. In the synthesis under consideration, on the other hand, the absence of side reactions of the pure reaction partners is very important, since most of the final products of formula I are insoluble in various solvents.

Their recrystallization, possibly from dimethylformamide, can be carried out only with low yields at the expense of their partial decomposition. Obviously, processes of this kind cannot be carried out on an industrial scale.

The specific significance of the high reactivity mentioned above is due to the fact that 2-formylquinoxaline-1,4-dioxide reacts with azomethines in the process of the invention much faster than when reacting 2-formylquinoxaline-1,4-dioxide with amines and hydrazines such as this is possibly known from the literature.

It has been noted that 2-formylquinoxaline-1,4-dioxide reacts in any solvent (polar, apolar, protic or aprotic) mostly at the same rate and quantitatively with aldazine or ketazine as well as aldimine or ketimine.

For this reason, it is clear that it is most advantageous to work in an aqueous environment, preferably when the reaction product is expected to be insoluble in water. The reactivity of 2-formylohinoxaline-1,4-dioxide in exchange reactions is so high that it reacts even in the heterogeneous phase at a rate similar to that of the homogeneous phase.

The azomethine derivatives used as reaction partners are quite different in nature. They are mostly compounds known from the literature, although they include new derivatives. It will be apparent to one skilled in the art that this reaction, as it follows, and its nature, is very general; it is therefore sufficient to give here only a few examples concerning the composition of the azomethine reactants.

These derivatives may be azomethines formed from aldehydes or ketones with amine or hydrazine derivatives. Based on our experiments with aldehydes and ketones, it has been unequivocally confirmed that these reactions proceed in the same way and quickly, including aliphatic reactants such as acetaldehyde, diethyl ketone, cycloaliphatic reactants such as cyclopentanone or cycloheptanone, aromatic reactants, for example salicylaldehyde and benzaldehyde, or heteroaromatic reactants, such as pyridinaldehyde, inidazolidone and furfural, to form compounds of Formula I.

Since the reaction conditions and the partners specified above are very different, it is possible in some cases to choose a very rational synthesis method. For example, an aldazine or ketazine-type reaction partner is reacted with 2-formylquinoxaline-1,4-dioxide as well as in the reaction mixture in which it is formed without being isolated.

By using this favorable sequence of operations, considerable labor and equipment savings can be achieved.

The process of the present invention offers further advantages when the azomethine reaction component is derived from an aldehyde or ketone component which is liquid. That is, if aldehyde or ketone is liberated from the azomethine reactant during reaction with 2-formylquinoxaline-1,4-dioxide during the reaction, they can be reused to form the azine methine and then to repeat the reaction with 2-formylquinoxaline-1, 4-dioxide.

By repeating a series of these operations several times in succession, the reaction times are shortened, a lot of work and effort is saved, and the establishment of some new equipment becomes unnecessary.

This method, which requires only a single device, is particularly valuable if the equilibrium reaction can be favorably influenced by azomethine formation and then the aldazine or ketazine, which is formed almost in theoretical yield, is reacted according to the above process with 2-formylquinoxaline- 1,4-dioxide.

Some representatives of the compounds of formula I, which are generally formed in excellent yield (about 96-98 in aqueous reactions in the same apparatus), are formed in less than one hour. It is unnecessary to describe in detail the most typical examples for this sequence of operations. It follows from the nature of the reaction embodiment of the basic idea of the invention that only optimum parameters have to be determined in order to achieve the highest yields for all compounds of the general formula I.

Starting materials can be prepared by methods described in the literature. Thus, 2-formylquinoxaline-1,4-dioxide can be prepared according to British patent applications 1 308 370, 1 215 815 and 1 305 138, longer according to German Offenlegungsschrift 1 927 337, while azomethines can be prepared, for example, by the method described in Chemistry of the Carbon-Nitrogen Double Bond (Int., New York, 1970).

According to the process of the invention, the quinoxaline dioxide derivatives of the general formula I

O

wherein Q is as defined above, prepared by reaction of an azomethine derivative of the Formula II, i

(II)

R in which

Q has the above meaning,

R represents a phenyl, hydroxyphenyl, pyridyl, carboxyl or alkyl group,

R 6 represents a hydrogen atom or a methyl group;

R @ 1 and R @ 2 together with the carbon atom to which they are attached may be cycloalkylidene or 1,3-diazacyclopentylidene-2-group with 2-formylquinoxaline-1,4-dioxide of formula III

O

0 at a temperature of 0 to 150 ° C, preferably 80 to 110 ° C.

Summarizing the advantages of the process of the invention, it can be said that 2-formylquinoxaline-1,4-dioxide reacts more rapidly in the exchange reactions performed with azomethines than the rate of the earlier known reactions with amine and hydrazine derivatives, thereby achieving significant savings on equipment, effort and work.

Using the conditions of the invention, the use of a solvent or solvent mixture results in the preparation of purer products.

In this case, the exchange reaction with 2-formylquinoxaline-1,4-dioxide can be carried out in a single apparatus, without hindrance, in the same reaction mixture in which the azomethines were formed, without isolating them from the mixture. This results in further savings in equipment, labor and effort.

The process of the invention is illustrated by the following examples.

Example 1

To a solution of 21.2 g (0.2 mol) of benzaldehyde in 200 ml of water containing 2 ml of concentrated hydrochloric acid is added dropwise a solution of 18.0 g (0.2 mol) of methyl carbazate in 50 ml of water at normal temperature.

A white slurry was formed for 10 minutes. After a further 10 minutes, a solution of 38.0 g (0.2 mol) of 2-formylquinoxaline-1,4-dioxide in 400 ml of hot water is added dropwise, then the reaction mixture is kept in a water bath at 95-100 ° C for 20 minutes. . The precipitated yellow crystals were collected by filtration and washed hot with a little ethanol.

Yield: 45.0 g (85.8%) of methyl - ^ - ^{chinoxalinylmethylenJkarbazát-N1, N4-dioxide.}

Melting point: 258-259 ° C (dec.).

Example2

5.7 g (0.11 mol) of 98% hydrazine hydrate was 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 at normal temperature for 2 hours, then methanol and traces 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 the reaction mixture is stirred for 0.5 hour in the presence of 0.5 ml of acetic acid.

The obtained azomethine derivative melts at 169-171 ° C. The product is stirred for about 1 hour with 19 g (0.1 mol) of 2-formylquinoxaline-1,4-dioxide in water acidified with concentrated hydrochloric acid. The obtained yellow methyl- (2-quinoxalinylmethylene) carbazet-N ', N'-dioxide is filtered off and washed.

Yield: 16.8 g (73.8%), m.p. 260-261 ° C (dec.).

Example 3 '.....' ·

The azomethine derivative prepared as in Example 7 from 10.8 g (0.1 mol) of pyridinium-2-aldehyde was reacted in a similar manner to Example 7 with 2-formylquinoxaline-1,4-di oxide.

There was thus obtained methyl (2-quinoxalinylmethylene) carbazate-N ¹ , N * -dioxide in 80% yield. M.p .: 260 ° C (dec.). Example 4

The azomethine derivative, prepared as described in Example 7, from 8.6 g (0.1 mol) of imidazolidone- (2) is reacted with 19 g (0.1 mol) of 2-formylquinoxaline-1,4-dioxide, obtained in 93% yield of the desired methyl (2-quinoxalinylmethylene) carbazate-11'-N, N-dioxide. Melting point: 260-261 ° C (dec.).

Example5

A solution of 19 g (0.1 mol) of 2-formylquinoxaline-1,4-dioxide in 250 ml of a 1% aqueous hydrochloric acid solution was added dropwise hot to a solution of 10.1 g (0.1 mol) of semicarbazone acetaldehyde in 70 ml of ethanol. After heating the reaction to boiling for one hour, the yellow precipitate is filtered off with suction while hot, washed with ethanol to give 22 g (80%) of quinoxaline- (2-aldehyde) -semicarbazone-N ¹ , N -dioxide. Mp 288-290 ° C.

Example 6

Following the procedure of Example 5, from 5.9 g (0.1 mol) of acetaldehyde oxime and 19 g (0.1 mol) of 2-formylquinoxaline-1,4-dioxide gave 2-quinoxalinylaldoxime-1,4-dioxide in 91% yield. Mp 248-249 ° C.

Example 7

Using the procedure described in Example 5 using 13.1 g of semicarbazone glyoxylic acid, quinoxaline-2-aldehyde semicarbazone-N ', N-dioxide is obtained in 94% yield. Melting point: 289-291 ° C.

Example 8

As described in Example 5 using 16.2 g (0.1 mol) benzaldehydaminoguanidinu as starting material was obtained in 90% yield (2-chinoxalinylInetl-ylene) aminoguanidin-> ^N, N-dioxide Melting point: 286 ° C .

Example 9

Using the procedure described in Example 5, using 18.8 g (0.1 mol) of phenylhydrazone of cyclohexanone, 82% yield of (2-quinoxalinylmethylene) phenylhydrazine-N, N-Dioxide was obtained. Mp 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.

The reaction mixture is stirred for 15 minutes at normal temperature, then the resulting azomethine derivative is reacted with 19 g (0.1 mol) of 2-formylquinoxaline-1,4-dioxide. The reaction mixture is stirred for 30 minutes at a temperature of 95-100 ° C.

The resulting orange-yellow 2- (3 ', 4 ^#, 5' -trimethoxybenzoyDhydrezonoformylchinóxalin-1, 4-dioxide was filtered hot and washed with a small amount of ethanol. Yield: 38.8 g (97.4%), m.p. 255 ° C.

Example 11

As in Example 10, from an azomethine derivative prepared from 10.6 g (0.1 mol) of benzaldehyde and 21.4 g (0.1 mol) of lauric hydrazide and 19 g (0.1 mol) of 2-forraylquinoxelin-1. 4-dioxide gives 33.2 g (88.7%) of 2-laurpylhydrazonoformylquinoxaline-1,4-dioxide, m.p. 233 [deg.] C,

Example 12

By the method of Example 10, reacting an azomethine derivative prepared from 10.6 g (0.1 mol) of benzaldehyde and 15.0 g (0.1 mol) of phenylacetic hydrazide with 19 g (0.1 mol) of 2-formylquinoxaline -1.4-dioxide, 31.8 g (98.4 (8) 2- (phenylacetyl) hydrazonoformyl quinoxaline-1,4-dioxide, m.p. 256 DEG C.) were obtained.

Example 13

As described in Example 10, by reacting an azomethine derivative prepared from 20.0 g (0.1 mol) of naphthylacetic acid hydrazide and 10.6 g (0.1 mol) of benzaldehyde with 19 g (0.1 mol) of 2-formylquinoxaline- Of 1,4-dioxide gave 33.4 g (89.9%) of 2- (1'-naphthylacetyl) hydrazonoformylquinoxaline-1,4-dioxide, m.p. 247 ° C.

Example 14

As described in Example 10, by reacting a Schiff base prepared from 10.6 g (0.1 mol) benzaldehyde and 15.2 g (0.1 mol) p-hydroxybenzoic hydrazide with 2-formylquinoxaline-1,4-dioxide 30.8 g (93%) of 2- (p-hydroxybenzoyl) hydrazonoformylquinoxaline-1,4-dioxide of melting point 308 DEG C. are obtained.

Example 15

As described in Example 10, by reaction of a Schiff base prepared from 15.1 g (0.1 mol) of p-aminobenzoic hydrazide and 10.6 g (0.1 mol) of benzaldehyde with 2-forraylquinoxaline-1,4-dioxide, 28.5 g (88.2%) of 2- (p-aminobenzoyl-hydrazonoformyl-quinoxaline-1,4-dioxide), m.p.

Example 16

Using the procedure described in Example 10, using 22.2 g (0.1 mol) of benzaldehyde-nicotinoylhydrezone, 26.4 g (85.4%) of 1- (nicotinoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide melting in 270 ° C.

Example 17

Using the procedure described in Example 10, using 22.2 g (0.1 mol) of benzaldehyde isonicotinoyl hydrazone, 29.0 g (93.8%) of 2- (isonicotinoyl) hydrazonoformyl quinoxaline-1,4-dioxide melting at 268 ° C were obtained.

Example 18

Using the procedure described in Example 10, using 19.6 g (0.1 mol) of acetaldehyde (p-chlorobenzoyl) hydrazone as the starting material, 32.2 g of (94 R) 2- (p-chlorobenzoyl) hydrazonoformyl quinoxaline- was obtained. 1,4-dioxide, mp 273-274 ^C C.

Example 19

Using the procedure described in Example 10, using 29.2 g (0.1 mol) of decanaldehyde-furan-2-carbonylhydrazone as the starting material, 2- (2-furanoyl) hydrazonoformyl-quinoxaline-1,4-dioxide, m.p. M.p.

Example 20

Using the procedure described in Example 10, starting from 26.6 g (0.1 mol) of benzaldehyde- (3-nitrobenzoyl) hydrazone, 32.6 g (92%) of 2- (3'-nitrobenzoylhydrazonoformylquinoxaline-) were obtained. 1,4-dioxide, m.p. 289-290 ° C.

Example 2,

Using the procedure described in Example 10, starting from 25.6 g (0.1 mol) of benzaldehyde- (5-nitrofuranoyl-2) hydrazone, 84% yield of 2- (5'-nitro-2'-furanoyl) was obtained. ) hydrazonoformyl quinoxaline-1,4-dioxide, m.p. 265 ° C.

Example 22

Using the procedure described in Example 10, starting with 17.8 g (0.1 mol) of acetaldehyde (o-hydroxybenzoyl) hydrazone, 2- (salicyloyl) hydrazonoformyl quinoxaline-1,4-dioxide was obtained. Melting point: 280 ° C, yield: 83%.

Example 23

Using the procedure described in Example 10, starting with 27.1 g (0.1 mol) of benzaldehyde-caprooylhydrazone, 2- (caprinoyl) hydrazonoformylquinoxaline-1,4-dioxide was obtained. Yield: 88%, mp 237-238 ° C.

Example 24

Using the procedure described in Example 10, starting with 22.1 g (0.1 mol) of acetone- (p-nitrobenzoyl) hydrazone as starting material, 2- (p-nitrobenzoylhydrazonoformylquinoxaline-1,4-dioxide) was obtained. 91.8%, mp 275-276 ° C.

Example 25

Using the procedure described in Example 10, starting with benzaldehyde-beta-phenylpropionylhydrazone, 2- (beta-phenylpropionyl) hydrazonoformylquinoxaline-1,4-dioxide was obtained in 91% yield. Mp 241 ° C.

Example 26

Using the procedure described in Example 10, starting with benzaldehyde stearyl hydrazone, 2- (stearoyl) -hydrazonoformylquinoxaline-1,4-dioxide was obtained in 76% yield. M.p .: 233 ° C.

Example 27

Using the procedure described in Example 10, starting from benzaldehyde diisoylhydrazone, 2- (anisoyl) hydrazonoformyl quinoxaline-1,4-dioxide was obtained in a yield of 80.3%. Melting point: 260 ° C.

Example 28

Using the procedure described in Example 10, starting with cyclopentanone-piperidine-4-carbonylhydrazone, 2- (piperidino-4-carbonyl) hydrazonoformyl-quinoxaline-1,4-dioxide was obtained in 76% yield. Melting point: 185-188 ° C.

Example 29

Using the procedure described in Example 10, starting from benzaldehyde- (2-hydroxy-3-naphthoyl) hydrazone as starting material, 2- (2'-hydroxy-3-naphthoyl) hydrazonoformylquinoxaline-1,4-dioxide was obtained in a yield of 97 56 Melting point: 260 ° C.

Example 30

Using the procedure described in Example 10, starting from benzaldehyde-benzoylhydrazone, 2- (benzoyl) hydrazonoformylquinoxaline-1,4-dioxide was obtained in a yield of 84.62%. Mp 278 ° C.

Example 31

Using the procedure described in Example 10, starting with benzaldehyde-heptanoylhydrazone as starting material, 2- (heptanoyl) hydrazonoformylquinoxaline-1,4-dioxide was obtained in a yield of 87 > 2 56. Melting point: 241 ° C.

Example 32

Using the procedure described in Example 10, starting from benzaldehyde benzylyl hydrazone, 2- (benzylyl) hydrazonoformyl quinoxaline-1,4-dioxide was obtained in 89% yield. Melting point: 267 ° C.

Example 33

A mixture containing 190 g (1 mol) of 2-formyl-quinoxaline-1,4-dioxide, 130 g (1 mol) of methyl 2-isopropylidenecarbazine and 100 ml of anhydrous acetonitrile is stirred on a water bath for 1.5 hours at 70 ° C. .

The initially dark yellow suspension turned to light yellow. After cooling, the product was filtered off, washed with acetonitrile and then dried.

Yield: 250 g (96%) methyl- (2-quinoxalinylmethylene) karbazét ^N-1 ^ Ν dioxide. Mp .: 252-254 ° C.

Example 34

100.75 S of 2-formylquinoxaline-1,4-dioxide are dissolved in 1250 ml of 5056 aqueous isopropanol. To the solution is added a solution of 75.45 g of 2-isopropylidene-carbazic acid methyl ester in a mixture of 12 ml of acetone and 28 ml of water.

The reaction mixture is heated to 60-65 ° C, then quenched with 12 mL of hydrochloric acid, boiled for one hour and then cooled. The product is filtered off, washed first with methanol, then with water and finally with methanol again and then dried.

Yield: 135.5 g (97.5%) of methyl (2-quinoxalinylmethylene) carbazet-N ¹ , N ⁴ -dioxide. Melting point: 235-255 ° C.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of the c'ninoxaline-1,4-di oxide derivatives of the general formula (I) in which: Q is hydroxyl, -NH-COOCH, -NH-CO-NF-or -NH-C (= NH) -NH ₂ or a group of the formula -NH-S ^, wherein R ^ is phenyl, or a group of the formula -NH-CO-R1, wherein R1 is an alkyl group, a phenyl group optionally substituted by 1 to 3 methoxy, hydroxyl, amino, nitro or halogen atoms, naphthylmethyl, hydroxynaphthyl, pyridyl, furyl, nitrofuryl , piperidyl, benzyl, phenethyl or alpha, alpha, alpha-diphenylhydroxymethyl group, characterized in that the azomethine derivative of the general formula II, Q is as defined above, R1 represents a phenyl, hydroxyphenyl, pyridyl, carboxyl or C1-6 alkyl group, R ₁ represents a hydrogen atom or a methyl group; R @ 1 and R @ 2, together with the carbon atom to which they are attached, can be a C1-4 cycloalkylidene or 1,3-diazacyclopentylidene-2-group reacted with 2-methyl-quinoxaline-1,4-dioxide of formula III