KR970005911B1 - Process for preparing quinoline carboxylic acid derivatives - Google Patents

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Description

Process for preparing quinoline carboxylic acid derivative

The present invention relates to 1-substituted-7- (substituted or substituted with piperazine) -6-fluoro-8- (substituted or substituted with fluorine) -4-oxo-1,4-di of the general formula (I). Hydro-quinoline-3-carboxylic acid derivatives

And pharmaceutically usable salts. R ¹ in general formula (I) is a substituted or unsubstituted phenyl group with one or two halogen atoms or a group of the general formula —CH ₂ CR ⁶ R ⁷ R ⁸ (R ⁶ , R ⁷ and R ⁸ are hydrogen or halogen); R ² is piperazinyl or 4-methyl-piperazinyl; R ³ is hydrogen or fluorine general formula (I) (R ² is piperazinyl, 4-methyl-piperazinyl, R ¹ is general structure —CH ₂ CR ⁶ R ⁷ R ⁸ (R ⁶ R ⁷ and R ⁸ Is a group of hydrogen or halogen) and R ³ is fluorine) and the 1-substituted carboxyl derivatives exhibit potent antibacterial action (J. Med. Chem. 1986, 29, 445; Drugs of Fut. 1984, 9, 246; 23rd Intersci, Conf. Antimicrob.Agents Chemother. 1983, Abst. 658, 7th Int. Symp. Fut. Trends Chemother. 1986, 86). Such compounds can be prepared by reacting 6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with a cyclic amine. (Belgian Patent Specification No. 887874, UK Patent specification 2057444, Austrian patent specification 537813 and European patent specification 1064489). General formula (I) (R ¹ is a substituted or unsubstituted phenyl group with one or two halogen atoms, R ² is piperazinyl or 4-methyl-piperazinyl, and R ³ is

Another group of 7-substituted-quinoline-3-carboxylic acids of hydrogen) (2th Intersci. Conf. Antimicrob Agents Chemother. 1984., Abst. 72-78., Antimicrob. Agents Chemother. 1987). , 619, Antimicrob.Agents Chemother. 1986., 192-208). These compounds were reacted with 1-substituted phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amine at 100 ° C. for 20 hours in the presence of a solvent. (European Patent Specification 131839, J. Med. Chem. 1985, 1558., J. Med. Chem. 1987, 504). According to the present invention, the general formula (I) (R ¹ is substituted with one or two halogen atoms or unsubstituted phenyl or the general formula -CH ₂ CR ⁶ R ⁷ R ⁸ (R ⁶ , R ⁷ and R ⁸ is hydrogen Or halogen), R ² is piperazinyl, 4-methyl-piperazinyl, and R ³ is hydrogen or fluorine) to provide a novel process for the preparation of quinoline-3-carboxyl, Compound of general formula (II) as salt

Wherein R is halogen, 2 to 6 carbon atoms as aliphatic acyloxy group, 7 to 11 carbon atoms as aromatic acyloxy group, R ⁴ is fluorine or chlorine, R ¹ and R ² are Amine of the general formula (III)

(Wherein R ⁵ is hydrogen or methyl) or a salt to obtain a compound of the general formula (IV) (R, R ¹ , R ² , R ³ are as described above) and hydrolysis after or without separation, Compounds of the general formula (I) are obtained as independent salts or salts. Compound of general structure (IV)

An advantage of the present production process is that the compound of general formula (I) can be prepared in a simple manner in high yield and short reaction time. Boron derivatives of general formula (IV) are also new compounds. Boron derivatives of the general formula (IV) presently invented are converted to quinoline-3-carboxylic acid of the general formula (I) without separation by the preferred realistic preparation method thereof. The boron derivative of general formula (II) can be reacted with the amine of general formula (III), if desired, using an inert organic solvent and an acid as binder. Acid amides (e.g., dimethylformamide, dimethylacetamide), ketones (e.g. acetone, methylethylketone), ethers (e.g. dioxane, tetrahydrofuran, diethyl) as inert organic solvents Ethers), esters (eg, ethyl acetate, methyl acetate, ethyl propionate), sulfoxides (eg, dimethyl sulfoxide), alcohols (eg, methanol, ethanol, 1-decanol, buta Can be used. As acid binders, organic or inorganic bases can be used. Examples of the organic base group include trialkyl amines (eg, triethylamine and tributyamine), and cyclic amines (eg, pyridine, 1,5-diazabicyclo / 5.4.0 / undec-5 -En, 1,5-diazabicyclo / 4.3.0 / -non-5-ene, 1,4-diazabicyclo- / 2.2.2 / octane), and as inorganic base, hydroxide and alkali carbonate Alternatively, alkaline earth metals may be used. Therefore, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide may be preferentially used as the acid binder, or an amine of the general formula (III) may be used in excess. The boron derivative of general formula (II) and the amine of general formula (III) may be reacted at a temperature between 0 and 200 ° C. depending on the solvent used. The reaction time varies from 30 minutes to 10 hours, which varies with the reaction temperature. If the reaction is carried out at a high temperature, the reaction time is shortened. The reaction conditions described above are preferred values and other conditions may also be used. The compounds of the general formula (IV) are hydrolyzed to form the quinoline-3-carboxylic acid of the general general formula (I), which is under acidic or basic conditions, after or without separation. The compound of the general formula (IV) is precipitated from the reaction mixture, for example, by separation by cooling or by filtration, centrifugation or the like. Basic hydrolysis is preferably carried out by heating, wherein a hydroxide, a carbonate of an alkali metal, or a hydroxide of an alkaline earth metal is used as the aqueous solution. At this time, it is preferable to use sodium carbonate, potassium carbonate, and calcium hydroxide aqueous solution. At this time, an organic amine (for example, triethyl amine) may be used in the hydrolysis process. Acidic hydrolysis is preferably completed using an aqueous mineral acid, wherein the compound of general formula (IV) is preferably subjected to hydrolysis by heating with addition of aqueous hydrochloric acid solution hydrogen, bromine, sulfuric acid or phosphoric acid. Hydrolysis can also be done with auxiliaries or with organic acids (eg, acetic acid, propionic acid, etc.). Hydrolysis of the compound of formula IV may also be carried out in an aqueous medium in the presence of an organic solvent that is miscible with water. For this purpose, for example, alcohols (e.g., methanol, ethanol), ketones (e.g., acetone), ethers (e.g., dioxane), acidamides (e.g., dimethyl formamide) , Sulfoxide (eg, dimethyl sulfoxide) or pyridine. The quinoline-3-carboxylic acid of general structure (I) can be obtained by separation. For example, the precipitated crystals are separated by appropriately adjusting the pH value of the aqueous solution, or the aqueous reaction mixture is separated by filtration, centrifugation, or lyophilization. Compounds of general structure (I) are converted by methods known as pharmaceutically usable salts. It is therefore desirable to be able to form acid addition salts. For example, hydrochloride halides, sulfonic acids, sulfuric acids, or salts formed with organic acids. Preference is given to forming chlorides, bromide, arylsulfonates, methanesulfonates, maleates, fumarates, benzoates and the like. Compounds of general formula (I) form salts with alkali, alkaline earth metals or other metal ions. Thus, sodium, potassium, magnesium, silver, copper salts and the like are produced. Compounds of general formula (I) and pharmaceutically usable salts of the compounds can be converted to hydrates (eg hemihydrates, trihydrates, etc.) by known methods. Looking at the present invention from a more advanced point of view, it provides a new compound of the general formula (IV) (R, R ¹ , R ² and R ³ as mentioned above). Starting materials of the general formula (III) are 1-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (European patent specification 131839) or 1-ethyl -6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (British patent specification 2057440) to a boron derivative (e.g., a compound of general formula (V)

(Where R is halogen, aliphatic acyloxy group containing 2 to 6 carbon atoms, aromatic acyloxy group containing 7 to 11 carbon atoms) or fluoroborate or organic mediating reaction in water Can be. A more detailed description of the present invention is described as follows without limiting the protection of the examples described below.

1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -difluoro-boron React with 3 g of piperazine at 8 ° C. in dimethyl sulfoxide at a temperature of 100 ° C. for 3 hours. 12.6 ml of sodium hydroxide, which is a 6w / v% aqueous solution, is added, followed by heating for 2 hours for hydrolysis. After the reaction mixture was filtered, the pH value was adjusted to 7 using 96w / v% acetic acid and diluted with 15 ml of water. The reaction mixture of crystals is cooled overnight, and the precipitated crystals are filtered off and washed with water and dried. Thus, 1.61 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid is obtained. Melting Point: 234-236 ℃

Analyzed from Structural Formula C ₁₆ H ₁₇ F ₂ N ₃ O ₃ :

Theoretic value (%): C; 56.90, H; 5.07, N; 12.45

Found (%): C; 56.75, H; 5.02, N; 12.48

Example 2

1.99 g (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -bis (diacetate-O) Boron is reacted with 1.29 g of piperazine at 11 ° C. in 8 ml of dimethyl sulfoxide for 2 hours. 20 ml of sodium hydroxide, in a 3 w / v% aqueous solution, are added. The reaction mixture was reluxed for one hour and filtered to adjust the pH to 7 using acetic acid having 96 w / v%. After cooling, the precipitated crystals were filtered and dried by diluting with 10 ml of water. From this, 1.59 g of Ocre index 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid is obtained.

Melting Point: 234 ℃

Analyzed from Structural Formula C ₁₆ H ₁₇ F ₂ N ₃ O ₃ :

Theoretic value (%): C; 56.90, H; 5.07, N; 12.45

Found (%): C; 57.03, H; 5.11, N; 12.51

Example 3

According to Example 2, 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ ) -bis (Propionato-O) -boron is reacted with 0.64 g of piperazine in 4 ml of dimethyl sulfoxide. 6.3 ml of sodium hydroxide, in a 6 w / v% aqueous solution, are added and the reaction mixture is refluxed for 1 hour. After filtration, the pH value was adjusted to 7 using 96 w / v% acetic acid, and then 10 ml of water was added, and the reaction mixture was cooled overnight. The precipitated crystals are filtered off, washed with water and dried. From this, 0.74 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid is obtained.

Melting Point: 232-236 ℃

Analyzed from Structural Formula C ₁₆ H ₁₇ F ₂ N ₃ O ₃ :

Theoretic value (%): C; 56.90, H; 5.07, N; 12.45

Found (%): C; 56.85, H; 5.00, N; 12.39

Example 4

According to Example 1, 1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ )- Difluoro-boron is reacted with 1.5 g of 1-methyl-piperazine in 8 ml of dimethyl sulfoxide. Thereafter, 1.54 g is obtained.

Melting Point: 237-240 ℃

Analyzed from Structural Formula C ₁₆ H ₁₇ F ₂ N ₃ O ₃ :

Theoretic Value (%): C; 58.10, H; 5.45, N; 11.91

Found (%): C; 58.00, H; 5.46, N; 11.95

Example 5

Based on Example 2, 1.99 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ )- Bis- (acetate-O) -boron is reacted with 1.5 g of 1-methyl-piperazine. 1.5 g are obtained therefrom.

Melting Point: 238-240 ℃

Analyzed from Structural Formula C ₁₆ H ₁₇ F ₂ N ₃ O ₃ :

Theoretic Value (%): C; 58.10, H; 5.45, N; 11.91

Found (%): C; 58.19, H; 5.53, N; 11.87

Example 6

Based on Example 3, 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O ³ , O ⁴ )- Bis- (propionate-O) -boron

React with 0.75 g of 1-methyl-piperazine. Thereby, 0.79 g of is obtained.

Melting Point: 239-240 ℃

Analyzed from Structural Formula C ₁₆ H ₁₇ F ₂ N ₃ O ₃ :

Theoretic Value (%): C; 58.10, H; 5.45, N; 11.91

Found (%): C; 57.95, H; 5.37, N; 11.90

Example 7

0.46 g of ³ , O ⁴ ) -bis (acetateto-O) -boron is reacted with 0.6 g of N-methyl-piperazine and 5 ml of dimethyl sulfoxide at 110 ° C. for 1 hour. After adding 10 ml of 5w / v% sodium hydrogen carbonate aqueous solution, the reaction mixture was refluxed for 2 hours, and the pH was adjusted to 7 with 96w / v% acetic acid. The reaction mixture is cooled to precipitate precipitated crystals and cooled with cold water. From this, 3.45 g is obtained.

Melting Point: 282-284 ℃

The obtained carboxylic acid is dissolved in a weak hydrochloric acid solution under heating, and the solution is evaporated in vacuo to obtain a hydrochloric salt. The product decomposes above 270 ° C.

Analyzed from Structural Formula C ₂₁ H ₁₉ F ₂ N ₃ O ₃ :

Theoretic value (%): C; 63.15, H; 4.79, N; 10.52

Found (%): C; 69.27, H; 4.89, N; 10.35

Claims (10)

The compound of general formula (II) is reacted with a piperazine derivative of general formula (III) to obtain a compound of general formula (IV), which is separated or without hydrolysis and converted into a salt if necessary, or By releasing from the salt, to prepare the compound of the general formula (I) and a pharmaceutically usable salt thereof.

Wherein R is a halogen atom, an aliphatic acyloxy group containing 2-6 carbon atoms or an aromatic acyloxy group containing 7-11 carbon atoms, R ¹ is a phenyl group substituted with 1 or 2 halogen atoms, and R is ² is a piperazinyl or 4-methyl-piperazinyl group, R ³ is hydrogen or fluorine, R ⁴ is fluorine or chlorine, and R ⁵ is hydrogen or methyl group. The method of claim 1, wherein the compound of general formula (II) is reacted with an amine compound of general formula (III) in the presence of an organic solvent selected from acidamides, sulfoxides, ketones, alcohols, ether esters. The method of claim 2, wherein dimethyl sulfoxide is used as the organic solvent. The method of claim 1, wherein the compound of general formula (II) is reacted with the compound of general formula (III) in the presence of an acid binder. 5. A process according to claim 4 wherein an excess of amine or a compound of formula III is used as the acid binder. The method of claim 1 wherein the hydrolysis is carried out in an acid medium. 7. The method of claim 6, wherein the organic or inorganic acid is used as the acid medium. The method of claim 1 wherein the hydrolysis is carried out in an alkali medium. The method according to claim 8, wherein an alkali metal hydroxide, alkaline earth, metal hydroxide or organic base is used as the alkali medium. Compound of general structure (IV).

Wherein R is a halogen atom, an aliphatic acyloxy group containing 2-6 carbon atoms or an aromatic acyloxy group containing 7-11 carbon atoms, R ¹ is a phenyl group substituted with 1 or 2 halogen atoms, R ² is piperazinyl or 4-methyl-piperazinyl and R ³ is hydrogen or fluorine.