FI85370C - 2- (2,4-dichloro-5-fluorobenzoyl) -3-ethoxy-acrylic acid ethyl ester - Google Patents

Description

1,85370 2- (2,4-Dichloro-5-fluoro-benzoyl) -3-ethoxy-acrylic acid ethyl ester

Divided separated from patent application 822442.

5

The invention relates to 2- (2,4-dichloro-5-fluorobenzoyl) -3-ethoxyacrylic acid ethyl ester

O

F \ / C-C-GOOC-Hc 10 ^ -1? H IX) ci ^^ = 1 oc2h5 This compound is useful as an intermediate e.g. in the preparation of the therapeutically useful 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acids of formula (I) -V25 described in parent application 822442 wherein R is hydrogen, methyl, ethyl or β-hydroxyethyl and their pharmaceutically acceptable acid addition salts and hydrates, as well as novel intermediates for the preparation of the above compounds.

It is known that 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acid ____; the absence of antibacterial properties fj. Chem. 23] ./ (1980) 1358J.

The 1-cyclopropyl-6-fluoro-35,4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acids of formula (I) and their pharmaceutically acceptable acid addition salts and hydrates have a clearly better antibacterial effect than known quinolone and azaquinolone carboxylic acids.

The compounds of formula (I) have a clearly better antibacterial activity against both gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa.

The process according to the parent application for the preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-10 piperazine-quinoline-3-carboxylic acids of the formula (I) is characterized in that the piperazine or methyl, ethyl or / or 3-Hydroxyethyl-piperazine is reacted with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of formula 15

F ^ COOH

I I J (II) at 20 to 200 ° C and optionally converting the resulting compound of formula (I) into an acid addition salt or hydrate.

The above process is preferably carried out in a diluent such as dimethyl sulfoxide, Ν, Ν-dimethylformamide, hexamethylphosphoric acid trisamide, sulfolane, water, alcohol or pyridine at a temperature of 20 to 200 ° C, preferably 80 to 180 ° C. ° C. The reaction can be carried out at normal pressure, but also at elevated pressure, especially with low-boiling diluents. Generally, the working pressure is from about 1 to about 100 bar, preferably from 1 to 10 bar.

In carrying out the process, 1 to 5 moles of 3,853,70 alkylpiperazine (1 to 15 moles in the case of piperazine), preferably 2 to 3 moles of alkylpiperazine (5 to 10 moles in the case of piperazine) are used per mole of the carboxylic acid of formula (II).

The resulting 7-piperazine-quinolone-3-carboxylic acids of formula (I) may be salified with an organic or inorganic acid, if desired. Suitable acids for salt formation include, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, acetic acid, citric acid and benzenesulfonic acid.

If 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are used as reactants in the above process, the reaction procedure can be shown as follows. diagram: F 'V ^ rr' 'cooh / - \ cAaJ + 2CH3VJ-H * 20

O

ργ ^%. / <ίγ <: οοΗ r ^ _ J + XHC1

- 25 Δ - J

As antibacterial agents of the formula (I), mention may be made, in particular, of 7-piperazine, 7- (4-methylpiperazine), 7- (4-ethylpiperazine) and 7- (4- / 3-: hydroxyethylpiperazine) - 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceutically acceptable acid addition salts and alkali metal salts of these compounds.

In addition, the parent application relates to an intermediate of formula (II) which is 7-chloro-1-cyclopropyl-6-fluoro-4,85370 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and which can be prepared by malonic ester synthesis according to the following reaction procedure. according to the schedule; this reaction scheme also describes the preparation and use of a compound of the invention; 5 0 F ^ XOCl .C00C2H5 _ »-C00C ^ i

YT -K MgOEt F ^ C-CH

ci ^^ An -> rÄn coocj a, cooc2h5 Lr Li

Iv VII vin i? ° F ^ ^ C-C-COOClH, FA-CH2CO3C3H,

Ai, CH x- dXXn

15 Cl Cl I '' CI ^ VNCI

UCj rij x rx.

t> ~ m2 V · 20 o

II

FtTc ^ -cooRi cu 25 C1

A

: VI

• - A

-j n 0

30 wycooH

II

35 5 85370

Accordingly, malonic acid diethyl ester (VII) IV is acylated in the presence of magnesium alcoholate to acyl malonic ester VIII (Organicum, 3rd edition, 1964, p. 438).

Partial saponification and decarboxylation of VIII in an aqueous medium with catalytic amounts of p-toluenesulfonic acid gives, in good yields, aroyl-acetic acid ethyl ester IX, which is converted to o-formic acid triethyl-3-fluoro-5-fluoro-5-fluoro-5-fluoro-5-fluoro-5-fluoro-acetic anhydride. acrylic acid ethyl ester X. Reaction of X 10 with cyclopropylamine in a solvent such as methylene chloride, alcohol, chloroform, cyclohexane or toluene results in a slightly exothermic reaction to the desired intermediate VI.

The cyclization reaction VI -> 11 (R 1 = alkyl) is carried out at a temperature in the range of about 60-280 ° C, preferably in the range of 80-180 ° C.

As the diluent, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, hexamethylphosphoric triamide and preferably N, N-dimethyl-formamide can be used.

Suitable acid scavengers for this reaction step are potassium t-butanolate, 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.

The 2,4-dichloro-5-fluorobenzoyl chloride IV and the corresponding carboxylic acid used as a starting material for this synthetic route, as well as the 3-fluoro-4,6-dichloro-30-ritoluene XI required for the preparation of IV, were not yet known in the literature.

The following reaction scheme shows the preparation of these precursors or intermediates from 2,4-dichloro-5-methylaniline XII.

85370 CH., Ci ^ i? Θ K NaNO2, H3Ow> j hn (ch3) 2 n = n-n (ch3) 5 Cl 2 Cl • 'ill XI Ia

LHF

10 CH,

Cl

15 XI

V

cci3 'ci

XIII

., V

; 25 COOH

: Cl i ϊχ,: v l *::: Cl

30 XV

V

COC1 '· λγ 35 Cl

IV

i: 7 85370

Accordingly, 2,4-dichloro-5-methylaniline (XII) is diazotized with NaNO and the resulting diazonium salt is converted with trimethylamine to triazene (Xlla).

Triazene (Xlla) is dissolved in excess anhydrous 5 HF. The triazene is then cleaved to 2,4-dichloro-5-methyldiazonium fluoride and dimethylamine. Without intermediate isolation, this solution is thermally decomposed at 130-140 ° C to give 3-fluoro-4,6-dichlorotoluene XI (yield 77.7% of theory).

3-Fluoro-4,6-dichlorotoluene XI is chlorinated at a temperature in the range of 110-160 ° C under UV irradiation to 2,4-dichloro-5-fluoro-1-trichloromethylbenzene XIII.

Saponification of XIII with 95% sulfuric acid results in 2,4-dichloro-5-fluorobenzoic acid XV, which is converted to carboxylic acid chloride IV by thionyl chloride.

The compounds of the formula I are characterized by an excellent antibacterial activity against gram-positive and gram-negative bacteria, in particular compared to the compounds known from DE patent application P 3 033 157.8 and DE application-20 publication 2 804 097, as shown in Table I.

The compounds known from the applicant's EP patent 4279 as well as from DE application 2 840 910 also have a much weaker antibacterial effect than the new ones: the compounds of the formula I, such as those in Tables II and III

. ·. it turns out.

8 85370

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In an experiment performed (Danley multipoint inoculator, isosensitest agar, Oxoid), a compound of formula I wherein R is β-hydroxyethyl proved to be more potent than the known reference compounds 2-4, as shown in Table IV.

O

/ "Λ 1 1 1) HO-CH2-CH2-N2-X HCl (Compound according to the invention, e.g. 2)

F C00H

ΛΛ _ X J

2) HO-CH2-CH2-N2-N

4.4. 4. ·, CH0-CH = CH ~ (known reference 2 2 compound) o πΤ I i 3) HO-CH2-CH2-I ^ _ .. _. .. CH - CH - CH ..

(known reference compound 223): 0

F COOH

4> H0-CH, -CH., - N / 1 2 2 N_ / |

(known reference CH

compound) · :; h3c ch3 12 8 5 3 70

Table IV

____. - <·

The test compound

Stock 2 4 3 1

Sscherichia coli Neumann 0.5 1 0.5 0.015 455/7 64 64 64 2 A261 0.5 0.25 0.25 0.015

Klebsiella sp. 63 122 0.062 8085 121 0.062 .---—------- 1

Proteus mirabilis 8223 64 32 32 2 8175 444 0.25

A

P. vulgaris 1017 0.5 0.25 0.5 0.031

Morqanella morganii 932 0.5 0.5 0.25 0.031 11006 121 0.062. m. - - - - - - - -----— -

Providencia sp. 12012 2 22 0.062 12052 128 64 64 8

Serratia marcescens 16040 128 128 64 4

Staphylococcus FK 422 4 4 2 0,125 aUreUS 1756 421 0,125 —_122__4_2 -] - 0,125- 'Streptococcus 27101 8 8 4 0,5 I (Enterococcus) 9790 8 8 8 0,5

Pseudomonas aeru- Walter 8 4 4 0,5 Ginosa Ellsworth 4 881 13 85370

The following examples illustrate the invention.

Example 1

5 O

F ^ i ^ COOH

Λ 10

A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 28.5 g of N-methylpiperazine and 120 ml of anhydrous dimethyl sulfoxide is heated 1.5 hours at 135-140 ° C.

The solvent is distilled off under reduced pressure and the residue is suspended in about 50 ml. It is filtered off with suction, washed with IVO, dried in a vacuum oven at 80 [deg.] C. with CaCl2 and recrystallized from glycol monomethyl ether. 14.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (4-methylpiperazine) -4-oxoquinoline-3-carboxylic acid with a decomposition point of 248-250 ° C are obtained. .

Example 2

“? COOH

25 FnY

H 2 CH 2 CH 2 -N 2 N 2 O 30 Suspension of 2.81 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 5.2 g of N-O-hydroxyethylpiperazine in 25 ml of dimethyl sulfoxide, heated for 2 hours at 135-140 ° C.

The solvent is distilled off under reduced pressure, the residue is boiled rapidly with 20 ml of t 2 O, left to stand at room temperature overnight, the precipitate is filtered off with suction under ice-cooling, washed with water and dried in vacuo over CaCl 2 at 14,85370 at 80 ° C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-6-hydroxyethylpiperazine) -quinoline-3-carboxylic acid with a decomposition point of 237-9 ° C are obtained.

Example 3 5 0

F ^^ ilCOOH

^ Δ 10

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 anhydrous piperazine and 100 ml of dimethyl sulfoxide, heated for 2 hours at 135-140 ° C. The solvent is distilled off under reduced pressure, the residue is suspended in a pad, filtered off with suction and washed with water. For further purification, the wet crude product is boiled with 100 ml of water, filtered off with suction at room temperature, washed with H 2 O and dried in a vacuum oven over CaCl 2 at 100 ° C to constant weight. 19.6 g of 1-cyclopropyl-6-fluoro-1,4- are obtained. dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acid; ‘Poa with a decomposition point of 255-257 ° C.

The compound prepared according to Example 3 is dissolved hot in 50 ml of 10% hydrochloric acid. To the filtered solution is added 150 ml of ethanol, cooled with ice, filtered off with suction and washed with alcohol and dried in vacuo at 100 ° C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acid hydrochloride are obtained in the form of colorless crystals having a decomposition point of 308-310 ° C. .

15 85370

Example 4

„F? .COOH

c FvvV

5 || 1) X HI

H-C - N H A

3 A ^ Δ

A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazine-quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N, N-dimethylformamide, heated for 2.5 hours at 70-80 ° C. The solvent is distilled off in vacuo and the residue is suspended in water. Suction filtered, washed with water and pressed against the clay. 1.15 g of 1-cyclopropyl-6-fluoro-7- (ethylpiperazine) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydroiodide with a decomposition point of 306 ° C are obtained.

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. Mix with 5 ml of carbon tetra-2S chloride and add dropwise, when the reaction has begun: a mixture of 160 g of malonic acid diethyl ester VII, 100 ml of abs. ethanol and 400 ml of anhydrous ether to give a rapid reflux. After quenching the reaction, boil for an additional 2 hours, cool to 30 ° C with ice-ice / gun-30 tons. . To -10 ° C and a solution of 227.5 g of 2,4-dichloro-5-fluoro-benzoyl chloride IV in 100 ml of absolute ether is slowly added dropwise at this temperature. Stir for 1 hour at 0 ° C ... -5 ° C, allow to reach room temperature overnight and cool under ice-cooling with a mixture of 35 ml of ice water and 25 ml of concentrated sulfuric acid. The phases are separated and extracted twice with ether.

85370 BC

The combined ether solutions are washed with saturated NaCl solution, dried over Na2SO4 and the solvent is removed in vacuo. 349.5 g of 2,4-dichloro-5-fluoro-benzoyl-malonic acid diethyl ester VIII are obtained as a crude product.

To an emulsion of 34.9 g of crude 2,4-dichloro-5-fluoro-benzoylmalonic acid diethyl ester VIII in 50 ml of water is added 0.15 g of p-toluenesulfonic acid. Boil under good stirring for three hours, extract the cooled emulsion several times with methylene chloride, wash the combined CH2Cl2 solutions once with saturated NaCl solution, dry over Na2CO2 and distill off the solvent in vacuo. Fractionation of the residue under reduced vacuum gives 21.8 g of 2,4-dichloro-5-fluorobenzoylacetic acid ethyl ester (IX), boiling point 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 for two hours at 150 ° C. . The volatiles are then distilled off in a water jet vacuum and finally in a small vacuum at a bath temperature of 120 ° C. 25.2 g of crude 2- (2,4-dichloro-5-fluorobenzoyl) -3-ethoxyacrylic acid ethyl ester X remain. It is sufficiently pure for the further reaction.

To a solution of 24.9 g of 2- (2,4-dichloro-5-fluorobenzoyl) -3-ethoxyacrylic acid ethyl ester X (or -20 the coefficient ηβ is 1.5445; the IR spectrum is shown in the accompanying figure ) In 80 ml of ethanol, 4.3 g of cyclopropylamine are added dropwise under ice-cooling and with stirring. After the exotherm has subsided, the mixture is stirred for a further hour at room temperature, the solvent is removed in vacuo and the residue is recrystallized from cyclohexane / petroleum ether. 22.9 g of 2- (2,4-dichloro-5-fluoro-benzoyl) -3-cyclopropylamino-acrylic acid ethyl ester VI (Rf = CH2-H2) are obtained, m.p. 89-90 ° C.

i7 85370

To a solution of 31.9 g of 2- (2,4-dichloro-5-fluorobenzoyl) -3-cyclopropylamino-acrylic acid ethyl ester VI (Rf = 100 in anhydrous dioxane) is added portionwise under ice-cooling and stirring portionwise. 5.44 g of 80% sodium hydride are then stirred for 30 minutes at room temperature and for 2 hours under reflux and the dioxane is removed in vacuo, the residue (40.3 g) is suspended in 150 ml of water, 6.65 g of potassium hydroxide are added and the mixture is heated. The warm solution is filtered and washed with IVO, then acidified with semi-concentrated hydrochloric acid under ice-cooling to pH 1-2, the precipitate is filtered off, washed with water and dried in vacuo at 100 ° C to give 27.7 g. g of 7-chloro-1-cyclo-15-propyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid II, mp 234-237 ° C.

Claims (1)

18 85370 Claim: 2- (2,4-dichloro-5-fluorobenzoyl) -3-ethoxy-acrylic acid ethyl ester. 2- (2,4-Dichloro-5-fluoro-benzoyl) -3-ethoxy-acryloxy-ethyl ester.