NO146746B - PROCEDURE FOR PREPARING THE SHIFT BASES OF 2-FORMULA-CHINOXALIN-1,4-DIOXYDER - Google Patents

Description

The present invention relates to an improved process for the production of known Schiff bases from 2-formyl-quinoxaline-1,4-dioxyd. The importance of the quinoxaline-1,4-dioxyd derivative has increased strongly recently, although its anti-bacterial effect has previously been described. (J. K. Landquist, J. Chem. Soc. 1953, 2816).

The practical use of these compounds is hindered by two factors, namely on the one hand due to the relatively cumbersome preparation of quinoxaline-1,4-dioxide and on the other hand due to the fact that some of the derivatives obtained causing toxic side effects. (Hurst and co-workers, Brit. J. Pharmacol. 8, 297, 1953). This drawback precluded the use of the compounds in human therapy, and at that time modern animal feed technologies had not yet been developed. Quinoxaline-1,4-dioxide was previously prepared by reacting o-phenylene-diamine with adjacent dioxo compounds (glyoxal and their derivatives).

In the first step, quinoxaline derivatives were obtained whose substituents were in the 2- and/or 3-position, depending on the glyoxal component used. In the next step, these intermediate products were subjected to oxidation with peracetic acid. This non-selective oxidation was responsible for the interruption of development in this area. Although specific oxidizing agents have subsequently appeared (e.g. m-chloro-perbenzoic acid), this has not led to a positive change in this area. M. J. Haddadin and Issidorides (Tetr. Letters. 36, 3253, 1965) have noted that benzofuroxan readily reacts with enamines to form quinoxaline-1,4-dioxyd derivatives. Furthermore, it was found that benzofuroxan in the presence of base can react with various oxo compounds containing an active methylene group.

On the basis of this teaching, quinoxaline-1,4-dioxyd derivatives containing substituents in the 2- and 3-, respectively 6- or 7-position can be prepared.

Quinoxaline-1,4-dioxyd derivatives which in the 2-position contain a formyl-carboalkoxy-hydrazone group and in the 3-position hydrogen, an alkyl or carboxy group exhibit particularly favorable properties. These compounds are effective against the most diverse microorganisms, and against gram-positive and gram-negative strains, which has been shown in both in vitro and in vivo tests (U.S. Patent No. 3,371,090 and 3,493,572, DOS 2,015,676).

According to the previously known methods, these compounds are produced in two ways. One method consists in oxidation of the corresponding 2-methyl-quinoxaline-1,4-dioxides with selenium dioxide and then reaction of the aldehyde intermediates with an amine of general formula III. This reaction is illustrated in the reaction scheme

A:

In the formula, R denotes a hydrogen atom or an alkyl group and Q denotes a -OH or NHR' group, where R' denotes -CONH2, -(C=NH)NH2, COOR'' (R'1=C^_^-alkyl ) etc. or groups such as 1-hydantoinyl, 3-oxazolidin-2-yl.

A disadvantage of this method is that the oxidation with selenium dioxide is a cumbersome method. Selenium dioxide is an expensive and toxic oxidizing agent. (Rabjohn N., Org. Reactions, 5, 331, 1949).

The second possibility, which is illustrated in reaction core B, consists in reacting the 2-formyl derivative of the dialkyl acetal with a compound of general formula III. In this formula, R and Q are the previously indicated alkyl groups and R' is an alkyl group: The starting materials used can be prepared by reacting the oxoaldehyde-dialkyl acetal of general formula IV

where R and R<2> have the previously stated meanings and where n is equal to 0 or 1, with the corresponding benzofuroxan. Although the use of the starting materials indicated above is advantageous, the preparation of the oxo compound is fraught with significant difficulties (BRD patents no. 1 254 138 and 1 252 193 and USP no. 2 421 559).

According to a new method, 2-formyl-quinoxaline-1,4-dioxyd is produced by thermal cleavage of a lactone of general formula V

(British, Patent No. 1,263,677). This method avoids the use of selenium dioxide and the oxoaldehyde acetal used above, however, this method is also fraught with disadvantages, as the lactone itself can only be produced in several steps.

The above-mentioned oximes of 2-formyl-quinoxaline-1,4-dioxides can be easily prepared from benzofuroxan. However, these oximes are unsuitable for further reactions leading to the 2-formyl derivatives which exhibit biological properties.

Various modifications of the method according to D. Nightingale und J.R. Janes (J. Am. Chem. Soc. 66, 352, 1944) has not led to good results.

Surprisingly, it has now been found that the nitrone derivative of 2-formyl-quinoxaline-1,4-dioxide reacts easily with various compounds of the type t^N-Q and that the desired Schiff bases can be obtained in this way with high yield. (The term nitrone denotes compounds containing a group of the formula --CH=^,-.

The present invention therefore relates to a method for the preparation of compounds of general formula I

where

R denotes hydrogen or alkyl with 1 - 6 carbon atoms and

Q represents hydroxyl, -NH-CO-NH2, -NH-CS-NH2, -NH-COO-(C1_6)-alkyl, -NH-COO-aralkyl or 3-oxazolidin-2-yl, provided that when Q is - NH-COO-(C1-6)alkyl, R is a C1-6-alkyl group. The new method is characterized by the fact that a nitron- derivative of general formula II where R has the previously stated meanings and Ar denotes a p-di (C 1 -g)alkylaminophenyl group is reacted with an amine of general formula III

or with its acid addition all in the presence of an acidic component.

The starting material of general formula III can be used as free bases or as acid addition salts, mineral acid addition salts are preferably used. Hydrochloric acid salts of the compound of general formula II can also be used as starting material.

The reaction according to the present invention is carried out in the presence of components with an acidic character. For this purpose, mineral acids are preferably used, e.g. hydrochloric acid, hydrobromic acid, sulfuric or nitric acid, perchloric acid or strong organic acids, e.g. acetic acid or benzoesulfonic acid. Generally speaking, all acids whose pKa value is less than 1 can be used.

Lower aliphatic acids, in particular acetic acid, are preferably used as reaction medium, but lower alkanols and their esters with lower aliphatic acids can also be used (e.g. ethyl acetate, butyl acetate, etc.). The component with an acidic character is used as a small, fixed catalytic quantity.

The reaction can be carried out at room temperature or at a temperature between room temperature and the boiling point of the reaction mixture. The reaction occurs immediately after mixing the starting materials and the desired Schiff base precipitates out within a short time.

The reaction mixture is worked up according to known methods, such as e.g. by filtration, centrifugation, etc.

The reaction time is relatively short and amounts to from 1 to 4 hours.

The starting material of general formula II can be prepared according to commonly known methods. 2-methyl-3-R derivatives can be prepared by reacting benzofuroxan of general formula VI

with a methyl alkyl ketone in the presence of a base. As methyl-alkyl-ketone can e.g. acetone, methyl ethyl ketone, methyl propyl ketone, etc. are used. When acetone is used, a 2-methyl derivative is obtained, when methyl ethyl ketone is used, a 2,3-dimethyl derivative is obtained.

The 2-methyl-quinoxaline-1,4-dioxyd derivative thus obtained can be easily converted to nitrone (Elina und co-workers, Him. Farm. Zs. 1/5, 10, 1967), since p-nitroso -di-methyl-aniline or another corresponding p-nitroso-phenyl derivative is used, which at least contains an electron-donating group. The reaction especially at room temperature in alkaline-methanolic medium.

The method according to the present invention entails significant advantages compared to the known methods.

The selenium dioxyd oxidation is completely eliminated, in addition, hard-to-reach starting materials such as oxo-aldehyde diacetal or ketone are not used.

The starting materials (2-methyl-quinoxaline-1,4-dioxyd and the nitroso compounds or their stable hydrochlorides) are cheap and readily available compounds. The reaction can be carried out in a simple way and requires no complicated apparatus or reaction conditions. The method is well suited for implementation on an industrial scale. The final product is obtained in a very pure form, so that further purification is usually not necessary.

The invention is further illustrated in the following examples.

Example 1

2- formyl- quinoxaline- 1, 4- dioxyd- carbomethoxyhydrazone

120 g of N-(p-dimethylaminophenyl)-α-(2-quinoxalinyl-1,4-dioxyd)-nitrone, 800 ml of 96% acetic acid and 30 ml concentrated hydrochloric acid introduced with stirring. After brief stirring, the mixture was filtered, 52 g of methylcarbazate hydrochloride was added to the filtrate. The temperature of the mixture was raised to 50 - 55° C using a water bath, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was then allowed to stand overnight and the precipitate was separated, washed with water and ethanol. After drying, 78.0 g of a yellow product with a melting point of 237 - 239° C were obtained. The product was poorly soluble and could be purified as follows: In a mixture of 150 ml of chloroform and 150 ml of 96% acetic acid, this was heated for 1 - 2 hours under reflux cooling. After cooling, the product was filtered, washed with alcohol and dried. 76.0 g of dry product with melting point 245 - 246.5° C was obtained.

Analysis for formula cnH]_o°4N4:

Calculated: C 50.38, H 3.84, N 21.37

Found: C 50.64, H 3.6 , 21.08

In the IR spectrum, a characteristic ester band appeared at 1760 cm"<1>.

The nitrone used as starting material can be prepared in the following way: To a solution of 40 g of NaOH in 2000 ml of methanol, 97 g of 2-methyl-quinoxaline-1,4-dioxide was added in portions while stirring. 171.7 g of p-nitroso-dimethylaniline hydrochloride was added in portions at room temperature to the green colored fine suspension obtained. Then the mixture, which had turned into a fine dark colored suspension, was stirred for 6 hours. After standing overnight, the product was separated. The nitrone obtained was first washed with water, then with methanol and finally dried.

136.2 g (76% yield) with melting point 202 - 204° C were obtained.

Analysis for formula ci7Hi6°3N4:

Calculated: C 62.96, H 4.94, N 17.28

Found: C.62.98, H 4.99, N 17.14

Example 2

2- formyl- 3- methyl- quinoxaline- 1, 4- dioxyd- carbomethoxyhydrazone

1.6 ml of concentrated hydrochloric acid was added dropwise to a mixture of 6.76 g of N-(p-dimethylaminophenyl)-α-(3-methyl-2-quinoxalinyl-1,4-dioxyd)-nitrone and 50 ml of acetic acid with stirring . The mixture was stirred and 3.0 g of methylcarbazate hydrochloride was added to the filtrate. The reaction mixture was stirred at 60 - 70° C. for 3 -

3^ hours. After cooling, the reaction mixture was allowed to stand for a short time and was then separated. The precipitate was washed with ethanol and dried. 3.8 g of product was obtained which was then heated with 15 ml of chloroform for 1 hour.

After filtration, 3.7 g of a yellow product with a melting point of 251 - 252° C were obtained.

Analysis for formula C^2<H>2.2<N>4°4<:>

Calculated: C 51.17, H 4.38, N 20.28

Found: C 51.04, H 4.12, N 19.98

The methyl nitrone derivative used as starting material was prepared as follows: To a mixture of 76.0 g of 2,3-dimethyl-quinoxaline-1,4-dioxyd and 31.2 g of NaOH in 1480 ml of methanol, at 20 - 22 ° C added 124 g of p-nitroso-dimethylaniline hydrochloride. The reaction mixture was stirred for 5 hours and then allowed to stand overnight. After decanting, the precipitate was washed thoroughly with water and dried. It was

obtained 74.5 g of product which melted at 190 - 191.5°C.

Example 3

3-( 2- quinoxalinyl- methylene- 1, 4- dioxyd)- oxazolid- 2- one

A mixture of 65 ml of acetic acid, 6.48 g of N-(p-dimethyl-aminophenyl)-d-(2-quinoxalinyl-1,4-dioxyd)-nitron and 1.6 ml of concentrated hydrochloric acid was added as indicated above 2, 0 g of 3-amino-oxazolid-2-one. The temperature rose slowly. The mixture was stirred for 1 hour, separated and then washed with alcohol. 4.8 g of a product melting at 245 - 247°C were obtained.

Analysis for formula C^2<H>^<qN>4°4<:>

Calculated: C 52.55, H 3.68, N 20.43

Found: C 52.25, H 3.69, N 20.30

Example 4

2- formyl- quinoxaline- 1, 4- dioxyd- thiosemicarbazone

As described above, 6.48 g of N-(p-dimethylamino-phenyl)α-(2-quinoxalinyl-1,4-dioxyd)-nitrone, 56 ml of acetic acid, 2 ml of concentrated hydrochloric acid and 1.82 g of thiosemicarbazide respectively were mixed. The resulting mixture was stirred for 1 hour. 4.7 g of a product was obtained which was mixed with 30 ml of a 10% ammonia solution which was then filtered. The product was washed well with water and was then boiled in 30 ml of dimethyl sulfoxide for 10 minutes. After cooling, the mixture was filtered, the precipitate was washed with ethanol and dried. Melting point: 261 - 262°C.

Example 5

2- formyl- 3- methyl- quinoxaline- 1, 4- dioxyd- semicarbazone

A mixture of 6.76 g of N-(p-dimethylaminophenyl-d-(3-methyl-2-quinoxalinyl-1,4-idoxyd)-nitrone, 65 ml of acetic acid and 2 ml of concentrated hydrochloric acid was added as described above to 2.23 g of semicarbazide hydrochloride. The mixture was stirred at 40 - 50°C for 1 hour, and then at room temperature for 5 hours, after which it was allowed to stand overnight. After filtration, washing and drying, 2.2 g of impure product was obtained, which was mixed with 50 ml of a dilute ammonia solution which was then suctioned off. The product was washed with ethanol and dried. After recrystallization from acetic acid, 1.8 g of yellow colored semicarbazone with melting point 241°C was obtained.

Analysis for formula C^G^N^O^:

Calculated: C 50.58, H 4.24, N 26.81

Found: C 49.83, N 4.15, N 27.20

Example 6

2- formyl- 3- methyl- quinoxaline- 1, 4- dioxyd- oxime,

A solution was prepared from 6.76 g of N-(p-dimethylamino-phenyl)-d-(3-methyl-2-quinoxalinyl-1,4-dioxyd)-nitrone, 50 ml of acetic acid and 2 ml of concentrated hydrochloric acid as before described, added dropwise to a solution of 1.4 g of hydroxylamine in 5 ml of water. The temperature was raised to approx. 40° C. and the mixture was stirred at this temperature for 3^ hours. The product was filtered off. 1.8 g of product with a melting point, after recrystallization from ethanol, of 209° C was thus obtained.

The product had the same properties as the quinone obtained by oxidation of 2,3-dimethylquinone oxides with selenium dioxide.

Claims (1)

Procedure for the preparation of compounds of genes real formula I where R denotes hydrogen or alkyl with 1 - 6 carbon atoms and Q denotes hydroxyl, -NH-CO-NH2, -NH-CS-NH2, -NH-COO-(C1_g)-alkyl, -NH-COO-aralkyl or 3-oxazolidine -2-yl, provided that when Q is -NH-COO-(C1_g)alkyl R is a C1_g alkyl group, characterized in that a nitrone derivative of general formula where R has the previously stated meanings and Ar denotes a p-di (C 1 -g)alkylaminophenyl group is reacted with an amine of general formula III or with its acid addition all in the presence of an acidic component.