DE1091120B - Process for the preparation of substituted anthranilic acid amides - Google Patents

Description

Process for the preparation of substituted anthranilic acid amides The present invention relates to a process for the preparation of therapeutically valuable, substituted anthranilic acid amides of the general formula in which Ri and R, alkyl radicals, R, and R, hydrogen or alkyl radicals and R, hydrogen or one or more substituents, such as halogen, alkyl or alkoxy "groups. These new compounds are prepared by processes known per se, for example according to one of the following reactions: 1 mol of a substituted isatoic anhydride is reacted at 10 to 120 ° C. with 1 to 3 mol of a primary or secondary amine. The solvent used can be water, alcohols and other organic solvents such as dioxane, tetrahydrofuran, chloroform, carbon tetrachloride, ethylene chloride, benzene or toluene; however, it is also possible to dispense with the use of solvents. One uses 1 mol of a substituted anthramilic acid amide at 10 to NO'C either with 1 to 1.5 or with 2 to 3 mol of an alkylating compound in which R is equal to R, or in succession with 1 to 1.1 mol of two different compounds alkylating compounds. As alkylating compounds, for. B. dialkyl sulfates, haloalkyls, haloacetic acids or p-toluenesulfonic acid alkyl esters. The addition of 1 to 2 mol of a base, such as sodium hydroxide, potassium carbonate, pyridine or triethylamine, is advantageous, but not absolutely necessary. The reaction can also be carried out in a solvent such as water, alcohol or dioxane. 1 mol of a reactive derivative of a substituted anthranilic acid is reacted at 0 to 120 ° C. with 1 to 3 mol of a primary or secondary alkylamine.

As a reactive derivative of substituted anthranilic acid can one z. B. an ester, an acid halide, an acid azide or a symmetrical one or use mixed acid anhydride so that Y is e.g. B. an ester group, a May mean halogen, azido or acyloxy.

R denotes an alkyl radical or one after conversion by hydrogen substitutable radical. Such radicals are, for. B. the benzyl or carbobenzoxy radical, which can be removed again by catalytically excited hydrogen. In the Cases in which R4 in the end product obtained according to the invention is hydrogen should, namely, according to this procedure, the hydrogen after the reaction has taken place be introduced in order to avoid side reactions. So it has to be done with this implementation can be assumed from an anthranilic acid derivative that does not work on nitrogen Hydrogen is substituted.

If appropriate, 1 mol of a base is added to the reaction mixture so that hydrogen halide formed, for example when using the acid halide, is bound. Inorganic substances such as sodium hydroxide or potassium carbonate, tertiary amines or a second mole of the primary or secondary amine used in the reaction can be used as the base.

The reaction is expediently carried out in a solvent such as water, alcohol, dioxane, tetrahydrofuran, dimethylformamide, pyridine, chloroform or benzene. In this formula, Z represents halogen.

1 mole of a substituted o- halobenzamide is reacted with 1 to 5 moles of a primary or secondary, aliphatic amine at 50 to 300 ° C., advantageously with the addition of agents that split off hydrogen halide, such as copper powder, alkali carbonates or alkali amides. Suitable solvents are water, dioxane and high-boiling hydrocarbons such as toluene or xylene; however, it is not necessary to use a solvent. 1 mol of a substituted anthranilic acid amide, which still has at least 1 hydrogen atom on the nitrogen in the carbonamide group, is reacted with 1 to 1.5 mol of an alkylating compound. As an alkylating compound z. B. haloalkyls, dialkyl sulfates or alkyl p-toluenesulfonates. Expediently, 1 mol of an alkali metal or an alkali metal compound, such as sodium amide, sodium hydride or potassium carbonate, is allowed to act on the substituted anthranilic acid amide before the reaction with the alkylating compound. The reactions are carried out at 50 to 300.degree . C., hydrocarbons such as benzene, toluene, xylene or tetralin are used as solvents. In those cases in which R, in the end product is intended to mean hydrogen, the radical R, in the reaction product is used in a known manner, e.g. B. with catalytically excited hydrogen, replaced by hydrogen.

The substances obtained according to the invention are very strong antipyretic, anti-inflammatory and analgesic effects with very low toxicity. A particular advantage is the good solubility of their salts, especially theirs, in water Hydrochloride. Injection of the solutions does not cause irritation or tissue damage.

The superiority of the compounds over common antipyretic-anti-inflammatory drugs and over chemically related substances known from the literature can be seen from the following comparison: Substance TS 1 sw Anthranilic acid methylamide .... 3.2'C 4611/0 Anthranilic acid ethylamide ...... 2.2'C 45 0 / 'A N-ethylanthranilic acid ........ - - N, N-dimethylanthranilic acid ... - - N-methylanthranilic acid methyl amide ............... , ...... 5.0- C 800 /, 5-chloro-N-methylanthranilic acid- B methylamide ........ ....... 4.1'C 620/0 5-methyl-N-methylanthranil- acid methylamide ........... 5,4'C 690 /, Salicylamide .................. 2,2'C 401) /, Acetylsalicylic acid ............ 1.4'C 550/0 3,5-15ioxo-1,2-diphenyl- C 4-n-butyl-pyrazolidine ....... 1,0'C 510 /, Phenacetin .................. 3,5-C 180 /, TS: Maximum temperature decrease in the rat, 100 mg / kg. SW: Leveling reduction in formalin baiting of the rat paw 200 mg "kg. A: Substances known from the literature. B: exposed substances. C: Usual antip # retika-antiphlogistila. Example 1 N-methylanthranilic acid methylamide 173 g of N-methylanthranilic acid anhydride were introduced into 300 ml of a 120% strength aqueous solution of methylamine with stirring. After the reaction, which proceeded with heating, was cooled, filtered off with suction, washed and dried. Recrystallization from methanol-water; M.p. 88'C, yield 154 g.

Example 2 N-ethylanthranilic acid methylamide hydrochloride 19 g of N-ethylisatoic anhydride were poured over with 60 ml of a 350% strength aqueous methylamine solution while cooling and shaking. After the main reaction had ended, the mixture was heated on the water bath for a further 10 minutes and then cooled. The precipitated product was dissolved in ether and hydrogen chloride was passed into the dried ethereal solution. 8 g of melting point 167'C crystallized.

Example 3 N-methylanthranilic acid n-propylamide hydrochloride 36g N-methylisatoic anhydride and 12g of n-propylamine were heated 15 minutes long at 100'C. After cooling, it was dissolved in ethanol, decolorized with charcoal and treated with 20 ml of concentrated hydrochloric acid. 22 g of the substance sought crystallized out. F. 1500C. was diluted with water, filtered off with suction and crystallized from Athangl. Yield 6 g, m.p. 51 <C.

Example 6 5-Methyl-N-5 methylanthranilsäuremethylamid 5g-i # iethyl-N-methylisatoic anhydride were dissolved in 20 ml of a 3511 / jgen aqueous methylamine solution was added. When the reaction had ended, excess amine was distilled off. The precipitate was filtered off with suction and crystallized from ethyl acetate-petroleum ether. Yield 1.2 g, mp 77'C.

EXAMPLE 7 N-methylanthranilic acid methylamide hydrochloride 6.3 g of dimethyl sulfate were added dropwise to 7.5 g of methyl anthranilic acid at 120.degree. C. and then kept at this temperature for a further 30 minutes. After cooling, the mixture was neutralized with sodium carbonate solution, extracted with ether and, after drying, hydrogen chloride was passed into the ether. 6 g of melting point 213 ° C. crystallized.

Example 8 N, N-dimethylanthranilic acid methylamide 19.5 g of N-methylanthranilic acid methylamide and 12.1 ml of dimethyl sulfate were heated together on the steam bath for 30 minutes. After cooling, the mixture was made alkaline with 2N sodium hydroxide solution and extracted with ether. After the ether had evaporated, the residue was fractionally distilled. Yield 12 g, bp " ... 179 to 181 ° C. Example 9 N, N-dimethylanthranilic acid dimethylamide 17.8 g of N-methylanthranilic acid dimethylamicl and 11.2 ml of dimethyl sulfate were heated together for 30 minutes on the steam bath -Natronlauge made alkaline and extracted with chloroform. After evaporation of the chloroform, the residue was subjected to fractional distillation. yield 1 1 g, Kp "m. 163 to 166'C. EXAMPLE 10 N, N-dimethylanthranilic acid methylamide 9, Og N, N-dimethylanthranilic acid chloride were poured over with 20 ml of a 350 l strength aqueous methylamine solution and heated until a clear solution had occurred. The excess methylamine was then evaporated off, the solution made alkaline with 2 u sodium hydroxide solution and extracted with ether. After the ether had evaporated, the residue was fractionally distilled. Yield 5 g, bp 5 ... 179 to 180 ° C. Example 11 5-Chloro-N-methylanthranilic acid methylamide Example 4 N-methylanthranilic acid dimethylamide 10 g of N-methylisatoic anhydride were poured over with log 4011 /, aqueous dimethylamine solution. After the reaction had subsided, the mixture was boiled for a further 15 minutes. After cooling, the reaction product was filtered off with suction and dissolved in ethanol. Yield 6.0 g, mp 860C.

Example 5 N-Methylanthranilsäurediäthylamid 30g N-methylisatoic anhydride and 50 g of diethylamine were heated for 30 minutes at 80'C. Then 10 g of 6-chloro-N-methylisatoic anhydride were introduced into 50 ml of a 350% aqueous methylamine solution and heated to the boil for 30 minutes. After the methylamine had evaporated, an oil remained which was taken up in ethyl acetate and crystallized after concentration. Recrystallization from ethanol-water. Yield 2.8 g, m.p. 85'C.

Example 12 N, N-Dimethylaiithranilsä, uredimethvlamid 8.7 g of N, N-dimethylanthranilic acid methylamide and 2.0 g of sodium amide were refluxed together in 60 ml of absolute toluene for 18 hours. After the evolution of ammonia had ended, the mixture was cooled to 30 ° C. and 4.0 ml of methyl iodide were added. The solution was heated to boiling for a further 2 hours, then the separated sodium iodide was filtered off and fractionated in vacuo. Yield in the main fraction 6.2 g, boiling point 5 ", m. 163 to 167'C.

Example 13 N-Methylanthranüsäuremethylamid 16.9 g of o-chlorobenzoic acid methylamide, 120 ml of 400 mg methylamine solution, 8 g of copper (1) chloride and 3 g of copper powder were heated together for 5 hours in a steel bomb at 250.degree. C. with frequent shaking . After cooling, excess methylamine was distilled off, the residue made Congo acidic with hydrochloric acid and filtered. The filtrate was neutralized with 2N sodium hydroxide solution, and the precipitate was filtered off with suction and recrystallized from methanol-water. Yield 5.6g, m.p. 88'C.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of substituted anthranilic acid amides of the general formula in which R, and R, alkyl radicals, 1Z2 and R4 are hydrogen or alkyl radicals and R, hydrogen or one or more substituents, such as halogen, alkyl or alkoxy groups, are characterized in that a) 1 mol of one is in a manner known per se substituted isatoic anhydride of the general formula with 1 to 3 mol of a primary or secondary amine of the general formula at 10 to 120'C, or b) 1 mol of a substituted anthranilic acid amide of the general formula treated either with 1 to 1.5 or 2 to 3 mol of an alkylating compound or successively with 1 to 1.1 mol each of two different alkylating compounds at 10 to 120 ° C, or c) 1 mol of a reactive derivative of a substituted anthranilic acid in general Formula in which R6 denotes an alkyl radical or a radical which can be substituted by hydrogen after the reaction and Y denotes an ester group, a halogen, azido or acvloxy group, with 1 to 2 mol of a primary or secondary amine of the general formula at 0 to 120'C and, if R4 'M is intended to mean hydrogen, the radical R, replaced by hydrogen in a known manner, or d) 1 mole of a substituted o-halobenzamide of the general formula in which Z denotes a halogen radical, with 1 to 5 mol of a primary or secondary aliphatic amine of the general formula at 50 to 300'C, or e) 1 mol of a substituted anthranilic acid amide of the general formula Reacts at 50 to 300'C with 1 to 1.5 mol of an alkylating compound and, if the radical R in the end product is intended to mean hydrogen, the radical R is replaced by hydrogen in a known manner. 2. The method according to claim 1, b) or c), characterized in that 1 to 2 mol of a base such as sodium hydroxide, potassium carbonate, pyridine or triethylamine is added to the reaction mixture. 3. The method according to claim 1, d), characterized in that 1 to 2 mol of a hydrogen halide-releasing agent, such as copper powder, alkali metal carbonate or alkali amide, is added to the reaction mixture. 4. The method according to claim 1, e), characterized in that the substituted anthranilic acid amide is first reacted with 1 mol of an alkali metal or an alkali metal compound such as sodium, sodium amide, sodium hydride or potassium carbonate. 5. The method according to claim 1, b), e) or 4, characterized in that the alkylating compounds used are dialkyl sulfates, haloalkyls, haloacetic acids or alkyl p-toluenesulfonates. 6. The method according to claims 1 to 5, characterized in that the reaction is carried out in a solvent such as water, alcohols, dioxane, tetrahydrofuran, chloroform, carbon tetrachloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, pyridine or dimethylformamide. Considered publications: Beilstein, Handbuch der Organic Chemistry, 4th Edition, Hptw. Vol. 14, pp. 320, 325, 327; Swiss patent specification No. 186 668.