CA1237431A - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro- quinoline-3-carboxylic acid, esters and process for their preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to compounds of formula IX
which as intermediates in the preparation of anti-bacterial agents and to a process for preparing a compound of formula II

(II) wherein R1 is hydrogen or an alkyl group which process comprises cyclizing a compound of formula VI

(VI)

Description

~37~31 This application is a first of three divisional applica-tions all of which are divided out oE parent application serial num-ber 409,435, filed on August 13, 1982.
This first divisional application relates to compounds of formula II, and salts and hydrates thereof, which are intermediates useful in the preparation of compounds of the invention of the parent application and further relates to a process or preparing a compound of formula II

F ~ ~COOR (II) Cl or a salt or hydrate thereof wherein Rl is hydrogen or an alkyl group which process comprises cyclizing a compound of formula VI

F (i~
~ I_COOR (VI ) Cl H~

wherein R iS as defined above and, where required, forming a salt or hydrate thereof.
The second divisional application relates to compounds of formula IX, also intermediates for preparing compounds of the x "~ - 1 -`- ~L23~4L3~
- la - 23189-5416D

invention of the parent application, and further to a process for preparing a compound of formula IX

o F~ C (IX) Cl or a salt or hydrate -thereof, wherein Rl is hydrogen or alkyl, which process comprises partial hydrolysis and decarboxylation of a com-pound of formula VIII
o /COOR
F ~ C - CH (VIII) Cl ~ COOR

wllerein Rl is as defined above and, where required, forming a salt or hydrate thereof.
The third divisional applica-tion relates to compounds of formula X, also intermediates for preparing compounds of the inven-tion of the parent application, and further to a process for pre-paring a compound of formula X

F

~ 1 CH (X) Cl or a salt or hydrate thereof, wherein Rl is hydrogen or alkyl, which comprises reacting a compound of formula IX

- la -~3~
- lb 23189-5416D

F

CH2COORl (IX) ~ Cl Cl wherein Rl is as defined above, with triethyl o-formate/acetic an-hydride and, where required forming a salt or hydrate thereo.
The invention of the parent application relates to certain new l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-pipera 2 ino-quinoline-3-carboxylic acids which are compounds of formula I, to a process for their production and to their use in feed additives and as anti-bacterial agents.
It has already been disclosed that l-ethyl-6-Eluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3~carboxylic acids possess an-tibacterial properties [J. Med. Chem. 23, 1358 ~1980)].
According to the invention of the parent application we now provide, as new compounds, l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of the g~neral formula F ~ "~ ~ COOH
A ~ N ~

~ ~1 or salts or hydrates thereof, in which R denotes a hydrogen atom or a methyl, ethyl. or ~-hydro-ethyl groupO The compounds of I have an antibacterial action superior to that of the known quinolone-- lb -.3 t .

~2~3~
-- lc --carboxylic acids and azaquinolone-carboxylic acids. The compounds I exhibit their superior antibacterial activity against both gram positive and gram negative bacteria, including Pseudomonas aeruginosa.
According to the invention of the parent application we further provide a process for the production of a compound I
in which (a) 7-chloro-1-cyclopropyl-6-fluoro-1 r 4 -dihydro-4-oxo-quinoline-3-carboxylic acid of the formula o F ~ COOR
~ tII) Cl ~ ~

3~31 -in which Rl denotes a hydrogen atom, is reacted with piperazine or a piperazine derivative of the general formula R~N ~ H (III) in which R has the meaning given above, or (b) a compound of the formula (II), as given in reaction variant (a) in which R1 denotes an alkyl group, is reacted with a compound of formula (III) as defined in reaction variant (a), if appropriate in the presence of an acid-bind-ing agent (such as triethylamine, l,LI-diaza-bicyclo~2,2,2]-octane or 1,8-diaza-bicyclo[5,4,0]undec-7-ene) and the 7-piperazino-quinolone-3-carboxylic acid ester obtained is hydrolysed under alkaline conditions to give a compound of formula (I), and the compound of formula (I) obtained by reaction variant (a) or (b) i5 converted, if desired, into a salt or hydrate thereof.
The reaction variant (a) is preferably carried out in a diluent (such as dimethylsulphoxide, N,N-dimethyl-formamide, hexamethyl-phosphoric acid trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature between 20 and 200C, preferably between 80 and 180G.
The reaction variants can be carried out under normal pressure, but also under elevated pressure, in partic-ular in the case of a low-boiling solvent. In general, the reaction is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.
In carrying out reaction variants 1 to 5 mol of alkyl-piperazine ~in the case of piperazine 1 to 15 mol), preferably 2 to 3 mol of alkylpiperazine (in the case of piperazine 5 to 10 mol), are employed per mol of carboxylic acid, or carboxylic acid ester of formula (II).

~e A _1 353 ~L~379L3~

Among the new l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid salts and hydrates of the formula I those salts orhydrates th~t are pharmaceutically accep~
table are particularly important and are preferred.
The new free l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of the general formula (I) and their salts and hydrates can be interconverted in any suit-able manner; methods for such interconversion are known in the art~
Thus the 7-piperazino-quinoline-3-carboxylic acids o formula (I) obtained can, if required, be converted into a salt using an organic or inorganic acid. Examples of acids which are suitable for salt formation are hydrohalic acids, such as hydro-chloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid.
If 7-chloro-1-cyclopropyl-6-fluoro 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are used as starting materials in reaction variant (a), the course of the reaction is illustrated by the following equation:

F ~ COOH /--~
Cl ~ N~ 3 ~3~
- 3a F,~/COON

The following may be mentioned individaully as active~
compounds of formula I: 7-piperazino-, 7-(4-methylpiperazino)-, 7-(4-ethylpiperazino)-, 7-(4-~-hydroxyethylpiperazinO)-l-cyclo-propyl-6-fluoro-1,4~

P` ~23 dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceuti-cally tolerated acid addition salts or alkali metal salts of these compounds.
The starting compounds of formula (II) can be prepared ~ia a malonic ester synthesis, according to the following equation:
C' ~ OCl ~ COOC~5 C r~ 11 c o o C2 ~5 IY YII VIII

O O
~I 11 F~ C C COOC2 H~ F C-CH2 COOC2 H5 C 1~ CH ~ ~~C 1 ~ C 1 X IX

F ~ 1 CH
Cl HN ~

¦ VI

C ~ OOR~

II
Le A 21 353 ~237~3~L

According to this ecuation, dieihyl malorlate of formula ~VII) is acylated with a compound of formula (~) in the presence of magnesium alcoholate to give the acylmalonate of formula (VIII) (Organicum, 3rd edition 1964, page 438).
The ethyl aroylacetate of formul2 (IX) is obt~ned in good yield by partial hydrol~sis ard decarbo~yl2tion of the compound of formul~ (~III) in an aqueous ~edium containinO a catalytic amcunt cf p-toluenesulpilon c acid, and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate of formula (~). The reaction of the com~ound of formula (X) with cyclopropylamine in a solvent (such as methylene chloride, alcohol, chloroform, cyclohe.cane or toluene) leads to the desired intermediate product of formula (VI) in a slightly exothermic reaction.
The cyclisation reaction VI . ~ TI (Rl -alkyl) is carried out in a temperature range from 60 to 280C, preferably 80 to 1~0C.
Dioxane~ dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethylphosphoric acid triamide and pre-ferably N,N-dimethylformamide can be used as diluents.
Potassium t-butanolate, butyl-lithium, lithium-phenyl, phenyl magnesium bromide, sodium ethylate and particularly preferably sodium h~dride or potassium car bonate are suitable acid-binding aGents for this reaction staGe. It can be advantageous to emplo~ an e~cess of 10 mol% of base.
The 2,4-dichloro-5-fluoro-benzoyl chloride of formula (IV) used as a starting materlal for this synthesis route, the corresponding carboxylic cciq, and the 3-fluoro-4,6-dichlorotoluene o~ formula (.~I) re~uired for the pre-paration of formula (~V) were not yet Xnown in the liter-ature.
The equation below shows the preparation of these :
Le A 21 353 ~ ` .

~;237~3~
., o precursors or intermediate products, starting from 2,4-dicnloro-5-methyl-aniline of formula (',~
Cl ~ 1. NaN02, H30 ~ Cl ~

NH2 HN(CH3)2 N=W-N(CH3)2 XIIa XII ~ HF

C ~ 1 F

¦ XI

Cl F

XIII

COOH
Cl ~ F
`I ~v COCl (r~) Cl~
I F
Cl Le A 21 353 _ . _ :~37 According to this equaticn, 2,4-dichloro-5-~ethyl-aniline o~ for~ula (XII) is diazotis~d by means c~
MaN02, and the resulting diazonium salt is converted nto the triazene of ~ormula (XIIa), using dimethylamine.
T~e triazene of formula (XIIa) is dissolved in excess anhydrous P~. In this step, the triazene is cleaved to give 2,4-dichloro-5-~ethyl-diazcr.ium fluoride and dimet~.y'amine. Without intermediate isolatior., this soluticn is cleaved ther-nally at 130 to 140 to Oive 3-fluoro-4,6-dichlorotoluene XI, N2 being split off ~Yield: 77.7% of theory).
The 3-fluoro-4,6-dichlorotoluene o~ formula (XI) is chlorinated in a temperature range from 110 to 160C, under W irradiation, to give 2,4-dichloro-5-fluoro-1-trichloro-methylbenzene of formula tXIII).
The hydrolysis of the compound of formula (XIII) with 95 per cent sulphuric acid leads to 2,4-dichloro-5-fluoro-benzoic acid of formula (XV), which is converted with thionyl chloride into the carboxylic acid-chloride of formula (~1).
The compounds I are distinguished by a particularly good antibacterial action against gram positive and gram negati-~e bacteria, in particular in comparison with the co~.pounds of German Patent Application P 30 33 157.8 of 3.9.1980 and DE-OS
(German Published Specification) 2,804,097, as can be seen from the table below.

Le A 21 353 3~

'~ o o ;o ~o~
~ oO o = o o o o a~

o ~ a 0 ~ U~ L~ o ~o 0~` ~ ~ O ~C ;~

o~l o-~-o l~ o~ 0 0,~ . ~.~

C) ~1 :~S CoO ~: u~3 0 O r~ ¢ ~ ~1 O O ~ ::5 S
~ 3 o o 3 O r1 (1) ~d ~ a~ o a~ St ~ E~
tr~ ~ ~:1 ~ ~ h i:4 ~ ¢

Le A 21 353 :

~2~7~
g As stated above, the invention of the parent applica-tion also relates to the use in human and veterinary medicine as antibacterial agents OL the compounds I.
The invention of the parent appllcation provides a pharmaceutical composition containing as active ingredient a compound I in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.
The invention of the parent application further provides a pharmaceutical composition containing as active ingredient a compound I in the form of a sterile and/or physiologically isotonic aqueous solution.
The invention of the parent application also provides a medicament in dosage unit form comprising a compound I.
The invention of the parent application also provides a medicament in the form of tablets (including lozenges and gran-ules), dragees, capsules, pills, ampoules or suppositories compri-sing a compound I.
"Medicament" as used in this Specification means phy-sically discrete coherent portions suitable for medical adminis-tration. "Medicament in dosage unit form" as used in -this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple ~up to four times) or submul-tiple (down to a fortieth) of a daily dose of the active compound in association with a carrier and/or en-closed within an envelope. Whether the medicament contains a daily dose ~237~3~L

or, for example, a half, a -third ox a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical composition may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gela-tine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) dis-integrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators, e.g. quaternary ammonium compounds;
(g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bento-nite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions can have the customary coatings~
envelopes and protective matrices, which may contain opacifiers.

- lOa - ~ ~3~43~

They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, oE polymeric substances or waxes.
The ingredient can also be made up in microencap-sulated form together with one or several of the abovementioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene :~23~43~L

glycols and fats (e.g. cocGa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions ~hich are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulcse derivatives, polyetnylene glycols, silicones, bentonites, silicic acid, talc and zinc o{ide or mixtures of th-se substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mi~tures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent)l such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acatate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example ground nut oil), glycerol, tetrahydrofurfuryl alcohol~ polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral ad~inistration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters ?, micro-Le ~ 21 353 ~37~3~

crystalline cellulose, aluminium me-tahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
All the pharmaceutical eompositions according to the invention of the parent application can also contain eolouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
In addition to a compound I, the pharmaceutieal eompositions and medieaments ean also contain other pharmaeeuti-cally aetive eompounds. They may also contain a plurality of eompounds I.
Any diluent in the medieaments may be any of those mentioned above in relation to the pharmaceutical eompositions.
Sueh medicaments may include solvent~ of moleeular weight less than 200 as sole diluent.
The discrete coherent portions eonstituting the medieament will generally be adapted by virtue of their shape or paekaging for medieal administration and may be, for example, any of the following: tablets (ineluding lozenges and granulates), pills, dragees, eapsules, suppositories and ampoules. Some of these forms may be made up Eor delayed release of the aetive ingredient. Some, sueh as eapsules, inelude a protective envelope whieh renders the portions of the medicament physieally diserete and eoherent.
The produetion of the above-mentioned pharmaeeutical 12 ~237~3~
- a ~

compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
This invention of the parent application further provides a method of combating - 13 - ~237~3~

(including prevention, relief and cure of~ the a~ove-mentioned diseases in human and non-human animals, which comprises adminis-tering to the animals a compound I alone or in admixture with a diluent or in the form of a medicament.
The invention of the parent application further pro-vides a ~eed additive comprising an active compound I in admixture with a feed additive-carrier.
The Examples which follow further illustrate ihe invention of the parent application and of the three divisional applications.

Example 1 F ~ ~ COOH

3 ~

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-methyl-piperazine and 120 ml of anhydrous dimethylsulphoxide was heated at 135 to 140C ~or lo 5 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in approx. 50 ml of H2O. The suspension was filtered under suction, and the residue was rinsed with H2O, dried in a vacuum drying cabinet at 80C over CaC12, and recrystallised from glycol monomethyl ether.
14.5 g of 10 cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methylpiperazino)-4-oxo-quinoline-3-carboxylic acid which decomposes at 248 to 250 C
were obtained.

~3~7~3~
- 13a -Example 2

2 2 ~/ COOH

A suspension of 2. 81 of 7-chloro-1-cyclopropyl-- ~237~3~a 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 5.2 g of N-~-hydroxyethylpiperazine in 25 ml of di-methylsulphoxide was heated at 135 to 140C for 2 hours.
The solvent was distilled off under a fine vacuum, the residue was boiled for a short ti~e with 20 ml of H20 and left to stand overnight at room temperature, and the pre-cipitate was filtered off under suction, while cooling with ice, and was washed with water and dried in vacuo over CaC12 at 80C. 2.1 g of l-cyclopropyl-o-fluoro-1,4-dihydro-4-oxo-7-(4-~-hydroxyethylpiperazino)-quino-line-3-carboxylic acid which decomposed at 237 to 239C
were obtained.
Example 3 o F ~ OOH

15 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-sulphoxide was heated at 135 to 140C for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in H20, filtered off under suction and washed with water. For further purification, the moist crude product was boiled with 100 ml of water, fil-tered off under suction at room temperature, washed with H20 and dried over CaC12 in a vacuum drying cabinet at 100 C until its weight remained constant. 19.6 g of l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which decomposed at 255 to 257C were obtained.
The compound prepared according to Example 3 was dissolved in 50 ml of hot 10 per cent hydrochloric acid.
150 ml of ethanol were added to the filtered solution, the Le A 21 353 .

.

~ ~743 mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloride were obtained as colourless crystals which decomposed at 308 to 310C.
~xam~le 4 -~ ~ COOH

a) A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazi~o-quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of ~,N-dimethylformamide was heated at 70 to 80C for 2.5 hours. The solvent was distilled of~` in vacuo, and the residue was suspended in water. The product was filtered off under suction, rinsed with H20 and pressed on clay.
1.15 g of 1-cyclopropyl-6-fluoro-7-(ethylpiperazino~-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydro-iodide which decomposes at 306C were obtained.
b) The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid used as the starting material was prepared as follows:
24.3 g of magnesium turnings were suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride were added and, when the reaction had started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was addedd~opwise~
a vigorous reflux being observed. After the reaction had ceased, the mixture was heated at the boil for a fur-ther 2 hours and was cooled with dry ice/acetone at -5C
to -10C and a soluticn of 227.5 g of 2~4-dichloro-5-Le A 21 353 -~:37~3~

fluoro-benzoyl chloride in 100 ml of absolute ether was slowly added dropwise at this temperature. The mix-ture was stirred for 1 hour at 0C to -5C and was allowed to reach room temperature overnight~ and a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid was allowed to run in while coolin~ with ice. The phases were separated and T~ere extracted twice with ether.
The combined ether solutions were washed with saturated NaCl solution and àried with Na2S04, ard the solvent was stripped off in vacuo. 349.5 g of diethyl 2,4-di~
chloro-5-fluoro-benzoyl-malonate were obtained as the crude product.
0.15 ~ of p-toluenesulphonic acid was added to an emulsion of 34.9 ~ of crude diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate in 50 ml of water. The emulsion was heated at t~e boil for 3 hours while stirring thoroughly, and, when cold, was extracted several times with methylene chloride~ the combined C~2C12 solutions were washed once with saturated NaCl solution and dried with Na2S04, and the solvent was distilled off in vacuo. Fractionation of the residue under a fine vacuum gave 21.8 ~ of ethyl 2,4-dichloro-5-fluoro-benzoyl acetate IX of boiling point 127 to 142C/0.09 mbar.
A mixture of 21.1 ~ of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and 18.55 g of acetic anhydride was heated at 150C for 2 hours. The volatile constituents ~ere then distilled off under a waterjet vacuum and finzlly under a fine vacuum, at a bath temperature of 120C. 25.2 g of crude ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate remained It was sufficiently pure for the further reactions.
4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 ~ of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acryIate in 80 ml of ethanol while Le A 21 353 . _ - 17 - 12~7~

cooling with ice and stirring. When the exothermic reaction had ceased, the mixture was stirred for another hour at room tempera-ture, the solvent was stripped off ln vacuo, and the residue was recrystallised from cyclohexane/petroleum ether. 22.~ g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acryla-te l = C2H5) of melting point 8~ to 90C were obtained.

3.44 g of 80 per cent sodium hydride were added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (R -- C2H5) in lO0 ml of anhydrous dioxane while cooling with ice and stirring. The mix-ture was then stirred at room temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped of ln vacuo.
The residue (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was re~luxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H2O. The filtrate was then acidified to pH = l to 2 with semiconcentrated hydrochloric acid, while cooling with ice, and the precipitate was filtered off under suction, washed with water and dried in vacuo at 100C. 27.7 g of 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (Rl = H) of melting point 234 to 237C were obtained in this manner.
The invention of the parent application also comprises pharmaceutically acceptable bioprecursors of the active compounds.
For the purposes of this specification the term 'pharmaceutically acceptable bioprecursor' of an active compound means a compound having a structural formula different from the - 17a - 1 %374~1 active compound but which nonetheless, upon administration to an animal or human heing is converted in the patient's body to the active compound.

Claims (18)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of formula II

(II) or a salt or hydrate thereof, wherein R1 is hydrogen or an alkyl group which process comprises cyclizing a compound of formula VI

(VI) wherein R1 is as defined above and, where required, forming a salt or hydrate thereof.

2. A process according to claim 1 wherein the compound of for-mula VI is obtained by reacting a compound of formula X

(X) wherein R1 is as defined above, with cyclopropylamine.

3. A process according to claim 2 wherein the compound of for-mula X is obtained by reacting a compound of formula IX
(IX) wherein R1 is as defined above, with triethyl o-formate/acetic an-hydride.

4. A process according to claim 3 wherein the compound of for-mula IX is obtained by partial hydrolysis and decarboxylation of a compound of formula VIII
(VIII) wherein R1 is as defined above.

5. A process according to claim 1 wherein R1 is hydrogen.

6. A process according to claim 2 wherein R1 is hydrogen.

7. A process according to claim 4 wherein R1 is hydrogen.

8. A process according to claim 1 wherein R1 is ethyl.

9. A process according to claim 2 wherein R1 is ethyl.

10. A process according to claim 4 wherein R1 is ethyl.

11. A process for preparing 7-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid which comprises reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate with cy-clopropylamine followed by cyclizing the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate so formed at a tempera-ture of from 60°C to 280°C.

12. A process according to claim 11 wherein sodium hydride is used as a binding agent in the cyclization reaction.

13. A process according to claim 12 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained by reacting diethyl malonate with 2,4-dichloro-5-fluoro-benzoyl chloride in con-tact with magnesium ethoxide followed by partial hydrolysis and de-carboxylation of the diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate so obtained in contact with a catalytic amount of p-toluenesulphonic acid followed by reacting the ethyl 2,4-dichloro-5-fluoro-benzoyl acetate so obtained with ethyl o-formate and acetic anhydride.

14. A compound of formula II
(II) wherein R1 is hydrogen or an alkyl group, or a salt or hydrate thereof.

15. A compound according to claim 14 wherein R1 is hydrogen or ethyl or a salt or hydrate thereof.

16. The compound 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

17. The compound ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate.

18. A salt or hydrate of a compound according to claim 16 or 17.