KR0130886B1 - Process for preparing fluoro quinoline derivatives - Google Patents

Abstract

The present invention is a novel method for preparing the fluoro quinoline derivative of the following formula (I) and a method for preparing a pharmaceutically acceptable salt thereof.

In the above formula, R ₃ is hydrogen or methyl ethyl group or lower alkyl group having 3 or less carbon atoms.

Description

[Name of invention]

Method for preparing fluoroquinolone derivatives

Detailed description of the invention

The present invention relates to a method for producing a fluoro quinoline derivative represented by the following structural formula (I).

In the above formula, R ₃ is hydrogen, methyl group, ethyl group or lower alkyl group having 3 or less carbon atoms.

Useful raw materials for preparing the compound of formula (I) are 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or 1-cyclo Methods for preparing propyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid compound are described in European Patent Nos. 133,093, 117,473, German Patent No. 3,142,854, Korea Published Patent Publication Nos. 83-7642, 84-6989, 84-6990, 84-7877, 85-4962 and the like.

In the method described in the patent, 2,4-dichloro-5-fluoro benzoic acid is used as a starting material. Since this method requires the use of hydrogen fluoride to synthesize the starting material, a special apparatus is required, and the process is long, It has the disadvantage of low yield.

Meanwhile, 1-cyclopropyl-6-fluoro-7-pyrerazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (ciprofloxacin) is prepared and described in European Patent No. 3314856, Japanese Patent Nos. 64-40460, 61-36265 (above Bayer AG) and US Patent 4,833,270 (American Cyanamid. Co), Japanese Patent Nos. 60-72885, 63-45261, and Korean Patent Application No. 87 -1893, J. Org. Chem., 55, 773, J. Med. Chem., 34, 168 (above Warner-Lambert Co), ES 548,375, ES 540,226, ES 542,441, 132,845 Europe In addition to patents 287,951, Korean Patent Application Nos. 87-1190 (Sino-Foreign Pharmaceuticals), 85-4962 (Dong-A Pharmaceutical), 91-3634, 91-3630, 90-1079, 90-1078 No. 90-2054 (hereinafter referred to as KIST), Korean Patent Publication No. 90-2041 (JeongJuang), ES 2,006,977, ES 2,015,442 (hereinafter Union Quimico Farm. SA), and the like.

The manufacturing method developed by Bayer AG is the most common method used to prepare not only ciprofloxacin, but also various kinds of quinolone antibacterial agents. It is a 4 to 7 step using 2,4-dichloro-5-fluoro anacid as a starting material. It is a method to manufacture over. This method is relatively good in yield but has the disadvantage of using a long and expensive starting material.

American Cyanamid Co.'s manufacturing process uses expensive 2-amino-4,5-difluoro anhydrous acid as the starting material, and has the same manufacturing process as Bayer A.G., which has a long manufacturing process and low yield.

Warner-Lambert is prepared by using 2,4,5-trifluoro-1-bromobenzene as a starting material and introducing a carboxylic acid group to prepare 2,4,5-trifluoro benzoic acid, The process also has a seven-step process, the process has a long process steps and low yields.

The method described in ES 548,375 and ES 540,226 is a method in which cyclopropyl is introduced using a base such as potassium carbonate using cyclopropyl bromide at the N-1 position, and the yield is very low and expensive cyclopropyl bromide is introduced. The method according to Korean Patent Publication No. 87-1190 (Sino-Pharmaceuticals) has the same disadvantages as the existing method although the manufacturing method is a six-step process.

Korean Patent Publication No. 90-2041 (Cheil Jedang) has the disadvantage of using an expensive phase transfer catalyst in the condensation reaction between the parent nucleus and the piperazine.

Accordingly, the present invention provides a method for preparing a fluoroquinoline derivative with a simple, economical, high yield, unlike the conventional method, and a short manufacturing process step.

Hereinafter, the present invention will be described in detail.

The present invention provides a process for preparing a compound of formula (III) by formylating a compound of formula Z (II), and reacting a compound of formula (III) obtained above with a compound of formula (IV) Fluoroquinoline of formula (I), which comprises preparing a compound of formula (V) and condensing the compound of formula (V) obtained above with the compound of formula (VI) using alumina. It is characterized by the method for preparing the derivative.

In the above formula,

R ₁ is chlorine or bromine atom,

R ₂ is a lower alkyl group having 5 or less carbon atoms,

R ₃ is hydrogen, a methyl group, an ethyl group or a lower alkali group having 3 or less carbon atoms.

Referring to the present invention in more detail as follows.

In the method for preparing a fluoroquinolone derivative according to the present invention, first, as a first step, the compound of formula (II) is formylated to prepare the compound of formula (III).

That is, the compound of formula III is added to a mixture of formic acid (HCO ₂ H), sodium formate (HCO ₂ Na) and acetyl chloride (CH ₃ COC1) at a temperature of 0 ℃, and then reacted for about 30 minutes To prepare a compound of formula (III).

The composition ratio of the mixture is 3: 1.1: 1 equivalent of formic acid: sodium formate: acetyl chloride relative to Structural Formula (II), and the reaction may be carried out by increasing the ratio thereof.

The compound of formula (II) may be prepared by refluxing the compound of formula (II) for about 3 hours in the presence of formic acid (HCO ₂ H) alone.

The compound of formula (II) can be obtained using inexpensive, easy to obtain 3-chloro-4-fluoro aniline or 3,4-difluoro aniline as starting material, which is described in J. Chem. Soc. Chem. Commun, 1987, pp. 897-898.

On the other hand, the second step is to prepare a compound of formula (V) by reacting the compound of formula (III) obtained in the step with the compound of the formula (IV).

That is, the compound of formula III is phosphorus oxcyclolide (POC1 ₃ ), phosgene (COC1 ₂ ), diphosgene, triphosgene, thionyl chloride (SOC1 ₂ ), phosphorus oxybromide (POBr ₃ ) Or phosphorus pentachloride (PC1 ₅ ) 2 to 10 equivalents, preferably 3 equivalents, added at 25 to 150 ° C., preferably 80 to 90 ° C., and then the alkylmalonyl chloride represented by the above formula (IV) The compound of formula (V) is prepared by reacting with lead or monoalkylmalonate and making the liquid basic with a 50% aqueous solution of caustic soda (HaOH).

Examples of the alkylmalonyl chloride include methyl malonyl chloride, ethyl malonyl chloride, isopropyl malonyl chloride, and t-butyl malonyl chloride.

Carbon tetrachloride, benzene, toluene, xylene or acetonitrile may be used as the solvent of the reaction, and particularly preferred is benzene or toluene. If necessary, the solvent may not be used.

In the reaction, the reaction ratio of the compound of formula (III) to the compound of formula (IV) is 1: 150-2 equivalents, preferably 1: 0.5 equivalent, 25-150 ° C., preferably 80-90 The reaction is carried out for about 1 hour at a temperature of ℃.

The third step is to prepare a fluoro quinolone derivative of the formula (I) desired in the present invention by condensation reaction of the compound of formula (V) obtained with the compound of formula (VI) using alumina.

That is, the condensation reaction method of the compound of formula (V) and the amine derivative such as the pyrazine derivative of formula (VI) obtained in accordance with the present invention is used in the equivalence ratio of the mother nucleus and the pyrazine with no addition of base and alumina ( Al ₂ O ₃ ) is reacted at 2 to 10 equivalents, preferably 2 to 4 equivalents at a temperature of 60 to 120 ° C. for 6 to 24 hours, yielding a high yield of 90 to 98%. Prepare a fluoroquinolone derivative.

As the solvent used in this reaction, acetonitrile dimethylformamide is preferably used, and acetonitrile and dimethylformamido are particularly suitable.

As the alumina used in the present invention, an activated acidic alumina, an activated neutral alumina, an activated basic alumina, and the like are used, and among them, a basic active alumina is preferable.

The reaction ratio of the compound of formula (V) to the compound of formula (VI) to alumina is preferably 1: 1.05: 1 to 4. In particular, in the case of using basic activated alumina, it is preferable to react the alumina in 1 to 2 equivalents, and in the case of using acidic or neutral alumina, it is preferable to increase the alumina to 3 to 4 equivalents.

In the above formula (V), when Z is a fluorine atom, it is preferable to react the reaction ratio at 60 ° C. for 6 hours using a basic active alumina at an equivalent ratio of 1: 1.05 to 1-2, and Z is a chlorine atom. It is preferable to make it react at 120 degreeC for 24 hours. In addition, when acidic and neutral alumina is used, it is preferable to heat-reflux the alumina to 3 to 4 equivalents and react for 10 to 12 hours. General properties of alumina with acid and base duality are described in Solid Acids and Bases (by Kozo Tanabe, Acakemic press, 1970).

Acceptable salts of the fluoroquinolone derivatives of the above formula (I) are optionally addition salts obtained by reaction with organic or inorganic acids, such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, citric acid, succinic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, asbestos Colvin acid, vitamin geulrul acid, methanesulfonic acid, benzenesulfonic acid, p - toluenesulfonic acid, or sodium, potassium, calcium or magnesium as the tertiary or quaternary C ₁ -C _It is prepared by addition of ₄ alkyl ammonium.

The following examples are intended to illustrate the invention in more detail, and unless otherwise indicated, percentages, ratios, etc., are by weight.

Example 1; Preparation of 3-chloro-4-fluoro-N-cyclopropylformanilide.

1 ml of formic acid and 0.83 g of sodium formate were added dropwise 0.78 ml of acetyl chloride at 0 ° C., followed by stirring for 30 minutes at the same temperature, followed by 2 g of 3-chloro-4-fluoro-N-cyclopropyl aniline 0.3% It was dissolved in ㎖ dropwise at the same temperature and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and 20 ml of ethyl acetate and 20 ml of water were added to separate the layers. The organic layer was washed with 20 ml of 5% sodium bicarbonate and 20 ml of brine. Anhydrous manganese was added, the organic layer was dried, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography with a mixed solution of ethyl acetate and nucleic acid [1: 9] to give 3-chloro-4-fluoro-N-cyclo. 2 g of propylformanilide (yield: 88%) were obtained.

Elemental Analysis: C ₁₀ H ₉ C1FNO

Calculated Value: C; 56.22, H; 4.25, N; 6.56

Found: C; 56.13, H; 4.14, N; 6.49

Example 2; Preparation of 3-chloro-4-fluoro-N-cyclopropylformanilide.

In Example 1, the mixture was refluxed for 3 hours in the presence of 10 ml of formic acid without using sodium formate and acetyl chloride, thereby obtaining 1.74 g (yield: 76%) of 3-chloro-4-fluoro-N-cyclopropylformanile. .

Example 3; Preparation of 3,4-difluoro-N-cyclopropylformanilide.

3,4-difluoro-N-cyclopropylformanilide using 1.82 g of 3,4-difluoro-N-cyclopropylaniline instead of 3-chloro-4fluoro-N-cyclopropylaniline in Example 1 1.95 g (92% yield) was obtained.

Elemental Analysis: C ₁₀ H ₉ FNO

Calculated Value: C; 60.91, H; 4.60, N; 7.10

Found: C; 60.85, H; 4.54, N; 6.96

Example 4; Preparation of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

12.5 g of 3-chloro-4-fluoro-N-cyclopropylformanilide (58.51 mmol) was added to 14 ml of phosphorus oxcyclolide at 80 ° C, and after 10 minutes, 8 g of methylmalonyl chloride was stirred at the same temperature. After the addition, the mixture was stirred for 1 hour. The reaction solution was poured into 24 ml of iced water, adjusted to pH 14 with 50% caustic soda water, stirred overnight at room temperature, and neutralized with 10% hydrochloric acid to crystallize. The product was filtered off, washed with water and dried at 60 ° C. under reduced pressure to yield 16 g of crude product. This solid was separated and purified through elution gel gel column chromatography, 14.3 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (yield 87%) Got.

Elemental Analysis: C ₁₀ H ₉ C1FNO ₃

Calculated Value: C; 55.43, H; 3.22, N; 4.97

Found: C; 55.36, H; 3.15, N; 4.88

Example 5; Preparation of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxokunolin-3-carboxyl using 7.7 g of mono ethylmalonate instead of methylmalonyl chloride in Example 4 An acid 13.5 g (yield: 82%) was obtained.

Example 6; Preparation of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

After adding 36.6 g of phosphorus pentachloride and 12.5 g of 3-chloro-4-fluoro-N-cyclopropylformanilide to 60 ml of dried benzene, the mixture was refluxed for 2 hours, and then 4 g of methylmalonyl chloride was added at the same temperature. It was added dropwise and stirred for 1 hour. The procedure was followed in the same manner as in Example 4 to obtain 14 g of 1-cyclopropyl-6-fluoro-7-chloro1,4-dihydro-4-oxoquinoline-3-carboxylic acid (yield: 85%). .

Example 7; Preparation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-cafic acid.

11 g of 3,4-difluoro-N-cyclopropyl formanilide was added to 14 ml of phosphorus oxcyclolide at 80 ° C., and after 10 minutes, 8.4 g of ethylmalonyl chloride was added at the same temperature, followed by stirring for 1 hour. The reaction solution was poured into 30 ml of iced water to pH 14 with 50% caustic soda water, stirred overnight at room temperature and neutralized with 10% hydrochloric acid to crystallize. The product was filtered, dried with water under reduced pressure, washed with water, and dried at 60 ° C., and the solid was separated and purified through preparative Kagel column chromatography to give 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo. Quinoline-3-carboxylic acid -12.2 g (yield 83%) was obtained.

Elemental Analysis: C ₁₄ H ₁₀ F ₂ O ₃

Calculated Value: C; 58.487, H; 3.42, N; 5.28

Found: C; 58.82, H; 3.35, N; 5.21

Example 8; Preparation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carrine using 9.1 g of isopropylmalonyl chloride instead of ekymalonyl chloride in Example 7 An acid 12.8 g (yield: 87%) was obtained.

Example 9; Preparation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 7 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carrine using 10 g of t-butylmalonyl chloride instead of ekymalonyl chloride An acid 11.8 g (yield: 80%) was obtained.

Example 10; Preparation of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

1.1 g of 3,4-difluoro-N-cyclopropylformanilide and 1.2 ml of methylmalonyl chloride were dissolved in 12 ml of toluene, followed by stirring at 40 ° C overnight. After concentration under reduced pressure, the solvent was removed, and 14 ml of water was added thereto, followed by stirring for 1 hour. Then, 17 ml of glacial acetic acid and 1.78 ml of concentrated sulfuric acid were added and refluxed for 1 hour. The resulting solid was filtered and dried to form 1-cyclopropyl-6,7. 1.25 g (yield: 85%) of -difluoro-1,4-dihydro-4-oxoquinoline-carboxylic acid were obtained.

Example 11; Preparation of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

To 8 ml of benzene, 2 ml of thionyl chloride, 1 g of 3-chloro-4-fluoro-N-cyclopropylformanilide, and 0.71 ml of ethylmalonyl chloride were added, and the mixture was stirred overnight at 75 ° C. After concentration under reduced pressure, the solvent was removed, 13.8 ml of glacial acetic acid, 12 ml of water and 1.44 ml of concentrated sulfuric acid were added thereto, and the mixture was heated to reflux for 1 hour, and then the resulting solid was filtered and dried to obtain 1-cyclopropyl-7-chloro-6-fluoro-1, 1 g (yield: 81%) of 4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.

Example 12; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

0.14 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.05 g of piperazine and 0.05 g of basic alumina obtained in Example 4 were dried. 5 ml of acetonitrile were mixed, heated to reflux and stirred for 24 hours, and the resulting solid product was filtered after cooling the mixture. The solid product was added to a solvent of chloroform: methanol = 3: 1, and the insoluble solid was removed by filtration under celite. The solid product was stirred for 20 minutes, and the filtrate was dried under reduced pressure to give 0.16 g (95%) of the title compound. Got it.

Elemental Analysis: C ₁₇ H ₁₈ FN ₃ O ₃

Calculated Value: C; 61.62, H; 5.47, N; 12.68

Found: C; 61.60, H; 5.42, N; 12.70

Example 13; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 12, 1 mL of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4 was reacted with 5 ml of dimethylformamide in place of acetonitrile and reacted at 120 DEG C for 12 hours. 0.162 g of oxoquinoline-3-carboxylic acid (yield: 98%) was obtained.

Example 14; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 12, 1-cyclopropyl-6-fluoro-7-piperazinyl was used by using 0.2 g (4 equivalents) of acidic alumina instead of basic alumina and reacting by heating under reflux in acetonitrile 5 ml for 24 hours at 120 ° C. 0.15 g (91%) of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.

Example 15; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 12, 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro- was prepared in the same manner as in Example 14, using 0.15 g (3 equivalents) of neutral alumina instead of basic alumina. 0.154 g (yield: 93%) of 4-oxoquinoline-3-carboxylic acid was obtained.

Example 16; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 14, 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-di was reacted using 5 ml of dimethylformamide in the same manner as in Example 13 above. 0.157 g (yield: 95%) of hydro-4-oxoquinoline-3-carboxylic acid was obtained.

Example 17; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 1 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4- using 5 ml of dimethyl formamide instead of acetonitrile as a reaction solvent in the same manner as in Example 13 above. 0.148 g (yield: 90%) of dihydro-4-oxoquinoline-3-carboxylic acid was obtained.

Example 18; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

0.265 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.088 g of piperazine and 0.102 g of basic alumina obtained in Example 7 were acetic anhydride. It was mixed with 5 ml of nitrile and stirred at 60 ° C for 6 hours. After cooling, the mixture was distilled under reduced pressure to remove the solvent, and 10 ml of water was added thereto, followed by acidification (pH 2 to 3) with 10% aqueous hydrochloric acid solution. The insoluble solids were removed by filtration under celite and the filtrate was neutralized with 10% caustic soda water to filter the resulting solids. The obtained solid product was dried under reduced pressure to obtain 0.324 g (98%) of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Elemental Analysis: C ₁₇ H ₁₈ FN ₃ O ₃

Calculated Value: C; 61.62, H; 5.47, N; 12.68

Found: C; 61.28, H; 5.50, N; 12.74

Example 19; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 18, 5 ml of dimethylformamide instead of acetonitrile was used as a reaction solvent, and the solid formed after the reaction at 60 ° C. for 3 hours was filtered, washed with water, and then chloroform: methanol-3: 1 in 20 to 30 minutes. Stirred. The subsequent procedure was the same as in Example 13, 0.321 g (97%) of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Got.

Example 20; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 18, 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4- was carried out in the same manner as in Example 19 after reaction under the same conditions using 0.404 g of acidic alumina instead of basic alumina. 0.314 g (yield: 95%) of dihydro-4-oxoquinoline-3-carboxylic acid was obtained.

Example 21; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

In Example 18, using 0.303 g of neutral alumina instead of basic alumina, the reaction was carried out in the same manner as in Example 19, followed by 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4- 0.308 g (93%) of dihydro-4-oxoquinoline-3-carboxylic acid was obtained.

Example 22; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride.

0.33 g of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in chloroform: methanol = 3: 1 solvent, and then dissolved in methanol. 20 ml of saturated hydrochloric acid solution was added and stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained solid surplus under cooling, and the resulting solid was filtered and dried under reduced pressure to yield 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-di. 0.35 g (95%) of hydro-4-oxoquinoline-3-carboxylic acid hydrochloride was obtained.

Elemental analysis: C ₁₇ H ₁₉ C1FN ₃ O ₃

Calculated Value: C; 58.54%, H; 5.49%, N; 12.05%

Found: C; 58.60%, H; 5.95%, N; 12.12%

Example 23; Preparation of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid lactate.

0.33 g of 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in chloroform: methanol = 3: 1 solvent and lactic acid 0.11 g Was added and stirred for 2-3 hours. The reaction solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained solid surplus under cooling, and the resulting solid was filtered and dried under reduced pressure to yield 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4- 0.38 g (93%) of dihydro-4-oxoquinoline-3-carboxylic acid lactate was obtained.

Elemental analysis: C ₂₁ H ₂₄ FN ₃ O ₇

Calculated Value: C; 56.12%, H; 5.38%, N; 9.35%

Found: C; 56.38%, H; 5.99%, N; 9.38%

Differences between the manufacturing method for the structural formula (V) according to the present invention and the prior art are summarized as follows.

[Method of notification]

[Method according to the present invention]

In the above formula, R ₁ , R ₂ are as described above, and X is a halogen atom such as chlorine or fluorine.

In addition, conventionally known condensation reaction methods are generally those which use DBU, triethylamine, potassium carbonate, etc. as a base, or an excess of pyrerazine in a dimethyl sulfoxide or pyridine solvent, and react at a high temperature. In the case of using DBU, by-products are produced due to the change of substances by oxidation of DBU itself, and the price is expensive.

However, the cost of the condensation reaction according to the present invention is low, and the production of other side products at relatively low temperatures is completely avoided by using alumina having Lewis acid properties and Broensted base properties. It has the advantage of obtaining the fluoroquinolone derivative of formula (I) in a high yield and a simple process without.

In addition, the experimental results of the compound of Structural Formula (I) obtained by the method of the present invention and the compound of Structural Formula (I) obtained by the existing method are shown in the following scheme.

(Existing method)

(Method according to the present invention)

In the above formula, Z, R ₃ are the same as above.

In the preparation method of the compound of formula (I), the difference between the known method and the method according to the present invention and the effects thereof are as follows in Table 1.

TABLE 1

In the method for preparing the compound of formula (I), the difference between the known method and the method according to the present invention and the effects thereof are as follows in Table 2.

TABLE 2

1) American Cyanamid, etc.

2) C-7: chlorine; For the process according to the invention using acetonitrile and alumina (basic), heated to reflux for 12 hours.

3) Bayer AG. Etc

Claims (16)

(1) forming a compound of formula (III) by formylating a compound of formula (II), and (2) reacting a compound of formula (III) obtained above with a compound of formula (IV) Preparing a compound of the following structural formula (V), and (3) condensing the compound of the following structural formula (V) obtained above with the following structural formula (IV) using alumina. Method for preparing fluoro quinoline derivatives. Wherein R ₁ is a chlorine or bromine atom, R ₂ is a lower alkyl group of up to 5 carbon atoms, and R ₃ is hydrogen, a methyl group, an alkyl group or a lower alkyl group of 3 or less carbon atoms. The method of claim 1, wherein step (1) is performed by adding the compound of formula II to a formic acid, sodium formate and acetyl chloride mixture having an equivalent ratio of 3: 1.1: 1. The method of claim 2, wherein the reaction of step (1) is carried out at a temperature of 0 ° C. The method according to claim 1, wherein step (1) is performed by adding the compound of formula II only to formic acid and refluxing. The method of claim 1, wherein the step (2) comprises the step of replacing the compound of formula III by phosphorus oxcyclolide, phosgene, diphosgene, triphosphogen, thionyl chloride, phosphorus oxybromide or phosphorus pentachloride. Reacting with the above formula (IV) in the presence of A process according to claim 1 or 5, characterized in that the reaction ratio of the compound of formula (III) to the compound of formula (IV) is 1: 0.5 to 2 equivalents, preferably 1: 0.5 equivalent. The method according to claim 1 or 5, wherein the compound of formula (III) and the compound of formula (IV) are carried out at a temperature of 25 to 150 ° C, preferably 80 to 90 ° C. 6. Process according to claim 1 or 5, characterized in that the reaction of step (2) uses carbon tetrachloride, benzene, toluene, xylene or acetonitrile as solvent, preferably benzene or toluene or no solvent. A process according to claim 1, characterized in that the alumina of step (3) is made using acidic alumina, neutral alumina or basic alumina, preferably basic alumina. The method of claim 1, wherein the condensation reaction of step (3) is carried out at a temperature of about 60 to 120 ℃. A solvent according to claim 1, wherein the solvent in the condensation reaction of step (3) is acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylenephosphoramide or hexamethylene postriamide, preferably acetonitrile or Characterized in that by using dimethylformamide, The method of claim 1, wherein the reaction ratio of Structural Formula (V): Structural Formula (VI): Alumina is 1: 1.05: 1 to 4 equivalents. The method according to claim 12, wherein when the alumina is acidic alumina or neutral alum L, 3 to 4 equivalents are used. The method of claim 1, 12 or 13, wherein the reaction conditions are heated to reflux for 10 to 12 hours. 13. The method according to claim 12, wherein when the alumina is basic alumina, sea bream is used using 1 to 2 equivalents. According to claim 1, 12 or 15, the reaction conditions are reacted for 6 hours at 60 ℃ when the C-7 atom is fluorine, heated for 24 hours when the C-7 atom is chlorine Characterized by the above.