QUINOLINE CARBOXYLIC ACID BORIC ACID ANHYDRIDES AND PROCESS FOR THE PREPARATION THEREOF

Abstract: The invention relates to new quinoline-3-carboxylic acid anhydrides of general formula (I) (wherein R stands for cyclopropyl, a group of the general formula -CH2CR<5>R<6>r<7> (wherein R<5>, R<6> and R<7> stand for hydrogen or halogen), or phenyl optionally substituted by 1 or 2 halogen, R<1> and R<2> stand for halogen, or an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or an aromatic acyloxy group containing 7 to 11 carbon atoms, R<3> stands for chlorine or fluorine and R<4> stands for hydrogen or fluorine) and to the process for the preparation thereof which comprises reacting a compound of general formula (II), (wherein R, R<3> and R<4> are the same as stated above, R<8> stands for hydrogen or alkyl containing 1 to 4 carbon atoms) with a compound of the formula (III): HBF4, or a borone derivative of the general formula (IV): BX3 (wherein X stands for fluorine, chlorine or bromine) or an ether complex thereof, or a triacyloxy borate derivative of the general formula (V): -B(OCOR<9>)3 (wherein R<9> stands for alkyl containing 1 to 5 carbon atoms optionally substituted by halogen, or aryl containing 6 to 10 carbon atoms). The compounds of general formula (I) are new intermediates for the preparation of known quinoline-3-carboxylic acids showing antibacterial activity.

Description: QUINOLINE CARBOXYLIC ACID BORIC ACID ANHYDRIDES AND PROCESS FOR THE PREPARATION THEREOF This invention relates to new /l-substituted-6- f luoro- 7-substituted-S-optionally f luoro-su " bstituted-4- oxo-1, 4-dihydro-qruinoline-3-carboxylic-ac!d-boric acid/- anhydride derivatives of the general Formula I and to the proc ess f or the preparation thereof . In the general F ormula I R stands f or cyclopropyl , or a group of the general Formula -CH 2 CR 5 R 6 R 7 /wherein R 5 , R 6 and R 7 stand for hydrogen or halogen/ or pheny] optionally substituted by 1 or 2 halogen, R 1 and R2 are the same or different and stand for haloge or an aliphatic acyloxy group containing 2- to 6 carbon atoms being optionally substituted by halogen, or an aromatic acyloxy group containing 7 to 11 carbon atoms, 3 R stands for chlorine or fluorine and R * ^ stands for hydrogen or fluorine. The ethyl/l-p-fluorophenyl-6-fluoro-7-chloro-4- oxo-1,4-dihydro-quinoline-3-carbox late/ is an inter¬ mediate or the preparation of 1-p-fluo ophe:-l l-6- fluoro-l,4-dihydro-4-oxo-7-/4-methyl-l-piperazinyl/- 3-q . uinoline-carboxylic acid of antibacterial activity /24th Intersci. Conf. Antimicrob. Agents. Chemother. 1984. Abst. 72-78./. The latter compound can be prepared from ethyl-/l-p-fluorophenyl-6-fluor-7-chloro-4-oxo-l,4- dihydro-quinoline-3-carbox late/ in two steps. The 1-p- luorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-/4-meth l-l- piperazinyl-3-quinoline-carboxylic acid can be prepared by reacting 1-p-fluorophenyl-6-fluoro-7-chloro-l,4-di- hydro-4-oxo-quinolirιe-3-carboxylic acid /obtained by hydrolysing the ester/ with 1-methyl-piperazine in the presence of a solvent at a temperature of 100 °C for 20 hours /European Patent Specification No. 131839/. The ethyl-/l-cyclopropyl-6-fluoro-7-chloro-4-oxo- 1,4-dihydro-quinoline-3-carbox late/ is an intermediate for the preparation of l-cyclopropyl-6- luoro-l,4-dihyd 4-oxo-7-/l-piperazinyl/-3-quinoline-carbox lic acid showing also antibacterial activity /Eur.J.Clin. icro- biol. 1983., 2 f 111/. The latter compound can be obtain f om ethyl-/l-cyclopropyl-6- luoro-7-chloro-4-oxo-l,4- dihydro-quinoline-3-carbox late/ in two steps. After hydrolysing the ester l-cyclopropyl-6- luoro-7-chloro- l,4-dihydro-4-oxo-quinoline-3-carbox lic acid thus ob¬ tained is reacted with piperazine in the presence of a solvent at a temperature of 135-140 °C for two hours and thus l-cyclopropyl-6- luoro-1,4-dihydro-4-oxo-7/l piperazinyl/-quinoline-3-carboxylic acid can be prepa /German Off. No. 30 33 157 and No. 31 4 854/. The l-substituted-6,7,8-trifluoro-4-oxo-l,4-dih quinoline-3-carboxylic acid derivatives /GB patent specification No. 2057440, Belgian patent specificati 887574 ! European patent specifications No. 106489 and 15049, German patent specification No. 3433924, Japan patent specifications No. 60006684 and 61085381, Port patent specification No. 80187/ are intermediates for preparation of 7-substituted-6,8-difluoro-l,4-dihydro oxo-quinoline-3-carboxylic acid derivatives /J. Med. C 1986. .29, 445; Drugs Fut. 1984. 9, 2 6; 23rd Intersci. Conf. Antimicrob. Agents Che other. 1983. Abstr. 658; 7th Int. Symp. Fut. Trends Chemother. 1986, 80./. According to the present invention l-/optionall halo-substituted/ethyl-6,8-difluoro-l,4-dihydro-4-oxo 7-substituted-quinoline-3-carboxylic acid derivatives, l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-/optionall substituted piperazino/-quinoline-3-carboxylic acid derivatives and l-substituted-6- luoro-l,4-dihydro-4- oxo-7/optionally substituted piperazino/-quinoline-3- carboxylic acid derivatives can be prepared in a simp manner by applying the new compounds of the general Formula I as starting material. The compounds of the general Formula I /wherein R, R , R , R and R^ are the same as stated above/ ca be obtained by reacting a compound of the general Formul /wherein R, R 3 and R4 are the same as stated above and p R stands for hydrogen or alkyl containing 1 to 4 carbon atoms/ and fluoro.borate of the Formula III HBF, /HI/ or a borone trihalide of the general Formula IV EX, / ■ π /wherein X stands for fluorine, chlorine or bromine/ or an ether complex thereof or a triacyloxy borate derivat of the general Formula V B/OCOR 9 /, A/ /wherein R y stands for aϋyl containing 1 to 5 carbon atoms optionally substituted by halogen or aryl contain 6 to 10 carbon atoms/. Borone t i luoride, borone tribromide, borone tri chloride and complexes or aqueous solutions of these compounds can be used as compounds of the general Formu IV. Preferably complexes of ethers or alcohols may be applied /e.g. a complex of borone trifluoride with tetra hydrofuran, diethyl ether, ethanol or propanol/. If desired the solutions of borone trihalide and aliphatic hydrocarbons /e.g. hexane/ or halohydrocarbons /e.g. di- chloro methane/ or carboxylic acids /e.g. acetic acid, trifluoro acetic acid, propionic acid/ may be applied. The fluoroborate of the Formula III, the bor#-trι- halides and its complexes of the general Formula IV and the triacyloxy borate derivatives of the general Formula V can be applied in a molar ratio of 50:1, preferably 5: related to the compounds of the general Formula II. However, if desired, other molar ratio may also be used. The reaction may also be carried out in the presen of a solvent. As solvent one may use water, ketones /e.g acetone, methyl ethyl ketone/, hydrocarbons /e.g. hexane benzene, toluene/, ethers /e.g. diethyl ether, dioxane, tetraϊryd ofuran/ or organic acids /e.g. acetic acid, propionic acid, trifluoro acetic acid/. If desired the reagents can be reacted at room temperature. If- he -reaction is carried out- t higher temperature, the reaction time can be shortened. One may preferably carry out the reactions at a temperature ranging from 20 to 150 °C, but the reaction temperature depends on the solvent applied. The compounds of the general Formula I precipitate from the reaction mixture spontaneously or on cooling and thus can be separated e.g. by filtration. Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples. Example 1 4.6 g of acetic acid are added to the mixture of 0.93 g of boric acid and 1.5 mg of zinc chloride whereupo the suspension is heated slowly under stirring. A clear solution is obtained at 80 C. A solution of 3.1 g of ethyl-/l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4~oxo quinoline-3-carboxylate/ with 5 ml of hot 96 w /v% acetic acid is added dropwise to the clear solution at 100 C. The reaction mixture is stirred at 110 °C for two hours, then cooled to 10 C and diluted with 10 ml of water. The suspension thus obtained is stirred at 10 °C for two hours. The precipitated cream-coloured crystals are fil¬ tered, washed with water and ethanol and dried. Thus 4.02 g of /l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro- 4-oxo-quinoline-3-carboxylate-0 ,0 /bis/acetato-θ/-boron are obtained. The product decomposes at 254-256 C. Analysis for the Formula C- j^ H-, .0 7 NBC1F Calculatedt C=49.86% H=3.45% N=3.42% Found: C=50.03 H=3.41% N=3.50#. Example 2 3.0 g of ethyl-/l-ethyl-6,7,8-trifiuoro-l,4-dihydr 4-oxo-quinoline-3-carboxylate/ are stirred in 15 ml of 50 w /v % a ueous hydro en-fluoro-borate solution at 80-90 °C for 2.5 hours. The precipitation of the crysta from the clear solution begins after half an hour where¬ upon a thick suspension is obtained. The reaction mixtur is cooled to room temperature and crystallized overnigh by cooling on ice. The precipitated crystals are filtere and washed with water and methanol. After drying 3.1 g of /l-eth l-6,7»8-trifluoro-1, -dihydro-4-oxo-quinoline- 3-carboxylate-_ ,0 /-difluoro-borone are obtained. The product decomposes at 289 C. Analysis for the Formula C 12 H,-,BF 5 0 5 : Calculated: 0=45.18% H=2.21% N=4.40% Found: C=45.26% H=2.18% N=4.32%. Example 3 A mixture of 0.93 g of boric acid and 6.9 g of propionic acid anhydride is stirred at 95-100 °C for 30 minutes. A solution of 3.0 g of ethyl/l-eth 1-6,7,8-tri- fluoro-l,4-dihydro-4-oxo-quinoline-3-carbox late/ in 12 ml of warm propionic acid is added to the reaction mixt under steady heating. The red solution thus obtained is stirred at 110 °C for 5 hours and then cooled to room temperature and diluted with 150 ml of water. The pre¬ cipitated crystals are filtered, washed with water and methanol and dried. Thus 4.1 g of /l-eth 1-6,7,8-tri- fluoro-l > 4-dihydro-4-oxo-quinoline-3-carboxylate-_0 3, _4/- bis/propionato-()/-borone are obtained. The product de¬ composes at 195-196 C. Analysis for the Formula C 18 H-, 7 BF,N0 7 : Calculated: C=50.6l% H=4.01% E=3.29% Found: C=50.72% H=4.11% N=3.31%. Example 4 10 ml of acetic acid anhydride are added to the mixture of 1.85 g of boric acid and 20 mg of zinc chlori The suspension is stirred while the temperature of the mixture rises to 80 °C and then decreases. Stirring is continued for a further hour at 110 °C, whereupon a solution of 6,0 g of ethyl-/l-ethyl-6,7,8-trifluoro-1,4- dihydro-4-oxo-quinoline-3-carboxylate/ in 20 ml of warm 96 w /v% acetic acid is added dropwise. The reaction mixture is stirred at 110 °C for two hours and cooled t room temperature. 150 ml of water are added to the reac tion mixture and the suspension thus obtained is stirre under cooling for 3 hours. The precipitated crystals ar filtered, washed with water and methanol and dried. Thu 7.7 g of /1-ethy1-6,7,8-trifluoro-l,4-dihydro-4-oxo- quinoline-3-carbox late-0 3,04/bis/acetato-0/-borone are obtai ?d; _r The product decomposes -at 211 °C, Analysis for the Formula C^II- j^ BF ^ O ^ : Calculated: C=48.15% H=3.28% N=3.52% Found: C=48.12% H=3.28% N=3.54%. Example 5 3.64 g /0.01 mole/ of l-/4'- luoro-phenyl/-6- fluoro-7-chlo o-l,4-dihydro-4-oxo-quinoline-3-carbox l acid ethyl ester are added to 30 ml of 50 v /v% aqueous hydrogen tetrafluoro borate/lll/ solution under stirri whereupon the reaction mixture is heated to 110 °C. Th solution thus obtained is stirred at 110 °C for two hours while the precipitation begins. The reaction mix is cooled and crystallized overnight by cooling with i The precipitated crystals are filtered, washed with 5 of water and 5 ml of methanol. Thus 3.66 g of /1-/4'- fluoro-phenyl/-6-fluoro-7-chloro-l,4-dihydr0-4-oxo- quinoline-3-carboxylate-0 3,04/-difluoro-borone are obt as white crystals, M.p. : 324-326 °C, Analysis for the Formula C- j Hy O^BF.Cl: Calculated: C=50.11% ?I=1,84% N=3.65% Found: C=50.21% H=1.92% N=3.68%. Example 6 4.59 g of- acetic acid are added to the mixture o 0,93 g of .boric acid and 1,5 mg of zinc chloride where upon the suspension is heated slowly under stirring, A clear solution is obtained at 80 °C. A solution of 3.6 g /0.01 mole/ of l-/4'-fluoro-phenyl/-6-fluoro-7-chlor l,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester in 20 ml of hot 96 w /v% acetic acid is added dropwise to the clear solution at 100 °C. The reaction mixture is stirred at 110 °C for 3 hours, cooled and diluted with 10 ml water. The mixture is crystallized, overnight by cooling with ice. The precipitated white crystals are filtered, washed with 5 ml of water and 5 ml of ethanol. Thus 4.54 g of crystalline /1-/4'- fluoro-phenyl/-6-fluoro-7-chloro-l,4-dihydro-4-oxo- quinoline-3-carboxylate-0 3,04/bis/acetato-θ/-borone are obtained. The product decomposes at 248-250 °C, Analysis for the Formula Cg Q H- j ^NO ^ BF Cl: Calculated: C=.51.82% H=2.83% N=3.02% Found: C=52.01 H=2.91% N=3.< Example 7 5.3 g of 97 w v propionic acid anhydride are added to the mixture of 0.93 g of boric acid and 1,5 mg of zinc chloride whereupon the suspension is heated slowly under stirring, A clear solution is obtained at 90 °C, 3.64 g /0.01 mole/ of l-/4'-fluoro-phenyl/-6- fluoro-7-chloro-l,4-dihydro-4-oxo-quinoline-3-carboxyli acid ethyl ester are added to the solution and the reaction mixture is stirred at 110 °C for half an hour then cooled and diluted- with 6 ml of water. The mixture is crystallized overnight by coolin with ice. The pre¬ cipitated crystals are filtered and washed with 5 ml of water and 5 ml of ethanol. Thus 4.72 g of crystalline /l-/4'-fl oro-phenyl/-6-fl oro-7-chloro-l,4-dihydro-4- oxo-quinoline-3-carboxalate-0 3, _4/-difluoro-borone are obtained. The product decomposes at 278-280 °C, Analysis for the Formula C 22 H 17 N0 7 BF 2 C1: Calculated: C=53.75% H=3.49% N=2.85% Found: C=53.71% H=3.39% N=2.79%

Claims: What we claim is: 1, Process for the preparation of compounds of the general Formula I wherein R stands for cyclopropyl, a group of the general 5 6 7 5 6 7 Formula -CHgCR R - wherein R , R and R 1 stand for hydrogen or halogen -, or phenyl optionally 15 substituted by 1 or 2 halogen, R 1 and R2 stand for halogen, or an aliphatic acyloxy group containing 2 to 6 carbon atoms being optiona substituted by halogen, or an aromatic acyloxy group containing 7 to 11 carbon atoms, -Z - -s-fcamls for--hydrogen or fluorine and R stands for hydrogen or fluorine/, which comprises reacting a compound of the general Formula II 25 /II/ /wherein R, R3 and R4 are the same as stated above, R8 stands for hydrogen or alkyl containing 1 to 4 carbon atoms/ with a compound of the Formula III HBF 4 /III/ or a borone derivative of the general Formula IV B 3 /IV/ /wherein X stands for fluorine, chlorine or bromine/ o an ether complex thereof, or a triacyloxy borate deriv of the general Formula V B/OCOR 9 / 3 A/ q /wherein R stands for alkyl containing 1 to 5 carbon atoms optionally substituted by halogen, or aryl contai ing 6 to 10 carbon atoms/. 2. Process according to Claim 1 which comprises reacting a compound of the general Formula II with a compound of the general Formula III in aqueous medium. 3. Process according to Claim 1 which comprises reacting a compound of the general Formula II with a compound of the general Formula IV in the presence of a solvent. 4. Process according to Claim 1 which comprises reacting a compound of the general Formula II with a compound of the general Formula V in the presence of a solvent. 5. Compounds of the general Formula I R stands for cyclopropyl, a group of the general Formula -CHgR R R 7 /wherein R 5 , R 6 and R 7 stand for hydrogen or halogen/, or phenyl optionally substituted by 1 or 2 halogen, R 1 and R2 stand for halogen, or an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or an aromatic acyloxy group containing 7 to 11 carbon atoms, R stands or chlorine or fluorine and R stands for hydrogen or fluorine/.

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: C07F5
IPC codes: A61K31, A61P31, C07D215, C07F5