JP2640441B2 - Intermediate for producing 8-methoxyquinolone carboxylic acid having excellent selective toxicity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate for producing a novel quinolone carboxylic acid derivative which is extremely excellent as an antibacterial agent and a method for producing the same.

[0002]

2. Description of the Related Art Quinolone carboxylic acid antibacterial agents are developed from nalidixic acid to pyromidic acid and further to pipemidic acid, and are used as therapeutic agents for urinary tract infections effective against aerobic gram-negative bacteria.

In recent years, norfloxacin developed by the present inventors has shown activity not only against aerobic gram-negative bacteria but also against gram-positive bacteria, and its antibacterial activity has been significantly enhanced. It is now widely used in clinical practice, and has made dramatic progress in this field. Since then, ofloxacin and ciprofloxacin having similar substituents have been developed.
Further, recently, the cyclopropyl group is at the 1-position and a 6,8-difluorinated product (JP-A-60-126271, JP-A-60-214773)
And 6-fluorine-8-chloride (JP-A-60-126271 and JP-A-61-1667).

[0004] However, as for the 8-methoxy compound, a few compounds having the following structures described in JP-A-60-214773 are known as known compounds, but advantageous properties as antibacterial agents are described. Not.

[0005]

SUMMARY OF THE INVENTION Ciprofloxacin has a stronger antibacterial activity than norfloxacin.
However, the antibacterial activity against Gram-positive bacteria is considerably inferior to that of Gram-negative bacteria. Furthermore, when administered orally to animals or humans, it is not possible to obtain efficacy as expected from its in vitro activity, and it is said that there is a problem in oral absorbability or bioavailability.

According to the study of the present inventors, some of the 6,8-difluorinated product and the 6-fluoro-8-chlorinated product have a problem in oral absorption depending on the substituent at the 7-position. It was considered unusable as a drug due to spleen atrophy and delayed toxicity.

On the other hand, gram-positive bacteria such as methicillin-cepham-resistant Staphylococcus aureus and Staphylococcus epidermidis, which are highly resistant to β-lactam antibiotics, especially third-generation cephams, and enterococci and streptococci. Has once again become a clinical problem.

Furthermore, with the spread of anaerobic bacteria tests due to the development of clinical testing techniques, it has been found that anaerobic bacteria resident on the skin and mucous membranes have become the causative bacteria of opportunistic infections. In respiratory infections, intraperitoneal infections, chronic otitis media, sinusitis, and other gynecological areas, 50 to 80% of cases are detected by anaerobic bacteria alone or mixed with aerobic bacteria. I have. The combination is about 95% E. coli, enterococci, other streptococci and anaerobic bacteria. Under such circumstances, the rate of acquiring resistance of anaerobic bacteria, which has been conventionally sensitive to drugs such as clindamycin, is increasing, and this is posing a serious problem in selecting chemotherapeutic agents.

[0009]

Means and Action for Solving the Problems The present inventors have
As a result of intensive research aimed at solving these problems and developing a truly clinically useful drug, 8-methoxyquinolone carboxylic acid was found to be unparalleled in aerobic gram-negative bacteria as well as gram-positive bacteria. In addition to showing activity, the quinolone carboxylic acid-based drug showed a strong antibacterial activity against anaerobic bacteria, mycoplasma, and the like, which had only weak activity.

Also, 8-methoxyquinolone carboxylic acid is
Excellent selectivity between eukaryotes and prokaryotes, not only shows very good absorption when administered orally to animals, but also shows a wide safety margin in oral and parenteral administration,
Since it does not exhibit a particularly problematic toxic effect, it is very useful as a pharmaceutical for humans and livestock, and as an antibacterial agent for fish and shellfish and plants.

The present invention relates to an intermediate for producing the above-mentioned 8-methoxyquinolonecarboxylic acid, which is represented by the general formula [I]: [Wherein, R represents hydrogen or a lower alkyl group. ] The novel quinolone carboxylic acid derivative represented by these.

Next, an example of a method for producing the compound of the present invention will be described below. (In the formula, Hal represents a halogen atom, and R ¹ and R ² represent the same or different lower alkyl groups.)

The compound of the present invention represented by the general formula [I] is derived to 8-methoxyquinolone carboxylic acid useful as an antibacterial agent by the following synthetic route.

[0014] (Wherein R is the same as above, R ³ is (Where n is 1 or 2, R ⁴ is a hydrogen atom, a lower alkyl group, an acyl group, an alkoxycarbonyl group or an aralkyl group, and R ⁵ and R ⁶ are each independently a hydrogen atom, a lower alkyl group, Represents a substituted lower alkyl group, a cycloalkyl group or a phenyl group.) (Where k is 0, 1 or 2, l is 0, 1 or 2, and m is 0
Or a 1, R ⁷ is a hydrogen atom, a halogen atom, a lower alkyl group or a hydroxyl group, R ⁸ is a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, R ⁹ is a hydrogen atom, a lower alkyl group, an acyl group, It represents an alkoxycarbonyl group or an aralkyl group. Or an azetidino group, a pyrrolidino group, a 3-hydroxypyrrolidino group, a piperidino group, a morpholino group or a thiomorpholino group. )

[0015]

EXAMPLES Next, the compounds of the present invention and the method for producing the same will be described in detail with reference to Examples.

Example 1 Synthesis of 3-methoxy-2,4,5-trifluorobenzoic acid

[0017] 1,2,3,4-tetrafluoro benzene 50g of Burden et al method [Tetrahedron 22 2541 (1966)] in accordance with the colorless oily perform bromination and methoxylation 1-bromo-3-methoxy - 22.21 g of 2,4,5-trifluorobenzene
Obtained. A solution of 22 g of the obtained oil in 37 ml of anhydrous N-methyl-2-pyrrolidone was charged into a pressure-resistant tube, 10 g of cuprous cyanide was added, and the mixture was heated at 140 to 150 ° C. for 4.5 hours. After cooling, 44 g of ferric chloride hexahydrate and 11 ml of concentrated hydrochloric acid (60 ml) were added to the reaction solution, and the mixture was heated to 50 to 60 ° C and stirred for 20 minutes. The reaction solution was extracted with ether, and the organic layer was washed with a dilute aqueous hydrochloric acid solution, then with water, and further with a saturated saline solution. The sodium sulfate was dried and concentrated, and the residue was distilled under reduced pressure to obtain 14.25 g of 3-methoxy-2,4,5-trifluorobenzonitrile as a colorless oil. Boiling point 94 ° C / 8mmHg

To 14.2 g of the obtained oil, 8.5 ml of concentrated sulfuric acid and 40 ml of water were added, followed by stirring at 110 ° C. for 1 hour. After cooling, the reaction solution was poured into 50 ml of ice water, the precipitated crystals were collected by filtration, washed with water, and the obtained crystals were recrystallized from a mixed solution of methylene chloride and n-hexane to give 3-methoxy-2,4,4 as white needles. 11.59 g of 5-trifluorobenzamide was obtained. 130-133 ° C

Next, 150 ml of 18N sulfuric acid was added to the crystals, and the crystals were heated at 100 ° C. for 3.5 hours. After cooling, 400 ml of water was added, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from n-hexane to obtain 9.61 g of the target compound as colorless needles.

Melting point: 98-101 ° C. Elemental analysis: C ₈ H ₅ F ₃ O ₃ Calculated: C; 46.62, H: 2.45 Analytical: C; 46.68, H: 2.48

Example 2 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-
Synthesis of methoxy-4-oxo-3-quinolinecarboxylic acid

3-methoxy-2,4,5-trifluorobenzoic acid
50 ml of thionyl chloride was added to 9.4 g, and the mixture was refluxed for 3 hours. After the thionyl chloride was distilled off, the residue was distilled under reduced pressure to give 8.86 g of 3-methoxy-2,4,5-trifluorobenzoyl chloride as a yellow oil.
I got Boiling point 108 ~ 112 ℃ / 20mmHg

A solution of 7 g of diethyl malonate in 35 ml of anhydrous toluene was added dropwise to 5.9 g of magnesium ethoxide to give 50-60
Warmed at 2 ° C. for 2 hours. Then, after cooling to -10 ° C, a solution of 8.86 g of the above acid chloride in 10 ml of anhydrous toluene was added dropwise over 15 minutes. After stirring at -5 ° C to 0 ° C for 1 hour, ice water containing 8 ml of concentrated sulfuric acid
30 ml was added and the toluene layer was separated. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain 13.64 g of a brown oil of diethyl-3-methoxy-2,4,5-trifluorobenzoylmalonate.

To 13.55 g of the obtained oil, 20 ml of water and p-
14 mg of toluenesulfonic acid was added, and the mixture was refluxed for 9 hours. After cooling, the reaction solution was extracted with methylene chloride, and the organic layer was washed with 7% sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated, and yellow oily 3-methoxy-2,4,5-
10.29 g of ethyl trifluorobenzoyl acetate was obtained.

Acetic anhydride was added to 9.79 g of the obtained ethyl acetate.
9.6 g and 8.4 g of ethyl orthoformate were added, and the mixture was refluxed for 3 hours. Further, 3.2 g of acetic anhydride and 8.8 g of ethyl orthoformate
Was added and refluxed for 8 hours. The reaction solution was concentrated and a brownish oily 2- (3-methoxy-2,4,5-trifluorobenzoyl)-
9.73 g of ethyl 3-ethoxyacrylate was obtained.

9.73 g of the obtained oil was dissolved in 20 ml of ethanol, and 2.0 g of cyclopropylamine was added dropwise under ice cooling.
After stirring at room temperature for 2 hours, the mixture was concentrated, and the residue was purified by silica gel column chromatography [solvent; n-hexane: ethyl acetate = 5: 1] to give 2- (3-methoxy-2,4,5-trifluoro yellowish crystals. 7.52 g of ethyl benzoyl) -3-cyclopropylaminoacrylate was obtained.

Melting point 56-58 ° C. Elemental analysis: C ₁₆ H ₁₆ F ₃ NO ₄ Calculated: C; 55.98, H: 4.70, N: 4.08 Analysis: C; 56.07, H: 4.66, N: 4.07

6.68 g of the obtained crystals were dissolved in 26 ml of anhydrous dimethylformamide, and 1.31 g of sodium fluoride was added thereto.
Refluxed for hours. After cooling, the reaction solution was poured into ice water (100 ml), and the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethyl acetate to give colorless needles of 1-cyclopropyl-6.7-difluoro-1,4-.
4.53 g of ethyl dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate was obtained.

Melting point: 178-180 ° C. Elemental analysis: C ₁₆ H ₁₅ F ₂ NO ₄ Calculated: C; 59.44, H: 4.68, N: 4.33 Analysis: C; 59.34, H: 4.59, N: 4.33

Next, a mixture of 30 ml of acetic acid, 4 ml of concentrated sulfuric acid and 22 ml of water was added to 4.5 g of the crystals, and the mixture was refluxed for 1 hour. After cooling, 100 ml of ice water was added, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 4 g of the desired product as a colorless powder.

Melting point: 185-186 ° C. Elemental analysis: C ₁₄ H ₁₁ F ₂ NO ₄ Calculated: C; 56.95, H: 3.76, N: 4.74 Analysis: C; 56.68, H: 3.70, N: 4.74

Example 3 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-
Synthesis of ethyl methoxy-4-oxo-3-quinolinecarboxylate

To 54.0 g of 2-chloro-4,5-difluoro-3-methoxybenzoic acid was added 266 ml of thionyl chloride, and the mixture was refluxed for 4 hours. After the thionyl chloride was distilled off, the residue was distilled under reduced pressure to obtain 54.39 g of 2-chloro-4,5-difluoro-3-methoxybenzoyl chloride as a colorless oil. Boiling point 90-100 ℃ / 3mmHg

A solution of 43.25 g of diethyl malonate in 190 ml of anhydrous toluene was added dropwise to 32.08 g of magnesium ethoxide, and the mixture was heated at 50 to 60 ° C. for 2.5 hours. Next, after cooling to −20 ° C., a solution of 52.0 g of the above acid chloride in 60 ml of anhydrous toluene was added dropwise over 30 minutes. After stirring at -5 ° C to 0 ° C for 1 hour, 450 ml of ice water containing 70 ml of concentrated sulfuric acid was added, and the toluene layer was separated. The aqueous layer was extracted with toluene, and the organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give diethyl-2-chloro-4,5-difluoro-3-methoxybenzoylmalonate 8 as a pale yellow oil.
5.87 g were obtained.

To 85.87 g of the obtained oil, 150 ml of water and p
-0.1 g of toluenesulfonic acid was added and the mixture was refluxed for 9 hours. The cooled reaction solution was extracted with chloroform, and the organic layer was washed with 7% sodium hydrogen carbonate and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was distilled under reduced pressure to obtain 34.65 g of ethyl 2-chloro-4,5-difluoro-3-methoxybenzoylacetate as a pale yellow oil. Boiling point 110-120 ° C / 6mm
Hg

Acetic anhydride 24.0 g was added to the obtained ethyl acetate 24.0 g.
After adding 0.93 g and 18.22 g of ethyl orthoformate and refluxing for 5 hours, the reaction solution was concentrated and a brownish oily 2- (2-chloro-4,5-) was obtained.
Ethyl difluoro-3-methoxybenzoyl) -3-ethoxyacrylate was obtained.

The obtained oil was dissolved in 60 ml of ethanol, and 5.62 g of cyclopropylamine was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the precipitated crystal was collected by filtration, washed with ether, and then colorless needle-like ethyl 2- (2-chloro-4,5-difluoro-3-methoxybenzoyl) -3-cyclopropylaminoacrylate was added at 16.0%.
g was obtained.

Melting point: 87-88 ° C. Elemental analysis: C ₁₆ H ₁₆ ClF ₂ NO ₄ Calculated: C; 53.41, H: 4.48, N: 3.89 Analysis: C; 53.40, H: 4.53, N: 3.93

1.0 g of the obtained crystals were added little by little to a suspension of 0.14 g of 60% sodium hydride in 6 ml of anhydrous dioxane under ice cooling, and the mixture was refluxed for 1 hour. After cooling, 20 ml of water was added, and the precipitated crystals were collected by filtration, washed successively with a small amount of methanol and ether, and washed with colorless needles of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-4-oxo. 0.68 g of ethyl-3-quinolinecarboxylate was obtained.

Melting point: 177-178 ° C.

Reference Example 1 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methyl-1-piperazinyl) -4-oxo-3-
Synthesis of quinoline carboxylic acid

1-cyclopropyl-6,7-difluoro-1,4-
Dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 200 mg, 2-methylpiperazine 140 mg and anhydrous DMSO
3 ml of the mixture was stirred on a 70-95 ° C. oil bath for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography [developing solvent; chloroform-methanol-concentrated aqueous ammonia (20: 6: 1)], and recrystallized from methanol to obtain 50 mg of the desired product as white powdery crystals. I got

Melting point: 162 ° C. Elemental analysis: C ₁₉ H ₂₂ FN ₃ O ₄ .1 / 2H ₂ O Calculated: C; 59.37, H: 6.03, N: 10.93 Analysis: C; 59.95, H: 6.01, N: 10.81

Claims (1)

(57) [Claims] 1. A compound of the general formula [I] [Wherein, R represents hydrogen or a lower alkyl group. An intermediate for producing 8-methoxyquinolone carboxylic acid represented by the formula: