AU593961B2 - Process for the preparation of quinoline carboxylic acids - Google Patents
Process for the preparation of quinoline carboxylic acids Download PDFInfo
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- AU593961B2 AU593961B2 AU82177/87A AU8217787A AU593961B2 AU 593961 B2 AU593961 B2 AU 593961B2 AU 82177/87 A AU82177/87 A AU 82177/87A AU 8217787 A AU8217787 A AU 8217787A AU 593961 B2 AU593961 B2 AU 593961B2
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- dihydro
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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
-
- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
A process for the preparation of quinolinecarboxylic acids of the formula (I) <IMAGE> 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
1-P1198/JGS/SW/4736T/9
AUSTRALIA
PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Application Number: Lodged: Complete Specification Lodged: Accepted: Published: -49.
gad -Priority: ,,Related Art: o TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: SActual Inventor: Address for Service: BAYER AKTIENGESELLSCHAFT D-5090 Leverkusen, Bayerwerk, Germany Michael Preiss ARTHUR S. CAVE CO.
Patent Trade Mark Attorneys Goldfields House 1 Alfred Street SYDNEY N.S.W. 2000
AUSTRALIA
Complete Specification for the invention entitled "AN FTMPRVBD- "PROCESS e fEPAR\TroN OF Ocn irGlINE CRF o xLUCe. FC S The following statement is a including the best method of full scription of this invention performing it known to me:- ASC 49 The invention relates to a new process for the preparation of quinolinecarboxylic 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.
The invention relates to a process for the preparation of compounds of the formula (I) 0 X 2
I)
o0 10 o 0 00 o 0 0 000 o o 0 00 O 0 0 0 0 0. 15 0 in which 1 R represents methyl, ethyl, propyl, isopropyL, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyL, methoxy, amino, methylami0io, dimethylamino, ethylamino, phenyl, 4-fluorophenyl or 2,4-difluorophenyl, 2 2' R represents CN or COOR wherein R denotes hydrogen, C 1
-C
4 -alkyl or methyl-2-oxo-1,3-dioxol-4-yl)-methyl, or
R
2 represents CON(C 1
-C
4 -alkyl) 2 R represents a cyclic amino group, such as 0 1 I a a i 1
CN-
S N-, H4-1 N-, R4-N SN-, R6 R4-N N-, R4-NMN-, 0 N-, Le A 24 862 Foreign countries 1 t N\
NL\N-
r r L N"1 wherein o o 099 0 *m 15 0 4 R represents hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFCI 2
CFCL
2 -S0 2
CH
3 0-CO-S-, benzyl, 4-aminobenzyl or
CH
3 Y CH 2 R represents hydrogen or methyl, R represents hydrogen, alkyl with 1 to 4 carbon atoms, phenyl or benzyLoxymethyl, R represents hydrogen, amino, methyLamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethy!, dimethylaminomethyl, hydroxyL or hydroxymethyl and R represents hydrogen, methyl, ethyl or chlorine, or R represents the group
R
9
N-
R
10 in which R and R 0 are identical or different and represent hydrogen or a branched or unbranched alkyl, alkenyl or alkynyl radical which has 1 to 12 carbon atoms and can optionally be substituted by hydroxyl groups, alkoxy, alkylmercapto or dialkylamino groups with 1 to 3 carbon atoms in each alkyl radical, the nitrile group or the alkoxycarbonyl group with 1 to 4 carbon atoms in Le A 24 862 2 20 8 o i I o the alcohol part, or an aryl or heteroaryl radical, or furthermore denotes C 3
-C
6 -cycloalkyl, X represents halogen, in particular fluorine or chlorine, or nitro or Ci-C 4 -alkylsulphonyl or
C
1
-C
4 -alkyLsulphonyloxy and A represents N or C-R, wherein 11 R represents hydrogen, halogen, such as fluorine, bromine or chlorine, methyl or nitro and R together with R can form a bridge of the structure
-O-CH
2
-CH-CH
3
-S-CH
2
-CH-CH
3 or -CH 2
-CH
2
-CH-CH
3 which is characterized in that compounds of the formula 00 15 (II) 000 a 0 0 02 e
II
4 1 t° 1
R
1 wherein 11 2 R R A and X have the abovementioned meaning and Y represents halogen, in particular fluorine or chlorine, or nitro or C 1
-C
4 -alkylsulphonyl or
C
1
-C
4 -alkylsulphonyloxy, are reacted with amines of the formulae R7
R
6 SN-H, C N-H, HO-C N-H, R4-N N-H, Le A 24 862 3 O N-H, S N-H, R 4 -N N-H, R 4 -N N-H, N N-H ~N-H N N-H, or R 9 g
N-H
wherein 4 5 6 7 8 9 10 11
R
4
R
5
R
6
R
7
R
8 R, R and R 1 have 00 t the abovementioned meaning, o without solvents, at temperatures between 20 0 C and 200 0 C, if 0 #appropriate under pressure, preferably under 1 200 bar.
o 4 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. The 0@ I *0 compounds of the formula (II) are reacted with the amines by metering them into the liquid amines.
0 It is to be described as decidedly surprising that (a) the reaction of (II) with the amines proceeds at a very much S 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 in spite of the excess of amine no increased substitution of X takes place.
I 4 0205g/CB 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 a 0 4o 0 0 a 4 (I 0 04 I I 00 4a L-l u*b 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 1:1 to 1:50, preferably 1:2 to 1:10 and especially preferably 1:3 to 1:5. The reaction temperature is to 200 0 C and the range is preferably 80 to 180 0
C,
especially preferably 120 to 160 0
C.
Amines which are preferably used in the process according to the invention are those of the formula
R
9
N.
NH
R
10 wherein 9 1 R and Ri are identical or different and 15 represent hydrogen or a branched or unbranched 4 o alkyl, alkenyl or alkynyL radical which has 1 to 12 carbon atoms and can optionalLy be substituted S; by hydroxyl groups, aLkoxy, alkyLmercapto or dialkylamino groups with 1 to 3 carbon atoms in each alkyl radicaL, the nitrile group, an alkoxycarbonyl group with 1 to 4 carbon atoms in the S't alcohol part or an aryl or heteroaryL radical, or furthermore denote C 3
-C
6 -cycloaky.
Amines which are also particularly preferred for the process according to the invention are cyclic amines, such as morpholine, piperidine, thiomorpholine, pyrroLidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyL)-piperazine, N-formylpiperazine, 2methyLpiperazine, 1,2-dimethylpiperazine, cis- and trans- 2,5-dimethyLpiperazine, cis- and trans-2,6-dimethylpiperazine, 2-ethyLpiperazine, 2-propypiperazine, 2isopropylpiperazine, 2-isobutylpiperazine, 2-piperazinone, 1-methyl-2-piperazinone, 1-ethyl-2-piperazinone, Le A 24 862 2-cyclohexytpiperazime, 2-phenyLpiperazine, 2(-hoo phenyl )-piperazine, 2-C4-fLuorophenyl)-piperazine, 2-C4bromophenyL)-piperazine, 2-C4-methyLphenyL )-piperazine, 2-C4-biphenyL)-piperazine, 2-(4-methoxyphenyL )-piperazime, 2-C4-benzyLoxyphenyl )-piperazine, 2-(4-hydroxyphenyl piperazine, 2-(4-nitrophenyL )-piperazime, 2-(3--nitrophenyl )-piperazine, 2-(4-piperidinophenyL )-piperazime, 2-(3,4-dimethoxyphenyL )-piperazine, 2-(3,4,5-trinjethoxyphenyL )-piperazine, 2-(3,4-dimethoxy-6-nethyL )-piperazime, 2-(2-thienyt)-piperazine and 3-aminopyrroLidine and 3aminomethyLpyrroLidine.
The quinoLinecarboxyLic acids of the formula (II) are prepared as described below: Example A 6-Ch Loro-1-cycLopropyL-7,8-di fLuoro-1 ,4-d ihydro-4-oxo-3qu inoIi necarboxyL ic acid 00 C 1 OO 0 FlOO It 4 (015.75 (0.65 mof of magnesi4-rifum fiingsy a~ur stirred in 40 mlr ofuethno andr 2n mLeoft caron sttra i whlrd and after 50 o uther recto hasr startoed,g (0.64 25 mL of ice-wthel manat in. 80 ml cofcentaoed 250 ml of t8 un6r2deddowssa 5 o60 h 446 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 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 of ethyl (5-chloro-2,3,4-trifluoro-benzoyl)-acetate of boiling point 1100/0.9 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 o °oo 1600 with 95 g of acetic anhydride for 2 hours and the omixture is then concentrated at 120 to 1300 under normal o ae 20 pressure and then under a high vacuum. 115 g (92% of 0 0 «0 theory) of ethyl 2-(5-chLoro-2,3,4-trifLuoro-benzoyl)-3o oo Sethoxy-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 S 25 of ethanol, while cooling with ice, and the mixture is 0 C4 ,I 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 of ethyl 2-(5-chLorc-2,3,4-triiLuorobenzoyl)-3-cyclopropyLamino-acrylate of melting point 71 to 730 are obtained. According to the 1 H-NMR spectrum, a cis-trans mixture is present.
47 g (0.14 mol) of this compound are heated at 160 to 1700 in 230 ml of dimethylformamide with 9.7 g (0.23 mol) of sodium fluoride for 2 hours. The reaction Le A 24 862 7 mixture is poured into 400 mL of ice-water and the precipitate is filtered off with suction, washed with water and dried. 44 g of ethyl -6-chLoro-1-cycLopropyL- 7,8-difLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyLate of melting point 169 to 1720 are isolated.
33 ml of concentrated sulphuric acid are added to 44 g (0.13 mol) of the quinoLonecarboxylic acid ester in 300 ml of glacial acetic acid and 179 ml of water and the mixture is heated at 150 0 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-lcyc Iop ropy 1-7, 8-d ifLuo ro-1, 4-dihyd ro-4-oxo-3-qu inoLimecarboxyLic acid of melting point 200 to 204 0 are iso- L at edl.
Example B 8-ChLoro-l-cycLopropyL-6,7-difLuoro-1,4-dihydro-4-oxo-3- 0 o quinolinecarboxylic acid 4C 1 3Cor-,5-trfur-ezy 00Krdei rece an4gu~ toEapeA h4rcs asn thog the Io~wn stgs 9ty 94c~r-,,5ti~o--enoL-c t as th *no 9yed 42,m9igpit7-!) ty -3 -Choro-2,4,5-trifLuoro-benzoy l -thx-chridae isud yi~:9oLethyL 2(3-choro-2,4,5-tr ifLuoro-enyL-ctae sth benzyL )-3-cycLopropyL-aminoacryLate (yield: 67%, melting point 78-800), ethyl 8-chLoro-1-cycLopropyL-6.7-difLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyLate (yield: 85%, melting point 154-1570) and 8-chLoro-1-cycLo- Le A 24 862 -8p ropy L-6,7-d if Iuoro-1, 4-dihydro-4-oxo-3-qu inoLinecar boxyLic acid (yield: 97.6%, meLting point 189-1920).
Example C 6,8-0 ichLoro-1-cycopropy-7-fuoro-1-dihydro. oo..3 quinoLinecarboxyLic acid 0 Cl CO
FX
ichLoro-2,4-difLuoro-benzoyL fluoride is reacted analogously to Example A, the process passing through the followiing stages: ethyl (3,S-dichloro-2,4-difLuoro-benzoyL )-acetate (yield: 43%, boiLing point 133 0 /2.5 mm Hg), ethyl 2-(3,5-dichLoro- £-,4-difL--r)ro-benzoyL )-3-ethoxy-acryLate (crude yield: 91% @9oil), ethyl 2 3 ,5-dichLoro-2,4-difLuoro-benzoyL)-3-cy-clopropyl-aminoacryLate (yield: 96%, melting point 71-740), ethyl 6,8-dichLoro-1-cyc LopropyL--7-fLuoro-1,4-dihydro-4-oxo- 09, 3 -quinoLinecarboxyLate (yield: 97%, melting point 215-2170, with decomposition) and 6 8 -""chLoro-1-cycLopropyL-7fLuoro'-1,4-dihydro-4-oxo-4-quinoL ine-carboxyL ic acid (yield: 93%, melting point 204-2060).
999~20 Other quinoLinecarboxyLic acids, in particular cycLopropyL-6,7,8-tri fLuoro-1,4.-dihydro-4-oxo-3-quino- LinecarboxyLic acids, can be prepared in accordance with the following equation: Le A 24 862 -9- I I
F??F
F
(1) COOC
*CH
2 COOC2
H
Mg (OEt) 2 (2) C OOC, *0 0 000 00 0 000 00004*
I
00 4 0 0 I 0 00 04 4 00 00 0 001 0 44 04 4 I 4.4 0 I f I WF
CH
F HN
'OOH
-4 (7) (II) Le A 24 862 10
I
According to this equation, diethyl malonate (2) is acylated with 2,3,4,5-tetrafluorobenzoy chloride (1) in the presence of magnesium ethylate to give the aroylmalonate (Organicum, 3rd edition 1964, page 438).
Instead of 2,3,4,5-tetrafluorobenzoy fluoride can also be used.
Partial hydrolysis and decarboxylation of in an aqueous medium with catalytic amounts of sulphuric acid or p-toLuenesuphonic acid gives a good yield of the ethyl aroylacetate which is converted into ethyl 2-(2,3,4,5-tetrafluorobenzoy)-3-ethoxy-acryLate with triethyl o-formate/acetic anhydride. The reaction of with cyclopropylamine in a soLvent, such as, for example, methylene chloride, alcohoL .iCLoroform, cyclohexane or toluene, gives the desired intermediate product in a slightly exothermic reaction.
The cyclization reaction is carried 00 0 0 0 0. out in a temperature range of about 60 to 3000C, preferably 80 to 1800C.
20 DiLuents which can be used are dioxane, dimethylsulphoxide, N-methylpyrrolidone, sulpholane, hexamethylphosphoric acid triamide and, preferably, N,N-dimethylformamide.
Possible acid-binding agents for this reaction :0 25 stage are potasium tert.-butanolate, butyl-lithium, 0 alithium-phenyl, 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 mot of base.
The ester hydrolysis of which takes place in the last step under basic or acid conditions leads to 1cyclopropy1-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quino- Linecarboxylic acid.
The 2,3,4,5-tetrafluorobenzoy chloride used as the starting material for this synthesis route was Le A 24 862 11 1~ i obtained in the customary manner from 2,3,4,5-tetraftuoro-benzoic acid, which is known from the Literature Yakobson, V.N. Odinokov and N.N. Vorozhtsov Jr., Zh. Obsh. Khim. 36, 139 (1966)), with thionyL chloridle.
It has a boiling point of 75-80 0 C/17 mbar. 2,3,4,5- Tetrafluorobenzoyl fluoridle has a boiling point of 46 to 47 0 C/20 mbar(n 20 '1.4375)..
Other quinolinecarboxylic acids can be prepared as follows: q~* 1,~
$E
o I E 0 00 U 01 U I I
EU
I U
IOU
0 01 Le A 24 862 12 0
S+~C
2 H MgOEt -cooc H Cl! 1 2 1 NOCH IV VII VIII 0
II
0C 2
H
0 It F -~cCH2C0C 2 L>-HH2 *2 42 4 429 24 44 2 14~ 42-2044 4 1 49 2 4 9 0 05 2 0' 2 0 0 24 2 2 4 224 22 0 0 2 0 00 0
CH!
HN,'-
00OR 1 Le A 24 862 13 11 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 exhyl 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 cyclization reaction VI II (R1 alkyl) is carried out in a temperature range from about 600 to 280°C, preferably 800 to 1800C.
i Diluents which can be used are dioxane, dimethyLsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethyl- 20 phosphoric acid triamide and, preferably, N,N-dimethylformamide.
Possible acid-binding agents 1'ar this reaction Sstage are potassium t-butanolate, butyllithium, phenyllithium, phenylmagnesium bromide, sodium ethylate and, S 25 particularly preferably, sodium hydride or potassium carbonate. it may be advantageous to use an excess of 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 3fluoro-4,6-dichlorotoluene XI required for the preparation of IV are known from European Patent A2-0,078,362.
Preferred compounds which can be prepared by the process according to the invention are described in European Patent A2-0,078,362, page 4, lines 10 to 16, European Patent A-i 0,049,355, Examples 1 to 19, DE-OS Le A 24 862 14 (German Published Specification) 3,420,743, page 35, Line 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-1-cycLopropyL-7-(1,4-diazabicycLo[3.2.1)-oct-4-yL)-1,4-dihydro- 4-oxo-3-quinol inecarboxylic acid, 1-cycLopropyL-7-C1,4diazabicycLo[3.2.1]-oct-4-yL)-6-fLuoro-1,4-dihydro-8methyL-4-oxo-3-quinoL inecarboxyLic acid, 7-(1,4-diazabicycLoE3.2. 1)oct-4-yL)-6-fLuoro-1-(2-fLuoroethyL)-1,4dihydro-4-oxo-3-quinoL inecarboxyL ic acid, 7-C 1,4-diazabicycLo[3.2.1]oct-4-yL)-6-fLuoro-l-(4-fLuorophenyL)-1,4dihydro-4-oxo-3-quinoL inecarboxyLic acid, 1-cycLopropyL- 7-(1,4-diazabicycto[3.2. ljoct-4-yL)--6-fLuoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxyLic acid, 7-C 1,4-diazabicycLo[3.2.1]oct-4-yL)-1-ethyL-6-fLuoro-1,4-dihydro-4oxo-1,8-naphthyridine-3-carboxyLic acid, 7-(1,4-diaza- 04 bicycLoE3.2. 1]oct-4-yL )-1-ethyL-6-fLuoro-1,4-dihydro-4o# 20 oxo-3-quinoLinecarboxyLic acid, 7-C1,4-diazabicycLo- 1]oct-4-yL)-9-fLuoro-6,7-dihydro-5-methyL-1-oxo-lH, 0 00 5H-benzo~i,jlquinoline-2-carboxyLic acid, 7-(1,4-diazabicycLoEL.2. 1]oct-4-yLJ-6-fLuoro-1-(4-fLuorophenyL)-1,4dihydro-4-oxo-1,8-naphthyridine-3-carboxyL ic acid, ethyL -ccoopl7C4-diazabicycLo[3.2. 1]oct-4-yL)-6- 4 4 fLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxylate, methyL-2-oxo-1,3-dioxoL-4-yL-methyL 1-cyclopropyL-7-( diazabicycLo[3.2. 1]oct-4-yI.)-6-fLuoro-1,4-dihydro-4-oxo- 3-quinoL inecarboxyLate, 1-cyct.opropy1-7-C 1,4-diazabicycLoE3. 1. 1)hept-4-yL )-6-fLuoro-1,4-dihydro-4-oxo-3quinoL inecarboxyLic acid, 1-cycLopropyL-7-( 1,4-diazabicycLoE3.1.1)hept-4-yL)-6,8-difLuoro-1,4-dihydro-4-oxo-3- ,uinoL inecarboxyLic acid, 8-chLoro-1-cycLopropyL-7-( 1,4diazabicycLo[3.1.llhept-4-yL)-6-fLuoro-1,4-dihydro-4-oxo- 3-quinoL inecarboxyL ic acid, 1-cycLopropyL-7-C 1,4-diazabicycLo[3.1.llhept-4-yL)-6-fLuoro-1,4-dihydro-8-methyL- Le A 24 862 15 4 -oxo-3-quinot inecarboxyl ic acid, 1-cycLopropyl-7-( 1,4diazabicyco3.1.]hept4yL-6-f~uooro-1,-dihyo..4..oxol, 8 -naphthyridine-3-carboxyL ic acid, methyl 1-cycLopropyL- 7 -(,4-diazabicyc31Lo[e.1..4....4yL.6-fLuoro-14dihydro-4-oxo-3-quinoL inecarboxyLate, 1-cycLopropyL-6,8difLuoro-1,4-dihydro-7-(8-methyI.-3,8-diazabicycLo[3.2.1)oct- 3 -yL)-4-oxo-3-quinoL inecarboxyl ic acid, 8-chLorocycLopropyL-6-fLuoro-1,4-dihydro-7-...methy-3,8diazabicycLoE3.
2 .lloct-3-yl)-4-oxo-3-quinoL inecarboxyLic acid, l-cycLopropyL- 6 -fLuoro-1,4-dihydro-7-(8methyL38di azabicycLo[ 3 .2.lloct-3-yL)-4-oxo-1,8-naphthyridine3 carboxyL ic acid, 1-cyc LopropyL-6-fLuoro-1,4-dihydro-7quinoL inecarboxyL ic acid, 1-cycLopropyL-6,8-difLuor-o-1,4dihydro-7-(3-methyL-3,8-diazabicycLoE3.2. lloct-8-yL oxo-3-quinoLinecarboxyL ic acid, 8 -chLoro-l-cycLopropyL- 6 -fLuoro-1,4-dihydro-7-(3-methyL-3,8-diazabicycLo[3.2,..3 oct- 8 -yL)- 4 -oxo-3-quinoLinecarboxyLic acid, 1-cycLopropyL-7-(2,5-diazabicycLo[?..lhept-2-yL )-6-fLuoro-1,4dihydro-4-oxo-3-quinoL inecarboxyL ic acid, 1-cycLopropyL- 7-(2,5-diazabicycLo[2.2. llhept-?-yL )-6,8-difLuoro-1,4- 00 dihydro-4-oxo-3-quinoLinecarboxyLic acid, 8-chLoro-1cycLopropyL-7-(2,5-diazabicycLo[2.2. 1J-hept-2-yL fLuoro-1,.4-dihydro-4-oxo-3-quinoL inecarboxyL ic acid, 1cylpoy-7-(2,5-diazabicyc~oE2..Jhept-2-yL).6- 06.fLuoro-l, 4 -dihydro-4-oxo-1,8-naphthyridine3carboxyL ic acid, 1-cycLopropyL-6-ftuoro-1,4-dihydro-7-[5(..hydroxy.
0 0 I Linecarboxyl ic acid, l-cycLopropyL-6--fLuoro-1,4-dihydro- 0 0 u030 4-oxo-7-E5-(2-oxopropyL )-2,5-diazabicycLoE2.2. 1]hept-2y LI-3-quinoLinecarboxyLic acid, l-cycLopropyL-6-fLuoro- 1,4-dihydro-7-(5-methyL-2,5-diazabicycLo[2.2.l]hept-2yL )-4-oxo-3-quinoL inecarboxyt ic acid, 1-cyctopropyL-6,8difLuoro-1,4-dihydro-7-(5-methyL-2,5-diazabicycLoE2.2.1>hept- 2 -yL)-4-oxo-3-quinoLinecarboxyLic acid, 8-chLoro-1cyctopropyL-6-fLuoro-1,4-dihydro-7-(5-methy-2,5-diaza.
Le A 24 862 16 bicycto[2.2.l)hept-2-yt)-4-oxo-3-quinotinecarboxyLic acid, 1-cycLopropyL-7-C8-ethyL-3,8-diazabicycLo[3.2. 1)oct-3-yL)-6-fLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxy- I ic acid, 1-cycLopropyL-6-fLuoro-1,4-dihydro-4-oxo-7-E8- (3-oxobutyL)-3,8-diazabicycLoE3.2. 1)oct-3-yL]-3-quino- I inecarboxyl ic acid, 7-E8-C4-aminobenzyl )-3,8-diazabicycLo[3.2.1)oct-3-yL)-l-cycLopropyL--6-fLuoro-1,4-dihydro- 4-oxo-3-quinoL inecarboxyLic acid, 1-cycLopropyt-7-(2,5diazabicycLoE2.2.2]act-2-yt)-6-fLuoro-1,4-dihydro-4-oxo- 3-quinotinecarboxyLic acid, 1-cycLopropyL-7-C2,5-diazabicycLo[2.2.2]oct-2-yL)-6,8-difLuoro-1,4-dihydro-4-oxo- 3-quinoLinecarboxyl ic acid, 8-chLoro-1-cycLopropyL-7- (2,5-diazabicycLoE2.2.2]oct-2-yL)-7-fLuoro-1,4-dihydro- 4-oxo-3-quinoL inecarboxyl ic acid, 1-cycLopropyL--7-(2,5diazabicycLo[2.2.2Joct-2-yL )-6-fLuoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxyL ic acid, 1-cycLopropyL-6f Iuoro-1,4-dihydro-7-( 5-me thyL-2, 5-diazabicyc bC? oct-2-yL)-4-oxo-3-quinotinecarboxybic acid, 1-cycLopropyL-6,8-difLuoro-1,4-di hydro-7-(5-methyL-2,5-di azabicycLoE2.2.2]oct-2-yL)-4-oxo-3-quinoL inecarboxyLic acid, 8-chLoro-1-cyc IopropyL-6-f Luoro-1 ,4-d 4 2,5-diazabicycLoC2.2.2]oct-2-yL )-4-oxo-3-quinoL inecarboxyLic acid, 1-cycLopropyL-7-(3,9-diazabicycLoC3.3. 1]non-3-yI)-6-fLuoro-1,4-dihydro-4-oxo-3-quinoLilecarboxytic acid, 1-cycLopropyl-6-fLuoro-1,4-dihydro-7-(7hydroxy-3,9-diazabicycLo[3.3. 1]non-3-yL)-4-oxo-3-quino- LinecarboxyLic acid, 1-cycLopropyL-6-fLuoro-1,4-dihydro- 7-(3-oxa-7,9-diazabicycLo[3.3.1)non-7-yL)-4-oxo-3-quino- LinecarboxyLic acid, 7-(5-aLLvI-2,5-diazabicycLo[2.2. 1]hept-2-yL )-1-cyc LopropyL-6-fLuor o-1,4-dihydro-4-oxo-3quinoLinecarboxylic acid, 1-cyclv?-opyL-6-fLuoro-1,4dihydro-4-oxo-7-C5-propargyL-2,5-diazabicycLo[2.2.2]oct- 2-yL)-3-quinoL inecarboxytic acid, 1-cycLopropyL-7-C1,4diazabicycLo[3.2.1]oct-4-yL)-6-fLuoro-1,4-dihydro-4-oxo- 3-quinotinecarboxyLic acid hydrochloridle of melting point 322 0 C. 1-cyctopropyL-7-(1,4-diazabicycLo[3.2. 1)oct-4-yl Le A 24 862 17 6-ftuoro-1,4-dihydro-4-oxo-3-quinotinecarboxyL ic acid hemiembonate of melting point from 271 0 C. 8-chloro-1cycLopropyL-7-C1,4-diazabicycLo[3.2.1)oct-4-yI)-6-fLuoro- 1,4-dihydro-4-oxo-3-quinoL inecarboxyl ic acid hydrochLoridle hydrate of melting point 310()C, 1-cycLopropyl- 7-C 1,4-diaz abicyc Lo[3 iloc t-4-yL)-6, 8-dif L uCro-1, 4dihydro-4-oxo-3-quinoLinecarboxyLic acid of melting point 275-282 0 C. 1-cycLopropyL-7-( 1,4-diazabicycLoE3.2. ijoct- 4-yL)-1,4-dihydro-6-nitro-4-oxo-3-ruinoLinecarboxyLic acid hydrochloridle of melting point 303-307 0 C, 1-cycLopropyL-7-(1,4-diazabicycLo[3.2.1]oct-4-yL)-6-fLuoro-1,4dihydro-4-oxo-1,8-flaphthyr idine-3-carboxyL ic acid hydrochloridle of melting point >300 0 C, 7-(1,4-diazabicycLo- 13.2.lloct-4-yL)-1-ethyL-6,8-diflUoro-1,4-dihydro-4-oxo- 3-quinolinecarboxyLic acid hydrochloridle of melting point 308-312O C, 10-C 1,4-diazabicycLoE3.2. ljoct-4-yL fLuoro-2,3-dihydro-3-methyL-7-o7H-pyrido[1,2,3-de]- E1,416ft* ae6-carboxyLic acid hydrochloridle of melting point 355 0 C. 7-(1,4-diazabicycLo[3.2.1]oct-4yL )-6,8-difLuoro-1,-(4-fLuorophenyl }-1,4-dihydro-4--oxo-3quinoLinecarboxyLic acid hydrochloridle of melting point 310-314O C, 1-c ycLopropyL-7-( 1,4-diazabicycLoE3.2. 1Joct-4-yL)-6-fLuoro-1,4-dihydro8-nitro-4-o3-quinoLinecarboxyLic acid of melting point 215-232 0
C.
The 7-ch Loro-1-cyc LopropyL-6-f Luoro-1 ,4-di hydroi -4ox: -qinLinarboxLic acd required for 3is t40 ml of concentrated sulpric acid whiladed coling with ice and stirring. 20.9 g of 2,4-dichLoro-5- Le A 24 862 -18 1 fluorobenzoic acid are introduced in portions into this nitrating mixture, whereupon the temperature rises to 50 0 C. The mixture is then heated at 90 100 0
C
for a further 3 hours, cooled to room temperature and poured onto 350 mL of ice-water 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 0
C
in vacuo. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitrobenzoic acid are obtained. The product is sufficiently pure for further reactions. A sample recrystallized from toluene/petroleum ether gives crystals of melting point 1920C.
b) 2,4-Dichloro-5-fLuoro-3-nitro-benzoyl chloride a o, OC FI 0I Cl C
NO
2 106.6 g of 2,4-dichloro-5-fLuoro-3-nitro-benzoic 20 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 pressre and the residue is fractionated under a fine vacuum. 104.7 g of 2,4-dichloro-5-fluoro-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 0 C form.
c) Ethyl (2,4-dichloro-5-fLuoro-3-nitro-benzoyl)-acetate Le A 24 862 19 F COCH2COOC2H5 C1 I C1
NO
2 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 0 C, and a solution of 109.2 g of 2,4-dichloro-5-fluoro-3-nitro-benzcyl chloride in 50 ml of toluene is slowly added dropwise. Thereafter, the mixture is stirred at 0°C for 1 hour, brought to room so temperature overnight and warmed at 40 500C for a 8 further 2 hours. A mixture of 160 ml of water and 10.4 mL 0 I" of concentrated sulphuric acid is added to the reaction 15 mixture, while cooling with ice, and the organic phase aD 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 20 diethyl (2,4-dichloro-5-fluoro-3-nitro-benzoyl)-malonate oare obtained as a crude product. After addition of 200 ml of water and 0.6 g of 4-toluenesulphonic 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-cyclopropyl-6-fluoro-1,4-dihydro-8-nitro- 4-oxo-3-quinolinecarboxylic acid Le A 24 862 20 ii I i 3 1 244.8 g of ethyl (2,4-dichLoro-5-fluoro-3-nitrobenzoyl)-acetate are heated at 150 160 0 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-5-fLuoro-3-nitrobenzoyl)-3-ethoxy-acryLate as an oily residue.
5.9 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 200C for 1 hour. The product which has precipitated is filtered o r off with suction, after addition of 100 ml of water, and is washed with ethanol/H 2 0 and dried. 32.8 g of mim., ethyl 2-(2,4-dichloro-5-fluoro-3-nitro-benzoyl)-3-cyclo- 15 propylamino-acrylate of melting point 143 1460C are obtained.
3.1 g of .1,8-diazabicyclo5.4.0]undec-'-ene (DBU) are added to 7.8 g of the abovementioned compound 'S in 30 ml of anhydrous dioxane and the mixture is heated 20 at 1000C 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-1-cyclopropyl-6fluoro-1,4-dihydro-8-nitro-4-oxo-3-quinolinecarboxylate are obtained as a crude product. After recrystallization from acetonitrile, the pale brown crystals have a melting point of 174 175 0
C.
Yield: 6 g.
7-(5-Benzyl-2,5-diazabicyclo[2.2.13hept-2-yl)-1- Le A 24 862 21 cyc Iop ropyL-6-f Iuo ro-1, 4-dihydro-4-oxo-3-quinoLinecarboxyLic acid of melting point 205 214 0
C.
1-Cyc Iop ropy 1-6-f Iuo ro-1, 4-dihyd ro-7-( 8-me thyL- 3,8-diazabicycLo[3.2.l)oct-3-yL)-4-oxo-3-quinoLinec'arboxyLic acid of melting point 273 278 0
C.
1-Cyc lop ropy 1-6-fl uoro-1 ,4-d ihy'dro-7- 1,4-diazabicycLoE3.2.13oct-4-yL)-4--oxo-3-quinoLinecarboxyLic acid hydrochloride of melting point >300 0
C.
1.1 g of ethyl 1-cycLopropyL-7-C1,4-diazabicycLo- 1)-oct-4-yL)-6,8-difLuoro-1,4-dihydro-4-oxo-3quinoLinecarboxyLate of melting point 1 9 6 19 9 O C.
7-(1,4-OiazabicycLoE3.2.l]oct-4-yL)-6,8-difLuoro- 1-(2,4-difLuorophenyL)-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid hydrochloridle of meLting point 329- 3 31 0
C.
7-(1,4-DiazabicycLoE3.2.ljoct-4-yL)-6,8-difLuoro- 1,4-dihydro-l-methyLamino-4-oxo-3-quinoL inecarboxyL ic 000 o00 ai yrclrd fmligpit3035C Other active compounds which can be prepared according to the invention are 6-chLoro-7-E3-(4-chLoro- 0 00 phenyL )-l-piperazinylJ-l-cycLopropyL-8-fLuoro-1,4-dio hydro-4-oxo-3-qujnoLinecarboxyLic acid, 6-chLoro-1-cycLopropyL-8-fLuoro-7-E3-(4-fLuorophenyL )-l-piperaz inyL 1,4-dihydro-4-oxo-3-quinoLinecarboxyLic acid, bromophenyL )-l-piperaz inyL ]-6-chLoro-1-cyc Lopropy(L-8fLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyL ic acid, 6chLoro-1-cyc LopropyL-8-f Luoro-1,4-dihydro-8-E3-(4-methiyLphenyL)-l-piperazinyL)-4-oxo-3-ctuinoLinecarboxyL ic acid, a 7-E3-C4-biphenyLyL)-l-piperazinyL]-6-chLoro-1-cycLopropyL-8-fLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyL ic acid, 6-chLoro-1-cy-cLopropyL-8-fLuoro-1 ,4-dihydro-7-[3- C4-methoxytphenyt)-1-piperazinyL)-4-oxo-3-quinoLinecarboxyl ic acid, 6-chLoro-1-cycLoprcopyL-8-fLuoro-1,4dihydro-7-[3-(4-hydroxyphenyL)-1-piperazinyL]-4-oxo-3quinoL inecarboxyL ic acid, 8-chLoro-1-cycLopropyL-6fLuoro-1,4-dihydro-4-oxo-7-(3-phenyL-1-piperazinyL)-3- Le A 24 862 -22 quinot inecarboxylic acid, 8-chLoro-l-cycLopropyL-6fLuoro-1,4-dihydro-4-oxo-7-EC4-nitrophenyL)-l-piperazinyLI-3-quinoL inecarboxyl ic acid, 8-chLoro-1-cycLopropyL- 6-fLuoro-1,4-dihydro-4-oxo-7-E3-C4--piperidino-phenyL)-1piperazinyL)-3-quinoL inecarboxyl ic acid, 8-chloro-1cycLopropyL-6-fLuoro-1,4-dihydro-4-oxo-7-E3-C3,4-dimethoxy-phenyL)-l-piperazinyl]-3-quinoL inecarboxyl ic acid, 8-chLoro-1-cycLopropyL-6-fLuoro-1,4-dihydro-4-oxo-7-E3- (3,4,5-trimethoxy-phenyL)-l-piperazinyL]-3-quinoLinecarboxyt ic acid, 8-chLoro-l-cycLopropyL-6-fLuoro-1,4dihydro-4-oxo-7-[3-(2-thienyL)-1-piperazinyL]-3-quino- I inecarboxyl ic acid, 8-chLorc'-1-cycLopropyl--6-fLuoro-1,4dihydro-4-oxo-7-piperidino-3-quinoL inecarboxyL ic acid, 7-(3-amino-1-pyrroLidinyL)-8-chioro-1-cyciopropyL-6fLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxylic acid, 6,8-dichLoro-l-cycLopropyL-1,4-dihydro-4-oxo-7-(l-piper- .0 a z in y L-3-quinoLinecarboxyLic acid, 7-(4-acetyL-1-piperazinyl )-6,8-dichLoro-1-cycLopropyL-1,4-dihydro-4-oxo-3- 00 quinoLinecarboxyL ic acid, 7-(4-acetyL-1-piperazinyL)-6chLoro-1-cyc LopropyL-8-fluoro-1,4-di hydro-4-oxo-3quinoL inecarboxyL ic acid, 6-chLoro--1-cycLopropyL-8fLuoro-1,4-dihydro-7-(4-isopropyL-1-piperazinyL )-4-oxo- 3-quinoLinecarboxyL ic acid, 6-chLoro-1-cycLopropyL-8- 25fLuoro-1,4-dihydro-4-oxo-7-morphoL ino-3-quinolimeacid, 6-chLoro-1-cycLopropyL-8-fluoro-1,4o dihydro-4-oxo-7-thiomorphol ino-3-qujinoL inecarboxyL ic acid and 8-chtoro-1-cycLopropyl-7-C4-ethyL-3-oxo-1-piperaz inyL)-6-fLuoro-1,4-dihydro-4-oxo-3-quinoLinecarboxyLic t1 4 a c id.
According to the invention, the free carboxyLic acids are as a rule initially obtevined and are then 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 Le A 24 862 23 de r ivativye.
Examp Les ExampLe 1 606 parts by weight of 1-cycLopropyL-7--chLoro-6fiuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyL ic acid and 575 parts by weight of piperazine are heated at 150 to 160 0 C in a suitable reactor for 30 minutes. The reaction mixture is diluted with water, 1-cycLopropyL-6fLuoro-1,4-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-1,4-dihydro-4-oxo-3-quinoL inecarboxylic acid and 129 parts by weight of piperazine are reacted as in Example 1. 1-Cyc LopropyL-6-fLuoro-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 1500 C. 94 parts by weight of 1-cycLopropyL-7chLoro-6-fLuoro-1,4-dihydro-4-oxo-3-quinoL inecarboxyL ic acid are metered into this melt in the course of minutes. The mixture is cooled to 1000 C and water is added. 1-CycLopropyL--6-fLuoro-1,4-dihydro-4-oxo-7-C1piperazinyL)-3-quinoLinecarboxyLic acid thereby crystallizes out in a yield of 78% with a purity of 97.2%.
ExaMPie 4 150 parts by weight of piperazine are reacted with 102 parts by weight of 1-cycLopropyL-6,7-difLuoro- 1,4-dihydro-4-oxo-3-quinoLinecarbuxyLic acid as in Example 3. 1-Cyc LopropyL-6-fLuoro-1,4-dihydro-4-oxo-7- 1-piperazinyL)-3-quinoL inecarboxylic acid is obtained in a yield of 76% with a purity of 97.5%.
Example parts by weight of 1-cycLopropyL-7--chLoro-6- A 24 86? 24 7 0 0 0', o 0 0 000 ~i0C~000 0 0 00 0 0 0 0 C 0', o 0~ 00 a o 00 00 O 000 0 00 0 0 0 0 00 00 4 0 4 fLuoro-1,4-dihydro-4-oxo-3-quino.inecarboxyL ic acid are added to 122 parts by weight of 1-ethyl-piperazine, which has been heated to 140 to 150 0 C, in the course of minutes. After cooLing to 100 0 C, water is added, 1cyc LopropyL-6-fLuoro-1 ,4-d ihydro-4-oxo-7-(4-ethyL-1piperazinyL)-3-quinoL inecarboxylic acid crystallizing out in a yield of 76% and a purity of 98.2%.
Le A 24 862
Claims (8)
1. Process for the preparation of compounds of the formula (I) "0 a 01 0 00 a o 040 0 0 0 0 04 0 00 in whic h R 1represents methyl, ethyl, propyL, isopropyL, cycLopropyL, vinyL, 2-hydroxyethyL,
2-f LuoroethyL, aethoxy, amino, methyLamino, dimethyLamino, ethyLamino, phenyL, 4-f LuorophenyL or 2,4-di- fluorophenyL, R 2 represents CN or COOR 2 1 R 20denotes hydrogen, C 1 -C 4 aLkyL or methyL-2-oxo'-1,3-dioxoL-4-yL )-methyL, or Rrepresents CON(C 1 -C 4 -aLkyL) 2 Rrepresents a cyclic amino group, selected from wherein 0 oR 00 0 O~ S HO-CN- N-6 0 N- N;LJ C 91, Le A 24 862 26 wherein R represents hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxo- propyl, 3-oxobutyl, phenacyL, formyl, CFC12-S-, CFCL 2 -S0 2 CH 3 0-CO-S-, benzyl, 4-aminobenzyl or CH 3 *CH2-, 0 R represents hydrogen or methyl, R 6 represents hydrogen, alkyl with 1 to 4 carbon atoms, phenyL or benzyloxymethyl, 7 R represents hydrogen, amino, methyLamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyL, dimethylaminomethyl, hydroxyL or hydroxymethyl and R represents hydrogen, methyl, ethyL or chlorine, Sor 3 V R represents the group 4 N- R 1 0 in which 9 10 R and R are identical or different and S" represent hydrogen or a branched or unbranched '1 alkyl, alkenyl or alkynyl radical which has 1 to 12 carbon atoms and can optionally be substituted by hydroxyl groups, alkoxy, alkylmercapto or dialkylamino groups with 1 to 3 carbon atoms in each alkyl radical, the nitrile group or the alkoxycarbonyl group with 1 to 4 carbon atoms in the alcohol part, or an aryl or heteroaryl radi- cal, or furthermore denotes C 3 -C 6 -cycloalkyl, X represents halogen, in particular fluorine or chlorine, or nitro or C 1 -C 4 -alkylsulphonyl or Le A 24 862 27 C l-C4-aLkyLsuLphonyLoxy and A represents N or C-R11I wherein R 1represents hydrogen, haLogen, such as fluorine,. bromine or chlorine, methyL or nitro and Rtogether with R 1, can form the structure -O-CH 2 -CH-CH 3 -S-CH 2 -CH-CH 3 a bridge of or -CH 2 -CH 2 -CH-CH 3 characterized in that compounds of the formula (II) o 4 0 0 40 0 0 o 0 00 0 0 4 00 o 4 (4 00 0 4 4 40 40 4 o 0 4 9 44 *004 V 4 II R R A and X have the abovementioned meaning and Y represents halogen, in particular fluorine or chlorine, or nitro or Cl-C 4 aLkyLsuLphonyL or C 1-C4-aLkyLsuLphonyLoxy, are reacted with amines of the formulae R 7 R 6 *0 4 9£ P8N-H, 8 l 0 N-H C NH R 4 -N N -H C H, N--e'N R4 -NKZN R4- NKN -H N-H, Le A 24 862 H 28 or R 9 N-H 1 0 wherein 4 5 6 7 8 9 10 11 R 4 R 5 R 6 R 7 R 8 R, R and R 11 have the abovementioned meaning, without solvents, at temperatures between 20 0 C and 200 0 C, if appropriate under pressure, characterized in that the compounds of the formula (II) are reacted with the amines in a ratio of 1:1 to 1:50 by metering them into the liquid amines. 2. Process according to Claim 1, characterized in that the compounds of the formula (II) are reacted with the amines in a 0 ratio of 1:2 to 1:10. I o
3. Process according to any one of Claims 1 to 2, characterized in that the compounds of the formula (II) are o04' reacted with the amines at 80 to 180 0 C. 4
4. Process according to any one of Claims 1 to 2, 0 4 4 characterized in that the compounds of the formula (II) are reacted with the amines at 120 to 160 0 C. Process according to any one of Claims 1 to 4, characterized in that l-cyclopropyl-7-chloro-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with piperazine without a solvent.
6. Process according to any one of Claims 1 to 4, characterized in that l-cyclopropyl-6,7-difluoro-l,4-dihydro- 4-oxo-3-quinolinecarboxylic acid is reacted with piperazine. 0177g/CB 29 0177g/CB L M
7. Process according to any one of Claims 1 to 4, characterized in that l-cyclopropyl-7-chloro-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid is metered into piperazine which has been heated to 140 to 150 0 C, the mixture is cooled, water is added and the reaction product is crystallized out.
8. Process according to Claim 7, characterized in that l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline- o, carboxylic acid is used as the starting substance. o 9. Process according to any one of Claims 1 to 4, o characterized in that 1-cyclopropyl-7-chloro-6-fluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with 0 o a 1-ethyl-piperazine, 13-hydroxyethylpiperazine or a l-methylpiperazine. A process according to Claim 1 and substantially as herein described with reference to any one of the foregoing examples thereof.
11. A product prepared by the process of any one of the preceding claims. DATED this 22nd day of February, 1989. BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys, ARTHUR S. CAVE CO. -3i4'/Z 30 1968E
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3641312 | 1986-12-03 | ||
| DE19863641312 DE3641312A1 (en) | 1986-12-03 | 1986-12-03 | METHOD FOR PRODUCING CHINOLINE CARBONIC ACIDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8217787A AU8217787A (en) | 1988-06-09 |
| AU593961B2 true AU593961B2 (en) | 1990-02-22 |
Family
ID=6315377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU82177/87A Expired AU593961B2 (en) | 1986-12-03 | 1987-12-03 | Process for the preparation of quinoline carboxylic acids |
Country Status (25)
| Country | Link |
|---|---|
| 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) | FI875289A (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 |
| WO1991004972A1 (en) * | 1989-10-06 | 1991-04-18 | Pfizer Inc. | 1,4-dihydro-4-oxo-3-quinoline derivatives as selectively toxic mammalian antibacterial agents |
| 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 |
| WO2005026147A1 (en) | 2003-09-10 | 2005-03-24 | Kyorin Pharmaceutical Co., Ltd. | 7-(4-substituted 3- cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative |
| US8222407B2 (en) | 2007-05-24 | 2012-07-17 | 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU512940B2 (en) * | 1977-05-16 | 1980-11-06 | Kyorin Seiyaku K.K. | Quinoline carboxylic acid derivatives |
| 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 |
| AU566416B2 (en) * | 1984-02-17 | 1987-10-22 | Warner-Lambert Company | 1,8- - naphthyridine or hydroquineline derivatives |
Family Cites Families (7)
| 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 |
| 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 |
| 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 AT AT87117130T patent/ATE73446T1/en not_active IP Right Cessation
- 1987-11-20 DE DE8787117130T patent/DE3777370D1/en not_active Expired - Lifetime
- 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 CS CS878688A patent/CS270577B2/en not_active IP Right Cessation
- 1987-11-30 NZ NZ222736A patent/NZ222736A/en unknown
- 1987-12-01 FI FI875289A patent/FI875289A/en not_active Application Discontinuation
- 1987-12-01 DD DD87309727A patent/DD270904A5/en not_active IP Right Cessation
- 1987-12-01 JP JP62301624A patent/JPS63145268A/en active Pending
- 1987-12-02 HU HU875424A patent/HU199823B/en unknown
- 1987-12-02 ZA ZA879040A patent/ZA879040B/en unknown
- 1987-12-02 UA UA4203762A patent/UA8017A1/en unknown
- 1987-12-02 PT PT86252A patent/PT86252B/en unknown
- 1987-12-02 PH PH36159A patent/PH24489A/en unknown
- 1987-12-02 SU SU87A patent/SU1482526A3/en active
- 1987-12-02 KR KR1019870013716A patent/KR970005191B1/en not_active IP Right Cessation
- 1987-12-02 DK DK198706331A patent/DK174929B1/en not_active IP Right Cessation
- 1987-12-02 PL PL1987269185A patent/PL158614B1/en unknown
- 1987-12-02 IE IE327987A patent/IE64261B1/en not_active IP Right Cessation
- 1987-12-02 CN CN198787107230A patent/CN87107230A/en active Pending
- 1987-12-03 AU AU82177/87A patent/AU593961B2/en not_active Expired
-
1992
- 1992-04-08 GR GR920400663T patent/GR3004301T3/el unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU512940B2 (en) * | 1977-05-16 | 1980-11-06 | Kyorin Seiyaku K.K. | Quinoline carboxylic acid derivatives |
| 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 |
| AU566416B2 (en) * | 1984-02-17 | 1987-10-22 | Warner-Lambert Company | 1,8- - naphthyridine or hydroquineline derivatives |
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Owner name: BAYER HEALTHCARE AG Free format text: FORMER OWNER WAS: BAYER AKTIENGESELLSCHAFT |