PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACIDS

Abstract: The invention relates to a new process for the preparation of compounds of general formula (I), (wherein R stands for piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group) and pharmaceutically acceptable salts thereof which comprises reacting a compound of general formula (II), (wherein R<1> and R<2> stand for halogen, for an aliphatic acyloxy group containing 2 to 6 carbon atoms and optionally substituted by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms) with a piperazine derivative of general formula (III), (wherein R<3> stands for hydrogen, methyl or ethyl) or a salt thereof and subjecting the compound of general formula (IV) thus obtained, (wherein R, R<1> and R<2> 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 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 QUI OLIΪTΞ CARΞOXΪLIC ACID This invention relates to a new process for the preparation of l-cyclopropyl-7-substituted-β- luoro-4- oxo-l,4-dihydro-quinoline-3-carboxylic acid derivatives and pharmaceutically acceptable salts thereof. It is known that the l-cyclopropyl-7-substituted- 6- l oro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I /wherein R stands for 4-methyl-piperazinyl or 4-ethyl-piperazinyl group/ possess high antibacterial activity /Eur. J. Clin. Microbiol. 1983, 2 , page 111; J. Clin. Pharmacol. 1985, 15., page 82; Drugs Ξxptl. Clin, Res. 1985, 5, page 317./ • The quinoline carboxylic acids of the general Formula I can be prepared by reacting 1-cyclopropyl-β- fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid and a cyclic amine in the presence of a solvent at a tempera¬ ture of 135-140 °C for 2 hours /German Off. 3.033.157; German Off. 3.142.854/. According to the present invention there is pro¬ vided a new process for the preparation of 1-cyclepropy1- 7-substituted-6-fluoro-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid derivatives of the general Formula I /wherein R has the same meaning as stated above/ which comprises reacting a compound of the general Formula II /wherein R "~ I and R2 are the same or different and stand for halogen, for an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms/ with a cyclic a ine of the general Formula /wherein R stands for hydrogen, methyl or ethyl/ or a salt thereof and subjecting the compound of the general Formula IY 1 2 /wherein R, R ~ and R are the same as stated above/ thus obtained to hydrolysis. The ad-vantage of the process of the present inven- tion is that it makes the desired compound of the general Formula I available in a simple manner v/ith high yields and in a short reaction time. According to a preferred form of embodiment of the process of the present invention the borate derivative of the general Formula IV /wherein R, R and R are as stated above/ is converted into the desired quinoline-3- ca ox lie acid of the general Formula I without isolation The borate derivatives of the general Formula IV are new compounds. The borate derivatives of the general Formula II and the cyclic amine of the general Formula III can be reacted optionally in the presence of an inert organic solvent and an acid binding agent. As inert organic solvents preferably acid amides /e.g. dimethyl formamide, dimethyl acetamide/, ketones /e.g. acetone, methyl ethyl ketone/, ethers /e.g. dioxane, tetrahydrofuran, diethyl ether/, esters /e.g. ethyl acetat methyl acetate, ethyl propionate/, sulfoxides /e.g. di¬ methyl sulfox ' ide/, alcohols /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. pyridine, l,5-diazabicyelo/5.4.0/undec-5- ene, l,5-diazabicyclo/4.3.0/non-5-ene, 1,4-diazabicyclo- /2.2.2/octane/ can be mentioned, v/hile as Inorganic base preferably hydroxides or carbonates of alkali or alkaline earth metals can be applied. Thus as acid binding agent preferably potassium carbonate, potassium hydrogen carbon sodium hydroxide, calcium hydroxide, etc. or an excess of the amine ox the general Formula III can be used. The borone derivative of the general Formula II and the Crclic amine of the general Formula III can be reacted at a temperature ranging from 0 to 200 °C, depending on the solvent used. The reaction, time may vary between half an hour and 10 hours depending on the reaction temperature. If the reaction is carried out at an elevated temperature, the reaction time can be shortened. The above reaction conditions are but prefer¬ able values and other conditions may be used as well. Tne borates of the general Formula IT /wherein R, R ~ and R are as stated above/ can be hydrolysed 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 /wherein R is as stated above/ precipitates from the reaction mixture e.g. on cooling and can be separated e.g. by filtration or centrifuging, if desired. Basic hydrolysis may preferably be carried out by heating an aqueous solution of hydroxydes or carbonates of alkali metals or hydroxides of alkaline earth metals, One may preferably use an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide, potassium hydroge carbonate. Organic amines /e.g. trie hy1 amine/ may also be applied in the hydrolysis step. Acidic hydrolysis may preferably be accomplished by using an. aqueous mineral acid. One may preferably proceed ~ o hydrol sing a borate of the general Formula IV by heating same with an aqueous solution of hydro¬ chloric acid, hydrogen bromide, sulf ric acid or phosphoric acid. Hydrolysis may also be accomplished by using organic acids /e.g. acetic acid, propionic acid, etc/. Hydrolysis of the compounds of the general Formula IV may also be carried out in aqueous medium in the presence of a water-miscible organic solvent. For this purpose e.g. alcohols /e.g. methanol, ethanol/, ketones /e.g. acetone/, ethers /e.g. dioxane/, acid amides /e.g. formamide, dimethyl formamide/, sulfoxides /e.g. di¬ methyl sulfoxide/_,or pyridine may be used. The quinoline-3-carboxylic acid of the general Formula I thus obtained may be isolated e.g. by adjusting the pH value of the aqueous solution to a suitable value and separating the precipitated crystals e.g. by filtra- tion or centrifuging or by liophylization of the aqueous reaction mixture. The compounds of the general Formula I can be converted into pharmaceutically acceptable salts thereof by me h-ods known per se. Thus preferably acid addition salts formed with hydrogen halides, sulfonic acids, sul uric acid or organic acids. One may preferably form chlorides, bromides, 4-methyl-phenyl-sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc. The compounds of the general Formula I form salts with alkali or alkaline earth metals or other metal ions as well. Accordingly sodium, potassium, magnesium, silver, copper salts, etc, may be prepared. The compounds of the general Formula I and pharma¬ ceutically acceptable salts thereof can be converted into hydrates /e.g. hemihydrates, trihydrates, etc./ Dj methods known per se. According to a further aspect of the present in¬ vention there are provided new compounds of the general Formula IV /wherein R, R 1 and R 7 ~ are as stated above/. The starting materials of the general Formula II can be prepared e.g. by reacting I-cyclopropyl-6- luoro- 7-chlor0-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid /German Off. 3.141.854/ with a borone derivative /such as a compound of the general Formula V /wherein R 1, R2 and R5 stand for halogen, for an aliphat acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms/ or with fluoroborate in an aqueous or an organic medium. Further details or the present invention are to be found in_ the following Examples without limiting the scope of protection to the said Examples. Example 1 4.1 g of /l-cyclopropyl-β-fluoro-7-chloro-l,4-di- hydro-4-oxo-quinoline-3-carboxylate-0 ,0 /-bis/aceto-0/- borone and 2,8 g of piperazine anhydride are heated in 16 ήl of dimethyl sulfoxide to 110 °C under stirring. 40 ml of a 3 W /v % aqueous sodium hydroxide solution are added to the brownish-red solution and the reaction mixture is boiled under reflux for an hour. The hot pale yellow solution is filtered and the pH value is adjusted to 7 by adding 1.8 ml of 36 % acetic acid. The reaction mixture is cooled to room temperature, the precipitated white crystals are filtered, washed with water and methan and dried. The crude product is purified by boiling in 10 ml water. Thus 2.99 g of 1-cyclopropyl-β-fluoro-7- /l-piperazinyl/-l,4-dihydro-4-oxo-q_uinoline-3-carboxylic acid are obtained. The product decomposes at 255 C. Analysis for the Formula C 17 H la £ύO.,: Calculated: C=61.62 % H=5.48 % N " =12.68 % Found: C=61.5S % H=5.50 % ΪT=12.61 %. Example 2 By reacting /l-cyclopropyl-6-fluoro-4-chloro-l,4- dihydro-4-oxo-quinoline-3-carboxylate-0 ,0 ■ /" "b i s / ce ^ a ' fco "*0 borone and U-methyl-pipera ine according to Example 1. l-cyclopropyl-6- luoro-7-/4-methyl-piperasino/-l,4-di- hydro-4-oxo-quinoline-3-oarboxylic acid is prepared. The product decomposes at 248-250 °C. Example 5 4.1 g of /l-cyclopropyl-6-fluoro-7-chloro-l,4-di- hydro-4-oxo-qι inoline-5-carboxyla e-0 , 0 ' /-bis/acetato-0/- borone and 3.7 g of lϊ-ethyl-piperazine are heated in 16 ml of dimethyl sulf oxide to 90 °C under stirring. Af ter 10 minutes 40 ml of a 3 w / ~ A aqueous sodium hydroxide solution are added and the reaction mixture is boiled f or an hour under reflux. Zhe hot solution is filtered and the pH value is adjusted to 7 with 96 % ac etic acid. The reaction mixture is cooled, the precipitated crystals are filtered and wasiied with water. Thus 3.3 g of 1-cyclo- propyl-7-/4-ethyl-piperazi_ayl/-6-f luoro-1, 4-dihydro-4- oxo-quinoline-3-carboxyiic acid are obtained. .p . : 183-185 °C . Analysis for the Formula C η H o FϊT,0, : 19 άά 3 3 Calculated: 0=63.35 H=6.17 N=11.69 Found: C=63.31 H=6.21 F=11.70 Example 4 3.3 g of /l-cyclopropyl-6-f luoro-7-chloro-l, 4-di- hydro-4-oxo-quinoline-3-carboxylate-0 , 0 /-dif luoro-boron are reacted with 3.7 g of N-ethyl-piperazine according to Example 3. Thus 3.4 g of l-cyclopropyl-7-/4-ethyl-l- piperazinyl/-6-f luoro-1, 4-dihydro-4-oxo-quinoline-3- carboxyllc acid are obtained v/hich in admixture ' at any ratio with the product of Example 3 no depression of the melting point occurs.

Claims: WHAT V/E CLAIM IS: 1. Process for the preparation of compounds of the general Formula I /wherein R stands for piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group/and pharmaceutically accept¬ able salts thereof which comprises reacting a. compound of the general Formula II 2 /wherein R~ and R stand for halogen, for an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms/ with a piperazine derivative of the general Formula III /wherein R stands for hydrogen, methyl or ethyl/ or a salt thereof and subjecting the compound of the general Formula IV thus obtained /wherein R, R and R are as stated above/ to hydrolysis after or without isolation and if desired converting the compound of the general Formula I thus obtained into a salt thereof or setting free the acid from its salt. 2. Process according to Claim 1 which comprises reacting a compound of the general Formula II with a piperazine derivative of the general Formula III in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester. 3. Process according to Claim 2 which comprises using dimethyl sulfoxide as organic solvent. 4. Process according to Claim 1 v/hich 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 genera Formula III 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 cut tne reaction ~DJ using as acid an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acid. 8. Process according to Claim 1 v/hich comprises carrying out the hydrolysis in a basic medium. 9. Process according to Claim 8 which comprises using as a base an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous triethyl amine solution. 10. Compounds of the general Formula IV /wherein R stands for piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group, R 1 and R2 stand for halogen for an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or for an aromat acyloxy group containing 7 to 11 carbon atoms/

Inventors: BALOGH MARIA, HERMECZ ISTVAN, HORVATH AGNES, KERESZTURI GEZA, MARMAROSI KATALIN, PAJOR ANIKO, RITLI PETER, SIPOS JUDIT, VASVARI LELLE, BALOGH, MARIA, HERMECZ, ISTVAN, HORVATH, AGNES, KERESZTURI, GEZA, MARMAROSI, KATALIN, PAJOR, ANIKO, RITLI, PETER, SIPOS, JUDIT, VASVARI, LELLE
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1988
Main classification: C07D215
IPC codes: A61K31, A61P31, C07D215, C07D401, C07F5