SU411685A3 - - Google Patents

Description

This invention relates to a process for the preparation of new heterocyclic carboxylic acids, which may be used in agriculture. Cyclization with the formation of a quinoline ring by intramolecular condensation is known. The application of the known method allowed us to obtain new quinoline derivatives with valuable properties. The proposed method for the preparation of heterocyclic carboxylic acids of the formula or their salts. where Ph is 1,2-phenylene residue substituted by a group of the formula Xi-A — R, where R is a cycloaliphatic residue, A is a direct bond between X and R or a bivalent aliphatic residue, Xi is oxygen or sulfur, or a group of formula X2 -R, Xz - oxygen or sulfur; R is the highest aliphatic residue; R is a carboxyl group esterified to an ester, carbamyl, hydrazinocarbonyl or cyano group; R2 is hydrogen or a lower alkyl group; Rs is hydrogen, an unsubstituted or substituted aliphatic or cycloaliphatic hydrocarbon residue, or 4-0 esters of their tautomers, is due to the fact that a compound of the formula Ph Ph, Ri, Ra, Rs has the indicated value of a functionalized oxyl group, for example, an ether, anhydride , carbamyl, hydrazinocarbonyl or cyano;

R is the esterification of an ester of a carboxyl cadaver, carbamyl soil, oxycyancarboyl group, or cyan group; or tautomers of such compounds, in which Cs is hydrogen, are subjected to cyclization by intramuscular condensation, with the selection of the target product in free form, in the form of a racemate or by transferring it to a salt or by separation of the racemate into stereoisomers.

Example 1. A mixture of 8 g of N- (4-cyclopronylmethoxy-3-n-decycloxyphenyl) aminomethylenemalonic acid diethyl ether and 48 ml of diphenyl ether is heated under reflux for 20 minutes under a nitrogen atmosphere. After cooling, the mixture is diluted with pentane; the resulting precipitate is filtered and recrystallized from dimethylformampa. So get 6-cyclopropylmethoxy-7 - "- decycloxy-4oxy-3-quinolinecarboxylic acid ethyl ester with m. PL. 253 to 254 ° C.

Similarly, using N- (4-cyclopropylmethoxy-3-n-decyloxyphenyl) - aminomethylenemalonic acid dimethyl ester as the starting material, 6-cyclopropylmethylCi-7-decyloxy-4-hydroxy-3-quinoline-carboxylic acid methyl ester is obtained. 254- 255 ° C.

The original product is obtained as follows.

To a solution of 55 g of pyrocatechin in 250 ml of anhydrous ethanol, first 20 g of sodium hydroxide and then 86.5 g of cyclopropylmethylbromide are added with stirring; the latter is added dropwise over one hour. The mixture was heated under reflux for 24 hours with stirring, then concentrated to approximately 1/3 of the original volume. The concentrate is diluted with water, the mixture is extracted with methylene chloride; the organic extract is washed with water, dried, filtered and evaporated. The residue is distilled, boiling at 90-94 ° (0.4 mmHg). The fraction is a pyrocatechol monocyclopropylmethyl ester.

A mixture of 28.3 g of pyrocatechino monocyclopropylmethyl ester, 6.8 g of sodium hydroxide, and 100 ml of benzene is boiled under reflux for 30 dm. After cooling, the resulting precipitate is filtered off and 300 ml of benzene is added; 23.9 g of benzoyl chloride are added to the cooled ice-cold mixture with stirring over 30 minutes. The mixture is then stirred at 25 ° C for 4 hours, then 200 ml of a 20% aqueous solution of sodium hydroxide and 200 ml of water are washed out. The organic layer is separated, filtered and evaporated, the residue is distilled. Boiling at 173-PbS (0.3 mmHg), the fraction is a 2-cycloproduct

pilmethoxyphenyl ester of benzoic acid.

To a solution of 25 g of benzoic acid 2-cyclopropylmethoxyphenyl ester in 210 ml of glacial acetic acid, 25.2 g of fuming nitric acid are added with stirring at room temperature over 15 minutes. The mixture is heated to 100 ° for 20 minutes, then poured into 200 ml of ice-cold

water. The precipitate obtained is filtered and recrystallized from isopropanol. In this way, the benzoic acid 2-cyclopropylmethoxy-5-nitrophenyl ester is obtained with an mp. 96-99 ° C.

A mixture of 40 g of 2-cyclopropylmethoxy-5-nitrophenyl ester of benzoic acid, 150 ml of 95% ethanol and 11.5 g of a 50% aqueous solution of sodium hydroxide is boiled for 2 hours under reflux and evaporated under reduced pressure. The residue is dissolved in 300 ml of water, the solution is acidified with 40 ml of concentrated hydrochloric acid and extracted with 300 ml of methylene chloride. The organic extract is stirred for 2 hours with 500 ml of a 10% aqueous solution of sodium bicarbonate, then the organic layer is separated. The aqueous solution is extracted with methylene chloride, the combined organic solutions are dried,

filtered out. The residue is treated with hexaia and thus obtained 4-cyclopropylmethoxy-3-oxynitrobenzene with m. Pl. 104-105 C. A mixture of 18 g of 4-cyclopropylmethoxy-3-oxynitrobenzene, 130 ml of toluene and 3.44 g of sodium hydroxide is refluxed with stirring for one hour, then evaporated under reduced pressure. The residue is dissolved in 130 ml of dimethylformamide, 0.4 g of sodium iodide and 19 g of n-decyl bromide are added and the mixture is stirred under nitrogen at room temperature for 17 hours, then diluted with 500 ml of codes and extracted with methylene chloride.

The organic extract is washed with water, dried, filtered and evaporated. The residue is recrystallized from n-hexane to give 4-cyclopropylmethoxy-3-n-decyloxynitrobenzene, m.p. 59-61 ° C.

A mixture of 10.5 g of 4-cyclopropylmethoxy-3-n-decyloxynitrobenzene, 100 ml of anhydrous ethanol and 0.5 g of platinum oxide is hydrogenated under a pressure of 3 atm until the absorption of hydrogen is complete. 6.5 g of ethoxymethylenemalonic acid diethyl ester are added to the mixture, then the whole is heated under reflux for three hours, then filtered to form a mixture. The filtrate is evaporated under reduced pressure; at the same time receive

diethyl ester of M- (4-cyclopropylmethoxy-3-n-decyloxyphenyl) - aminomethylenemalonic acid.

Example 2. 18 ml of M- (4-cyclopropylmethoxy-3-n-tetradecyloxyphenyl) -aminomethyliimonyl acid acid diethyl ester is added to a ml of refluxing eutectic mixture of diphenyl ether and biphenyl. The mixture is heated under reflux for 8 minutes, cooled quickly and diluted with hexane. The resulting precipitate is filtered and washed with hexane; Thus, 6-cyclopropylmethoxy-7-n-tetradecyloxy-4-hydroxy-3-hINoline-carboxylic acid ethyl ester is obtained with m.p. 237-238 ° C.

The starting product can be obtained as described in Example 1, with equivalent amounts of starting materials being used; the corresponding 4-cyclopropylmethoxy3-n-tetradecyloxy-nitrobenzene melts at 63-64 ° C, and the diethyl ester of N- (4-piclopropylmethoxy-3 - n - tetradecyloxymethyl) is aminomethylenemalonic acid at 56-57 ° C.

Example 3. A mixture of 1 g of diethyl ester of 6-cyclopropylmethoxy-7-n-decyloxy-4-hydroxy-3-quinolinecarboxylic acid and 20 ml of methanol is heated in an autoclave for 10 minutes at approximately 200-250 ° C and cooled to room temperature, then evaporated under reduced pressure. The residue is recrystallized from dimethylformamide to obtain 6-cyclopropylmethoxy-7-n-dennloxy-4-hydroxy-3-quinolinecarboxylic acid methyl ester with a melting point of 200 mg. 254-256 ° С, the ester is identical with the product obtained in order 1.

Example 4. A mixture of 13 g of L- {3-cyclopropylmethoxy-4-n-decyloxyphenyl) -methylaminomalonic acid acid diethyl ester and 80 ml of diphenyl ether is boiled for 20 minutes under reflux and after cooling is diluted with pentap. The precipitate formed is filtered off and washed with ethanol, acetone and ether. The 7-cyclopropylmethoxy-6-n-decyloxy-4-hydroxy-Zincoline carboxylic acid ethyl ester is obtained with mp. 234- 235 ° C.

The original product can be obtained as follows.

To a solution of 22 g of pyrocatechin, 200 ml of acetone and 450 g of anhydrous potassium carbonate, 46.4 g of n-decyl bromide are added without dispensing. The mixture is heated for 36 hours under a nitrogen atmosphere under reflux, then filtered. The filtrate is evaporated under reduced pressure, the residue is distilled. Ch.cha at 40-144 ° C (0.4 mmHg). Sample 6 is a mono-n-decyl ether ether pyrocatechol. Pyrocatehindi "-lecyl ester ether c. m.p. .198-200 ° C (0.3 mmHg. Art.) - Receive: approximately, in

the same amount. .

A mixture of 12 g of pyrocatechin mono-n-decyl ester, 1.9 g of sodium hydroxide and 50 ml of benzene is heated under stirring for 30 minutes under reflux and evaporated. A mixture of 7.7 g of chloride is slowly added to the residue while cooling.

benzoyl and 150 ml of benzene; The mixture is stirred for 4 hours at room temperature, washed with 200 ml of 2% vop-south sodium hydroxide solution with water, dried, filtered and evaporated under reduced pressure. The residue is distilled, boiling at 175-180 ° C (0.1 mmHg). The fraction is the 2-n-decyloxyphenyl ether benzoic acid.

11.8 g of benzoic acid 2-n-decyloxyphenyl ester are dissolved in 100 ml of glacial vinegar; while stirring, 12 ml of nitric acid smoke are added dropwise and the mixture is heated on a steam bath for 20 minutes, then cooled to 30 ° C and 125 ml of ice water is added slowly. The aqueous mixture is extracted with methylene chloride; the organic extract is washed with water, dried, filtered and evaporated. Get 2 - / - / - decyloxy-5-nitrophenyl complex

benzoic acid ester.

A mixture of 78 g of 2-n-decyloxy-5-nitrophenyl ester of benzoic acid, 235 ml of ethanol and 18 g of a 50% aqueous solution of sodium hydroxide is heated for 2.5 hours under reflux and vyutarny under reduced pressure. The residue is dissolved with 200 ml of water; the solution is acidified with 50 ml of concentrated hydrochloric acid and extracted with methylene chloride. The organic extract is washed with a 10% aqueous solution of sodium hydrogencarbonate and water, dried, filtered and evaporated. The 4-n-decyloxy-3-oxycytrobenzene thus obtained melts at 53-54 ° C.

A mixture of 12.5 g of 4-n-decyloxy-3-oxynitrobenzene, 85 ml of toluene, 1.7 g of sodium hydroxide, 0., 18 g of sodium iodide and 85 ml of dimethylformamide are boiled under stirring for one hour under reflux. 10.2 g of cyclopropylmethyl bromide (85%) are then added dropwise with stirring; the mixture is stirred at 120 ° C for 24 hours, then diluted with water and extracted with methylene chloride. The organic extract is washed with water, dried, filtered and evaporated. The residue is recrystallized from n-hexane and get 3-cyclopropylmethoxy-4-n-decyloxynitrobenzene, with so pl. 61-62 ° C. A mixture of 12 g of 3-cyclopropylmethoxy-4-h-lecyloxynitrobenzene, 200 ml of anhydrous ethanol and 0.8 g of platinum oxide is hydrogenated under a pressure of 3 atm and at room temperature until the absorption of hydrogen is complete. 7.4 g of ethoxymethylenemalonic acid diethyl ester are added to the mixture and boiled for 3 hours with stirring under reflux, then filtered in hot form. The filtrate is evaporated under reduced pressure. Thus, diethyl p-ester M- (3-cyclopropylmethoxy-4-l / -decyloxyphenyl) is obtained and the minomethylenem of lonic acid is obtained.

Example 5. To 75 m. Of: refluxing of diphenyl ether, 12.8 g of diotnyl Jfipa N- (4-cyclopropylmethoxy-3-dodecyloxyphenyl) aminomethylenemalon, oi acid, are added; the mixture is boiled for 30 minutes under reflux, then cooled, diluted with nentane and filtered. The precipitate is washed out with pentane; 6-cyclopropylmethoxy-7-n-dodepyloxy-4-hydroxy-3-quinoline-carboxylic acid ethyl ester is obtained with mp. 210-213 ° C.

The original product can be obtained as follows.

A mixture of 5 g of 4-cyclopropylmethoxy-3-oxynitrobenzene, 35 ml of toluene, and 0.92 g of sodium hydroxide is boiled for one hour with stirring under reflux and evaporated under reduced pressure. The residue is dissolved in 35 ml of dimethylformamide; Then add 0.1 g of sodium iodide and 5.73 g of n-dodecylbromide and stir the mixture for 40 hours at 120 ° C in a nitrogen atmosphere. Then it is cooled, diluted with 100 ml of water and extracted with methylene chloride. The organic extract is dried, filtered and evaporated. 4-cyclopropiomethoxy-3-n-dodepiloxynitrobenzene is obtained.

A mixture of 9 g of 4-cyclopropylmethoxy-3-n-decyloxynitrobenzene, 150 ml of anhydrous ethanol and 6.5 g of platinum oxide is hydrogenated until the end of the mixture is hydrogen; at a pressure of 3 atm and room temperature. Then, 5 g of ethoxymethylenemaloic acid diethyl ester is added and the mixture is heated under nitrogen at reflux for 5 hours, then filtered and the filtrate is evaporated under reduced pressure. In this way, N- (4cyclopropylmethoxy-3-n-dodecyloxyphenyl) aminomethylenemalonic acid diethyl ester is obtained, m.p. 67 ° C.

Example 6. A mixture of 10 g of N- (4-cyclopropylmethoxy-3-α-octyloxyphenyl) -aminomethylenemalonic acid diethyl ester and 65 g of diphenyl ether are heated for 20 minutes under a nitrogen atmosphere under reflux. After cooling, the mixture is diluted with pentane; the precipitate formed is filtered off and recrystallized from dimethylformamide. 6-cyclopropylmethoxy-4-hydroxy-7 “-octyloxy-3-quinolinecarboxylic acid ethyl ester is obtained with mp. 256-258 ° C.

If H- (4-cyclopropylmethoxy-3-octyloxyphenyl) -am inomethylenemalonic acid dimethyl ester is used in the above described method as is the starting material, TQ forms 6-cyclopropyl-methoxy-4-hydroxy-7-n-methyl ester. .- - Octyloxy-3-quinolinecarboxylic acid: Art. square 258-259.5 ° C. - The original product can be obtained as follows.

A mixture of 36 g of 4-cyclopropylmethoxy-3-oxynitrobenzene, 260 ml of toluene and 6.88 g of sodium hydroxide is boiled under stirring for one hour under reflux, then

evaporated under reduced pressure. The residue is dissolved in 260 ml of dimethylformamide, 0.15 g of sodium iodide and 38 g of noctilbromide are added and the mixture is heated under stirring under nitrogen atmosphere for 29 hours under reflux, then diluted with 500 ml of water and extracted with methylene chloride. The organic extract is washed with water, dried, filtered and evaporated.

The residue is recrystallized from γ-hexane and thus 4-cyclopropylmethoxy-3 - "- octyloxynitrobenzene is obtained, m.p. 48-49 ° C.

A mixture of 9 g of 4-cyclopropolymethoxy-3-n-octyloxynitrobenzene, 100 ml of anhydrous ethanol and 0.5 g of platinum oxide is hydrogenated until the absorption of hydrogen is complete at a pressure of 3 atm and room temperature. 6.1 g of ethoxymethylenemalonic acid diethyl ester are added to the mixture and the mixture is heated under reflux for 3 hours, then filtered while hot. The filtrate is evaporated under reduced pressure to give N- (4-cyclopropylmethoxy-3-α-octyloxyphenyl) aminomethylenemalonic acid diethyl ester.

Example 7. A mixture of 0.6 g of ethyl ester of 6-cyclopropylmethoxy-7- -decyloxy-4oxy-3-quinolinecarboxylic acid, 1.5 g of anhydrous datr acetate and 15 ml of anhydride

The acetic acid is heated under reflux with stirring for 3 hours, then reduced under reduced pressure. The residue is treated with methylene chloride; the solution is evaporated, the residue is recrystallized from a mixture of ether with pentane. The 4-acetyloxy-6-cyclopropylmethoxy-7-δ-Iloxy-3-quinolinecarboxylic acid ethyl ester thus obtained melts at 101.5-102 ° C.

Example 8. To 400 ml of a boiling eutectic mixture of diphenyl ether and biphenyl were added 40 g of diethyl ester of N- (2-cyclopropylmethyl-3- -decyloxyphenyl) -aminomethylenemalonic acid. Mixture

reflux for 10 minutes

then quickly cooled, diluted with 800 ml

heptane and left to stand for two days at

room temperature.

The precipitate is filtered off,

wash out 200 ml of heptane and recrystallize from aqueous methanol. Thus, 8-cyclopropylmethoxy-7-n-decyloxy-4-hydroxy-3-quinoline-carboxylic acid ethyl ester monohydrate is obtained, melting

at 99-102 ° C. A mixture of 12 g of the named monohydrate and 100 ml of toluene is refluxed until water stops flowing into the water separator. The solution is evaporated, the residue is treated with salmon

by ether. The anhydrous compound melts at 75-78 ° C.

The original product can be obtained as follows. To a mixture of 100 g of 2-cyclopropylmethoxyphenyl benzoate, 2400 ml of vinegar