WO1987003595A1 - Norfloxacin intermediate - Google Patents

Norfloxacin intermediate Download PDF

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Publication number
WO1987003595A1
WO1987003595A1 PCT/HU1986/000068 HU8600068W WO8703595A1 WO 1987003595 A1 WO1987003595 A1 WO 1987003595A1 HU 8600068 W HU8600068 W HU 8600068W WO 8703595 A1 WO8703595 A1 WO 8703595A1
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Prior art keywords
general formula
carbon atoms
compounds
halogen
acyloxy group
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PCT/HU1986/000068
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French (fr)
Inventor
István HERMECZ
Géza KERESZTURI
Lelle Vasvári
ágnes Horváth
Mária BALOGH
Gábor KOVÁCS
Péter RITLI
Judit Sipos
Anikó PAJOR
Zoltán MÉSZÁROS (deceased)
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.)
Meszaros Marta (legal Heir And Representative Of
Meszaros Zoltanne (legal Heir And Representative
Chinoin Private Co Ltd
Original Assignee
Meszaros Marta (legal Heir And Representative Of
Meszaros Zoltanne (legal Heir And Representative
Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
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Priority to KR1019870700687A priority Critical patent/KR940009028B1/en
Priority to AT87900246T priority patent/ATE53212T1/en
Priority to DE8787900246T priority patent/DE3671628D1/en
Priority to JP62500207A priority patent/JPH0742299B2/en
Publication of WO1987003595A1 publication Critical patent/WO1987003595A1/en
Priority to NO873247A priority patent/NO169076C/en
Priority to FI873443A priority patent/FI84072C/en
Priority to DK412587A priority patent/DK412587A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07F5/04—Esters of boric acids

Definitions

  • This invention relates to new intermediates useful in the preparation of Norfloxacin . More particularly it is concerned with new anhydrides of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and boric acida and a proceas for the preparation thereof.
  • the latter compounds can be prepared in two steps by reacting ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4- -dihydro-quinoline-3-carboxylate with a cyclic amine at a temperature above 100 °C in the presence of a solvent for several hours and subjecting the ethyl-1- -ethyl-6-fluoro-7-aubstituted-4-oxo-1,4-dihydro-quinoline-3-carboxylate thus obtained to hydrolysis; the order of aucceaaion of the said two steps can be changed, if desired (Japanese patent specifications Nos.
  • R and R 1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms
  • reacting a compound [
  • R 3 , R 4 and R 5 stand for an alkyl group comprising 1-4 carbon atoms and optionally substituted by halogen or for an aryl group compriaing 6-10 carbon atoms).
  • the reaction of the quinoline-3-carboxylic acid of the general Formula II and the borone derivative of the general Formula III can preferably be carried out in an optionally halogenated organic carboxylic acid - which may also contain the corresponding acid anhydride - at a temperature between 0 and 200 oC.
  • the compound of the general Formula I thus formed precipitates from the reaction mixture either spontaneously or under cooling and can be separated e.g. by filtration.
  • reaction may however also be carried out in an other solvent (e.g. aulfoxide, amidea, pyridine, aromatic hydrocarbons), if desired.
  • an other solvent e.g. aulfoxide, amidea, pyridine, aromatic hydrocarbons
  • the borone derivatives of the general Formula III can be used in a molar ratio of 1-50 molea reltted to 1 mole of the quinoline-3-carboxylie acid derivative of the general Formula II.
  • a mixture of 9.3 g of boric acid and 70 g of propionic anhydride is stirred at 100 °C for 15 minutes whereupon the reaction nixture is heated to the boiling point. After half an hour the temperature is lowered to 110 °C and 29.8 g of e thyl-1-ethyl-6-fluoro-7-chloro- -4-oxo-1, 4-dihydro-quinoline-3-carboxylate are added.
  • the reaction mixture which turna to a thick suspension within some minutes , is stirred at 110 oC for 2 hours , then cooled to room temperature and diluted with 300 ml of water. The reaction nixture is cooled and the precipitated crystals are filtered.
  • a mixture of 46.3 g of boric acid and 345 g of propionic anhydride is stirred at 100 °C for 15 minutes whereupon the reaction mixture is heated to boiling. After half an hour the reaction temperature is lowered to 110 °C and 134.5 g of 1-ethyl-6-fluoro-7-chloro-4-oxo- -1,4-dihydro-quinoline-3-carboxylic acid are added. The reaction mixture is stirred at 110 °C for 2 hours and cooled under 10 oC. The reaction mixture ia diluted with 150 ml of water and allowed to crystallize in a refrigerator overnight. Next morning the precipitated crystals are filtered, washed with water and dried in vacuo.
  • a mixture of 9.3 g of boric acid and 54.1 g of acetic anhydride is heated at 110 °C for 30 minutes.
  • the reaction mixture is cooled to 80 °C and 29.8 g of ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are added.
  • the reaction mixture is stirred at 110 °C for 2 hours, cooled below 10 °C and diluted with 100 ml of water.
  • the cooled reaction mixture is allowed to crystallize in a refrigerator overnight. Next morning the precipitated crystals are filtered, washed with water and dried.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cephalosporin Compounds (AREA)
  • Catalysts (AREA)
  • Thin Film Transistor (AREA)

Abstract

A process for the preparation of compounds of general formula (I), (wherein R and R1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally substituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound of general formula (II), (wherein R2 stands for hydrogen or alkyl comprising 1-4 carbon atoms) with a borone derivative of general formula (III), (wherein R3, R4 and R5 stand for an alkyl group comprising 1-4 carbon atoms and optionally substituted by halogen or for an aryl group comprising 6-10 carbon atoms). The new compounds of general formula (I) are useful pharmaceutical intermediates.

Description

NORFLOXACIN INTERMEDIATE
This invention relates to new intermediates useful in the preparation of Norfloxacin . More particularly it is concerned with new anhydrides of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and boric acida and a proceas for the preparation thereof.
It is known that ethyl-1-ethyl-6-fluoro-7-chloro-4- -oxo-1,4-dihydro-quinoline-3-carboxylate /Journal of Medicinal Chemistry 23, 1358 (1980); Japanese patent specification No. 8033,453/ is an intermediate uaeful in the preparation of 1-ethyl-6-fluoro-7-subatituted- -4-oxo-1,4-dihydro-quinoline-3-carboxylic acida having antibacerial effect (Ann. Microbiol /Paria/ 1981, 132A, 267; Journal of Medicinal Chemiatry 1980, 23, 1358; Pathol. Biol. 1982, 30, 394; Cyo Yakuri, 1983, 25, 475; Pathoi. Biol. 1983, 31, 501; Antimicrob. Agents Chemother. 1980, 17, 103; 1981, 19, 188; 1981, 20, 265; CR. Seances Acad. Sci., Ser. 3, 1981, 292, 37/.
The latter compounds can be prepared in two steps by reacting ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4- -dihydro-quinoline-3-carboxylate with a cyclic amine at a temperature above 100 °C in the presence of a solvent for several hours and subjecting the ethyl-1- -ethyl-6-fluoro-7-aubstituted-4-oxo-1,4-dihydro-quinoline-3-carboxylate thus obtained to hydrolysis; the order of aucceaaion of the said two steps can be changed, if desired (Japanese patent specifications Nos. 79,138,582 and 80,33,453; Belgian patent specifications Nos. 863,429; 870,917; 879,106 and 890,223; DOS No. 2,840,910 and French patent publication No. 2,424,919).
The above processes are accompanied by several drawbacks. The reaction time uaed is long. Moreover the halogen/amine group replacement reaction is not selective and in addition to the desired chloro/mine reaction in position 7 also a fluoro/amine exchange in position 6 takes place to a considerable extent. It has been found that the selectivity of the desired halogen/amine replacement reaction in position 7 can be increased significantly by reacting a cyclic amine with an anhydride of the general Formula I (wherein R and R1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms). A further advantage of this process is that the reaction time is aignificantly shorter.
According to the preaent invention there is provided a process for the preparation of compounds of the general Formula I
Figure imgf000004_0001
(wherein R and R1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound [
Figure imgf000004_0002
(wherein R2 stands for hydrogen or alkyl comprising
1-4 carbon atoms) with a borone derivative of the general Formula III
Figure imgf000005_0001
(wherein R3, R4 and R5 stand for an alkyl group comprising 1-4 carbon atoms and optionally substituted by halogen or for an aryl group compriaing 6-10 carbon atoms).
The reaction of the quinoline-3-carboxylic acid of the general Formula II and the borone derivative of the general Formula III can preferably be carried out in an optionally halogenated organic carboxylic acid - which may also contain the corresponding acid anhydride - at a temperature between 0 and 200 ºC. The compound of the general Formula I thus formed precipitates from the reaction mixture either spontaneously or under cooling and can be separated e.g. by filtration.
The reaction may however also be carried out in an other solvent (e.g. aulfoxide, amidea, pyridine, aromatic hydrocarbons), if desired.
The borone derivatives of the general Formula III can be used in a molar ratio of 1-50 molea reltted to 1 mole of the quinoline-3-carboxylie acid derivative of the general Formula II.
Further detaila of the preaent invention are to be found in the following Examples without limiting the scope of protection to the said Examples.
Example 1
A mixture of 9.3 g of boric acid and 70 g of propionic anhydride is stirred at 100 °C for 15 minutes whereupon the reaction nixture is heated to the boiling point. After half an hour the temperature is lowered to 110 °C and 29.8 g of e thyl-1-ethyl-6-fluoro-7-chloro- -4-oxo-1, 4-dihydro-quinoline-3-carboxylate are added. The reaction mixture , which turna to a thick suspension within some minutes , is stirred at 110 ºC for 2 hours , then cooled to room temperature and diluted with 300 ml of water. The reaction nixture is cooled and the precipitated crystals are filtered. Thus 41.5 g of 1-ethyl- -6-fluoro -7-chlorc-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid-borone-di( propionyloxy) -anhydride are obtained, yield: 97.7 %; Mp . : 252 °C (decomposition) . Analysis for the Formula C18H18BFClNO7 calculated C = 50.79 %, H = 4.26 %, N = 3.29 %; found C = 50.94 %, H = 4.15 %, N = 3.41 %.
Example 2
A mixture of 46.3 g of boric acid and 345 g of propionic anhydride is stirred at 100 °C for 15 minutes whereupon the reaction mixture is heated to boiling. After half an hour the reaction temperature is lowered to 110 °C and 134.5 g of 1-ethyl-6-fluoro-7-chloro-4-oxo- -1,4-dihydro-quinoline-3-carboxylic acid are added. The reaction mixture is stirred at 110 °C for 2 hours and cooled under 10 ºC. The reaction mixture ia diluted with 150 ml of water and allowed to crystallize in a refrigerator overnight. Next morning the precipitated crystals are filtered, washed with water and dried in vacuo. Thua 208.6 g of 1-ethyl-6-fluoro-7-chloro-4-oxo- -1,4-dihydro-quinoline-3-carboxylic acid- borone-di(propionyloxy)-anhydride are obtained, yields 98 %. The product melts at 269 °C (decomposition). A mixture of the product-formed with any amount of the compound prepared according to Example 1 shows no melting point depression. Example 3
A mixture of 9.3 g of boric acid and 54.1 g of acetic anhydride is heated at 110 °C for 30 minutes. The reaction mixture is cooled to 80 °C and 29.8 g of ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are added. The reaction mixture is stirred at 110 °C for 2 hours, cooled below 10 °C and diluted with 100 ml of water. The cooled reaction mixture is allowed to crystallize in a refrigerator overnight. Next morning the precipitated crystals are filtered, washed with water and dried. Thus 33.5 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline- -3-carboxylic acid-borone-di(acetoxy)-anhydride are obtained. Yield: 84.4 %. The product decompoaes at 274 °C.
Analysis for the Formula C16H14 FGlBNO7 calculated C = 48.34 %, H = 3.54 %, N = 3.52 %; found C = 48.48 %, H = 3.43 %, N = 3.57 %.
Example 4
2.74 g of boric acid and 22.6 g. of acetic acid anyhdride are reacted in the presence of 2 mg of zinc chloride. The boric acid is gradually added to the acetic acid anhydride while the reaction temperature raises to 88 °C. The temperature of the reaction mixture is then slowly raised to 110 °C and 8.79 g. of ethyl- -1-ethyl-6-fluoro-1,4-dihydro-7-chloro-4-oxo-3-quinoline- -carboxylate are added, which had been previously dissolved in 18 ml. of hot 96 % by W/V acetic acid. The orange-red clear solution is stirred for 2 hours at 110 °C and then allowed to cool. The precipitated crystals are filtered and washed several times with water and once with methanol and dried. 10.8 g (92.1 %) off- -white (1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo- -3-quinoline-carboxylate-03,04)-bis(acetate-0)-boron are obtained, decomposing at 273 °C. Analysis for the formula C1 6H14BClFNO7 calculated: C= 48.35 % H = 3.55 % N = 3.52 % found: C =48.2 % H = 3.5 % N = 3.2 %.

Claims

WHAT WE CLAIMS IS :
1. Compounds of the general Formula I
Figure imgf000009_0001
(wherein R and R1 stand for an aliphatic acyloxy group compriaing 2-5 carbon atoma and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms).
2. Process for the pre paration of compounds of the general Formula I
Figure imgf000009_0002
(wherein R and R1 stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally substituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound of the general Formula II
Figure imgf000010_0001
(wherein R2 atanda for hydrogen or alkyl compriaing
1-4 carbon atoma) with a borone derivative of the general Formula III
Figure imgf000010_0002
(wherein R3, R4 and R5 stand for an alkyl group comprising
1-4 carbon atoma and optionally aubatituted by halogen or for an aryl group comprising 6-10 carbon atoms ).
3. Process according to Claim 2 which comprises carrying out the reaction of the compounds of the general Formulae II and III in the presence of a solvent.
4. Proceaa according to Claim 2 which comprises carrying out the reaction of the Compounds of the general Formulae II and III at a temperature between 0 and
150 ºC.
5. Compounds of the general Formula I whenever prepared by the process according to any of Claims 2-4.
6. A process as aubatantially described herein with particular references to the Examples.
PCT/HU1986/000068 1985-12-09 1986-12-09 Norfloxacin intermediate Ceased WO1987003595A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1019870700687A KR940009028B1 (en) 1985-12-09 1986-12-09 Norfloxacin intermediate
AT87900246T ATE53212T1 (en) 1985-12-09 1986-12-09 NORFLOXACIN INTERMEDIATE.
DE8787900246T DE3671628D1 (en) 1985-12-09 1986-12-09 NORFLOXACIN INTERMEDIATE.
JP62500207A JPH0742299B2 (en) 1985-12-09 1986-12-09 Norfloxacin intermediate
NO873247A NO169076C (en) 1985-12-09 1987-08-03 ANHYDRIDES OF 1-ETHYL-6-FLUOR-7-CHLORO-4-OXO-1,4-DIHYDRO-QUINOLIN-3-CARBOXYLIC ACID AND ACID ACID
FI873443A FI84072C (en) 1985-12-09 1987-08-07 MELLANPRODUKT FOER FRAMSTAELLNING AV NORFLOXACIN OCH FOERFARANDE FOER DESS FRAMSTAELLNING.
DK412587A DK412587A (en) 1985-12-09 1987-08-07 QUINOLINE DERIVATIVES AND THEIR PREPARATION

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU854693A HU196218B (en) 1985-12-09 1985-12-09 Process for preparing quinoline carboxylic acid boric acid anhydrides
HU4693/85 1985-12-09

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US (1) US4803274A (en)
EP (1) EP0250535B1 (en)
JP (1) JPH0742299B2 (en)
KR (1) KR940009028B1 (en)
AT (1) ATE53212T1 (en)
CA (1) CA1284800C (en)
CS (1) CS265228B2 (en)
DD (1) DD252608A5 (en)
DE (1) DE3671628D1 (en)
DK (1) DK412587A (en)
FI (1) FI84072C (en)
HR (1) HRP930558A2 (en)
HU (1) HU196218B (en)
NO (1) NO169076C (en)
SI (1) SI8612108A8 (en)
SU (1) SU1604156A3 (en)
WO (1) WO1987003595A1 (en)
YU (1) YU45388B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR880100232A (en) * 1987-04-08 1989-01-31 Chinoin Gyogyszer Es Vegyeszet Quinoline carboxylic acid boric acid anhydrides and process for the preparation therefor
US5091530A (en) * 1987-04-08 1992-02-25 Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt. Baron chelates of quinoline carboxylic acids
GR910100517A (en) * 1991-12-30 1993-08-31 Kyorin Seiyaku Kk (6,7-substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03,04) bis (acyloxy-0)
ES2077490A1 (en) * 1992-11-18 1995-11-16 Marga Investigacion Trimethyl silicon esters and chelate solvates of quinoline-3-carboxylic acids. Preparation and application to the quinolone process
GR960100116A (en) * 1995-04-12 1996-12-31 Quimica Sintetica S.A. FRIDAY METHOD 1-CYCLOPROPYLO-6-FLUORO-1,4-DIFFICULTY-7 - [(1S, 4S) -5-METHYLO-2.5-DIAZABIKYKLO [2.2.1] -ΕΠΤ-2Ξ-ΥΛΟ -4] -3-QUINOLINOCARBOXYLIC OXY AND THESE CHANGES.

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US5380845A (en) * 1987-06-24 1995-01-10 Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt. Process for the preparation of quinoline carboxylic acid derivatives
CN116462631A (en) * 2023-04-24 2023-07-21 青海夏都医药有限公司 Synthetic method of norfloxacin
CN119264049A (en) * 2024-09-30 2025-01-07 中南大学 A kind of synthetic method of norfloxacin

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR880100232A (en) * 1987-04-08 1989-01-31 Chinoin Gyogyszer Es Vegyeszet Quinoline carboxylic acid boric acid anhydrides and process for the preparation therefor
US5091530A (en) * 1987-04-08 1992-02-25 Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt. Baron chelates of quinoline carboxylic acids
GR910100517A (en) * 1991-12-30 1993-08-31 Kyorin Seiyaku Kk (6,7-substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-03,04) bis (acyloxy-0)
ES2077490A1 (en) * 1992-11-18 1995-11-16 Marga Investigacion Trimethyl silicon esters and chelate solvates of quinoline-3-carboxylic acids. Preparation and application to the quinolone process
GR960100116A (en) * 1995-04-12 1996-12-31 Quimica Sintetica S.A. FRIDAY METHOD 1-CYCLOPROPYLO-6-FLUORO-1,4-DIFFICULTY-7 - [(1S, 4S) -5-METHYLO-2.5-DIAZABIKYKLO [2.2.1] -ΕΠΤ-2Ξ-ΥΛΟ -4] -3-QUINOLINOCARBOXYLIC OXY AND THESE CHANGES.

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CS265228B2 (en) 1989-10-13
HUT44566A (en) 1988-03-28
US4803274A (en) 1989-02-07
CA1284800C (en) 1991-06-11
DE3671628D1 (en) 1990-07-05
JPS63501955A (en) 1988-08-04
DD252608A5 (en) 1987-12-23
DK412587D0 (en) 1987-08-07
FI873443A0 (en) 1987-08-07
NO873247L (en) 1987-08-03
HRP930558A2 (en) 1996-04-30
ATE53212T1 (en) 1990-06-15
FI84072C (en) 1991-10-10
YU210886A (en) 1987-12-31
SI8612108A8 (en) 1996-10-31
FI84072B (en) 1991-06-28
EP0250535B1 (en) 1990-05-30
NO169076B (en) 1992-01-27
DK412587A (en) 1987-08-07
SU1604156A3 (en) 1990-10-30
YU45388B (en) 1992-05-28
EP0250535A1 (en) 1988-01-07
HU196218B (en) 1988-10-28
CS908986A2 (en) 1988-03-15
FI873443A7 (en) 1987-08-07
KR940009028B1 (en) 1994-09-29
KR880700803A (en) 1988-04-12
JPH0742299B2 (en) 1995-05-10
NO169076C (en) 1992-05-06
NO873247D0 (en) 1987-08-03

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