KR930000439B1 - Process for preparation of quinolone derivatives - Google Patents

Abstract

A method for preparing 1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinylquinoline-3- carboxylic acid of formula (I) comprises (a) preparing 3-acetyl-1- cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline of formula (II) from 1-(2,4- dichloro-5-fluorophenyl)-1,3-butandion, (b) reacting (II) with N- ethoxycarbonyl piperazine in the presence of Cu as a catalyst, (c) oxidizing the obtd. cpd., and (d) hydrolyzing it in an alkali soln. Cpd. (I) has a good antibacterial activity against both gram negative and gram positive bacteria.

Description

Method for preparing quinolone derivative

The present invention relates to a method for producing a quinolone derivative, in particular 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazinyl-quinoline- represented by the following structural formula (I) A method for producing 3-carboxylic acid in high yield.

In general, the quinolone derivative of formula (I) exhibits excellent antibacterial effects against gram negative bacteria and gram positive bacteria.

Various preparation methods are described in Korean Patent Nos. 23468 and 23842, US Patent Nos. 4,547,503 and 4,559,341, and German Patent No. 3,142,854 as a method of preparing the quinolone derivative represented by the above formula (I).

Particularly, among these methods, the preparation method of Structural Formula (I) in the descriptions of Korean Patent Nos. 23468 and 23842 refers to 2,4-dichloro-5-fluorobenzoyl chloride and diethyl of Structural Formula (A) The malonate is reacted in the presence of magnesium alcoholate to prepare acylmalonate of formula (B), which is then hydrolyzed and decarboxylated in an aqueous medium containing para-toluenesulfonic acid to yield ethyl of formula (C). Aroyl acetate is prepared, and then reacted with triethyl-0-formate / acetic anhydride to 2- (2,4-dichloro-5-fluoro-benzoyl) -3- of formula (D) Prepare oxy-acrylate.

Next, the compound of formula (D) is reacted with cyclopropylamine to prepare a compound of formula (E), and the compound of formula (E) is cyclocyclized to prepare the following formula (F), and then G) is prepared and the piperazine is reacted to prepare the compound of formula (I) as the target compound. This is expressed as a reaction scheme as follows.

On the other hand, as a known production method for producing 2,4-dichloro-5-fluorobenzoyl chloride of formula (A) used as a starting material here 2,4-dichloro-5-methyl- of the formula (a) Aniline is diazotized using sodium nitrite, and the prepared diazonium salt is converted to triagen of the following formula (b) using dimethylamine, and then dissolved in excess HF to give 2,4-dichloro-5-methyl After preparing diazonium fluoride, it is pyrolyzed at 130 to 140 ° C. to prepare 3-fluoro-4,6-dichlorotoluene of the following structural formula (c).

Next, 3-fluoro-4,6-dichlorotoluene of the structural formula (c) was chlorinated with UV irradiation at a temperature of 110 to 160 ° C to give 2,4-dichloro-5-fluoro- of the following structural formula (d). After preparing 1-trichloro-methylbenzine, it was hydrolyzed to prepare 2,4-dichloro-5-fluoro-benzoic acid of the following formula (e), which was reacted with thionyl chloride to obtain the above formula (A). To prepare 2,4-dichloro-5-fluorobenzoyl chloride (see Korean Patent No. 23842). This is expressed as a reaction scheme as follows.

As another method for preparing the above formula (A), from 2,4-dichloro-5-fluorobenzene of the following formula (f) 2,4-dichloro-5-fluorobenzope of the following formula (g) After the paddy is prepared, it is oxidized to prepare 2,4-dichloro-5-fluoro-benzoic acid of formula (h), which is reacted with thionyl chloride to produce 2,4-dichloro-5 of formula (A). Prepare fluorobenzoyl chloride (see German Patent No. 3,435,392). This is expressed as a reaction scheme as follows.

Among the methods for producing the quinolone derivative of the above formula (I), the preparation methods described in Korean Patent Nos. 23468 and 23842, and U.S. Patent Nos. 4,547,503 and 4,559,341 are described in 2, 4-Dichloro-5-fluorobenzoyl chloride is used as a starting material, and it is not easy to purchase or acquire such starting material, and even if prepared in-house, the 2,4-dichloro-5- of formula (a) It was difficult to use the starting materials, such as to be prepared from aniline through a five step process or to be prepared from the 2,4-dichloro-5-fluorobenzene of formula (f) through a three step process.

In particular, when preparing 2,4-dichloro-5-fluorobenzoyl chloride of the above formula (A) from 2,4-dichloro-5-methyl-aniline of the above formula (a), it is necessary to use fluoric acid. Not only has the disadvantage of design and design, but also has a problem that is not suitable for mass production industrially, and other methods are improved because the manufacturing process of Structural Formula (A) as a starting material is long and the yield is uneconomical. There was a lot of room.

On the other hand, looking at the preparation method described in Korean Patent Nos. 23468 and 23842, the ethyl aroyl acetate of the formula (C) is prepared from 2,4-dichloro-5-fluorobenzoyl chloride of the formula (A) Expensive magnesium alcoholate must be used, which must undergo a complex process of hydrolysis and decarboxylation.

In addition, when the piperazine is reacted with the compound of the above formula (G), as a side reaction, the dimer having two substituted aromatic compounds in the piperazine, or the amide formed by the reaction of the pyrazine oxide of the aromatic compound is produced or the piperazine in the 6 position. This substituted compound may be produced as an impurity.

Therefore, the removal of impurities generated after the reaction is not easy, the purity is low, and the yield is low, there is an industrially uneconomical problem.

In addition, when the piperazine reacts with the compound of the above formula (G), the reaction temperature must be high, and the use of piperazine in an amount of 5 to 10 moles per mole of the free carboxylic acid as a starting material is an unfavorable shaving disadvantage. It is pointed out.

Therefore, the present invention is to prepare a quinolone derivative represented by the above structural formula (I) of high purity in an economical manner using a starting material that can be easily obtained without using a difficult reaction process or expensive raw materials, unlike the prior art. The purpose is to provide a new method.

Hereinafter, the present invention will be described in detail.

The present invention is 4-cyclopropylamine-3- represented by the following structural formula (V) from 1- (2,4-dichloro-5-fluorophenyl) -1,3-butanedione represented by the following structural formula (III). (2,4-Dichloro-5-fluorobenzoyl) -4-ethoxy-3-butanedione was prepared and reacted in the presence of a base to give 3-acetyl-1-cyclopropyl-7- of the following formula (VI). Chloro-6-fluoro-1,4-dihydro-4-oxoquinoline is prepared, and then reacted with one side of protected N-ethoxycarbonyl piperazine under an inert organic solvent, oxidized, and then in alkaline solution. In the preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid represented by the above structural formula (I), When reacting the following structural formula (VI) with N-ethoxycarbonyl piperazine protected on one side, the copper or copper compound is used as a catalyst. It shall be.

Referring to the present invention in more detail as follows.

The present invention is to prepare the target compound in high yield by using copper or copper compound as a catalyst, unlike the prior art in the preparation of the quinolone derivative of the formula (I), first, the following formula (II) and N-acetyl 2-pyrrolidone was reacted at room temperature to prepare 1- (2,4-dichloro-5-fluorophenyl) -1,3-butanedione of the above formula (III), followed by the formula (III). 3) reacted with triethylortho formate to prepare 3- (2,4-dichloro-5-fluorobenzoyl) -4-ethoxy-3-butanedione of the following formula (VI), Reaction with propylamine affords 4-cyclopropylamine-3- (2,4-dichloro-5-fluorobenzoyl) -3-butanedione of formula (V).

This was then reacted under a base to prepare 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline of formula (VI), which was either copper or Reacting with a copper compound as a catalyst to one side of the protected N-ethoxycarbonyl pyrazine and an inert organic solvent, 3-acetyl-1-cyclopropyl-7- (4-ethoxycarbonyl-) 1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline was obtained and then oxidized to 1-cyclopropyl-7- (4-ethoxycarbonyl of the following structural formula: -1-piperazinyl) -6-fluoro-1,4-4-oxoquinoline-3-carbonylic acid was prepared, and the compound was hydrolyzed to prepare the compound of formula (I). That's how you do it. This is expressed as a reaction scheme as follows.

According to the invention the compound of formula (H) is prepared according to the method described in German Patent No. 3,435,392 and the structure (III) is prepared according to the method described in Chem. Ber. 130. 1088 (1970). Wherein, the formula (III) is reacted with trimethyl or triethylamine in the presence of 2 mol or more of acetic anhydride at 120 ~ 150 ℃ for 1 to 3 hours to prepare the enol ether of the formula (IV) Next, the cyclopropylamine is reacted with the inol ether of the structural formula (IV) obtained at 0 to 50 ° C. using an inert solvent such as methanol, ethanol, methylene chloride, benzene, or the like to obtain enaminone of the structural formula (V). Manufacture.

Then, it is heated to a high boiling point such as N, N-dimethylformamide or N, N-dimethylacetamide in the presence of a base selected from a base such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium methoxide and potassium tert-butoxide. The above formula (VI) is prepared by cycling under an organic solvent.

The compounds of formulas (V) and (VI) can be prepared according to the method described in Korean Patent Publication No. 90-11758.

Thus prepared N-ethoxycarbonyl piperazine protected by one side of the formula (VI) inert organic solvents such as N, N-dimethylformamide, tetrahydrofuran, dioxane, N, N-dimethylacetamide , An organic solvent selected from pyridine, preferably a pyridine solvent, using a copper compound as a catalyst and reacting at 110 to 120 ° C. to dimers, amides, and compounds substituted with piperazine at the 6 position or the 6, 7 position It can prevent the formation of impurities such as compounds in which piperazine is substituted at the same time.

In particular, the reason why one side uses a protected N-ethoxycarbonyl piperazine is that the compound substituted at the 6-position or simultaneously substituted at the 6- and 7-positions is produced to suppress the side reaction.

In addition, since the copper compound used as a catalyst in the reaction of N-ethoxycarbonyl piperazine increases the reactivity of the chlorine substituent in aromatics and reduces the reactivity of fluoro, that is, the sequence of nucleophilic reactivity in general aromatics (F> Cl> Br> I) is replaced with I> Br> Cl >> F to produce dimers, amides, and piperazine substituted at 6-positions, and compounds simultaneously substituted at 6- and 7-positions. The compound of the above structural formula (VII) of high purity is prepared in a high yield of 96% or more because it suppresses and enhances reactivity.

Here, the copper compound as a catalyst includes all compounds of copper monovalent and copper divalent including copper monomers, of which copper or copper monovalent compounds are most effective, for example cuprous chloride, cuprous bromide, and iodide 1 Copper, cuprous cyanide, cuprous oxide, and the like.

In this manner, the compound of the structural formula (III) is oxidized in a potassium hypochlorite, sodium hypochlorite, potassium hypobromite, sodium hypobromite solution prepared by reacting a halogen compound of Cl, Br, or I in sodium hydroxide solution or potassium hydroxide solution. Reaction produces the acid of the said structural formula.

At this time, Preferably it is made to react with potassium hypobromide solution at 10-30 degreeC, and the compound of the structural formula (VII) can be obtained in high yield. Then, when the compound of formula (V) is hydrolyzed in an alkaline solution, particularly lithium hydroxide solution, it is possible to easily prepare the quinolone derivative of the above formula (I).

Further, the 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid or a salt thereof of the above formula (I) of the present invention may be Interconversion is possible and this method is known in the art.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited by the Examples.

[Production Example 1]

Preparation of Starting Material 1- (2,4-Dichloro-5-fluorophenyl) -1,3-butanedione (III)

To 112.7 g of a 40 wt% solution of boron fluoride (BF ₃ -2CH ₃ COOH) in acetic acid was added 31.05 g (0.15 mol) of 2,4-dichloro-4-fluoroacetophenone at room temperature. The solution was stirred for 1 hour at room temperature and 45.9 g (0.45 mole) of acetic anhydride were added over 10 minutes. The mixture was then heated at 40 ° C. for 8 hours and left at room temperature for 16 hours with stirring. The crystal slurry was filtered in active atmosphere and dehydrated to obtain about 46 g of boron fluoride (BF ₂ ) complex.

The wet solid is placed in 73.8 g of anhydrous sodium acetate solution dissolved in 675 ml of water, and the mixture is heated at reflux for 90 minutes. It was then extracted three times (200, 120 and 100 ml) with n-hexane, and the organic extract was washed with 150 ml of substituted sodium dicarbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated at room temperature for 5 days. After elapsed, 6.65 g of boron fluoride (BF ₂ ) complex was added to the reaction liquid, and the mixture was allowed to stand. The treatment was carried out as above to obtain 3,8 g of the title compound, which was obtained as 28.5 g of a pale pink solid (yield: 76%). Collected.

As a result of analysis by spectroscopy, the title compound (III) was found to exist in both solid and solution state, and the sample determined from n-hexane had a melting point of 68 to 69 ° C.

[Production Example 2]

Preparation of Starting Material 1- (2,4-Dichloro-5-fluorophenyl) -1,3-butanedione (III)

11.8 g (0.295 mole) of 60% sodium hydroxide in mineral oil and 80 ml of n-hexane were placed in a 500 ml three-necked flask, an addition funnel was installed, refluxed and stirred for 10 minutes under a nitrogen stream, and then the solvent was removed.

Repeated twice with 80 ml of n-hexane, if necessary, then added 100 ml of anhydrous ethyl ether and removing the solvent again, followed by adding 230 ml of anhydrous ethyl ether, to which 2,4-dichloro-5-fluoroacetophenone 30.3 was added. g and 18.6 g of N-acetyl-2-pyrrolidone were added dropwise at room temperature.

The mixture was stirred at room temperature for 1 hour and heated at reflux for 3 hours. Then cool to -5 ° C and carefully add 65 ml of 30% acetic acid. The ether phase is decanted and washed with 100 ml of 5% sodium dicarbonate solution, washed with 50 ml of water and dried over anhydrous sodium sulfate.

The residue obtained after filtration and solvent distillation was purified by low pressure distillation, then distilled at 118-133 ° C. and 0.15 mm screened. After sufficiently purifying to the next step, 27.7 g (yield 76%) of 1- (2,4-dichloro-5-fluorophenyl) -1,3-butanedione were obtained.

[Manufacture example 3]

Preparation of 3- (2,4-dichloro-5-fluorobenzoyl) -4-ethoxy-3-butan-2-one (IV)

In a three-necked flask equipped with a distillation unit, 27.4 g (0.11 mole) of 1- (2,4-dichloro-5-fluorophenyl) -1,3-butanedione, 23.7 g (0.16 mole) of triethylolsoformate, and anhydrous 27.5 g (0.25 mol) of acetic acid are added and the mixture is slowly heated until the internal temperature reaches 140 ° C. and the volatile reaction product is distilled off. After 2 hours at this temperature, the mixture is cooled and the residual volatile compounds are distilled at a temperature of 95 to 100 ° C. and a pressure of 2 to 3 mmHg.

This gives 33.5 g (99.8%) of the residue as the title compound. It is used in the next step without any purification process.

[Production Example 4]

Preparation of 4-cyclopropylamine-3- (2,4-dichloro-5-fluorobenzoyl) -3-buten-2-one (V)

33.5 g of 3- (2,4-dichloro-5-fluorobenzoyl) -4-ethoxy-3-butan-2-one obtained in Preparation Example 3 was immediately cooled, followed by 6.3 g of cyclopropylamine in 100 ml of free ethanol. After dropwise addition, the mixture was stirred at room temperature for 2 hours. 80 ml of water was slowly added dropwise, cooled, filtered and washed with ethanol and water to give 32 g (92%) of 4-cyclopropylamine-3- (2,4-dichloro-5-fluorobenzoyl) -3-butene-2- One was prepared.

Production Example 5

Preparation of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline (VI)

36 g of 4-cyclopropylamine-3- (2,4-dichloro-5-fluorobenzoyl) -3-buten-2-one and 16.0 g of calcium carbonate were added to 110 ml of N, N-dimethyformamide solution. The mixture was refluxed for time, cooled, and 32 ml of water was added dropwise, followed by cooling.

The filtered compound was stirred in water for 15 minutes, filtered again, and washed with water to obtain 27 g (85%) of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo Quinoline was prepared.

Example 1

Under nitrogen, 20 g of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline, 40 g of N-ethoxycarbonylpiperazine and 0.3 g of copper were added to 80 ml of pyridine. After reacting for 2 to 3 hours at 110-120 ° C., the solvent was removed under reduced pressure, and 300 ml of water was added to the residue. The resulting solid was filtered, washed with water, and dried to 3-acetyl-1-cyclopropyl-7- Prepare 28.1 g (98%) of (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline.

H NMR δ (CDCl ₃ ): 1.16-1.36 (m, 7H), 2.76 (s, 3H), 3.18-3.28 (n, 4H), 3.42-3.46 (m, 2H), 3.6-3.7 (m, 4H) , 4.08-4.3 (q, 2H), 7.2-7.3 (d, 1H), 8.55 (s, 1H).

Example 2

Pyridine 20 g of 3-acetyl-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline, 40 g of N-ethoxycarbonylpiperazine and 0.5 g of cuprous chloride under nitrogen After adding to 80ml and reacting at 110 ~ 120 ℃ for 2 ~ 3 hours, the solvent was removed under reduced pressure, 300ml of water was added to the residue, the resulting solid was filtered, washed with water and dried to give 3-acetyl-1-cyclopropyl- Prepare 28.1 g (98%) of 7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline.

H NMR δ (CDCl ₃ ): 1.16-1.36 (m, 7H), 2.76 (s, 3H), 3.18-3.28 (n, 4H), 3.42-3.46 (m, 2H), 3.6-3.7 (m, 4H) , 4.08-4.3 (q, 2H), 7.2-7.3 (d, 1H), 8.55 (s, 1H).

Example 3

Example 2 3-acetyl-1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro using 0.7 g of cuprous bromide instead of 0.5 g of cuprous chloride in the process Prepare 27.8 g (96.8%) of -1,4-dihydro-4-oxoquinoline.

Example 4

15% of 32.5 g of 3-acetyl-1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline and 160 ml of ethanol In 120 ml of potassium hypobromide solution, stirred at room temperature for 3 hours, ethanol solution was removed under reduced pressure, insoluble matter was filtered off, 40% sodium bisulfide was added to decompose unreacted sodium hypobromide, and acidified with hydrochloric acid. Solids were filtered and washed with water to prepare 1-cyclopropyl-7- (4-ethoxycarbonyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3-carbohydrate Prepare 29.1 g (89%) of carbonic acid.

Melting Point: 296 ~ 304 ℃

Example 5

25.9 g of the carboxylic acid compound obtained in Example 4 and 10.0 g of 98% lithium hydroxide were added to 350 ml of water and refluxed for 4 hours. After cooling, 400 ml of 1N hydrochloric acid was added, and the filtrate was filtered with 10% ammonium hydroxide solution to pH 7.2. After cooling, the mixture was cooled to 5-10 ° C., filtered, washed with water and dried to prepare 19.3 g (90%) of cyclofloxacin.

Melting Point: 250 ~ 255 ℃

[Comparative Example]

A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.11 g of anhydrous piperazine and 100 ml of dimethylsulfoxide was added 130 Heat at C-140 C for two hours.

The solvent is distilled off under high vacuum, the residue is suspended in water, filtered off with suction and washed with water. To purify the moist composition is boiled with 100 ml of water, filtered off with suction at room temperature and washed with water and dried over CaCl ₂ in a vacuum drying cabinet at 100 ° C. until content is reached.

This yields 19.6 g (84.63%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid which decomposes at 255 to 257 ° C.

Claims (1)

3-acetyl-1-cyclopropyl-7-chloro- of formula (VI) from 1- (2,4-dichloro-5-fluorophenyl) -1,3-butanedione represented by formula (III) 6-Fluoro-1,4-dihydro-4-oxoquinoline is prepared and reacted with one side of protected N-ethoxycarbonylpiperazine under an inert organic solvent, followed by oxidation, followed by the following structural formula (식) Was prepared and hydrolyzed in alkaline solution to give 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3 represented by the following structural formula (I): In preparing a carboxylic acid, a quinolone characterized by using copper or a copper compound as a catalyst when reacting a compound represented by the following structural formula (VI) with a protected N-ethoxycarbonyl piperazine on one side Process for the preparation of derivatives.