WO1991016287A1 - Procede de preparation de 1,2,4-trifluorobenzene et de 1-chloro-3,4-difluorobenzene - Google Patents

Procede de preparation de 1,2,4-trifluorobenzene et de 1-chloro-3,4-difluorobenzene Download PDF

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Publication number
WO1991016287A1
WO1991016287A1 PCT/US1991/001937 US9101937W WO9116287A1 WO 1991016287 A1 WO1991016287 A1 WO 1991016287A1 US 9101937 W US9101937 W US 9101937W WO 9116287 A1 WO9116287 A1 WO 9116287A1
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WO
WIPO (PCT)
Prior art keywords
chloro
fluoroaniline
process according
fluoro
nitrobenzene
Prior art date
Application number
PCT/US1991/001937
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English (en)
Inventor
Tamim F. Braish
Original Assignee
Pfizer Inc.
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 Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO1991016287A1 publication Critical patent/WO1991016287A1/fr
Priority to FI924577A priority Critical patent/FI924577A/fi

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/20—Diazonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens

Definitions

  • This invention relates to a process for the preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene and to 2,4-difluorophenyl-1-diazoniumtetrafluoroborate and 1-fluoro-4-chlorophenyl-2-diazoniumtetrafluoroborate which are novel intermediates in such preparation.
  • the final product 1,2,4-trifluorobenzene and 1-chloro-3,4- difluorobenzene are useful chemical intermediates for the preparation of quinolone antibacterials such as those disclosed in United States Patents 4,571,396 and 4,861,779.
  • 1,2,4-trifluorobenzene is prepared, in 60% overall yield, from 2,4-difluoroaniline, a relatively inexpensive and commercially available starting material.
  • 1-chloro-3,4-difluorobenzene is by the Sandmeyer reaction of 3,4-difluoroaniline (NaNO 2 in the presence of HCl).
  • 3,4-difluoroaniline is not easy to prepare and therefore is not a relatively cheap starting material.
  • 1-chloro-3,4-difluorobenzene is prepared, in 27% overall yield, from 1,4-dichloro-2-nitrobenzene, a very inexpensive and commercially available starting material.
  • G.C. Finger and C.W. Kruse, J. Am. Chem. Soc. 78, 6034 (1956) refer to replacement of aromatic chloro and nitro groups by fluoro groups.
  • M.P. Doyle, and W.J. Bryker, J. Org. Chem. 44, 1572- 1574 (1979) refer to synthesis of arenediazonium tetrafluoroborate salts from aromatic amines, tert-butyl nitrite, and boron trifluoride etherate.
  • the present invention relates to a process for the preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4- difluorobenzene comprising reacting 2,4-difluoroaniline or 5-chloro-2-fluoroaniline with C 1 to C 6 alkylnitrite in the presence of borontrifluoride etherate complex or with an alkali metal or alkaline earth metal nitrite in the presence of tetrafluoroboric acid and heating the resulting diazonium salt to obtain 1,2,4-trifluorobenzene or 1-chloro-3,4-diflurobenzene.
  • the present invention also relates to 2,4-difluorophenyl-1-diazoniumtetrafluoroborate and 1-fluoro-4-chlorophenyl-2-diazoniumtetrafluoroborate which are the diazonium salts formed in the foregoing process and to the process for their preparation described above.
  • 2,4-difluoroaniline or 5-chloro-2-fluoroaniline is reacted with a C 1 -C 6 alkylnitrite in the presence of borontrifluoride etherate complex or with an alkali metal or alkaline earth metal nitrite in the presence of tetrafluoroboric acid.
  • Suitable nitrites include isoamyl nitrite and sodium nitrite.
  • one of the starting materials is reacted with tert-butyl nitrite in the presence of borontrifluoride etherate complex.
  • the temperature of the reaction can be between about -20°C and about +20°C, but is preferably about -5°C.
  • the solvent should be an inert solvent.
  • Suitable solvents include chlorinated solvents (e.g., methylene chloride, and chloroform), ethereal solvents (e.g., diethylether, diisopropylether, monoglyme, and diglyme) and aromatic solvents (e.g., benzene, toluene, and chlorobenzene), but diglyme is the preferred solvent for this reaction.
  • the thermal decomposition of the tetrafluoroborate diazonium salt is carried out at temperatures ranging between about 150°C and about 280°C, the preferred temperature being about 195°C for the preparation of 1,2,4-trifluorobenzene and about 185°C for the preparation of 1-chloro-3,4-difluorobenzene.
  • High boiling solvents such as decane may be used for this reaction, but it is preferred to conduct the thermal decomposition without any solvents.
  • the pressures of the foregoing reactions are not critical, for example, the pressures may be in the range of about 0.5 to about 2 atmospheres, but it is preferred to run the reactions at ambient pressure (i.e. about one atmosphere).
  • 1,4-dichloro-2-nitrobenzene is heated with potassium fluoride in sulfolane.
  • the temperature for this reaction is between 140 and 220°C, but preferably the reaction is run at
  • This reaction may be run under a pressure of 10 to 3000 PSI, but preferably at 50 PSI, or it may be run under atmospheric pressure by using phase transfer hydrogenations. Alternatively this reduction could be accomplished utilizing zinc or tin in acidic media or iron powder in the presence of ammonium chloride.
  • 1,2,4-Trifluorobenzene or 1-chloro-3,4-difluorobenzene may be used to prepare the quinolone antibiotic danofloxacin (disclosed in United States Patent 4,861,779) as outlined in the following reaction scheme:
  • 4,571,396 and and 4,861,779 and the pharmaceutically acceptable acid addition salts thereof are useful in the treatment of bacterial infections of broad spectrum, particularly the treatment of gram-positive bacterial strains.
  • the quinolone antibacterials may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • animals are advantageously contained in an animal feed or drinking water in a concentration of 5-5000 ppm, preferably 25-500 ppm. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously.
  • a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic.
  • compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1-50 mg/kg/day, advantageously 0.2-10 mg/kg/day given in a single daily dose or up to 3 divided doses.
  • the quinolone antibacterials can be administered to humans for the treatment of bacterial diseases by either the oral or parenteral routes, and may be administered orally at dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dose or up to 3 divided doses.
  • dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day.
  • intramuscular administration may be a single dose or up to 3 divided doses
  • intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.
  • 1,4-dichloro-2-nitrobenzene (100 g, 0.52 mol) was dissolved in 300 ml of sulfolane and potassium fluoride

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

On prépare du 1,2,4-trifluorobenzène et du 1-chloro-3,4-difluorobenzène en faisant réagir une 2,4-difluoroaniline et une 5-chloro-2-fluoroaniline, respectivement, avec du t-butyl nitrite en présence d'un complexe d'éthérate de trifluorure de bore, après quoi on procède à la décomposition thermique des sels de diazonium obtenus 2,4-difluorophényle-diazoniumtétrafluoroborate et un fluoro-4-chloro-phényle-2-diazoniumtétrafluoroborate.
PCT/US1991/001937 1990-04-12 1991-03-22 Procede de preparation de 1,2,4-trifluorobenzene et de 1-chloro-3,4-difluorobenzene WO1991016287A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI924577A FI924577A (fi) 1990-04-12 1992-10-09 Foerfarande foer framstaellning av 1,2,4-trifluorbenzen och 1-klor-3,4-difluorbenzen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50837290A 1990-04-12 1990-04-12
US508,372 1990-04-12

Publications (1)

Publication Number Publication Date
WO1991016287A1 true WO1991016287A1 (fr) 1991-10-31

Family

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Application Number Title Priority Date Filing Date
PCT/US1991/001937 WO1991016287A1 (fr) 1990-04-12 1991-03-22 Procede de preparation de 1,2,4-trifluorobenzene et de 1-chloro-3,4-difluorobenzene

Country Status (7)

Country Link
EP (1) EP0525019A1 (fr)
JP (1) JPH05502453A (fr)
CA (1) CA2078215A1 (fr)
FI (1) FI924577A (fr)
IE (1) IE911209A1 (fr)
PT (1) PT97308A (fr)
WO (1) WO1991016287A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817724A (zh) * 2010-05-19 2010-09-01 浙江天宇药业有限公司 1,2,4-三氟苯的制备方法
CN116730795A (zh) * 2023-08-11 2023-09-12 山东国邦药业有限公司 一种三氟苯乙酸中间体1,2,4-三氟苯的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0022959A1 (fr) * 1979-07-14 1981-01-28 Bayer Ag Procédé de préparation de tétrafluoroborates de diazonium dans une solution diluée aqueuse
EP0077501A1 (fr) * 1981-10-21 1983-04-27 Bayer Ag Procédé pour la préparation de composés fluoroaromatiques substitués en position ortho

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4216340A (en) * 1979-05-02 1980-08-05 Merck & Co., Inc. Preparation of 5-(2,4-difluorophenyl)salicylic acid and derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0022959A1 (fr) * 1979-07-14 1981-01-28 Bayer Ag Procédé de préparation de tétrafluoroborates de diazonium dans une solution diluée aqueuse
EP0077501A1 (fr) * 1981-10-21 1983-04-27 Bayer Ag Procédé pour la préparation de composés fluoroaromatiques substitués en position ortho

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817724A (zh) * 2010-05-19 2010-09-01 浙江天宇药业有限公司 1,2,4-三氟苯的制备方法
CN116730795A (zh) * 2023-08-11 2023-09-12 山东国邦药业有限公司 一种三氟苯乙酸中间体1,2,4-三氟苯的合成方法
CN116730795B (zh) * 2023-08-11 2023-10-27 山东国邦药业有限公司 一种三氟苯乙酸中间体1,2,4-三氟苯的合成方法

Also Published As

Publication number Publication date
PT97308A (pt) 1992-01-31
EP0525019A1 (fr) 1993-02-03
JPH05502453A (ja) 1993-04-28
CA2078215A1 (fr) 1991-10-13
IE911209A1 (en) 1991-10-23
FI924577A0 (fi) 1992-10-09
FI924577A (fi) 1992-10-09

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