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AU622256B2 - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents
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AU622256B2 - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents

Process for the preparation of quinoline carboxylic acid derivatives

Info

Publication number
AU622256B2
AU622256B2 AU47480/90A AU4748090A AU622256B2 AU 622256 B2 AU622256 B2 AU 622256B2 AU 47480/90 A AU47480/90 A AU 47480/90A AU 4748090 A AU4748090 A AU 4748090A AU 622256 B2 AU622256 B2 AU 622256B2
Authority
AU
Australia
Prior art keywords
general formula
process according
acid
compound
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU47480/90A
Other versions
AU4748090A (en
Inventor
Maria Balogh
Istvan Hermecz
Agnes Horvath
Geza Kereszturi
Aniko Pajor
Peter Ritli
Judit Sipos
Lelle Vasvari
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chinoin Private Co Ltd
Original Assignee
Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt filed Critical Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Publication of AU4748090A publication Critical patent/AU4748090A/en
Application granted granted Critical
Publication of AU622256B2 publication Critical patent/AU622256B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Quinoline Compounds (AREA)

Description

PROCESS FOR TEE PREPARATION OP QUINOLIKE CARBOXYLIC ACID DERIVATIVES
This invention relates to a new process for the preparation of 1- (optionally halo-substituted) -ethyl-7- (3, 4, 5-substituted piperazine)-6 , 8-difluoro-4-oxo-l , 4-dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I
and pharmaceutically acceptable salts thereof.
In the general Formula I
R 1 and R3 stand for hydrogen or C1-4 alkyl,
R2 stands for C1-4 alkyl,
R4, R5 and R6 stand for hydrogen or halogen.
It is known that a group of the 7-(3,4,5-substituted--piperazine)-quinoline-3-carboxylic acid derivatives of the general Formula I processes high antibacterial activity (Antimicrob. Agents Chemother. 1987, 31, 854; Drugs of Fut. 1986, 11, 578; 26th Intersci. Conf. Antimicrob. Agents Chemother. 1986, Abst. 430-431; 25th Intersci. Conf.
Antimicrob. Agents Chemother. 1985, 567). These compounds can be prepared by reacting 6,7,8-trifluoro-4-oxo-1,4- -dihydro-quinoline-3-carboxylic acid and cyclic amines (German patent specification 3 433924, Japanese patent specifications 60142980, 61 85381, 61 65 882). According to the present invention there is provided a new process for the preparation of quinoline-3-carboxylic acid derivatives of the general Formula I (wherein R1 and R3 stand for hydrogen or C1-4 alkyl, R2 stands for C1-4 alkyl,
R4, R5 and R6 stand for hydrogen or halogen.)
and pharmeceutically acceptable salts thereof which comprises reacting a compound of the general Formula II
(wherein R stands fpr halogen, an aliphatic acyloxy group containing 2 to 6 carbon atoms or aromatic acyloxy group containing 7 to 11 carbon atoms and R4, R5, R6 have the meanings defined above)with an amine of the general Formula II
(wherein R1, R2 and R3 have the meanings defined above) or a salt thereof and subjecting the compound of the general
Formula IV
thus obtained (wherein R, R1, R2, R3, R4, R5 and R6 are as stated above) to hydrolysis after or without isolation and if desired converting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt.
The advantage of the process of the present invention is that it enables the preparation of the compounds of the general Formula I in a simple manner, with very high yields and in a short reaction time.
The boron derivatives of the general Formula IV are new compounds.
According to a preferred form of realization of the process of the present invention the boron derivative of the general Formula IV is converted into the desired quinoline-3--carboxylic acid of the general Formula I without isolation.
The boron derivatives of the general Formula II can be reacted with the amine of the general Formula III if desired in the presence of an inert organic solvent and an acid binding agent.
As inert organic solvent preferably an acid amide
(e.g. dimethyl formamide, dimethyl acetamide), a ketone (e..g. acetone, methyl ethyl ketone), an ether (e.g. dioxane, tetrahydrofuran, diethyl ether), an ester (e.g. ethyl acetate, methyl acetate, ethyl propionate), a sulfoxide (e.g. dimethyl sulfoxide), an alcohol (e.g. methanol, ethanol, 1-decanol, butanol) a nitrile (e.g. acetonitrile) halogenated organic solvents (e.g. chloroform, dichloroethane) may be used.
As acid binding agent an organic or inorganic base may be used. From the group of organic bases trialkyl amines (e.g. triethyl amine, tributyl amine), cyclic amines (e.g. pyridine,
,a,
1,5-dιzahicyclo/5,4,0/undec-5-ene, 1,5-diazabicyclo/4.3.0/-non-5-ene, 1,4-diazabicyclo/2.2.2/octane) can be mentioned, while as inorganic base preferably hydroxides or carbonates of alkali or alkaline earth metals can be applied. Thus as acid binding agent advantageously potassium carbonate,
potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc. or an excess of the amine of the general
Formula III can be used.
The boron derivative of the general Formula II and the amine of the general Formula III can be reacted at a temperature between 10 and 200 °C, depending on the solvent used.
reaction time may vary between 0,1-10 hours. The reaction time depends on the reaction temperature, too. If the reaction is carried out at higher temperature, the reaction time can be shortened. The above reaction conditions are preferable values and other conditions may be used as well.
The compounds of the general Formula IV can be hydrolysed to the desired quinoline-3-carboxylic acids of the general Formula I, after or without isolation, under acidic or basic conditions. The compounds of the general Formula IV precipitates from the reaction mixture e.g. on cooling and can be separated e.g. by filtration or centrifuging, if desired.
Basic hydrolysis may be preferably carried out by heating, with the aid of a hydroxide or carbonate of an alkali metal or an alkaline earth metal hydroxide, used as aqueous solution.
One may preferably use an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide. However, organic amines (e.g. triethyl
amine) may also be applied in the hydrolysis step.
Acidic hydrolysis may preferably be accomplished by using an aqueous mineral acid. One may preferably proceed by hydrolysing a compound of the general Formula IV by heating with an aqueous solution of hydrochloric acid, hydrogen bromide,
sulfuric acid or phosphoric acid. Hydrolysis may also be
accomplished with the aid of an organic acid (e.g. acetic acid, propionic acid, etc.).
Hydrolysis of the compounds of the general Formula IV may also be carried out in aqueous medium in the presence of a watermiscible organic solvent. For this purpose e.g. alcohols (e.g. methanol, ethanol), a ketone (e.g. acetone), an ether (e.g.
dioxane), an acid amide (e.g. dimethyl formamide), a sulfoxide (e.g. dimethyl sulfoxide), or pyridine may be used.
The quinoline-3-carboxylic acid of the general Formula I thus obtained may be isolated e.g. adjusting the pH value of the aqueous solution to a suitable value and separating the precipitated crystals e.g. by filtration or centrifuging or by liophylizing the aqueous reaction mixture.
The compounds of the general Formula I can be converted into pharmaceutically acceptable salts thereof in a known manner. Thus preferably acid addition salts can be formed, e.g. salts formed with hydrogen halides, sulfonic acids, sulfuric acid or organic acids. One may form preferably
chlorides, bromides, aryl sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc. The compounds of the general Formula I form salts with alkali or alkaline earth metals or other metal ions as well. Accordingly the sodium, potassium, magnesium, silver, copper salts, etc. may be
prepared.
The compounds of the general Formula I and pharmaceutically acceptable salts thereof can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) by methods known per se.
According to a further aspect of the present invention there are provided new compounds of the general Formula IV (wherein R, R1, R2, R3, R4, R5 and R6 are as stated above).
The starting materials of the general Formula II can be prepared by reacting 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro -quinoline-3-carboxylic acid (GB patent specification
2.057.440) with a boron derivative (e.g. with a compound of the general Formula V ;
(wherein R is halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms) or with fluroborate in aqueous or in organic medium. Further details of the present invention are to be found in the following Examples without limiting the scope of
protection to the said Examples.
Examsle 1
31,9 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate-O3,O4)-difluoro-boron are reacted with 57,1 g of 2,6-dimethyl-piperazine in 150 ml of dimethyl
sulfoxide at 100 °C for 3 hours. A 3 w/v % aqueous solution of 400 ml of sodium hydroxide are added and hydrolysis is carried out by heating for 2 hours. The reaction mixture is filtered, the pH value is adjusted to 7 with 96 w/v % acetic acid. The crystalline reaction mixture is cooled overnight and the precipitated crystals are filtered, washed with water and dried. Thus 29,9 g of 7-/3,5-dimethyl-piperazino/ 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained. M.p. is 232-234 °C.
Analysis for the Formula C18H21F2N3O3:
Calculated: C = 59 , 17 % H = 5, 80 % N = 11, 49 %
Found: C = 59,05 % H = 5,91 % N = 11,45 %
Example 2
According to Example 1 31,9 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O3, O4)-difluoro-boron are reacted with 50,1 g of 2-methyl-piperazine in 150 ml of dimethyl sulfoxide. Thus 30,6 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-piperazino)- -quinoline-3-carboxylic acid are obtained. M.P. is 238-240 ºC
Analysis for the Formula C17H19F2N3O3:
Calculated: C = 58,11 % H = 5,45 % N = 11,96 %
Found: C = 58,01 % H = 5,55 % N = 12,07 %
Example 3
According to Example 1 39,9 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O3, O4)-bis-(acetato-O)-boron are reacted with 50,1 g of 2-methyl--piperazine in 150 ml of dimethyl sulfoxide. Thus 30,2 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-piperazino)-quinoline-3-carboxylic acid are obtained.
M.P. is 237-239 °C
Analysis for the Formula C17H19F2N3O3:
Calculated: C = 58,11 % H = 5,45 % H = 11,96 %
Found: C = 57,97 % H = 5,53 % H = 11,90 %
Example 4
According to Example 1 42,7 g of (1-ethyl-6,7,8-tri- fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O3, O4)-bis- (propionato-O)-boron are reacted with 50,1 g of 2-methyl- piperazine. Thus 28,7 g of 1-ethyl-6,8-difluoro-1,4-dihydro -4-oxo-7-(3-methyl-piperazino)-quinolin-3-carboxylic acid are obtained.
M.p. is 237-239 °C
Analysis for the Formula C17H19F2N3O3:
Calculated: C = 58,11 % H = 5,45 % N = 11,96 %
Found: C = 57,99 % H = 5,52 % N = 12,10 %

Claims (10)

CLAIMS:
1. Process for the preparation of compounds of the general Formula I
(wherein
R1 and R3 stand for hydrogen or C1-4 alkyl,
R2 stands for C1-4 alkyl,
R4, R5 and R6 stand for hydrogen or halogen)
and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II
(wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms,and R4, R5, R6 have the
meanings defined above) with a piperazine derivative of the general Formula III
(wherein R1, R2, and R3 have the meanings defined above) or a salt thereof and subjecting the compound of the general
Formula IV
thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if desired converting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt.
2. Process according to Claim 1 which comprises reacting a compound of the general Formula II with an amine of the general Formula III in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether, ester or nitrile.
3. Process according to Claim 2 which comprises using dimethyl sulfoxide as organic solvent.
4. Process according to Claim 1 which comprises carrying out the reaction of the compounds of the general Formula II and III in the presence of an acid binding agent.
5. Process according to Claim 4 which comprises using an
amine or an excess of the compound of the general Formula VI as acid binding agent.
6. Process according to Claim 1 which comprises carrying out the hydrolysis in acidic medium.
7. Process according to Claim 6 which comprises carrying out the reaction by using an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acid.
8. Process according to Claim 1 which comprises carrying out the hydrolysis in alkaline medium.
9. Process according to Claim 8 which comprises using an alkaline metal hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous triethyl amine solution.
10. Compounds oi the general Formula IV
(wherein
R1 and R3 stand for hydrogen or C1-4 alkyl,
R2 stands for C1-4 alkyl,
R4, R5 and R6 stand for hydrogen or halogen).
AU47480/90A 1988-12-22 1989-12-15 Process for the preparation of quinoline carboxylic acid derivatives Ceased AU622256B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU6560/88 1988-12-22
HU886560A HU203746B (en) 1988-12-22 1988-12-22 Process for producing quinoline-carboxylic acid derivatives

Publications (2)

Publication Number Publication Date
AU4748090A AU4748090A (en) 1990-07-10
AU622256B2 true AU622256B2 (en) 1992-04-02

Family

ID=10971814

Family Applications (1)

Application Number Title Priority Date Filing Date
AU47480/90A Ceased AU622256B2 (en) 1988-12-22 1989-12-15 Process for the preparation of quinoline carboxylic acid derivatives

Country Status (11)

Country Link
JP (1) JP2825641B2 (en)
KR (1) KR0146335B1 (en)
CN (1) CN1031190C (en)
AT (1) AT397385B (en)
AU (1) AU622256B2 (en)
FR (1) FR2640974B1 (en)
GB (1) GB2245562B (en)
HU (1) HU203746B (en)
IL (1) IL92821A0 (en)
WO (1) WO1990006922A1 (en)
YU (1) YU47215B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2077490B1 (en) * 1992-11-18 1996-10-16 Marga Investigacion TRIMETILSILILIC ESTERS AND SOLVATES OF CHELATES OF QUINOLIN-3-CARBOXYL ACIDS. PREPARATION AND APPLICATION TO THE QUINOLON PROCESS.
NZ260530A (en) * 1994-05-16 1997-06-24 Nigel Paul Maynard Organoborate complexes of divalent metal; use as timber treament agents
ES2092963B1 (en) * 1995-04-12 1997-12-16 Sint Quimica Sa PROCEDURE FOR THE PREPARATION OF ACID 1-CICLOPROPIL-6-FLUORO-1, 4-DIHIDRO-7- (1S, 4S) -5-METHYL-2,5-DIAZABICICLO (2.2.1) HEPT-2-IL) -4 -OXO-3-QUINOLINCARBOXILICO AND ITS SALTS.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239538A2 (en) * 1986-03-26 1987-09-30 Ciba-Geigy Ag Process for the preparation of 1,4-diamino-2,3-dicyanoanthraquinones
AU1572188A (en) * 1987-04-08 1988-11-04 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Process for the preparation of quinoline carboxylic acids
AU1597988A (en) * 1987-04-08 1988-11-04 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122470A (en) * 1982-12-27 1984-07-14 Dai Ichi Seiyaku Co Ltd Preparation of quinoline-3-carboxylic acid derivative
US4550167A (en) * 1983-05-23 1985-10-29 Ethyl Corporation Preparation of 1-alkyl-1,4-dihydro-4-oxo-7-(4-pyridyl)-3-quinoline carboxylic acid
JPS6078986A (en) * 1983-10-07 1985-05-04 Dai Ichi Seiyaku Co Ltd Preparation of oxazine derivative
JPS6165882A (en) * 1984-09-06 1986-04-04 Hokuriku Seiyaku Co Ltd 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinyquinoline-3-carboxylic ester derivative and its preparation
JPS6185381A (en) * 1984-10-04 1986-04-30 Hokuriku Seiyaku Co Ltd Preparation of 1-ethyl-6, 8-difluoro-1, 4-dihydro-4-oxo-7-piperazinylquinoline-3-carboxylic acid derivative
HU196782B (en) * 1985-12-09 1989-01-30 Chinoin Gyogyszer Es Vegyeszet Process for production of quinoline carbonic acid
CA1306750C (en) * 1985-12-09 1992-08-25 Istvan Hermecz Process for the preparation of quinoline carboxylic acide
JPS6419069A (en) * 1987-07-14 1989-01-23 Dainippon Pharmaceutical Co Production of polyhalogenoquinoline derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239538A2 (en) * 1986-03-26 1987-09-30 Ciba-Geigy Ag Process for the preparation of 1,4-diamino-2,3-dicyanoanthraquinones
AU1572188A (en) * 1987-04-08 1988-11-04 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Process for the preparation of quinoline carboxylic acids
AU1597988A (en) * 1987-04-08 1988-11-04 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof

Also Published As

Publication number Publication date
CN1043712A (en) 1990-07-11
YU47215B (en) 1995-01-31
HUT52086A (en) 1990-06-28
FR2640974B1 (en) 1994-02-18
AT397385B (en) 1994-03-25
GB9018360D0 (en) 1990-10-24
FR2640974A1 (en) 1990-06-29
HU203746B (en) 1991-09-30
GB2245562B (en) 1992-12-23
GB2245562A (en) 1992-01-08
JPH03502803A (en) 1991-06-27
AU4748090A (en) 1990-07-10
CN1031190C (en) 1996-03-06
YU243789A (en) 1991-02-28
KR910700245A (en) 1991-03-14
IL92821A0 (en) 1990-09-17
JP2825641B2 (en) 1998-11-18
KR0146335B1 (en) 1998-08-17
WO1990006922A1 (en) 1990-06-28
ATA902489A (en) 1993-08-15

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