DD250929A5 - PROCESS FOR THE PREPARATION OF CHINOLIN CARBONESURES - 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

Field of application of the invention

The invention relates to a novel process for the preparation of 1-ethyl-6-fluoro-7- (4-optionally substituted piperazine) -4-oxo-i ^ -dihydro-quinoline-S-carboxylic acids of general formula I, wherein

R is hydrogen or methyl

and their pharmacologically acceptable salts. This forms intermediates of the general formula VII. In formula VII

R ¹ and R ^{2 are} an optionally substituted by halogen aliphatic acyloxy group having 2-6 carbon atoms or an aromatic acyloxy group having 7-11 carbon atoms, while R is in turn hydrogen or methyl. The intermediates of formula VII are new.

Characteristic of the known state of the art

It is known that the quinolinecarboxylic acids of general formula I are used on a large scale because of their excellent antibacterial activity for the cure of diseases of the urinary tract, as well as systematic bacterial diseases (J. Pharm. Sci. 1984, 73, 1379; Eur. J. Chem Antit. 1983, 9, 47, J. Antimicrob., Chemother 1984, 133, Suppl., 99, 107, and 113).

The quinolinecarboxylic acid containing R as hydrogen is prepared by reacting i-ethyl-e-fluoro-chloro-1-oxo-1-dihydroquinoline-3-carboxylic acid of the formula II with piperazine (BE-PS 863429 and 870576, JP-OS 8033453 and J. Med Chem.1980, 23.1358). In another preparation process, a hydrolysis of the ethyl-1-ethyl-6-fluoro-7-piperazin ^ -oxo-IAdihydro-quinoline-S-carboxylate takes place (BE-PS 879106 and 890223).

A common disadvantage of the above processes is that replacement of the chlorine atom at the 7-position with piperazine must be carried out under difficult reaction conditions for 5-19 hours at 115-175 ° C, optionally under pressure. In addition, the reaction is not selective, because under the above circumstances, the fluorine atom in the 6-position also partially reacts with the piperazine (J.Med.Chem., 1980, 23, 1358).

The quinolinecarboxylic acid of the formula I which contains a methyl group as R is obtained by reacting 1-ethyl-e-fluoro-1-chloro-1-oxo-1-dihydro-quinoline-S-carboxylic acid of the formula II with 1-methylpiperazine carried out (BE-PS 870576) and 870917; Japanese Laid-Open Patent Publication No. 8033453 and J. Med. Chem. 1980, 23,1358). Another preparation method consists in the methylation of 1-ethyl-6-fluoro ^ -piperazin ^ -oxo-IA-dihydro-quinoline-S-carboxylic acid of the formula IV (BE-PS 870 917 and FR-PA 2424919). A common disadvantage of these methods is that the reaction is also carried out under difficult reaction conditions at 110-15O ⁰ C in a reaction time of 7-16 hours. The yield of the process is only 55-66%. In addition, the workup of the reaction mixture is complicated.

Object of the invention

The aim of the invention is to avoid the disadvantages of the known methods.

Explanation of the essence of the invention

The invention is therefore based on the object to provide a process for the preparation of quinonecarboxylic acids of the general formula I, wherein R is hydrogen or methyl, which is characterized by shorter reaction times and better

Yields. ·

According to the invention, the carboxylic acids of the general formula I in which R is hydrogen or methyl can be prepared in a simple manner and in good yield with a short reaction time by reacting a borate derivative of the general formula V in which R ¹ and R ² may be the same or different and represent an optionally halogenated aliphatic acyloxy group having 2-6 carbon atoms or an aromatic acyloxy group having 7-11 carbon atoms, with an amine of the general formula VI, wherein R is hydrogen or methyl, and the like 'obtained borate derivatives of the general formula VII, wherein R ¹ and R ^{2 are} as defined above, hydrolyzed.

The borate derivatives of general formula V and VII are new compounds. According to an advantageous embodiment of the process, the borate derivatives of general formula VI, wherein R ¹ and R ^{2 are} as defined above, are converted without islation into the quinoline-3-carboxylic acid of general formula I.

The borate derivative of general formula V are optionally reacted in the presence of an inert organic solvent and an acid-binding agent with the amine of general formula VI.

As the inert organic solvent, acid amides, e.g. Dimethylformamide, dimethylacetamide; Ketones, such as acetone or methyl ethyl ketone; Ethers, such as dioxane, tetrahydrofuran or diethyl ether; Esters, such as ethyl acetate, methyl acetate or ethyl propionate; Sulfoxides, such as dimethyl sulfoxide or alcohols, such as methanol, ethanol, 1-decanol or butanol can be used.

Acid-binding agents may be organic or inorganic bases. Suitable organic bases are triethylamine, tributylamine, cyclic amines, such as pyridine, I, O-diazabicycMSAO and jundec-O-ene, 1,5-diazabicyclo (4.3.0) non-5-ene, 1,4-diazabicyclo (2.2.2) octane and as inorganic bases, the hydroxides and carbonates of alkali metals and alkaline earth metals are used. So z. B. as acid-binding agents potassium carbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide are used. If desired, can serve as the acid-binding agent, an excess of the amine of general formula Vl.

The boron derivatives of the general formula V and the amines of the general formula Vl can be accomplished within 0.5-10 hours depending on the used solvent at 0-200 ⁰ C. The selected reaction time also depends on the selected reaction temperature. By increasing the reaction temperature, a shorter reaction time can be selected. If desired, other conditions may be chosen.

The borates of the general formula VII, wherein R ¹ and R ^{2 are} as defined above, can, if desired, after isolation under acidic or basic conditions, be converted into the quinoline-S-carboxylic acid derivatives of the general formula I by hydrolysis.

The compound of the general formula VII separates out after cooling from the reaction mixture, and the product can optionally be isolated by filtration or centrifugation.

In the hydrolysis carried out under basic conditions, preference is given to using hydroxides of the alkali metals or carbonate salts of the alkali metals, and hydroxides of the alkaline earth metals in aqueous solution. According to a particularly preferred embodiment of the process according to the invention, the hydrolysis of the compound of general formula VII is carried out by heating with an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, potassium carbonate or calcium hydroxide. If desired, the hydrolysis can be carried out using organic bases, e.g. B. of triethylamine, perform.

In the hydrolysis carried out under acidic conditions, it is preferable to use an aqueous solution of mineral acids. According to a particularly advantageous embodiment of the method according to the invention, the hydrolysis of the borates of the general formula VII z. B. by heating with an aqueous solution of hydrogen chloride, hydrogen bromide, sulfuric acid and phosphoric acid. If desired, can be used in the hydrolysis of organic acids, eg. For example, use acetic acid or propionic acid.

If desired, the hydrolysis of the compounds of general formula VII can be carried out in an aqueous medium in the presence of a water-miscible organic solvent. As organic solvents are alcohols, for example, methanol, ethanol; Ketones, e.g. Acetone; Ether, e.g. dioxane; Säureamide.z. As formamide, dimethylformamide or sulfoxides, such as dimethyl sulfoxide or pyridine used.

The isolation of the quinoline-3-carboxylic acid of general formula I is z. Example by adjusting the pH of the aqueous solution to an appropriate value and by centrifuging or filtering the precipitated crystals or by lyophilization of the aqueous reaction mixture.

If desired, the quinoline-3-carboxylic acid of the general formula I can be converted into pharmacologically acceptable salts by methods known per se. Acid addition salts are preferably prepared, as well as chlorides, bromides, arylsulfonates, methanesulfonates, maleates, fumarates, or benzoates. For this one uses hydrogen halides, sulfonic acids, sulfuric acid or organic acids.

If desired, salts with alkali and alkaline earth metals or other metal ions may also be formed. So can

z. For example, salts of sodium, potassium, magnesium, silver or copper ions can be produced.

If desired, the hydrates, such as hemihydrates or trihydrates of the compound of general formula I or their pharmacologically acceptable salts, are prepared in a manner known per se.

The quinoline derivatives of the general formula V used as starting materials, in which R ¹ and R ^{2 are} as defined above, are obtained, for example, by reacting i-ethyl-S-fluoro-y-chloro-oxo-i-dihydro-quinoline-S -carboxylic acid (BE-PS 863429) and various boron derivatives, such as boron derivatives of general formula VIII, wherein R ³ , R ⁴ and R ^{5 is} an optionally substituted by halogen alkyl group having 1-5 carbon atoms or an aryl group having 6 to 10 carbon atoms or an aryl group having 6-10 carbon atoms, optionally prepared in an organic solvent.

Further details of the process can be found in the following examples, without limiting the invention to the examples.

embodiments example 1

19.5 g of [i-Ethyl-e-fluoro-T-chloro ^ oxo-i ^ -dihydro-quinoline-S-carboxylic acid-boron-diipropionyloxylJ anhydride with 11.9 g of piperazine in 72ml of dimethylsulfoxide in one hour at 110 ⁰ C implemented. The reaction mixture is cooled to 90 ° C and an aqueous solution of 116 ml 6G / V .-% sodium hydroxide is added. The aqueous reaction mixture is heated for one hour with gentle boil and then cooled to room temperature. The pH of the solution is adjusted to 7 with a 96G / V% acetic acid solution. The reaction mixture is allowed to stand in the refrigerator overnight. The precipitated crystals in the morning are filtered, washed with water and dried under reduced pressure at 90-95 ° C to constant weight. 14.0 g (95.9%) of i-ethyl-e-fluoro-oxy-piperazine-i-dihydro-quinoline-S-carboxylic acid are obtained. Decomposition point: 221-222 ° C (dichloromethyne-methanol)

Analysis C ₁₆ H ₁₃ FN ₃ O ₃ :

calculated: C = 60.18%, H = 5.68%, N = 13.16%; found: C = 60.07%, H = 5.74%, N = 13.18%;

Preparation of the starting material:

A mixture of 9.3 g of boric acid and 70 g of propionic anhydride is stirred at 100 ⁰ C for 15 minutes. Then the reaction temperature is raised to the boiling point. After half an hour, the temperature of the reaction mixture is lowered to 11O ⁰ C, and it leads to 29.8 g of ethyl (1-ethyl-6-fluoro-7-chloro-4-oxo-1 ^ -dihydro-quinoline-S-carboxylate ) to the reaction mixture. The reaction mixture becomes a thick suspension within a few minutes, which is stirred for 2 hours at 110 ^° C. and then cooled to room temperature, after which the reaction mixture is diluted with 300 ml of water.

The reaction mixture is cooled, the precipitated crystals are filtered. This gives 41.5 g (97.7%) of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid boro-di (propionyloxy) anhydride, decomposition point: 252 ⁰ C.

Analysis C ₁₃ H ₁₈ BFCINO ₇

calculated: C = 50.79%, H = 4.26%, N = 3.29%,

found: C = 50.94%, H = 4.15%, N = 3.41%.

Example 2

19.5 g of [i-ethyl-e-fluoro-chloro-oxo-IAdihydro-quinoline-S-carboxylic acid boro-di-lpropionyloxyll-anhydride and 13.8 g of 4-methylpiperazine are dissolved in 72 ml of dimethyl sulfoxide at 110 ⁰ C implemented for 2 hours. The reaction mixture is cooled to 9O ⁰ C and 116ml of a 6Gew./Vol.-%igen aqueous sodium hydroxide solution are added. The aqueous reaction mixture is boiled gently for one hour and then cooled to room temperature. The pH of the solution is adjusted to 7 with 96% (w / v) acetic acid. The reaction mixture is allowed to crystallize in the refrigerator. The crystals are filtered after 5 hours, washed with water and dried at 85 ⁰ C under reduced pressure to constant weight. This gives 13.9 g (91.2%) of 1-ethyl-6-fluoro-7- (4-methyl-piperazine) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, decomposition point: 269-271 ⁰ C (dimethylformamide-methanol)

Analysis Ci ₇ H ₂ OFN ₃ O ₃

calculated: C = 61.5%, H = 6.05%, N = 12.60%; found: C = 61.37%, H = 5.91% ,. N = 12.47%.

2 g of i-ethyl-β-fluoro-1-methylpiperazine M-oxo-1-dihydro-S-carboxylic acid are boiled in 30 ml of absolute ethanol. To the boiling solution is added 0.61 g of methanesulfonic acid. Within a few minutes, crystals are separated from the resulting solution. After 10 minutes, the reaction mixture is cooled to 0 ^° C. and crystallized in a refrigerator overnight. The next day, the precipitated crystals are filtered, washed with ethanol and dried under reduced pressure at 90-95 ⁰ C to constant weight. This gives 2.3 g (89.3%) of 1-ethyl-6-fluoro-7- (4-methyl-piperazine) -4-oxo-1,4-dihydroquinino-3-carboxylic acid in the form of a Methansuifonsäuresalzes. Decomposition point: 285-287 ° C. Analysis C ₁₈ H ₂₄ FN ₃ O ₆ S

calculated: C = 50.34%, H = 5.63%, N = 9.78%; found: C = 50.12%, H = 5.81%, N = 9.79%.

Preparation of the starting material:

9.3 g of boric acid and 70 g Propionsäu rea η hyd chloride are mixed together and the mixture is stirred at 100 ⁰ C for 15 minutes. The temperature of the mixture is then raised to the boiling point. After half an hour, the temperature of the reaction mixture is reduced to 110 ° C, and there are 29.8 g ÄthyHI-ethyl-e-fluoro-chloro → -oxo-M-dihydro-quinoline-S-carboxylate) to the mixture. After a few minutes, a thick suspension is obtained, which is stirred for 2 hours at 110 ^° C. and cooled to room temperature and then diluted with 300 ml of water. The reaction mixture is cooled and the precipitated crystals are filtered. 41.5 g (97.7%) of i-ethyl-e-fluoro-chloro-oxo-1-dihydro-quinoline-S-carboxylic acid boro-di (propionyloxy) anhydride are obtained. Decomposition point: 252 ° C

Analysis C ₁₈ H ₁₈ BFCINO ₇

calculated: C = 50.79%, H = 4.26%, N = 3.29%; found: C = 50.94%, H = 4.15%, N = 3.41%.

Example 3

19.9 g of [i-ethyl-e-fluoro-1-chloro-oxo-i-dihydro-quinoline-S-carboxylate-O ³ , 0 ⁴ (-bis) acetate-O] -boron and 15.0 g of 1-methyl -pierazine are reacted in 100 ml of dimethyl sulfoxide at 110-115 ⁰ C for 2 hours together.

The mixture is allowed the reaction mixture to 80-90 ⁰ C to cool, and 126 ml of an aqueous solution of sodium hydroxide to 6Gew./Vol.-%igen. The reaction mixture is then allowed to boil slightly for one and one-half hours, then charcoal is added and the mixture is filtered. After cooling to room temperature, the pH of the solution is adjusted to 6.5 by addition of a 96% / v / v acetic acid solution. The reaction mixture is allowed to stand for half a day at ^{0 0} C, the precipitated crystals are filtered and washed with water and methanol. This gives 14.3 g (85.8%) of 1-ethyl-6-fluoro-7- (4-methyl-piperazine) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

Decomposition point: 268-270 ⁰ C (recrystallized from a mixture of dimethylformamide and methanol). The above product shows no melting point depression after blending with a product of Example 2.

Preparation of the starting product:

A mixture of 9.3 g of boric acid and 54.1 g of acetic anhydride (95%) is slowly heated and maintained at 100 ⁰ C for 30 minutes. Then, 29.8 g of ethyl O-ethyl-e-fluoro-1-chloro-1-oxo-1-dihydroquinoline-S-carboxylate) is added to the mixture. Within a few minutes, the first crystals are separated, the suspension paste is stirred for 2 hours at 110 ⁰ C, then the mixture is cooled to 1O ⁰ C and 100 ml of cold water to. The precipitated crystals are filtered. 38.7 g (97.5%) of {1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-quinolinecarboxylate O ³ ; O ⁴ - (bis) acetate-0] -boj, m.p .: 278 ° C. Analysis for the formula C ₁₆ H ₁₄ BCIFNO ₇

calculated: C = 48.35%, H = 3.55%, N = 3.52%; found: C = 48.49%, H = 3.46%, N = 3.71%.

Example 4

3.97 g of [i-ethyl-e-fluoro-1-chloro-oxo-M-dihydro-quinoline S-caroxylate O ³ , O ⁴ (-bis) acetate-0] boron and 3, O 0 g 1-methylpiperazine are reacted in 40 ml of dimethyl sulfoxide for 250 hours at 25 ⁰ C with each other.

To the reaction mixture was added 20 ml of an aqueous solution 6Gew./Vol.%igen sodium hydroxide, and heated in 30 minutes to the reaction mixture to 110 ⁰ O. The mixture is heated for half an hour under gentle boil, filtered hot and cooled. The pH of the solution is adjusted to 7 by addition of a 96% / v / v acetic acid solution. The reaction mixture is allowed to crystallize in the refrigerator overnight, the precipitated crystals are filtered and washed with a little water. 2.8 g (84%) of drap-colored crystals are obtained. After recrystallization from a mixture of dimethylformamide and methanol to give 1-ethyl-6-fluoro-4-oxo-7- (1-methyl-piperazine) -1,4-dihydro-quinoline-3-carboxylic acid, which after drying to constant weight in vacuo at 95 ⁰ C at 267-269 ⁰ C decomposes. The product shows after mixing with a product according to Example 2 in any ratio no melting point depression.

Example 5

7.95 g of [i-ethyl-e-fluoro-chloro-oxy-i-dihydro-S-quinolinecarboxylate O ³ , 0 ⁴ (-bis) acetate-0] -boron and 5.17 g of piperazine are dissolved in 30 ml Dimethyl sulfoxide reacted at 110 ° C for 1 hour together. The reaction mixture is cooled to 9O ⁰ C, and then added 30ml of a 6Gew./Vol.%igen aqueous solution of sodium hydroxide. The mixture is heated to 110 ⁰ C within 30 minutes and stirred for a further half hour at this temperature. The mixture is filtered while warm, cooled to room temperature and the pH is adjusted to 6.5 by addition of 96% / v / v acetic acid. After standing for one day, the precipitated crystals are filtered and washed with water. The product obtained is 4.2 g (66%) of 1-ethyl-6-fluoro-7-piperazine-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, which after mixing with a product prepared according to Example 1, no Melting point depression shows.

Examples

3.97 g of [i-ethyl-e-fluoro-chloro-oxy-i-dihydro-quinoline-S-carboxylate-O ³ , O ⁴ (-bis) acetate-ol-boron and 2.58 g of piperazine are added in 20 ml of dimethyl sulfoxide 180 hours at 25 ⁰ C reacted together. To the reaction mixture is added 20 ml of a 6% w / v% aqueous solution of sodium hydroxide, and the temperature of the mixture is raised to 110 ° C. in 30 minutes. The mixture is cooked gently for half an hour and filtered warm and cooled. The pH is adjusted to 7 with a 96% / v / v acetic acid solution. The reaction mixture is allowed to crystallize in the refrigerator overnight, the precipitated crystals are filtered and washed with water. 3 g (94%) of light-pink crystals are obtained. After recrystallization from a mixture of dichloromethane and methanol to obtain 1-ethyl-6-fluoro-l-oxo-T-piperazine-IAdihydrochinolin-S-carboxylic acid, which is dried in vacuo at 90-95 ⁰ C to constant weight and then at 220-222 ⁰ C melts. After mixing with the product of Example 1 in any ratio, the mixture shows no melting point depression.

Example?

2.0 g of [i-ethyl-e-fluoro-T-chloro-oxo-1-dihydro-S-quinolinecarboxylate-O ³ , 0 ⁴ (-bis) -acetate-0] -boron and 1.3 g of piperazine are dissolved in 40 ml of abs. Ethanol heated for 10 days on a water bath under reflux. To the mixture is added 12 ml of a 6% w / v aqueous solution of sodium hydroxide, and the mixture is refluxed for 2 hours. After cooling to room temperature, the pH of the solution is adjusted to 6.5 by addition of a 96% strength by weight solution of acetic acid, the precipitated yellowish crystals are filtered. This gives 1.55 g (97%) of 1-ethyl-6-fluoro-4-oxo-7-piperazine-1,4-dihydroquinoline-3-carboxylic acid which, after recrystallization, from a mixture of dichloromethane and methanol at 220.degree. 222 ⁰ C decomposes. The substance thus obtained shows no melting point depression with the product of Example 1.

R N

COOH

C ₂ H ₅

ZSO SZ3

(I)

COOH

C ₇ H

2 ⁿ 5

(I)

COOH

C ₂ H ₅

(12)

C ₇ H

2 ⁿ 5

406244

NH NH

(3ΖΓ)

in the)

• OCOR

B OCOR

OCOR- im.)

-5 2.87- 40624 ^

Claims (9)

A process for the preparation of 1-alkyl-6-fluoro-7- (4-optionally substituted piperazine) -4-oxo-adihydro-quinoline-S-carboxylic acids of the general formula: in which R is hydrogen or methyl and their pharmacologically applicable Salts, characterized in that a compound of the general formula V, wherein R ¹ and R ^{2 are} an optionally halogen-substituted aliphatic acyloxy group having 2-6 carbon atoms or an aromatic acyloxy group having 7-11 carbon atoms, with an amine of the general formula VI, wherein R is as defined above, or reacted with a salt thereof, and the resulting compound of general formula VII wherein R, R ¹ and R ^{2 are} as defined above, hydrolyzed without isolation or isolation, and the resulting compound of general formula If desired, it is converted into a salt or liberated from its salt. 2. The method according to claim 1, characterized in that the compound of general formula V with the amine of general formula Vl, wherein R, R ¹ and R ^{2 are} as defined above, in the presence of an organic solvent, in particular an acid amide, a Sulfoxides, a ketone, an alcohol, an ether or an ester. 3. The method according to claim 2, characterized in that one uses as an organic solvent dimethyl sulfoxide. Process according to claim 1, characterized in that the compound of the general formula V is reacted with the compound of the general formula VI, wherein R, R ¹ and R ^{2 are} as defined above, in the presence of an acid-binding agent. 5. The method according to claim 4, characterized in that the acid-binding agent used is an amine or an excess of the compound of general formula V. 6. The method according to claim 1, characterized in that one carries out the hydrolysis in an acidic medium. 7. The method according to claim 6, characterized in that one uses as the acid of the acidic medium, an organic or an inorganic acid, in particular hydrochloric acid, sulfuric acid or acetic acid. 8. The method according to claim 1, characterized in that the hydrolysis is carried out in an alkaline medium. 9. The method according to claim 8, characterized in that alkali metal hydroxide, alkaline earth metal hydroxide or an organic base, preferably an aqueous solution of triethylamine is used as the lye for the alkaline medium. For this 2 pages formulas