CS206993B1 - A method for separating an oxolinic acid isomer - Google Patents

Abstract

The invention relates to a method for separating the positional isomer of oxolinic acid of formula I, i.e. 1-ethyl-5, oxolinic acid of formula /1/. carboxylic acid, from acid /II/, i.e. 1-ethyl-6, 7-methylenedioxy-4-quinolone-3-carboxylic acid. Oxolinic acid is a chemotherapeutic agent with high efficacy, especially against gram-negative microbes; This substance is significantly used in the treatment of urinary tract infections. It is an effective component of preparations known under various trade names.

Description

(54) A method for separating the positional isomer of oxolinic acid

The invention relates to a method for separating the positional isomer of oxolinic acid of formula I, i.e. 1-ethyl-5, oxolinic formula

/ 1 /.

carboxylic acids, from acid (II), i.e. 1-ethyl-6,7-methylenedioxy-4-quinolone-3-carboxylic acids.

Oxolinic acid is a chemotherapeutic agent with high efficacy especially against gram-negative microbes; This substance is used in the treatment of urinary tract infections. It is an effective part of preparations known under various trade names.

2DB 983

For the first time, he prepared oxolinic acid by Kaminsky with a multi-stage synthesis [J. Med.

Chem. 11, 160, 1968, U.S. Pat. No. 3,172,811, French Pat.

The core step of the synthesis is the cyclization reaction of diethyl ester of (3,4-methyl endioxoanilino) methylene / malonic acid to ethyl ester of oxolinic acid. Basically, two methods of carrying out the cyclization reaction are known from the literature. According to the cited US patent specification, the cyclization reaction is carried out thermally at a temperature of about 250 ° C, for example in a diphenyl ether environment.

This reaction, as can be seen, requires relatively drastic conditions and strict adherence to them. Although this reaction is manageable under laboratory conditions, operational implementation is very difficult and places high demands on equipment.

The cyclization reaction of Japanese Patent No. 18,141, carried out in the presence of acid catalysts such as phosphorus oxychloride, phosphoric acid, boron trifluoride etherate or a mixture of acetic acid and sulfuric acid, substantially simplifies this step of the synthesis. The cyclization takes place under relatively mild reaction conditions with high yields and allows for an easy operational implementation from a technological point of view

However, the quality of the oxolinic acid thus prepared is, according to a binding analytical evaluation, unsatisfactory for use in human medicine, because it is a mixture of two substances, oxplinic acid and undesirable by-products. .

A detailed study of the individual methods of acid cyclization according to the cited Japanese patent has revealed that the product of cyclization is always said mixture of oxolinic acid and undesirable side components. Isolation of this material with its physico-chemical analysis revealed that the undesirable component is the positional isolaer of oxolinic acid of formula I. It is formed during the cyclization reaction and its content in oxolinic acid is 3 to 5% by weight, depending on the method used.

Attempts to purify oxolinic acid by crystallization, for example, from ethanol, methanol, dimethylformamide, from organic acids, such as ootic or formic, from inorganic acids, such as concentrated or dilute hydrochloric acid, have failed. Attempts to extract the isomer were also unsuccessful. The precipitation of oxolinic acid via sodium or potassium salts, or the procedure associated with the isolation of these salts, was poorly effective. Although some methods have been able to reduce the isomer content, they have been very unprofitable and uneconomical.

surprisingly, it has been found that the separation of the positional isomer of oxolinic acid of formula I from oxolinic acid of formula II can be easily and very efficiently accomplished by the process of the present invention, characterized in that the starting mixture of ethyl oxolinic acid and ethyl isomer thereof , preferably from 20% hydrochloric acid or from a C 1 -C 3 aliphatic acid, preferably from oic acid, whereupon the pure ethyl ester of oxolinic acid is alkalinized, for example by treatment with a 5-7% sodium hydroxide solution, and the oxolinic acid is isolated by acidification such as carbon dioxide gas.

Crystallization of the crude cyclization product in the form of a mixture of the positional isomer of oxolinic acid and ethyl ester of oxolinic acid under the above conditions has proven to be an optimal route to obtain pure acid, easily feasible with minimal equipment and operating / technical requirements. In particular, the method of choice is crystallization from 20% hydrochloric acid, (yielding a completely pure, well-crystalline oxolinic acid ethyl ester hydrochloride); the hydrochloride of the positional isomer remains almost quantitatively in the mother liquor.

For the further process, i.e. for the release of oxolinic acid, which is a routine matter, still wet crystalline hydrochloride, as obtained by crystallization, is applicable. The process of the invention provides pure oxolinic acid free of the positional isomer in a yield of about 85% of theory. .

Podrobnosti Further details are given in the examples.

EXAMPLE 1 g of a mixture of ethyl oxoline ester and its isomer is added with stirring to 150 ml of 20% hydrochloric acid, and the resulting dispersion is heated to a temperature of 80 to 85 DEG C. Upon reaching this temperature, the mixture of ethyl esters is heated. dissolve. If the solution is not clear or contains insoluble parts, it becomes clear by filtration. The clear filtrate was gradually cooled to 10-15 ° C and maintained at this temperature for 1 hour with occasional stirring. The product starts to precipitate upon cooling at 65 ° C. * The crystallized product is filtered off with suction, washed thoroughly (about 30 ml) with 20% hydrochloric acid, cooled to 15 ° C. The wet product obtained is further processed. The obtained oxo-linonic acid ethyl ester hydrochloride is a white crystalline solid, m.p. 74-75 ° C (ethanol-ether). 08 993

The still wet product was dissolved in 170 ml of water and the solution was neutralized with 20% sodium hydroxide solution. Ethyl oxolinate was precipitated. Further addition of the sodium hydroxide solution adjusts its total concentration to 5-7% by weight. The mixture is heated with stirring to 90-95 ° C when the suspension dissolves. Heating is continued for an additional hour, 0.3 g of activated carbon is added, stirred for about 5 minutes and filtered. Oxolinic acid precipitates from the filtrate at 25-30 ° C with gaseous carbon dioxide, which is filtered off with suction, thoroughly washed with water (about 150 ml) and dried at 70 ° C. Yield 23.2 g, 86.0% of theory. to the starting ethyl ester. The product is completely pure, free of the positional isomer of the formula I, on the basis of the chromatography on this layer.

Example 2 g of a mixture of ethyl oxolinate and its isomer is dissolved in 90 ml of glacial acetic acid at boiling. If the solution is cloudy or contains undissolved parts, it is filtered. The filtrate is cooled to 20 DEG C. and after 2 hours of cooling, the precipitated product is suction filtered with occasional stirring and washed with 20 ml of acetic acid. The still wet product was used for further work-up similar to Example 1. Yield 20.8 g (77.0% of theory) based on the starting ethyl ester. The product is free of the positional isomer.

Claims (1)

BACKGROUND OF THE INVENTION (II), characterized in that the starting mixture of ethyl oxolinate and ethyl isomer thereof is crystallized from a dilute mineral acid, preferably from 20% hydrochloric acid or from an aliphatic acid having 1 to 3 carbon atoms, preferably acetic acid, whereupon the pure ethyl oxolinic acid ester obtained is alkali-saponified, for example by treatment with 5 to 7% sodium hydroxide solution, and the oxolinic acid is isolated by acidification, for example with carbon dioxide gas.