CA2078215A1

CA2078215A1 - Process for the preparation of 1,2,4- trifluorobenzene and 1-chloro-3, 4- difluorobenzene

Info

Publication number: CA2078215A1
Application number: CA002078215A
Authority: CA
Inventors: Tamim F. Braish
Original assignee: Individual
Current assignee: Pfizer Ltd Great Britain
Priority date: 1990-04-12
Filing date: 1991-03-22
Publication date: 1991-10-13
Also published as: JPH05502453A; FI924577L; FI924577A7; FI924577A0; EP0525019A1; IE911209A1; WO1991016287A1; PT97308A

Abstract

1,2,4-Triflurobenzene 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 borontrifluoride etherate complex, followed by the thermal decomposition of the resulting diazonium salts 2,4-difluorophenyl-1-diazoniumtetrafluoroborate and 1-fluoro-4-chlorophenyl-2-diazoniumtetrafluoroborate.

Description

WQ91/16287 2 0 7 8 21~ PCT/US91/0193~
.. . ' ' ,~.

5PROC~SS FOR PREPARATION OF 1.2.4-TRIFLUOROBENZENE
AN~ 1-CHLORO-3.4-DIFLUOROB~NZ~NE
Back~round 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 l-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 ~,861,779.
The reported synthesis of 1,2,4-trifluorobenzene (G. Schiemann; Journal F. Prakt. ~hemie, 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 tetrafluoro-boric acid and thermally decomposing the resulting salt at 150C 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, l-chloro-3,4-difluorobenzene is prepared, in 27% overall yield, from 1,4-dichloro-2-nitro-benzene, a very inexpensive and commercially availablestarting 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.

.

, WO 91tl6287 ~ PCI/US91/01g37 2~82~

M.P. Doyle, and W.J. Bryker, J. ora. Chem. 44 1572-1574 (1979) refer to synthesis of arenediazonium tetrafluoroborate salts from aromatic amines, tert-butyl nitrite, and boron trifluoride etherate.
SSummary 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 Ct 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-difluoro-phenyl-l-diazoniumtetrafluoroborate and l-fluoro-4-chloro-phenyl-2-diazoniumtetrafluoroborate which are the diazonium salts formed in the foregoing process and to the process for their preparation described above.
~etailed Description of the Invention The process of the present invention may be represented as follows: ~-B ~

[~ r X=CI or F
In accordance with this invention 2,4-difluoroaniline or 5-chloro-2-fluoroaniline is reacted with a C~-C6 alkylnitrite in the presence of borontrifluoride etherate complex or with a~ 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 -20C and about +20C, but is preferably about -5C. The solvent should be an inert solvent. Suitable solvents include chlorinated solvents (e.q., 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 150C and about 280C, the preferred temperature being about 195C for the preparation of 1,2,4-trifluorobenzene and about 185C 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:

Cl F F' [~3,NO~ ~,N02 ~ N H~

1,4-dichloro-2-nitrobenzene is heated with potassium fluoride in sulfolane. The temperature for this reaction is between 140 and 220C, but preferably the reaction is run at 185C. Other metal fluorides may also be used such as NaF

W O 91/16287 2 ~ 7 8 2 I ~ PC~r/US91/01937 and CsF; and while sulfolane is the best solvent for this transformation, dimethylformamide, 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:

2 o 7 8 2 1 ~i PCr/US91/01937 r~x ~r~cH, bl~ch ~ .
x ~ cl o. ~

o o o 0 ~OH ~--~OE~

h~ l I V

r =

b )` ~:
V Vl ~ OH

I;H~ V ¦ ¦

.

W O 91/16287 ! . P(~r/US91/01937 207821~

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 rinq closure of compound V to compond VI. Heating the nucleus VI in the presence of (S,S)-2-methyl-2,5-diazabicyclot2.2.1]heptane and an amine base provides the quinolone antibiotic danofloxacin VII.
Similar chemistry is described in European Patent 15 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 drin~ing water in a concentration of 5-5000 ppm, WO91/16287 2 ~ 7 8 2 t ~ PCT/US91/01937 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 csndition 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-difluoro~henvl-1-diazonium tetrafluoroborate 10 g (77.5 mmol) of 2,4-difluoroaniline was dissolved in 20 ml of dimethoxyethane and added to a cold (-5C) 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 -15C 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 -5C and allowed to stir at that temperature for WO91/t6287 - PCT/US91/01937 2 ~ 7 ~ 2 ~ ~ !

1 hour. The product was filtered and dried at high vacuum to yield 17.2 g of the salt in 97% yield. M.P. = 130-135C.
Exam~le 2 1,2.4-Trifluorobenzene 55 g (45.6 mmol) of the terafluoroborate diazonium salt prepared as described in Example l was heated neat in a flask equiped with a distillation head to 195C for 1 hour.
2 g of the trifluorobenzene was collected via distillation at 86-88C and trapped at 0C. 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 q, 1.05 mol) was added. The mixture was heated to 185C
lS 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 lOX200 ml portions of hexane and the combined organic layers were washed twice with 100 ml portions of water and dried. Evaporation of the solvents 2~ provided 48 grams of the title compound as an oil (51%
yield). This oil could be distilled (68C, 2.2 mm of Hg) but was used as the starting material for Example 4 without further purification.
Exam~le 4 255-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 S0 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 desired aniline (90% yield).
Exam~le 5 4-Chloro-l-fluoroDhenyl-2-diazoniumtetrafluoroborate 359 g (57.1 mmol) of 5-chloro-2-fluoroaniline was dissolved in lS ml of dimethoxyethane and added to a cold W091/16287 2 0 7 8 2 ~ ~ PCT/US91/Ot937 _g_ (-soc) 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 -15C 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 -5C 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. =
140-145C.
Exa~p~e_6 l-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 185C for 1 hour. 2.2 g of the title compound was collected via distillation at 118-120C and trapped at 0C. (60% yield).

Claims

-10-

1. A process for the preparation of 1,2,4-tri-fluorobenzene 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 tetra-fluoroboric acid and heating the resulting diazonium salt to obtain 1,2,4-trifluorobenzene or 1-chloro-3,4-difluoro-benzene.

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-di-chloro-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-difluoro-phenyl-1-diazoniumtetrafluoroborate and 1-fluoro-4-chloro-phenyl-2-diazoniumtetrafluoroborate comprising reacting 2,4-difluoroaniline or 5-chloro-2-fluoroaniline, respect-ively, 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 tetra-fluoroboric 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-di-chloro-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.