GB2083817A

GB2083817A - Process for the preparation of 2-methylene-quinoxaline-1,4-dioxide derivatives

Info

Publication number: GB2083817A
Application number: GB8127507A
Authority: GB
Original assignee: Egyt Gyogyszervegyeszeti Gyar
Current assignee: Egyt Gyogyszervegyeszeti Gyar
Priority date: 1980-09-12
Filing date: 1981-09-11
Publication date: 1982-03-31
Also published as: PT73655B; IT8123898A0; AR226749A1; IL63803A0; DE3136092A1; BE890300A; YU218781A; ES8206492A1; FI812835L; DK405181A; CA1154770A; FR2490226A1; SE8105427L; IT1139962B; PT73655A; ES505442A0

Abstract

2-Methylene-1,4-dioxide derivatives of the general formula (I> <IMAGE> wherein A represents a hydroxyl or an amino group, or a group of the general formula -NH-COOR1, wherein R1 denotes a C1-4 alkyl group; or a group of the general formula -NH-CX-NH2, wherein X stands for oxygen or sulfur; or a group of the formula -NH-C(=NH)-NH2; or a group of the general formula -NH-R2, wherein R2 represents C1-6 alkyl, phenyl, benzyl, hydroxyl or hydroxy-(C2-4alkyl); or a group of the general formula -NH-CO-R3, wherein R3 stands for a C1-20alkyl group, a phenyl group optionally substituted by one, two or three identical or different substituent(s) selected from the group consisting of hydroxyl, amino, nitro, C1-4alkyl, C1-4 alkoxy or halogen; a piperidyl, a pyridyl, a furyl, a nitrofuryl, a pyrazinyl, a pyrimidyl, a naphthyl, a hydroxynaphthyl, a phenylalkyl, an 1,2,4-triazinyl, an alpha , alpha -diphenyl- alpha - hydroxymethyl, a cyanomethyl, a halomethyl or a hydroxymethyl group, are prepared by dehydrating new compounds of the general formula (II> <IMAGE> wherein A has the same meanings as above. The compounds of the general formula (I) possessing bactericidal and weight-gain increasing properties can be obtained in a high purity with an excellent yield by the process according to the invention. A process for the preparation of the new compounds of formula (II) is also disclosed.

Description

SPECIFICATION Process for the preparation of 2-methylene-quinoxaline- 1 ,4-dioxide derivatives This invention relates to a new process for the preparation of 2-methylene-quinoxaline-1 4- dioxide derivatives known to posses bactericidal and weight-gain increasing effects.The compounds prepared according to the invention are encompassed by the general formula (I)

wherein A represents a hydroxyl or an amino group, or a group of the general formula -NH-COOR" wherein R, denotes a C, 4 alkyl group; or a group of the general formula -NH-CX-NH2, wherein X stands for oxygen or sulfur; or a group of the formula -NH-C(= NH)-NH2; or a group of the general formula -NH-R2, wherein R2 represents C1 6 alkyl, phenyl, benzyl, hydroxyl or hydroxy-(C2 4alkyl); or a group of the general formula -NH-CO-R3, wherein R3 stands for a C, 20 alkyl group, a phenyl group optionally substituted by one, two or three identical or different substituent(s) selected from the group consisting of hydroxyl, amino, nitro, C14 alkyl, C14 alkoxy or halogen; a piperidyl, a pyridyl, a furyl, a nitrofuryl, a pyrazinyl, a pyrimidyl, a naphthyl, a hydroxynaphthyl, a phenylalkyl, an 1,2,4-triazinyl, an a,a-diphenyl-a-hydrnxymethyl, a cyanomethyl, a halomethyl or a hydroxymethyl group.

The term "alkyl group" used in the specification and claims covers straight-chained or branched saturated aliphatic hydrocarbyl groups, such as methyl, ethyl, n-propyl, isopropyl, nbutyl, sec.-butyl, and tert.-butyl. The term "alkoxy group" refers to groups derived from the alkyl groups mentioned above, such as methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

Preferred representatives of the "hydroxy-(C24 alkyl)" groups are the hydroxyethyl, hydroxypropyl, hydroxyisopropyl and the hydroxybutyl groups. The term "halogen" may stand for all the four halogen atoms, such as fluorine, chlorine, bromine and iodine. The term "halomethyl group" refers to methyl groups substituted by a halogen atom, such as fluoromethyl, chloromethyl, bromomethyl and iodomethyl.

It is known from the US patent specifications Nos. 3,371,090 and 3,493,572 that the compounds of the general formula (I) can be prepared by reacting 2-formyl-quinoxaline-1,4- dioxide or the dialkyl-acetal thereof with a reactant containing a primary amino group. The reaction is unfavourable because of the moderate yield(about 80%)and the relatively long reaction time, which, in certain cases, can be as long as 24 hours. Besides, the main reaction is accompanied by different side-reactions, and the desired compound is contaminated with the side-products thus-formed. The purification of the end-product requires complicated operations and can be carried out only at the expense of high losses of substance.

According to a further known method the compounds of the general formula (I) are produced by reacting 2-formyl-quinoxaline-1 ,4-dioxide or the corresponding dialkyl-acetal with a Schiff base(Hungarian patent specification No. 171,738).

Now it has been found that the compounds of the general formula (I) can be prepared economically in an excellent purity by dehydrating a 2-hydroxymethyl-quinoxaline-1 ,4-dioxide derivative of the general formula (II)

wherein A has the same meanings as above.

The dehydration can be carried out in two different ways: either thermally, that is by heating the compound of the general formula (II), or by using a dehydrating agent.

When dehydrating under thermal conditions a suspension of the compound of the general formula (11) is preferably heated in a suitably inert solvent until no more water is split off. As suitably inert solvent, water, aliphatic alcohols, such as isopropanol or butanol, or aromatic hydrocarbons, such as toluene or xylene are preferably used. The reaction is preferably carried out at the boiling point of the solvent, generally at 40 C to 150 C. When using an organic solvent immiscible with water the thermal dehydration can be carried out by continually removing the water obtained from the system, e.g. in form of an azeotrope. In this way the reaction may also be monitored.

When dehydrating according to the other method, dehydrating agents generally used for such purpose (e.g. polyphosphoric acid, sulfuric acid, and calcium chloride,) are used.

The 2-hydroxymethyl-quinoxaline-1 ,4-dioxide derivatives of the general formula (II) used as starting substances are new compounds which can be prepared by reacting a 2-methylene quinoxaline-1 ,4-dioxide derivative of the general formula (Ill)

wherein Q represents an oxygen atom or two alkoxy groups containing 1-4 carbon atoms each, with a carboxylic hydrazide of the general formula (IV) A-N H2 (IV) wherein A has the same meanings as above.

As the dehydration of the compounds of the general formula (II) is carried out quickly, the side-product formation is eliminated and the compounds of the general formula (I) can be obtained economically, almost quantitatively.

Further details of the invention are illustrated by the following non-limiting Examples: Preparation of the starting substances of the general formula (11): 0.1 mole of 2-formyl-quinoxaline-1,4-dioxide dissolved in water or dimethylformamide is reacted with 0.1 mole of a compound of the general formula (IV) in the presence of 2 drops of concentrated hydrochloric acid or piperidine. The separated product is filtered off, washed with water and dried.

Example 1 Preparation of 2-(methoxycarbonyl-hydrazono-methylene)-quinoxaline-1,4-dioxide 28.0 g (0.1 mole) of 2-(α-)methoxycarbonyl-hydrazino-(-α-hydroxymethyl)-quinoxaline-1,4-diox- ide are admixed with 150 ml of water and the mixture is boiled for an hour under stirring. Then it is cooled, the separated product is filtered off and washed with water. 25.4 g (98%) of desired compound are obtained.

M.p.: 257-258 C.

Example 2 Preparation of 2-(3', 4', 5'- trimethoxybenzoyl-hydrazonomethylene)-quinoxaline-1,4-dioxide 41.6 g (0.1 mole) of 2-(α-) 3,4,5-trimethoxybenzoyl-hydrazino(-α-quinoxaline- 1,4-dioxide are dehydrated in 250 ml of isopropanol, in the presence of 2 drops of sulfuric acid at 50 C to 60 C, under stirring. After cooling the reaction mixture the separated product is filtered off and washed. 39.0 g(98%) of desired compound are obtained. M.p.: 255-256 C.

Example 3 Preparation of 2-(cyanoacetyl-hydrazono-methylene)-quinoxaline-1,4-dioxide 27.2 g(0.1 mole)of 2-(α-)cyanoacetyl-hydrazone(-α-hydroxymethyl)-quinoxaline-1,4-dioxide are suspended in 200 ml of toluene, and the reaction mixture is kept at 1 20 C for an hour. Then it is cooled, and the separated product is filtered off. 26.0 g(97%)of desired compound are obtained. M.p.: 244-245"C.

Example 4 Preparation of 2-(3l, 4,, 5'-trimethoxybenzoyl-hydrazonomethylene)-quinoxaline- 1,4-dioxide 4.1 6 g(0.01 mole) of 2-(α-)3', 4', 5'- trimethoxybenzoylhydrazino(-α-hydroxymethyl)-quinoxal- ine-1,4-dioxide mixed with 40 g of polyphosphoric acid are allowed to react at 25"C for 3 hours, then the reaction mixture is poured into a 10% cold sodium hydroxide solution. The separated precipitate is filtered off and washed with water until neutral. 38.6 g(97%) of desired compound are obtained. M.p.: 256-256.5"C.

The compounds listed in the following Table are prepared by the methods of the previous Examples:

Method Example (No. of the Temperature M.P. (No.) A Medium Example) ( C) ( C) Yield 5 -NH-CO-NH2 water 1 90-95 288-89 91 6 -OH isopropanol 2 50 248-49 95 7 -NH-C(NH)-NH2 water 1 80-90 286-87 93 8 -NH-C6H5 water 1 90-95 247-48 89 9 -NH-laurinoyl water 1 80-90 233-34 95 10 -NH-CO-C6H5 water 1 90-95 256-57 98 11 -NH-CO-naphthyl-1 isopropanol 2 60 247-48 97 12 -NH-CO-C6H5-p-OH water 1 50-55 307-08 98 13 -NH-CO-C6H5-p-NH2 water 1 80-85 291-92 95 14 -NH-CO-piridyl-3 methanol 2 50 270-71 94 15 -NH-CO-piridyl-4 butanol 2 50 268-69 96 16 -NH-CO-C6H5-p-Cl water 1 50 273-74 97 17 -NH-CO-furyl-2 xylene 3 120 261-62 95 18 -NH-CO-C6H5-2-NH2 water 1 60 289-90 94 19 -NH-CO-furyl-5-NO2 methanol 2 50 265 95 20 -NH-CO-C6H5-2-OH water 1 50 280 94 21 -NH-caprinoyl water 1 90-95 237-38 97 22 -NH-CO-C6H5-p-NO2 water 1 90-95 275-76 95 23 -NH-CO-(CH2)2-C6H5 isopropanol 2 50 241 98 24 -NH-stearinoyl butanol 2 50 233-34 90 25 -NH-CO-C6H5-p-OCH3 xylene 3 110 260 91 26 -NH-CO-piperidyl-4 isopropanol 2 60 185-86 90 27 -NH-CO-naphthyl(2)-2-OH water 1 90-95 261 98 28 -NH-heptanoyl methanol 2 55-60 241-42 97 29 -NH-CH3 water 1 80-90 183 89 30 -NH-C4H9 water 1 90-95 230-31 92 31 -NH-benziloyl toluene 3 110 252-53 96 32 -NH-(CH2)2-OH xylene 3 130 258-59 89 33 -NH-CS-NH2 water 1 90-95 292-93 88 34 -NH-CO-C(C6H5)2 water 1 50 267 97 OH

Claims

1. A process for the preparation of 2-methylene-quinoxaline-1 4-dioxide derivatives of the general formula (I)

wherein A represents a hydroxyl or an amino group, or a group of the general formula -NH-COOR1, wherein R, denotes a C14 alkyl group; or a group of the general formula -NH-CX-NH2, wherein X stands for oxygen or sulfur; or a group of the formula -NH-C(= NH) NH2; or a group of the general formula -NH-R2, wherein S2 represents C12 alkyl, phenyl, benzyl, hydroxyl or hydroxy-(C2 4 alkyl); or a group of the general formula -NH-CO-R3, wherein R3 stands for a C, 20 alkyl group, a phenyl group optionally substituted by one, two or three identical or different substituent(s) selected from the group consisting of hydroxyl, amino, nitro, C14 alkyl, C14 alkoxy or halogen; a piperidyl, a pyridyl, a furyl, a nitrofuryl, a pyrazinyl, a pyrimidyl, a naphthyl, a hydroxynaphthyl, a phenylalkyl, an 1,2,4-triazinyl, an a,a-diphenyka- hydroxymethyl, a cyanomethyl, a halomethyl or a hydroxymethyl group, which comprises dehydrating a compound of the general formula (II)

wherein A has the same meanings as above.

2. A process as claimed in claim 1, wherein the dehydration is carried out in an inert solvent, at the boiling point thereof.

3. A process as claimed in claim 2, wherein the inert solvent is water, an aliphatic alcohol or an aromatic hydrocarbon.

4. A process as claimed in claim 1, wherein the dehydration is carried out using a dehydrating agent.

5. A process as claimed in claim 4, wherein the dehydrating agent is polyphosphoric acid, sulfuric acid or calcium chloride.

6. A process as claimed in claim 1 substantially as hereinbefore described.

7. A process as claimed in claim 1 substantially as hereinbefore described with reference to the Examples.

8. Compounds of formula (II) as defined in claim 1.

9. A process for the preparation of a compound of formula (II) as defined in claim 1 which comprises reacting a compound of formula (III)

wherein Q represents an oxygen atom or two alkoxy groups containing from 1 to 4 carbon atoms, with a carboxylic hydrazide of formula A-NH2 wherein A is as defined in claim 1.

10. A process as claimed in claim 9 substantially as hereinbefore described.