EP0527154A1 - Verfahren zur herstellung von 3,4-difluoranilin - Google Patents

Verfahren zur herstellung von 3,4-difluoranilin

Info

Publication number
EP0527154A1
EP0527154A1 EP19910907990 EP91907990A EP0527154A1 EP 0527154 A1 EP0527154 A1 EP 0527154A1 EP 19910907990 EP19910907990 EP 19910907990 EP 91907990 A EP91907990 A EP 91907990A EP 0527154 A1 EP0527154 A1 EP 0527154A1
Authority
EP
European Patent Office
Prior art keywords
hydroxylamine
difluoroaniline
fluoro
fluorobenzene
acid
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.)
Withdrawn
Application number
EP19910907990
Other languages
English (en)
French (fr)
Inventor
Tamim F. Braish
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.)
MTG Divestitures LLC
Original Assignee
Pfizer Hospital Products Group 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 Hospital Products Group Inc filed Critical Pfizer Hospital Products Group Inc
Publication of EP0527154A1 publication Critical patent/EP0527154A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/10—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of unsubstituted hydrocarbon radicals or of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the present invention relates to a novel method for preparing 3,4-difluoroaniline. This compound is useful in the preparation of quinolone antibacterials as described in United States Patent 4,833,270.
  • United States Patent 4,145,364 refers to the prepara ⁇ tion of monofluoroanilines via a Bamberger rearrangement or an arylhydroxylamine route.
  • the patent indicates that the arylhydroxylamine route "suffers from the disadvantage of concomitant formation of corresponding unfluorinated aniline, as well as the symmetrical azo and azoxy com ⁇ pounds" and that "considerable tar is formed making product isolation difficult.”
  • the patent also refers to the preparation of monofluoroanilines and difluoroanilines by treating aromatic azides with anhydrous hydrogen fluoride. T.J. Broxton et al., J. Org.
  • Chem., 42, 643-649 (1977) refer to the effect of oxygen and nitrogen atmospheres on thermolysis of arenediazonium salts.
  • the process of the present invention is advantageous in that it uses hydroxylamines which are relatively stable compared to aromatic azides. The latter are used as starting materials in the process of U.S. Patent 4,145,364.
  • Azides are not stable and tend to decompose when warmed or when left for a long period of time at room temperature. Furthermore, hydroxylamines are, in most cases, crystalline and can be conveniently purified should the need arise.
  • the process of the present invention does not result in the formation of a significant amount of unfluorinated material or tar. I have found that the use of anhydrous conditions and the exclusion of oxygen avoid such undesir ⁇ able results.
  • the present invention relates to a process for pre ⁇ paring 3,4-fluoroaniline comprising reacting 1-hydroxyl- amine-3-fluorobenzene with anhydrous hydrogen fluoride in the absence of oxygen.
  • oxygen is excluded by conducting the reaction under an inert atmosphere such as nitrogen or argon.
  • the solvent for the foregoing reaction is preferably pyridine.
  • l-hydroxylamine-3- fluorobenzene is prepared by hydrogenating 3-fluoro-1-nitro- benzene.
  • the hydrogenation is preferably accomplished by reacting the latter compound with hydrazine hydrate in the presence of platinum on carbon in an alcoholic solvent such as ethanol.
  • the present invention also relates to the novel compound 3-fluoro-1-hydroxylamine.
  • the reaction of l-hydroxylamine-3-fluorobenzene with hydrogen fluoride should be conducted in an inert solvent.
  • Suitable solvents include acetonitrile and pyridine. Pyridine is a preferred solvent.
  • the reaction will generally be conducted at a temperature from about 0°C to about 50°C, preferably from about 20°C to 25°C. The temperature is most preferably 25°C.
  • the hydrogenation of 3-fluoro-l-nitrobenzene is preferably accomplished by reacting the compound with hydrazine in the presence of platinum on carbon. Other sources of hydrogen such as ammonium formate and other hydrogenation catalysts such as Raney Nickel may also be used.
  • Suitable solvents for the hydrogenation reaction include most alcohols. The preferred solvent is ethanol.
  • the reaction temperature will generally be from about -20°C to about 50°C, preferably from about 0°C to about 5°C. The temperature is most preferably 0°C.
  • the pressures of the foregoing reactions are not critical. The reactions will generally be conducted at a pressure of about 0.5 to about 2 atmospheres, preferably at ambient pressure (generally about one atmosphere) .
  • 3,4-Difluoroaniline may be reacted as described in United States Patent 4,833,270 to provide 1-cyclopropyl- 6,7-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, which may be used to prepare various quinolone antibiotics, including danofloxacin.
  • an aqueous solution of 3,4-difluoroaniline and hydroxylamine hydrochloride containing hydrochloric acid is reacted with an aqueous solution of chloral hydrate and sodium sulfate at the reflux temperature, then filtered while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)-aceta ide.
  • the latter compound is reacted with concentrated sulfuric acid with heat, then added to cracked ice, giving 5,6-difluoro- lH-indole-2,3-dione.
  • a basic aqueous solution of the dione is treated with hydrogen peroxide and heat, and then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid.
  • the 2-amino-4,5-difluorobenzoic acid is added to a mixture of anhydrous copper at 0-5°C, and then added to a dilute mineral acid, giving 2-chloro-4,5-difluorobenzoic acid.
  • a solution of 2-chloro-4,5-difluorobenzoic acid in acetonitrile containing a catalytic amount of dimethyl- formamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro- 4,5-difluorobenzoic acid chloride, which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, which is then added to ice water and acidified to pH 2.5, giving (2-chloro-4,5-difluoro- benzoyl)propanedioic acid diethyl ester.
  • a solution of the diethyl ester in p-dioxane and water is heated at reflux, and then evaporated and distilled, giving 2-chloro-4,5- difluoro- ⁇ -oxobenzenepropanoic acid ethyl ester.
  • a solution of the ethyl ester and triethyl orthoformate in acetic anhydride is heated at 150°C for 2 hours, giving 2-chloro- ⁇ -(ethoxymethylene)-4,5-difluoro- ⁇ -oxobenzenepro- panoic acid ethyl ester.
  • Cyclopropylamine is added to a solution of the latter ethyl ester in ethanol, giving 2-chloro- ⁇ -[ (cyclopropylamino)methyleneJ-4,5-difluoro- ⁇ - oxobenzenepropanoic acid ethyl ester, which is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving l-cyclopropyl-6 ,7-difluoro- l,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, which is then refluxed with acid, giving 1-cyclopropyl- 6 ,7-difluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
  • Danofloxacin may be prepared by reacting the acid thus prepared with (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and an amine base
  • Quinolone antibacterials such as danofloxacin (dis ⁇ closed in U.S. Patent 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 of U.S. Patent 4,861,779 may be administered alone, but will generally be ad inis- tered 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 concen ⁇ tration of 5-5000 ppm, preferably 25-500 ppm.
  • compounds can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously.
  • parenteral adminis ⁇ tration they ar best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to made the solution isotonic.
  • compounds can be administered intra ⁇ muscularly 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.
  • Example 1 l-Hvdroxylamine-3-fluorobenzene 3-Fluoro-l-nitrobenzene (20 g, 0.14 mol) was dissolved in 400 ml of ethanol and 5% platinum on carbon (2.0 g, 10 weight %) was added. The mixture was then cooled with an ice bath to 0°C and hydrazine hydrate (13.8 ml, 0.28 mmol) was added dropwise over a period of 45 minutes. After an additional stirring period of 30 minutes, the reaction mixture was filtered through diatomaceous earth (Celite (trademark)) and the solvent was evaporated under vacuo. The residual oil was suspended in 400 ml of water and extracted with 3x500 ml of methylene chloride.
  • Example 2 3.4-Difluoroaniline A plastic bottle was charged with 75 ml of HF - pyridine under an inert atmosphere at 0°C and to that 1-hydroxylamine-3-fluorobenzene (5.0 g, 39.4 mmol) was added carefully. The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. The reaction mixture was carefully quenched with 2 1 of sat- urated aqueous NaHC0 3 solution and extracted with 5 x 500 ml portions of methylene chloride. The combined organic solvents were washed with saturated CuS0 4 solution (3x) , dried (MgS0 4 ) and evaporated to produce 4.6 g of an oil in 90% yield. NMR(CDC1 3 ) : S 6.95 (q, IH) , 6.55 (m, IH) , 6.34 (m, IH) , 3.6 (broad, 2H) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19910907990 1990-05-01 1991-04-12 Verfahren zur herstellung von 3,4-difluoranilin Withdrawn EP0527154A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51726490A 1990-05-01 1990-05-01
US517264 1990-05-01

Publications (1)

Publication Number Publication Date
EP0527154A1 true EP0527154A1 (de) 1993-02-17

Family

ID=24059091

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910907990 Withdrawn EP0527154A1 (de) 1990-05-01 1991-04-12 Verfahren zur herstellung von 3,4-difluoranilin

Country Status (6)

Country Link
EP (1) EP0527154A1 (de)
JP (1) JPH05502036A (de)
CA (1) CA2080596A1 (de)
IE (1) IE911444A1 (de)
PT (1) PT97530A (de)
WO (1) WO1991017138A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010036533A1 (de) 2010-07-21 2012-01-26 Dr. Ing. H.C. F. Porsche Aktiengesellschaft Elektrofahrzeug mit Elektromaschinen an einer Vorderachse und einer Hinterachse

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19610571A1 (de) * 1996-03-18 1997-09-25 Basf Ag Verfahren und Zwischenprodukte zur Herstellung von Pyridyl-4-Fluoranilinen
AU9264398A (en) * 1997-09-05 1999-03-29 Basf Aktiengesellschaft Method for producing (hetero)aromatic hydroxylamines
CN116606214A (zh) * 2023-07-19 2023-08-18 山东国邦药业有限公司 一种3,4-二氟苯胺的合成方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145364A (en) * 1977-11-30 1979-03-20 Merck & Co., Inc. Preparation of fluorinated anilines
IL97026A (en) * 1990-02-07 1995-01-24 Ciba Geigy Pyrimidinylphenyl hydroxylamine derivatives, their preparation and their use as microbicides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9117138A1 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010036533A1 (de) 2010-07-21 2012-01-26 Dr. Ing. H.C. F. Porsche Aktiengesellschaft Elektrofahrzeug mit Elektromaschinen an einer Vorderachse und einer Hinterachse
DE102010036533B4 (de) 2010-07-21 2023-05-11 Dr. Ing. H.C. F. Porsche Aktiengesellschaft Elektrofahrzeug mit Elektromaschinen an einer Vorderachse und einer Hinterachse

Also Published As

Publication number Publication date
PT97530A (pt) 1992-02-28
WO1991017138A1 (en) 1991-11-14
CA2080596A1 (en) 1991-11-02
IE911444A1 (en) 1991-11-06
JPH05502036A (ja) 1993-04-15

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