HU195801B - Process for producing 1-ethyl-6-fluoro-7-piperazino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid - Google Patents

Abstract

Process for the preparation of 1-ethyl-6-fluoro-7- (4-optionally substituted piperazine) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acids. The invention relates to a process for the preparation of 1-ethyl 6-fluoro-7- (4-optionally substituted piperazine) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acids of the general formula I in which R is hydrogen or methyl. The above compounds are known. They are characterized by their excellent antibacterial effects. The invention provides a cost effective process for preparing these compounds. For example, a mixture of boric acid and propionic anhydride is reacted with ethyl (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate) to give 1-ethyl-6-fluoro To obtain 7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid boro-di (propionyloxy) anhydride. Formula I

Description

The present invention relates to the preparation of 1-elyl-6-fluoro-7-piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof.

Because of its outstanding anti-monomeric activity, the chiral carboxylic acid of formula 1 is widely used in medicine for the treatment of urinary tract and systemic bacterial diseases (Eur. J. Chemother. Antibiot. 1983, 3, 9 and 47; J. Antiraicrob. Chemother. 1984). , 13, Suppl., 99, 107, and 113).

The quinolinecarboxylic acid of formula I can be obtained, for example, by reaction of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid II with piperazine (Belgian Patent Nos. 863,429, 870,576), Japanese Patent Application Laid-Open No. 80 33, 453 and J. Med. Chem. 1980, 23, 1358), or ethyl (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro) -quinoline-3-carboxylate) and piperazine by hydrolysis of ethyl 1-ethyl-6-fluoro-7-piperazole-1,4-dihydroquinoline-3-carboxylate of formula IV (879 106 and 890 Belgian Patent Nos. 223).

A common disadvantage of these processes is that the exchange of the seven-position chlorine atom with piperazine is carried out under vigorous reaction conditions at 115-175 ° C for 5-19 hours, optionally under pressure. In addition, the reaction is non-regioselective and, under the above conditions, the 6-position fluorine atom also partially reacts with piperazine (J. Med. Chem. 1980, 23,

1358.). No. 59,122,470. According to the method disclosed in Japanese Patent Application L-ethyl-6-fluoro-7-substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic acids with boron trifluoride or hydrogen fluoroborate in ethyl 1-ethyl. (1-Ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline) prepared from 6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate They prepared 3-carboxylate-0 ^3, OV-difluoromethylene compounds by Borja-through.

The disadvantage of the process is that the fluoroboric acid or boron trifluoride used is extremely corrosive and toxic, which is a major difficulty when applied to large scale industrial applications. The treatment of the mother liquor produced during the process raises environmental concerns.

According to the present invention, the borate derivatives of formula V (wherein R ¹ and R ² are C 2 -C acyloxy groups) and the carboxylic acid of formula VI can be prepared by a simple route, regioselectively, with good yield, short reaction time and non-corrosive reagents. hydrolysis of borate derivatives of formula VII (wherein R ¹ and R ² are as defined above) formed by the reaction of an amine.

In a preferred embodiment of the process, the borate derivatives of formula V (wherein R ¹ and R ² are as defined above) are converted into quinoline-3-carboxylic acid I without isolation.

The borate derivatives of formula V are optionally reacted with an amine of formula VI 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, sulfoxides. such as dimethyl sulfoxide, alcohols such as methanol, ethanol, 1-decanol, butanol.

Organic and inorganic bases may be used as acid scavengers. Organic bases include trialkylamines such as triethylamine, tributylamine, cyclic amines such as 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, while inorganic bases include hydroxides and carbonates of alkali metals and alkaline earth metals, such as potassium carbonate, potassium bicarbonate, sodium hydroxide and calcium hydroxide. If desired, an excess of the amine of formula VI may be used as an acid scavenger.

The boron derivatives of formula V and the amine of formula VI are also reacted at 0 to 200 ° C, depending on the solvent used, for a reaction time of 0.5 to 10 hours. 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 borates of formula VII (wherein R ¹ and R ² are as defined above) are optionally hydrolyzed, if desired, under acidic or basic conditions to the quinoline-3-carboxylic acid derivative of formula I. The compound of Formula VII, for example, precipitates out of the reaction mixture upon cooling and may optionally be recovered by filtration or centrifugation.

Hydrolysis under basic conditions is preferably carried out in the form of an aqueous solution of the alkali metal hydroxides or carbonate salts and of the alkaline earth metal hydroxides. In a particularly preferred embodiment of the process, the hydrolysis of the compounds of formula VII is carried out by heating with an 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. According to a particularly preferred embodiment of the process a

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The hydrolysis of borates of the formula Vir is, for example, hydrochloride, hydrogen bromide; by heating with an aqueous solution of sulfuric acid and phosphoric acid. If desired, the hydrolysis may also be carried out using organic acids such as acetic acid, porionic acid.

If desired, hydrolysis of compounds of formula VII 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 side and then 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 salts in a manner known per se. Preferably, acid addition salts may be formed, for example, with hydrogen halides, sulfonic acids, sulfuric acids, organic acids. If desired, salts with alkaline and alkaline earth metals and other metal ions may also be used. Salts formed with, inter alia, sodium, potassium, magnesium, silver, copper ions can be prepared.

If desired, hydrates, such as hemihydrates, trihydrates of the compound of formula I or pharmaceutically acceptable salts thereof, may be prepared in a manner known per se.

Exemplary quinoline derivatives of formula V (wherein}? 'And R ² are as defined above) include, for example, 1-ethyl-G-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. bonic acid (Belgian patent 863 429) and various skin derivatives such as boron compounds of formula VII (wherein R ³ , R 'and R ⁵ are C 2 -C 6 aliphatic acyloxy groups, optionally in organic media can be produced.

Further details of the process are set forth in the Examples, without limiting the invention to the Examples.

Examples

Example 1

1. 19.5 g (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid boron (propionyloxy anhydride and 11.9 g piperazine) in 72 ml Reaction in dimethyl sulfoxide for 1 hour at 110. The reaction mixture was cooled to 90 and 116 mL of 6% sodium

aqueous hydroxide solution. The aqueous reaction mixture was refluxed 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 overnight in the refrigerator, and the next morning the precipitated crystals were filtered, washed with water and dried under reduced pressure at 90-95 ° C to constant weight. 14.0 (95.9%) of 1-ethyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid are obtained. Decomposition point '. 221-222 ° C (dichloromethane n-inethanol)

Analysis: Calculated: C, 60.18; H, 5.68; N, 13.16. Found: C, 60.07; H, 5.74; N, 13.18. %.

Preparation of starting material:

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. is added to the reaction mixture. The reaction mixture, which became a thick slurry within a few minutes, was stirred at 110 ° C for two hours and then cooled to room temperature and diluted with 300 ml of water. The reaction mixture is cooled and the precipitated crystals are filtered off. Yield: 41.5 g (97.7%) of (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboneaboro-borobipropionoyloxy) anhydride, m.p. decomposes. Analysis: Calculated: C, 50.79; H, 4.26; N, 3.29; Found: C, 50.94; H, 4.15; N, 3.41. %.

Example 2

(1-Ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinolinecarboxylic acid borobiacetoxy) anhydride and 1.3 g of piperazine were refluxed in 40 ml of absolute ethanol for 10 hours on a water bath. The reaction mixture was then treated with 12 ml of a 6% aqueous solution of sodium hydroxide and refluxed for 2 hours. After cooling to room temperature, the solution was adjusted to pH 6.5 with 96% v / v acetic acid, and the precipitated yellow crystals were filtered off.

1.55 g (97%) of 1-ethyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid are obtained, which is recrystallized from dichloromethane-methanol at 220-222 ° C. decomposes. The material thus prepared, when mixed with the material obtained in Example 1, does not show melting point depression.

Preparation of starting material:

2.74 g of boric acid are reacted with 22.6 g of acetic anhydride in the presence of 2 mg of zinc chloride in 3195Cl. Boric acid was added gradually to the acetic anhydride while the temperature of the reaction mixture was raised to 88 ° C. The temperature of the reaction mixture was slowly raised to 110 ° C and ethyl (1-elyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinolinecarboxylate) (8.79 g) was added, previously dissolved in 18 mL of 96% w / v eric acid. Λ orange red sharp solution for 2 hours. Stir at 110 ° C and allow to cool. The precipitated crystals were filtered off, washed several times with water, once with methanol and dried to give 10.8 g (92.1%) of a butter-colored (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid (boron diacetoxy) anhydride is obtained which decomposes at 273 ° C.

Analysis: Calculated: C, 48.35; H, 3.55; N, 3.52; Found: C, 48.2; H, 3.5; N, 3.2 %.

Example 3

39.8 g of (1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid boron di (propionyloxy anhydride) and 17.2 g of piperazine are reacted with 160 ml of dimethyl sulfoxide for 1 hour at 110 C. A solution of 3% (w / v) sodium hydroxide in water (400 ml) was added to the reaction mixture and refluxed for 1 hour, then cooled to 60 ° C and treated with 7.5 ml of 96% acetic acid. The pH is adjusted to 7. The thick mass is diluted with 200 mL of cold water and then cooled in a refrigerator for 1 hour at 5 DEG C. The precipitated crystals are filtered off, washed with 2 x 100 mL of cold water and then 20 mL of cold methanol under vacuum. Dry at C to constant weight to give 25.9 g of butter-colored 1-elyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid, m.p. 218-220 ° C.

The material thus prepared, when mixed with the material prepared in Example 1 in any ratio, does not show a decrease in the melting point.

Example 4

(1-ethyl-6-fluoro-7-chloro-4-oxo-l, 4-dihydro-3-quinolinecarboxylate tO ^3, OU bíszfacetát-O), 39.8 g of boron and 17.2 g of piperazine are reacted in 160 ml in dimethyl sulfoxide for 15 minutes at 110 ° C. An aqueous solution of 3% (w / v) sodium hydroxide (400 mL) was added and the mixture was refluxed for 1 hour. The reaction mixture was cooled to 60 ° C and adjusted to pH 7 with 7.5 mL of 96% acetic acid. The light crystalline mass was diluted with 200 mL of water, cooled at 5 ° C for 1 h, and the precipitated crystals were filtered off, washed with 2 x 100 mL of cold water and 20 mL of methanol, and dried under vacuum at 100 ° C.

(g, 27.6 g of 1-ethyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinolin-3-carb)) is obtained with m.p. 218-220 ° C. When mixed with any of the compounds of Examples 1 to 4, it does not show a melting point reduction.

Example 5

39.8 g of (l-ethyl-6-fluoro-7-chloro-4-oxo-l, 4-dihydro-3-quinolinecarboxylate O ^5, 0 ⁴⁾ -bis (steel lO) boron and 25.8 g Piperazine was reacted in 160 ml of dimethyl sulfoxide for 15 minutes at -8090 ° C, then 400 ml of a 3% aqueous solution of sodium hydroxide were added and the mixture was refluxed for 1 hour. After cooling to 50 ° C, the mixture was adjusted to pH 7 with 96 ml of 96% acetic acid and diluted with 200 ml of water. After cooling at 5 ° C for 1 hour, the precipitated crystals are filtered off, washed with cold water (2 x 100 ml) and cold methanol (20 ml), and dried at 100 ° C under vacuum to constant weight.

28 g of 1-ethyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid are obtained, m.p. 219-220 ° C. shows no decrease.

Example 6

0.9938 g of (1-ethyl-6-fluoro-7-chloro-4-oxo-1,1-dihydro-5-quinolinecarboxylate-O ³ , O ⁴ ) -bis (steel-O) wine and 1, The piperazine (0767 g) was treated with 3 ml of d-ethylsulfoxide for 30 minutes at 110 ° C, then 12.5 ml of a 5% aqueous solution of sodium bicarbonate was added and refluxed for 2 hours. The cooled reaction mixture was acidified to pH 6.8 with 0.55 mL of 96% acetic acid and then cooled to 5 ° C overnight. The precipitated crystals are filtered off and washed with cold water. After drying, 0.757 g of 1-ethyl-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid is obtained, m.p. 217-220 ° C and any of the material prepared in Example 1. when mixed at a ratio does not show a decrease in melting point.

Claims (9)

A process for the preparation of a compound of formula I and pharmaceutically acceptable salts thereof, comprising the steps of: R ¹ and R ² are aliphatic acyloxy groups having from ² to 6 carbon atoms, are reacted with an amine of formula VI or a salt thereof to give a compound of formula VII, wherein Π ¹ and R ² are, after isolation as described above, hydrolyzed with or without isolation and the resulting compound of formula 1 is optionally converted into its salt or liberated from its salt. 2. A process according to claim 1 wherein the compound of formula V is a compound of formula VI wherein R ¹ and R ³ are as defined in claim 1 in the presence of an organic solvent, preferably an acid amide, an azuloxide, a ketone, an alcohol, an ether or an ester. 3. A process according to claim 2 wherein the organic solvent is dimethylsulfoxide. The process of claim 1, wherein the compound of formula V and the compound of formula VI wherein R ¹ and R ³ are as defined in claim 1 in the presence of an acid acceptor. 5. A process according to claim 4, wherein the acid acceptor is an amine or an excess of a compound of formula V. The process of claim 1, wherein the hydrolysis is carried out in a bbvss medium. The process according to claim 6, wherein the acid is organic or inorganic. lead, preferably hydrochloric acid, sulfuric acid, acetic acid. The process according to claim 1, wherein the hydrolysis is carried out in an alkaline medium. 9. The process according to claim 8, wherein the alkali is an alkali hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous solution of triethylamine.