HU203746B - Process for producing quinoline-carboxylic acid derivatives - Google Patents

Description

The present invention relates to 1- (optionally substituted with one halogen) ethyl-7- (3 and / or 5-substituted-1-piperidinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acids of formula (I) and relates to the new preparation of their pharmaceutically acceptable salts.

It is known that 7- (3 and / or 5-substituted-1-piperazinyl) quinolinecarboxylic acid of formula (I) wherein R * is hydrogen or C 1-4 alkyl, R ² is C 1-4 alkyl, R ⁴ hydrogen or halogen) have outstanding antibacterial activity (Drugs Fut. 1986, 11, 578; Antimicrob. Agents Chemother. 1987, 31, 854; 26th Internt. Conf. Antimicrob. Agents Chemother. New Orleans, Abst. 430-431, 1986). *, 25th Int., Conf. Antimicrob. Agents Chemother. 1987,31854; 26th Intersci. Conf. Antimicrob. Agents Chemother. New Orleans, Abst. 430-431, 1986; 25th Intersci. Conf. Antimicrob. Agents Chemother. Minneapolis, Abst. 567.1985).

The compounds of formula (I) may be prepared by reaction of 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with cyclic amines (U.S. Pat. No. 3,433,924; U.S. Pat. No. 142980/83; Japanese Patent Nos. 85381/86 and 65882/86).

According to the present invention, ethyl 7- (3- and / or 5-substituted 1-piperazinyl) 6,8-difluoro-1,4-dihydro-4-oxo-quinoline of formula (I) is optionally substituted by a halogen atom. -3-Carboxylic acid k (wherein R ¹ , R ² and R ⁴ are as defined above) can be prepared in a simple manner and in a very short time using a very short reaction time to obtain the borate derivatives of formula (dy) lower alkanoyloxy group ^R4 during the same as defined above) and the cyclic amines of formula (Π) salt thereof (wherein R ¹ and R ² are as stated above), reacting the resulting borate of formula (IV) derivatives (mdy R ¹ , R ² , R ⁴ and R are as defined above). In a preferred embodiment of the process, the borate derivatives of formula (IV) are converted into quinoline-3-carboxylic acids (I) without isolation. The intermediates of formula (TV) are novel compounds. The new process is advantageous over the known process referred to above in that the final product can be adjusted with better yield and shorter reaction time based on the same starting material.

The borate derivatives of formula (Π) are reacted, if desired, with the cyclic amines of formula (ΙΠ) in the presence of an inert organic solvent and an acid acceptor.

Suitable organic solvents include acid amides such as dimethylformamide, dimethylacetamide, ketones such as acetone, methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran, diethyl ether, esters such as ethyl acetate, methyl acetate, ethyl propionate, sulfoxides, dimethyl sulfoxides, alcohols such as methanol, ethanol, 1-decanol, butanol, halogenated organic solvents such as chloroform, dichloroethane.

Organic and inorganic bases may be used as acid binders. Organic bases include trialkylamines such as triethylamine, tributylamine, cyclic amines such as pyridine, 1,5-diazabicyclo [5,4,0] undex-5-ene, 1,5-diazabicyclo [4,3,0] non-5-ene, 4-diazabicyclo [2,2,2] octane, while inorganic bases include hydroxides and carbonates of alkali metals and alkaline earth metals. Thus, potassium carbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide can be used as acid binders. If desired, an excess of amines of formula (ΙΠ) may be used as an acid acceptor.

The skin derivatives of the formula (Π) and the amines of the formula (is) are also reacted, depending on the solvent used, at a temperature of 10-200 ° C for a reaction time of 0.1 to 10 hours. The reaction time used depends on the reaction temperature chosen. Raising the rewetting temperature allows for a shorter reaction time.

If desired, circumstances other than those described above may be employed.

The borates of the general formula (TV) can be hydrolyzed, if desired, under acidic or basic conditions to the quinoline-3-carboxylic acid derivatives of the general formula (I). Depending on the solvent, for example, the compound of formula (IV) is separated from the reaction mixture by cooling, which may then be recovered by filtration or centrifugation, or optionally by filtration or centrifugation, or optionally by evaporation.

In the case of hydrolysis under basic conditions, an aqueous solution of the hydroxides or carbonate salts of the alkali metals and of the hydroxides of the alkaline earth metals is preferably used. In a particularly preferred embodiment of the process, the hydrolysis of the compounds of formula (TV) is carried out by heating with an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, potassium carbonate or calcium hydroxide. If desired, the hydrolysis may be carried out using organic bases such as triethylam.

For hydrolysis under acidic conditions, an aqueous solution of mineral acids is preferred. In a particularly preferred embodiment of the process, the hydrolysis of the borates of formula (IV) is carried out by heating with, for example, an aqueous solution of hydrochloric, hydrobromic, sulfuric or phosphoric acid. If desired, the hydrolysis may also be carried out using organic acids such as acetic acid, propionic acid.

If desired, hydrolysis of the compounds of formula (TV) in an aqueous medium is carried out in the presence of a water-miscible organic solvent. Organic solvents include alcohols such as methanol, ethanol, ketones such as acetone, ethers such as dioxane, acid amides such as formamide, dimethylformamide, sulfoxides such as dimethyl sulfoxide, and pyridine.

For example, the quinoline-3-carboxylic acids of the formula (I) formed are adjusted, for example, to the pH of the aqueous solution and the crystals precipitated.

It can be isolated, for example, by centrifugation or filtration or by lyophilization of the aqueous reaction mixture.

If desired, the quinoline-3-carboxylic acids of formula (I) may be converted into their pharmaceutically acceptable salts in known manner. Preferably, acid addition salts such as hydrogen halides, sulfonic acids, sulfuric acids, organic acids can be formed to form Idorides, bromides, 4-methylphenylsulfonates, methanesulfonates, maleate, fumarates, benzoates, alkali metal and other alkali metal salts. can also be applied. Thus, salts with, inter alia, sodium, potassium, magnesium, calcium, silver, copper ions can be prepared.

If desired, hydrates of the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be prepared in a manner known per se.

The starting quinoline derivatives of formula (Π) (wherein R ⁴ and R are as defined above) can be prepared, for example, from 1-ethyl-6,7,8-trifluoro-4-oxole, 4-dihydroquinoline-3-carboxylic acids (2 British Patent No. 057,440) and various boron derivatives, for example, by reacting boron derivatives of formula (V) wherein R is halogen or C2-C5 alkanoyloxy or tetrafluoroboric acid in aqueous or organic media.

Further details of the process are set forth in the Examples, without limiting the invention to the Examples.

Examples

Example 1

9.31 g of (l-Ethyl-6,7,8-trifluoro-l, 4-dihydro-4-oxoquinoline-3-karboxflát 0 ^3, O ⁴⁾ difluoro-boron compound

57.1 g of 2,6-dimethylpiperazine are reacted in 150 ml of dimethylsulfoxide at 100 ° C for 3 hours.

400 ml of a 3% (w / v) aqueous sodium hydroxide solution are added to the reaction mixture and the mixture is heated to reflux for 2 hours while still being cooled and adjusted to pH 7 with 96% acetic acid. The crystalline mass thus obtained was cooled overnight. The precipitated crystals are filtered off, washed with water and dried.

29.9 g of 7- (3,5-dimethyl-1-piperazinyl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, m.p. 232-234 ° C.

Analysis calculated for C ₁₈ H ₂₁ F ₂ N ₃ ) ₃ : C, 59.17; H, 5.80; N, 11.49. Found: C, 59.05; H, 5.91; -11.45%.

Example 2

9.31 g of (l-Ethyl-6,7,8-trifluoro-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O ^3, 0 ⁴⁾ difluoro-boron compound

50.1 g of 2-methylpiperazine were reacted in 150 ml of dimethylsulfoxide at 100 ° C for 3 hours.

400 ml of a 3% aqueous sodium hydroxide solution were added to the reaction mixture and hydrolyzed again to reflux for 2 hours. The mixture was filtered while still hot and adjusted to pH 7 with 96% acetic acid. The crystalline mass thus obtained was cooled overnight. The precipitated crystals are filtered off, washed with water and dried.

30.6 g of 7- (3-methyl-1-piperazinyl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, m.p. 238-240 ° C.

Analysis calculated for C ₁₇ H ₁₉ F ₂ N ₃ O ₃ C-58.11% H-5.45% N-11.96% Found: C-58.01% H-5.55% N-12 , 07%.

Example 3

39.9 g of (l-ethyl-6,7,8-trifluoro-l, 4-dihydro-4-oxoquinoline-3-carboxylate / 7 ³ 0 ⁴⁾ diacetate-boron compound

50.1 g of 2-methylpiperazine are reacted with ISO ml dimethylsulfoxide 2. as described in Example.

Work-up gives 30 <2g7- (3-methyl-1-piperazinyl) 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, m.p. melted.

Analysis calculated for C ₁₇ H ₁₉ F ₂ N ₃ O ₃ : C-58.11; H-5.45; N-11.96%. Found: C-57.97; H-5.53% N -11.90%.

The product obtained above, when mixed with the material prepared in Example 2, shows no decrease in melting point.

Example 4

42.7 g of (1-ethyl-7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate- ³ , 0 ⁴ ) -dipropolyol-AT-boron

50.1 g of 2-methylpiperazine were reacted under the conditions described in Example 2

28.7 g of 7- (3-methyl-1-piperazinyl) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid are obtained, m.p. 237-239'C.

Analysis calculated for C ₁₇ H _{17 7} F ₂ N ₃ O ₃ : C-58.11; H-5.45; N-11.96%. Found: C-57.99; H-5.52% N -12.10%.

The product, when mixed with the material prepared in Example 2 in any ratio, does not show a decrease in the melting point

Example 5

4 (2 g of [l- (2-fluoroethyl) -6,7,8-trifluoro-l, 4-dihydro-4-quinolone-3-carboxylate 0 ^3, O ^4] di & cetane boron compound and 35 Chloroform (2 ml) was added with stirring at room temperature (3.4 g), and the resulting yellow slurry was stirred at room temperature to give a solution which was stirred for a further 2 and a half hours. The solvent was evaporated in vacuo to a residue. 40 ml of a 4% sodium hydroxide solution are added and the mixture is refluxed for 1 hour, the solution is cooled, acidified to pH 6.5 with 86% acetic acid, and the precipitated crystals are filtered off with suction and washed with cold methanol.

3.06 g (84.6%) of 7- (3-methyl-1-piperazinyl) -1- (2-fluoroethyl) -6,8-difluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid is obtained, m.p. 238-240 ° C.

Analysis calculated for C ₁₇ H ₁₈ N ₃ O ₃ F ₃ : C, 55.28; H, 4.91; N, 11.37. Found: C, 55.20; H, 4.94; N -11.40%

Preparation of starting compounds

HU 203 746 Β

Example 6

0.92 g boric acid, 3.17 g ethyl [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dlhydro-4-oxo-3-quinoline carboxylate] and 6.5 ml 96 Acetic anhydride (4.6 g) was added and the mixture was stirred at 110 ° C for 1 hour. The resulting brown solution was cooled to 10 ° C and 50 ml of ice water was added. added. The precipitated crystals were filtered off with suction and washed with cold methanol, 3.9 g (93.5%) of [1- (2-fluoroethyl) 6.7.8-trifluoro-1,4-dihydro-4-oxoquinoline as white crystals. 3-carboxy-b through ^3, 0 ^4] diacetate-boron compound having a decomposition point of 220 ° C;

Calcd for C ₁₆ H ₁₂ BF ₄ NO ₇ Calculated: C - 46.07% H - 2.90% N - 3.35% F 18.22% Found: C - 46.12% H - 2, 82% N - 3.35% F -18.23%

Example 7

3.0 g of ethyl (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate) in 15 ml of a 50% aqueous solution of tetrafluoroboric acid for 2.5 hours at 80-90 ° C. After stirring for about half an hour, crystal precipitation begins. At the end of the reaction time, a thick slurry was obtained. The reaction mixture was cooled to room temperature and allowed to stand overnight in the refrigerator. -dihydro-4-oxo-quinoline-3-carboxylate- ³ , 0 ⁴ ) -difluoro-boron] is obtained which decomposes at 289 ° C.

Analysis calculated for C ₁₂ H ₇ BF ₃ NO ₃ : C-45.18; H-2.21; N-4.40; Found: C, 45.26; H-2.18; N, 4.32. %

Example 8 A mixture of boric acid (6.9 g) and propionic anhydride (6.9 g) was stirred at 95-100 ° C for 30 minutes. Ethyl (1-ethyl6.7.8-trifluoro-1,4-dihydro-4-oxo-3quinol) was added (3.0 g). Carboxylate is dissolved in 12 ml of propionic acid while warm and added to the above solution without interrupting the heating of the reaction mixture. The resulting red solution was stirred at 110 ° C for 5 hours. Then cooled to room temperature and water (150 ml) was added. The precipitated crystals were collected by filtration with water and washed with a little methanol, after drying, 4.1 g of [(l-ethyl-6,7,8-trifluoro-l, 4-dihydro-4-oxoquinoline-3-carboxylic acid-O ^3, 0 ⁴ ) -dipropionate-boron], which decomposes 195-196 ° C

Analysis: Calculated for C _t gHj ₇ BF ₃ NO ₇ : C, 50.61% H, 4.01% N, 3.29%. Found: C, 50.72% H-4, 11% N-3. 31%

Claims (7)

⁶ PATENT CLAIMS A process for the preparation of a compound of formula (I) and pharmaceutically acceptable salts thereof R ¹ is hydrogen or (C 1 -C 4) alkyl, R ² is (C 1 -C 4) alkyl, R ⁴ is hydrogen or halogen, characterized in that a compound of formula ( R 15 is halogen or C 2 -C 5 alkanoyloxy and R ⁴ is reacted with a piperazine derivative (ΙΠ) or a salt thereof as defined above, wherein ^R1 and ^R2 are as defined above - and the resulting (IV) 20 compounds of the formula R ¹ , R ² , R ⁴ and R are as defined above, after isolation or without isolation and the resulting compound of formula (I) is optionally, if known, converted into its pharmaceutically acceptable salt from its yuccum salt. 2. The process of claim 1 wherein the compounds of formula (Π) and (ώ) wherein R ¹ , R ² , R ⁴ and R are as defined in claim 1 in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester. 3. A process according to claim 2 wherein the organic solvent is glazed with dimethylsulfoxide. A process according to claim 1 wherein the compounds of formula (Π) and (ΙΠ) wherein R ¹ , R ² , R ⁴ and R are as defined in claim 1 in the presence of an acid acceptor 5. A process according to claim 4 wherein the acid acceptor is an amine or an excess of a compound of formula (IH) The process of claim 1, wherein the hydrolysis is carried out in an alkaline medium 7. The process according to claim 6, wherein the alkali is an alkali metal hydroxide, an alkaline earth metal hydroxide or an aqueous solution of an organic base, preferably triethylamine.