1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro-quinoline-3-carboxylic acid

The present invention relates to the compound l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-7-chloro-quinoline-3-carboxylic acid.

The compound according to the invention is employed as a starting compound in the preparation of l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acids of the general formula

<img file="IL76998A_D0001.tif" />

or salts or hydrates thereof, in which

R denotes a hydrogen atom or a methyl, ethyl or β-hydroxyethyl group.

The compounds of formula I have an antibacterial action superior to that of the known quinolone-carboxylic acids ׳.arid azaquinolone-.carboxylic acids. They and their preparation are described and claimed in Israel Patent Application No. 66243 from which this application was divided out.

The compound according to the invention can be prepared via a malonic ester synthesis, according to the following equation:

<img file="IL76998A_D0002.tif" />

+ cooc₂h₅

MgOEt ch₂^xcooc₂h₅ c

<img file="IL76998A_D0003.tif" />

Cl

״

C-CH

C00C₂H5 cooc₂h₅

VII

VIII

F,

Cl

11 ^c-c-cooc₂h״

H ^{2 ר}CH ¹ ic₂ h₅

<img file="IL76998A_D0004.tif" />

cooc₂h₅

<img file="IL76998A_D0005.tif" />

According to this equation, diethyl malonate of formula (VII) is acylated with a compound of formula (IV) in the presence of magnesium alcoholate to give the acylmalonate of formula (VIII) (Organicum, 3rd edition 1964, page 438).

The ethyl aroylacetate of formula (IX) is obtained in good yield by partial hydrolysis and decarboxylation of the compound of formula (VIII) in an aqueous medium containing a catalytic amount of ptoluenesulphonic acid, and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,4dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate of formula (X). The reaction of the compound of formula (X) with cyclopropylamine in a solvent (such as methylene chloride, alcohol, chloroform, cyclohexane or toluene) leads to the desired intermediate product of formula (VI) in a slightly exothermic reaction.

The cyclisation reaction VI —4 II (10 = alkyl) is carried out in a temperature range from 60° to 280°C, preferably 80° to 180°C. The free acid (10 = H) is obtained by conventional means.

Dioxane, dimethylsulphoxide, N-methylpyrrolidone, sulpholane, hexamethylphosphoric acid triamide and preferably Ν,Ν-dimethylformamide can be used as diluents.

Potassium t-butanolate, butyl-lithium, lithium-phenyl, phenyl magnesium bromide, sodium ethylate and particularly preferably sodium hydride or potassium carbonate are suitable acid-binding agents for this reaction state. It can be advantageous to employ an excess of 10 mol% of base.

The 2,4-dichloro-5-fluoro-benzoyl chloride of formula (IV) used as a starting material for this synthesis route, the corresponding carboxylic acid, and the 3-fluoro-4,6-dichlorotoluene of formula (XI) required for the preparation of formula (IV) were not yet known in the literature.

The equation below shows the preparation of these precursors or intermediate products, starting from 2,4-dichloro-5-methyl-aniline of formula (XII).

<img file="IL76998A_D0006.tif" />

According to this equation, 2,4-dichloro-5methyl-aniline of formula (XII) is diazotised by means of NaNO₂, and the resulting diazonium salt is converted into the triazene of formula (Xlla), using dimethylamine.

The triazene of formula (Xlla) is dissolved in excess anhydrous HF. In this step, the triazene is cleaved to give 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is cleaved thermally at 130 to 140° to give 3-fluoro-4,6dichlorotoluene XI, N₂ being split off (Yield: 77.7% of theory).

The 3-fluoro-4,6-dichlorotoluene of formula (XI) is chlorinated in a temperature range from 110 to 160°C, under UV irradiation, to give 2,4-dichloro-5fluoro-l-trichloro-methylbenzene of formula (XIII).

The hydrolysis of the compound of formula (XIII) with 95 percent sulphuric acid leads to 2,4dichloro-5-fluoro-benzoic acid of formula (XV), which is converted with thionyl chloride into the carboxylic acid-chloride of formula (IV).

The example which follows illustrates the invention further.

Example:

24.3 g of magnesium turnings were suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride were added and, when the reaction had started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was added dropwise, a vigorous reflux being observed. After the reaction had ceased, the mixture was heated at the boil for a further 2 hours and was cooled with dry ice/acetone at -5°C to -10°C and a solution of

227.5 g of 2,4-dichloro-5-fluoro-benzoyl chloride in 100 ml of absolute ether was slowly added dropwise at this temperature. The mixture was stirred for 1 hour at 0°C to -5°C and was allowed to reach room temperature overnight, and a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid was allowed to run in while cooling with ice. The phases were separated and were extracted twice with ether. The combined ether solutions were washed with saturated NaCl solution and dried with Na ״SO.,. and the solvent was stripped off in vacuo.349.5 ־ g of diethyl

2,4-dichloro-5-fluoro-benzoyl-malonate were obtained as the crude product.

0.15 g of p-toluenesulphonic acid was added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-

5-fluoro-benzoyl-malonate in 50 ml of water. The emulsion was heated at the boil for 3 hours while stirring thoroughly, and, when cold, was extracted several times with methylene chloride, the combined CH₂C1₂ solutions were washed once with saturated NaCl solution and dried with NajSO^, and the solvent was distilled off in vacuo.

Fractionation of the residue under a fine vacuum gave

21.8 g of ethyl 2,4-dichloro-5-fluoro-benzoyl acetate

IX of boiling point 127 to 142°C/0.09 mbar.

A mixture of 21.1 g of ethyl 2,4-dichloro-5fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and 18.55 g of acetic anhydride was heated at 150°C for 2 hours. The volatile constituents were then distilled off under a waterjet vacuum and finally under a fine vacuum, at a bath temperature of 120°C. 25.2 g of crude ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxyacrylate remained. It was sufficiently pure for the further reactions.

4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5fluoro-benzoyl)-3-ethoxy-acrylate in 80 ml of ethanol while cooling with ice and stirring. ׳ When the exothermic reaction had ceased, the mixture was stirred for another hour at room temperature, the solvent was stripped off in vacuo, and the residue was recrystallised from cyclohexane/petroleum ether. 22.9 g of ethyl

2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylaninoacrylate (R^ = CLH,.) of melting point 89 to 90°C were obtained.

3.44 g of 80 percent sodium hydride were added in portions to a solution of 31.9 g of ethyl

2-(2,4-dichloro-5-fluoro-benzoyl) -3-cyclopropylaminoacrylate (R^ = C2H5) Ιθθ ml of anhydrous dioxane while cooling with ice and stirring. The mixture was then stirred at room temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped off in vacuo. The residue (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was refluxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H^O. The filtrate was then acidified to pH = 1 to 2 with semiconcentrated hydrochloric acid, while cooling with ice, and the precipitate was filtered off under suction, washed with water and dried in Vacuo at 100°C. 27.7 g of 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3-carboxylic acid (R¹ = H) of melting point 234 to 237°C were obtained in this manner.