Method of producing 3-quinoline carboxalic acid derivatives or their salts
专利摘要:
Novel quinoline-3-carboxamides of the formula <IMAGE> I wherein R1 is in the 5,6,7 or 8-position and is selected from the group consisting of hydrogen, halogen, -CF3, -OCF3, -SCF3, straight chain alkyl of 1 to 4 carbon atoms, branched alkyl of 3 to 5 carbon atoms and alkoxy of 1 to 4 carbon atoms, R2 is selected from the group consisting of hydrogen and methyl, R3 is selected from the group consisting of thiazolyl, 4,5-dihydrothiazolyl, pyridinyl, oxazolyl and imidazolyl and R4 is selected from the group consisting of hydrogen, hydroxyl, alkyl of 1 to 4 carbon atoms, phenyl and benzyl with the proviso that when R1 is in the 7 or 8-position and is halogen, -CH3, -OCF3 or -SCF3 and R4 is hydrogen, R3 is not thiazolyl, pyridinyl or oxazolyl and the non-toxic, pharmaceutically acceptable acid addition salts when R3 is imidazolyl or 4,5-dihydrothiazolyl having analgesic activity and their preparation and novel intermediates therefore. 公开号:SU867299A3 申请号:SU772450451 申请日:1977-02-10 公开日:1981-09-23 发明作者:Алле Андре;Клеманс Франсуа;Дерае Роже;Ле Мартре Одиль 申请人:Руссель-Юклаф (Фирма); IPC主号:
专利说明:
While stirring in an inert gas stream, 6.3 g of 4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid chloride are introduced into 90 cm of pyridine. Then 2.35 g of 2-imino-2, 3,4,5-tetrahydro-thiazole are introduced in solution in 15 cm of pyridine. The reaction mixture is kept under stirring for 18 hours. Pyridine is evaporated and 11.5 g of residue are obtained, which is treated with 40 cm of a 10% potassium carbonate solution. Extract with ethyl acetate and combine the organic layers. The resulting product is chromatographed, eluting with benzene-ethanol (9: 1), and the residue obtained is taken to dryness. The latter is recrystallized in ethanol to obtain 1.93 g of 4-hydroxy-N- (4,5-dihydro-2-thiazolyl) -8-trifluoromethyl-3-quinoline-carboxamide, melting at 267-268 ° C. Example 2. 4-hydroxy-N- (1H-imidazol-2-yl) -8-trifluoromethyl-3-quinolinecarboxamide hydrochloride. a) 4-Oxy-M- (1H-imidazol-2-yl) -8-trifluoromethyl-3-quinoline-carboxamide. Acting as in Example 1, but proceeding from 11.57 g of 4-hydroxy-8-trifluoromethyl-3-quinoline carboxylic acid chloride and 5.52 g of 2-amino-imiazole sulfate,. 3.9 g of 4-hydroxy-M- (1H-imidazol-2-yl) -8-trifluoromethyl-3-chenoline-carboxamide are obtained, melting pr 211 ° C, b) To 3.2 g of the product obtained, which is in suspension in 250 cm of water, add 10 cm of 1N. hydrochloric acid solution. The resulting suspension is heated at 40-50 ° C and the insoluble matter is filtered off. The aqueous filtrate is concentrated to 30 cm. The precipitate obtained is filtered off with suction, washed with water and dried. Thus, 4-hydroxy-N- (1H-imidazol-2-yl) -8-trifluoromethyl-3-quinolinecarboxamide dihydrate is obtained. Elemental analysis: C, (4. Nd. Found,%: C 42.9; H 3.4; F 15.0; N 14.1; C1 9.2. Calculated,%: C 42.60; H 3.57; F 14.44; N 14.19; C1 8.98. Example 3. 4-Oxy-6- (1-methylethyl) -N- (2-thiazolyl) -Z-chirin,. carboxamide. Acting as in Example 1, but starting from 10.74 g of 4-hydroxy-6- (1-methylzthyl) -3-quinolinecarboxylic acid chloride and 3.9 g of 2-aminothiazole, I obtain 1.28 g of 4-hydroxy-6- (1-methylethyl) -N- (2-thiazolyl) -3-chi olincarboxeylide, melting at a temperature above 340.С. ( Elemental analysis: C - 313.381. H 4.7; Found,%; C, 61.3; N 13.1; S 10.1. Calculated,%: C, 61.32; H 4.82; N 13.41 S 10.23. 4-OXI-6- (1-methylethyl) -3-quinoline carboxylic acid chloride is prepared as follows. a) 4- (1-methylethyl) -phenylaminomethylene} -malonic acid ethyl ester. 33.80 g of 4-isopropylaniline and 54.06 g of ethoxymethyliimonic acid ethyl ester are mixed with stirring in an inert gas stream. The mixture is heated at 130 135 ° C to distill ethanol. Cooling gives 76.3 g of 4- (1-methylethyl) phenylaminomethylenemalonic acid ethyl ester, melting at about 35 ° C. b) 4-OXY-6- (1-methylethyl) -3-quinolinecarboxylic acid ethyl ester. While stirring in a stream of inert gas, 90 g of the product obtained are mixed with 90 g of diphenyl ether. The resulting mixture is heated at 260-270 ° C to distill ethanol. The remainder of the mixture is cooled, 30 cm of acetone is added. In this way, a precipitate is obtained, which is filtered off with suction, concentrated in acetone and ether, and dried. Thus, 34.5 g of ethyl acetate are obtained. 4-hydroxy-6- (1-methylethyl) -3-quinolinecarboxylic acid ester, which is sublimated at about 269-270 ° C. c) 4-hydroxy-b- (1-methylethyl) -3-quinoline-carboxylic acid. Three stirring. In the inert gas stream, 34.5 g of the obtained Q-product in 150 cm of water are introduced. To the resulting suspension was added a solution containing 15 g of sodium hydroxide tablets in solution in 150 cm of water. The resulting suspension is heated under reflux. An aqueous solution is obtained which is washed with ether and acidified to pH 1 with concentrated hydrochloric acid. A precipitate is obtained, which is filtered off with suction, washed with water and dried. In this way, 29.6 g of product is obtained, which is consumed in the next phase. After recrystallization of this product, 22.87 g of 4-hydroxy-6- (1-methylethyl) -3-quinolinecarboxylic acid are obtained. M.p. 298 ° C. d) 4-hydroxy-6- (1-methylethyl) -3-quinolinecarboxylic acid chloride With stirring, 10 g of the obtained crude product is introduced into 300 cm of anhydrous benzene. To the resulting suspension was added 3.8 cm of chloride thionyl and heated under reflux for about 2.5 hours. After cooling, a precipitate is obtained, which is sucked off and turned into a dough with a small amount of anhydrous benzene. Thus, 10.74 g of 4-hydroxy-6- (1-methylethyl) -3-quinolinecarboxylic acid chloride are obtained, melting at 25 ° C. Example 4. 4-hydroxy-2-methyl-N - (2-thiazolyl.) -8-trifluoromethyl-3-quinolinecarboxamide. Acting as in Example 1, but starting from 4-hydroxy-2-methi-8-trifluoromethyl-3-quinoline-carboxylic acid chloride and 2-aminothiazole, 4-hydroxy-2-methyl-M- (2-thiazolyl) -8- is obtained trifluoromethyl-3-quinoline carboxamide, melting at. The starting 4-hydroxy-2-methyl-8-trifluoromethyl-3-quinolinecarbamide acid chloride is prepared as follows. a) 1- (2-Triprop-methyl-phenyl-amino) -ethylidene-malonic acid ethyl ester. 48.4 g of acetylmalonic acid diethyl ester and 38.7 g of trifluoromethylaniline are smeared. The reaction mixture is heated for 1 hour at 100 ° C, then it is cooled and dried at room temperature for five days. The resulting solution is taken up in ether, washed with water to pH b, dried, treated with activated charcoal and brought to dryness. An oil is obtained which is chromatographed on silica; eluant - cyclohexane-ethyl acetate (9.:1). The product with R 0.12 was isolated and thus 42.7 g of C1- (2-trifluoromethylphenylamino) ethylidene-small novol ethyl ester was obtained. Elemental analysis: C H 345,308. Found,%: C 55.7; H 5.5; M 3.5; F 14.6. Calculated,%: C 55.65; H 5.25; N 4.05; F 16.5. b) 4-hydroxy-2-methyl-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester. 5 g of the obtained product is introduced into 10 cm of diphenyl ether. The resulting suspension is heated to 240 ° C. Allow to cool to room temperature. The diphenyl ether is evaporated and the resulting crystals are taken up in 20 cm of isopropyl ether. After filtration, 2.9 g of 4-hydroxy-2-methyl-8-trifluoromethyl-3-quinoline-carboxylic acid ethyl ester, melting at 165 ° C., are obtained. c) 4-Oxy-2-methyl-8-trifluoromethyl-3-quinolinecarboxylic acid. 19.4 g of the obtained product are introduced into the suspension in 162 cm 1 n. caustic soda solution. The resulting suspension was heated under reflux for 5 hours, washed with ether and acidified to pH 1 with 1N. hydrochloric acid. A precipitate is obtained which is filtered, washed with water and dried. Thus, 16.6 g of 4-OK-si-2-methyl-8-trifluoromethyl-3-quinolinecarboxylic acid, melting at 260 ° C., are obtained. d) 4-hydroxy-2-methyl-8-trifluoromethyl-3-quinolinecarboxylic acid chloride. Acting as in phase g of Example 3, 4-hydroxy-2-methyl-8-trifluoromethyl-3-quinolinecarboxylic acid chloride is obtained. Example 5. 4-hydroxy-M- (2-thiazolyl) -3-quinolinecarboxamide. Acting as in Example 1, but starting from 9 g of 4-hydroxy-3-quinoline-carboxylic acid chloride and 4.35 g of 3-aminothiazole, 4.3 g of 4-oKCH-N- (2-thiazolyl) -3-quinopincarboxamide are obtained, melt at 349-350 ° C. 4-hydroxy-3-quinoline carboxylic acid chloride is prepared as follows. Introduce 8.2g of 4-hydroxy-3-quinolinecarboxylic acid in 160 cm of benzene. To the resulting suspension was added 3.8 cm of thionyl chloride. The half suspension is heated for 1 hour under reflux. After cooling, a precipitate is obtained. . which is sucked off, converted into a dough with a small amount of anhydrous benzene, and dried. Thus, 9 g of 4-hydroxy-3-quinoline-carboxylic acid chloride are obtained, melting at a higher temperature. Example 6. 2-Ethyl-4-hydroxy-M-. - (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide. Under stirring and in an inert gas, 11 g of 2-ETHYL-4-OXI-8-TRIFORO-3-3-quinolinecarboxylic acid, 3.85 g of amino-2-thiazole and 7.94 g of dicyclohexylcarbodiimide are introduced into 110 cm of dimethylformamide. The reaction mixture is kept under stirring for 72 hours, filtered, dimethylformamide is evaporated from the filtrate and the residue is taken up in 100 cm of a 5% sodium bicarbonate solution. Filter, wash with water until pH = 6 and obtain 11.9 g of crude product. The product obtained is purified by chromatography and eluted with a mixture of methylene chloride and ethyl acetate (9: 1). The fraction having Rj of about 0.18 is collected, brought to dryness and 7.6 g of product is obtained which is recrystallized: comfort in acetic acid. 6.5 g of 2-ethyl 4-oxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinoline-carboxamide are obtained in the form of colorless crystals. M.p. 240 ° C. Elemental analysis:. N About .Fj - 367,348. Found,%: C 52.6; H 3.5} 0 11.4 N 9.0; F 15.3. Calculated,%: C 52.30 H 3.30 11.44; N 8.72; F 15.51. The starting 2-ethyl-4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid is prepared as follows. a) (trifluoromethyl) -phenyl7-propanamide, 48.3 g of 0-trifluoromethylaniline and 36.42 g of triethylamine are added to 480 cm of acetone. Within 0.5 hours, keeping the temperature at 20-30 ° C, 33.3 g of propionyl chloride is added. The mixture is left in contact for 12 hours, filtered, the filtrate is collected, the acetone is evaporated and the resulting residue is taken up 500 cm ethyl acetate Washed with 10% potassium carbonate solution, and then with water until pH b, 1 n. hydrochloric acid solution and then re-water to pH b. It is dried over magnesium sulphate, treated with activated carbon, evaporated and collected 65 g of crude product, which is purified by washing in ice essence. 43 g of N-G2- (tryptermomethyl) phenyl-propanamide are obtained. m.p. b) The acid chloride M-G2- (trifluoromethyl) -phenyl-propanimic acid. 19 g of phosphorus pentachloride in 25 cm of toluene are introduced into suspension and 18 g of N-2- (trifluoromethyl) -phenyl-propanamide in a solution of 150 cm of toluene are added for about 15 minutes. At the end of the evolution of gas, the mixture is heated with a condenser for 1.5 hours, and then the toluene is evaporated in a vacuum. Collected 19 g of the acid chloride (trifluoromethyl) -phenyl-J-propanimic acid (yellow maslo). c) 2-G1- (2 -. (trifluoromethyl) -phenylamino) -prop-1-ylidene -malonic acid ethyl ester. 3.64 g of magnesium is introduced into 3.4 cm of absolute ethanol and 0.34 cm of carbon tetrachloride, left in contact for several minutes and 88.5 cm of anhydrous ether are added over a period of about 20 minutes. Then, within 15 minutes, 24 g of malonic acid ethyl ester in 13.6 cm of absolute ethanol and 17 cm of anhydrous ether are added. The reflux is maintained for 1 hour. Then the ether is evaporated, replacing it gradually with 40 cm of dry toluene. After that, 20 cm of toluene is added and the azeotropic mixture is toluene-ethanol. T. Kip, TB-TT With 68% ethanol). When pure toluene is distilled, the refrigerator is re-set, allowed to reach room temperature, and the organomagnesium compound of malonic acid ester is obtained. The resulting compound is poured over 30 minutes at room temperature with 35, chlorohydride M-H 2 - (trifluoromethyl) -phenyl 3 g-propanimidoyl in a solution in 30 cm of dry toluene. Incubated for 0.5 h at room temperature and poured onto the mixture. 150 cm 2 n. hydrochloric acid solution and 150 g of ice. Extracted with ether, washed with 5% sodium bicarbonate solution, and then with water to pH 6. Dried over magnesium sulfate, treated with activated charcoal and evaporated. 53 g of ethyl 2-G1- (2- (trifluoromethyl) -phenyl-aminob) -prop-1-ylideZ-malonic acid (yellow oil) are obtained. d) 2-ETHYL-4-OXY0 -8-trifluoromethyl-3-quinoline-carboxylic acid ethyl ester. 53 g of ethyl 2-fl- (2- (trifluoromethyl) -phenylamino) -prop-1-ylidene} -malonic acid in 50 cm of diphenyl ether are introduced into the suspension and heated for 30 minutes in a bath at. Ethanol is distilled. The diphenyl ether is evaporated and the residue is taken up in 100 cm of isopropyl ether. After filtration and washing twice with 10 cm of isopropyl ether, 19 g of 2-ethyl-4-hydroxy-8-trifluoromethyl-3-quinoline- ethyl are collected. carboxylic acid. .T. p / 1.129S. e) 2-Ethyl-4-hydroxy-8-trifluoromethyl 5 -3-quinoline-carboxylic acid 5 g of ethyl 2-ETIH-4-OXY-8-Grifluoromethyl-3-quinoline-carboxylic acid ethyl acetate is dissolved in 25 cm of sodium hydroxide at 36 ° and 50 cm 0 ethanol. The mixture is heated under reflux for 3.5 hours, allowed to cool and the ethanol is evaporated. 100 cm is added. 5 of ice water, washed with methylene chloride, and then slowly acidified with an addition of 2N. hydrochloric acid solution, keeping the temperature below 15 ° C. Filter off insoluble 0 substance, washed with water to pH 6 and get 4.4 g of 2-ethyl-4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid T. PP. 174s. Example 7. 4-OXY-2- (1-methyl (ethyl) -N -) - 2-thiazolyl-8-trifluoro5 methyl-3-quinoline carboxamide. Under stirring and in an atmosphere of "gaseous gas, 6.3 g of 4-hydroxy-2- (1-methyl) -ethyl-8-trifluoromethyl-3-quinolinecarboxylic acid, 2.1 g 0 amino-2-thiazole and 4.74 g. Dicyclohexylcarbodiimide in 130 cm of dimethylformamide. The reaction mixture is kept under stirring for 72 hours, filtered, the dihydrate: ethyl formamide is evaporated from the filtrate, and the residue is taken up in 50 cm of a 5% sodium bicarbonate solution. Filter, wash with water until pH b and obtain 8 g of crude product. 0 The crude product is purified by chromatography and eluted with a mixture of methylene chloride-ethyl acetate (9: 1). An R-t fraction of about 0.25 is collected, brought to dryness and 6 g of product are obtained, which 5 will recrystallize in acetone. 4.2 g of 4-OXY-2- (1-methylChethyl) -N) -2-thiazolyl-8-trifluoromethyl-3-quinoline-carboxamide are obtained in the form of colorless crystals. T. LL. 213C. Elemental analysis: CA - ,, tt SF, 381,368. Found,%: C 53.6; H 3.7; N 10.9 S8.6; F 15.1. Calculated,%: C 53.53; H 3.70 iN 11.02; S 8.40; F 14.94. The starting 4-hydroxy-2 (1-methyl) -ethyl-8-trifluoromethyl-3-quinoline-carboxylic acid is prepared as follows a) (trifluoromethyl) -phenyl 7-2-methylpropanamide. g. In 470 cm of acetone, 46.7 g of o-trifluoromethylanaline and 32.6 g of triethylamine are injected. The temperature was maintained at about 34.5 g of isobutyryl chloride over 15 minutes. They are kept for another 30 minutes at 15 ° C and ayut again to reach room temperature. Leave in contact for 12 hours, filter, collect the filtrate, evaporate the acetone, and collect the resulting residue in 700 cm of acetic acid ethyl ester. It is washed with a 10% potassium carbonate solution and then with water to pH 6, and then 1 in. with a solution of hydrochloric acid and once again with water to pH 6. They are dried over cinnamon, magnesium and magnesium, treated with activated carbon, evaporated and 68 g of crude product is collected, which is purified by washing with hexane cm. 60 g of (trifluoromethyl) -phenylZ-2-methylpropanamide are obtained. .Т ,,. ПЛ.114С. b) N-f2- (trifluoromethyl) -phenyl -2-methylpropanimic acid chloride. 11, .45 phosphorus pentachloride in 25 cm of toluene is introduced into the suspension and 11.56 g of M-H2- (trifluoromethyl) -phenyl -2-methIlpropanamide in a solution of 200 cm of toluene are added over 15 minutes. At the end of the gas separation, the mixture is heated under reflux for 1.5 hours, and then the toluene is evaporated in vacuo. 12.4 g of N-2- (trifluoromethyl) -phenyl-3-methyl-propanimic acid chloride (yellow oil) are collected. c) (2- (trifluoromethyl) -phenylamino) -2-methylprop-1-ylideZ-malonic acid ethyl ester. Acting as in phase in Example 6, but starting from 1.34 g of magnesium and 8.8 g of ethyl malonic ester, an organomagnesium organic compound of ethyl malonic ester is obtained. 12.4 g of the acid chloride; N- 2- (trifluoromethyl) -phenyl -2-methylpropanimic acid in solution in 10 cm of dry toluene was added to the compound obtained over a period of about 30 minutes at room temperature. Stand 45 minutes at room temperature and pour in a mixture of 50 cm 2 n. hydrochloric acid solution and 50 g of ice. The mixture is extracted with ether, washed with 5% sodium bicarbonate solution and then with water to pH 6. Dried over magnesium sulfate, treated with activated charcoal and evaporated. “18 g of (2- (trifluoromethyl) -phenylamino) -2-methyl-prop-1-ylidene-malonic acid ethyl ester (yellow oil) are obtained. d) 4-hydroxy 2- (1-methyl) -ethyl-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester. 16 g of 2-l- (2-trifluoromethyl) -phenylamino) -2-methyl-prop-1-ylidene-malonic acid ETHYL ester is dissolved in 16 cm of diphenyl ether and heated for 15 minutes in a bath at 240.C. Ethanol is distilled. The diphenyl ether is evaporated and a brown oil is obtained, which is consumed without much purification in the next phase. e) 4-OXY-2- (1-methyl) -ethyl-8-trifluoromethyl-3-quinoline-carboxylic acid. 14 g of 4-hydroxy-2- (1-methyl) -ethyl-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester is dissolved in 75 cm of sodium hydroxide solution at 36 and 150 cm of ethanol. Heat with reflux for 6 h, allow to cool and evaporate the ethanol. 150 cm of ice water is added, washed with methylene chloride, and then slowly acidified with an addition of 2N. hydrochloric acid solution, maintaining the temperature below 15 ° C. The insoluble material is filtered off, washed with water until pH 6 and 6.9 g of 4-hydroxy-2- (1-methyl) -ethyl-8-trifluoromethyl-3-quinoline-carboxylic acid are obtained; M.p. 204 ° C. . Example 8. 4-Hydroxy-2-propyl-N - (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide. Acting as in Example 6, but starting with 6.3 g of 4-hydroxy-2-propyl-8-trifluoromethyl-3-quinoline-carboxylic acid and 2.1 g of amino-2-thiazole, in the presence of dicyclohexylcarbodiimide in dimethylformamide, 2.5 g are obtained 4 -oxy-2-propyl-UH (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide as, colorless crystals. mp. 222 C after recrystallization in acetic acid. N30.5 Elemental analysis: 381.36. Found: C 53.6 H 3.7; N 11.0: .S 8.5, - F 14.9. Calculated,%: C 53.53; H 3.70; N 11.02; S 8.40; F 14.94. The starting 2-propyl-4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid is prepared as follows. a) N - 2- (trifluoromethyl) -phenyl-butanamide. Acting as in phase a of Example 6, but starting from 32.2 g of o-trifluoromethylaniline- and 23.44 g of butyryl chloride, 24.4 g of (trifluoromethyl) -phenyl-butanamide are obtained; T.nn .. es) The acid chloride (trifluoromethyl) -phenyl-butanimic acid. Acting as in Phase B of Example 6, but starting from 23.1 g of (trifluoromethyl) -phenyl-butanamide and 22.9 g of phosphorus pentachloride, 24.8 N- 2- (trifluoromethyl) -phenyl-butanimido acid chloride (oil) is obtained. c) (2- (trifluoromethyl) -phenylaminio-but-1-ylidene) -malonic acid ethyl ester. Acting as in Phase 6 of Example 6, but starting from 24.8 g of N- 2- (trifluoromethyl) -phenyl-butanimido acid chloride and an organo-ethoxymagnesium compound of ethyl malonic ester, 37 g of ethyl ester 15a (2- (trifluoromethyl) -phenylamino -but -1-ylidene) -malonic acid (oil). d) 4-OXY-2-PROPIL-8-trifluoromethyl-3-quinolinecarboxylate ethyl ester acid. Acting as in phase g of Example 6, but starting from 37 g of 2- 1- (2- (trifluoromethyl) -phenylamino) but-1-ylidene -malonic acid ethyl ester, 15.6 g of 4-hydroxy-2 ethyl ester are obtained. -propyl-8-trifluoromethyl-3-quinolinecarboxylic acid, mp 98 ° after recrystallization in hexane. e) 4-hydroxy-2-propyl-8-trifluoromethyl-3-quinolinecarboxylic acid. Operating as in phase d of Example 6, but starting from 13.5 g of 4-hydroxy-2-propyl-3-trifluoromethyl-3-quinoline-carboxylic acid ethyl ester, 12.3 g of 4-hydroxy-2-propyl-8-trifluoromethyl are obtained. -3-quinolinecarboxylic acid; M.p. after recrystallization in isopanol. Example 9. 2-Butyl-4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide. Acting as in Example B, but starting from 6.8 g of 2-butyl-4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid and 2.17 g of amino-2-thiaol, in the presence of dicyclohexylcarbodiimide and in dimethylformamide, a crude product is obtained which is dissolved in 1N. sodium hydroxide and precipitated by adding hydrochloric acid. 4.15 g of 2-butyl-4-OKCH-N- (2-thiazole: l) -8-trifluoromethyl-3-quinoline-carboxamide are collected in the form of colorless crystals, m.p. recrystallization field in isopropanol Elemental analysis: C.N., F, N 0.5 - 395.407. 6 3 3 2 Found,%: C 54.8; H.4.1; F 14.5; N 10.4; S 8.3. Calculated,%: C 54.68; H 4.08) F .14.41; N 10.62; S 8.11. The starting.-Butyl-4-hydroxy-8-trifluoromethyl-3-quinoline carboxylic acid is prepared as follows. a) N (trifluoromethyl) -phenylJ-pentanamide. Acting as in Phase A of Example 6, but starting from 32.22 g of o-trifluoromethylaniline and 26.52 g of valeric acid chloride, 20.63 g (trypteropermetyI) -phenyl-pentaneamr are obtained (a; m.p. b) The acid chloride (trifluoromethyl) -phenyl-pentanimic acid. Acting as in phase B. Example 6, but starting from 20 g (trifluoromethyl) -phenyl pentanamide and 19 g of phosphorus pentachloride, 22.05 g of (trifluoromethyl) -phenyl-pentanimido acid chloride (oil) is obtained. c) (2- (trifluoromethyl) -phenylamino-pent-1-ylidenemalonic acid ethyl ester. Acting as in phase in Example 6, but starting from 22.05 g of N-2- (trifluoromethyl) -phenol-pentanimido acid chloride and prepared from 14.62 g of ethyl ethomagnesium organic ethyl ester of malonic acid ethyl ester of malonic acid, 31.68 g are obtained ethyl water About 2- l- (2- (trifluoromethyl) -phenyl5 amino) -pent-1-ylidene -malonic acid ester (oil). d) 2-butyl-4-scsi-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester. Acting as in Phase D of Example 6, JHO based on 30.7 g of ethyl (2- (trifluoromethyl) phenylamino) -pent-1-ylidene -malonic acid ethyl ester, 10 g of 2-butyl-4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester are obtained; m.p. 68-69 C. e) 2-Butyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylic acid. Acting as in Phase D of Example 6, but starting from 9.9 g of 2-butyl-4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester, 7.42 g of 2-butyl-4-hydroxy-8- trifluoromethyl 3-quinolinecarboxylic acid; So pl, l40 14iC after recrystallization in isopanol. C. p. Im ep 10. 4-OXY-2- (2-methyl) -propyl} -N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide. Acting as in Example 6, but starting from 10.02 g of 4-OXY-2-G (2-methyl) -propyl-8-trifluoromethyl-3-kinoline carboxylic acid and 3.2 g of amino-2-thiazole, in the presence of dicyclohexylcarbodiimide and in dimethylformamide, 4.03 g of 4-hydroxy-2-G (2-methyl) -propyl-3-N- (2-thiazolyl) -8-trifluoromethyl-3-quin, olincarboxamide are obtained in the form of colorless crystals; mp. 170171С after recrystallization in isopropanol. The starting 4-OXY-2- (2-methyl) -propyl -8-trifluoromethyl-3-quinolinecarboxylic acid is prepared as follows. a) (trifluoromethyl) -phenyl-3-methylbutanamide. Acting as in phase a of Example b, but starting from 40.28 g of o-trifluoromethyl analyte and 33.16 g of acid chloride and isovaler of a novel acid, 45.85 g of N-12- (trifluoromethyl) -phenyl-3-methylbutaneamide are obtained; m.p. 99-100 ° C. b) N- (2- (triphosphormethyl) -3-methylbutanolimide acid chloride Acting as in phase b of Example 6, but starting from 45 g (trifluoromethyl-phenyl-3-methylbutanamide and 42.02 g of phosphorus pentachloride, 47.95 g of N-2- (trifluoromethyl) -phenyl-3-methyl-butanimido acid chlorohydride are obtained (oil ). c) (2- (trifluoromethyl) -phenylamino) -3-methylbut-1-ylidenemalonic acid ethyl ester. Acting as in phase in Example 6, but starting from 47.95 g of N- 2- (trifluoromethyl) -phenyl-3-methyl-butanimido acid chloride. and an organomagnesium organic compound of malonic acid ethyl ester prepared from 31.89 g of malonic acid ethyl ester to obtain 72.45 g of (2- (trifluoromethyl) -phenylamino) -3-methylbut-1-ylidene-malonic acid ethyl ester (oil). d) 4-OXY-2- (2-methyl) -propyl -8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester. Acting as in phase g of Example 6, but starting from 72.45 g of ethyl 2-G1- (2- (trifluoromethyl) -phenylamine) -3-methylbut-1-ylidene-malonic acid, 44.7 g of ethyl ester 4 -OXI-2- (2-methyl) -propyl) -8-trifluoromethyl-3-quinolinecarboxylic acid m.p. . e) 4-OXY-2-G (2-methyl) -propyl-8-trifluoromethyl-3-quinoline-carboxylic acid. Acting as in Phase D of Example 6, but starting from 20.14 g of 4-OXY-2- (2-ythyl) propyl -8 ethyl ester: trifluoromethyl-3-quinolinecarboxylic acid, 17.15 g of 4-hydroxy- 2- (2-methyl) -propyl -8-trifluoromethyl-3-quinolinecarboxylic acid m.p. . Example 11. 2,4-Dio.xy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide. A mixture of 6.02 g of 2I ethyl ester of Dioxy-8-trifluoromethyl-3-quinolinecarboxylic acid in 200 cm of xylene and 2 g of amino-2-thiazole is heated under reflux for 2 hours in the presence of 20 g of K2 siliporite. After recrystallization in acetic acid, 5.54 g of 2,4-dioxy-M- (2-thiaoolyl) -8-trifluoromethyl-3-quinolinecarboximide are obtained in the form of colorless crystals} L. Pl. , Elemental analysis: S. ,, HgFj N.OiS "355,297. Found.%: C 47.3; H 2.2; 0 N 11.8; F 16.2; S 9,2. Calculated: C 47.33 H 2.27; N 11.83; F 16.04; S 9.02. I 2,4-Dioxy-8-trifluoromethyl-3-quinolinecarboxylic ethyl ester 5 acid is obtained as follows. a) Methyl ester of 2-amino-3- (trifluoromethyl) -benzoic acid. g24, 62 g of 2-amino-3- (trifluoromethyl) benzoic acid is introduced into 200 cm of anhydrous methanol. Gaseous hydrochloric acid was refluxed for 22 hours. Was evaporated, taken up in ether, washed with water, then with a 10% carbonate solution and subsequently neutralized to water. The ether fraction was evaporated to give 20.64 g of 2-amino-3- (trifluoromethyl) benzoic acid methyl ester as an oil; M.p. 56-5if C, 0 b) Methyl ester of 2- (3-ethoxy-3-oxopropionylamino) -3-triformethylbenzoic acid. 24.4 g of methyl 2-c1mino-3- (trifluoromethyl) benzoate 5 and 18.36 g of methylene chloride are introduced into 66 cm of anhydrous benzene. Heated under reflux for 1 hour, washed with water, then with a 10% aqueous solution of potassium carbonate and subsequently brought to neutrality with water. Evaporated and prepared. 35.75 g of methyl 2- (3-ethoxy-3-oxopropionylamino) -3-trifluoromethylbenzoic acid, m.p. 87 ° C. five c) Ethyl 2,4-dioxy-8-trifluoromethyl-3-quinoline-carboxylic acid. 35.66 g of 2 (3-ethoxy-3-oxopropionylamino- (3-tri0 fluoromethyl) benzoic acid methyl ester is introduced into 800 cm of anhydrous ether in the presence of sodium ethylate prepared from 2.69 g of sodium and 54 cm of ethanol. the product is sucked off, dissolved in water in 5 days and adjusted to pH 1 by addition of 20% hydrochloric acid. Collect 30.56 g of ethyl ether. 2,4-dioxy-8-trifluoromethyl-3-quinolinecarboxylic acid; M.p. , 0 EXAMPLE 12 4-Hydroxy-2-phenyl-—N- (2-thiazolyl) -8-trifluoromethyl-3-quinoline carboxamide. Act as in Example 6, but the outcome is 8.9 g of 4-hydroxy-2-phenyl-8-tri5 fluoromethyl-3-quinoline-carboxylic acid and 2.70 g of amino-2-thiazole, in the presence of 6.12 g of dicyclohexylcarbod imide and in 60 cm of dimethylformamide. a crude product is obtained which is dissolved in 1N. an aqueous solution of sodium hydroxide and re-precipitated by the addition of hydrochloric acid. 4.42 g of 4-hydroxy-2-phenyl-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide are collected in the form of colorless crystals; m.p. 238c after recrystallization in acetic acid. Elemental analysis: 17 s. 415,397. Naidon,%: C 58.0; H 2.8; F 13.8; N 10.0; S 8.0. Calculated,%: C 57.83; H 2.91; F 13.72; N 10.11; S 7.72. The starting 4-hydroxy-2-phenyl-8-trifluoromethyl-3-quinolinecarboxylic acid is prepared as follows. a) N- 2- (trifluoromethyl) -phenyl-beisamide. Acting as in phase a of Example 6, but starting from 40.28 g of o-trifluoromethyl aniline and 35.14 g of benzoyl chloride, in the presence of 25.3 g of triethylamine and in a medium of 400 cm of acetone, 41.45 g (trifluoromethyl) -phenyl - benzam schA; Tpl, 14 6 C. b) N- (2- (trifluoromethyl) -phenyl-benzenecarboximic acid chloride. Act as in phase 6 of Example 6, but starting from 26.52 g of (trifluoromethyl) -phenyl-benzamide It 22, 9 g of phosphorus pentachloride, in suspension in 160 cm2 of dry toluene, 28.8 g of (trifluoromethyl) -phenyl-benzenecarboxyimido acid chloride (oil) are obtained. C) 2-phenyl- (2- (tr fluoromethyl) -phenylamino) methylene ethyl ester - little new acid. Acting as in Phase B of Example 6, but starting from 2.6 g of (trifluoromethyl) phenylbenzenecarboximic acid chloride and organic ethoxymagnesium compound of malonic acid, prepared from 2.68 g of magnesium and 17.6 g of ethyl malonic ester, 32.6 g of 2-phenyl- (2- (trifluoromethyl) -phenylamino) -methylene -malonic acid ethyl ester are obtained: Tp 84 ° g) 4-hydroxy-2-phenyl-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester. lots. Acting as in Phase D of Example 6, but starting from 31.56 g of ethyl 2-phenyl- (2-, (trifluoromethyl) -phenyl amino) -methylene -malonic acid in 32 cm см of diphenyl ether, 23.56 g of ethyl ester 4 are obtained -oxy -2-phenyl-8-trifluoromethyl-3-hinrlincarboxylic acid; M.p. . e) 4-hydroxy-2-phenyl-8-trifluoromethyl-3-quinolinecarboxylic acid. I act as in phase d of Example 6, but proceeding from 12.64 g of ethyl 4-hydroxy-2-phenyl-8-trifluoromethyl-3-quinolinecarboxylic ester, 35 cm of caustic chathra solution at 36 ° C. and 70 cm of ethanol at 95 ° C, and, heating under reflux for 5,5 hours, 9.06 g of 4-hydroxy-2-phenyl-8-trifluoromethyl-3-quinoline carboxylic acid is obtained; m.p. 204 ° C. Example 13. 4-hydroxy-2-phenylmethyl-N- (2-thiazolyl) -8-trifluoromethyl-3-quinoline-carboxamide. Acting as in Example 6, but starting from 8.6 g of 4-hydroxy-2-fe1} ylmethyl-8-trifluoromethyl-3-quinolinecarboxylic acid and 2.47 g of amino-2-thiazole, in the presence of 5.59 g of dicyclohexylcarbodiimide and in 125 cm of dimethylformamide, a crude product is obtained, which is dissolved in 1N. an aqueous solution of sodium hydroxide and re-precipitated by the addition of hydrochloric acid. 2.76 g of 4-hydroxy-2-phenylmethyl-N- (2-thiazolyl) -8-trifluoromethyl-3-quinoline-carboxamide are collected in the form of crystals slightly colored in ocher color; T pl 256S. Elemental analysis; Cr N ;, d FjN jOnS. Found,%: C 58.6; H 3.2; F 13.4; N 9.7; S 7.6. Calculated,%: C 58.74; H 3.28; F I, 27; N 9.78; S 7.46. The starting 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-3-quinoline-carboxylic acid is prepared as follows: a) N-2-1 (trifluoromethyl) -phenyl-benzene-acetamide. I act as in phase a of Example 6, but proceeding from 40.28 g of o-trifluoromethylaniline and 42.5.g of phenylacetic acid chloride, in the presence of 27.83. g of triethylamine, and in an environment of 4QO smbenzene get 29,85 g (trifluoromethyl) -phenyl-benzene-acetamide; M.p. after recrystallization in hexane. b) The acid chloride (trifluoromethyl) -phenyl-benzene-ethanimic acid. Acting as in phase B of Example 6, but starting from 27.92 g of (trifluoromethyl) -phenyl-benzene-acetamide and 22.9 g of phosphorus pentachloride, in a suspension in 170 cm of dry toluene, 30.4 g of (trifluoromethyl) -phenyl chloride - - benzeneethanimic acid c) 2-H2-phenyl-1- (2- (trifluoromethyl) -phenylamino) ethyl-1-ylidene-malonic acid ethyl ester. Acting as in phase in Example 6, but starting from 30.4 g of (trifluoromethyl) -phenyl-benzene-ethanimic acid chloride and organic ethoxymagnesium compound malonic acid ester prepared from 2.68 g of magnesium and 17.6 g of malonic ethyl ester 44.56 g of 2- t2-phenyl-1- (2- (trifluoromethyl) -phenylamino) -ethyl-1-ylylene-malonic acid ethyl ester d) 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-3-quinolinecarboxylic acid ethyl ester. Acting as in phase g of Example b, but starting from 44.5 g of 2- 2-phenyl-1- (2- (trifluoromethyl) -phenylamino) ethyl-1-ylidene-malonic acid ethyl ester in 45 cm of diphenyl ether, is obtained after chromatography 12.7 g of ethyl 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-3-quinolinecarboxylic acid, m.p. after recrystallization in ethanol. e) 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-3-quinoline-carboxylic acid. Acting as in phase d of Example 6, but starting from 9.4 g of ethyl 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-3-quinoline-carboxylic acid, 25.2 cm of sodium hydroxide solution and 51 cm of ethanol at, and, heating under reflux, 7.3 g of 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-3-quinolinecarboxylic acid are boiled; T, pl. 252 ° C.
权利要求:
Claims (1) [1] 1. Vuler K. and Pearson D. Organic syntheses. M., Mir, 1973, p. 384-390. .
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同族专利:
公开号 | 公开日 JPS52116479A|1977-09-29| JPS623152B2|1987-01-23| FR2340735B1|1978-11-03| IL51413D0|1977-04-29| ZA77787B|1978-03-29| SE7700804L|1977-08-12| BE851306A|1977-08-10| FR2340735A1|1977-09-09| IE44879L|1977-08-11| NL7701398A|1977-08-15| AU508345B2|1980-03-20| DE2705446A1|1977-08-18| DD129552A5|1978-01-25| DK150512B|1987-03-16| CA1089464A|1980-11-11| AU2221877A|1978-08-17| IE44879B1|1982-05-05| DE2705446C2|1989-10-12| US4107310A|1978-08-15| ES455804A1|1978-01-16| IL51413A|1980-09-16| DK150512C|1987-11-16| SE441528B|1985-10-14| GB1572482A|1980-07-30| LU76742A1|1977-08-19| DK56077A|1977-08-12| CH620437A5|1980-11-28|
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