CS269728B1 - Process for the preparation of 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-1-carboxylic acid - Google Patents

Abstract

The solution relates to a method for preparing 7-chloro-6-fluoro-1~(4-fluorophenyl)-1,4- -dihydro-4-oxoquinoline-3-carboxylic acid of formula I CS 269728 B l characterized in that 1-(4-aminophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is subjected to diazotization in a 30 to 70% solution of hydrogen fluoride in pyridine and subsequent dediazonization by heating the resulting solution to a temperature of 50 to 90 oC. The compound of formula I i serves as an intermediate for the preparation of the antibacterial preparation difloxacin.

Description

The invention relates to a process for the preparation of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula I

(AND).

A number of substituted 1-aryl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids are known to be highly effective against a wide range of bacteria. The most effective compounds have a cyclic amine residue, often piperazine, in position 7 and a 4-fluorophenyl group in position 1 (Rádl, S., Zikán, V.: Ďeskoslov. Farm. 36, 180, 1987). The key intermediate for the preparation of these compounds is the compound of formula I. The known method of preparation of this compound is difficult and is based on 2,4-dichloro-5-fluorobenzoic acid, which is poorly available (Chu, D.T.W. et al. J. Med. Chem. 28, 1558, 1985).

The disadvantage of the difficult preparation of the compound of formula I and the difficult availability of the starting materials is eliminated by the present invention. The compound of formula I can be prepared according to the invention by diazotizing a solution of the readily available 1-(4-aminophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in a 30 to 70% solution of dry hydrogen fluoride in pyridine, using alkaline nitrite and by decomposing the diazonium fluoride thus formed by heating the reaction mixture to a temperature of 50 to 90 °C, preferably to 70 °C.

The preparation method according to the invention is simple and provides the desired substance in a purity suitable for further processing into difloxacin or similar antibacterial preparations. The examples given provide further details, but are intended to illustrate the invention only and not to limit it.

Example 1

To a solution of dry hydrogen fluoride (12 g) in pyridine (13 g) was added 1.66 g (5 mmol) of 1-(4-aminophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid at -20 °C and the mixture was stirred for 30 minutes at room temperature. After cooling to 0 °C, 0.42 g (6 mmol) of sodium nitrite was added and the mixture was stirred for 30 minutes at room temperature. Then the temperature was gradually increased to 70 °C over 30 minutes and the reaction mixture was maintained at this temperature for 1 hour. After cooling, the reaction mixture was poured onto 200 g of ice and left to stand overnight, then the insoluble fraction was filtered off with suction and washed with water. 1.05 g of the substance (62%) with a melting point of 260 to 264 °C was obtained.

Example 2

To a solution of dry hydrogen fluoride (10 g) in pyridine (5 g) was added 0.99 g (3 mmol) of 1-(4-aminophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxoequinoline-3-carboxylic acid at 0 °C and the mixture was further processed in the same manner as in Example 1. 0.6 g (60%) of a substance with the same properties as in Example 1 was obtained.

Claims (1)

SUBJECT OF THE INVENTION Method for preparing 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula I (AND). characterized in that 1-(4-aminophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is subjected to diazotization in a 30 to 70% solution of hydrogen fluoride in pyridine and subsequent dediazonization by heating the resulting solution to a temperature of 50 to 90 °C.