HU196783B - Process for production of quinoline carbonic acid - Google Patents

Abstract

(A) Quinoline-carboxylic acid cpds. of the formula (I) and their salts are prepd. by reacting cpds. of the formula (V) with piperazine cpds. of the formula (VI) or their salts to give cpds. of the formula (VII) and then hydrolysing these. (B) Borate cpds. of the formula (VIII) are new. - R1 and R2 are each 2-6C aliphatic acyloxy opt. halogen-substd. or 7-11C aromatic acyloxy; R is H or CH3. - Cpds. of formula (V) are also claimed.

Description

The present invention relates to a novel process for the preparation of 1-ethyl-6-fluoro-7- (4-methyl-piperazino) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and its pharmaceutically acceptable acid addition salts.

Quinoline carboxylic acid of the formula I is known to be widely used for the treatment of urinary tract and systemic bacterial diseases due to its outstanding antibacterial activity (J.Pharm.Sci. 1984, 73, 1379).

Preparation of quinolinecarboxylic acid of formula I or reaction of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-aminol-3-carboxylic acid of formula II with 1-methylpiperazine (870, 576) and U.S. Patent Nos. 870,917, Japanese Patent Publication No. 80,33,453, and J.Med.Chem. 1980, 23,1358) or 1-ethyl-6-fluoro-7-puperazino-4-oxo-1 of formula III. By methylation of 4-dihydroquinoline-3-carboxylic acid (Belgian Patent No. 870,917 and French Patent Publication No. 2,424,919). A common disadvantage of the processes is that the reaction is carried out under vigorous reaction conditions at 110-150 ° C for 7-16 hours. Process yields range from 55% to 66%. In addition, the reaction mixture is difficult to process.

According to the present invention, 1-ethyl-6-fluoro-7- (4-methylpiperazino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid of formula I can be prepared in a simple manner with good yield and short reaction time. borate derivatives (wherein R * and R ² are the same or different; borate derivatives of formula VI formed by the reaction of an acanoyloxy group of from 2 to 6 carbon atoms with an amine or salts of formula V (wherein R ¹ and R ² In a preferred embodiment of the process, the borate derivatives of formula VI (wherein R ¹ and R ² are as defined above) are converted without isolation into the quinoline-3-carboxylic acid of formula (I).

The borate derivatives of formula IV are reacted with a cyclic amine of formula V, optionally in the presence of an inert organic solvent and an acid acceptor.

Suitable organic solvents include acid amides such as dimethylformamide, dimethylacetamide, ketones such as acetone, methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran, diethyl ether, esters such as ethyl acetate, methyl acetate, ethyl propionate, sulfoxide, dimethyl sulfoxide, alcohols such as methanol, ethanol, 1-decanol, butanol.

Organic and inorganic bases such as triethylamine, tributylamine, cyclic amines such as pyridine, 1,5-diazabicyclo [5.4.0] undec-5-ethane, 1,5-diazabicyclo [4,3,0] non-5 are used as acid binders. and the inorganic base include hydroxides and carbonates of alkali metals and alkaline earth metals. Thus, potassium carbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide can be used as acid binders. If desired, an excess of the amine of formula V may be used as an acid scavenger.

The boron derivative (IV) and the amine (V) are also reacted at a temperature of 0 to 200 ° C for 0.5 to 10 hours, depending on the solvent used. The reaction time used depends on the reaction temperature chosen. Increasing the reaction temperature allows a shorter reaction time. If desired, circumstances other than those described above may be employed.

The wine routes of Formula VI (wherein R * and R ² are as defined above, if desired, after isolation, can be hydrolyzed under acidic or basic conditions to the quinoline-3-carboxylic acid derivative of Formula I. The compound of Formula VI, e.g. from which it may thus be obtained by filtration or centrifugation if desired.

Hydrolysis under basic conditions preferably includes hydroxides or carbonate salts of alkali metals, as well as aqueous solutions of hydroxides or alkaline earth metals. In a particularly preferred embodiment of the process, the hydrolysis of the compounds of formula VI is carried out by heating with aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium hydroxide. If desired, the hydrolysis may be carried out using organic bases such as triethylamine.

For hydrolysis under acidic conditions, an aqueous solution of mineral acids is preferred. In a particularly preferred embodiment of the process, the hydrolysis of the borates of formula VI is effected by heating with, for example, aqueous solutions of hydrogen chloride, hydrobromic acid, sulfuric acid and phosphoric acid. If desired, the hydrolysis may also be carried out using organic acids such as acetic acid, propionic acid.

If desired, hydrolysis of the compounds of Formula VI in an aqueous medium is carried out in the presence of a water miscible organic solvent. Organic solvents include alcohols such as methanol, ethanol, ketones such as acetone, ethers such as dioxane, acid amides such as formamide, dimethylformamide, sulfoxides such as dimethyl sulfoxide, and pyridine.

The resulting quinoline-3-carboxylic acid of Formula I can be isolated, for example, by adjusting the pH of the aqueous solution to one which is followed by separating the precipitated crystals, for example by centrifugation or filtration, or by lyophilizing the aqueous reaction mixture.

If desired, the quinoline-3-carboxylic acid of the formula I can be converted into its pharmaceutically acceptable acid addition salts in a known manner. Preferably, acid addition salts such as hydrogen halides, sulfonic acids, sulfuric acids, organic acids are formed to form the corresponding chlorides, bromides, arylsulfonates, methanesulfonates, maleate, fumarates, benzates.

The starting quinoline derivatives of formula IV (wherein R ¹ and R ² are as defined above) are, for example, 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (863,429). and the various boron derivatives, such as the boron derivatives of formula VII (wherein R ³ , R ⁴ and R ⁵ are C 1 -C 5 alkyl) optionally by reaction in an organic medium.

Further details of our process are given in the Examples.

1.) 19.5 g (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid dipropionyloxy boronic acid) anhydride and 13.8 g 4-methyl Piperazine was reacted in 72 ml of dimethyl sulfoxide at 110 ° C for two hours. Reaction 21

The mixture was cooled to 90 ° C and 116 ml of a 6% aqueous solution of sodium hydroxide were added. The aqueous reaction mixture was refluxed gently for 1 hour and then cooled to room temperature. The solution was adjusted to pH 7 with 96% acetic acid. The reaction mixture was allowed to crystallize by placing in a refrigerator and after 5 hours the crystals were filtered off, washed with water and dried at 85 ° C under reduced pressure to constant weight. 13.9 g (91.2%) of 1-ethyl-6-fluoro-7- (4-methylpiperazino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid are obtained.

Melting point: 269-271 ° C (dinethylformamide-methanol) Analysis calculated for C ₁₇ H ₂₀ FN ₃ O ₃ : C, 61.25; H, 6.05; N, 12.60. C = 61.37%, H = 5.91%, N = 12.47%.

1'-Ethyl-6-fluoro-7- (4-methylpiperazino) -4-oxo-1,4-dihydro-3-carboxylic acid is boiled in 30 ml of absolute ethanol and 0.61 ml of the boiling solution is added. g of methanesulfonic acid was added. After a few minutes, the resulting solution begins to precipitate crystals. After 10 minutes, the reaction mixture was cooled to 0 ° C and allowed to crystallize overnight in a refrigerator. The next day, the precipitated crystals were filtered off, washed with ethanol and dried under vacuum at 90-95 ° C to constant weight. 2.3 g (89.3%) of the methanesulfonic acid salt of 1-ethyl-6-fluoro-7- (4-methylpiperazino) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid are obtained, m.p. Decomposes at ° C. Calcd for C _B H ₃ O ₆ S ₂ iFN O: C = 50.34%, H 5.63%, N 9.78% Found: C = 50.12%, H = 5, 81%, N = 9.79%.

2.) A mixture of boric acid (9.3 g) and propionic anhydride (70 g) was stirred at 100 ° C for 15 minutes and the temperature of the reaction mixture was brought to reflux. After half an hour the temperature of the reaction mixture was lowered to 110 ° C and ethyl (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate) (29.8 g) was added. reaction. The reaction mixture, which became a thick slurry within a few minutes, was stirred at 110 ° C for two hours and then, after cooling to room temperature, diluted with water (300 ml) and water (300 ml). The reaction mixture is cooled and the precipitated crystals are filtered off. 41.5 g (97.7%) of (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid dipropionyloxy-boronic anhydride are obtained, m.p. Decomposes at 252 ° C.

Analysis of Cj _b Hi ₈ BFC1NO ₇ :

date; C, 50.79; H, 4.26; N, 3.29; Found: C, 50.94; H, 4.15; N, 3.41.

Claims (7)

Claims A process for the preparation of a compound of formula I and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula IV: wherein: R ¹ and R ² are C 2 -C 6 alkanoyloxy g) with the piperazine derivative of formula V or a salt thereof and the resulting compound of formula VI - in the formula R ¹ and R ² are, after or isolated above, hydrolyzed and The resulting compound of formula I is optionally converted into its salt or liberated therefrom. 2. A process according to claim 1 wherein the compound of formula IV and the compound of formula V wherein 25 ^R1 and ^R2 are each as defined above, is reacted with an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester present. 3. A process according to claim 2, wherein the organic solvent is dimethyl sulfoxide. The process of claim 1, wherein the compound of formula IV and the compound of formula V are present - where in the formula ^R * and R ² are as defined in claim 1 in the presence of an acid acceptor. 5. A process according to claim 4, wherein the acid binder is an excess of a compound of formula V, The process of claim 1, wherein the hydrolysis is carried out in an alkaline medium. 7. The process according to claim 6, wherein the alkali is an alkali metal hydroxide, an alkaline earth metal hydroxide, or an aqueous solution of an organic base, preferably triethylamine.