KR970005910B1 - Process for the preparation of quinoline carboxylic acids - Google Patents

Abstract

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Description

Method for preparing quinoline carboxylic acid

The present invention relates to 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives and pharmaceutically usable salts thereof. The 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivative of the general formula (I)

Wherein R represents a piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group. It has high antibacterial activity. (Eur. J. Clin. Microbiol. 1983, 2, page 111; J. Clin. Pharmacol. 1985, 25, page 82; Drugs Exptl. Clin. Res. 1985, 5, page 317.) Quinoline carboxylic acid was reacted with 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amine at 135-140 ° C. for 2 hours. It can manufacture by making it react. (German Off. 3.033.157; German Off. 3.142.854). According to the present invention the 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivative of the general formula (I), wherein R is the same as Has a meaning) in the general formula (II)

Wherein R ¹ and R ² are the same or different and represent a halogen, an aliphatic acyloxy group containing 2-6 carbon atoms optionally substituted by halogen, or an aromatic acyloxy group containing 7-11 carbon atoms) And cyclic amines of general formula (III)

(Wherein R ³ represents hydrogen, methyl or ethyl) or a salt thereof to make a compound of general formula (IV)

(Where R, R ¹ and R ² are the same as those mentioned above). An advantage of the process according to the invention is that the desired compound of general formula (I) can be produced in a short reaction time by a simple method of obtaining a high yield. According to a preferred specific method of the present invention, the borate derivatives of general formula (IV), wherein R, R ¹ and R ² are as mentioned above, are not separated and converted to the desired quinoline-3-carboxylic acid of general formula (I). do. Borate derivatives of general formula (IV) are novel compounds. The borate derivatives of general formula (II) and the cyclic amines of general formula (III) can be optionally reacted in the presence of an inert organic solvent and an acid binder. Inert organic solvents are preferably acid amides (e.g. dimethylformamide, dimethylacetamide), ketones (e.g. acetone, methyl ethyl ketone), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether) , Esters (eg ethyl acetate, methyl acetate, ethyl propionate), sulfoxides (eg dimethyl sulfoxide), alcohols (eg methanol, ethanol, l-decanol, butanol) can be used. As acid binders, organic or inorganic bases can be used. Trialkylamines (eg triethylamine, tributylamine), cyclic amines (eg pyridine, 1,5-diazabicyclo (5.4.0) undec-5-ene, 1, 5-diazabicyclo (4.3.0) non-5-ene, 1,4-diazabicyclo- (2.2.2) octane) may be mentioned, while the inorganic bases are preferably hydroxides of alkali or alkaline earth metals. Or carbonates may be applied. Thus, as the acid binder, preferably potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide or the like or an amine excess of the general formula (III) can be used. The boron derivative of general formula (II) and the cyclic amine of general formula (III) may be reacted at a temperature in the range of 0-200 ° C. depending on the solvent used. The reaction time may vary between 30 minutes and 10 hours depending on the reaction temperature. If the reaction is carried out at a high temperature, the reaction time can be shortened. However, the above reaction conditions are preferable values, and of course, other reaction conditions can also be used. The borate salts of general formula (IV), wherein R, R ¹ and R ² are as mentioned above, are separated with or without the separation of the desired quinoline-3-carboxylic acid of general formula (I) under acidic or basic conditions. Can be disassembled. The compounds of formula IV can be precipitated from the reaction mixture by cooling or the like and separated by filtration or centrifugation if desired. Basic hydrolysis can be preferably carried out by heating an aqueous solution of an alkali metal hydroxide or a carbonate or an alkali earth metal hydroxide. Aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide and potassium hydrogencarbonate can be preferably used. Organic amines (eg triethylamine) can also be applied to the hydrolysis step. Acidic hydrolysis can be preferably performed by using an aqueous inorganic acid. The borate salt of the general formula (IV) can be preferably hydrolyzed by heating with an aqueous solution of hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid. Hydrolysis can also be performed using organic acids (for example, acetic acid, propionic acid, etc.). Hydrolysis of the compound of general formula (IV) can also be carried out in a water-soluble medium in the presence of an organic solvent, miscible with water. For this purpose, for example, alcohol (e.g. methanol, ethanol), ketone (e.g. acetone), ether (e.g. dioxane), acid amide (e.g. formamide, diethylformamide), sulfoxide Seeds (eg dimethylsulfoxide) or pyridine can be used. The quinoline-3-carboxylic acid of general structure (I) thus obtained can be separated by adjusting the pH value of the aqueous solution to an appropriate value, and the precipitated crystals can be separated by filtration or centrifugation or lipophilic of the water-soluble reaction mixture. Compounds of general formula (I) may be converted into their pharmaceutically usable salts essentially by known methods. The acid addition salts are thus preferably formed with hydrogen halides, sulfonic acids, sulfuric acid or organic acids. Chloride, bromide, 4-methyl-phenyl-sulfonic acid salt, methanesulfonic acid salt, maleic acid salt, fumaric acid salt, benzoate and the like can be preferably formed. Compounds of general formula (I) also form salts with alkali or alkaline earth metals or other metal ions. Therefore, sodium, potassium, magnesium, silver, copper salt, etc. can be manufactured. Compounds of general formula (I) and their pharmaceutically usable salts can be converted essentially to known hydroxides (eg hemihydrates, trihydroxides, etc.) by known methods. According to another aspect of the present invention there is provided a novel compound of the general formula (IV), wherein R, R ¹ and R ² are as mentioned above. Starting material of the general formula (II) was 1-cyclopropyl-6fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (German Off. 3.141.854). Boron derivatives such as compounds of

Wherein R ¹ , R ² and R ⁵ represent a halogen, an aliphatic acyloxy group containing 2-6 carbon atoms optionally substituted by halogen or an aromatic acyloxy group containing 7-11 carbon atoms) or fluoroborate It can be prepared by reacting with water-soluble or organic media. The following examples illustrate the invention in more detail, but the examples do not limit the scope of the invention.

4.1 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -bis (acetate-O) -boron; 2.8 g of piperazine anhydride are heated to 110 ° C. under stirring in 16 ml of dimethyl sulfoxide. 40 ml of 3w / v% aqueous sodium hydroxide solution is added to the reddish brown solution and the reaction mixture is heated under reflux for 1 hour. Filter the hot pale yellow solution and add 1.8 ml of 96% acetic acid to adjust the pH to 7. The reaction mixture is cooled to room temperature and the precipitated white crystals are filtered off, washed with water and methanol and dried. The crude product is purified by heating in 10 ml water. Thus 2.99 g of 1-cyclopropyl-6-fluoro-7- (1-lipininyl) -1,4-dihydro-4-oxo-quinoline-3-peracid are obtained. The product decomposes at 255 ° C. Analysis of Molecular Formula C ₁₇ H ₁₈ FN ₃ O ₃ :

Theoretic Value (%): C; 61.62, H; 5.48, N; 12.68

Found (%): C; 61.58, H; 5.50, N; 12.61

Example 2

1-Cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -bis (acetate-O) -boron and N- Methyl-piperazine was reacted according to Example 1 to yield 1-cyclopropyl-6-fluoro-7- (4-methyl piperazino) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. Manufacture. The product decomposes at 248-250 ° C.

Example 3

4.1 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -bis (acetate-O) -boron; 3.7 g of N-ethyl-piperazine is heated under stirring to 90 ° C. in 16 ml of dimethyl sulfoxide. After 10 minutes, 40 ml of 3w / v% aqueous sodium hydroxide solution is added and the reaction mixture is heated under reflux for 1 hour. Filter the hot solution and adjust the pH value to 7 with 96% acetic acid. The reaction mixture is cooled and the precipitated crystals are filtered off and washed with water. Thus 3.3 g is obtained.

Melting Point: 183-185 ℃

Analysis of Molecular Formula C ₁₉ H ₂₂ FN ₃ O ₃ :

Theoretic Value (%): C; 63.35, H; 6.17, N; 11.69

Found (%): C; 63.31, H; 6.21, N; 11.70

Example 4

3.3 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -difluoro-boron was prepared in Example 3 Reaction with 3.7 g of N-ethyl-piperazine. Thus, 3.4 g of 1-cyclopropyl-7- (4-ethylpiperazinyl) -6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was obtained, which was mixed with the product of Example 3 Melting decreases do not occur in mixtures mixed at any rate.

Claims (9)

A compound of the general formula (II) is then reacted with a piperazine derivative of the general formula (III) or a salt thereof to form a compound of the general formula (IV), and hydrolyzed to obtain a compound of the general formula (I), if necessary A process for preparing compounds of general formula (I) and pharmaceutically usable salts thereof by converting them to salts or freeing the acid from the salts

Wherein R is a piperazinyl, 4-methyl piperazinyl or 4-ethyl-piperazinyl group, and R ¹ and R ² are aliphatic acyl containing 2-6 carbon atoms optionally substituted by halogen, halogen Or an aromatic acyloxy group containing 7 to 11 carbon atoms, and R ³ represents hydrogen, methyl or ethyl. The process according to claim 1, wherein the compound of general formula (II) and the piperazine derivative of general formula (III) are reacted in the presence of acid amide, sulfoxide, ketone, alcohol, ether or ester as organic solvent. The process according to claim 2, wherein dimethyl sulfoxide is used as the organic solvent. The process according to claim 1, wherein the reaction of the compounds of the general formulas (I) and (III) is carried out in the presence of an acid binder. The process according to claim 4, wherein an excess of an amine or a compound of the general formula (III) is used as the acid binder. The method of claim 1 wherein the hydrolysis is carried out in an acidic medium. The process according to claim 6, wherein the reaction is carried out using hydrochloric acid, sulfuric acid or acetic acid as the acid. The method of claim 1 wherein the hydrolysis is carried out in a basic medium. The method of claim 8, wherein an alkali metal hydroxide, an alkaline earth metal hydroxide, or an organic base is used as the base.