IE64261B1 - Process for the preparation of quinolinecarboxylic acids - Google Patents
Process for the preparation of quinolinecarboxylic acidsInfo
- Publication number
- IE64261B1 IE64261B1 IE327987A IE327987A IE64261B1 IE 64261 B1 IE64261 B1 IE 64261B1 IE 327987 A IE327987 A IE 327987A IE 327987 A IE327987 A IE 327987A IE 64261 B1 IE64261 B1 IE 64261B1
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- IE
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- Prior art keywords
- cyclopropyl
- dihydro
- oxo
- quinolinecarboxylic acid
- chloro
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Optical Fibers, Optical Fiber Cores, And Optical Fiber Bundles (AREA)
Abstract
A process for the preparation of quinolinecarboxylic acids of the formula (I) in which R<1>, R<2> and R<3>, X and A have the meaning given in the description, which are used as such or in the form of their esters, salts, prodrugs etc. as antibacterial agents in human and veterinary medicine and as agents stimulating the immune defence.
Description
The invention relates to a new process for the preparation of guinolinecarboxylic acids which are used as such or in the form of their esters, salts, prodrugs and the like as antibacterial agents in human and veterinary medicine and as agents which stimulate immune defence.
DE-A 2,804,097, DE-A 2,656,574, Processes for the preparation of guinolonecarboxylic acid derivatives which are substituted in the 7-position by cyclic amines have already been disclosed in EP-A-0,195,841, US-P 4,448,962, EP-A-0,078,362, EP-A-0,167,763 and EP-A-0,126,355. In these processes the cyclic amines, however, are not employed in pure form, i.e. without solvent and water of hydration. The yields and product purities obtained by these processes are not satisfactory. Surprisingly, it has now been found that completely dispensing with additional solvents and using the pure amine which is free from water of hydration or water of crystallisation is accompanied by various advantages. The invention therefore relates to a process for the preparation of compounds of the formula (I) Ri in which R1 represents methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-fluoroethyl, 4-fluorophenyl or 2,4-difluorophenyl, R2 represents CN or COOR2’, where R2' denotes hydrogen or Cx-C^-alkyl, represents a cyclic amino group, such as N-, R6 wherein R* represents hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyl or 2-oxopropyl, R5 represents hydrogen or methyl, R6 represents hydrogen or alkyl with 1 to 4 carbon atoms, R7 represents hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl or hydroxymethyl, R8 represents hydrogen, methyl, ethyl or chlorine, X represents halogen, in particular fluorine and chlorine, and A represents C-R11, wherein R11 represents hydrogen or halogen, which is characterised in that compounds of the formula (II) (II) wherein R1, Rz, A and X have the abovementioned meaning, and Y represents halogen, in particular fluorine and chlorine, are reacted with solvent-free amines of the formulae N-H, R4 > N^T^N-H wherein R*, Rs, R®, R7, R® and R11 have the abovementioned meaning, dispensing with the use of solvents at temperatures 20°C and 200«C.
The amines mentioned are the reactant and solvent at the same time in the process according to the invention. If the amines are solid at room temperature, they are melted and the reaction with (II) is then carried out in the melt.
It is to be described as decidedly surprising that a) the reaction of (II) with the pure amines proceeds at a very much higher rate than when an additional solvent is used, that b) the reaction proceeds at lower temperatures, which means fewer by-products are formed, and that c) in spite of the excess of amine no increased substitution of X takes place.
The last finding is all the more surprising, since in fact if (II) is metered into the amine, an almost infinitely large excess of amine is present at least at the start.
The advantages of the process according to the invention are accordingly: - a purer product (fewer by-products) due to the lower reaction temperature - a saving in time due to the higher rate of reaction - economic advantage by dispensing with an additional solvent.
The ratio of the compounds (II) to the amines can be 1:2 to 1:10, preferably 1:3 to 1:5. The reaction temperature is 20°C to 200°C and the range is preferably 80°C to 180°C, especially preferably 120°C to 160°C.
Amines which are preferably used in the process according to the invention are the following: cyclic amines, such as morpholine, piperidine, thiomorpholine, pyrrolidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)-piperazine, 2-methylpiperazine, 1,2-dimethylpiperazine, cis- and trans-2,5-dimethylpiperazine, cis- and trans-2,6-dimethylpiperazine, 2-ethylpiperazine, 2-propylpiperazine, 2-isopropylpiperazine and 2-isobutylpiperazine.
The guinolinecarboxylic acids of the formula (II) are prepared as described below: Example A 6-Chloro-l-cyclopropyl-7,8-dif luoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid COOH .7 g (0.65 mol) of magnesium filings are stirred in 40 ml of ethanol and 2 ml of carbon tetrachloride, and after the reaction has started, 103 g (0.64 mol) of diethyl malonate in 80 ml of ethanol and 250 ml of toluene are added dropwise at 50 to 60°. The mixture is subsequently stirred at this temperature for 1 hour and cooled to -5 to -10°, a solution of 138 g (0.65 mol) of -chloro-2,3,4-trifluorobenzoyl fluoride in 63 ml of toluene is added dropwise and the mixture is stirred at 0*C for a further hour and left to stand overnight at room temperature. Thereafter, the mixture is warmed at 40 to 50* for a further 2 hours and cooled, and 250 ml of ice-water and 38.5 ml of concentrated sulphuric acid are added. The organic phase is separated off, the aqueous phase is extracted with 2 portions of 150 ml of toluene and the combined organic phases are washed with saturated sodium chloride solution, dried with sodium sulphate and concentrated. 200 ml of water are added to the residue (the addition of 0.4 g of 4-toluenesulphonic acid is advantageous here) and the mixture is heated under reflux for 5 hours for de-ethoxycarboxylation. It is extracted with 3 portions of 200 ml of methylene chloride, the extracts are washed with saturated sodium chloride solution, dried with sodium sulphate and concentrated and the residue is distilled under a high vacuum. 103 g (56.5%) of ethyl (5-chloro-2,3,4-trifluoro-benzoyl)-acetate of boiling point 110®/0.9 mm Hg are obtained. 103 g (0.37 mol) of the resulting ester and 83 g (0.56 mol) of triethyl orthoformate are heated at 150 to 160° with 95 g of acetic anhydride for 2 hours and the mixture is then concentrated at 120 to 130° under normal pressure and then under a high vacuum. 115 g (92% of theory) of ethyl 2-(5-chloro-2,3,4-trifluoro-benzoyl)-3ethoxy-acrylate are obtained as an oil. 14.8 g (0.26 mol) of cyclopropylamine are added dropwise to 84.1 g (0.25 mol) of this compound in 170 ml of ethanol, while cooling with ice, and the mixture is stirred at room temperature for 2 hours. Thereafter, it is stirred with 170 ml of water and cooled in ice and the precipitate which has separated out is filtered off with suction, washed with water and a little methanol and dried. 47 g (54%) of ethyl 2-(5-chloro-2,3,4-trifluorobenzoyl )-3-cyclopropylamino-acrylate of melting point 71 to 73° are obtained. According to the 1H-NMR spectrum, a cis-trans mixture is present. g (0.14 mol) of this compound are heated at 160 to 170° in 230 ml of dimethylformamide with 9.7 g (0.23 mol) of sodium fluoride for 2 hours. The reaction mixture is poured into 400 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 44 g (99%) of ethyl 6-chloro-l-cyclopropyl-7,8-difluorol,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 169 to 172® are isolated. ml of concentrated sulphuric acid are added to 44 g (0.13 mol) of the quinolinecarboxylic acid ester in 300 ml of glacial acetic acid and 179 ml of water and the mixture is heated at 150®C for 2 hours. The reaction mixture is stirred into 400 ml of ice-water and the precipitate is filtered off with suction, washed with water and dried. 37 g (95% of theory) of 6-chloro-lcyclopropyl-7,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecar boxy lie acid of melting point 200 to 204® are isolated.
Example B 8-Chloro-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid 3-Chloro-2,4,5-trifluoro-benzoyl chloride is reacted analogously to Exaunple A, the process passing through the following stages: ethyl (3-chloro-2,4,5-trifluoro-benzoyl)-acetate as the enol (yield: 42%, melting point 72-75®), ethyl 2-(3chloro-2,4,5-trif luoro-benzoyl-3-ethoxy-acrylate (crude yield: 95% oil), ethyl 2-(3-chloro-2,4,5-trifluorobenzyl)-3-cyclopropyl-aminoacrylate (yield: 67%, melting point 78-80®), ethyl 8-chloro-l-cyclopropyl-6,7-difluorol,4-dihydro-4-oxo-3-quinolinecarboxylate (yield: 85%, melting point 154-157®) and 8-chloro-l-cyclopropyl-6,7dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (yield: 97.6%, melting point 189-192°).
Example C 6,8-Dichlorο-1-eyelopropy1-7-fluoro-1,4-dihydro-4-oxo-3guinolinecarboxylic acid 3,5-Dichloro-2,4-difluoro-benzoyl fluoride is reacted analogously to Example A, the process passing through the following stages: ethyl (3,5-dichloro-2,4-difluoro-benzoyl)-acetate (yield:43%, boiling point 133°/2.5 mm Hg), ethyl 2-(3,5dichloro-2,4-dif luoro-benzoyl) -3-ethoxy-acrylate (crude yield: 91% oil), ethyl 2-(3,5-dichloro-2,4-difluorobenzoyl )-3-cyclopropyl-aminoacrylate (yield: 96%, melting point 71-74°), ethyl 6,8-dichloro-l-cyclopropyl-7-fluorol,4-dihydro-4-oxo-3-guinolinecarboxylate (yield: 97%, melting point 215-217°, with decomposition) and 6,8dichloro-l-cyclopropyl-7-f luoro-1,4-dihydro-4-oxo-4quinoline-carboxylic acid (yield: 93%, melting point 204-206°).
Other quinolinecarboxylic acids, in particular cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids, can be prepared in accordance with the following equation: F\X^XCOC1 AA cooc2h5 Mg(OEt)2 cooc2h5 (2) (4) (5) (6) (7) (II) According to this equation, diethyl malonate (2) is acylated with 2,3,4,5-tetrafluorobenzoyl chloride (1) in the presence of magnesium ethylate to give the aroylmalonate (3) (Organicum, 3rd edition 1964. page 438).
Instead of (1), 2,3,4,5-tetrafluorobenzoyl fluoride can also be used.
Partial hydrolysis and decarboxylation of (3) in an aqueous medium with catalytic amounts of sulphuric acid or p-toluenesulphonic acid gives a good yield of the ethyl aroylacetate (4), which is converted into ethyl 2(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acrylate (5) with triethyl o-formate/acetic anhydride. The reaction of (5) with cyclopropylamine in a solvent, such as, for example, methylene chloride, alcohol, chloroform, cyclohexane or toluene, gives the desired intermediate product (6) in a slightly exothermic reaction.
The cyclisation reaction (6) -> (7) is carried out in a temperature range of about 60 to 300°C, preferably 80 to 180°C.
Diluents which can be used are dioxane, dimethylsulphoxide, N-methylpyrrolidone, sulphoiane, hexamethylphosphoric acid triamide and, preferably, Ν,Ν-dimethylformamide .
Possible acid-binding agents for this reaction stage are potassium tert.-butanolate, butyl-lithium, lithiumphenyl, phenyl-magnesium bromide, sodium methylate, sodium hydride, sodium or potassium carbonate and, particularly preferably, potassium or sodium fluoride. It may be advantageous to use an excess of 10 mol % of base.
The ester hydrolysis of (7) which takes place in the last step under basic or acid conditions leads to 1-cyclopropyl-6,7,8-trif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
The 2,3,4,5-tetrafluorobenzoyl chloride (1) used as the starting material for this synthesis route was obtained in the customary manner from 2,3,4,5-tetrafluoro-benzoic acid, which is known from the literature (G.G. Yakobson, V.N. Odinokov and N.N. Vorozhtsov Jr., Zh. Obsh. Khim. 36. 139 (1966)), with thionyl chloride. It has a boiling point of 75-80®C/17 mbar. 2,3,4,5-Tetrafluorobenzoyl fluoride has a boiling point of 46 to 47°C/20 mbar (n£°: 1.4375).
Other guinolinecarboxylic acids can be prepared as follows: ♦ CH /cooc2h5 »2 MgOEt ^cooc2h5 -- c xc II ^COOC?Hc -CH ^cooc2h5 IV VII -C-C00C2Hc II 2 s CH I oc2h5 O™; xc VIII I -ch2cooc2h5 IX C-COOR1 VI Ο OOR1 II According to this equation, diethyl malonate (VII) is acylated with IV in the presence of magnesium alcoholate to give the acylmalonate VIII (Organicum, 3rd edition 1964. page 438).
Partial hydrolysis and decarboxylation of VIII in an aqueous medium with catalytic amounts of p-toluenesulphonic acid gives a good yield of the ethyl aroylacetate IX, which is converted into ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-acrylate X with triethyl o-formate/acetic anhydride. The reaction of X with cyclopropylamine in a solvent, such as, for example, methylene chloride, alcohol, chloroform, cyclohexane or toluene, leads to the desired intermediate product VI in a slightly exothermic reaction.
The cyclisation reaction VI -> II (R1 = alkyl) is carried out in a temperature range from about 60° to 280®C, preferably 80e to 180eC.
Diluents which can be used are dioxane, dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethylphosphoric acid triamide and, preferably, N,N-dimethylf ormamide.
Possible acid-binding agents for this reaction stage are potassium t-butanolate, butyllithium, phenyllithium, 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-fluoro-benzoyl chloride IV used as the starting material for this synthesis route and the corresponding carboxylic acid, and also the 3-fluoro-4,6dichlorotoluene XI reguired for the preparation of IV are known from EP-A2-0,078,362.
Preferred compounds which can be prepared by the process according to the invention are described in EP-A2-0,078,362, page 4, lines 10 to 16, EP-A-1 0,049,355, Examples 1 to 19, DE-OS (German Published Specification) 3,420,743, page 35, line 20 to page 37, line 11 and DE-OS (German Published Specification) 3,318,145, page 31, line 1 to page 32, line 13.
Other compounds which can be prepared by the process according to the invention are: 6-chloro-l-cyclopropyl7-(1,4-diazabicyclo[ 3.2.1] -oct-4-yl )-1,4-dihydro-4-oxo3- quinolinecarboxylic acid, l-cyclopropyl-7-(1,4-diazabicyclo [3.2.1] -oct-4-yl) -6-fluoro-1,4-dihydro-8-methyl-4oxo-3-quinolinecarboxylic acid, 7-(l,4-diazabicyclo[3.2.1] oct-4-yl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro4- oxo-3-quinolinecarboxylic acid, 7-(1,4-diazabicyclo[3.2.1] oct-4-yl) -6-f luoro-1- (4-f luorophenyl )-1,4-dihydro4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-(1,4diazabicyclo[3.2.1]oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo1,8-naphthyridine-3-carboxylic acid, 7- (1,4-diazabicyclo[3.2.1] oct-4-yl)-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, 7-(1,4-diazabicyclo[3.2.1] oct-4-yl)-l-ethyl-6-fluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 7-(l,4-diazabicyclo[3.2.1]oct4-yl)-9-fluoro-6,7-dihydro-5-methyl-l-oxo-lH,5H-benzo[i, j]quinoline-2-carboxylie acid, 7-(1,4-diazabicyclo[3.2.1] oct-4-yl) -6-f luoro-1- (4-f luorophenyl )-1,4-dihydro4-oxo-l, 8-naphthyridine-3-carboxylic acid, ethyl 1cyclopropyl-7 - (1,4-diazabicyclo [3.2.1] oct-4-yl) -6-f luoro14 1,4-dihydro-4-oxo-3-quinolinecarboxylate, 5-methyl-2-oxo1,3-dioxol-4-yl-methyl l-cyclopropyl-7-(1,4-diazabicyclo[3.2.1] oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, l-cyclopropyl-7-(1,4-diazabicyclo[3.1.1]hept-4-yl)-6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-(1,4-diazabicyclo[3.1.1] hept-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-7-(1,4diazabicyclo[ 3.1. l]hept-4-yl, -6-f luoro-1,4-dihydro-4-oxo3-quinolinecarboxylic acid, l-cyclopropyl-7- (1,4-diazabicyclo [3.1.1] hept-4-yl) -6-f luoro-1,4-dihydro-8-methyl-4oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-(1,4diazabicyclo[ 3.1.1 ]hept-4-yl) -6-f luoro-1,4-dihydro-4-oxol,8-naphthyridine-3-carboxylic acid, methyl l-cyclopropyl-7- ( 1,4-diazabicyclo[3.1.1]hept-4-yl)-6-fluoro-1,4dihydro-4-oxo-3-quinolinecarboxylate, l-cyclopropyl-6,8dif luoro-1,4-dihydro-7- (8-methyl-3,8-diazabicyclo[ 3.2.1]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid, 8-chloro-lcyclopropyl-6-f luoro-1,4-di hydro-7-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluor-1,4-dihydro-7-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-oxo-l,8-naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-l,4-dihydro-7-(3methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-4-oxo-3quinolinecarboxylic acid, l-cyclopropyl-6,8-dif luoro-1,4dihydro-7- (3-methyl-3,8-diazabicyclo [ 3.2.1] oct-8-yl) -4oxo-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl6- f luoro-1,4-dihydro-7- (3-methyl-3,8-diazabicyclo [ 3.2.1]oct-8-yl)-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7 - (2,5-diazabicyclo[2.2.1]hept-2-yl)-6-fluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl7- (2,5-diazabicyclo[2.2.1]hept-2-yl,-6,8-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid, 8-chloro-lcyclopropyl-7-(2,5-diazabicyclo[2.2.1]-hept-2-yl)-7fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1cyclopropyl-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-6f luoro-1,4 -dihydro- 4 -oxo-1,8 -naphthyridine-3-carboxy lie acid, l-cyclopropyl-6-f luoro-1,4-dihydro-7-[ 5- (2-hydroxyethyl ) -2,5-diazabicyclo [ 2.2.1] hept-2-yl) -4-oxo-3-quino15 linecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro4-OXO-7 - [ 5 - (2-oxopropyl) -2,5-diazabicyclo[ 2.2.1]hept-2yl)-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro1.4- dihydro-7-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2yl)-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6,8dif luoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-4-oxo-3-quinolinecarboxylic acid, 8-chloro-lcyclopropyl-6-f luoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-(8-ethyl-3,8-diazabicyclo[3.2.1]oct-3yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[8-(3oxobutyl )-3,8-diazabicyclo [3.2.1] oct-3-yl) -3-quinolinecarboxylic acid, 7-[8-(4-aminobenzyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-l-cyclopropyl-6-fluoro-1,4-dihydro-4oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-(2,5diazabicyclo[2.2.2]oct-2-yl)-6-fluoro-1,4-dihydro-4-oxo3-quinolinecarboxylic acid, l-cyclopropyl-7- (2,5-diazabicyclo [2.2.2] oct-2-yl) -6,8-dif luoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-7-(2,5diazabicyclo[2.2.2]oct-2-yl)-7-fluoro-1,4-dihydro-4-oxo3- quinolinecarboxylic acid, l-cyclopropyl-7- (2,5-diazabicyclo[2.2.2 ]oct-2-yl) -6-f luoro-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro1.4- dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) 4- oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6,8dif luoro-1,4 -dihydro-7- (5-methyl-2,5-diazabicyclo [2.2.2]oct-2-yl)-4-oxo-3-quinolinecarboxylic acid, 8-chloro-lcyclopropyl-6-f luoro-1,4-dihydro-7- (5-methyl-2,5-diazabicyclo[2.2.2 ] oct-2-yl) -4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-(3,9-diazabicyclo[3.3.1]non-3-yl)-6fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,1cyclopropyl-6-fluoro-1,4-dihydro-7-(7-hydroxy-3,9-diazabicyclo[3.3.1]non-3-yl) -4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-4-oxo-3-quinolinecarboxylic acid, 7-(5-allyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -1-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(516 propargyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -3-quinolinecarboxylie acid, l-cyclopropyl-7-(l,4-diazabicyclo[3.2.1 ]oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 322 °C, 1cyc lopropy 1-7- (1,4-diazabicyclo[ 3.2.1] oct-4-yl) -6-fluoro1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hemi embonate of melting point from 271°C, 8-chloro-l-cyclopropyl-7(1,4-diazabicyclo [3.2.1] oct-4-yl) -6-fluoro-1,4-dihydro4-oxo-3-quinolinecarboxylic acid hydrochloride hydrate of melting point 310°C, l-cyclopropyl-7-(1,4-diazabicyclo[3.2.1]oct-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 275-282°C, 1-cyclopropyl-7- (1,4-diazabicyclo [3.2.1 ] oct-4-yl )-1,4-dihydro6-nitro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 303-307°C, 1-cyclopropyl-7-(1,4-diazabicyclo[ 3.2.1]oct-4-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid hydrochloride of melting point >300®C, 7-(1,4-diazabicyclo[3.2.1]oct-4-yl)-1ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 308-312®C, 10-(1,4-diazabicyclo [3.2.1 ]oct-4-yl)-9-fluoro-2,3dihydro-3-methyl-7-oxo-7H-pyrido[ 1,2,3-de] [ 1,4 ]benzoxacine-6-carboxylic acid hydrochloride of melting point 355®C, 7-(1,4-diazabicyclo[ 3.2.1]oct-4-yl,-6,8-difluoro1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 310-314°C, 1-cyclopropyl-7 - (1,4-diazabicyclo[ 3.2. 1]oct-4-yl)-6fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylic acid of melting point 210-232°C.
The 7-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-8-nitro4-oxo-3-quinolinecarboxylic acid required for this is obtained via the following stages: a, 2,4-Dichloro-5-fluoro-3-nitro-benzoic acid ml of concentrated nitric acid are added dropwise to 34 ml of concentrated sulphuric acid while cooling with ice and stirring. 20.9 g of 2,4dichloro-5-fluorobenzoic acid are introduced in portions into this nitrating mixture, whereupon the temperature rises to 45 - 50®C. The mixture is then heated at 90 - 100°C for a further 3 hours, cooled to room temperature and poured onto 350 ml of icewater and the precipitate is filtered off with suction and washed with water. The moist crude product is dissolved in 30 ml of hot methanol and 150 ml of water are added to the solution.
The precipitate is filtered off with suction in the cold, washed with methanol/water and dried at 80°C in vacuo. 21.2 g of crude 2,4-dichloro-5-fluoro-3nitro-benzoic acid are obtained. The product is sufficiently pure for further reactions. A sample recrystallised from toluene/petroleum ether gives crystals of melting point 192°C. b) 2,4-Dichloro-5-fluoro-3-nitro-benzoyl chloride 106.6 g of 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are heated at the boiling point under reflux with 250 ml of thionyl chloride for 2 hours. The excess thionyl chloride is then distilled off under normal pressure and the residue is fractionated under a fine vacuum. 104.7 g of 2,4-dichloro-5fluoro-3-nitro-benzoyl chloride pass over at 110 115°C/0.08-0.09 mbar. When left to stand, crystals of melting point 35 to 37°C form. c) Ethyl (2,4-dichloro-5-fluoro-3-nitro-benzoyl) acetate 2.1 g of carbon tetrachloride are added to 10.1 g of magnesium filings in 21 ml of ethanol and, when the evolution of hydrogen has started, a mixture of 66.6 g of diethyl malonate, 40 ml of ethanol and 150 ml of toluene are added dropwise at 50 - 60°C. The mixture is subsequently stirred at this temperature for 1 hour and cooled to -5 to -10*C, and a solution of 109.2 g of 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride in 50 ml of toluene is slowly added dropwise. Thereafter, the mixture is stirred at 0°C for 1 hour, brought to room temperature overnight and warmed at 40 - 50*C for a further 2 hours. A mixture of 160 ml of water and 10.4 ml of concentrated sulphuric acid is added to the reaction mixture, while cooling with ice, and the organic phase is separated off. The aqueous phase is extracted with toluene, the combined organic extract is washed with saturated sodium chloride solution and dried with sodium sulphate and the solvent is stripped off. 144.5 g of diethyl (2,4-dichloro-5-fluoro-3-nitrobenzoyl)-malonate are obtained as a crude product. After addition of 200 ml of water and 0.6 g of 4toluenesulphonic acid, this is heated under reflux for 3 hours, the mixture is extracted with methylene chloride, the extract is dried with sodium sulphate and the solvent is distilled off in vacuo. 118 g of substituted benzoyl acetate are obtained as a crude product. This is sufficiently pure for the further reactions. d) 7 -Chloro-1 -eye lopropy 1- 6 -f luoro-1,4 -dihydro-8-nitro 4-oxo-3-quinolinecarboxylic acid O OOH Cl 244.8 g of ethyl (2,4-dichloro-5-fluoro-3-nitrobenzoyl)-acetate are heated at 150 - 160°C with 166 g of triethyl orthoformate and 185 g of acetic anhydride for 3 hours. The mixture is concentrated in vacuo to give 270 g of ethyl 2-(2,4-dichloro-5fluoro-3-nitro-benzoyl)-3-ethoxy-acrylate as an oily residue. .9 g of cyclopropylamine are added dropwise to 38 g of this intermediate stage in 80 ml of ethanol while cooling with ice and the mixture is stirred at 20°C for 1 hour. The product which has precipitated is filtered off with suction, after addition of 100 ml of water, and is washed with ethanol/H20 (1:1) and dried. 32.8 g of ethyl 2-(2,4-dichloro-5-fluoro-3nitro-benzoyl)-3-cyclopropylamino-acrylate of melting point 143 - 146°C are obtained. 3.1 g of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to 7.8 g of the abovementioned compound in 30 ml of anhydrous dioxane and the mixture is heated at 100°C for 4 hours. The solvent is distilled off in vacuo, the residue is taken up in methylene chloride/water, the methylene chloride phase is separated off and dried with sodium sulphate and the methylene chloride is distilled off. 7.2 g of ethyl 7-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-8-nitro4-oxo-3-quinolinecarboxylate are obtained as a crude product. After recrystallisation from acetonitrile, the pale brown crystals have a melting point of 174 - 175®C. Yield: 6 g. 7-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 205 - 214®C. l-Cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8diazabicyclo[3.2.1]oct-3-yl)-4-oxo-3-quinolinecarboxylic acid of melting point 273 - 278®C. l-Cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-l,4diazabicyclo[3.2.1]oct-4-yl)-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point >300°C. 1.1 g of ethyl 1-cyclopropy1-7-(1,4-diazabicyclo[3.2.1]oct-4-yl) -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 196-199®C. 7-(1,4-Diazabicyclo[3.2.1]oct-4-yl)-6,8-difluoro-1-(2,4difluorophenyl) -1,4 - dihydro-4-oxo-3-quinol inecar boxy lie acid hydrochloride of melting point 329-331®C. 7-(1,4-Diazabicyclo[3.2.1] oct-4-yl)-6,8-difluoro-1,4dihydro-l-methylamino-4-oxo-3-quinolinecarboxylic acid hydrochloride of melting point 300-305®C.
Other active compounds which can be prepared according to the invention are 6-chloro-7-[3-(4-chlorophenyl)-1piperazinyl]-l-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid, 6-chloro-l-cyclopropyl-8fluoro-7-[3- (4-fluorophenyl)-1-piperazinyl]-1,4-dihydro4-oxo-3-quinolinecarboxylic acid, 7-[3-(4-bromophenyl)1-piperazinyl]-6-chloro-1-cyclopropy1-8-fluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chloro-lcyclopropyl-8-f luoro-1,4-dihydr O-8- [3 - (4-methylphenyl) 1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 7-[3-(4biphenylyl) -1-piperazinyl ]-6-chloro-l-cyclopropyl-8fluoro-1,4-dihydro-4-oxo-3-guinolinecarboxylic ac id, 6- chloro-l-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4methoxyphenyl)-1-piperazinyl ]-4-oxo-3-quinolinecarboxylic acid, 6-chloro-1-eyelopropy1-8-fluoro-1,4-dihydro-7—[3— ( 4-hydroxyphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-( 3-phenyl-l-piperazinyl) -3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-6-fluoro-l,4dihydro-4-oxo-7-[(4-nitrophenyl)-1-piperazinyl]-3-quinolinecarboxylicacid, 8-chloro-l-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-[3-(4-piperidino-phenyl)-1-piperazinyl]3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-6f luoro-1,4-dihydro-4-oxo-7- [3-(3,4-dimethoxy-phenyl) -1piperazinyl]-3-quinolinecarboxylic acid, 8-chloro-lcyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4,5trimethoxy-phenyl) -l-piperazinyl]-3-quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo7- [ 3- (2-thienyl) -1-piperazinyl ] -3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo7-piperidino-3-quinolinecarboxylic acid, 7-(3-amino-lpyrrolidinyl) -8-chloro-l-cyclopropyl-6-f luoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid, 6,8-dichlorol-cyclopropyl-l,4-dihydro-4-oxo-7-(1-piperazinyl)-3quinolinecarboxylicacid, 7-(4-acetyl-1-piperazinyl)-6,8dichloro-l-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-(4-acetyl-l-piperazinyl)-6-chloro-lcyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 6-chloro-l-cyclopropyl-8-fluoro-1,4dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 6-chloro-l-cyclopropyl-8-fluoro-1,4dihydro-4-oxo-7-morpholino-3-quinolinecarboxylic acid, 6-chloro-l-cyclopropyl-8-f luoro-1,4-dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxylic acid and 8-chloro-lcyclopropyl-7- (4-ethy 1-3-oxo- 1-piperazinyl) -6-f luoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid.
According to the invention, the free carboxylic acids are as a rule initially obtained and can then be converted into salts, esters, prodrugs and the like by known methods.
The compounds which can especially preferably be prepared by the process according to the invention are ciprofloxacin and the corresponding 1-ethyl-piperazine derivative.
Examples Example 1 606 parts by weight of l-cyclopropyl-7-chloro-6-fluoro1.4- dihydro-4-oxo-3-quinolinecarboxylic acid and 575 parts by weight of piperazine are heated at 150 to 160°C in a suitable reactor for 30 minutes. The reaction mixture is diluted with water, l-cyclopropyl-6-fluoro1.4- dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid being obtained in a yield of 71% with a content of about 98%.
Example 2 133 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid and 129 parts by weight of piperazine are reacted as in Example 1. l-Cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-quinolinecarboxylic acid is obtained in a yield of 70% with a content of 98.5%.
Example 3 143 parts by weight of piperazine are heated at 140 to 150®C. 94 parts by weight of l-cyclopropyl-7-chloro-6fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are metered into this melt in the course of 20 minutes. The mixture is cooled to 100°C and water is added. 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3quinolinecarboxylic acid thereby crystallises out in a yield of 78% with a purity of 97.2%.
Example 4 150 parts by weight of piperazine are reacted with 102 parts by weight of l-cyclopropyl-6,7-difluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid as in Example 3. l-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid is obtained in a yield of 76% with a purity of 97.5%.
Example 5 parts by weight of l-cyclopropyl-7-chloro-6-fluoro10 l,4-dihydro-4-oxo-3-quinolinecarboxylic acid are added to 122 parts by weight of 1-ethyl-piperazine, which has been heated to 140 to 150°C, in the course of 30 minutes. After cooling to 100eC, water is added, l-cyclopropyl-6f luoro-1,4-dihydro-4-oxo-7- (4-ethyl-1-piperaz inyl) -315 quinolinecarboxylic acid crystallising out in a yield of 76% and a purity of 98.2%.
Claims (8)
1. Process for the preparation of compounds of the formula (I) Ri 5 in which R 1 represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
2. -hydroxyethyl, 2-fluoroethyl, 4-fluorophenyl or 2,4-difluorophenyl, R 2 represents CN or COOR 2 ', where R 2 ' denotes 10 hydrogen or C x -C A -alkyl, R 3 represents a cyclic amino group, such as N~, Ν ^Λ’ I_I · LJ V JI wherein R* represents hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyl or 2-oxopropyl, R 3 represents hydrogen or methyl, R 8 represents hydrogen or alkyl with 1 to 4 carbon atoms, R 7 represents hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxyl or hydroxymethyl, R 8 represents hydrogen, methyl, ethyl or chlorine, X represents halogen, in particular fluorine and chlorine, and A represents C-R 11 , wherein R 11 represents hydrogen or halogen, characterised in that compounds of the formula (II) (II) wherein R 1 , R 2 , A and X have the abovementioned meaning, and Y represents halogen, in particular fluorine and chlorine, are reacted with solvent-free amines of the formulae I_| . wherein 5 R*, R 3 , R®, R 4 * * 7 , R® and R u have the abovementioned meaning, dispensing with the use of solvents with the pure amines, in a ratio of 1:2 to 1:10 at temperatures between 20®C and 200®C. 10 2. Process according to Claim 1, characterised in that l-cyclopropyl-7-chloro-6-f luoro-1,4-dihydro-4-oxo3-quinolinecarboxylic acid is reacted with piperazine without a solvent at 120° to 160°C.
3. Process according to Claims 1 and 2, characterised 15 in that 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4oxo-3-quinolinecarboxylic acid is reacted with piperazine without a solvent at 120*C to 160°C.
4. Process according to Claims 1 and 2, characterised in that l-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro4-oxo-3-quinolinecarboxylic acid is metered into piperazine which has been heated to 140°C to 150°C, the mixture is cooled, water is added and the reaction product is crystallised out. -
5. Process according to Claim 4, characterised in that l-cyclopropyl-6,7-dif luoro-1,4-dihydro-4-oxo-3» 5 guinolinecarboxylic acid is used as the starting substance.
6. Process according to Claim 1, characterised in that l-cyclopropyl-7-chloro-6-f luoro-1,4-dihydro-4-oxo3-quinolinecarboxylic acid is reacted with 1-ethyl10 piperazine, 2-hydroxyethylpiperazine or 1-methylpiperazine.
7. A process according to Claim 1 for the preparation of a compound of the formula (I) given and defined in Claim 1, substantially as hereinbefore described with 15 particular reference to the accompanying Examples.
8. A compound of the formula (I) given and defined in Claim 1, whenever prepared by a process claimed in a preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863641312 DE3641312A1 (en) | 1986-12-03 | 1986-12-03 | METHOD FOR PRODUCING CHINOLINE CARBONIC ACIDS |
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| IE873279L IE873279L (en) | 1988-06-03 |
| IE64261B1 true IE64261B1 (en) | 1995-07-26 |
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| IE327987A IE64261B1 (en) | 1986-12-03 | 1987-12-02 | Process for the preparation of quinolinecarboxylic acids |
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| Country | Link |
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| EP (1) | EP0274033B1 (en) |
| JP (1) | JPS63145268A (en) |
| KR (1) | KR970005191B1 (en) |
| CN (1) | CN87107230A (en) |
| AT (1) | ATE73446T1 (en) |
| AU (1) | AU593961B2 (en) |
| CS (1) | CS270577B2 (en) |
| DD (1) | DD270904A5 (en) |
| DE (2) | DE3641312A1 (en) |
| DK (1) | DK174929B1 (en) |
| ES (1) | ES2038156T3 (en) |
| FI (1) | FI875289A7 (en) |
| GR (1) | GR3004301T3 (en) |
| HU (1) | HU199823B (en) |
| IE (1) | IE64261B1 (en) |
| IL (1) | IL84627A (en) |
| NO (1) | NO174199C (en) |
| NZ (1) | NZ222736A (en) |
| PH (1) | PH24489A (en) |
| PL (1) | PL158614B1 (en) |
| PT (1) | PT86252B (en) |
| SU (1) | SU1482526A3 (en) |
| UA (1) | UA8017A1 (en) |
| YU (1) | YU45049B (en) |
| ZA (1) | ZA879040B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN166416B (en) * | 1985-09-18 | 1990-05-05 | Pfizer | |
| AU5449590A (en) * | 1989-04-28 | 1990-11-29 | Daiichi Pharmaceutical Co., Ltd. | Anti-hiv drug |
| US5385913A (en) * | 1989-10-06 | 1995-01-31 | Pfizer Inc. | 1,4-dihydro-4-oxo-3-quinoline derivatives as selectively toxic mammalian antibacterial agents |
| FI921475A0 (en) * | 1989-10-06 | 1992-04-03 | Pfizer | 1,4-DIHYDRO-4-OXO-3-QUINOL DERIVATIVES WITH SELECTIVE TOXIC ANTIBACTERIA AEMENN HOS DAEGGDJUR. |
| JP2613139B2 (en) * | 1990-07-19 | 1997-05-21 | エスエス製薬 株式会社 | Quinolonecarboxylic acid derivatives |
| ES2050613B1 (en) * | 1992-10-16 | 1996-03-16 | Iteve S A | NEW PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF THE ACID 1-CICLOPROPIL-3-QUINOLINCARBOXILICO. |
| US6034100A (en) * | 1993-03-10 | 2000-03-07 | Otsuka Pharmaceutical Co., Ltd. | Method for inhibiting cytokine secretion |
| WO1998042341A1 (en) * | 1997-03-25 | 1998-10-01 | Sankyo Company, Limited | Anti-fiv agent |
| KR100454750B1 (en) * | 2002-06-20 | 2004-11-03 | 삼성에스디아이 주식회사 | Blue light-emitting compound for organic electroluminescent device and organic electroluminescent device using the same |
| JP4639149B2 (en) | 2003-09-10 | 2011-02-23 | 杏林製薬株式会社 | 7- (4-Substituted-3-cyclopropylaminomethyl-1-pyrrolidinyl) quinolonecarboxylic acid derivatives |
| CA2688008A1 (en) | 2007-05-24 | 2008-11-27 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
| CN101671302B (en) * | 2008-12-30 | 2011-03-30 | 广东海康兽药有限公司 | Production process of enrofloxacin antibacterial drug for fowl and livestock |
| CN101899044B (en) * | 2010-08-16 | 2012-07-18 | 常州市勇毅生物药业有限公司 | Method for synthesizing Gemifloxacin main ring compound |
| CN113912540A (en) * | 2021-12-15 | 2022-01-11 | 山东国邦药业有限公司 | Synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5365887A (en) * | 1976-11-22 | 1978-06-12 | Kyorin Seiyaku Kk | Substituted quinoline*arboxylate and process for preparing same |
| DE2656574A1 (en) * | 1976-12-10 | 1978-06-15 | Schering Ag | 1-Alkyl-4-oxo-1,4-di:hydro-1,6-naphthyridine-3-carboxylic acid derivs. - with antibacterial activity esp. effective in the urinary tract |
| JPS53141286A (en) * | 1977-05-16 | 1978-12-08 | Kyorin Seiyaku Kk | Novel substituted quinolinecarboxylic acid |
| JPS5845426B2 (en) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | Substituted quinoline carboxylic acid derivatives |
| DE3142854A1 (en) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| DE3318145A1 (en) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| IL74244A (en) * | 1984-02-17 | 1988-06-30 | Warner Lambert Co | Quinoline derivatives,their preparation and pharmaceutical compositions containing them |
| DE3420743A1 (en) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-6,8-DIHALOGEN-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
| JPS61205258A (en) * | 1985-03-08 | 1986-09-11 | Kyorin Pharmaceut Co Ltd | Quinolonecarboxylic acid derivative and production thereof |
-
1986
- 1986-12-03 DE DE19863641312 patent/DE3641312A1/en not_active Withdrawn
-
1987
- 1987-11-17 NO NO874788A patent/NO174199C/en not_active IP Right Cessation
- 1987-11-20 DE DE8787117130T patent/DE3777370D1/en not_active Expired - Lifetime
- 1987-11-20 AT AT87117130T patent/ATE73446T1/en not_active IP Right Cessation
- 1987-11-20 EP EP87117130A patent/EP0274033B1/en not_active Expired - Lifetime
- 1987-11-20 ES ES198787117130T patent/ES2038156T3/en not_active Expired - Lifetime
- 1987-11-26 YU YU2156/87A patent/YU45049B/en unknown
- 1987-11-27 IL IL84627A patent/IL84627A/en not_active IP Right Cessation
- 1987-11-30 NZ NZ222736A patent/NZ222736A/en unknown
- 1987-11-30 CS CS878688A patent/CS270577B2/en not_active IP Right Cessation
- 1987-12-01 DD DD87309727A patent/DD270904A5/en not_active IP Right Cessation
- 1987-12-01 JP JP62301624A patent/JPS63145268A/en active Pending
- 1987-12-01 FI FI875289A patent/FI875289A7/en not_active Application Discontinuation
- 1987-12-02 IE IE327987A patent/IE64261B1/en not_active IP Right Cessation
- 1987-12-02 HU HU875424A patent/HU199823B/en unknown
- 1987-12-02 CN CN198787107230A patent/CN87107230A/en active Pending
- 1987-12-02 KR KR1019870013716A patent/KR970005191B1/en not_active Expired - Fee Related
- 1987-12-02 SU SU87A patent/SU1482526A3/en active
- 1987-12-02 PH PH36159A patent/PH24489A/en unknown
- 1987-12-02 ZA ZA879040A patent/ZA879040B/en unknown
- 1987-12-02 DK DK198706331A patent/DK174929B1/en not_active IP Right Cessation
- 1987-12-02 UA UA4203762A patent/UA8017A1/en unknown
- 1987-12-02 PL PL1987269185A patent/PL158614B1/en unknown
- 1987-12-02 PT PT86252A patent/PT86252B/en unknown
- 1987-12-03 AU AU82177/87A patent/AU593961B2/en not_active Expired
-
1992
- 1992-04-08 GR GR920400663T patent/GR3004301T3/el unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |