FR2490226A1 - PROCESS FOR THE PREPARATION OF 2-METHYLENE-QUINOXALINE-1,4-DIOXIDE DERIVATIVES - Google Patents

Abstract

PROCESS FOR PREPARING 2-METHYLENE-QUINOXALINE-1,4-DIOXIDE DERIVATIVES REPRESENTED BY GENERAL FORMULA I BELOW: (CF DRAWING IN BOPI) THESE DERIVATIVES ARE OBTAINED BY DEHYDRATION OF 2-HYDROXYMETHALYL-1,4- QUINO CORRESPONDING DIOXIDES, HOT OR IN THE PRESENCE OF DEHYDRATING AGENT.

Description

The present invention relates to a novel process

  for the preparation of 2-methylene-quinoxaline-1,4-di-

  known for their bactericidal effects and their ability to

to increase weight gain.

  The compounds prepared in accordance with the present invention are represented by the following general formula (I): ## STR1 ## wherein A represents a hydroxyl or amino group, or a group of general formula -NH-COOR1, wherein R1 is C1-C4 alkyl; or a group of general formula -NH-CX-NH2, where X represents an oxygen or sulfur atom; or a group of formula -NH-C (= NH) -NH2;

  or a group of general formula -NH-R2, where R2 represents

  C1-C6 alkyl group, or phenyl group, ben-

  zyl, hydroxyl or hydroxy-C 2 -C 4 alkyl; or a group of general formula -NH-CO-R3, wherein R3 is C1-C20 alkyl, a group

  phenyl optionally substituted with one, two or three

  identical or different radicals selected from the group consisting of hydroxyl, aminO-, nitro-, C1-C4 alkyl,

  C1-C4 alkoxy or a halogen atom; a piper radical

  trypyl, pyridyl, furyl, nitrofuryl, pyrazinyl, pyrimidyl, 1,2,4-triazinyl, ", o-diphenyl-d-hydroxymethyl, cyanomethyl, halomethyl or hydroxymethyl which may also represent

  a naphthyl, hydroxynaphthyl or phenylalkyl group.

  The term "alkyl group" used in the context of

  the present invention comprises hydrocarbyl

  phagestic saturated straight or branched chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,

  sec-butyl, tert-butyl, etc. The term "alkoxy group"

  refers to groups derived from the alkyl groups mentioned above, such as methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, and the like. Preferred representatives of the "C 2 -C 4 hydroxyalkyl" groups are the radicals

  hydroxyethyl, hydroxypropyl, hydroxyisopropyl and hydroxyethyl

  butyl. The term "halogen atom" may represent 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.

  He is known by the patents of the United States of America

  Nos. 3,371,090 and 3,493,572, that the compounds of general formula

  (I) can be prepared by reacting 2-formyl

  quinoxaline-1,4-dioxide or its dialkyl acetal, with a reagent containing a primary amine group. The reaction is not

  advantageous because it provides an average return (

  80%) and requires a relatively long reaction time

  which in some cases can reach 24 hours. Of

  Moreover, the main reaction is accompanied by various reactions.

  and the desired compound is contaminated by the byproducts thus formed. Purification of the product

  final process requires complex operations and can not be

  only at the expense of high losses of substance.

  According to another known method, the compounds of general formula (1) are produced by reacting

  2-Formyl-quinoxaline-1,4-dioxide or the corresponding dialkyl-acetal

  laying, with a Schiff base (Hungarian patent application

171 738).

  The Applicant has now highlighted that the

  compounds of the general formula (I) can be prepared by

  economic and with an excellent degree of purity, by

  hydration of a 2-hydroxymethyl-quinoxaline-1,4-derivative

  dioxide which corresponds to the general formula (II) below:

O OH

  ## STR1 ## wherein:

A is as defined above.

  Dehydration can be done in two different ways.

  fers: either thermally, that is to say by heating the compound of general formula (II), or with the aid of an agent

dehydration.

  When carrying out the dehydration under thermal conditions, it is preferable to heat the suspension of the compound of general formula (II) in an indifferent solvent,

  until no more water is separated. As an indif-

  it is preferable to use water, alcohols

  aliphatics such as isopropanol or butanol, hydrocarbons

  aromatic compounds such as toluene or xylene. The reaction is preferably carried out at the boiling point of the solvent,

  generally at a temperature between 40 and 150 C.

  When a water-immiscible organic solvent is used, the thermal dehydration can be carried out by continuously removing the water resulting from the system, for example, in the form of an azeotrope. In this way, the reaction can also be followed. When dehydration is performed according to the other

  method, the dehydrating agents are generally

  for this purpose (eg polyphosphoric acid,

  sulfuric acid, calcium chloride, etc.).

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

N CH = Q

& NX v - (III) in which:

  Q represents an oxygen atom or two alkoxy groups;

  each containing 1 to 4 carbon atoms, with a carboxylic hydrazide of the general formula (IV) below:

A-NH (IV)

  wherein A is as defined above.

  As the dehydration of the compounds of the general formula

  (II) is carried out rapidly, the formation of secondary products

  is avoided and the compounds of the general formula (I) can

  can be obtained almost quantitatively, in an in-

  from the economic point of view.

  In addition to the foregoing provisions, the invention

  still takes other dispositons, which will emerge from the

following description.

  The invention will be better understood using the complement

  description which will follow, which refers to examples of

  implementation of the method which is the subject of the present invention.

  It should be understood, however, that these examples

  implementation, are given solely for the purpose of

  tion of the subject-matter of the invention, of which they do not constitute

no way a limitation.

  Preparation of starting substances of general formula (I):

  0-1 mole of 2-formyl-quinoxaline-1,4-

  dissolved in water or dimethylformamide, with 0.1 mol of a compound of general formula (IV) in the presence of

  2 drops of concentrated hydrochloric acid or piperidine.

  The product that is deposited is separated by filtration, washed at

water and dried.

Example 1

  Preparation of 2- (methoxycarbonyl-hydrazono-methylene) -quinoline

xaline-1,4-dioxide

  28.0 g (0.1 mol) of 2- (methoxycarbonyl)

  hydrazino) -α-hydroxymethyl] quinoxaline-1,4-dioxide with ml of water and the mixture is boiled for one hour with stirring. The system is then cooled, the product that is deposited is separated by filtration and washed at

  the water. 25.4 g (98%) of the desired product are obtained.

Mp = 257-258C.

Example 2

  Preparation of 2- (3 ', 4', 5 ', - trimethoxybenzoylhydrazonomethyl)

ene) quinoxaline-1,4-dioxide

  41.6 g (0.1 mole) of 2-ú <-113,4,5-trimethoxy are dehydrated.

  benzoyl-hydrazino- ("-hydroxymethyl) -quinoxaline-1,4-dioxide in 250 ml of isopropanol in the presence of 2 drops of sulfuric acid at 50-60 ° C. with stirring. The product which is deposited is separated by filtration and washed to give 39.0 g (98%) of the compound.

research. Mp = 255-256 C.

Example 3

  Preparation of 2- (cyanoacetyl-hydrazono-methylene) -quinoxaline

1,4-dioxide

  27.2 g (0.1 mole) of 2- [o] -cyanoacetylhydrazino- (O (-

  -hydroxymethyl) -quinoxaline-1,4-dioxide are suspended in 200 ml of toluene and the reaction mixture is maintained

  at 120 C for one hour. It is then cooled and the

  duit that is deposited is separated by filtration. We obtain

  26.0 g (97%) of the title compound. Mp = 244-245C.

Example 4

  Preparation of 2- (3 ', 4', 5'-trintetboxybenzoyl-hydrazono-methyl)

  eene) -quinoxaline-1,4-dioxide 4.16 g (0.01 mol) of 2- [ú <D-3 ', 4', 5'-tri are mixed

  methoxybexoyl-hydrazino-5-hydroxymethyl-quinoxaline-1,4-

  dioxide, with 40 g of polyphosphoric acid and allowed to react at 25 ° C. for 3 hours; the reaction mixture is then poured into cold 10% sodium hydroxide solution. The precipitate which is deposited is separated by filtration and washed with water until neutral. We get 3d, 6 g (97%)

  of the desired product. Mp = 256-256.5 ° C.

  The compounds listed in the following table are prepared according to the methods described in

previous examples.

W r '> bJ i.-

L o TABLE L o

Example * nr e Temperature P.f.

  tD O.Jmilieu the example) C (C) Yield

1 example)

  -N (H-CO-NiH 2) 1 90-95 288-89 91 6 -OH isoprupanol 2 50 245-49 99 7 -NIC / N} / - NH 2 water 1 80-90 286- & 7 93 8 -Ni-C 6 water 1 90-95 247-48 e 9 '-NHlaurin; water 1 80--90 233-34 95 -fH-CO-C615 water 1 90-95 256-57 98 11' NH-CO-naphthyl-1 isopropanol 2 60 247-48 97 12 -NH-CO-C615-p-01 water 1 5055 307-08 98 13 -NH-CO-C 6H-p-m2 water 1 80-85 291-92 95 14 -NH-CO pyridyl 3 methanol 2 50 270-71 94 -NH-UGO-piridyl-butt; 1i0i 2 50 268-69 96 16 water 16 -NH-CO-C6115-P-Cl water1 50 273-74 97 17 -NiH-O 1-2xylene 120 261-62 95 1 water n 1. -NH-C0-C H5-2-141h water L & 60 289-30 94 i9 -NH-COfur r1-5-N02 methanol 2 50 265 95 ## STR2 ## ## EQU1 ## -NH; -C0- / cH2 /, - C5i1% i2so pun. D -NH-CO-C6H15-xylene-1H-O-piperid: 1-4 isDpropanoDl-14H-CO-nitro-2-yl) -2H-heptanoel methanol-1H- C113 water -Nlf-C4! 9 water 411-c M water -benzilo. toluene -Iil "- / 5C / 2-0 xylene -HII-CS-i; 1] [, water

çII-2 # 0-Cl / 0 2 water ..

01! 2

method (n of

l1'exemple)

  2- 3. Temperature (oC) o 0.o '-95' -95 -60 -90 -95 -95 OW (o, e)

237-38

j - I

-I7 -7.

241-42

230-31

252-53

258-39

292-93

Yield ns 9o go S.1 w v> 1 w o Ln

Example,

  i; As is apparent from the foregoing, the invention is in no way limited to those of its modes of implementation, of realization and of application which have just been described.

  more explicitly; on the contrary, it embraces all

  variants that may come to the mind of the technician in the field, without departing from the scope or scope,

the present invention.

Claims (7)

  1. Process for the preparation of 2-methylene derivatives   quinoxaline-1,4-dioxide represented by the following general formula (1): embedded image in which: OA represents an amino or hydroxyl group, or a group of general formula -NH-COOR1, in which R1 represents a C1-C4 alkyl group;   or a group of general formula -NH-CX-NH2, where X is   has an oxygen or sulfur atom or a group of formula -NH-C (= NH) -NH2; or a group of the general formula -NH-R2, wherein R2 is C1-C6 alkyl, phenyl, benzyl, hydroxyl or hydroxy- (C2-C4) alkyl;   or a group of general formula -NH-CO-R3, where R3 represents   C1-C20 alkyl radical, phenyb optionally   replaced by one, two or more identical or different substituents   fers, selected from the group consisting of amino, nitro-, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen; piperidyl, pyridyl and furyl groups,   nitrofuryl, pyrazinyl, pyrimidyl, 1,2,4-triazinyl, o, w-   diphenyl-α-hydroxymethyl, cyanomethyl, halomethyl or hydroxymethyl may also represent a group   naphthyl, hydroxynaphthyl or phenylalkyl, which process is   characterized in that a compound of the general formula (II) is dehydrated hereinafter N CH-NH-A 1l   in which A is as described above.   2. Method according to claim 1, characterized in that the reaction is carried out in an indifferent solvent, at boiling point of it.   3. Process according to claim 2, characterized in that water, aliphatic alcohols or   aromatic hydrocarbons as an indifferent solvent.   4. Process according to claim 1, characterized in that   that the reaction is carried out in the presence of a dehydrating agent dratant.   5. Method according to claim 4, characterized in that   that polyphosphoric acid, sulphate   furic acid or calcium chloride as a dehydrating agent   tion. 6. As new industrial commodities used   for the preparation of the 2-methylene quinoxaline derivatives   -1,4-dioxides of general formula (I) using   the process according to any one of claims 1 to 5,   the new derivatives of 2-hydroxymethyl-quinoxaline-1,4-di-   oxide characterized in that they meet the general formula (II) according to claim 1.   7. Process for preparing new derivatives of 2-   hydroxymethyl-quinoxaline-1,4-dioxide according to claim   6, characterized in that a derivative of 2- is reacted   methylene-quinoxaline-1,4-dioxide which corresponds to the general formula (III) below: or N and -Q N (III) in which:   Q represents an oxygen atom or two alkoxy groups;   each containing 1 to 4 carbon atoms, with a carboxylic hydrazide of the following general formula (IV): A-NH2   wherein A is as defined in claim 1.