DK142497B - Process for the preparation of methyl 3- (2-quinoxalinylmethylene) carbazate-N1, N4-dioxide compounds. - Google Patents

Description

(¾) (11) PUBLICATION 142497 DENMARK (5 ”Cl 'c 07 D 241/52 (21) Application No. 2 ^ 07/77 (22) Filed on Jub. J 977 (24) Lebedeg 1 · Jun 1977 (44) The application presented and the petition filed on the 10th of January, 1 1-9 80

DIRECTORATE OF

PATENT AND TRADEMARKETS (30) Priority beget * f «on

15. jun. 1976, 696263, US

OD PFIZER INC., 255 East 42nd Street, New York, New York, US.

(72) Inventor: Leonard J. Czuba, 31 Neptune Court * New London, Connecticut, US. .-: (74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Engineering Company.

(64) Process for the preparation of methyl 2- (2-quinoxalinylmethylene) carbaz at-N1, N4-dioxide compounds. r

The invention relates to a particular process for the preparation of methyl 3- (2-quinoxalinylmethylene) carbazate-N 2, N 2 -dioxide compounds of the general formula I set forth in claim 1, which have antibacterial and veterinary properties.

Continuing efforts to find novel compounds that are active against bacteria and protozoa and act as growth promoters in pigs and poultry have over the years led to the development of a variety of organic prototype compounds, including numerous analogous quinoxaline-1 4-Dioxides: J. Chem. Soc., 2,22497,2052 (1956); Helv. Chim. Acta., 29, 95 (1946); Tetrahedron Letters, 3253 (1965); J. Org. Chem., 31, 4067 (1966); Angew. Chem. Internat. Edit., 8, 596 (1969); U.S. Patents Nos. 3,679,679, 3,728,345, 3,773,987, 3,763,162, 3,767,657, 3,883,145, 3,818,007, 3,433,871, and 3,371,090, and Belgian Patent 721,728.

A process for the preparation of 3-substituted (2-quinoxa-linylmethylene) carbazate-N ^, ΝΝ-dioxides is described in U.S. Patent No. 3,839,326, according to which a 2-bis (halogen) methylquinoxa-lin derivative react with hydroxylamine or a suitable hydrazino-carboxylic acid ester in the presence of a primary or secondary amine and water.

The process according to the invention is characterized by the characterizing part of claim 1.

The compounds of formula I wherein R is different from hydrogen, alkyl of 1-6 carbon atoms and CONHCH3 are novel.

The process of the invention can be used to prepare methyl 3- (2-quinoxalinylmethylene) carbazate-N 2, N 2 -di oxide compound having a variety of 3-substituents on the quinoxaline nucleus. The 2-halo methylquinoxaline derivatives which serve as starting materials for the process of the invention are more readily and economically prepared than the corresponding 2-bis (halogen) methylquinoxaline compounds used as starting materials in the process of U.S. Patent No. 3,839,326.

The process of the invention can be illustrated by the scheme of the following reaction in which anhydrous potassium carbonate is used as alkali metal carbonate and as hydrazine of formula III N-methoxycarbonyl-N'-trifylhydrazine is used: 3 H2497 oo-F3 t T2 SO2 K2CO3 + NH W. Jk \ I '+ JX sX nh ψ CH2X ioa ^ so ^ c * 4, COOCH, j ^ o III i

II

wherein R and X are as defined in claim 1.

In a preferred embodiment of the process of the invention, a 2-halo methylquinoxaline N 2, N 2 dioxide, preferably the 2-bromomethyl quinoxaline compound, is heated to a temperature of 75-85 ° C in a reaction inert solvent such as acetonitrile. equivalents of N-methoxycarbonyl-N'-trifylhydrazine in the presence of one or two equivalents of anhydrous potassium carbonate until the reaction is substantially complete (about 1-2 hours). Preferably, the reaction is carried out with an equimolar amount of potassium carbonate and N-methoxycarbonyl-N'-trifylhydrazine.

The 2-halo-methylquinoxaline starting compounds can be prepared by the general methods described in DS patent specification no.

3 753 987, J. Chem. Soc., 2052 (1956) and Chemistry of Heterocyclic Compounds, 940 (1967). The halogen may be chlorine or bromine. The preferred intermediates are the 2-bromomethylquinoxaline compounds which facilitate the reaction and provide maximum yield. These compounds are prepared from the 2-methylquinoxaline-1,4-dioxides by the methods described in J. Chem. Soc., 322 (1943), U.S. Patent Nos. 3,474,097, 3,553,208 and 3,660,398, and British Patent No. 1,215,815.

N-methoxycarbonyl-N 3 -triylhydrazine, N-methoxycarbonyl-N'-tresylhydrazine, N-methoxycarbonyl-N'-methanesulfony Hydrazine and N-methoxycarbonyl-N '-tosylhydrazine are novel compounds which are the subject of Danish patent application no. 2972/78. They can be prepared by the general procedure described in J. Org. Chem., 40, 3450 (1975). By way of example, N-methoxycarbonyl-N'-trifylhydrazine is prepared by dropwise addition of a solution of triflinic anhydride in methylene chloride to a methylene chloride solution containing an equimolar amount of methylcarbazate and a slight molar excess of triethylamine at -78 ° C. allowed to warm to room temperature and stirred for about 16 hours. The mixture is concentrated under vacuum at room temperature and then the residue is extracted with several portions of ether. The ether extract is concentrated under vacuum at room temperature to a waxy solid which is used directly in the subsequent reaction without further purification. Alternatively, the removal of triethylamine and the use of two equivalents of methyl carbazate give the crystalline product.

In carrying out the process of the invention, a "1 4 * suspension of the 2-halo methylquinoxaline-N, N-dioxide in a reaction-inert solvent such as acetonitrile is heated under stirring at a temperature of 75-85 ° C, preferably at reflux temperature. molar equivalents, preferably a slight molar excess, of anhydrous powdered potassium carbonate and N-methoxycarbonyl-N'-trifylhydrazine are added to the suspension in one portion, in the case of a solid being separated within a few minutes, heating is continued for 30-40 Where no solid is separated, heating is continued until thin layer chromatography indicates the absence of the 3-substituted 2- 14 halo methylquinoxaline-N, N-dioxide. The reaction mixture is filtered and the filtrate concentrated under vacuum at room temperature to give an amber oil which crystallizes from absolute ethanol.

The quinoxaline derivatives prepared by the process of the invention show strong antibacterial effects against Gram-positive and Gram-negative bacteria. As a result of this activity, the compounds are useful as industrial antimicrobial agents, e.g. for water treatment, slime control, paint preservation and wood preservation, as well as for topical application as disinfectants.

U2497 5

Furthermore, the compounds prepared by the process of the invention are useful in veterinary medicine for treating infections in animals. For oral administration, dosages of 1 to 60 mg / kg body weight may be used. In the case of poultry and molluscs, a compound is conveniently administered by mixing with feed or as a diluted solution or suspension, for example a 0.1 percent solution, for drinking purposes.

The compounds of the process according to the invention are preferably administered by subcutaneous or intramuscular injection at a dose of from about 10 to about 100 mg / kg body weight. Media suitable for parenteral injection may be either aqueous such as water, isotonic saline and isotonic dextrose, or non-aqueous such as vegetable oils, glycerol, propylene glycol and sorbitol.

The compounds of the process according to the invention are useful for promoting the growth and feeding of animals, e.g. poultry and pigs. The addition of one or more of the quinoxaline N1, Ν 2 -dioxide compounds described herein to feed or beverage solution at a low level of 0.1 - 100 mg / kg body weight per day. day over a greater portion of the animal's active growth period results in an acceleration of the growth rate and improves feed efficiency (decreases the number of kg of feed required to produce 1 kg of growth).

The following examples serve to illustrate further the preparation of the novel intermediates of formula III and the preparation of the final products by the process of the invention.

EXAMPLE I

N-Methoxycarbonyl-N1-trifylhydrazine

Triflic anhydride (55 »4 mmol) in methyl en chloride (40 ml) was added dropwise to a solution of methyl carbazate (55.5 mmol) and triethylamine (58.9 mmol) in methylene chloride (200 ml) Ted -78 ° C stirring. One resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated at room temperature under vacuum and the residue was extracted with reflux ether (3 100 ml). Bone combined ethereal extract was concentrated under vacuum at room temperature to give a waxy solid (5.26 g, about 67 $). The NMR spectrum of the crude product was consistent with the expected product contaminated with the triethylamine salt of triflinic acid. Bet raw material was used directly for subsequent reactions without further purification.

Methyl carbazate (336 mmol) was added over 20 minutes with stirring to a solution of triflinic anhydride (178 mmol) in methylene chloride (2000 ml) under a nitrogen atmosphere at -78 ° C.

Bone resulting solution was allowed to warm to room temperature and stirred for 20 hours. Bone resulting thick white suspension was concentrated under vacuum at room temperature to give a white solid. Better material was triturated with diethyl ether (450 ml) and collected to give the methyl carbazate salt of triflinic acid. The biethyl ether filtrate was concentrated under vacuum at room temperature to give 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%), mp: 107 - 109 ° 0.

Analysis:

Calcd. For C 21 O N 2 S: C 16.21 - H 2.25 - N 12.61

Found: C 16.24 - H 2.20 - N 12.68.

EXAMPLE II

7 142497 N-Methoxycarbonyl-N1-tresylhydrazine

The procedure of Example I is repeated using triethyl chloride instead of triflinic anhydride.

EXAMPLE III

N-Me thoxy carbonyl-N * -methanesulfonylhydrazine

Pyrldine (0.02 mol) was added with stirring to a solution of methanesulfonyl chloride (0.02 mol) and methylcarbazate (0.02 mol) in chloroform (30 ml). The resulting solution was heated to reflux for about 4 hours and then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum at room temperature to give a white oil. Concentration of an ethyl acetate solution of the oil gave a white solid (4.86 g). Light white solid was chromatographed on a ......

sea; jelly containing 300 g of silica gel 60 (sold by E. Merck,

Larmstadt, Federal Republic of Germany) and developed with chloroform / methanol (98: 2) to give the pure product as a white solid (2.5 g, 74 #), m.p. 108 - 109 ° C.

Analysis:

Calculated for C C ^H₂O ^NgS: C 21.45 - H 4.80 - N 16.67

Found: C 22.13 - H 4.89 - N 16.78.

EXAMPLE IV

N-methoxycarbonyl-N '-tosylhydrazin

Pyridine (0.3 mole) was added with stirring to a solution of p-toluenesulfonyl chloride (0.3 mole) and methylcarbazate (0.3 mole) in chloroform (500 ml), until the resulting solution was heated to reflux for about 3 hours and then stirred overnight at room temperature. The reaction mixture was poured into 1N hydrochloric acid (300 ml) with stirring and then diluted with water (900 ml).

The resulting suspension was filtered and the material dried to give a white crystalline solid (52.8 g, 72 $), m.p. 149 - 150 ° 0.

Analysis:

Calcd for C 9 H 20 O 4 N 2 S: C 44.50 - H 4.96 - N 11.48 Bound: C 44.12 - H 4.88 - N 11.61.

EXAMPLE V

Methyl 3- (2-quinoxalinylmethylene) carbazate N, N

1 A

A suspension of 2-bromomethylquinoxaline-N, N-dioxide (6 mmol) in acetonitrile (70 ml) was heated to reflux with stirring. Powdered anhydrous potassium carbonate (6.52 mmol) and N-methoxycarbonyl-N'-trifylhydrazine (6.6 mmol) were added to the suspension in one portion. A solid is separated from the resulting solution within a few minutes. The mixture was heated to reflux for a total of 1.5 hours. The solid was collected, washed successively with two 20 ml portions of acetonitrile and two 20 ml portions of ether and dried to constant weight to give a dark yellow. solid (1.89 g, about 100 per cent). The crude product was suspended in 5 $ sodium bicarbonate solution (50 ml) for 30 minutes, collected, washed with water and then recrystallized from acetic acid (30 ml). The recrystallized product was washed with two 20 ml portions of acetic acid / ether (1: 1) and then with two 20 ml portions of ether to give the product as a yellow crystalline powder, mp: 243 ° C. (U.S. Pat.

3 571 090).

EXAMPLE 71 U 2497 9

The procedure of Example V is repeated using the appropriate 3-substituted 2-bromomethylquinoxaline-N, 1, Ν 2 -dioxide to obtain the following compounds of the formula:

FRV

Ψ 3 O 'R_ Melting point (° C) _ $ Yield CH2OH 208-210 (dec) 27 CH (OH) CH3 145 (dec) 12 COC6H5 220 (dec) 57 CONHCH2 * 244 (dec) 9 COCH3 258 (dec) dec.) 5 * US Patent 3,839,326

The following Table I shows the antibacterial spectra of the compounds not previously reported. These tests were carried out in the preparation of test tube containing nutrient liquid with gradually increasing concentrations of each compound and inoculation of the nutrient fluids with the specified organism.

The minimum inhibitory concentration given in Table I is the minimum concentration of the compound (in pg / ml), whereby the microorganism did not grow. The grafting was performed under standard conditions as described in Proc. Soc. Exp. Biol. & Med., 122, 1107 (1966).

10 142497

TABLE I

R

h A

ffi a i

ISLAND

O o O I

a a o o

w cn O.

D KO

and ui a

Organism_ __ u »

Staphylococcus aureus 01A005 5.12 3.12 <0.39 0.73 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 egui 021001 <0.39 1.56 <0.39 <0.39

Salmonella typhimurium 58D001 3.12 12.5 3.12 58D011 1.56 12.5 50 3.12

Salmonella Dublin 58U001 3.12 6.25 12.5 3.12

Salmonella choleraeusis 58B242 3.12 6.25 12.5 3.12

Pasteurella multocida 59A001 <0.39 3.12 6.25 0.78 59A002 <0.39 3.12 12.5 1.56 59A006 <0.39

Claims (2)

142497 11 A process for the preparation of methyl 3- (2-quinoxalinylmethylene) carbazate-N 2, Ν 2 -dioxide compounds of the general formula OXX / N₂S ^^CH = NNHCOOCH3O ... wherein R "means hydrogen, alkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl or - ^ 1 -CON ^ 5, -K2 1,2 where R and R are each independently hydrogen, alkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms or aminoalkyl of 1-6 carbon atoms, characterized in that a compound of formula o 'in' O ... II wherein R has the above meaning and X means chlorine or bromine, is reacted with 1-2 equivalents of an alkali metal carbonate and 1-2 equivalents of a hydrazine of the formula R "NHNHCOOCH3 ... III wherein Rw means CF2 SOg, CF ^ C ^ SOg, CH ^ SOg or CH ^ CgH ^ SC ^, in a reaction inert solvent at a temperature of 75 -85 ° C.