FI91400C - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents

Description

i 91400

Process for the preparation of quinolinecarboxylic acid derivatives

The invention relates to a new process for the preparation of quinolinecarboxylic acid derivatives of the formula I and their pharmaceutically acceptable salts.

F il COCH

\\ (I)

r2 "" I

R1 wherein R1 is phenyl which may be substituted by one or two halogen atoms, and R2 is piperazinyl or 4-methylpiperazinyl.

It is known that 8-fluoro analogues of the compounds of the formula I in which Rx is the group -CH2CR6R7R8 (in which R6, R7 and R8 denote hydrogen or halogen) have a high antibacterial activity (J. Med. Chem. 1986, 29, 445, Drugs of Fut. 1984, 9, 246; 23rd Intersci. Conf. An-25 timicrob. Agents Chemother. 1983, Abst. 658, 7th Int. Symp. Fut. Trends Chemother. 1986, 86). The compounds can be prepared by the reaction of 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with cyclic amines (BE patent 887 874, GB patent 2,057,444, AT patent 30,537). 813 and EP Patent 1,064,489).

It is also known that the compounds of the formula I described above have a strong antibacterial effect (24th Intersci. Donf. Antimicrob. Agents Chemother, 1984, Abst. 72-78., Antimicrob. Agents Chemother. 1987, 35 619, Antimicrob. Agents Chemother. 1986, 192-208). Nama 2 compounds can be prepared by the reaction of 1-substituted-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and cyclic amines in the presence of a solvent at 100 ° C for 20 hours (EP patent 131 839, 5 J. Med. Chem. 1985, 1558, J. Med. Chem. 1987, 504).

Several methods are known in the art for the preparation of oxazine derivatives, e.g. by reacting 6-fluoro-7-chloroquinolinecarboxylic acid or its ester with piperazine or N-methylpiperazine (see

EP 0 047 005 and US 4 146 719 (oxfloxacin); US 4,472,579 and DE 2,840,910 (norfloxacin); DE 28 43 66 (perfloxacin); EP 004 935 (cyprofloxacin); EP 090 424 (amifloxacin)).

The disadvantage of said known methods is that the amination with piperazine or N-methylpiperazine does not take place selectively at the 7-position, but the nucleophilic substitution reaction takes place at both the 6- and 7-positions.

The present invention is based on the finding that as the starting material used as the boronic anhydride derivative, a piperazine or N-methylpiperazine group can be selectively attached to the 7-position of the quinoline backbone. In addition, it has been found, moreover, that the process according to the invention is selective when a group containing a halogen atom is present at the 1-25 position of the quinoline supercharger.

The present invention relates to a new process for the preparation of the quinoline carboxylic acid derivatives of the formula I described above and their pharmaceutically acceptable salts. The methods are characterized in that the compound of formula

R \ / R

35 L I i

J (ID

Wherein R 1 is as defined above and R 1 is an aliphatic acyloxy group having 2 to 6 carbon atoms, or an aromatic acyloxy group containing 7 to 11 carbon atoms is reacted with an amine of the formula NH (III) 10 wherein R5 is hydrogen or methyl, or a salt thereof, and the resulting compound of formula R1010-,

TTY

wherein R, R1 and R2 are as defined above, are hydrolyzed with or without isolation and, if desired, the compound of formula (I) obtained is converted into a salt or the compound is liberated from its salt.

The process according to the present invention has the advantage that it can be used to prepare the compounds of the formula (I) in a simple manner, in very high yields and with a short reaction time.

The boron derivatives of formula (IV) are novel compounds.

According to a preferred embodiment of the present invention, the boron derivative of formula (IV) is converted to the desired quinoline-3-carboxylic acid of formula I without isolation.

The boron derivatives of formula (II) may, if desired, be reacted with amine 4 of formula (III) in the presence of an inert organic solvent granule and an acid scavenger.

As the inert organic solvent, an acid amide (e.g. dimethylformamide, dimethylacetamide), a ketone (e.g. acetone, methyl ethyl ketone), an ether (e.g. dioxane, tetrahydrofuran, diethyl ether), an ester (e.g. ethyl acetate, ethyl acetate, methyl acetate, e.g. , sulfoxide (e.g. dimethyl sulfoxide), alcohol (e.g. methanol, ethanol, 1-decanol, butanol).

An organic or inorganic base can be used as the acid scavenger. Among the group of organic compounds, mention may be made of trialkylamines (for example triethylamine, tributylamine), cyclic amines (for example pyridine, 1,5-diazabicyclo [5.4.0] udek-5-ene, 1,5-diazabicyclo [4.3.9] non-5-ene, 1,4-diazabicyclo [2.2.2] octane), while alkali or alkaline earth metal hydroxides or carbonates are preferably used from inorganic bases. Thus, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc., or an excess of the amine of formula (III) can be preferably used as the acid-binding agent.

The boron derivative of formula (II) and the amine of formula (III) may be reacted at a temperature of 0 to 200 ° C, depending on the solvent used. The reaction time ranges from half an hour to ten hours. The reaction time depends on the reaction temperature. If the reaction is carried out at a higher temperature, the reaction time can be shortened. The above reaction conditions are preferred, but other conditions can be well used.

The compounds of formula (IV) may be hydrolyzed, with or without isolation, to the desired quinoline-3-carboxylic acids of formula (I) under either acidic or basic conditions. The compound of formula (IV) 91400 5 precipitates from the reaction mixture, for example under cooling, and can be separated, for example, by filtration or centrifugation, if desired.

The basic hydrolysis can preferably be carried out by heating using an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate. Preferably, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide can be used. However, organic amines (for example triethylamine) can also be used in the hydrolysis step.

The acid hydrolysis can be preferably carried out using aqueous mineral acid. It is advantageous to proceed by hydrolysing a compound of formula (IV) by heating together with hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. The hydrolysis can be performed using an organic acid (e.g., acetic acid, propionic acid, etc.).

The hydrolysis of the compounds of formula (IV) can be carried out in an aqueous solution of myOs in the presence of a water-miscible organic solvent. For this purpose, alcohols (e.g. methanol, ethanol), ketone (e.g. acetone), ether (e.g. dioxane), acid amide (e.g. dimethylformamide), sulfoxide (e.g. dimethyl sulfoxide) or pyridine can be used.

The quinoline-3-carboxylic acid of formula (I) thus obtained can be isolated, for example, by adjusting the pH of the aqueous solution and separating the precipitated crystals, for example, by filtration or centrifugation or by lyophilization of the aqueous reaction mixture.

The compounds of formula (I) may be converted into their pharmaceutically acceptable salts in a known manner. Thus, acid addition salts can be advantageously formed, for example salts formed with hydrogen halides, sulfonic acids, sulfuric acid or organic acids. Preferably, chlorides, bromides, aryl sulfonates, methanesulfonates, maleates, fumarates, benzoates, etc. can be formed. The compounds of formula (I) form salts with alkali and alkaline earth metals and other metal ions. Thus, sodium, potassium, magnesium, silver and copper salts can be prepared.

The compounds of formula (I) and their pharmaceutically acceptable salts can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) si-10 nSnsS by known methods.

The starting materials of formula (II) can be prepared by the reaction of 1-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (EP Patent 131,839) with a boron derivative, for example a compound the formula is 15

R

B -R 00

R

Wherein R is an aliphatic acyloxy group having 2 to 6 carbon atoms, or an aromatic acyloxy group having 7 to 11 carbon atoms, in aqueous solution or in an organic solid.

The following examples illustrate the invention.

Example 1 1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O3, O *) -difluoroboron are reacted with 1.29 g with piperazine in 8 ml of 30 dimethyl sulfoxide at 100 ° C for three hours. A 6% w / v aqueous solution of 12.6 ml of sodium hydroxide is added and the hydrolysis is continued with heating for two hours. The reaction mixture is filtered, the pH is adjusted to 7 with 96% w / v acetic acid and diluted with 15 ml of water. The crystalline reaction mixture is cooled to 91400 overnight and the precipitated crystals are filtered off, washed with water and dried. 1.61 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid are thus obtained. Sp. is 234-236 ° C.

5 Analysis for C16H17F2N3O3:

Calculated: C 56.90 H 5.07 N 12.45%

Found: C 56.75 H 5.02 N 12.48%

Example 2 1.99 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-10-quinoline-3-carboxylate-03.04) -bis (diacetate-O) -boron are subjected to react with 1.29 g of piperazine in 8 ml of dimethyl sulfoxide at 110 ° C for two hours. 20 ml of 3% w / v aqueous sodium hydroxide solution are added. The reaction mixture is reacted for one hour, after which it is filtered and the pH is adjusted to 7 using 96% w / v acetic acid. Cool and dilute with 10 ml of water and filter the precipitated crystals and dry. There is thus obtained 1.59 g of ocranic acid 1-ethyl-6,8-difluoro-1,4-dihydro-4-octo-7-piperazinoquinoline-3-carbo-20-carboxylic acid. Sp. 234 C.

Analysis for the formula ^ 16 ^ 17 ^ 2 ^ 3 ^ 3 '

Calculated: C 56.90 H 5.07 N 12.45%

Found: C 57.03 H 5.11 N 12.51%

Example 3 According to Example 2, 1.06 g of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate-03.04) -bis- (propionate-O) boron reacted with 0.64 g of piperazine in 4 ml of dimethyl sulfoxide. 6.3 ml of a 6% w / v aqueous solution of sodium hydroxide are added and the reaction mixture is heated under reflux for one hour. Filter and then adjust the pH to 7 using 96% w / v acetic acid, add 10 ml of water and cool the reaction mixture over yOn. The precipitated crystals are filtered off, washed with water and dried. 0.74 g of 1-ethyl-6,8-difluoro-1,4-8 dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid are thus obtained. Sp. is 232-236 ° C.

Analysis for the formula ^ 16 ^ 17 ^ 2 ^ 3 ^ 3 ♦

Calculated: C 56.90 H 5.07 N 12.45% 5 Found: C 56.85 H 5.00 N 12.39%

Eslmerkkl 4

According to Example 1, 1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate-03.04) -difluoroboron is reacted with 1.5 g of with 1-me-10-piperazine in 8 ml of dimethyl sulfoxide. 1.54 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazine) quinoline-3-carboxylic acid are obtained. Sp. is 237-240 ° C.

Analysis for C 17 H 19 F 2 N 3 O 3: 15 Calculated: C 58.10 H 5.45 N 11.91%

Found: C 58.00 H 5.46 N 11.95%

Example 5

According to Example 2, 1.99 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate-03.04) -bis (acetate-O) boron are obtained and 1.5 g of 1-methylpiperazine to react with each other. 1.5 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazino) quinoline-3-carboxylic acid are thus obtained. Sp. 238 - 240 eC. Analysis for Formula 25 Calculated: C 58.10 H 5.45 N 11.91%

Found: C 58.19 H 5.53 N 11.87%

Example 6

According to Example 3, 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-4-carboxylate-30.04) -bis (propionate-O) -boron reacted with 0.75 g of 1-methylpiperazine. 0.79 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazino) quinoline-3-carboxylic acid is obtained.

Sp. 239-240 ° C.

35 Analysis for C 17 H 19 F 2 N 3 O 3:

Calculated: C 58.10 H 5.45 N 11.91%

Found: C 57.95 H 5.37 N 11.90% 91400 9

Example 7 0.46 g of 1- (4'-fluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate-03.04) -bis (acetate-O) boron is reacted with 0.6 g of N-5 methylpiperazine in 5 ml of dimethyl sulfoxide at 110 ° C for one hour. 10 ml of 5% w / v aqueous sodium hydrogen carbonate solution are added, the reaction mixture is heated under reflux for two hours, the pH of the fraction being adjusted to 7 with 96% w / v acetic acid. The reaction mixture is cooled and the precipitated crystals are filtered and washed with cold water. 0.35 g of 1- (4'-fluorophenyl) -6-fluoro-7- (N-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is thus obtained. mp. 282 - 284 eC. The carboxylic acid obtained from NS is dissolved in a dilute aqueous solution of hydrochloric acid without heating, and the solution is evaporated in vacuo to give 1- (4'-fluorophenyl) -6-fluoro-7- (N-methylpiperazinyl) -1,4-dihydro-4-oxoquinoline. The hydrochloride salt of -3-carboxylic acid. The product decomposes above 270 ° C.

Analysis for C21H19F2N3O3:

Calculated: C 63.15 H 4.79 N 10.52%

Found: C 63.27 H 4.89 N 10.35%

Claims (7)

A process for the preparation of quinolinecarboxylic acid derivatives of formula I and pharmaceutically acceptable salts thereof, COOH \ II (I) 10 in which formula R1 is phenyl, which may be substituted by one or two halogen atoms, and R2 is piperazinyl or 4-methyl-piperazinyl; characterized in that a compound of the formula R 1 / R 20 F x 2 wherein R 1 is the same as above and R is an aliphatic acyl oxy group of 2-6 carbon atoms or an aromatic acyloxy group of 7-11 carbon atoms is reacted with a amine of the formula R5β (III) R5 is R5 Sr vate or methyl, or a salt thereof, and the obtained compound of formula R \ 5 o x x Kb Kb (IV) YTT 10 in R , R 1 and R 2 are the same as above, hydrolyzed after Isolation or without isolation and, if desired, a obtained compound of formula (I) is converted to a salt or the compound is released from a salt thereof. A process according to claim 1, characterized in that a compound of formula (II) reacted with an amine of formula (III) in the presence of an organic solvent, preferably an acid amide, sulfoxide, a ketone, an alcohol, ether or ester. 3. The process of claim 2, wherein dimethyl sulfoxide is used as an organic solvent. 4. A process according to claim 1, characterized in that the reaction of the compounds of formulas (II) and (III) is carried out in the presence of an acid-binding agent. 5. A process according to claim 4, characterized in that as an acid binding agent an amine or excess of a compound of the formula (HD) is used. 6. A process according to claim 1, characterized in that the hydrolysis is carried out in an alkaline medium. 7. A process according to claim 6, characterized in that an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base are used, preferably an aqueous solution of triethylamine.