JPH05502453A - Method for producing 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 1.2.4-trifluorobenzene and 1-chloro-3,4-difluorobenze manufacturing method Mediocrity Ω! amount The present invention relates to 1,2,4-trifluorobenzene and 1-chloro-3,4-difluorobenzene. production process with benzene and a novel intermediate in such production, 2,4-di Fluorophenyl-1-diazonium tetrafluoroborate and 1-fluoro- e- for 4-chlorophenyl-2-diazonium tetrafluorocarbon I/- 1k final product 1,2,4-trifluorobenzene and 1-lytetra-3,4-diph Luorobenzene is described in U.S. Patent Nos. 4.571,396 and 4.861.779. Quinolones are useful chemical intermediates in the production of antimicrobial agents as disclosed.

The reported 1,2.4-)lifluorobenzene synthesis method [G. , Schjemann); Journal F, Pract, Chemie (Journa tF, Prakt, Chemie), Joori, 97-116 (1934)] takes a long time and the total number rate is very low. This synthesis method uses 1,4-difluorobenze The process begins with the nitration of relatively expensive starting materials, followed by reduction and tetrafluorophonation. Diazotization in the presence of uric acid and at 150°C Following the thermal decomposition of the salt produced, objective 1. ．． 2. Total number of 4-trifluorobenzene Obtained at a rate of 2.8%. In the method of the present invention, 1,2.44 refluorohensene is compared to 2,4-difluoroaniline, which is an inexpensive and commercially available starting material, It is obtained at a total number rate of 6096.

The reported formation properties of 1-chloro-3,4-difluorobenzene are Sandmeyer reaction of NaNO in the presence of luoroaniline (HCl) Meyer react, 1on). Starting material 3,4-di Fluoroaniline is not easy to manufacture and is therefore not a relatively inexpensive starting material. No. In the method of the present invention, 1-4-3,4-difluorobenzene is 1,4-dichloro-2-nitrobenze, an inexpensive and commercially available starting material Manufactured from 27% total quantity.

G, C, Fjnger and C, W, Cruse (C, W, Kruse), ”, ;x4. C, rA, V’), (J, Am... describes the substitution of a nitro group with a fluoro group.

M, B, Doyle (M, P, Doyle) and W, J, Briker (W, J, Bryker), nz4. t/1. =gu '71. ．． (J, q2s , Ch=m) ±1.1572-1574 (1979> is aromatic amine, nitrous acid Arrangeazonium from tert-butyl and boron trifluoride ether The synthesis of tetrafluoroborate salts is described.

Totsui Ω nose! The present invention provides that 2,4-difluoroaniline is 5-chloro-2-fluoroaniline. with c1-c6 alkyl nitrite in the presence of a boron trifluoride etherate complex, or alkali metal nitrites or alkaline earths in the presence of tetrafluoroboric acid. 1. React with metal nitrite and heat the generated diazonium salt. ．． 2.4 - obtaining trifluorobenzene or 1-chloro-3,4-difluorobenzene, ], 2.4-trifluorobenzene and l-chloro-3,4-diphthalate The present invention relates to a method for producing fluorobenzene.

The present invention also provides diazonium salts formed by the above method, 2,4-difluoro Phenyl-1-diazonium tetraborate and ]-fluoro-4-chlorophenylene The present invention also relates to 2-diazonium tetraborate and the above-mentioned method for producing them.

Expropriation of detailed deposit of vertical building According to the present invention, the method of the present invention can produce 2,4-difluor as shown below. Oloaniline is a combination of 5-chloro-2-fluoroaniline and boron trifluoride ether. with C1-C@alkyl nitrite in the presence of a 1/- complex or with tetrafluoroborous Reacts with alkali metal nitrites or alkaline earth metal nitrites in the presence of acids. 9 Suitable nitrite salts include isoamyl nitrite or sodium nitrite. . One of the starting materials was added to a nitrous acid jet in the presence of a boron trifluoride etherate body. -Preference is given to reacting with butyl. The reaction temperature was about -20℃ and about +20℃. The solvent may be an inert solvent, but preferably at a temperature of about -5°C. sell. Suitable solvents include chlorinated solvents (e.g. methylene chloride, chloroform), ether solvents such as diethyl ether, diimpropyl ether, monoglyme and dipropyl ether. glyme) and aromatic solvents (e.g. benzene, toluene and chlorobenzene). However, diglyme is the preferred solvent for this reaction. Tetrafluorobo I Thermal decomposition of /-diazonium salts is carried out at temperatures within the range of approximately 50°C to approximately 280°C. The preferred temperature for the production of 1.2.4-trifluorobenzene is approximately 195°C, and for the production of 1-chloro-3,4-difluorobenzene it is approximately The temperature is 185°C. It is possible to use a high-boiling solvent such as decane for this reaction. It can also be done with thermal decomposition! ! - Preference is given to carrying out without solvent.

The pressure of the reaction is not critical and may range, for example, from about 0.5 to about 2 atmospheres. However, the reaction can be carried out at ambient pressure (i.e., about 1 atm). preferable.

5-chloro-2-fluor used in the production of 1-chloro-3,4-difluorobenzene Oloaniline is produced as shown in the following reaction formula: ], 4-dichloro-2-di Trohenzene is heated with potassium fluoride in sulfolane. Because of this reaction The temperature is within the range of 140 to 220°C, and the temperature is 1.5. ] Fruit at 85°C. It is preferable to apply For example, other metals such as NaF and CsF compounds can also be used: sulfolane is the best solvent for this transformation. but also dimethylformamide, dimethylsulfoxide and dimethylacetamide Can be used. 4-chloro-1-fluoro-2-nitrohenzene produced Then, the carbon support f*f size was prepared in dimethoxyethane as a solvent in the presence of hydrogen. Hydrogenate with platinum to give aniline. Palladium and Laneni with carbon support Keckel's catalyst can also be used. Other solvents that can be used for this reaction include , for example ethyl acetate, acetic acid, ethanol, methanol or isopropyl alcohol There are polar solvents such as This reaction is carried out under pressure between 10 and 3000 PSI. can be carried out at 50PS1, but is preferably carried out at 50PS1. It can also be carried out under atmospheric pressure by using Alternatively, this reduction can be carried out in an acidic medium. using iron powder in the presence of zinc or tin or in the presence of ammonium chloride. It can also be carried out.

1.2.4-trifluorobenzene or j-talolo 3,4-difluorobenze The quinolone antibiotic danofloxacin (U.S. Patent No. 4) ．． 86L #4 shown in No. 779): X=CI or F I II III IV V Vl εII, Vll Preferred trihalobenzenes are Friedel-Cr aft) react with acetyl chloride under conditions to form acetophenone, and then This is treated with bleach (bl, each) to obtain benzoic acid m. Acid salts (arsenic acid) Activation of the acid as Thus, beta-keto ester (■) is formed. Then add beta-keto ester to anhydrous vinegar. Quino by treatment with triethylor I-formate in the presence of acid. by forming a lon nucleus, adding cyclopropylamine, and finally adding a base. Thus, compound (2) is ring-closed to obtain compound (2). nucleus ■(S,5)-2-methyl- Heating in the presence of 2,5-diazabicyclo[2,2,1]hebutane and amine base Then, the melon antibiotic danofloxacin ■ is formed. Similar chemistry is 198 As stated in European Patent Publication No. 303.291 published on February 15, 2009 There is. Also the use of compounds of formula I as starting materials for the production of quinolone antibiotics 198 Known from Coulomba Patent Application No. 342,849, published November 23, 1999 .

Quinolone Antimicrobial Agents of U.S. Patent Nos. 4.571,396 and 4.861.779 and its pharmaceutically acceptable acid addition salts for the treatment of a broad spectrum of bacterial infections. The 9-quinolone antibacterial agent, which is particularly useful in the treatment of Gram-positive bacterial strains, may be administered alone. However, in general, the pharmacology chosen with respect to the intended route of administration and standard pharmaceutical practice. a mixture of 1. administered. For example, these are administered orally , i.e. as a tablet containing excipients such as starch or rough sugar, or as capsules, alone or in admixture with excipients, or flavorings. Alternatively, it may be administered as an elixir or suspension containing a coloring agent. animal thirst In some cases, quinolone antibacterial agents should be added to the animal's P feed or drinking water at a concentration of 5 to 5000 ppm. Preferably, it is advantageous to include it at a concentration of 25 to 500 ppm. quinolone anti The fungal agent can be injected parenterally, for example intramuscularly, intravenously or subcutaneously. . For parenteral administration, these are active solutes - to make the solution isotonic. Use as a sterile aqueous solution that may contain sufficient salt or glucose to is the most suitable. In the case of animals, approximately 0 per day] in the same dose or in up to 3 divided doses. at a dose level of 1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day. , the compounds can be administered intramuscularly or subcutaneously.

Quinolone antibacterial agent TRM for the treatment of fungal diseases in humans by oral or parenteral route. Approximately 0.1 to 500 m can be administered in a single dose or in up to 3 divided doses per day. Administered orally at 5 g/kg/day, preferably 0.5 to 50 mg/kg/day x I/bel. can do. For intramuscular or intravenous administration, the dose level is approximately .01-2. 00 mg/kg/day, advantageously 0,5-50 mg/kg/day. Ru. Intramuscular administration may be a single dose or up to three divided doses, whereas intramuscular administration may be continuous. May contain drips. The weight and pain condition of the subject to be treated, as known to those skilled in the art (4F). Variations will necessarily occur depending on and the particular route of administration chosen.

The following examples further illustrate the method of the invention.

flood 24-Diflu Rofenyru-Diazoni Mu-Flu Roborate 2.4- Difluoroaniline 1.0g (77.5mmo I) in dimethoxyethane 1 Boron trifluoride nitrate in 35 ml of dimethoxyethane dissolved in 5 ml of dimethoxyethane 1 - In a solution of 16.5 g <116.3 mmol) at a low temperature (5°C), 30 minutes chicken/, add two! , :6 The mixture was cooled to -15°C and diluted with Add 3 ethane (9.58 g <93 mmol of t-butyl sublacenate in 1 ml) to 3 Add over 0 minutes:. Warm the reaction mixture to ζ3-5℃ and keep at this temperature for 1 hour. Stir for a while. The product was filtered and dried in a high vacuum and 72 g of salt was dissolved at 97°6 Obtained in yield. Melting point 130-135°C.

source 1.2.4-1-1 Fluorobenzene 5 g<4 of the tetrafluorobo-1/-todiazonium salt prepared as described in Example 3 Distill 5.6 mmo I) in a flask equipped with a vacuum cleaner ( r:teat) Heated to 195°C for 1 hour. 1~2g of refluorohensen was recovered by distillation at 86-89°C and wrapped at 0°C. t-r　a　p　pe　d　). This represents a 69% yield.

1.4-dichloro'0-2-diI-lobenzene (100 g, 0.52 mol) was Potassium fluoride (61 g, 1.05 mol) was dissolved in 300 ml of Ruphoran. ) and saw. After heating the mixture to 185°C for 24 hours, the reaction was cooled to room temperature. , 50Qml of water was added. Next, the aqueous layer was diluted with 200 m of xane and 1 part of XIO. The combined organic layers were washed twice with 1 part of 1.00 ml of water and dried. melt Evaporation of the agent gave 48 g of the title product as an oil (51% yield).

This oil could be distilled (68°C, 2.2mmHg); The starting material of Example 4 was used instead.

Shojo 5-ri-4-ro 2-fluoroaniline 4-chloro-1-fluoro-2-nitrobezene (10 g, 57.1 mrno 1) was dissolved in 20 ml of 1,2-dimethoxyethane and 1% platinum catalyst with carbon support was added. Hydrogenated in the presence of 1 g at 50 PSI pressure for 24 hours. Then filter the reaction mixture. The filtered solvent was evaporated under a nitrogen atmosphere to obtain 9 g (90% yield) of the desired aniline. 4-chloro-1-fluorophenyl-2-diazonium-1 to lafluorobol, -1-5-chloro-2-fluoroaniline 9g (57,1mmo I) Dissolved in 15 ml of methoxyethane and dissolved in 25 ml of dimethoxyethane. Boron etherate complex 12.2g (85.7mmo I) at low temperature (-5 °C) solution over a period of 30 minutes. Cool the mixture to -15°C and add dimethane. 7.1 g of nitrous Wlt-butyl in 20 ml of xyethane (68.5 mmo I ) was added over 30 minutes.

The mixture was warmed to -5°C and stirred at the same temperature for 1 hour. The product is F31 ! I.

After drying in high vacuum, 11.2 g of salt was obtained in 80% yield. Melting point 140-1 45℃.

Municipality 1-chloro-34-difluorobenzene 1-fluoronia-4-chlorophenyl -2-Diazonium tetrafluoroborate 6g (246 mmol) was vaporized. without adding water in a flask equipped with a distillation head (neat > 1.85℃) Heated. 2.2 g of the title compound were recovered by distillation at 118-120°C. , 60% yield when trapped at 0°C).

Summary↓ 1 2 1-Tofur lobenzene and 1-chloro-34-diflu lobenzene 1゛.

2. 4-difluorophenyl is 5-chloro-2-fluoroaniline, respectively. Produced by reacting t-butyl nitrite with boron trifluoride etherate in the presence of precious wood. Diazonium salt 2,4-difluorophenyl-1-diazonium tera Volley 1- and 1-fluoro-44-chlorophenyl-2-diazonium tetra Thermal decomposition of fluoroborate produces 1.2.44lifluorobenzene and ]-] Rolow 3.4-difluorobenze is produced.

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Claims (13)

[Claims] 1.2,4-difluoroaniline or 5-chloro-2-fluoroaniline nitrous C1-C6 alkyl in the presence of a boron trifluoride etherate complex, respectively; or alkali metal nitrites or alkaline earths in the presence of tetrafluoroboric acid. By reacting with metal nitrite and heating the generated diazonium salt, 1,2,4-t Is it possible to obtain refluorobenzene or 1-chloro-3,4-difluorobenzene? 1,2,4-trifluorobenzene and 1-chloro-3,4-difluoro Benzene manufacturing method. 2. The 5-chloro-2-fluoroaniline is 4-chloro-1-fluoro-2- A process according to claim 1, which is produced by reduction of nitrobenzene. 3. The 4-chloro-1-fluoro-2-nitrobenzene is 1,4-dichloro- The method according to claim 2, which is produced from 2-nitrobenzene by chlorine-fluorine exchange. Law. 4. The 2,4-difluoroaniline or 5-chloro-2-fluoroaniline Claim for reacting with t-butyl nitrite in the presence of boron trifluoride etherate complex The method described in Section 1. 5. The 5-chloro-2-fluoroaniline is converted into a boron trifluoride etherate complex. A method according to claim 1, characterized in that the reaction is carried out with tert-butyl nitrite in the presence of. 6. The 5-chloro-2-fluoroaniline is converted into a boron trifluoride etherate complex. 3. The method according to claim 2, wherein the reaction is carried out with tert-butyl nitrite in the presence of. 7.2,4-difluorophenyl-1-diazonium tetrafluoroborate and and 1-fluoro-4-chlorophenyl-2-diazonium tetrafluorobore A compound selected from the group consisting of: 8.2,4-difluoroaniline or 5-chloro-2-fluoroaniline with C1-C6 alkyl nitrite in the presence of boron trifluoride etherate complex, respectively. , or an alkali metal nitrite or an alkali in the presence of tetrafluoroboric acid. 2,4-difluorophenyl-1-difluorophenyl by reacting with earth metal nitrite. Azonium tetrafluoroborate and 1-fluoro-4-chlorophenyl-2 - A method for producing diazonium tetrafluoroborate. 9. The 5-chloro-2-fluoroaniline is 4-chloro-1-fluoro-2- 9. A process according to claim 8, which is produced by reduction of nitrobenzene. 10. The 4-chloro-1-fluoro-2-nitrobenzene is 1,4-dichloro -2-Nitrobenzene according to claim 9, which is produced by chlorine-fluorine exchange. Method. 11.2,4-difluoroaniline or 5-chloro-2-fluoroaniline A claim in which t-butyl nitrate is reacted in the presence of a boron trifluoride etherate complex. 8. The method described in 8. 12. The 5-chloro-2-fluoroaniline is converted into a boron trifluoride etherate complex. 9. The method according to claim 8, wherein the reaction is carried out with tert-butyl nitrite in the presence of the body. 13. The 5-chloro-2-fluoroaniline is converted into a boron trifluoride etherate complex. 10. The method according to claim 9, wherein the reaction is carried out with tert-butyl nitrite in the presence of the body.