EP0525019A1 - Process for preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene - Google Patents

Process for preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene

Info

Publication number
EP0525019A1
EP0525019A1 EP19910907690 EP91907690A EP0525019A1 EP 0525019 A1 EP0525019 A1 EP 0525019A1 EP 19910907690 EP19910907690 EP 19910907690 EP 91907690 A EP91907690 A EP 91907690A EP 0525019 A1 EP0525019 A1 EP 0525019A1
Authority
EP
European Patent Office
Prior art keywords
chloro
fluoroaniline
process according
fluoro
trifluorobenzene
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Withdrawn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
EP19910907690
Other languages
German (de)
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.)
Pfizer Inc
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 EP0525019A1 publication Critical patent/EP0525019A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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

Landscapes

  • 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.1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene are prepared by reacting 2,4-difluoroaniline and 5-chloro-2-fluoroaniline, respectively, with t-butyl nitrite in the presence of a boron trifluoride etherate complex, after which the diazonium salts obtained 2,4-difluorophenyl-diazoniumtetrafluoroborate and a fluoro-4-chloro-phenyl-2-diazoniumtetrafluoroborate are thermally decomposed.

Description

PROCESS FOR PREPARATION OF 1,2,4-TRIFLUOROBENZENE
AND 1-CHLORO-3,4-DIFLUOROBENZENE
Background of the Invention
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.
The reported synthesis of 1,2,4-trifluorobenzene
(G. Schiemann; Journal F. Prakt. Chemie. 140, 97-116 (1934)) is lengthy and has a very low overall yield. This synthesis starts with the nitration of 1,4-difluorobenzene, a relatively expensive starting material, followed by reduction, diazatization in the presence of tetrafluoroboric acid and thermally decomposing the resulting salt at 150°C to obtain the desired 1,2,4-trifluorobenzene in 2.8% overall yield. In the process of the present invention, 1,2,4-trifluorobenzene is prepared, in 60% overall yield, from 2,4-difluoroaniline, a relatively inexpensive and commercially available starting material.
The reported synthesis of 1-chloro-3,4-difluorobenzene is by the Sandmeyer reaction of 3,4-difluoroaniline (NaNO2 in the presence of HCl). The starting material, 3,4-difluoroaniline is not easy to prepare and therefore is not a relatively cheap starting material. In the process of the present invention, 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.
Summary of the Invention
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 C1 to C6 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.
Detailed Description of the Invention
The process of the present invention may be represented as follows:
In accordance with this invention 2,4-difluoroaniline or 5-chloro-2-fluoroaniline is reacted with a C1-C6 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. Preferably 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).
The 5-chloro-2-fluoroaniline used to prepare 1-chloro-3,4-difluorobenzene is prepared as shown in the following reaction scheme:
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
185°C. Other metal fluorides may also be used such as NaF and CsF; and while sulfolane is the best solvent for this transformation, dimethyIformamide, dimethylsulfoxide and dimethylacetamide may also be used. The resulting 4-chloro-1-fluoro-2-nitrobenzene is then hydrogenated to the aniline with platinum on carbon in dimethoxy ethane as the solvent and in the presence of hydrogen. Palladium on carbon and Raney nickel catalyst may also be used. Other solvents that may be used for this reaction include any polar solvent such as ethylacetate, acetic acid, ethanol, methanol or isopropyl alcohol. 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:
o
The desired trihalobenzene is reacted with acetyl chloride under Friedel-Crafts conditions to provide the acetophenone
II which in turn is treated with bleach to give the benzoic acid III. Activation of the acid as the acid chloride followed by treatment with the magnesium salt of ethyl-malonic acid, provides the beta-keto ester IV. The quinolone nucleus VI is then formed by treating the beta-keto ester with triethylorthoformate in the presence of acetic anhydride and addition of cyclopropylamine and finally adding base to achieve the ring closure of compound
V to compond VI. Heating the nucleus VI in the presence of
(S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and an amine base provides the quinolone antibiotic danofloxacin VII.
Similar chemistry is described in European Patent Application Publication Number 303,291 published
February 15, 1989. The use of componds of the formula I as a starting material for preparing quinolone antibiotics is also evident from European Patent Application Number 342,849 published November 23, 1989.
The quinolone antibacterials of United States Patent
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. For example, 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. In the case of animals, they 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. For parenteral administration, they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic. In the case of animals, 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. For intramuscular or intravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day. While 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.
The following examples illustrate the process of the present invention.
Example 1
2,4-difluorophenyl-1-diazonium tetrafluoroborate
10 g (77.5 mmol) of 2,4-difluoroaniline was dissolved in 20 ml of dimethoxyethane and added to a cold (-5°C) solution of 16.5 g (116.3 mmol) of borontrifluoride etherate complex in 35 ml of dimethoxyethane, over a period of 30 minutes. The mixture was cooled to -15°C and 9.58 g (93 mmol) of t-butyl nitrite in 30 ml of dimethoxyethane was added over a period of 30 minutes. The reaction mixture was warmed to -5°C and allowed to stir at that temperature for 1 hour. The product was filtered and dried at high vacuum to yield 17.2 g of the salt in 97% yield. M.P. = 130-135°C.
Example 2
1,2,4-Trifluorobenzene
5 g (45.6 mmol) of the terafluoroborate diazonium salt prepared as described in Example 1 was heated neat in a flask equiped with a distillation head to 195°C for 1 hour.
2 g of the trifluorobenzene was collected via distillation at 86-88°C and trapped at 0°C. This represents a 69% yield.
Example 3
4-chloro-1-fluoro-2-nitrobenzene
1,4-dichloro-2-nitrobenzene (100 g, 0.52 mol) was dissolved in 300 ml of sulfolane and potassium fluoride
(61 g, 1.05 mol) was added. The mixture was heated to 185°C for 24 hours, after which the reaction was cooled to room temperature and 500 ml of water was added. The aqueous layer was then extracted with 10X200 ml portions of hexane and the combined organic layers were washed twice with 100 ml portions of water and dried. Evaporation of the solvents provided 48 grams of the title compound as an oil (51% yield). This oil could be distilled (68°C, 2.2 mm of Hg) but was used as the starting material for Example 4 without further purification.
Example 4
5-chloro-2-fluoroaniline
4-chloro-1-fluoro-2-nitrobenzene (10 g, 57.1 mmol) was dissolved in 80 ml of 1,2-dimethoxyethane and hydrogenated at 50 PSI pressure in the presence of 1 gram of 1% platinum on carbon catalyst for 24 hours. The reaction mixture was then filtered and the solvent was evaporated under a nitrogen atmosphere to provide 9 g of the disired aniline (90% yield).
Example 5
4-Chloro-1-fluorophenyl-2-diazoniumtetrafluoroborate 9 g (57.1 mmol) of 5-chloro-2-fluoroaniline was dissolved in 15 ml of dimethoxyethane and added to a cold (-5°C) solution of 12.2 g (85.7 mmol) of borontrifluoride etherate complex in 25 ml of dimethoxyethane, over a period of 30 minutes. The mixture was cooled to -15°C and 7.1 g (68.5 mmol) of t-butyl nitrite in 20 ml of dimethoxyethane was added over a period of 30 minutes. The reaction mixture was warmed to -5°C and allowed to stir at that temperature for 1 hour. The product was filtered and dried at high vacuum to yield 11.2 g of the salt in 80% yield, M.P. = 140-145°C.
Example 6
1-chloro-3,4-difluorobenzene
6 g (246 mmol) of 1-fluoro-4-chlorophenyl-2-diazonium- tetrafluoroborate was heated neat in a flask equiped with a distillation head to 185°C for 1 hour. 2.2 g of the title compound was collected via distillation at 118-120°C and trapped at 0°C. (60% yield).

Claims

1. 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, respectively, with C1 to C6 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-difluorobenzene.
2. A process according to claim 1 wherein said 5-chloro-2-fluoroaniline is prepared by the reduction of 4-chloro-1-fluoro-2-nitrobenzene.
3. A process according to claim 2, wherein said 4-chloro-1-fluoro-2-nitrobenzene is prepared from 1,4-dichloro-2-nitrobenzene by chlorine-fluorine exchange.
4. A process according to claim 1 wherein said 2,4-difluoroaniline or 5-chloro-2-fluoroaniline is reacted with t-butylnitrite in the presence of borontrifluoride etherate complex.
5. A process according to claim 1 wherein said 5-chloro-2-fluoroaniline is reacted with t-butylnitrite in the presence of borontrifluoride etherate complex.
6. A process according to claim 2 wherein said 5-chloro-2-fluoroaniline is reacted with t-butylnitrite in the presence of borontrifluoride etherate complex.
7. A compound selected from the group consisting of 2,4-difluorophenyl-1-diazoniumtetrafluoroborate and 1-fluoro-4-chlorophenyl-2-diazoniumtetrafluoroborate.
8. A process for the preparation of 2,4-difluorophenyl-1-diazoniumtetrafluoroborate and 1-fluoro-4-chlorophenyl-2-diazoniumtetrafluoroborate comprising reacting 2,4-difluoroaniline or 5-chloro-2-fluoroaniline, respectively, with a C1 to C6 alkylnitrite in the presence of borontrifluoride etherate complex or with an alkali metal or alkaline earth metal nitrite in the presence of tetrafluoroboric acid.
9. A process according to claim 8, wherein said 5-chloro-2-fluoroaniline is prepared by the reduction of 4-chloro-1-fluoro-2-nitrobenzene.
10. A process according to claim 9, wherein said 4-chloro-1-fluoro-2-nitrobenzene is prepared from 1,4-dichloro-2-nitrobenzene by chlorine-fluorine exchange.
11. A process according to claim 8 wherein said 2,4-difluoroaniline or 5-chloro-2-fluoroaniline is reacted with t-butylnitrite in the presence of borontrifluoride etherate complex.
12. A process according to claim 8 wherein said 5-chloro-2-fluoroaniline is reacted with t-butylnitrite in the presence of borontrifluoride etherate complex.
13. A process according to claim 9 wherein said 5-chloro-2-fluoroaniline is reacted with t-butylnitrite in the presence of borontrifluoride etherate complex.
EP19910907690 1990-04-12 1991-03-22 Process for preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene Withdrawn EP0525019A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50837290A 1990-04-12 1990-04-12
US508372 1990-04-12

Publications (1)

Publication Number Publication Date
EP0525019A1 true EP0525019A1 (en) 1993-02-03

Family

ID=24022496

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910907690 Withdrawn EP0525019A1 (en) 1990-04-12 1991-03-22 Process for preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene

Country Status (7)

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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817724B (en) * 2010-05-19 2013-07-03 浙江天宇药业股份有限公司 Preparation method of 1,2,4-trifluoro-benzene
CN116730795B (en) * 2023-08-11 2023-10-27 山东国邦药业有限公司 Synthesis method of trifluoro-phenylacetic acid intermediate 1,2, 4-trifluoro-benzene

Family Cites Families (3)

* 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
DE2928486A1 (en) * 1979-07-14 1981-01-29 Bayer Ag METHOD FOR PRODUCING DIAZONIUM TETRAFLUOROBORATES IN DILUTED AQUEOUS SOLUTION
DE3141659A1 (en) * 1981-10-21 1983-05-05 Bayer Ag, 5090 Leverkusen METHOD FOR THE PRODUCTION OF FLUORAROMATS SUBSTITUTED IN O POSITION

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9116287A1 *

Also Published As

Publication number Publication date
JPH05502453A (en) 1993-04-28
FI924577A0 (en) 1992-10-09
WO1991016287A1 (en) 1991-10-31
PT97308A (en) 1992-01-31
IE911209A1 (en) 1991-10-23
CA2078215A1 (en) 1991-10-13
FI924577A (en) 1992-10-09

Similar Documents

Publication Publication Date Title
Gilman et al. Some reactions of o-halobromobenzenes with n-butyllithium
NZ194714A (en) Propenylamine derivatives and pharmaceutical compositions
Dickinson et al. Cyanocarbon Chemistry. XVII. Tricyanoethylene and Tricyanovinyl Chloride1
Franz et al. Reactions of diaryldialkoxysulfuranes with primary and secondary amines. Preparation and reactions of S, S-diaryl-N-alkylsulfilimines and oxidation of secondary amines to imines
Akiyama et al. Cyclic Acetylenes. IV. Synthesis of a Cyclic Tetraacetylene Containing Anthracene Nuclei
Montgomery et al. Competition between insertion and conjugate addition in nickel-catalyzed couplings of enones with unsaturated functional groups
JPS5919536B2 (en) Method for producing 5-aroyl-1-lower alkylpyrrole-2-acetic acid derivative
EP0525019A1 (en) Process for preparation of 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene
KR860001601B1 (en) Process for the preparation of indoles
Shvartsberg et al. Acetylenic derivatives of quinones
Kamijo et al. A novel one step conversion of alcohols into alkyl bromides or iodides
Nelson An important limitation in the reactions of 1-chloro-1-alkenes with n-or s-butyllithium
JP2002539180A (en) Method for producing cyclic α, β-unsaturated ketone
IE58428B1 (en) Process for nitration of phenol derivatives
FR2519631A1 (en) PROCESS FOR THE PREPARATION OF 3,3'- OR 3,4'-DIAMINO BENZOPHENONE
EP1070038B1 (en) New processes for the preparation of 3-bromoanisole and 3-bromonitrobenzene
US20040171863A1 (en) Process for poducing beta-oxonitrile compound or alkali metal salt thereof
CN1247504C (en) Process for preparing beta-halogen-alpha-phenyl ethyl alcohol compounds
KR950005770B1 (en) N-phenyl-s,2,6,6-tetrahalocyclo hexaneimine and process for preparing 2,2,6,6-tetrahalocyclohexaneimine derivative and 2,6-dihaloaniline derivative
Taylor et al. Highly stereoselective Friedel-Crafts alkylations via epoxide transannular reactions
US20030060621A1 (en) Process for preparing indolopyrrolocarbazole derivatives, intermediates therefor, and preparation process of the intermediates
IE911444A1 (en) Process for preparing 3,4-difluoroaniline
US3268546A (en) Certain 2-benzoxazolinone compounds having methoxy and halo substituents
WO2005099712A2 (en) Process for preparation of n-[3-(3-cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-n-ethylacetamide
Peng et al. The Synthesis of 4-Hydroxy-6-quinaldine Carbohydrazide1, 2

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19920928

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19931124

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19940607