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The invention relates to a novel method to the preparation of Chinolincarbonsäuren, those as such or in form of their esters, salts, Prodrugs etc. as antibacterial agents in the human and veterinary medicine as well as the immune defense stimulating agents used become.


Subject-matter of the invention is a method to the preparation of compound of the formula (I)
EMI8.1
in which R< 1> for methyl, ethyl, Propyl, Isopropyl, Cyclopropyl, vinyl, 2-Hydroxyethyl, 2-Fluorethyl, Methoxy, Amino, Methylamino, Dimethylamino, Ethylamino, Phenyl, 4-Fluorphenyl, 2,4-Difluorphenyl, R< 2> for CN or COOR< 2> min with R< 2> min in the importance of hydrogen, C1-C4-Alkyl, (5-Methyl-2-oxo-1,3 dioxol-4-yl) - methyl stands, for CON (C1-C4-Alkyl) for 2 stands, for R< 3> for a cyclic amino group how
EMI9.1
it stands where R< 4> for hydrogen, alkyl with 1 to 4 carbon atoms, 2-Hydroxyethyl, allyl, Propargyl, 2-Oxopropyl, 3-Oxobutyl, Phenacyl, Formyl, CFCl2-S, CFCl2-SO2, CH3O-CO-S, benzyle, 4-Aminobenzyl,
EMI9.2
R< 5> for hydrogen, methyl, R< 6> for hydrogen, alkyl with 1 to 4 carbon atoms, Phenyl, Benzyloxymethyl, R< 7> for hydrogen, Amino, Methylamino, Ethylamino, Aminomethyl, Methylaminoethyl, Ethylaminomethyl, Dimethylaminomethyl, Hydroxy, Hydroxymethyl, R< 8> for hydrogen, methyl, ethyl or chlorine, or R 3< stands> for the group
EMI10.1
stands,
in R< 9> and R< 1>< 0> same or various are and for hydrogen, a branched or unbranched alkyl, alkenyl or Alkinylrest with 1 to 12 carbon atoms, that by hydroxyl groups, Alkoxy, Alkylmercapto or dialkylamino groups with 1 to 3 carbon atoms in each alkyl radical, the nitrile, alkoxycarbonyl group with 1 to 4 carbon atoms in the alcohol part as well as an aryl or a hetero aryl residue substituted to be if necessary can and furthermore C3-C6-Cycloalkyl mean, X for halogen, in particular fluorine and chlorine or Nitro or C1-C4-Alkylsulfonyl or C1-C4-Alkylsulfoxyloxy and A for N or CR< 6> it stands where R< 6> for hydrogen, halogen such as fluorines, bromine or chlorine, methyl or Nitro stands and for R< 6> common with R< 1> a bridge of the structure
EMI11.1
to form it can which is characterized by the fact that one compounds of the formula (II)
EMI11.2
where R< 1>, R< 2>, A and X has the indicated above importance, and
Y for halogen, in particular fluorine and chlorine, or Nitro or C1-C4-Alkylsulfonyl or C1-C4-Alkylsulfoxyloxy stands, with amines of the formulas
EMI12.1
or
EMI12.2
where R< 4>, R< 5>, R< 6>, R< 7>, R< 8>, R< 9> and R< 1>< 0> the indicated above importance have,
bottom renouncement of the application of solvents with temperatures between 20 DEG C and 200 DEG C, if necessary bottom pressure, prefered at 1-200 bar, converts.


The amines mentioned are with the invention process reactant and solvents at the same time. If the amines are solid with room temperature, they are melted, the Reation with (II) become then in the melt conducted.


Is not to be called expressed surprising that A) the reaction of (II) with the amines with very much higher rate runs off than with use of an additional solvent that b) the reaction with deeper temperatures runs off, whereby fewer byproducts formed become and that C) despite the excess at amines increased substitution of X takes place.


Latter finding is the more surprising, because, if (II) into the amine in-dosed becomes, at least at the beginning an almost infinite large excess at amine is present.


The advantages of the invention process therefore are:

- Pure product (fewer byproducts) by the lower reaction temperature
- Saving of time by the higher reaction rate
- Economic advantage by elimination of an additional solvent.



The ratio of the compounds (II) umd the amines can do 1: 1 to 1: 50 amounts to, prefered 1: 2 to 1: 10, whole particularly prefered 1: 3 to 1: 5. The reaction temperature is about 20 to 200 DEG C, prefered becomes the range from 80 to 180 DEG C, to whole particularly prefered 120 to 160 DEG C.


Prefered ones become in the invention process amines of the formula
EMI14.1
used, where R< 9> and R< 1>< 0> same or various are and for hydrogen, a branched or unbranched alkyl, alkenyl or Alkinylrest with 1 to 12 carbon atoms, that by hydroxyl groups, Alkoxy, Alkylmercapto or dialkylamino groups with 1 to 3 carbon atoms in each alkyl radical, the nitrile, alkoxycarbonyl group with 1 to 4 carbon atoms in the alcohol part as well as an aryl or a hetero aryl residue substituted to be if necessary can and furthermore C3-C6-Cycloalkyl mean.


Particularly prefered is for the invention process also cyclic amines such as morpholine, piperidine, Thiomorpholin, Pyrrolidin, piperazine, N-Methylpiperazin, N-Ethylpiperazin, n (2-Hydroxyethyl) - piperazin, N-Formylpiperazin, 2-Methylpiperazin, 1,2-Dimethylpiperazin, cis and trans-2,5-Dimethylpiperazin, cis and trans-2,6-Dimethylpiperazin, 2-Ethylpiperazin, 2-Propylpiperazin, 2-Isopropylpiperazin, 2-Isobutylpiperazin, 2-Piperazinon, 1-Methyl-2-piperazinon, 1-Ethyl-2 piperazinon, 2-Cyclohexylpiperazin, 2-Phenylpiperazin, 2 (4-Chlorphenyl) - piperazin, 2 (4-Fluorphenyl) - piperazin, 2 (4-Bromphenyl) - piperazin, 2 (4-Methylphenyl) - piperazin, 2 (4-Biphenyl) - piperazin, 2 (4-Methoxyphenyl) - piperazin, 2 (4-Benzyloxyphenyl) - piperazin, 2 (4-Hydroxyphenyl) - piperazin, 2 (4-Nitrophenyl) - piperazin, 2 (3-Nitrophenyl) - piperazin, 2 (4-Piperidinophenyl) - piperazin, 2 (3,4-Dimethoxyphenyl) - piperazin, 2 (3,4,5-Trimethoxyphenyl) - piperazin, 2 (3,4-Dimethoxy 6-methyl) - piperazin, 2 (2-Thienyl) - piperazin and 3-Aminopyrrolidin and 3-Aminomethylpyrrolidin.


The Chinolincarbonsäuren of the formula (II) becomes like in the following described prepared:



Example A




6-Chlor-1-cyclopropyl-7,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbon-säure


EMI15.1



15.7 g (0.65 mol) magnesium splinters in 40 ml ethanol and 2 are mixed ml tetrachloromethane and after started reaction with 50 to 60 DEG dropwise with 103 g (0.64 mol) Malonsäurediethylester in 80 ml ethanol and 250 ml toluene staggered. One agitates 1 hour with this temperature after, cools on -5 to -10 DEG, drips a solution of 138 g (0.65 mol) 5-Chlor-2,3,4-trifluor benzoylfluorid in 63 ml toluene too, agitates still 1 hour with 0 DEG and leaves untouched over night with room temperature. Afterwards become still 2 hours on 40 to 50 DEG heated, cooled and with 250 ml ice water and 38.5 ml concentrated sulfur-outer staggered. The organic phase becomes separated, the aqueous phase with 2mal 150 ml toluene extracted, the combined organic phases with satisfied sodium chloride solution washed, with sodium sulfate dried and concentrated.


The residue becomes with 200 ml waters staggered (favourable is here the addition of 0,4 g 4-Toluolsulfonsäure) and the Desethoxycarboxylierung 5 hours bottom reflux heated. One extracted with 3mal 200 ml dichloromethane, washes distilled in the high vacuum with satisfied sodium chloride solution, dries with sodium sulfate, restricts and. One receives 103 g (56.5%) (5-Chlor-2,3,4 tri fluorine benzyle) - acetic acid ethyl esters with a boiling point of 110 DEG /0, 9 Torrs.


103 g (0.37 mol) of the obtained ester and 83 g (0.56 mol) Orthoameisensäuretriethylester become with 95 g acetic anhydride 2 hours on 150 to 160 DEG heated and subsequent normal pressure bottom with 120 to 130 DEG, afterwards in the high vacuum concentrated. One receives to 115 g (92% of the theory) 2 (5-Chlor-2,3,4-trifluor-benzoyl) - 3 - ethoxy acrylic acid more ethylester than oil.


84.1 g (0.25 mol) of this compound become in 170 ml ethanol bottom ice cooling dropwise with 14,8 g (0.26 mol) Cyclopropylamin staggered and 2 hours with room temperature agitated. Afterwards with 170 ml waters is mixed, in ice cooled, the failed precipitation aspirated, with water and little methanol washed and dried. 47 g (54%) become 2 (5-Chlor-2,3,4 trifluor benzoyl) - 3-cyclopropylamino-acrylsäureethylester of the melting point 71 to 73 DEG obtained. After that <1> H-NMR spectrum is present a cis trans mixture.


47 g (0.14 mol) of this compound become in 230 ml dimethylformamides with 9,7 g (0.23 mol) sodium fluoride 2 hours on 160 to 170 DEG heated. The reaction mixture is cast in in 400 ml ice water, the precipitation aspirated, with water washed and dried. One isolated 44 g (99%) 6-Chlor-1-cyclopropyl-7,8-difluor 1,4-dihydro-4-oxo-3-chinolincarbonsäure-ethylester of the melting point 169 to 172 DEG.


44 g (0.13 mol) of the Chinoloncarbonsäureesters become in 300 ml glacial acetic acid and 179 ml waters with 33 ml concentrated sulfuric acid staggered and 2 hours on 150 DEG C heated. The reaction mixture is stirred into 400 ml ice water, the precipitation aspirated, with water washed and dried. 37 g (95% of the theory) become 6-Chlor-1-cyclopropyl-7,8-difluor-1,4-dihydro 4-oxo-3-chinolincarbonsäure with a melting point of 200 to 204 DEG isolated.



Example B




8-Chlor-1-cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-chinolincarbon-säure

EMI18.1



One converts 3-Chlor-2,4,5-trifluor-benzoylchlorid analogous example A, whereby the subsequent steps will go through:


(3-Chlor-2,4,5-trifluor-benzoyl) - acetic acid ethyl esters as Enol (yield: 42%, melting point 72-75),
2 (3-Chlor-2,4,5-trifluor-benzoyl-3-ethoxy-acrylsäure ethyl ester (crude yield: 95% oil),
2 (3-Chlor-2,4,5-trifluor-benzyl-3-cyclopropyl-amino acrylic acid ethyl ester (yield: 67%, melting point 78-80 DEG),
8-Chlor-1-cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3 chinolincarbonsäure more ethylester (yield: 85%, melting point 154-157 DEG),
8-Chlor-1-cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3 chinolincarbonsäure (yield: 97.6%, melting point 189-192 DEG).



Example C




6,8-Dichlor-1-cyclopropyl-7-fluor-1,4-dihydro-4-oxo-3-chinolincarbon-säure

EMI19.1



One converts 3,5-Dichlor-2,4-difluor-benzoylfluorid analogous example A, whereby the subsequent steps will go through:


(3,5-Dichlor-2,4-difluor-benzoyl) - acetic acid ethyl ester (yield: 43%, boiling point 133 DEG /2, 5 Torrs),
2 (3,5-Dichlor-2,4-difluor-benzoyl) - 3-ethoxy-acrylsäure ethyl ester (crude yield: 91% oil),
2 (3,5-Dichlor-2,4-difluor-benzoyl) - 3-cyclopropyl-amino acrylic acid ethyl ester (yield: 96%, melting point 71-74 DEG),
6,8-Dichlor-1-cyclopropyl-7-fluor-1,4-dihydro-4-oxo-3 chinolincarbonsäure more ethylester (yield: 97%, melting point 215-217 DEG bottom decomposition),
6,8-Dichlor-1-cyclopropyl-7-fluor-1,4-dihydro-4-oxo-4 chinolincarbonsäure (yield: 93%, melting point 204-206 DEG).


Other Chinolincarbonsäuren, in particular Cyclopropyl 6,7,8-trifluor-1,4-dihydro-4-oxo-3-chinolincarbonsäuren can become in accordance with the subsequent reaction pattern prepared:
EMI20.1

EMI20.2



Afterwards Malonsäurediethylester (2) in presence of Magnesiumethylat with 2,3,4,5-Tetrafluorbenzoylchlorid (1) becomes acylated to the Aroylmalonester (3) (Organicum, 3. Aufl. 1964, S. 438).


At site of (1) also the 2,3,4,5-Tetrafluorbenzoesäurefluorid can become used.


By partial saponification and decarboxylation of (3) in aqueous medium with catalytic amounts sulfuric acid or p-toluenesulfonic acid one receives the Aroylessigsäureethylester (4) in good yield, which with o-formic acid-more triethylester/acetic anhydride in the 2 (2,3,4,5-Tetrafluorbenzoyl) - 3-ethoxy-acrylsäureethylester (5) turns into. The conversion of (5) with Cyclopropylamin in a solvent, like z. B. Methylene chloride, alcohol, chloroform, cyclohexane or toluene lead in light exothermic reaction to the desired intermediate (6).


The cyclization reaction (6) -> (7) becomes in a temperature range from approximately 60 to 300 DEG C, prefered 80 to 180 DEG C conducted.


As diluents can become Dioxan, dimethylsulfoxide, N-methylpyrrolidone, sulfolane, hexadecimal methyl phosphoric acid tri amide and prefered N, N-dimethylformamide used.


As acidic binders potassium third comes for this reaction step. - butanolat, Butyl lithium, lithium phenyl, Phenylmagnesiumbromid, Natriummethylat, sodium hydride, sodium or potassium carbonate and particularly prefered potassium or Natrium-fluorid in considerations. It can be favourable to use an excess of 10 mol % at base.


The ester hydrolysis of (7) bottom basic or acidic conditions, taking place in the final step, leads to 1-Cyclopropyl-6,7,8-trifluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure.


The 2,3,4,5-Tetrafluorbenzoylchlorid (1), used as starting material for this synthetic route, became from the literature-known 2,3,4,5-Tetrafluor-benzoesäure (G. G. Yakobson, V. N. Odinokov and N. N. Vorozhtsov Jr., Zh. Obsh. Khim. 36, 139 (1966) with thionyl chloride over usual manner obtained. It possesses a boiling point of 75-80 DEG C/17 mbar. The 2,3,4,5-Tetrafluorbenzoylfluorid possesses a boiling point of 46 to 47 DEG C/20 mbar (: 1,4375).


Other Chilonincarbonsäuren can become prepared as follows:
EMI23.1

EMI23.2



Afterwards Malonsäurediethylester (VII) with IV in presence from magnesium alcohol becomes to the ecyl malonic ester VIII acylated (Organicum, 3. Aufl. 1964, S. 438).


By partial saponification and decarboxylation of VIII in aqueous medium with catalytic amounts p-toluenesulfonic acid one receives the Aroylessigsäureethylester IX in good yield, with o-Ameisensäuretriethylester/acetic anhydride in the 2 (2,4-Dichlor-5-fluorbenzoyl) - 3-ethoxy-acrylsäureethylester X turns into. The conversion of X with Cyclopropylamin in a solvent, like z. B. Methylene chloride, alcohol, chloroform, cyclohexane or toluene lead in light exothermic reaction to the desired intermediate VI.


The cyclization reaction VI> II (R< 1> =Alkyl) becomes in a temperature range from approximately 60 DEG to 280 DEG C, prefered 80 DEG to 180 DEG C conducted.


As diluents Dioxan, dimethylsulfoxide, N-methyl-pyrrolidon, can become sulfolane, hexadecimal methyl phosphoric acid tri amide and prefered N, N-dimethylformamide used.


When acidic binders come for this reaction step potassium t-butanolat, butyllithium, Phenyllithium, Phenylmagnesiumbromid, Natriumethylat and particularly prefered sodium hydride or potassium carbonate in considerations. It can be favourable to use an excess of 10 mol % at base.


The 2,4-Dichlor-5-fluor-benzoylchlorid IV used as starting material for this synthetic route and the corresponding carbonic acid as well as for the preparation of IV required 3-Fluor-4,6-dichlortoluol XI are 78,362 known from EP-A2-00.


Prefered compounds, after the invention process the prepared to become to be able are in EP-A2 00 78 362, page 4, lines 10 to 16, EP-A-1 00 49 355, examples 1 to 19, DE-OS 34 20 743, page 35, line 20 to page 37, line 11 and DE-OS 33 18 145, page 31, line 1 to page 32, line 13 described.


Other compounds producible after the invention process are:


6-Chlor-1-cyclopropyl-7 (1,4-diazabicyclo [3.2.1] - oct-4 yl) - 1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] - oct-4-yl) - 6 - fluor-1,4-dihydro-8-methyl-4-oxo-3-chinolincarbonsäure,
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 6-fluor-1 (2-fluorethyl) - 1,4-dihydro-4-oxo-3-chinolincarbonsäure,
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 6-fluor-1 (4-fluorphenyl) - 1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carbonsäure,
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 1-ethyl-6-fluor-1,4 dihydro-4-oxo-1,8-naphthyridin-3-carbonsäure,
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 1-ethyl-6-fluor-1,4 dihydro-4-oxo-3-chinolincarbonsäure,
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 9-fluor-6,7-dihydro 5-methyl-1-oxo-1H, 5H-benzo [i, j] chinolin-2-carbonsäure,
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl] - 6-fluor-1 (4-fluorphenyl) - 1,4-dihydro-4-oxo-1,8-naphthyridin-3 carbonic acid,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäureethylester,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure (5-methyl 2-oxo-1,3-dioxol-4-yl-methyl) - esters,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.1.1] hept-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.1.1] hept-4-yl) - 6.8 - difluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
8-Chlor-1-cyclopropyl-7 (1,4-diazabicyclo [3.1.1] hept-4 yl) - 6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.1.1] hept-4-yl) - 6 - fluor-1,4-dihydro-8-methyl-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.1.1] hept-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.1.1] hept-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäuremethylester,
1-Cyclopropyl-6,8-difluor-1,4-dihydro-7 (8-methyl-3,8 diazabicyclo [3.2.1] oct-3-yl) - 4-oxo-3 chinolincarbonsäure,
8-Chlor-1-cyclopropyl-6-fluor-1,4-dihydro-7 (8-methyl 3,8-diazabicyclo [3.2.1] oct-3-yl) - 4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) - 4-oxo-1,8-naphthyridin-3-carbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (3-methyl-3,8-diazabicyclo [3.2.1] oct-8-yl) - 4-oxo-chinolincarbonsäure,
1-Cycloproyl-6,8-difluor-1,4-dihydro-7 (3-methyl-3,8 diazabicyclo [3.2.1] oct-8-yl) - 4-oxo-3-chinolincarbonsäure,
8-Chlor-1-cyclopropyl-6-fluor-1,4-dihydro-7 (3-methyl 3,8-diazabicyclo [3.2.1] oct-8-yl) - 4-oxo-3-cinolincarbonsäure,
1-Cyclopropyl-7 (2,5-diazabicyclo [2.2.1] hept-2-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (2,5-diazabicyclo [2.2.1] hept-2-yl) - 6.8 - difluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
8-Chlor-1-cyclopropyl-7 (2,5-diazabicyclo [2.2.1] - hept-2 yl) - 7-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (2,5-diazabicyclo [2.2.1] hept-2-yl) - 6 - fluor-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 [5 (2-hydroxyethyl) - 2,5-diazabicyclo [2.2.1] hept-2-yl] - 4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7 [5 (2-oxopropyl) - 2,5-diazabicyclo [2.2.1] hept-2-yl] - 3-chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) - 4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6,8-difluor-1,4-dihydro-7 (5-methyl-2,5 diazabicyclo [2.2.1] hept-2-yl) - 4-oxo-3-chinolincarbonsäure,
8-Chlor-1-cyclopropyl-6-fluor-1,4-dihydro-7 (5-methyl 2,5-diazabicyclo [2.2.1] hept-2-yl) - 4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (8-ethyl-3,8-diazabicyclo [3.2.1] oct-3 yl) - 6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7 [8 (3-oxo butyl) - 3,8-diazabicyclo [3.2.1] oct-3-yl] - 3 - chinolincarbonsäure,
7 [8 (4-Aminobenzyl) - 3,8-diazabicyclo [3.2.1] oct-3-yl] - 1 - cycloproyl-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (2,5-diazabicyclo [2.2.2] oct-2-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (2,5-diazabicyclo [2.2.2] oct-2-yl) - 6.8 - difluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
8-Chlor-1-cyclopropyl-7 (2,5-diazabicyclo [2.2.2] oct-2 yl) - 7-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-7 (2,5-diazabicyclo [2.2.2] oct-2-yl) - 6 - fluor-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) - 4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6,8-difluor-1,4-dihydro-7 (5-methyl-2,5 diazabicyclo [2.2.2] oct-2-yl) - 4-oxo-3-chinolincarbonsäure,
8-Chlor-1-cyclopropyl-6-fluor-1,4-dihydro-7 (5-methyl 2,5-diazabicyclo [2.2.2] oct-2-yl) - 4-oxo-3 chinolincarbonsäure,
1-Cyclopropyl-7 (3,9-diazabicyclo [3.3.1] non-3-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (7-hydroxy-3,9 diazabicyclo [3.3.1] non-3-yl) - 4-oxo-3 chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (3-oxo-7,9-diazabicyclo [3.3.1] non-7-yl) - 4-oxo-3-chinolincarbonsäure,
7 (5-Allyl-2,5-diazabicyclo [2.2.1] hept-2-yl) - 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure,
1-Cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7 (5-propargyl 2,5-diazabicyclo [2.2.2] oct-2-yl) - 3-chinolincarbonsäure,
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure, - hydrochloride of the melting point 322 DEG C.
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure Hemiembonat of the melting point starting from 271 DEG C.
8-Chlor-1-cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4 yl) - 6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure hydrochloride hydrate of the melting point 310 DEG C.
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6.8 - difluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure of the melting point 275-282 DEG C.
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 1.4 - dihydro-6-nitro-4-oxo-3-chinolincarbonsäure-Hydrochlorid of the melting point 303-307 DEG C.
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carbonsäure hydrochloride of the melting point >300 DEG C.
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 1-ethyl-6,8-difluor 1,4-dihydro-4-oxo-3-chinolincarbonsäure-Hydrochlorid of the melting point 308-312 DEG C.
10 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 9-fluor-2,3 dihydro-3-methyl-7-oxo-7H-pyrido [1.2.3-de] [1,4] benzoxacin 6-carbonsäure-Hydrochlorid of the melting point 355 DEG C.
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 6,8-difluor-1 (4 - fluorphenyl) - 1,4-dihydro-4-oxo-3-chinolincarbonsäure hydrochloride of the melting point 310-314 DEG C.
1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] oct-4-yl) - 6 - fluor-1,4-dihydro-8-nitro-4-oxo-3-chinolincarbonsäure of the melting point 215-232 DEG C.


The for this required 7-Chlor-1-cyclopropyl-6-fluor-1,4 dihydro-8-nitro-4-oxo-3-chinolincarbonsäure becomes obtained over the subsequent steps:



a) 2,4-Dichlor-5-fluor-3-nitro-benzoesäure

EMI32.1



Bottom ice cooling and agitation become 34 ml concentrated sulfuric acid dropwise nitric acid staggered concentrated with 40 ml. Into this Nitriergemisch one registers 20.9 g 2,4-Dichlor-5-fluorbenzoesäure by portion, whereby the temperature rises to 45-50 DEG C. Then still 3 hours on 90-100 DEG C heated, the mixture on 350 ml ice water poured, become the precipitation aspirated and with water, cooled down on room temperature, washed. The wet crude product becomes in 30 ml methanol hot dissolved and the solution with 150 ml waters staggered.


The precipitation becomes cold aspirated with methanol water washed and in the vacuo dried with 80 DEG C. 21.1 g crude 2,4-Dichlor-5-fluor-3-nitro benzoic acid obtained become. It is sufficient pure for the other conversions. A sample from toluene/petroleum ether recrystallized supplies crystals of the melting point 192 DEG C.



b) 2.4 Dichlor-5-fluor-3-nitro-benzoylchlorid

EMI33.1



106.6 g 2,4-Dichlor-5-fluor-3-nitro-benzoesäure become with 250 ml thionyl chloride 2 hours bottom reflux simmering heated. The excess thionyl chloride is then abdestilliert with normal pressure and the residue in the medium-high vacuum range fractionated. With 110-115 DEG C/0,08-0,09 mbar ignore 104.7 g 2,4-Dichlor-5-fluor-3-nitro-benzoylchlorid. When standing form crystals of the melting point 35 to 37 DEG C.



c) (2.4-Dichlor-5-fluor-3-nitro-benzoyl) - acetic acid ethyl esters

EMI33.2



10.1 g of magnesium splinters ethanol with 2,1 g tetrachloromethane staggered and after starts of the hydrogen development a mixture from 66,6 g Malonsäurediethylester, 40 ml ethanol and 150 become ml toluene with 50-60 DEG C dropwise added in 21 ml. One agitates 1 hour with this temperature after, cools on -5 to -10 DEG C and drips a slow solution of 109,2 g 2,4-Dichlor-5-fluor-3-nitro-benzoylchlorid in 50 ml toluene too. Afterwards 1 hour becomes with 0 DEG C agitated and still 2 hours on 40-50 DEG C heated, brought over night on room temperature. The reaction mixture becomes bottom ice cooling with a mixture from 160 ml waters and 10.4 ml konzentrieter sulfuric acid staggered and the organic phase separated. The aqueous phase becomes dried with toluene extracted and the combined organic extract with satisfied sodium chloride solution washed, with sodium sulfate and the solvent withdrawn. One keeps 144.5 g (2,4-Dichlor-5-fluor 3-nitro-benzoyl) more malonsäurediethylester - than crude product. This becomes after addition of 200 ml waters and 0.6 g 4-Toluolsulfonsäure 3 hours bottom reflux heated, which mixture with methylene chloride extracted, which extract with sodium sulfate dried and the solvent in the vacuo abdestilliert. 118 g of substituted Benzoylessigester become as crude product obtained. It possesses a purity sufficient for the other conversions.



7-Chlor-1-cyclopropyl-6-fluor-1,4-dihydro-8-nitro-4-oxo-3-chinolinca-rbonsäure

EMI34.1



244.8 g (2,4-Dichlor-5-fluor-3-nitro-benzoyl) - acetic acid ethyl esters become with 166 g Orthoameisensäuretriethylester and 185 g acetic anhydride 3 hours on 150-160 DEG C heated. One restricts in the vacuo and receives to 270 g 2 (2,4-Dichlor-5-fluor-3 nitro benzoyl) - 3-ethoxy-acrylsäure-ethylester as oily residue.


38 g of this intermediate stage become in 80 ml ethanol bottom ice cooling tropenweise and 1 hour staggered with 5,9 g Cyclopropylamin with 20 DEG C agitated. The failed product becomes after addition of 100 ml waters aspirated, with Ethanol/H2O (1: 1) washed and dried. One receives 32.8 g 2 (2.4 - Dichlor-5-fluor-3-nitro-benzoyl) - 3-cyclopropyl revision modification NO acrylic acid ethyl esters from the melting point 143-146 DEG C.


7.8 g of of the aforementioned compound become in 30 ml anhydrous Dioxan with 3,1 g (1,8-Diazabicyclo [5.4.0] undec-7-en (DBU) staggered and 4 hours on 100 DEG C heated. The solvent is abdestilliert in the vacuo, which residue in dichloromethane water received, which abdestilliert dichloromethane phase separated, with sodium sulfate dried and the methylene chloride. 7.2 g 7-Chlor 1-cyclopropyl-6-fluor-1,4-dihydro-8-nitro-4-oxo-3 become more chinolincarbonsäureethylester than crude product obtained. After recrystallization from Acetionitril the light brown crystals melt with 174-175 DEG C. Yield: 6 G.


7 (5-Benzyl-2,5-diazabicyclo [2.2.1] hept-2-yl) - 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure of the melting point 205-214 DEG C.
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (8-methyl-3,8 diazabicyclo [3.2.1] oct-3-yl) - 4-oxo-3-chinolincarbonsäure of the melting point 273-278 DEG C.
1-Cyclopropyl-6-fluor-1,4-dihydro-7 (5-methyl-1,4 diazabicyclo [3.2.1] oct-4-yl) - 4-oxo-3-chinolincarbonsäure-Hydrochlorid of the melting point >300 DEG C.
1.1 g 1-Cyclopropyl-7 (1,4-diazabicyclo [3.2.1] - oct-4 yl) - 6,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsäureethylester of the melting point 196-199 DEG C.
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 6,8-difluor-1 (2.4 - difluorphenyl) - 1,4-dihydro-4-oxo-3-chinolin-carbonsäure hydrochloride of the melting point 329-331 DEG C.
7 (1,4-Diazabicyclo [3.2.1] oct-4-yl) - 6,8-difluor-1,4 dihydro-1-methylamino-4-oxo-3-chinolincarbonsäure hydrochloride of the melting point 300-305 DEG C.


Usually first the free carboxylic acids obtained, thereafter into salts, become according to invention ester, Prodrugs etc. after known methods transfered to become to be able.


Those whole particularly prefered compounds producible after the invention process are Ciprofloxacin and the corresponding 1-Ethyl-piperazinderivat.



Examples




Example 1



606 Gew. - Parts 1-Cyclopropyl-7-chlor-6-fluor-1,4 dihydro-4-oxo-3-chinolincarbonsäure and 575 Gew. - Parts piperazine become in a suitable reactor 30 minutes on 150 to 160 DEG C heated. The reaction mixture becomes diluted with water, whereby in 71%iger yield 1-Cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7 (1-piperazinyl) - 3 - chinolincarbonsäure with a content of approx. 98% obtained becomes.



Example 2



133 Gew. - Parts 1-Cyclopropyl-6,7-difluor-1,4-dihydro-4 oxo-3-chinolincarbonsäure and 129 Gew. - Parts piperazine become 1 reacted as in example. One receives 3-chinolincarbonsäure with a content in 70%iger yield 1-Cyclopropyl-6-fluor-1,4-dihydro-4 oxo-7 (1-piperazinyl) - from 98,5%.



Example 3



143 Gew. - Parts piperazine become on 140 to 150 DEG C heated. Into this melt 94 Gew become. - Parts 1-Cyclopropyl-7-chlor-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure within 20 minutes in-dosed. One cools down on 100 DEG C and adds waters. Hiebei crystallized 1-Cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7 (1 - piperazin) - 3-chinolincarbonsäure in 78%iger yield with a purity from 97,2%.



Example 4



150 Gew. - Parts piperazine become with 102 Gew. - Parts 1-Cyclopropyl-6,7-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure as in example 3 reacted. One receives - 3-chinolincarbonsäure in an yield to 1-Cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7 (1-piperazinyl) from 76% with a purity from 97,5%.



Example 5



To 122 Gew. - Parts 1-Ethyl-piperazin, which became on 140 to 150 DEG C heated, 60 Gew become within 30 minutes. - Parts 1-Cyclopropyl-7-chlor-6-fluor-1,4-dihydro-4 oxo-3-chinolincarbonsäure given. After cooling on 100 DEG C water becomes added, whereby 1-Cyclopropyl-6 fluor-1,4-dihydro-4-oxo-7 (4-ethyl-1-piperazinyl) - 3 - chinolincarbonsäure in 76%iger yield and 98,2%iger purity crystallize.