DD202560A5 - PROCESS FOR PREPARING 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO CHINOLINE-3-CARBON ACID - Google Patents

Abstract

1. Claims (for the Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, NL, SE) Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids of the formula I see diagramm : EP0078362,P10,F3 in which R denotes hydrogen, methyl, ethyl or beta-hydroxyethyl, and their pharmaceutically usable acid addition salts, alkali metal salts and hydrates, except 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acid and its hydrochloride, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-methylpiperazino)-quinoline-3-carboxylic acid and 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-ethylpiperazino)-quinoline-3-carboxylic acid hydroiodide. 1. Claims (for the Contracting State LU) 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids of the formula I see diagramm : EP0078362,P11,F3 in which R denotes hydrogen, methyl, ethyl or beta-hydroxyethyl, and their pharmaceutically usable acid addition salts and hydrates.

Description

Berlin, 3.12.1982 AP G 07 D / 241 723/3

Process for the preparation of i-cyclopropyl-b-fluoro-i-dihydro-4-oxo-7-piperazino-Giiinoline-3-carboxylic acids

Field of application of the invention

The present invention relates to a process for the preparation of novel 1-gyolpropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, the antibacterial agents containing them and 3-dietary supplementants,

Characteristic of the known technical solutions

It is already known that 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids have antibacterial properties / J. Med · Gheni. 2ß , 1358 (198O) _7.

Object of the invention

The aim of the invention is to provide new compounds having improved antibacterial properties.

Explanation of the essence of the invention

It is the object of the invention to find new compounds having the desired properties and processes for their preparation.

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03/12/1982

AP G 07 D / 241 728/3 (61 184/18)

It has now been found that the new i-cyclopropyl-6-fluoro-1 ^ -dihydro ^ acids of the formula I

COOH

(D

in the

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R is hydrogen, methyl, ethyl or β-hydroxyethyl,

and their pharmaceutically acceptable acid addition salts and hydrates have an antibacterial activity superior to the known quinolone and azaquinolone carboxylic acids.

The compounds of the invention show their superior antibacterial activity against both Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa.

It has furthermore been found that i-cyclopropyl-6-fluoro-1-dihydro-1-oxo-T-piperazino-quinoline-S-carboxylic acids of the formula (I) are obtained when 7-chloro-1-cyclopropyl 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of formula II (R = H)

COOR ¹

(ID

with piperazine or Piperazxnderivaten of formula III

R-ϊΟτΗ

in which

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R has the meaning given above, implemented.

Further, the compounds of formula II (R = alkyl) with "III, optionally in the presence of an acid binder, such as triethylamine, 1,4-diaza-bicyclo / 2,2,27octane or 1, 8-diaza-bicyc ' lo / 5, 4, p_7undec-7-ene, and then alkalinize the resulting 7-piperazinoquinolone-3-carboxylic acid esters alkaline to I.

The reaction of II (R = H) with III is preferably conducted in a diluent such as dimethyl sulfoxide, N, N-dimethylformamide, hexamethyl-phosphoric acid trisamide, SuIfolan, water, an alcohol or pyridine, at temperatures of 20-200 ⁰ C, preferably 80 -180 ⁰ C, made. The reaction can be carried out at normal pressure, but also at elevated pressure, in particular at low-boiling diluent. In general, at pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

In carrying out the process is used for 1 mol of carboxylic acid II 1-5 moles of alkylpiperazine (in piperazine 1-15 moles), preferably 2-3 moles of alkylpiperazine (with piperazine 5-10 mol).

The resulting 7-piperazino-quinolone-3-carboxylic acids I can optionally be converted into an acid with an organic or inorganic acid. Salts suitable for salt formation are e.g. Halogenwasser-

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24 1

- ⁴ -

acids, such as hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid, acetic acid, citric acid and benzenesulfonic acid.

If, for example, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are used as reactants in the reaction of II with III, the course of the reaction can be represented by the following equation become:

2CH N NH 3 \ f

CH ₃

As new antibacterial agents may be mentioned in detail:

7-piperazino, 7- (4-methylpiperazino) -, 7- (4-ethylpiperazino) -, 7- (4-.beta.-hydroxyethylpiperazino) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid and pharmaceutically acceptable acid addition salts or alkali salts of these compounds.

The starting compounds II can be prepared by a Malonestersynthese according to the following reaction ^scheme : ^ί

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3

OCl

ClL

IV

.COOC ₂ H ₅

COOC ₂ H ₅

VII

MsOEt

Cl

CC-COOC ₂ H ₅

H CH

OC ₂ H ₅

COOC ₂ H ₅

COOC ₂ Π ₅

C-CH ^ Cl

VIII

0 0

F is C-CH ₂ COOC ₂ H ₅

Cl

O-

NH-

Cl

HN '

C-COOR ¹

VI

.COOR ¹

II

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Thereafter, malonic acid diethyl ester (VII) is acylated with IV in the presence of magnesium alcoholate to Acylmalonester VIII (Organicum, 3rd ed., 1964 , p 438).

By partial saponification and decarboxylation of VIII in aqueous medium with catalytic amounts of p-toluene

sulfonic acid is obtained in good yield the Aroylessigsäureethylester IX, which goes into the 2- (2,4-dichloro-5-fluoro-benzoyl) -Γ-3-ethoxy-ethyl acrylate with o-formic acid triethyl ester / acetic anhydride. The reaction of X with cyclopropylamine in a solvent, e.g. Methylene chloride, alcohol, chloroform, cyclohexane or toluene leads in a slightly exothermic reaction to the desired intermediate VI.

* 1

The cyclization reaction VI> II (R = alkyl) becomes

in a temperature range of about 60 ° to 28O ⁰ C, preferably 80 ° to 18O ⁰ C performed.

Dioxane, dimethylsulfoxide, N-methyl-pyrrolidone, sulfolane, hexamethylphosphoric triamide and preferably Ν, Ν-dimethylformamide can be used as diluents.

Suitable acid binders for this reaction stage are potassium tert-butoxide, butyl-lithium, lithium-phenyl, phenylmagnesium bromide, sodium ethylate and particularly preferably sodium hydride or potassium carbonate. It may be advantageous to use an excess of 10 mol% of base.

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The 2,4-dichloro-5-fluoro-benzoyl chloride IV used as starting material for this synthetic route and the corresponding carboxylic acid and also the 3-fluoro-4,6-dichlorotoluene XI required for the preparation of IV were not yet known from the literature.

The following formula scheme shows the preparation of these precursors or intermediates, starting from 2,4-dichloro-5-methyl-aniline XII.

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24 172 8.

Η.

Cl

Cl XII

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1. NaNO ₂ , H ₃ O

• HN (CH _{3) 2}

CH.

N = NN (CH ₃ ) ₂

Cl

XIIa HF

CH,

Cl

Cl XI

CCI,

Cl

Cl XIII

COOH

Cl

XV COCl

Cl

Cl IV

Thereafter, 2,4-dichloro-5-methyl-aniline (XII.) Is diazotized with the aid of NaNO ₂ and the resulting diazonium salt with dimethylamine converted into the triazene (XIIa).

The triazene (XIIa) is dissolved in excess anhydrous HF. The triazene splits into 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without interim isolation, this solution is thermally cleaved at 130-140 ° under ^ -cleavage in 3-fluoro-4,6-dichlorotoluene XI (yield) 77.7% of theory

The 3-fluoro-4,6-dichlorotoluene XI is chlorinated in a temperature range of 110 to 160 ° C under UV irradiation to 2,4-dichloro-5-fluoro-i-trichloromethylbenzene XIII.

The saponification of XIII with 95 percent. Sulfuric acid leads to 2,4-dichloro-5-fluoro-benzoic acid XV, which turns into the carboxylic acid chloride IV with T5 thionyl chloride.

The compounds according to the invention are distinguished by a particularly good antibacterial activity against gram-positive and gram-negative bacteria, in particular with respect to the compounds of German Patent Application P 30 33 157.8 from 03.09.1980 and DE-OS 28 04 097, as can be seen from the table below.

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HM N

JDOOH

Example 2 of the German (known from the patent application DE-OS 28 04 097) P 30 33 157.8 from 3.9.80

(inventive compound of formula I, R = H)

Staphylococcus aureus 133 8th 1 0.25 - 0.5 E. coli A 261 1 0,125 0.06 E. coli Neum. 1 0.25 0.06 Klebsiella 8085 1 0.25 0.06 Proteus 1017 0.5 0.06 0.03 Pseudomonas aeruginasa W 4 1 0.5

agar dilution test

DST (dexhase seusivity test) medium; 1-2 χ 10 germs / plate

2 Al 7 7 8 3 " ¹¹ " 3.12.1982

«-. / C w w AP C 07 D / 241 728/3

(61 184/18)

exemplary

The following examples illustrate the invention.

example 1

Gooh

A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-chinoic-3-carboxylic acid, 28.5 g of K-methylpiperazine and 120 ml of anhydrous dimethylsulfoxide Heated to 135-140 ⁰ C for 1.5 h. The solvent is i. Peinvak. distilled off and the residue suspended in about 50 ml HpO. It is suctioned off, washed with H ₂ O, dried in a vacuum oven at 80 × ⁰ C on CaCl ₂ and crystallized from glycol monomethyl ether. There are 14 »5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methyl-piperazino) -4-oxo-quinoline-3-carboxylic acid Zersp. 248-250 ⁰ C received.

Example 2

HIGH ₂ CH ₂

A suspension of 2.81 g of 7- [1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 5.2 g of H-.beta.-hydroxyethylpiperazine in 25 ml of dimethyl sulfoxide is heated at 135.degree.-140.degree. C. for 2 hours. The solvent is i. Feinvak. distilled off, the residue with 20 ml of H ₂ O boiled briefly, laughs over at room temp. stand

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- 12 -

let suck the precipitate with ice cooling, washed with water and i. Vacuum over CaCl ₂ at 80 ⁰ C dried. This gives 2.1 g of i-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-.beta.-hydroxyethylpiperazino) -quinoline-3-carboxylic acid Zersp. 237-9 ⁰ C.

Example 3

A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of water.

11) free piperazine and 100 ml of dimethyl sulfoxide is heated to 135-1'40 ⁰ C for 2 h. The solvent is i. Feinvak. distilled off, the residue suspended in H 2 O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled with 100 ml of water at room temp. filtered off, washed with H ₂ O and i. Vacuum drying oven dried over CaCl at 100 ⁰ C to constant weight. This gives 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid from Zersp. 255-257 ° C.

The compound prepared according to Example 3 is in 50 ml 10 percent. Hydrochloric acid dissolved hot. To the filtered solution is added 150 ml of ethanol, cooled with ice, filtered off and washed with alcohol and dried i. Vacuum at 100 ^° C. There are 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-

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241 728 3

oxo ^ -piperazino-quinoline-S-carboxylic acid hydrochloride as colorless crystals of Zersp. 308-310 ⁰ C received.

Example 4

^H 5 ^C 2 " ⁱ l_ / ^N

A mixture of 1.2 g of i-cyclopropyl-S-fluoro-i, 4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N , N-dimethylformamide is heated to 70-80 ⁰ C for 2.5 h. The solvent is i. Vak. distilled off and the residue suspended in water. It is suctioned off, washed with H ₂ O and pressed on clay. There are 1.15 g of 1-cyclopropyl-6-fluoro-7- (ethyl · piperazino) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydroiodide Zersp. 306 ° C received.

The starting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II is prepared as follows:

24.3 g of magnesium turnings are suspended in 50 ml of anhydrous ethanol. It is mixed with 5 ml of carbon tetrachloride and added dropwise, when the reaction has started, a mixture of 160 g of diethyl malonate VII, 100 ml of abs. Ethanol and 4 00 ml of anhydrous ether, with a vigorous reflux is observed. After the reaction has subsided for a further 2 h heated to boiling is cooled with dry ice / acetone to -5 ° C to -10 ⁰ C and

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at this temperature, a solution of 227.5 g of 2,4-dichloro-5-fluoro-benzoyl chloride IV in 100 ml abs. Ether slowly added dropwise. The mixture is stirred for 1 h at ^{0 0} C to -5 ⁰ C, allowed to come to room temperature overnight and allowed under ice-cooling, a mixture of 4 00 ml of ice water and 25 ml of conc. Run in sulfuric acid. The phases are separated and back-extracted twice with ether. The combined ether solutions are washed with saturated NaCl solution, dried with NaSO ₄ and the solvent i. Vak. deducted. This gives 349.5 g of 2,4-dichloro-5-fluoro-benzoyl-malonsäurediethylester VIII as a crude product.

An emulsion of 34.9 g of crude 2,4-dichloro-5-fluoro-benzoylmalonic acid diethyl VIII in 50 ml of water is treated with 0.15 g of p-toluenesulfonic acid. The mixture is heated with vigorous stirring for 3 h to boiling, the cooled emulsion extracted several times with methylene chloride, the combined CH-Cl ^ -slices washed once with saturated NaCl solution, dried with Na ₃ SO ₄ and the solvent is distilled i. Vak. from. Fractionation of the residue i.

Feinvak, provides 21.8 g of 2,4-dichloro-5-fluoro-benzoylessigsäureethylester IX of bp 127-142 ° C / 0.09 mbar.

A mixture of 21.1 g of 2,4-dichloro-5-fluoro-benzoyl-acetic acid ethyl ester IX, 16.65 g of o-formic acid ethyl ester and 18.55 g of acetic anhydride is heated to 150 ⁰ C for 2 h. Then in a water jet vacuum and finally in a fine vacuum at a bath temperature of 12O ⁰ C, the volatile components are distilled off. 25.2 g of crude 2- (2,4-dichloro-S-benzoyl-S-ethoxy-acrylic acid ethyl ester X remain behind. It is sufficiently pure for the further reactions.

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A solution of 24.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-ethoxy-ethyl acrylate in 80 ml of ethanol is added dropwise with ice cooling and stirring with 4.3 g of cyclopropylamine. When the exothermic reaction has subsided, the mixture is stirred for a further 1 h at RT, the solvent i. Vak. removed and the residue recrystallized from cyclohexane / petroleum ether. This gives 22.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -S-cyclopropylamino-acrylic acid ethyl ester VI (R ¹ = C ₃ H ₅ ) of mp 89-9O ⁰ C.

A solution of 31.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -S-cyclopropylamino-acrylic acid ethyl ester VI (R = C-Hc) in 100 ml of anhydrous dioxane is added in portions with ice cooling and stirring 3.44 g 80 percent. Sodium hydride added. The mixture is then stirred for 30 min. At room temperature and 2 h at reflux and the dioxane i. Vak. deducted. The residue (40.3 g) is suspended in 150 ml of water, mixed with 6.65 g of potassium hydroxide and refluxed for 1.5 h. The heat solution is filtered and washed with H 2 O afterward. Then with half konz. Hydrochloric acid with ice cooling to pH = 1-2 acidified, the precipitate filtered off with suction, washed with water and i.Vak. dried at 100 ⁰ C. This gives 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II (R ¹ = H) of mp. 234-237 ⁰ C.

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Claims (1)

A nce to the testimony; , Process for the preparation of i-cyclopropyl-6-fluoro-1,4-dihydro-4-o: x: o-7-piperazino-quinoline-3-carboxylic acids of the formula I (D, in the R represents hydrogen, methyl, ethyl or β-hydroxyethyl, their pharmaceutically usable acid addition salts and hydrates, characterized in that one piperazine, methyl, ethyl or ß-hydroxyethyl-piperazine with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-os: o-quinoline-3-carboxylic acid of the formula II COOH (ID at 20 to 200 ⁰ C and optionally converting the resulting compound of formula I into an acid addition salt or a hydrate.