CS262587B1 - 1,4-Dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxo-quinoline-3-carboxylic acid b. - Google Patents

Abstract

The solution relates to 1,4-dihydro-7-chloro-6-fluoro-1-(4-nitrophenyl)-4-oxo-quinoline-3-carboxylic acid of formula I, and a method for its preparation starting from alkyl 1,4-dihydro-7-chloro-6-fluoro-4-oxo-quinoline-3-carboxylate, where alkyl contains 1 to 4 carbon atoms, and 4-nitrohalobenzene, preferably 4-nitrofluorobenzene. 1,4-dihydro-7-chloro-6-fluoro-1-(4-nitrophenyl)-4-oxo-quinoline-3-carboxylic acid of formula I is a new, previously undescribed substance with antibacterial activity.

Description

The invention relates to 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylic acid of the formula I,

and a process for its preparation.

The high potency of a number of substituted 1,4-dihydro-1-phenyl-6-fluoro-4-oxo-quinoline-3-carboxylic acids against a number of bacteria is known (Chu, DTW et al., J. Med. Chem. 28, 1 558 (1985). However, the preparation of these compounds is difficult and the starting materials are difficult to obtain.

1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylic acid is a novel, yet undescribed substance, which is antibacterially active.

The readily available alkyl 1,4-dihydro-7-chloro-6-fluoro-4-oxoquinoline-3-carboxylates wherein the alkyl contains 1 to 4 carbon atoms is used as the starting compound. According to the invention, the starting ester can be arylated with 4-nitrohalobenzene, preferably 4-nitrofluorobenzene, in an aprotic solvent, preferably dimethylformamide or dimethylsulfoxide, after conversion to the alkali salt, preferably with an alkali hydride, hydroxide, or carbonate. The resulting alkyl 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylate can be converted to 1,4- by hydrolysis in an acidic or alkaline medium without further purification. dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylic acid of formula I.

1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxo-quinoline-3-carboxylic acid of the formula I showed antibacterial activity against Escherichia coli in in vitro tests (minimum inhibitory concentration = 64 mg / 1) and against Proteus vulgaris (minimum inhibitory concentration = 32 mg / l).

The process for preparing 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxo-quinoline-3-carboxylic acid of formula I is simple and the product is obtained in satisfactory yields by the process of the invention.

Further details are given in the following examples. The examples given are merely illustrative, not limiting.

Example 1

Ethyl 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylate

A mixture of 13.5 g of ethyl 1,4-dihydro-7-chloro-6-fluoro-4-oxoquinoline-3-carboxylate (50 mmol), 4-nitrofluorobenzene (7.5 g, 53 mmol) and 17.5 g of anhydrous potassium carbonate in 750 ml of dimethylformamide was heated at 100 ° C for 15 hours with stirring. The reaction mixture was then poured into 1000 ml of water and after cooling the insoluble material was aspirated. Crystallization from ethanol gave 11.9 g (161%) of m.p. Mp 263-265 ° C.

Example 2

Ethyl 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylate

A mixture of 2.7 g of ethyl 1,4-dihydro-7-chloro-6-fluoro-4-oxo-quinoline-3-carboxylate (10 mmol),

1.5 g of 4-nitrofluorobenzene (11 mmol) and 3 g of powdered potassium hydroxide in 25 ml of dimethyl sulfoxide were stirred at 90 ° C for 15 hours. The reaction mixture was then poured into 100 ml of water, cooled and the insoluble material was filtered off with suction. 2.1 g (54%) of m.p. 253 DEG-258 DEG.

Example 3 1,4-Dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxo-quinoline-3-carboxylic acid

A mixture of 7 g of ethyl 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylate (18 mmol), 50 ml of concentrated hydrochloric acid and 50 ml of acetic acid The mixture was refluxed under stirring for 4 hours, after which the insoluble matter was aspirated. Crystallization from pyridine gave 5.5 g (88%) of m.p. 305 DEG-308 DEG.

Example 4 1,4-Dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxoquinoline-3-carboxylic acid

To a stirred suspension of 2.7 g of ethyl 1,4-dihydro-7-chloro-6-fluoro-4-oxo-quinoline-3-carboxylate (10 mmol) in 25 ml of dimethylformamide was added 0.3 g of 80% sodium hydroxide ( 10 mmol) and the mixture was stirred at room temperature for 1 hour. After addition of 1.5 g of 4-nitrofluorobenzene (11 mmol), the mixture was stirred at 100 ° C for 15 hours. After partial cooling, the reaction mixture was poured into 100 ml of water, after cooling the insoluble material was aspirated. The still wet cake was transferred to a flask with a solution of 1.5 g of sodium hydroxide in 20 ml of water and the mixture was refluxed under stirring for 5 hours. After cooling, the reaction mixture was acidified with acetic acid and the insoluble material was filtered off with suction. Acetic acid crystallization gave 1.9 g (54%) of m.p. 305 DEG-309 DEG.

Claims (2)

1,4-Dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxo-quinoline-3-carboxylic acid of formula I 2. A process for the preparation of 1,4-dihydro-7-chloro-6-fluoro-1- (4-nitrophenyl) -4-oxo-quinoline-3-carboxylic acid of the formula I according to claim 1, characterized in that alkyl 1,4-dihydro-7-chloro-6-fluoro-4-oxoquinoline-3-carboxylate, wherein the alkyl contains 1 to 4 carbon atoms, using an alkali hydride, hydroxide, or carbonate in an aprotic solvent, preferably di262587 methylformamide or dimethylsulfoxide, to an alkali salt which is arylized with 4-nitrohalobenzene, preferably 4-nitrofluorobenzene, and the resulting ester is hydrolyzed in an acidic or alkaline medium to 1,4-dihydro-7-chloro-6-fluoro-1- ( 4-nitrophenyl) -4-oxoquinoline-3-carboxylic acid.