PROCESS FOR THE PREPARATION OF 1-METHYLAMINO-QUINOLINE-CARBOXYLIC ACID DERIVATIVES

Abstract: Process for the preparation of compounds of general formula (I), and pharmaceutically acceptable salts thereof (wherein R stands for piperazinyl or 4-methyl-piperazinyl) which comprises reacting a compound of general formula (II), (wherein R<1> and R<2> stand for halogen; an aliphatic acyloxy group comprising 2-6 carbon atoms and optionally substituted by halogen; or an aromatic acyloxy group comprising 7-11 carbon atoms) with a piperazine of general formula (III), (wherein R<3> represents hydrogen or methyl) or a salt thereof, hydrolysing the compound of general Formula (IV), thus obtained (wherein R, R<1> and R<2> are as stated above) without or after hydrolysis 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 enables the preparation of the compounds of general formula (I) in a simple manner, with high yields and in a short reaction time.

Description: PROCESS FOR THE PREPARATION OF l-METHYLAMINO-QuTNOLIUE- -CARBOXYLIC ACID DERIVATI ES This invention re lates to a ew proce ss f or the pre paration of 7-substituted-β-f luoro-1-methylamino- -4-oxo-l, 4-dihydro-quinoline-3-carboxylic acid deri¬ vatives and pharmaceutically acce ptab le salts there of . It is known that β-fluoro -l-methylamino-4-oxo- -l , 4-dihydro-quinoline-3-carboxylic acid derivative s of the general Formula I CH 3 (wherein R stands for piperazinyl or 4-methyl-pipera- zinyl) exhibit outstanding antibacterial effect (Jour¬ nal of Medicinal Chemistry 1984, 27, 1103; Antimicroba Agents and Chemotherapy 1984, ' 25 , 377; 1984, 2_6, 104; 275; 421; 781; 933; 1985, 27, 4 and 499; European Journal of Clinical Microbiology 1984, 3, 344; Clin. Therapy 1984, 7, 73). The said compounds can be prepared by reacting β -fluoro-7-chloro-l-methylamino-4-oxo-l,4-dihydro- -quinoline-3-carboxylie acid with a cyclic amine in pyϊidine or methoxyethanol, at the boiling point, under a protecting nitrogen atmosphere for 15-22 hours (Euro¬ pean patent specification No. 90, 424; Japanese patent specification No. 84 01,4β8; Journal of Medicinal Che¬ mistry 25, 377 /I984/). According to the present invention there is provide a process for the preparation of compounds of the gene¬ ral Formula I and pharmaceutically acceptable salts thereof (wherein R stands for piperazinyl or 4-methyl- -piperazinyl) which comprises reacting a compound of th general (wherein R 1 and R2 stand for halogen; an aliphatic acyl oxy group comprising 2-6 carbon atoms and optionally substituted be halogen; or an aromatic acyloxy group comprising 7-11 carbon atoms) with a piperazine of the general Formula III (wherein R represents hydrogen or methyl) or a salt thereof, hydrolysing the compound of the general Formula IV 1 p thus obtained (wherein R, R and R are as stated above) without or after hydrolysis and if desired converting the compound of the general Formula I thus obtained in¬ to a salt thereof or setting free the same from its salt. The process of the present invention enables the preparation of the compounds of the general Formula I in a simple manner, with very high yields and in a short reaction time. According to a preferred form of realization of the process of the present invention the borate derivatives of the general Formula IV are converted into the desire quinoline-3-carboxylic acids of the general Formula I without isolation. The borate derivatives of the general Formulae II and IV are new compounds. The reaction of the borate derivative of the gene¬ ral Formula II and the cyclic a ine of the general For- muJLa III may be carried out optionally in the presence of an inert organic solvent and an acid binding agent. As inert organic solvent e.g. an acid ' amide (e.g. dimethyl formamide, dimethyl acetamide), a ketone (e.g. acetone, methyl ethyl ketone), an ether -(e.g. dioxane, tetrahyd ofuran, diethyl ether), an ester (e.g. ethyl acetate, methyl acetate, ethyl propionate), a sulfoxide (e.g. dimethyl sulfoxide), an alcohol (e.g. ethanol, ethanol, 1-decanol, butanol, etc. ) may be used. As acid binding agent e.g. organic or inorganic bas can be used. From the group of organic bases preferably trialkyl amines ( e.g. triethyl amine, tributyl amine), cyclic amines (e.g. pyridine, l,5-diazabicyclo/5.4.0/- undec-5-ene, 1, 5-diazabicyclo/4.3.0/non-5-ene, 1,4-di- azabicyclo/2.2.2/octane) may be mentioned, while as in¬ organic base e.g. hydroxides or carbonates of alkali or alkaline earth metals may be applied. Thus it is preferred to use potaasium carbonate, potassium hydroge carbonate, sodium hydroxide, calcium hydroxide or an excess of the amine of the general Formula III as acid binding agent. The reaction of the borone derivative of the ge¬ neral Formula II and the amine of the general Formula III may be carried out at a temperature of 0-200 °C durcing 0.5-10 hours, depending on the solvent used. The reaction time depends on the reaction temperature too. If the reaction temperature is raised, the reac¬ tion time can be shortened. The above reaction condi¬ tions are but preferable intervals, while other reac¬ tion conditions can be applied as well. The borate of the general Formula IV thus obtained is subjected to acidic or basic hydrolysis - after or without isolation - to yield the desired quinoline-3- -carboxylic acid derivative of the general Formula I. The reaction product of the general Formula IV may be isolated e.g. by cooling the reaction mixture and separating the precipitated product e.g. by filtration or .cent ifuglng. Alkaline hydrolysis can preferably be carried out with the aid of a hydroxide or carbonate of an alkali metal or an alkaline earth metal hydroxide, preferably in the form of an aqueous solution. One may particular¬ ly preferably proceed by hydrolysing. the compound of the general Formula IV by means of heating with an aqueo solution of sodium hydroxide, potassium hydroxide, sodiu carbonate, potassium hydrogen carbonate, potassium car¬ bonate or calcium hydroxide. Hydrolysis may also be accomplished with the aid of an organic base (e.g. tri- ethyl amine). Acidic hydrolysis may preferably be carried out by using an aqueous mineral acid solution. One may par¬ ticularly advantageously proceed by heating with an aqueous hydrochloric acid, hydrogen bromide, suIfuric acid or phosphoric acid solution. Hydrolysis may also be accomplished with the aid of an organic acid (e.g. acetic acid, propionic acid, etc.). The hydrolysis of the compounds of the general For¬ mula IV may also be carried out in the presence of a water- iscible organic solvent. For this purpose e.g. alcohols (e.g. ethanol, ethanol), ketones (e.g. acetone ethers (e.g. dioxane), acid amides (e.g. formamide, dimethyl formamide), sulfoxides (e.g. dimethyl sulfoxide and pyridine may be used. The quinoline-3-carboxylie acid derivatives of the general Formula I thus obtained may be isolated e.g. by adjusting the pH value to " a suitable value and se¬ parating the precipitated crystals e.g. by centrifuging, filtration, or by liophylisation of the aqueous solu¬ tion. The quinoline-3-carboxylic acids of the general Formula I can be converted into the pharmaceutically acceptable salts thereof. One may preferably form acid addition salts, e.g. salts formed with hydrogen halidea, sulfonic acids, sulfuric acid or organic acids. Thua e.g. the chloriάea, bromidea, 4-methyl-phenyl-sulfonates, methaneaulf onatea, maleatea, fumaratea, benzonatea, etc. can be formed. The compounda of the general Formula I form salts with alkali or alkaline earth metals or other metal ions too; thus e.g. the sodium, potassium, • agne¬ sium, silver, copper salts, etc. can be prepared. The hydrates (e.g. hemihydratea, trihydratea) of the compounda of the general Formula I or pharmaceutically acceptable acid addition salts thereof may also prepared, if desired, by methods known per se. The starting materials of the general Formula II can be prepared e.g. by reacting β-f luoro-7-chloro-l- - e thy lamino-4-oxo-l,4-dihydro-quino line -3-carbox lie acid (European patent specification No. 90,424) with various borone derivatives, e.g. with a borone derivative of the general Formula V (wherein R 1 , R2 are as stated above and R 4. haa the aa e meaning aa R 1 or R2) orfluoro boric acid in an aqueous or organic medium. Further details αf the preaent invention are to be found in the following Examplea without limiting the acope of protection to the aaid Examples. Example I A mixture of 6.87 g of 4-methyl-piperazine and 7.26 g of an anhydride of β-f luoro-7-ehloro-l-methyl- amino-4-oxo -1 , 4-dihydro-quino line -3-car box lie acid and dif luoro boric acid formed with 3β ml of dimethyl sulf oxide is stirred at 110 °C for 3 hours. As the reaction proceeds yellow crystals pre cipitate gradually from the reaction mixture . The anhydride of β-fluoro- -l-methylamino-7- (4-methyl-piperazino )-4-oxo-l,4-dihydr -quinoline-3-carboxylic acid and difluoro boric acid thus formed is hydrolysed without isolation from the reaction mixture as follows : The reaction mixture is cooled to 80 C, whereupon 58 ml of a β weight/vol % aqueous sodium hydroxide solu tion are added within 5 minutes . The reaction mixture is heated to boiling and stirred for 2 houra under alig boiling. The aolution is cooled to room temperature and the pH ia adjusted to 7.2 by adding acetic acid. The crystalline mixture thus obtained ia allowed to crystal in a refrigerator overnight . Next morning the precipita ted crystals are fi ltered , washed twice with 10 ml of water each and with 5 ml of methanol. Thus 5.8 g of . β -f luoro-l-methylamino-7- (4-methyl-piperazino )-4-oxo-l, dihydro-quinoline-3-carboxylic acid are obtained, yield 7β. l %.- Mp. : 300-301 (decomposition; from dimethyl form amide ) . Analysis for the Formula C-, gH^ g . O calculated C = 57.47 %, H = 5.72 , N = 16.75 found C - 57. 71 , H = 5.70 , N = 16.68 Example 2 A mixture of 5. 18 g of piperazine and 6.37 g of an anhydride of 6-f luorό-7-chloro-l-methylamino-4-oxo-l, 4- -dihydro-quinoline-3-carboxylic acid and difluoro boric acid formed with 32 ml of dimethyl aulfoxide is stirred at 110 °C for 3 houra. To the reaction mixture 51 ml of a 6 weight/vol % aqueoua aodium hydroxide aolution are added and the aqueoua reaction mixture ia atirred under slight boiling for 2 hours. The reaction mixture is fil tered, the filtrate is evaporated in vacuo to two-third of its volume and the pH of the solution is adjusted to - a - 6.5-7 by adding acetic acid . The reaction mixture is allowed to cryatallize in a refrigerator overnight . Nex morning the precipitated crystala are filtered, waahed twice with 10 ml of water each and with 5 ml of methano Thua 5.3 g of β-f luoro-l-ethylamino-7-piperazino-4-cxo- -l, 4-dihydro-quinoline-3-earboxylic acid are obtained. Yield : 82 %. Mp . : 289-291 °C (decompoaition; from dimet formamide ) . Analyaia for the Formula calculated C = 5 β .24 %, H = 5.34 %, N = 12; 49 fonnd C = 56. 15 %, H = 5.37 , N = 12.61 A mixture of 1 g of β-f luoro-l-methylamino-7-pipera zino-4-oxo-l, 4-dihydro-quinoline-3-carboxylic acid and 1.5 ml of water is treated with O. β g of p-toluene- -sulfonic acid and the mixture is poured into 10 ml of methyl ethyl ke tone . The reaction mixture is allowed to crystallize in a refrigerator overnight . Next mornin the precipitated crystals are filtered and waahed with methyl ethyl ketone . Thus 1.3 of the p-toluene-aulfonat aalt of β -f luoro-l-methylamino-7-piperazine-4-oxo -l,4- -dihydro-quinoline-3-carboxylic acid are obtained, yie ld 84. 5 %. Analyaia for the Formula . CγHgO S calculated C = 53 ÷ β 5 , N = 11.3 found C = 53.89 , H = 4.9 β %, N = 11.2 Example 3 5 g of ethyl- β -fluoro-l-N-formyl-N-methylamino-7- -chloro-4-oxo-l,4-dihydro-quinoline-3-carbox late are atirred in 25 ml of a 50 weight/vol % aqueoua aolution of hydrogen fluoro borate at 90-95 °C for 4 houra. After one hour and a half the precipitation of cryatala gradually begina. The reaction mixture ia cooled to room temperature and allowed to cryatallize in a re¬ frigerator overnight. Next morning the precipitated crystals are filtered and waahed with ao e water. Thus 4.55 g of an anhydride of β -f luoro-7-chloro-l-methyl- am£no-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid and difluoro boric acid are obtained. Yield: 93.4 %• Mp.: 277 °C (decomposition). Analysis for calculated C found C = 41.59 , H = 2.34 %, N = 8.5 Exampl e 4 0.797 g. of _ ~ 6-fluoro-7-chlαro-l,4-dihydro- -l-(methyl-amiπo)-4-oxα-3-quiπoliπe-carboxylate-0. , _7- bis(acetate-0_)-bαrαn and 0.6 g. of 1-methyl-piperaziπe are reacted in the presence of 5 ml. of di ethyl- sulfoxide at 110 °C for 2 hours. Then an aqueous solu¬ tion of 6 % by W/V sodium hydroxide (5.1 ml.) is added and stirred for another 1 hour at 110 C. The mixture is then cooled to 40 °C and the pH value is adjusted to 6.5 with 96 % by W/V acetic acid. The mixture is then cooled to room temperature whereupon crystals are precipitated. The mixture is allowed to stand in a refrigerator overnight, then diluted with 15 ml. of water and the precipitated crystals are filtered, and washed with water and cold methanol. 0.56 g. (84 % ) of 6-fluoro-l,4-dihydro-l-(methylamiπo)-7-(4-methyl- -piperaziπo)-4-oxo-3-quinoline-carboxylic acid is obtained. Decomposition after recrys ' tallizatioπ from di ethylformamide at 293 °C. Analysis for the formula C-, ,H-, α ^N^O-, calculated: C = 57.48 % H = 5.73 % N = 16.76 % found: C = 58.0 % H = 5.9 % N = 16.9 % Preparation of the starting material 0.568 g. of boric acid and 3.28 g. of acetic acid anhydride are reacted in the presence of 1 mg. of zinc chloride while the temperature of the reaction mixture raises to 46 °C. The white suspension is slowly heated to 100 °C and 2.0 g. of ethyl/_ ~ 7-chloro- 6-fluoro-l,4-dihydro-l-(formylmethyl-amino)-4-oxo-3- -quinoline-carboxylate/ are added which had been previously dissolved in 10 ml. of 96 % by W/V acetic acid. The reaction mixture is further heated for 2 hours at 110 C. The solution is cooled to room temperature and diluted with 40 ml of cold water. The precipitated crystals are filtered, washed with water and cold abs. ethanol, dried. 1.75 g. off-white, crystalline / ~ 6-fluoro- -7-chlor0-1,4-dihydro-l-(me hy1-amino)-4-oxo-3-quiπoline- carboxylate-rj , _7-bis(acetate-0_)-boron are obtained. Decomposition: 272 C. Upon standing further 0.45 g. product crystallizes from the mother liquor. Analysis for the formula C-, ,-H, - j BClF^O-, calculated: C = 45.55 % H = 3.31 % N = 3.54 % found: C = 45.2 % H = 3.2 % N = 3.6 %. Example 5 0.797 g. of /_ " 6-fluoro-7-chloro-l,4-dihydro-l- -(methylamino)-4-oxo-3-quinolinecarboxylate-0_ , _7- bis(acetate-0_)-boron and 0.52 g. of piperaziπe are react¬ ed in the presence of 5 ml. of dimethylsulfoxide at 110 °C for 2 hours. An aqueous solution of 6 % by W/V sodium hydroxide (5 ml.) is then added to the reaction mixture which is then mildly boiled for 1 hour. The first crystals precipitate after 10 minutes. The reaction mixture is cooled to 40 C and the pH is adjusted to 6.5 by adding 96 % by W/V acetic acid whereafter the suspension is diluted. The precipitated crystals are filtered and washed with water and abs. ethanol. Yellowish- -beige 6-fluoro-l,4-dihydro-l-(methylaminα)-7-piperaziπα- -4-oxo-3-quinoline-carboxylic acid (0.42 g. 65 %) is obtained. Analysis for the formula: C, ,-H, - 7 FN 4 0- 5 calculated: C = 56.24 % H = 5.35 \ N = 17.49 % found: C = 55.9 % H = 5.5 \ N = 17.8 %. Example 6 0.426 g. /_ ~ 6-fluoro-7-chloro-l,4-dihydro-l- -(methylamino)-4-oxo-3-quinoline-carboxylate-0_ ,0_ _7- bis(propanoate-0_)-boron and 0.3 g. of l-methyl-piperazine are reacted in the presence of 2.5 ml. of di ethyl- sulfoxide for 2 hours at 110 C. Then an aqueous solution of 6 % by W/V of sodium hydroxide (2.5 ml.) is added and the mixture is further heated for 1 hour at the above temperature. The reaction mixture is then cooled to 40~°C and the pH is adjusted to 6.5 by adding 96 % by W/V acetic acid. Crystals immediately precipitate. The reaction mixture is allowed to stand overnight in the refrigerator and the_precipitated crystals are filtered, washed with some water and methanol. Thus 0.22 g. ( 66 %) of 6-fluoro-l,4-dihydro-l-(methylamino)-7-(4- -methyl-piperaziπe)-4-0X0-3-quinoline-carboxylie acid is obtained, decomposing at 294 °C after recrystalliza- tion from dimethylformamide. No depression of the melting point is observed when admixing the product at any ratio with the product of the previous Example. Preparation of the starting material 1. 5 g. of ethyl-6-fluoro-l-(N-formyl-N-methyl- -amiπo)-7-chloro-4-oxo-l,4-dihydro-quinoliπe-3-carboxylate are stirred in 25 ml of an 50 weight/vol % aqueous ' colution of hydrogen fluoroboric acid at 90-95 °C for 4 hours. After one hour and a half the precipitation of crystals begins. The reaction mixture is cooled to room temperature, then placed into a refrigerator and allowed to crystallize overnight. The precipitated crystals are filtered next morning and washed with some water. Thus 4.55 g of an anhydride of 6-fluoro-7-chloro- -l-(methyla iπo)-4-oxo-l,4-dihydro-quiπoliπe-3-carboxylic acid and difluoro boric acid are obtained, yield: 93.4 %. Mp.: 277 °C (decomposition). Analysis for the formula C,, H^BF- j ClN ^ O, calculated: C = 41.48 %, H = 2.21 %, N = 8.79 % found: C = 41.59 %, H = 2.34 % N = 8.58 -b 2. 5 g. of 6-fluoro-7-chloro-l-methylamino-4-oxό- -1,4-dihydro-quinoline-3-carboxylic acid are stirred in 25 ml of a 50 weight/vol % aqueous solution of hydrogen fluoro boric acid at 80-90 °C for 2 hours. After 45 minutes the precipitation of crystals begins. The reaction mixture is first cooled to room temperature and then allowed to crystallize for 2 hours at 0 C. The precipitated crystals are filtered, and washed with some water. Thus 4.95 g of an anhydride of 6-fluoro- -7-chloro-l-rnethylamiπα-4-oxo-l,4-dihydro-quinαliπe-3- -carboxylic acid and difluoro boric acid are obtained, yield 84.5 % . Mp. : 277 C (decomposition). A mixture of the product thus obtained with any amount of the compound prepared according to Example 1 shows no melt¬ ing point depression. A mixture of 1.42 g of boric acid and 10.7 g of propionic anhydride is stirred at 100 °C for 15 minutes whereupon the reaction mixture is heated to boiling point. After 30 minutes the temperature of the reaction mixture- is lowered to 110 C and 4.2 g of 6-fluoro-7- -chloro-l-methylamiπo-4-oxo-l,4-dihydrα-quinoline-3- -carboxylic acid are added. After some minutes the precipitation of crystals begins. The reaction mixture is stirred at 110 °C for 2 hours, cooled to 10 °C, whereupon 20 ml of water and 20 ml of ethanol are added to the crystalline suspension. The reaction mixture is allowed to crystallize in a refrigerator overnight. The precipitated crystals are filtered, washed with water and dried. Thus 6.12 g of (6-fluoro-7-chloro-l- -methylamino-4-oxo-l,4-dihydro-quinoline-3-carboxylic- acid-borone-dipropionyloxy)-anhydride are obtained. Yield: 93.5 %, mp. : 215 C (decomposition). Analysis for the formula C- , 7 H, 7 BFC1N 0 calculated: C = 47.86 %, H = 4.01 %, N = 6.56 %, found: C = 48.07 %, H = 3.87 %, N = 6.48 h .

Claims: WHAT WE CLAIM IS : 1. Process for the preparation of compounda of the general Formula I and pharmaceutically acceptable aalta thereof (wherein R atanda for piperazinyl or 4-methyl.piperazinyl) which comprises reacting a compound of the general Formula II /II/ (wherein R1 and R2 stand for halogen; an aliphatic acyl oxy group comprising 2-β carbon atoms and optionally substituted by halogen; or anaromatic acyloxy group co priaing 7-11 carbon atoms) with a piperazine of the general Formula III \ R 3 N 7 NH ^ /HI/ (wherein R" 5 represents hydrogen or methyl) or a salt thereof, hydrolysing the compound of £Jιe general Formul ed above) without or after hydrolyaia and if deaired con¬ verting the compound of the general Formula I thua ob¬ tained into a salt thereof or aetting free the aame from its salt. 2. Process according to Claim 1 which comprises carrying out the reaction of the compounds of the ge¬ neral Formula II and III (wherein R , R and R- are as stated in Claim 1) in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester. 3. Procesa according to Claim 2 which comprises usin dimethyl s Ifoxide as organic solvent. 4. Process according to Claim 1 which comprises reacting 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 ge¬ neral Formula III as acid binding agent. β. Process according to Claim 1 which comprises carrying out hydrolysis in acidic medium. 7. Process according to Claim β which comprises using an organic or .inorganic acid, preferably hydrochlor acid, sulfuric acid, or acetic acid. 8. Process according to Claim 1 which comprises carrying out hydrolysis in alkaline medium. 9. Process according to Claim 8 which comprises using an alkali metal hydroxide, alkaline earth metal hydroxide or an organic baae, preferably an aqueous solution of triethy1 amine. 10. Compounds of the general Formula IV (wherein R stands for piperazinyl or 4-methyl-piperazinyl and R 1 and R2 represent halogen; an aliphatic acyloxy group comprising 2-β carbon atoms and optionally substituted by halogen; or an aromatic acyloxy group comprising 7-11 carbon atoms). 11. Compounds of the general Formula I whenever prepared by the process according to any of Claim 1-9. 12, A proceas as substiantially described herein with particular reference to the Examplea.

Inventors: BALOGH MARIA, HERMECZ ISTVAN, HORVATH AGNES, KERESZTURI GEZA, KOVACS GABOR, PAJOR ANIKO, RITLI PETER, SIPOS JUDIT, SZUETS TAMAS, VASVARI LELLE, BALOGH, MARIA, HERMECZ, ISTVAN, HORVATH, AGNES, KERESZTURI, GEZA, KOVACS, GABOR, PAJOR, ANIKO, RITLI, PETER, SIPOS, JUDIT, SZUETS, TAMAS, VASVARI, LELLE
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1986
Main classification: C07D215
IPC codes: A61K31, C07D215, C07D401, C07D403, C07F5