JPS61118370A - Quinolonecarboxylic acid and its preparation - Google Patents

Abstract

NEW MATERIAL:The quinolinecarboxylic acid compound of formula I (R is H or lower alkyl; X is halogen). EXAMPLE:N-(3-chloro-4-fluorophenyl) acetamide. USE:A preparation intermediate of 8-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(substitut-ed amino)-4-oxo-3- quinolinecarboxylic acid, etc. which is a novel antibacterial agent. PREPARATION:The compound of formula I wherein R is lower alkyl can be prepared by reacting the novel compound of formula II (R<1> is lower alkyl; X and Y are halogen) with an alkyl orthoformate to obtain the compound of formula III (R<2> is lower alkyl), reacting the compound with cyclopropylamine, and cyclizing the resultant compound of formula IV.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a general formula (wherein,
R is hydrogen or a lower alkyl group, X is a halogen)
The present invention relates to a quinolone carboxylic acid compound represented by and a method for producing the same.

(Problem to be solved by the invention)
Compound 1 The compound of the present invention was synthesized for the first time by the present inventors.
8-Bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(substituted It is used as an intermediate in the production of amine)-4-oxo-3-quinolinecarboxylic acid, etc.

[Means for solving problems]

The compound represented by the general formula (I) is produced as described below.
In other words, the general formula [■]
: At least an equimolar amount of orthoformic acid ester with benzoyl acetate represented by
Air temperature to 200°C in acetic anhydride, preferably 100150°C
By heating at .degree. C. for several hours, a compound of the general formula R2 (representing a lower alkyl group, R1, X and Y being the same as above) can be produced.

(III) is then reacted with at least an equimolar amount of cyclopropylamine 8 in an inert solvent such as ethanol to obtain the general formula (IV) (wherein R', X and Y are the same as above) Derived from long-lasting compounds.

Furthermore, this (IV) is dissolved in a suitable solvent such as dioxane,
In the presence of a suitable base catalyst in a polar solvent such as alcohol, dimethylformamide, dimethyl sulfoxide, sulfolane, etc., at 0 to 200°C, preferably at 50 to 150°C,
By heating for several hours, a compound represented by the general formula (1') (wherein R1 and X are the same as above) can be produced.

In addition, the compound represented by the general formula [E
It can be derived into a quinolone carboxylic acid compound represented by the following formula:

Incidentally, the compound represented by the general formula (II), which is the starting material of the present invention, is also a new compound, and can be synthesized, for example, by the following route.

(Example) Next, the compound of the present invention and its production method will be explained in detail with reference to Examples.

Example 1 Synthesis of N-(3-chloro-4-fluorophenyl)acetamide 3-chloro-4-fluoroaniline 1009 (0,6
When acetic anhydride is added to 87IlIo, 2), heat is generated.

After standing for 30 minutes, the reaction solution was mixed with 1. The precipitate was collected by filtration, dissolved in 400ml of ethanol, and diluted with 600ml of hot water.
was added and allowed to cool with occasional stirring, and the precipitated crystals were collected by filtration to obtain the desired product 119.49. Melting point: 118-119°C Example 2 Synthesis of N-(3-chloro-4-fluoro-6-nitrophenyl)acetamide 55 g (0,293 mo, 9) of N-(3-chloro-4-fluorophenyl)acetamide was concentrated. Dissolved in 165 m of sulfuric acid and added concentrated nitric acid (dl, 4
2>154d was added dropwise at 5 to 10°C over 1 hour. After stirring at the same temperature for 1 hour, the reaction solution was poured into ice water, and the precipitate was collected by filtration, thoroughly washed with water, and recrystallized from acetonitrile to obtain 48.9 g of the desired product in the form of yellow needles.

Melting point 114-115°C Example 3 Synthesis of 3-chloro-4-fluoro-6-nitroaniline N-(3-chloro-4-fluoro-6-nitrophenyl)acetamide 30 g (0,129 mo, e)-fl hydrochloric acid 50d and 200 rIJl of ethanol, and the mixture was refluxed for 2.5 hours. 300 d of ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 24.99 of the desired product as yellow needle crystals. Melting point 149.5-150°C Example 4 Synthesis of 2-bromo 3-chloro-4-fluoro-6-nitroaniline 3-chloro-4-fluoro-6-nitroaniline 200
．． 3 g of bromine was dissolved in 1.5 ml of acetic acid, and while stirring at 50° C., 339 g of bromine was added dropwise over 80 minutes. Furthermore, after stirring at the same temperature for 2 hours, ice water 3. The precipitate was collected by filtration and washed with water. This precipitate was then mixed with 300 rIIi of concentrated hydrochloric acid and 1.2 liters of ethanol. The mixture was added to a mixture of p and refluxed for 8.5 hours. After cooling, the precipitate was collected by filtration and washed with water to obtain the desired product 235.69 as yellow needle-like crystals.

Melting point 146-147°C Example 5 Synthesis of 3-bromo-2,4-dichloro-5-fluoronitrobenzene 2-bromo-3-chloro-4-fluoro-6-nitroaniline 235.69% in anhydrous acetonitrile 1.5% ( Add 147 g of anhydrous cupric chloride to the solution, and while stirring at 60°C, add 135.2 g of tert-butyl nitrite to 70 g.
It was dripped in minutes. Cool the reaction solution with ice-cooled dilute salt 1.5. The organic layer was washed successively with water-cooled dilute hydrochloric acid and saturated brine. After drying the anhydrous sodium sulfate, it was concentrated and the residue was distilled to obtain the desired product 218.89 as a red-orange oil with a boiling point of 78-117°C/2sHg.

When this is recrystallized from methanol, the melting point is 65.5-6.
It is a yellow prism product with a temperature of 7.5°C.

Example 6 Synthesis of 3-bromo-2,4-dichloro-5-fluoroaniline Add 135.47 ml of iron powder to 140 d of water and heat at 50 to 60°C.
While vigorously stirring, 18 ml of hydrochloric acid was added dropwise. After the foaming subsided, 350 ml of hot ethanol was added, and then 218.8 g of 3-bromo-2,4-dichloro-5-fluoronitrobenzene was added dropwise at 52 to 76°C over 1 hour.

After further stirring for 75 minutes at the same temperature, 50% of benzene was added to the hot reaction solution.
0d was added to remove the insoluble matter by filtration, and the insoluble matter was washed successively with 100d of ethanol and 200d of benzene. The filtrate and washing liquid were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was recrystallized from aqueous ethanol to obtain 141.6 g of the desired product as light brown needles. Melting point 126-12
9.5°C Example 7 Synthesis of 3-bromo-2,4-dichloro-5-fluorobenzonitrile 141.6 g of 3-bromo-2,4-dichloro-5-fluoroaniline was dissolved in 900 parts of concentrated hydrochloric acid. -2~O'
Add sodium nitrite 56.69 to this while stirring at C.
A 120ml aqueous solution of was added dropwise over 40 minutes. Further at the same temperature 3
After stirring for 0 minutes, add 180 g of sodium borofluoride to the reaction solution.
The mixture was poured into a 700 d ice-water solution and stirred vigorously at 0°C for 20 minutes. After standing at the same temperature for 15 minutes, the precipitated crystals were collected by filtration, subjected to an ice-water method, and air-dried to obtain diazotetrafluoroborate having a wet weight of 1270.83.

To 800 ml of an aqueous solution of 989 copper cyanide, 142.49 potassium cyanide, and 29 SJ of sodium carbonate was added the aforementioned diazotetrafluoroborate little by little over 45 minutes while stirring at 9 to 10°C. Then, after stirring at air temperature for 2 hours,
Potassium cyanide (719 d) and benzene (700 d) were added and the mixture was further stirred for 30 minutes, the reaction solution was filtered, and insoluble materials were washed twice with benzene (300 d). The organic layer was separated, washed five times with 300 Ir11 of saturated brine, dried over anhydrous sodium sulfate, and concentrated. This residue was recrystallized from ethanol to obtain the desired product 75.59 as reddish brown prism crystals. Melting point 110.5~
112.5°C Example 8 Synthesis of 3-bromo-2,4,5-trifluorobenzonitrile A suspension of 123cj of potassium fluoride in 400 d of anhydrous dimethyl sulfoxide (DMSO) was stirred at 133°C, and 3-bromo-2,4,5-trifluorobenzonitrile was stirred at 133°C. 2,4-dichloro-5-fluorobenzonitrile 68.4! iF was added all at once. 5 hours at the same temperature 2
After stirring for 0 minutes, add ice water 1. The organic layer was washed with saturated brine and concentrated, and the resulting residue was distilled to a boiling point of 82.5℃/13Ml4Hg~80.0℃.
15.79 of the target product was obtained as a colorless oil which was distilled at 1sH9.

Example 9 Synthesis of 3-bromo-2,4,5-trifluorobenzoic acid 8 m of concentrated sulfuric acid was added to 13.9 g of 3-bromo-2,4,5-trifluorobenzonitrile and stirred for 20 minutes at an external temperature of ioo°C. Thereafter, the mixture was poured into 100 d of ice water, and the precipitate was collected by filtration and washed with water. Furthermore, the aqueous layer was extracted three times with 100 d of methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was combined with the previous precipitate and transferred to a silica gel column (developing solvent: methylene chloride → methylene chloride: methanol). = 10:1) to obtain 8.7 g of 3-bromo-2,4,5-trifluorobenzamide. Next, this was added to 50 d of 18N sulfuric acid, stirred for 4 hours at an external temperature of 100°C, poured into 200 d of ice water, the precipitate was collected by filtration, and recrystallized from methylene chloride/n-hexane to obtain 6.9 g of the desired product as colorless prism crystals. I got it. Melting point 1
25-127°C Example 10 Synthesis of 3-bromo-2,4,5-trifluorobenzoyl chloride 3-bromo-2,4,5-trifluorobenzoic acid 2.5
After adding 10 d of thionyl chloride to g and refluxing for 2.5 hours, the excess thionyl chloride was distilled off using a Widmer distillation column, and the residue was distilled to give a boiling point of 98-102°C/1BInInHg.
2.3 g of the target product was obtained as a colorless oil.

Example 11 Synthesis of diethyl 3-bromo-2,4,5-trifluorobenzoylmalonate 0.22 g of magnesium shavings and 1 part of absolute ethanol
．． After adding 5d and carbon tetrachloride o, iml and starting the reaction,
Add to this 1.4 g of diethyl malonate and 2 m of absolute ethanol.
11 and anhydrous toluene 6Ini at 50-60°
C was added dropwise over 25 minutes.

After stirring at the same temperature for 40 minutes, a 3d solution of 2.279% of 3-bromo-2,4,5-trifluorobenzoyl chloride in anhydrous toluene was added to the reaction mixture cooled to -8 to -4.5°C.
The mixture was added dropwise over a period of minutes and then stirred for 2 hours. A water-cooled dilute aqueous sulfuric acid solution was added to the mixture to dissolve the contents, the layers were separated, and the mixture was extracted four times with 6 d of toluene. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the desired product 3.259 as a pale yellow oil.

Example 12 Synthesis of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate 3.25 g of diethyl 3-bromo-2,4,5-trifluorobenzoylmalonate was emulsified by adding 4rrIl of water. 4 mg of para-toluenesulfonic acid was added to the mixture, and the mixture was refluxed for 3 hours with vigorous stirring. The extract was extracted four times with 8 d of methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then recrystallized from methylene chloride/n-hexane to obtain 1.51 g of the desired product.

Melting point 85-88°C Example 13 Synthesis of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate 3-bromo-2.4.5-Trifluorobenzoyl ethyl acetate 1.
5g, ethyl orthoformate i,og and acetic anhydride 1.2g
The mixture was stirred at an external temperature of 130° C. for 4.5 hours, and then concentrated to obtain 1.759 of the desired product as a yellow oil.

Example 14 Synthesis of ethyl 2-(3-bromo-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate Ice-cooled 2-(3-bromo-2,4,5-trifluorobenzoyl) -3-ethoxyethyl acrylate 1.75
9 in 5 ml of absolute ethanol, add 0.32 cyclopropylamine! 9 absolute ethanol 2III! 3 of the solution
It was dropped in 0 minutes. Further, after stirring at 5 to 20°C for 2.5 hours, the mixture was concentrated, and the residue was recrystallized from petroleum ether to obtain the desired product 1.389 as colorless prism crystals.

Melting point 74-76°C Example 15 Synthesis of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate 2-(3-bromo-2,4 , 5-trifluorobenzoyl)-3-cyclopropylamine ethyl acrylate 1.
359 was dissolved in 5d of anhydrous dimethylformamide, 0.23 g of sodium fluoride was added, and the mixture was stirred at 97 to 108°C for 1.5 hours. The hot reaction mixture was poured into 50 d of ice water, and the precipitate was collected by filtration, washed with water, and then recrystallized from methylene chloride/n-hexane to obtain 1.05 g of the desired product as colorless prism crystals. Melting point 163.5-168℃4.39(2H,Q
, J=7.2Hz, -CH2CH:l).

8.26 (IH, dd, J-9,7,8,4H2,5
-H＞.

8.68 (1H, S, 2-1-1>.

IR(KBr, an-”), 1730(
COO), 1600 (CO), 1450, 1310
．． 1270.1230.1200.11γ0, 10γ0
．． 1030.860.800゜Example 16 Synthesis of 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 8-bromo-1-cyclopropyl- Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate 1.09, acetic acid 4/Id! , 3 d of water, and 0.5 ml of concentrated sulfuric acid was stirred at an external temperature of 90 to 100° C. for 1 hour, and then at air temperature for 1 hour. The reaction solution was poured into 20 g of ice water, and the precipitate was collected by filtration and washed with water to obtain 0.82 g of the desired product in the form of colorless prism crystals. Melting point: 224-225.5°C8.
30 (1H, dd, J = 9.2. 8.4Hz, 5
-H＞.

8.96 (11-1, S, 2-H>, 13.
97 (1H, 5-br.

-COOH).

I R (K B r, cm'), 2700 (C
OOH), 1720 (COO).

Claims (3)

[Claims] (1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A quinolone carboxylic acid compound represented by (in the formula, R is hydrogen or a lower alkyl group, and X is a halogen). (2) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 is a lower alkyl group, and X and Y each independently represent a halogen) General formula [III] ▲Mathematical formulas, chemical formulas, tables, etc. are available▼(III) In the formula, R^2 represents a lower alkyl group, and R^1, X and Y are the same as above) A compound represented by is reacted with cyclopropylamine to form a compound represented by the general formula [IV] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] (wherein R^1, X and Y are the same as above) The general formula [I ′] ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I ′) (wherein R^^1 and X are the same as above) A method for producing a quinolone carboxylic acid compound. (3) A quinolone carboxylic acid compound represented by the general formula [I ′]▲There are mathematical formulas, chemical formulas, tables, etc.▼[I ′] (In the formula, R^1 is a lower alkyl group and X represents a halogen) is hydrated. General formula [I ″]▲ characterized by decomposition
There are mathematical formulas, chemical formulas, tables, etc.▼(I'') (In the formula, X is the same as above) A method for producing a quinolone carboxylic acid compound.