PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACID DERIVATIVES

Abstract: The invention relates to a new process for the preparation of compounds of general formula (I) (wherein R<1> stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general formula CH2CR<6>R<7>R<8> (wherein R<6>, R<7> and R<8> stand for hydrogen or halogen); R<2> stands for piperazinyl or 4-methyl-piperazinyl; R<3> stands for hydrogen or fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of general formula (II) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms, R<4> stands for fluorine or chlorine) with a piperazine derivative of general formula (III) (wherein R<5> stands for hydrogen or methyl) or a salt thereof and subjecting the compound of general formula (IV) thus obtained (wherein R, R<1>, R<2> and R<3> are as stated above) to hydrolysis after or without isolation and if desired converting the compound of general formula (I) thus obtained into a salt thereof or setting free the same from its salt. The compounds of general formula (I) are known antibacterial agents. The advantage of the process of the present invention is that it makes the desired compounds of general formula (I) available in a simple manner, with high yields and in a short reaction time.

Description: PROCESS FOR THE PREPARATION OF QU INOL INE CARBOXYL IC ACID DERIVATIVES This invention rel ates to a new process for the pre¬ paration of l-substituted-7-(optiαπally substituted pipera- zi ne ) -6 -f luoro-8-( optionally f] uoro-substituted)-4-oxo-l , 4- dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I and pharmaceutically acceptable salts thereof. In the general Formula I R 1 stands for pheπyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula - -CH 2 CR 6 R 7 R 8 (wherein R 6 , R 7 and R 8 stand for hydrogen or halogen); R^ stands for piperazlnyl or 4-methyl-piperazinyl; R- 5 stands for hydrogen or fluorine. It is known that a group of the 7-sυbstituted- carboxylic derivatives of the general Formula I (wherein R- stands for piperazinyl, 4-methyl-pipεrazinyl, R-"- stands for a group of the general Formula -CH 2 CR 6 R 7 R 8 (wherein R 6 , R 7 and R° stand for hydrogen or halogen) and R-^ stands for fluorine) possesses high antibacterial activity (J.Med. Chem. 1986, 73_, 445; Drugs of Fut. 1984, 9_, 246; 23rd Iπtersci. Cαπf. Anti- microb. Agents Chemαther. 1983, Abst. 658, 7th Int. Sy p. Fut. Trends Chemother. 1986, 86) . These compounds can be prepared by reacting 6,7,8-trifluαrα-4-cxo-l,4-dihydro-quiπαline-3- carbαxylic acid and cyclic amines (Belgian patent specifica¬ tion 887874, G3 patent specification 2057444, Austrian patent specification 537813 and European patent specification 1064489). Another group of the 7-substituted-quinoline-3- carboxylic acids of the general Formula I (wherein R-*- stands for pheπyl optionally substituted by 1 or 2 halogen atoms, R- staπds for piperaziπyl or 4-methyl-piperaziπyl and R- 5 stands for hydrogen) has also high antibacterial activity (24th Iπtersci. Conf. Aπtimicrob. A^πts Chemother, 1984, Abst. 72- 78., Amtimicrob. Agents Chemother. 1987., 619, Aπtimicrob. Agents Chemother. 1906., 192-208). These compounds can be pre¬ pared by reacting 1-substituted phenyl-6-fluoro-7-chlαro-4- oxo-1,4-dihydro-quinαline-3-carboxylic acid and cyclic amines in the presence of a solvent at a " temperature of 100 °C for 20 hours (European patent specification 131839, 3 . Med. Chem. 1985, 1558., 3 . Med. Chem. 1987. 504.). According to the present invention there is provided a new process for the preparation of quinoline-3-carboxylic acid derivatives of the general Formula I (wherein R-*- stands for phenyl optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH 2 CR 6 R 7 R 8 (wherein R 6 , R 7 and R 8 stand for hydrogen cr halogen), R^ stands for piperazinyl, 4-methyl-piperazinyl and R^ stands for hydrogen or fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II (wherein R stands for halogen, an aliphatic acyloxy group containing 2 to -6 carbon atoms or aromatic acyloxy group containing 7 to 11 carbon atoms, R* stands for fluorine or chlorine, R^ and R^ are as stated above) with an amine of the general Formula III * / \ R 5 N NH (III) \ / (wherein R^ stands for hydrogen or methyl) or a salt thereof and subjecting the compound of the general Formula IV acetone, methyl ethyl ketone), an ether (e.g. dioxaπe, tetra- hydrofuran, diεthyl ether), an ester (e.g. ethyl acetate, methyl acetate, ethyl propionate), a sulfσxide (e.g. dimethyl sulfoxide), an alcohol (e.g. methanol, ethanol, 1-decanol, butanol) may be used. As acid binding agent an organic or inorganic base may be used. From the group of organic bases trialkyl amines (e.g. triethyl amine, tributyl amine), cyclic amines (e.g. pyridiπe, 1,5-diazabicyclo/5 ,4,0/uπdec-5-ene, 1 ,5-diazabicyclo/4.3.0/- non-5-ene, l,4-diazabicyclc/2.2.2/octane) can be mentioned, while as inorganic base preferably hydroxides or carbonates of alkali or alkaline earth metals can be applied. Thus as acid binding agent advantageously potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc. or an excess of the amine of the general Formula III can be used. The boron derivative of the general Formula II and the amine of the general Formula III can be reacted at a tempera¬ ture between 0 and 200 °C, depending on the solvent used. The reaction time may vary between half an hour and 10 hours. The reaction time depends on the reaction temperature, too. If the reaction is carried out at higher temperature, the reaction time can be shortened. The above reaction conditions are preferable values and other conditions may be used as well. The compounds of the general Formula IV can be hydro- lysed to the desired quinoline-3-carboxylic acids of the general Formula I, after or without isolation, under acidic or basic conditions. The compound of the general Formula IV pre- s * -e ear. e 2. - _ 3 -=μ . f^€t-:el;3 *g a e: JCΠ * =1 FerπϊL'l wfrh an aqueous ~ elut hy_.' iπroπtide , suZ. " oπσ= J55TEs5 * 3 .te ~ ;xe. -r-re rr... a, — eeπce -la — -. - S---~^lSi 3 n - ace ") « ■ 3" εehsr f _ t L- ' eπca ~ ac ~ :ιε 3seιeιea * ,£-"; zrzy= :rifugιrg r lieeh-vli .- g ette e; verted into pharmaceutically acceptable salts thereof in a known manner. Thus preferably acid addition salts can be formed, e.g. salts formed with hydrogen halides, sulfonic acids, sulfuric acid or organic acids. One may form preferably chlorides, bromides, aryl sulfonates, methane sulfonates, maleates, fumarates, beπzoates, etc. The compounds of the general Formula I form salts with alkali or alkaline earth metals or other metal ions as well. Accordingly the sodium, potassium, magnesium, silver, copper salts, etc. may be pre¬ pared. The compounds of the general Formula I and pharma¬ ceutically acceptable salts thereof can be converted into hydrates (e.g. hemihydratεs, trihydrates, etc.) by methods known per se. According to a further aspect of the present invention there are provided new compounds of the general Formula IV (wherein R, R^, R^ and R- 5 are as stated above) . The starting materials of the general Formula II can be prepared by reacting l-phenyl-6-fluoro-7-chlorα-4-oxo-l,4- dihydro-quiπoliπe-3-carboxylic acid (European patent speci¬ fication 131.839) or l-ethyl-6,7,8-trifluoro-4-oxo-l,4-di- hydro-quinoliπe-3-carboxylic acid (GB patent specification 2.057.440) with a boron derivative (e.g. with a compound of the general Formula V (wherein R is halogen or an aliphatic acyloxy group containing - a - 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms) cr with fluoroborate in aqueous or in organic medium. Further details of the present invention are to be found in the following Examples without limiting the scope of protection to the said Examples. Example 1 1.59 g of (l-ethyl-6,7,8-trifluoro-l,4-dihydro-4-oxo- quiπαliπe-3-carboxylate-r_- 5 ,_0*)-difluoro-boron are reacted with 1.29 g of piperazine in S ml of dimethyl sulfoxide at 100 °C for 3 hours. A 6 w /v% aqueous solution of 12.6 ml of sodium hydroxide are added and hydrolysis is carried out by heating for 2 hours. The reaction mixture is filtered, the pH value is adjusted to 7 with 96 /v% acetic acid and diluted with 15 ml cf water. The crystalline reaction mixture is cooled overnight and the precipitated crystals are filtered, washed with water and dried. Thus 1.61 g of l-ethyl-6,8-difluoro-l,4-dihydro-4- oxo-7-piperazino-quinoline-3-carboxylic acid are obtained. M.p. is 234-236 °C. Analysis for the Formula C^ ^- F^^^" } '- Calculated: C=56.90% H=5.07% N=12.45% Found: C=56.75% H=5.02% =12.48%. Example 2 1.95 g of (l-ethyl-6,7,0-trifluoro-l,4-dihydro-4-oxo- quiπoline-3-carboxylate-rj ,rj 4 )-bis(diacetate-0_)-boron are re¬ acted with 1.29 g of piperaziπe in S ml of dimethyl sulfoxide at 110 π C for 2 hours. A 3 w /v% aqueous solution of 20 ml of 3 w /v 5 s sodium hydroxide are added. The reaction mixture is re- fluxed for an hour whereupon filtered and the pH value is adjusted to 7 with 96 /v% acetic acid. After cooling and diluting with 10 ml of water the precipitated crystals are filtered and dried. Thus 1.59 g of αchre coloured l-ethyl-6,8- difluoro-l,4-dihydro-4-oxo-7-piperazino-quiπoline-3-carboxylic acid are obtained. M.p. is 234 °C. Analysis for the Formula ^ι^ll^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 (l-ethyl-6,7,8-tri- fluoro-1 ,4-dihydro-4-oxo-quinoline-3-carboxylate-C ,Cr)-bis- (propiαnato-C -boron are reacted with 0.64 g of piperaziπe in 4 ml of dimethyl sulfoxide. A 6 ^ v 5 . of aqueous solution of 6.3 ml αf sodium hydroxide are added and the reaction mixture is refluxed for an hour. After filtration the pH value is adjusted to 7 with 96 w /v% acetic acid, 10 ml of water are added and the reaction mixture is cooled overnight. The pre¬ cipitated crystals are filtered, washed with water and dried. Example 6 According to Example 3 1.06 g of (l-ethyl-6,7,8-tri- fluoro-1 ,4-dihydro-4-cxo-quinoline-3-carboxylate-fJ^,rj *i )-bis- (ρropiαnato-_0_)-boron are reacted with 0.75 g of 1-methyl-pipe- raziπe. Thus 0.79 g of l-ethyl-6 ,8-difluoro-l ,4-dihydro-4-αxα- 7-(l-methyl-piperazino)-quinoline-3-carboxylic acid are ob¬ tained. M.p. is 239-240 °C. Analysis for the Formula C17H19F2N3U : Calculated: C=58.10% H=5.45% N=11.91% Found: C=57.95% H=5.37% N=11.90%. Example 7 0.46 g of l-( '-fluoro-phenyl)-6-fluoro-7-chloro-l,4- dihydro-4-oxo-quinoline-3-carboxylate-r^,r 4 )-bis(aceta o-0_)- boron are reacted with 0.6 g of N-methyl-piperaziπe in 5 ml of dimethyl sulfoxide at 110 °C for an hour. 10 ml of 5 w / S . aqueous sodium hydrogen carbonate solution are added, the re¬ action mixture is refluxed for 2 hours whereupon the pH value is 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. Thus 3.54 g of l-( '-fluoro¬ phenyl)-6-fluoro-7-(N-methyl-piperazinyl)-l,4-dihydro-4-oxo- quiπoline-3-carboxylic acid are obtained. M.p. is 282-284 °C. The carboxylic acid thus obtained is dissolved in a weak solution of hydrochloride acid under heating, the solution is evaporated in vacuo and thus the hydrochloric salt of l-(4'- ϊrszi .yl) -I --iihycrc- . " . 5* ,

Claims: CLAIMS : 1. Process for the preparation of compounds of the general Formula I 0 (wherein R! stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula - CH 2 CR 6 R 7 R 8 (wherein R 6 , R 7 and R 8 stand for hydrogen or halogen) ; R2 stands for piperaziπyl or 4-mεthyl-piperazinyl; R-5 stands for hydrogen or fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II thus obtained (wherein R, R 1 , R 2 and R- 5 are as stated above) to hydrolysis after or without isolation and if desired con¬ verting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt. 2. Process according to Claim 1 which comprises reacting a compound of the general formula II with an amine of the general Formula III in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketαπe, alcohol, ether or ester. 3. Process according to Claim 2 which comprises using dimethyl sulfoxide as organic solvent. 4. Process according to Claim 1 which comprises carrying out the reaction of the compounds of the general Formulae II and III in the presence of an acid binding agent. 5. Process according to Claim 4 which comprises using an amine or an excess of the compound of the general Formula VI as acid binding agent. 6. Process according to Claim 1 which comprises carrying out the hydrolysis in acidic medium. 7. Process according to Claim 6 which comprises carrying out the reaction by using an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acici .

Inventors: BALOGH MARIA, HERMECZ ISTVAN, HORVATH AGNES, KERESZTURI GEZA, RITLI PETER, VASVARI LELLE, BALOGH, MARIA, HERMECZ, ISTVAN, HORVATH, AGNES, KERESZTURI, GEZA, RITLI, PETER, VASVARI, LELLE
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1988
Main classification: C07D215
IPC codes: C07D215, C07F5