AU613035C - Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof - Google Patents

Description

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

This invention relates to new /1-substituted-6-fluoro- 7-substituted-8-optionally fluoro-substituted-4- oxo-1, 4-dihydro-q uinoline-3-carboxylic-acid-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 -CH₂CR₅R₆R₇ /wherein R⁵ , R⁶ and R⁷ stand for hydrogen or halogen/ or phenyl optionally substituted by 1 or 2 halogen, R ¹ and R² are the same or different and stand for halogen, 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,

R³ stands for chlorine or fluorine and

R ⁴ stands for hydrogen or fluorine. The ethyl/l-p-fluorophenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate/ is an intermediate for the preparation of 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-/4-methyl-1-piperazinyl/-3-quinoline-carboxylic acid of antibacterial activity /24th Intersci. Conf. Antimicrob. Agents. Chemother. 1984. Abst. 72-78./. The latter compound can be prepared from ethyl-/1-p-fluorophenyl-6-fluor-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate/ in two steps. The 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-/4-methyl-1-piperazinyl-3-quinoline-carboxylic acid can be prepared by reacting 1-p-fluorophenyl-6-fluoro-7-chloro-1,4-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-/1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate/ is an intermediate for the preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-7-/1-piperazinyl/-3-quinoline-carboxylic acid showing also antibacterial activity /Eur.J.Clin.Microbiol. 1983., 2, 111/. The latter compound can be obtained from ethyl-/l-cyclopropyl-6-fluoro-7-chloro-4-oxo-l, 4- dihydro-quinoline-3-carboxylate/ in two steps. After hydrolysing the ester 1-cyclopropyl-6-fluoro-7-chloro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid thus obtained is reacted with piperazine in the presence of a solvent at a temperature of 135-140 °C for two hours and thus 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7/1- piperazinyl/-quinoline-3-carboxylic acid can be prepared /German Off. No. 30 33 157 and No. 31 42 854/.

The 1-substituted-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives /GB patent specification No. 2057440, Belgian patent specification 887574, European patent specifications No. 106489 and 15049, German patent specification No. 3433924, Japanese patent specifications No. 60006684 and 61085381, Portugal patent specification No. 80187/ are intermediates for the preparation of 7-substituted-6,8-difluoro-1,4-dihydro oxo-quinoline-3-carboxylic acid derivatives /J. Med. Chem. 1986. 29, 445; Drugs Fut. 1984. 9, 246; 23rd Intersci. Conf. Antimicrob. Agents Chemother. 1983. Abstr. 658; 7th Int. Symp. Fut. Trends Chemother. 1986, 80./.

According to the present invention 1-/optionally halo-substituted/ethyl-6,8-difluoro-1,4-dihydro-4-oxo 7-substituted-quinoline-3-carboxylic acid derivatives, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-/optionall substituted piperazino/-quinoline-3-carboxylic acid derivatives and 1-substituted-6-fluoro-l,4-dihydro-4-oxo-7/optionally substituted piperazino/-quinoline-3-carboxylic acid derivatives can be prepared in a simple manner by applying the new compounds of the general Formula I as starting material.

The compounds of the general Formula I /wherein R, R¹, R², R³ and R⁴ are the same as stated above/ can be obtained by reacting a compound of the general Formula

/wherein R, R ³ and R⁴ are the same as stated above and

R⁸ stands for hydrogen or alkyl containing 1 to 4 carbon atoms/ and fluoroborate of the Formula III

HBF₄ /III/

or a borone trihalide of the general Formula IV

BX₃ / IV /

/wherein X stands for fluorine, chlorine or bromine/ or an ether complex thereof or a triacyloxy borate derivative of the general Formula V

B/OCOR⁹/₃ /v/

/wherein R⁹ stands for alkyl containing 1 to 5 carbon atoms optionally substituted by halogen or aryl containing 6 to 10 carbon atoms/.

Borone trifluoride, borone tribromide, borone tri- chloride and complexes or aqueous solutions of these compounds can be used as compounds of the general Formula IV. Preferably complexes of ethers or alcohols may be applied /e.g. a complex of borone trifluoride with tetra- hydrofuran, diethyl ether, methanol 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. one

The fluoroborate of the Formula III, the bore-tri-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 presence 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, tetrahydrofuran/ or organic acids /e.g. acetic acid, propionic acid, trifluoro acetic acid/. If desired the reagents can be reacted at room temperature. If the reaction is carried out at 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 whereupon the suspension is heated slowly under stirring. A clear solution is obtained at 80 C. A solution of 3.1 g of ethyl-/1-cyclopropyl-6-fluoro-7-chloro-1,4-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 ºC. The reaction mixture is stirred at 110 °C for two hours, then cooled to 10 ºC 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 filtered, washed with water and ethanol and dried. Thus 4.02 g of /1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0³,0⁴/bis/acetato-0/-boron are obtained. The product decomposes at 254-256 ºC. Analysis for the Formula C₁₇H₁₄O₇NBClF : Calculated: 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-/1-ethyl-6,7,8-trifiuoro-1,4-dihydr 4-oxo-quinoline-3-carboxylate/ are stirred in 15 ml of 50 ^w/v % aqueous hydrogen-fluoro-borate solution at 80-90 °C for 2.5 hours. The precipitation of the crystals from the clear solution begins after half an hour whereupon a thick suspension is obtained. The reaction mixture is cooled to room temperature and crystallized overnight by cooling on ice. The precipitated crystals are filtered and washed with water and methanol. After drying 3.1 g of /1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0³,0⁴/-difluoro-borone are obtained. The product decomposes at 289 ºC. Analysis for the Formula C₁₂H₇BF₅NO₃: Calculated: C=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-ethy1-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate/ in 12 ml of warm propionic acid is added to the reaction mixture 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 precipitated crystals are filtered, washed with water and methanol and dried. Thus 4.1 g of /l-ethy1-6,7, 8-tri- fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 ³,0⁴/-bis/propionato-0/-borone are obtained. The product decomposes at 195-196 ºC. Analysis for the Formula C₁₈H₁₇BF₃NO₇: Calculated: C=50.61% 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 chloride. 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-/1-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 to room temperature. 150 ml of water are added to the reaction mixture and the suspension thus obtained is stirred under cooling for 3 hours. The precipitated crystals are filtered, washed with water and methanol and dried. Thus

7.7 g of /1-ethy1-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 ³,0⁴/bis/acetato-0/-borone are obtained. The product decomposes at 211 °C,

Analysis for the Formula C₁₆H₁₃BF₃NO₇:

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 1-/4'-fluoro-phenyl/-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxyl acid ethyl ester are added to 30 ml of 50 ^w/v% aqueous hydrogen tetrafluoro borate/lll/ solution under stirring whereupon the reaction mixture is heated to 110 °C. The solution thus obtained is stirred at 110 °C for two hours while the precipitation begins. The reaction mixture is cooled and crystallized overnight by cooling with ice. The precipitated crystals are filtered, washed with 5 ml of water and 5 ml of methanol. Thus 3.66 g of /1-/4'-fluoro-phenyl/-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 ³,0⁴/-difluoro-borone are obtainedas white crystals, M.p. : 324-326 °C, Analysis for the Formula C₁₆H₇NO₃BF₄Cl:

Calculated: C=50.11% H=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 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 80 °C. A solution of 3.64g /0.01 mole/ of 1-/4'-fluoro-phenyl/-6-fluoro-7-chlor 1,4-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-0/-borone are obtained. The product decomposes at 248-250 °C,

Analysis for the Formula C₂₀H₁₃NO₇BF₂Cl:

Calculated: C=51.82% H=2.83% N=3.02% Found: C=52.01% H=2.91% N=3.07%.

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 1-/4'-fluoro-phenyl/-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic 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 cooling with ice. The precipitated crystals are filtered and washed with 5 ml of water and 5 ml of ethanol. Thus 4.72 g of crystalline /1-/4'-fluoro-phenyl/-6-fluoro-7-chloro-1,4-dihydro-4- oxo-quinoline-3-carboxalate-0 ³,0⁴/-difluoro-borone are obtained. The product decomposes at 278-280 °C, Analysis for the Formula C₂₂H₁₇NO₇BF₂Cl: Calculated: C=53.75% H=3.49% N=2.85% Found: C=53.71% H=3.39% N=2.79%

Claims (5)

1. 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

   Formula -CH₂CR⁵R⁶R⁷ - wherein R⁵, R⁶ and R⁷ 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 being optionally substituted by halogen, or an aromatic acyloxy group containing 7 to 11 carbon atoms, chlorine

   R³ stands for hydrogen or fluorine and R⁴ stands for hydrogen or fluorine/, which comprises reacting a compound of the general Formula 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

   HBF₄ /III/

   or a borone derivative of the general Formula IV

   BX₃ /IV/

   /wherein X stands for fluorine, chlorine or bromine/ or an ether complex thereof, or a triacyloxy borate derivative of the general Formula V

   B/OCOR⁹/₃ /V/

   /wherein R⁹ stands for alkyl containing 1 to 5 carbon atoms optionally substituted by halogen, or aryl containing 6 to 10 carbon atoms/.
2. 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. 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. 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. 5. Compounds of the general Formula I

   /wherein

   R stands for cyclopropyl, a group of the general Formula -CH₂R⁵R⁶R⁷ /wherein R⁵, R⁶ and R⁷ 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,

   R³ stands for chlorine or fluorine and

   R⁴ stands for hydrogen or fluorine/.