DK145716B - METHOD FOR PREPARING SCHIFF'S BASES OF 2-FORMULA-QUINOXALIN-1,4-DIOXIDE - Google Patents

Description

(19) DENMARK

ij | (12) SUBMISSION WRITING ου 145716 B

DIRECTORATE OF PATENT-06 TRADE MARKET

(21) Application No. 2669/74 (51) Int.Cl.3 C 07 D 241/52 (22) Filing day 15 · May 1974 C 07 0 413/12 (24) Race day 15 · May 1974 (41) Aim. available Nov. 17 1974 (44) Posted 7 Feb. 1983 (86) International application no.

(86) International filing day (85) Continuation day - (62) Master application no. -

(30) Priority May 16, 1973, Cl 1376, HU

(71) Applicant CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT., Budapest, HU.

(72) Inventor Jozsef Dukai, HU: Todor Pfliegel, HU: Miklosne

Barath, HU: Andras Kelemen, HU.

(74) Associate Engineering Company Budde, Schou & Co.

(54) Process for the preparation of Schiff's bases of 2-formyl quinoxaline-1,4-dioxide.

The present invention relates to a process for the preparation of known Schiff bases of 2-formyl-quinoxaline-1,4-dioxide. The importance of quinoxaline-1,4-dioxide derivatives has increased significantly in recent times, although their antibacterial action has already been described previously (J.K.Land-quist: J. Chem. Soc. 1953 · 286).

qq The practical application of these compounds has been Φ hindered by two factors, namely, on the one hand, the relatively elaborate production of quinoxaline-1,4-dioxides, and on the other C that some of the derivatives produced cause ^ side effects due to their toxicity. (Hurst et al., Brit. J. Phar macol. 8, 297, 1953). These disadvantages have excluded the compounds from the ^ human therapy, and at this time modern bovine feeding had not yet developed. The quinoxaline-1,4-dioxides have previously been readily prepared by reacting o-phenylenediamines with vieinal dioxo compounds (glyoxal and its derivatives). In the first step, quinoxa-line derivatives containing substituents at positions 2 and / or 3j are obtained depending on the glyoxal component used. This intermediate is subjected to oxidation with peracetic acid in the following step. This non-selective oxidation has been responsible for interrupting the development in this chemical field. Although specific oxidizing agents (e.g. m-chloro-perbenzoic acid) have subsequently emerged, no favorable change has occurred in this area.

According to M.J. Haddadine and Issidorides (Tetr. Letters, 56, 3253, 1965), it is known that benzofuroxanes readily react with enamines to form quinoxaline-1,4-dioxide derivatives. Furthermore, it has been found that in the presence of a base, benzofuroxane can react with various oxo compounds containing an active methylene group.

Due to the above-mentioned recognition, quinoxaline-1,4-dioxide derivatives containing substituents at positions 2 and 4 or 6 or 7- can be prepared.

Quinoxaline-1,4-dioxide derivatives containing at position 2 contain a formyl carbalkoxy-hydrazone group and at position 3 a hydrogen atom, an alkyl or carboxy group, have particularly favorable properties. These compounds are effective against the most diverse microorganisms against gram-positive and gram-negative strains, as evidenced by samples in vitro and in vivo (U.S. Patent Nos. 3,371,090 and 3-493 * 572 and German Publication No. 2,015. 676).

According to the known methods, these compounds can be prepared in two ways. One method consists in oxidation of the corresponding 2-methyl-quinoxaline-1,4-dioxide with selenium dioxide and further reaction of the aldehyde intermediate with an amine of the general formula NE2Q. This reaction is illustrated by Equation A.

0 0 g

w CH N CHO ^ N CH = NQ

V ^ 2 Y Y «yi / yv

I I -I 11 - “-> I

J, I

0 o o

A

In the formulas · R represents a hydrogen atom or one. alkyl group, and Q, represents a group -OH or NHR ', etc., wherein R 1 represents the group -CONH2, -CSNH2-, - (C = NH) -NH2, or a group -C00R ". wherein r" is a alkyl group having 1-4 carbon atoms, etc., or groups, such as a 1-hydanoyltinyl group or one. 5- ° xazolidin-2-yl group, etc.

A major disadvantage of this method is that the oxidation with selendi oxide is cumbersome. Namely, selenium dioxide is an expensive and toxic oxidant. (Rabjohn N., Org. Reactions, 5, 551, 1949).

The other option illustrated in Equation B is the reaction of 2-formyl derivatives of the dialkyl acetal with a compound of the general formula NH2Q. In this formula, R and Q have the same

ISLAND

meaning as above and R is an alkyl group: 0 OR 50

aN CH 2 N CH = NQ

Ί ^ L Jl 2 4 »ΙΟ o

B

The starting materials used can be prepared by reacting oxoaldehyde dialkyl acetals of the general formula IV

/ 0R2 R - C - (CH2) n - CH (IV) 0 n0R ^ 2 in which. R and R have the same meaning as above, and n is 0 or 1, with the corresponding benzofuroxane. Although the use of the above starting materials is advantageous, the preparation is. of the oxo compounds associated with significant difficulties (German Patent Nos. 1,254.1 ^ 8 and 1,252,193 and U.S. Patent No. 2,421,559).

According to a new method, the 2-formyl-quinoxaline-1,4-dioxide is produced by thermal decomposition of a laetone of the general formula (V) 0 t ι ^ γνλ I 'o (V) o / Noh (British patent no. In this method, the use of selenium dioxide and the oxoaldehyde acetals mentioned above is eliminated, but it is also unfortunate in this method that the lactones themselves can be produced by a multi-step process.

The above-mentioned oxymers of 2-formyl-quinoxaline-1,4-dioxide can be readily prepared from benzofuroxanes. However, these oximes are unable to participate in further reactions leading to the formation of the 2-formyl derivatives which have beneficial biological properties.

Various modifications of the method according to D. Nightingale and J.R. Janes (J. Am. Chem. Soc. 66, 352, 1944) has been unsuccessful.

Surprisingly, it has been found that the nitron derivatives of 2-formyl-quinoxaline-1,4-dioxides readily react with various compounds of the H2N-Q type, and that the desired Schiff bases can be prepared in this way immediately in high yield. . (The term "nine thrones" refers to compounds containing a group of the formula -CH = N-).

t

The invention relates to a process for the preparation of compounds of general formula I

¥ = n - q, x- ^ i r

Ψ R

wherein X represents a hydrogen atom, a halogen atom, an alkyl group of 1-6 carbon atoms or an alkoxy group of 1-6 carbon atoms, R represents a hydrogen atom or an alkyl group of 1-6 / carbon atoms, Q "represents a hydroxyl group, a group - NH-CO-NH 2, -NH-CS-NHg, or 3-oxazolidin-2-yl, which is characterized by the fact that nitron derivatives of the general formula (II) ¥ aN CH = N - Ar YE <n> wherein X and R have the same meaning as above and Ar represents an aromatic ring substituted in ortho and / or parasylation with at least one electron donating group, reacted with an amine of the general formula (III) NH 2 Q (III) wherein Q has the same meaning as in formula I, or with its acid addition salt in the presence of an acidic compound.

Said alkyl groups having 1-6 carbon atoms are straight or branched chain and may e.g. be methyl, ethyl, n-propyl, isopropyl, n-butyl and n-amyl groups.

Said alkoxy groups having 1-6 carbon atoms are straight or branched chain and may e.g. are methoxy, ethoxy, n-propoxy and isobutoxy groups.

In the starting materials of the general formula (II), Ar represents an aryl group, preferably a phenyl group, which contains at least one electron donating substituent in the ortho and / or para position. The following substituents are preferred: amino groups, alkylamino groups (e.g. methylamino groups and ethylamino groups), dialkylamino groups (e.g. dimethylamino groups and diethylamino groups), alkanoylamino groups (e.g. acetylamino groups and propionamido groups), hydroxy groups, eg chlorine, bromine and fluorine). As a group Ar, a dialkylaminophenyl group is particularly preferred.

The starting materials of general formula (III) can be used as free bases or as acidic addition salts. Preferably, mineral acid addition salts are used. Hydrochloric acid salts of the compounds of general formula (II) may also be used as starting materials.

The reaction of the present invention is carried out in the presence of substances having acidic properties. For this purpose, mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, hydrochloric or perchloric, especially hydrochloric or strong organic acids, e.g. acetic acid or benzenesulfonic acid. In general, all acids whose pK value is less than 1. a can be used

Preferably, low reaction aliphatic carboxylic acids, especially acetic acid, can be used as reaction media, but also low alkanols and their esters with lower aliphatic acids can be used successfully (eg ethyl acetate and butyl acetate). The acidic substance is used in a small, almost catalytic amount.

6 145716

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 starts shortly after the starting materials have been mixed together and the desired Schiff's base precipitates in a short time.

The reaction mixture is worked up using conventional methods (eg filtration, centrifugation, etc.).

The reaction time is relatively short and is 1-4 hours.

The starting materials of the general formula (II) can be prepared by conventional known methods. The 2-methyl-β-R derivative may be prepared by reacting benzofuroxane of the general formula (VI) X 1 O (VI) with a methyl-alkyl ketone in the presence of a base. As methyl-alkyl ketones, e.g. acetone, methyl-ethyl-ketone, methyl-propyl-ketone, etc. When using acetone, a 2-methyl derivative is obtained, using methyl-ethyl-ketone a 2,3-dimethyl derivative is obtained.

The 2-methyl-quinoxaline-1,1,1-dioxide derivatives thus prepared can be converted to nitrons by simple methods (Elina et al .: Him. Farm. Zs. 1/5, 10, 1967) by p-nitroso-dimethylaniline or other similar p-nitroso-phenyl derivatives containing at least one electron donating group are used. The reaction proceeds readily at room temperature in a basic methanolic medium.

The process of the present invention has significant advantages over known methods.

Selenium dioxide oxidation is completely eliminated, and starting materials3 which are difficult to prepare, such as oxoaldehyde diacetals or lactones, are also not used.

γ U 5716

The starting materials (2-methyl-quinoxaline-1,4-dioxides and the nitroso compounds or their more stable hydrochlorides) are inexpensive and readily available compounds. The reaction can be carried out in a simple manner and it is not necessary to use complicated apparatus or reaction conditions. The process is suitable for industrial scale implementation. The final products are available in extremely clean form and in general no further purification is necessary.

The products herein are known, chemotherapeutic agents.

The process according to the invention is explained in more detail by the following examples.

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

To a mixture of 65 ml of acetic acid, 6.48 g of N- (p-dimethylaminophenyl) -a- (2-quinoxalinyl-1,4-dioxide) nitron and 1.6 ml of concentrated hydrochloric acid is added 2.0 g of 3 -amino-oxazolid-2-one. The temperature rises slowly. Stir for 1 hour, after which the precipitate is separated by suction and washed with water. 4.8 g of a product are obtained which melts at 245-247 ° C (b).

Analysis for Formula C12H10N4 ° 4:

Calculated: C 52.55%, H 3.68%, N 20.43%

Found: C 52.25%, H 3.69%, N 20.30%

The nitron used as starting material can be prepared as follows: To a solution of 40 g of sodium hydroxide in 2000 ml of methanol, 97 g of 2-methyl-quin-oxaline-1,4-dioxide are added portionwise with stirring. To the resulting greenish-colored fine suspension was added portionwise at room temperature 171.7 g of p-nitroso-dimethylaniline hydrochloride. Then, the mixture, which has meanwhile become a fine, dark-colored suspension, is stirred for 6 hours. After standing overnight, the precipitate is separated by suction. The produced nitron is first washed with water and then with methanol and finally dried.

1 ^ 6.2 g (a yield of J6 $) of the product is obtained. It has a melting point of 202-204 ° C.

Analysis for the formula C ^H ^ gOO ^N N:

Calculated: C 62.96¾ H 4.94¾ N $ 17.28

Found: C $ 62.98, H 4.99¾ N $ 17.14.

145716 δ

Example 2 2-Formyl-quinoxaline-1,4-dioxide-thlosemicarbazone

A mixture of 6.48 g of nitron, 56 ml of acetic acid, 2 ml of concentrated hydrochloric acid and 1.82 g of thiosemicarbazide is stirred for 1.5 hours. 4.7 g of a product is obtained which is mixed with 30 ml of a 10% ammonia solution, after which the precipitate is separated by suction. It is washed well with water and the product is boiled for 10 minutes in 30 ml of DMSO. After cooling, the product is filtered off and washed with ethanol and dried. The melting point of the product is 261-262 ° C.

Example 3 2-Formyl-3-methyl-quinoxaline-1,4-dioxide semicarbazone

To a mixture of 6.76 g of N- (p-dimethylaminophenyl-α- (3-methyl-2-quinoxalinyl-1,4-dioxide) nitron, 65 ml of acetic acid and 2 ml of concentrated hydrochloric acid is added 2.23 g of semicarbazide The mixture is first stirred for 1 hour at 40-50 ° C and then for 5 hours at room temperature, after which the mixture is allowed to stand overnight. After filtration, washing and drying, 2.2 g of the crude product is mixed with 50 ml. The product is washed with ethanol and dried. After recrystallization from acetic acid, 1.8 g of the yellow-colored semicarbazone having a melting point of 24 ° C (b) is obtained. Analysis for the formula Ο ^ Η ^ Ν, -Ο ^:

Calculated: C $ 50.58, H $ 4.24, N $ 26.8l

Pound: C 49.8¾ H $ 4.15, N $ 27.20.

The methyl nitrone derivative used as starting material is prepared in a similar manner as described above:

To a mixture of 76.0 g of 2, J-dimethyl-quinoxaline-1,4-dioxide and 51.2 g of sodium hydroxide in 1480 ml of methanol is added 124 g of p-nitroso-dimethylaniline hydrochloride at 20-22 ° C. The reaction mixture is stirred for 5 hours and then allowed to stand overnight. After separation of the precipitate by suction, this is thoroughly washed with water and dried. 74.5 g of methyl-nitron are obtained, melting at 190-191.5 ° C.

145716 9

Example 4 2-Forinyl-3i-methyl-quinozaline-1,4-dioxide oxime

To a solution prepared from 6.76 g of methylnitron, 50 ml of acetic acid and 2 ml of concentrated hydrochloric acid, a solution of 1.4 g of hydroxylamine in 5 ml of water is added dropwise as described above. The temperature is raised to approx. 40 ° C and stirred at this temperature for 5.5 hours. The product is then filtered off. This gives 1.8 g of product, which melts at 209 ° C after recrystallization · from ethanol.

The product has the same properties as the quinone produced by the oxidation of 2,3-dimethylquinone oxide with selenium dioxide.

Claims (2)

10 145716 Patent claims. 1. A process for preparing Schiff's bases of 2-formylquinoxaline-1,4-dioxide derivatives of the general formula (I) 0 £ CH = N - Q * highC X (i)? wherein X represents a hydrogen atom, a halogen atom, an alkyl group of 1-6 carbon atoms or an alkoxy group of 1-6 carbon atoms, R represents a hydrogen atom or an alkyl group of 1-6 carbon atoms, and Q represents a hydroxyl group, a group -NH- CO-NHg, -NH-CS-NH2 or 3-oxazolidin-2-yl, characterized in that nitron derivatives of the general formula (II)? % .N CH = N - Ar V x— I (II) wherein X and R have the same meaning as above and Ar represents an aromatic ring substituted by at least one electron donating group in ortho and / or para position. with an amine of the general formula (III) NH 2 - Q, (III) wherein Q is as defined above, or with its acid addition salt in the presence of an acidic compound.