CH620911A5 - Process for the preparation of derivatives of quinoxaline 1,4-dioxide - Google Patents

Description

The subject of the invention is a process for preparing derivatives of quinoxaline 1,4-dioxide and an application of this process. More precisely, it is a process for the preparation of N!, N4-di-oxides of 2-quinoxalinylmethylenecarbazates substituted or not in position 3, and these compounds have antibacterial and veterinary properties.

Ongoing efforts to synthesize and discover new compounds that are active against bacteria and bt protozoa that act as growth promoters in pigs and poultry have resulted over the years in the development of a variety of organic compounds prototypes grouping numerous homologs of 1,4-quinoxaline dioxides: “J. Chem. Soc. ”, 2052 (1956); "Helv. Chim. Acta ”, 29, 95 (1946); "Tetrahydron letters", 3253 (1965); "J. Org. Chem. ", 31.4067 (1966); "Angew. Chem. Boarding school. Edit. ”, 8, 596 (1969); US patents Nos. 3679679; 3728345; 3753987; 3763162; 3767657; 3803145; 3818007; 3433871; 3371090; and Belgian Patent No. 721728.

In US Patent No. 3,389,326, a process is described for the preparation of N1, N4-dioxides of 2-quinoxalinylmethylene carbazate substituted in position 3, in which a 2-bis (halogeno) methylquinoxaline derivative is reacted with hydroxylamine or an ester of hydrazinocarboxylic acid in the presence of a primary or secondary amine and water.

The process according to the present invention for the preparation of a quinoxalinecarbazate 1,4-dioxide having the formula

O

■ ch = nnhcooch

O

in which R is hydrogen or a C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C7 alkanoyl, benzoyl or

Z * 1

CONT in which Ri and R2 are independently of the hydro- \ r2

C1 or C6 alkyl, C1 to C6 hydroxyalkyl or C1 to C6 aminoalkyl gene or radicals, is characterized in that a compound of formula O is reacted

*

O

in which R has the meaning already given and X is a chlorine or bromine atom, with one to two equivalents of an alkali metal carbonate and one to two equivalents of a hydrazine of formula

R "NHNHCOOCH3 (III)

wherein R "is CF3SO2, CF3CH2SO2, CH3SO2 or CH3C6H4SO2, in a solvent inert to the reaction and at a temperature between 75 and 85 ° C. Then, normally, the carbazate formed is isolated.

The compounds of formula I, in which R has a meaning other than hydrogen, C1-C6 alkyl and CONHCH3, are new compounds.

Preferably, a carbazate having the formula is prepared

*

5

10

15

20

25

30

35

40

45

50

55

60

65

3

620 911

wherein R 'is a C1-C6 hydroxyalkyl, alkanoyl radical

/ Rl in C2 to C7, benzoyl or CON ^, in which Ri and R2 are inde-

* 2

depending on hydrogen or C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 aminoalkyl, provided that when one of the symbols Ri and R2 is a methyl radical, the other is not hydrogen.

The process according to the invention which comprises the reaction of an N!, N4-dioxide of a 2-halomethylquinoxaline in a solvent inert with respect to the reaction and in the presence of an alkali metal carbonate , for example anhydrous potassium carbonate, with a hydrazine substituted by an alkylsulfonyl or arylsulfonyl radical, for example N-methoxycarbonyl-N'-trifylhydra-zine, can be represented by the following reaction scheme.

k2co3

cfo 1 J

so?

t ^

*

nh

1

nh

'CH2x

1

cooch iii

0 *

* = nniko2CH3 + cf3so ^ k +

According to a preferred embodiment of the process of the invention, an N ^ W-dioxide of a 2-halomethylquinoxaline, preferably the compound 2-bromomethylquinoxaline, is heated to a temperature between 75 and 85 ° C within of a solvent inert to the reaction, such as acetonitrile, with one to two equivalents of N-methoxycarbonyl-N'-trifylhydrazine in the presence of one to two equivalents of anhydrous potassium carbonate up to the reaction is substantially complete (approximately 1 to 2 h). Preferably, the reaction is carried out using equilibrium amounts of potassium carbonate and N-methoxycarbonyl-N'-trifylhydrazine. 50

The process according to the invention can be widely applied to the preparation of N ^ N ^ 2-quinoxalinylmethylenecar-bazates dioxide substituted in position 3 by an extended group of substituents. The 2-halomethylquinoxaline derivatives can be prepared more easily and more economically compared to the corresponding compounds 55 2-bis (halo) methylquinoxaline described in US Patent No. 3,839,326.

The starting substances, 2-halomethylquinoxalines, can be prepared by the general methods described in patent 60 USA No. 3753987, according to "J. Chem. Soc. ”, 2052 (1956) and“ Chemis-try of Heterocyclic Compounds ”, 940 (1967). The halogen can be chlorine or bromine. The preferred intermediates are 2-bromomethylquinoxaline compounds. These compounds can be prepared from 1,4-dioxides of 2-methylquinox-65 aline by the methods described in "J. Chem. Soc. ”, 322 (1943), and US Pat. Nos. 3474097, 3553208, 3660398 and British Patent No. 1215815.

N-methoxycarbonyl-N'-trifylhydrazine and N-methoxy-carbonyl-N'-tresylhydrazine are new compounds and can be prepared according to the general procedure described in "J. Org. Chem. ”, 40, 3450 (1975). For example, N-methoxycarbonyl-N'-trifylhydrazine can be prepared by adding a solution of trifylic anhydride (trifluoromethylsulfonic acid anhydride) in methylene chloride dropwise to a solution in methylene chloride. the equimolar amount of methyl carbazate, containing triethylamine in slight molar excess, at a temperature of - 78 ° C. The resulting mixture is allowed to come to room temperature, and stirred for about 16 h. The mixture is concentrated in vacuo at room temperature, then the residue is extracted with several portions of ether. The ether extract is then concentrated in vacuo at room temperature leaving a waxy solid which can be used directly in the subsequent reaction without further purification. Alternatively, the omission of triethylamine and the use of two equivalents of methyl carbonate gives the crystalline product.

To carry out in practice the process according to the invention, a suspension of the N ^ W-2-halomethylquinoxaline dioxide is heated in a solvent inert to the reaction, such as acetonitrile, with stirring at a temperature between 75 and 85 ° C, preferably at reflux temperature. One to two molar equivalents, preferably in a small molar excess, of pulverized anhydrous potassium carbonate and N-methoxy-carbonyl-N'-trifylhydrazine are then added to the suspension at one time. In the case where there is separation of a solid after a few minutes, heating is continued for 30 to 40 minutes, and the solid is then collected and dried. If there is no precipitation of a solid, we continue to heat; thin-layer chromatography indicates the absence of the 3-substituted 2-halomethylquinoxaline di-N-oxide. The reaction mixture is filtered, the filtrate is concentrated under vacuum at room temperature, and an amber oil is obtained which gives crystals from absolute ethanol.

The quinoxaline derivatives prepared by the process according to the invention exhibit strong antibacterial effects against Gram positive and Gram negative bacteria. Thanks to this activity, these compounds are valid as industrial antimicrobial agents, for example for the treatment of water, the fight against silt, the conservation of paints and the conservation of wood as well as in topical application as a disinfectant.

The compounds prepared by the process according to the invention can be used in veterinary medicine for the treatment of infections in animals. For example, when it is an oral administration, doses ranging from 1 mg to 60 mg per kilogram of body weight can be used. In the case of poultry and domestic animals, a compound is administered suitably by mixing it with food or in the form of a dilute solution or suspension, for example in the form of a 0.1% solution for the beverage.

The compounds prepared by the method of the invention may be administered preferably by subcutaneous or intramuscular injection at a dosage of from about 10 to 100 mg per kilogram of body weight. The vehicles which can be used during the parenteral injection can be aqueous such as water or isotonic saline or dextrose solutions, or they can be non-aqueous, for example fatty oils of vegetable origin, glycerol, propylene glycol and sorbitol.

The compounds prepared by the process according to the invention are useful for promoting the increase in weight and food consumption in animals, for example poultry and pigs. The addition of a small amount of one or more quinoxaline di-N-oxides according to the invention to food or beverage solutions, representing approximately 0.1 to 100 mg per kg of body weight per day for the greater fraction of the active growth period of the animal results in an acceleration of the growth rate and the food yield.

620 911

4

keep quiet (the number of kilos of food necessary for the production of one kilo of weight).

The following examples illustrate the invention.

Example 1:

N-Methoxycarbonyl-N'-trifluormethylsulfonylhydrazine.

A solution of 35.4 mmol of trifluoromethylsulphonic anhydride in 40 ml of methylene chloride was added dropwise to a solution of 35.5 mmol of methyl carbazate and 38.9 mmol of triethylamine in 200 ml of methylene chloride with stirring at -78 ° C. The resulting mixture was allowed to come to room temperature while being stirred for 16 h. The mixture was concentrated in vacuo at room temperature, and the residue was extracted with three times 100 ml of ether under reflux. The ethereal combined extract was concentrated in vacuo at room temperature, and 5.26 g of a waxy solid was obtained, yield about 67%. The NMR spectrum of the crude product corresponded to that of the expected product, contaminated with the triethylamine salt of trifluoromethylsulfonic acid. This raw material was used directly without further purification in the following reactions.

336 mmol of methyl carbazate were added over a period of 20 min with stirring to a solution of 178 mmol of trifluoromethylsulfonic acid anhydride in 2000 ml of methylene chloride in a nitrogen atmosphere at -78 ° C. allowed the resulting solution to return to room temperature, and stirred for 20 h. The resulting thick white solution was concentrated in vacuo at room temperature leaving a white solid. This material was triturated with 450 ml of diethyl ether and collected; the methylcarbazate salt of triflic acid (trifluoromethylsulfonic) was obtained. The ethereal filtrate was concentrated in vacuo at room temperature to provide a white solid which was triturated with hexane, collected, washed with hexane and dried to give the product as a white crystalline solid, yield 84% , pf 107-109 ° C.

Analysis for C3H5O4N2F3S:

Calculated; C 16.21 H 2.25 N 12.61%

Find; C 16.24 H 2.20 N 12.68%

Example 2:

N-Methoxycarbonyl-N'-veryylhydrazine.

The method of Example 1 can be repeated using tresyl chloride (2,2,2-trifluoroethylsulphonic acid chloride) in place of trifluoromethylsulfonic anhydride.

Example 3:

N-Methoxycarbonyl-N'-methanesulfonylhydrazine.

0.02 mol of pyridine is added with stirring to a solution of 0.02 mol of methanesulfonyl chloride and 0.02 mol of methyl carbazate in 30 ml of chloroform. The resulting solution is heated to reflux for about 4 h, then stirred overnight at room temperature. The reaction mixture is concentrated in vacuo at room temperature, and a white oil is obtained. The concentration of a solution of the oil in ethyl acetate gives 4.86 g of a white solid. This white solid is chromatographed on a column containing 300 g of silica gel 60 (E. Merck, Darmstadt, RFA) and developed with a mixture of chloroform / methanol (98/2), and the pure product is obtained under white solid form (2.5 g, 74%), mp 108-109 ° C.

Analysis for C3H8O4N2S:

Calculated: C 21.45 H 4.80 N 16.67%

Found: C 22.13 H 4.89 N 16.78%

Example 4:

N-Methoxycarbonyl-N'-tosylhydrazine.

0.3 mol of pyridine is added with stirring to a solution of

0.3 mol of p-toluenesulfonyl chloride and 0.3 mol of methyl carbazate in 500 ml of chloroform. The resulting solution is heated to reflux for about 3 h, then stirred overnight at room temperature. The reaction mixture is poured into 300 ml of 1 N-hydrochloric acid with stirring, and then diluted with 900 ml of water. The suspension obtained is filtered, and the material is dried to obtain a white crystalline solid (52.8 g, 72%), m.p. 149-150 ° C.

Analysis for C9H12O4N2S:

Calculated: C 44.30 H 4.96 NI 1.48%

Found: C 44.12 H 4.88 N 11.61%

Example 5:

N1, N4-3- (2-quinoxalinylmethylene) methyl carbazate.

A suspension of 6 mmol of N 2, N 4-2-bromomethylquinoxaline dioxide in 70 ml of acetonitrile is heated to reflux and with stirring. 6.52 mmol of pulverized anhydrous potassium carbonate and 6.6 mmol of N-methoxycarbonyl-N'-trifylhydrazine are added all at once to the suspension. During a few minutes, the nascent solution gives rise to the separation of a solid. The mixture is heated at reflux for a total of 1.5 h. The solid is collected and washed successively with twice 20 ml of acetonitrile and ether, and dried to constant weight. 1.89 g of a dark yellow solid are obtained, yield about 100%. The crude product is suspended in 50 ml of a 5% solution of sodium bicarbonate for 30 min, collected, washed with water and recrystallization is carried out from 30 ml of acetic acid. The recrystallized product is washed with twice 20 ml of a 1/1 mixture of acetic acid / ether and then with twice 20 ml of ether, and the product is obtained in the form of a powder. crystalline yellow, pf 243 ° C (USA patent N ° 3371090).

Example 6:

The method of Example 5 can be repeated using the N ^ N ^ 3-substituted 2-chloromethylquinoxaline dioxides suitable for obtaining compounds having comparable antibacterial activities, and corresponding to the formula

= nnhcooch3

O

r

CONH2

CONHCH2CHOHCH3

CONHCH2CH3

CON (CH3) 2

CONHCH2CH2CH3

CONH-n-C4H9

CONHCH2CH2NH2

CH2CH2OH

CHOHCH2CH3

COCH2CH3

COCH2CH2CH3

ch3

C2H5 C4H9

5

10

15

20

25

30

35

.40

45

50

55

60

65

5

620 911

Example 7:

The method of Example 5 is repeated using the N ^ N4-dioxides of 2-bromomethylquinoxaline substituted in 3 appropriate to obtain compounds having the following formula:

O

20

R

M.p. (° C)

% yield

CH2OH

208-210 (dec.)

27

CH (OH) CH3

145 (dec.)

12

COC6HS

220 (dec.)

57

CONHCH3 *

244 (dec.)

9

COCH3

238 (dec.)

5

»USA patent N ° 3839326.

Table I illustrates the antibacterial spectrum of the compounds unknown to date. The tests were carried out by preparing tubes of a nutritive culture medium containing gradually increasing concentrations of each compound, then inoculating the cultures with the specified microorganism. The minimum inhibition concentration indicated in Table I represents the minimum concentration of the compound, in micrograms per milliliter, at which the microorganism no longer grows. The tests were carried out under standardized conditions, described in “Proc. Soc. Exp. Biol. & Med. ", 122, 1107 (1966).

5 •

Table I

R

Organization

SC O

SE? U

1

rn

SC 0

X

0

X u

1

m

X

VO

8

u

1

m

SC

8

u

1

Staphylococcus aureus

01A005

5.12

3.12

<0.39

0.78

01A106

3.12

3.12

<0.39

0.78

Escherichia coli

51A203

3.12

6.25

6.25

1.56

51A266

0.78

6.25

6.25

1.56

51A218

3.12

6.25

6.25

6.25

Streptococcus pyogenes

020203

<0.39

0.78

<0.39

<0.39

Streptococcus equi

021001

<0.39

1.56

<0.39

<0.39

Salmonella typhimurium

58D001

3.12

12.5

25

3.12

58D011

1.56

12.5

50

3.12

Salmonella dublin

58U001

3.12

6.25

12.5

3.12

Salmonella cholerae suis

58B242

3.12

6.25

12.5

3.12

Pasteurella multocida

59A001

<0.39

3.12

6.25

0.78

59A006

<0.39

-

-

-

R

Claims (7)

620 911 2. Method according to claim 1, characterized in that potassium carbonate is used as the alkali metal carbonate. 2 CLAIMS 1. Process for the preparation of a carbazate of formula O S ^ NCH = nnhcooch o in which R is hydrogen or a C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C7 alkanoyl, benzoyl or —C (0) NRiR2, in which Ri and R2 are, independently hydrogen or C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or C 1 -C 6 aminoalkyl radicals, characterized in that a compound of formula is reacted O * o in which X is a chlorine or bromine atom, with one to two equivalents of an alkali metal carbonate and one to two equivalents of a hydrazine of formula R "NHNHCOOCH3 (III) in which R "is a radical CF3SO2—, CF3CH2SO2 -, CH3SO2— or CH3C6H4SO2—, in a solvent inert to the reaction and at a temperature between 75 and 85 ° C. 3. Method according to claim 1 or 2, characterized in that one uses as inert solvent vis-à-vis the reaction of acetonitrile. 4. Method according to one of claims 1 to 3, characterized in that a compound of formula II is used in which X represents a bromine atom. 5. Application of the method according to claim 1 to a hydrazine having the formula R "NHNHCOOCH3 (III) in which R "represents a radical CF3SO2 or CF3CH2SO2, obtained by reaction of methyl carbazate with an acid anhydride or a corresponding sulfonyl halide. 6. Application according to claim 5, characterized in that methyl carbazate is reacted with trifluoromethylsulfonic acid anhydride in an appropriate solvent at a reduced temperature. 7. Use according to claim 5, characterized in that methyl carbazate is reacted with tresyl chloride (2,2,2-trifhioroethylsulfonic chloride) in an appropriate solvent at a reduced temperature.