Preparation method of 1-bromo-2, 4, 5-trifluorobenzene

Abstract

The invention relates to a method for preparing 1-bromine-2, 4, 5-trifluorobenzene from 2, 4, 5-trifluoroaniline or a sulfate of 2, 4, 5-trifluoroaniline. The invention also relates to a method for preparing 1, 2, 4-trifluorobenzene from 2, 4, 5-trifluoroaniline, and then converting the 1, 2, 4-trifluorobenzene into 1-bromo-2, 4, 5-trifluorobenzene. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202180034353.1, application date March 10, 2021, and invention name “Method for preparing 1-bromo-2,4,5-trifluorobenzene”. Technical Field

[0002] The invention relates to a novel method for preparing 1-bromo-2,4,5-trifluorobenzene. Background Art

[0003] 1-Bromo-2,4,5-trifluorobenzene is a key intermediate in the synthesis of some pharmaceuticals, agricultural chemicals and other important fine chemical products.

[0004] For example, 1-bromo-2,4,5-trifluorobenzene is used to prepare the antimicrobial agrochemical product quinolone.

[0005] 1-Bromo-2,4,5-trifluorobenzene can be used in various antibacterial drugs, such as ciprofloxacin, moxifloxacin, gatifloxacin, and pefloxacin. 1-Bromo-2,4,5-trifluorobenzene is also an important intermediate in the synthesis of sitagliptin, a drug used to treat type 2 diabetes.

[0006] Chinese patent CN101168495 and Indian patent application 92 / DEL / 2015 report the bromination of 1,2,4-trifluorobenzene to prepare 1-bromo-2,4,5-trifluorobenzene.

[0007] Chinese patent CN101168495 discloses a method in which 1,2,4-trifluorobenzene is reacted with elemental bromine using iron powder and a free radical initiator (such as azobisisobutyronitrile) in the presence of an organic solvent (such as chloroform or carbon tetrachloride) to obtain 1-bromo-2,4,5-trifluorobenzene. The method disclosed in CN101168495 is cumbersome, involves many steps, and the product yield obtained is low. In addition, the solvent used therein is a chlorinated solvent, which is not suitable for large-scale industrial production.

[0008] Indian patent application 92 / DEL / 2015 also discloses a similar process, wherein 1,2,4-trifluorobenzene is reacted with elemental bromine using catalytic iron powder or ferric chloride to obtain 1-bromo-2,4,5-trifluorobenzene in good yield.

[0009] The article entitled "The continuous kilogram-scale process for the synthesis of 2,4,5-trifluorobromobenzene via Gattermann reaction using micro-reactors" by Deng Qiulin et al. discloses the synthesis of 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline. 2,4,5-trifluoroaniline is diazotized with sodium nitrite and hydrogen bromide to obtain 2,4,5-trifluorophenyl diazonium salt, which is then reacted with aqueous hydrogen bromide in the presence of copper powder to obtain 1-bromo-2,4,5-trifluorobenzene.

[0010] The disadvantage of this method is that it is a flow process involving micro and batch reactor models that are usually set up. The method disclosed by Deng et al. not only requires capital investment in a flow reactor, but also requires special operating expertise, making its commercial implementation difficult.

[0011] Furthermore, in a batch process, when 2,4,5-trifluoroaniline is diazotized using sodium nitrite and hydrogen bromide and then brominated using aqueous hydrogen bromide and copper (I) bromide, the entire reaction mass polymerizes.

[0012] In summary, there are a variety of methods that can be used to prepare 1-bromo-2,4,5-trifluorobenzene, each with advantages and disadvantages. There remains a need to develop alternative methods for preparing 1-bromo-2,4,5-trifluorobenzene. Specifically, there is a need in the art to develop a method for preparing 1-bromo-2,4,5-trifluorobenzene that avoids prior problems such as low yield, cumbersome process, special operating expertise, and polymerization of reactants.

[0013] The inventors of the present invention have conceived a new method for preparing 1-bromo-2,4,5-trifluorobenzene which is simple and suitable for commercial production. Summary of the invention

[0014] Purpose of the Invention

[0015] Some objects of the present invention are described below:

[0016] It is an object of the present invention to ameliorate one or more problems of the prior art, or at least to provide a useful alternative.

[0017] An object of the present invention is to provide a process for preparing 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate, which process uses reagents suitable for large-scale batch production.

[0018] Another object of the present invention is to provide a method for preparing 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate, wherein the reaction temperature can be easily controlled.

[0019] Another object of the present invention is to provide a process for preparing 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate, wherein the formation of polymer products or polymerization of the reaction materials is avoided.

[0020] Another object of the present invention is to provide a process for preparing 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate, the purpose of which is to avoid thermal decomposition of the diazotized intermediate.

[0021] Another object of the present invention is to provide a method for preparing 1-bromo-2,4,5-trifluorobenzene, wherein 1,2,4-trifluorobenzene is obtained from 2,4,5-trifluoroaniline.

[0022] Other objects and advantages of the present invention will become more apparent from the following description, which is not intended to limit the scope of the present invention. SUMMARY OF THE INVENTION

[0024] The present invention relates to a method for preparing 1-bromo-2,4,5-trifluorobenzene. The method comprises converting 2,4,5-trifluoroaniline or its sulfate into an intermediate. The intermediate is formed by reacting 2,4,5-trifluoroaniline or its sulfate with nitrosulphuric acid. The intermediate can also be formed by reacting 2,4,5-trifluoroaniline with sodium nitrite in the presence of an inorganic acid and a peracid. Subsequently, the intermediate is brominated to obtain 1-bromo-2,4,5-trifluorobenzene.

[0025] The present invention also relates to a method for preparing an intermediate 2,4,5-trifluorophenyl diazonium salt or 1,2,4-trifluorobenzene to prepare 1-bromo-2,4,5-trifluorobenzene. The method involves converting 2,4,5-trifluoroaniline or its sulfate into an intermediate. The intermediate is formed by reacting 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid to form 2,4,5-trifluorophenyl diazonium salt, or reacting 2,4,5-trifluoroaniline with sodium nitrite in the presence of an inorganic acid and a peracid to form 1,2,4-trifluorobenzene. DETAILED DESCRIPTION

[0026] The present invention discloses a method for preparing 1-bromo-2,4,5-trifluorobenzene. The first step is to convert 2,4,5-trifluoroaniline or its sulfate into an intermediate. The intermediate is formed by any one of the following methods:

[0027] 1. The intermediate is formed by the reaction of 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid.

[0028] 2. This intermediate is formed by the reaction of 2,4,5-trifluoroaniline with sodium nitrite in the presence of inorganic acid and peracid.

[0029] After the intermediate is formed, it is further brominated to obtain 1-bromo-2,4,5-trifluorobenzene.

[0030]

[0031] In one aspect, the present invention provides a method for preparing 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate.

[0032] A method for preparing 1-bromo-2,4,5-trifluorobenzene in one embodiment of the present invention is described below.

[0033] In the first step, 2,4,5-trifluoroaniline or its sulfate is diazotized with nitrosylsulfuric acid to give 2,4,5-trifluorophenyl diazonium salt.

[0034]

[0035] Subsequently, the 2,4,5-trifluorophenyldiazonium salt is reacted with a suitable brominating agent in the presence of a catalytic amount of a suitable metal bromide to give 1-bromo-2,4,5-trifluorobenzene.

[0036]

[0037] Typically, a metal bromide is added or generated in situ to obtain crude 1-bromo-2,4,5-trifluorobenzene.

[0038]

[0039] Although the purity of 2,4,5-trifluoroaniline or its sulfate does not affect the conversion rate, yield, purity of the product, etc. of the reaction, it is desirable that the purity of 2,4,5-trifluoroaniline or its sulfate exceeds 90%. Typically, the HPLC purity of 2,4,5-trifluoroaniline or its sulfate can be in the range of 92% to 98%.

[0040] The diazotization reaction is optionally carried out in the presence of a solvent.

[0041] The diazotization reaction is usually carried out at a temperature range of 0°C to 50°C, preferably at a temperature range of 0°C to 40°C, and more preferably at a temperature range of 15°C to 40°C.

[0042] The diazotization reaction is performed for 5 seconds to 12 hours, preferably, the reaction is performed for 5 seconds to 5 hours.

[0043] The nitrosylsulfuric acid used in the diazotization reaction is a 10 to 40 wt % nitrosylsulfuric acid solution, preferably a 25 to 40 wt % nitrosylsulfuric acid solution, more preferably a 30 to 40 wt % nitrosylsulfuric acid solution.

[0044] The molar ratio of 2,4,5-trifluoroaniline to nitrosylsulfuric acid in the diazotization reaction is selected from the range of 1:1 to 1:1.5.

[0045] The molar ratio of 2,4,5-trifluoroaniline sulfate:nitrosylsulfuric acid in the diazotization reaction is selected from the range of 1:1 to 1:1.5.

[0046] After the diazotization reaction is completed, the 2,4,5-trifluorophenyldiazonium salt is then reacted with a suitable brominating agent in the presence of a catalytic amount of a suitable metal bromide to give 1-bromo-2,4,5-trifluorobenzene.

[0047] The intermediate 2,4,5-trifluorophenyldiazonium salt may or may not be isolated. In particular, the 2,4,5-trifluorophenyldiazonium salt is not isolated.

[0048] Non-limiting examples of brominating agents suitable for brominating 2,4,5-trifluorophenyldiazonium salts include hydrogen bromide, elemental bromine, N-bromosuccinimide, and dibromoisocyanuric acid. Preferably, the brominating agent is hydrogen bromide or elemental bromine.

[0049] Hydrogen bromide is used as an aqueous hydrogen bromide solution having a concentration of 10% by weight to 48% by weight, preferably an aqueous hydrogen bromide solution having a concentration of 18% by weight to 48% by weight.

[0050] Alternatively, a 33 wt % solution of hydrogen bromide in acetic acid may also be used as the brominating agent.

[0051] Non-limiting examples of metal bromides suitable for the reaction of brominating 2,4,5-trifluorophenyldiazonium salts include copper (I) bromide and copper (II) bromide.

[0052] Suitable metal bromides for brominating 2,4,5-trifluorophenyldiazonium salts (used alone or in combination with copper (I) bromide or copper (II) bromide) include aluminum bromide, barium bromide, boron tribromide, cesium bromide, chromium bromide, cobalt bromide, dysprosium bromide, iron (II) bromide, iron (III) bromide, lithium bromide, magnesium bromide, phosphorus bromide, potassium bromide, sodium bromide, tin bromide, titanium bromide and zinc bromide. Preferably, the metal bromide is selected from copper (I) bromide and copper (II) bromide.

[0053] Alternatively, the copper bromide used for bromination of 2,4,5-trifluorophenyldiazonium salt can also be prepared in situ during the reaction, wherein the in situ generated metal bromide is formed in situ by reacting copper or copper oxide with a brominating agent selected from hydrogen bromide or bromine.

[0054] The amount of the metal bromide used is 1.0 to 10.0 wt % relative to 2,4,5-trifluoroaniline or its sulfate. Preferably, the amount of the metal bromide used is 2.5 to 3.0 wt % relative to 2,4,5-trifluoroaniline or its sulfate.

[0055] The bromination reaction is carried out in the absence of solvent.

[0056] The bromination reaction is carried out in the presence of a suitable solvent. Non-limiting examples of solvents suitable for the bromination reaction include nitrile, acetic acid, dimethyl sulfoxide, water and mixtures thereof. Preferably, the nitrile is acetonitrile.

[0057] The bromination reaction is usually carried out at a temperature ranging from 0°C to 150°C, preferably at a temperature ranging from 40°C to 110°C.

[0058] The bromination reaction is carried out for 0.5 hour to 12 hours, preferably 1 hour to 7 hours.

[0059] After the bromination reaction is completed, the reaction mixture is cooled to 25°C to 30°C and quenched by slowly adding water. The layers are then separated and the organic layer is washed with water. The resulting organic layer is processed into crude 1-bromo-2,4,5-trifluorobenzene. The resulting crude 1-bromo-2,4,5-trifluorobenzene is purified by fractionation to obtain pure 1-bromo-2,4,5-trifluorobenzene with a GC purity greater than 98.0%, preferably greater than 99.0%.

[0060] A method for preparing 1-bromo-2,4,5-trifluorobenzene in one embodiment of the present invention is described below.

[0061] In a first step 2,4,5-trifluoroaniline is converted to 1,2,4-trifluorobenzene which is then converted to 1-bromo-2,4,5-trifluorobenzene by any method known in the literature.

[0062] In the first step, 2,4,5-trifluoroaniline is converted to 1,2,4-trifluorobenzene by reaction with a deaminating agent such as sodium nitrite in the presence of a suitable peracid and an inorganic acid such as hydrogen chloride or sulfuric acid.

[0063]

[0064] The concentration of sodium nitrite used for deamination ranges from 10 wt % to 40 wt % of the sodium nitrite aqueous solution. Preferably, the concentration of the sodium nitrite aqueous solution is 40 wt %.

[0065] The inorganic acid used for deamination, such as hydrogen chloride or sulfuric acid, is used in a concentration of 30 wt % aqueous hydrogen chloride solution or 30 wt % aqueous sulfuric acid solution.

[0066] Non-limiting examples of peracids suitable for converting 2,4,5-trifluoroaniline to 1,2,4-trifluorobenzene include hydrogen peroxide, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, phthaloyl peroxide, and 2,4-dinitroperbenzoic acid. Preferably, the peracid is a 5 wt% aqueous solution of hydrogen peroxide.

[0067] The conversion of 2,4,5-trifluoroaniline to 1,2,4-trifluorobenzene is carried out at a temperature of 0 to 100°C, preferably at a temperature of 0 to 50°C, more preferably at a temperature of 0 to 10°C.

[0068] The conversion of 2,4,5-trifluoroaniline to 1,2,4-trifluorobenzene is carried out for 0.5 to 10 hours, preferably 1 to 6 hours.

[0069] After the reaction is complete, a 10 wt% aqueous sodium hydroxide solution is added to the reaction mixture, followed by dichloromethane. The resulting mixture is filtered, and the filtrate is allowed to settle to separate the layers. The resulting organic layer contains 1,2,4-trifluorobenzene. The intermediate 1,2,4-trifluorobenzene may or may not be separated.

[0070] The 1,2,4-trifluorobenzene thus obtained is converted into 1-bromo-2,4,5-trifluorobenzene by any reported general method for bromination of aromatic compounds or by the method disclosed in Chinese Patent CN101168495.

[0071]

[0072] In another aspect of the present invention, a method for preparing an intermediate of 1-bromo-2,4,5-trifluorobenzene is provided, the method comprising converting 2,4,5-trifluoroaniline or its sulfate into an intermediate, wherein the intermediate is formed by reacting 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid to form 2,4,5-trifluorophenyl diazonium salt, or reacting 2,4,5-trifluoroaniline with sodium nitrite in the presence of an inorganic acid and a peracid to form 1,2,4-trifluorobenzene.

[0073] In yet another aspect of the present invention, 1-bromo-monohalogenated benzene, 1-bromo-dihalogenated benzene and 1-bromo-trihalogenated benzene are prepared from monohalogenated aniline, dihalogenated aniline and trihalogenated aniline, respectively, according to the process of the present invention.

[0074] Various features and embodiments of the invention are illustrated in the following representative examples, which are intended to be illustrative rather than limiting.

[0075] Example:

[0076] Example 1: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0077] A mixture of 2,4,5-trifluoroaniline (5.0 g) and sulfuric acid (5.0 g) was contacted with nitrosylsulfuric acid and heated at 35° C. to 40° C. to obtain a reaction mixture comprising 2,4,5-trifluorophenyldiazonium salt. The reaction mixture was added to an aqueous solution of hydrogen bromide and copper (I) bromide at 100° C. to 105° C. and stirred for 2 hours. After the reaction was complete, the reaction was quenched by adding water. The reaction mass was extracted with dichloromethane to obtain 1-bromo-2,4,5-trifluorobenzene.

[0078] Example 2: Preparation of 1,2,4-trifluorobenzene

[0079] 2,4,5-trifluoroaniline (5 g) was added to a 30% aqueous solution of hydrogen chloride (12.4 g) at 0°C to 5°C and stirred. After 30 minutes, 5% hydrogen peroxide (10 g) was added and stirred for a further 30 minutes. A 40% aqueous solution of sodium nitrite was slowly added and stirred at 25°C to 30°C for 1 hour to obtain 1,2,4-trifluorobenzene.

[0080] Example 3: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0081] 2,4,5-Trifluoroaniline (42 g) was slowly added to concentrated sulfuric acid (98%, 42 g) at room temperature. Nitrosylsulfuric acid was added to the resulting mixture over a period of 90 minutes at room temperature and further stirred for 90 minutes at the same temperature to obtain a diazo solution.

[0082] After the reaction is complete, the obtained diazo solution is added to a stirred mixture of water, copper (I) bromide and aqueous hydrogen bromide solution at 90°C to 105°C over a period of 75 minutes. The reaction mixture is then stirred for 2.5 hours at the same temperature. After the reaction is complete, the reaction mixture is cooled and quenched with water. The layers are then separated, and the resulting organic layer contains a crude 1-bromo-2,4,5-trifluorobenzene having a GC purity of 86.77%.

[0083] Example 4: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0084] 2,4,5-Trifluoroaniline sulfate (300 g) was slowly added to nitrosylsulfuric acid at room temperature over a period of 60 minutes. The resulting mixture was then stirred at the same temperature for 3.0 hours to obtain a diazo solution.

[0085] After the reaction is complete, the resulting diazo solution is added to a stirred mixture of water, copper (I) bromide and aqueous hydrogen bromide at 45°C to 75°C over a 4 hour period. The reaction mixture is then stirred for 3.0 hours. After the reaction is complete, the reaction mixture is cooled and quenched by slowly adding water. The layers are then separated and the organic layer is washed with water. The resulting organic layer contains crude 1-bromo-2,4,5-trifluorobenzene (214 g) with a GC purity of 95.28%; crude yield: 82.8%.

[0086] The crude 1-bromo-2,4,5-trifluorobenzene was purified to give 188.9 g of the pure title compound with a GC purity greater than 99.0%; yield: 73.1%.

[0087] Example 5: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0088] 2,4,5-Trifluoroaniline sulfate (50 g) was slowly added to nitrosylsulfuric acid at room temperature over a period of 60 minutes. The resulting mixture was then stirred at the same temperature for 3.0 hours to obtain a diazo solution.

[0089] After the reaction is complete, the resulting diazo solution is added to a stirred mixture of acetonitrile, copper (I) bromide and aqueous hydrogen bromide at 50°C to 75°C over a period of 3.15 hours. The reaction mixture is then stirred at 50°C to 75°C for 3.0 hours. After the reaction is complete, the reaction mixture is cooled and quenched with water. The layers are then separated. The resulting organic layer contains crude 1-bromo-2,4,5-trifluorobenzene (35 g) with a GC purity of 90.52%; yield: 81.3%.

[0090] Example 6: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0091] 2,4,5-Trifluoroaniline sulfate (50 g) was slowly added to nitrosylsulfuric acid at room temperature over a period of 60 minutes. The resulting mixture was then stirred at the same temperature for 3.0 hours to obtain a diazo solution.

[0092] After the reaction is complete, the resulting diazo solution is added to a stirred mixture of dimethyl sulfoxide, copper (I) bromide and aqueous hydrogen bromide at 50°C to 75°C over a period of 3.15 hours. The reaction mixture is then stirred at 50°C to 75°C for 3.0 hours. After the reaction is complete, the reaction mixture is cooled and quenched with water. The layers are then separated. The resulting organic layer contains crude 1-bromo-2,4,5-trifluorobenzene (35 g) with a GC purity of 70.73%; yield: 81.3%.

[0093] Example 7: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0094] 2,4,5-Trifluoroaniline sulfate (350 g) was slowly added to nitrosylsulfuric acid at room temperature over a period of 90 minutes. The resulting mixture was then stirred at the same temperature for 3.0 hours to obtain a diazo solution.

[0095] After the reaction is complete, the resulting diazo solution is added to a stirred mixture of copper (I) bromide and hydrogen bromide in acetic acid at 35°C to 55°C over a period of 6.0 hours. The reaction mixture is then stirred at 65°C to 70°C for 2.15 hours. After the reaction is complete, the reaction mixture is cooled and quenched with water. The layers are then separated. The resulting organic layer contains crude 1-bromo-2,4,5-trifluorobenzene with a GC purity of 89.57%.

[0096] Example 8: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0097] 2,4,5-Trifluoroaniline sulfate (100 g) was slowly added to nitrosylsulfuric acid at room temperature over a period of 60 minutes. The resulting mixture was then stirred at the same temperature for 3.0 hours to obtain a diazo solution.

[0098] After the reaction is complete, the resulting diazo solution is added to a stirred mixture of water, copper oxide and aqueous hydrogen bromide solution at 50°C to 75°C over a period of 80 minutes. The reaction mixture is then stirred at 50°C to 75°C for 3.0 hours. After the reaction is complete, the reaction mixture is cooled and quenched with water. The layers are then separated and the organic layer is washed with water. The resulting organic layer contains crude 1-bromo-2,4,5-trifluorobenzene (68 g) with a GC purity of 95.35%; yield: 78.9%.

[0099] Example 9: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0100] 2,4,5-Trifluoroaniline sulfate (100 g) was slowly added to nitrosylsulfuric acid at room temperature over a period of 60 minutes. The resulting mixture was then stirred at the same temperature for 3.0 hours to obtain a diazo solution.

[0101] After the reaction is complete, the resulting diazo solution is added to a stirred mixture of water, copper (II) bromide and aqueous hydrogen bromide at 50°C to 75°C over a period of 80 minutes. The reaction mixture is then stirred at 50°C to 75°C for 3.0 hours. After the reaction is complete, the reaction mixture is cooled and quenched with water. The layers are then separated and the organic layer is washed with water. The resulting organic layer contains crude 1-bromo-2,4,5-trifluorobenzene (64 g) with a GC purity of 92.6%; yield: 74.3%.

[0102] Example 10: Preparation of 1,2,4-trifluorobenzene

[0103] 2,4,5-trifluoroaniline (4.48g) was slowly added to 30% by weight hydrogen chloride (12g) aqueous solution at 0°C to 5°C. The resulting mixture was then stirred at the same temperature for 30 minutes and 5% by weight hydrogen peroxide aqueous solution (9.0g) was slowly added at 0°C to 5°C over a 90-minute period. The resulting mixture was then stirred for 30 minutes and 40% by weight sodium nitrite aqueous solution (6.2g) was added to the mixture over a 60-minute period at the same temperature. The resulting reaction mixture was then stirred at 0°C to 5°C for 60 minutes. The reaction mixture was then heated to 25°C to 30°C and further stirred for 60 minutes. After the reaction was complete, 10% by weight sodium hydroxide aqueous solution (30g) was added to the reaction mixture, followed by dichloromethane (200g). The resulting mixture was filtered, and the filtrate was allowed to settle to separate layers. The resulting organic layer contained 1,2,4-trifluorobenzene.

[0104] Example 11: Preparation of 1,2,4-trifluorobenzene

[0105] 2,4,5-trifluoroaniline (4.48g) was slowly added to 30% by weight of sulfuric acid aqueous solution (32g) at 0°C to 5°C. The resulting mixture was then stirred at the same temperature for 30 minutes and 5% by weight of hydrogen peroxide aqueous solution (9.0g) was slowly added at 0°C to 5°C over a 90 minute period. The resulting mixture was then stirred for 30 minutes and 40% by weight of sodium nitrite aqueous solution (6.2g) was added to the mixture over a 60 minute period at the same temperature. The resulting reaction mixture was then stirred at 0°C to 5°C for 60 minutes. The reaction mixture was then heated to 25°C to 30°C and further stirred for 60 minutes. After the reaction was complete, 10% by weight of sodium hydroxide aqueous solution (65g) was added to the reaction mixture, followed by dichloromethane (200g). The resulting mixture was filtered, and the filtrate was allowed to settle to separate layers. The resulting organic layer contained 1,2,4-trifluorobenzene.

[0106] Comparative Example 1: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0107] 2,4,5-Trifluoroaniline (250 g) was slowly added to a 48 wt % aqueous solution of hydrogen bromide (752 g) at 25° C. to 30° C. over a period of 30 minutes. The resulting mixture was then stirred for 30 minutes and water (700 g) was added at the same temperature. A 40 wt % aqueous solution of sodium nitrite (315.9 g) was then added to the resulting mixture at 0° C. to 5° C.

[0108] After the reaction was completed, the resulting diazo solution was added to a stirred solution of copper (I) bromide (7.0 g) and 48 wt % aqueous hydrogen bromide (125.37 g) at 0° C. to 5° C. over a period of 90 minutes. The reaction mixture was then stirred at 70° C. to 75° C. for 2.0 hours. The reaction mixture was cooled to 25° C. to 30° C. to obtain a polymerized reaction mass.

[0109] Comparative Example 2: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0110] 2,4,5-trifluoroaniline (50 g) was slowly added to a 25 wt % aqueous solution of hydrogen chloride (111.65 g) at 25° C. to 30° C. over a period of 45 minutes. Water (94 g) was added to the resulting mixture at the same temperature. A 40 wt % aqueous solution of sodium nitrite (23.69 g) was then added to the resulting mixture at 0° C. to 5° C. over a period of 2.5 hours.

[0111] After the reaction was completed, the resulting diazo solution was slowly added to a stirred solution of copper (I) bromide (2.52 g) and 48 wt % aqueous hydrogen bromide (77.0 g) at 25° C. to 30° C. The reaction mixture was then stirred at 70° C. to 75° C. for 3.0 hours. The reaction mixture was cooled to 25° C. to 30° C. to obtain a polymerized reaction mass.

[0112] Comparative Example 3: Preparation of 1-bromo-2,4,5-trifluorobenzene

[0113] 2,4,5-Trifluoroaniline sulfate (79 g) was slowly added to a 4.46 wt% aqueous sulfuric acid solution (282.0 g) at 25° C. to 30° C. over a period of 30 minutes. A 40 wt% aqueous sodium nitrite solution (59.0 g) was then slowly added to the resulting mixture at −5° C. and stirred at the same temperature for 2.0 hours.

[0114] After the reaction was completed, the resulting diazo solution was slowly added to a stirred solution of copper (I) bromide (2.18 g) and 48 wt % aqueous hydrogen bromide (68.0 g) at 50° C. to 55° C. over a period of 35 minutes. The reaction mixture was then stirred at 70° C. to 75° C. for 2.0 hours. The reaction mixture was cooled to 25° C. to 30° C. to obtain a polymerized reaction mass.

[0115] From the results of Comparative Examples 1 to 3, it can be seen that when 2,4,5-trifluoroaniline or 2,4,5-trifluoroaniline sulfate is diazotized with sodium nitrite and an inorganic acid such as hydrogen chloride or sulfuric acid, and then brominated with copper (I) bromide and hydrogen bromide, the reaction mixture polymerizes. According to the method of the present invention, 2,4,5-trifluoroaniline or 2,4,5-trifluoroaniline sulfate is diazotized with a sulfuric acid solution of nitrosylsulfuric acid (instead of sodium nitrite), and then brominated with a suitable metal bromide and a brominating agent, a crude yield of 70% to 85% can be obtained, the purity is in the range of 70% to 96%, and the reaction mass does not polymerize.

[0116] Therefore, the process of diazotizing 2,4,5-trifluoroaniline or 2,4,5-trifluoroaniline sulfate with nitrosylsulfuric acid and then brominating with a suitable metal bromide and a brominating agent is creative and has strong industrial applicability.

[0117] The preparation of 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate salt using suitable reagents disclosed in the detailed description is novel in that there are no prior art methods of this kind involving the specific reagents shown in the specification.

[0118] The preparation of 1,2,4-trifluorobenzene from 2,4,5-trifluoroaniline is also novel and inventive.

[0119] Furthermore, it can be seen from the specification that the preparation of 1-bromo-2,4,5-trifluorobenzene from 2,4,5-trifluoroaniline or its sulfate and the preparation of 1,2,4-trifluorobenzene from 2,4,5-trifluoroaniline are inventive because the process is suitable for large-scale production, contributes to technological progress through yield and / or purity or by avoiding polymerization of reaction substances; and makes commercial production safe and economical.

[0120] The embodiments herein and various features thereof and advantageous details will be explained with reference to the non-limiting embodiments in the specification. The description of well-known components and processing techniques is omitted to avoid unnecessarily covering up the embodiments herein. The examples used herein are only for the convenience of understanding the mode in which the embodiments herein can be implemented, and further enable those skilled in the art to implement these embodiments. Therefore, these examples should not be construed as limiting the scope of the embodiments herein.

[0121] The description of the specific embodiments will fully reveal the general nature of the embodiments herein so that others can easily modify and / or adjust such specific embodiments for various applications by applying existing knowledge without departing from the general concept, and therefore, such adjustments and modifications should and are intended to be understood within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology used herein is for descriptive and not limiting purposes. Therefore, although the embodiments herein are described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be implemented with modifications within the spirit and scope of the embodiments described herein.

[0122] Although considerable emphasis has been placed herein on the specific features of the present invention, it is to be understood that various modifications may be made and that many changes may be made in the preferred embodiments without departing from the principles of the present invention. These and other modifications of the nature of the present invention or preferred embodiments will be apparent to those skilled in the art from the invention herein, whereby it is clearly understood that the foregoing descriptive matters are to be interpreted only as illustrations of the present invention and not as limitations.

Claims

1. A method for preparing 1-bromo-2,4,5-trifluorobenzene, the method comprising the following steps: converting 2,4,5-trifluoroaniline or its sulfate to an intermediate, wherein the intermediate is formed by reacting 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid or by reacting 2,4,5-trifluoroaniline with sodium nitrite in the presence of an inorganic acid and a peracid; and Bromination of the intermediate to obtain 1-bromo-2,4,5-trifluorobenzene, 2. The method of claim 1, comprising reacting 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid to obtain 2,4,5-trifluorophenyldiazonium salt as an intermediate.

3. The method of claim 2, wherein the molar ratio of 2,4,5-trifluoroaniline or its sulfate to nitrosylsulfuric acid is 1:1 to 1:1.5; and the concentration of nitrosylsulfuric acid in sulfuric acid is 30 wt % to 40 wt %.

4. The process of claim 1, comprising reacting 2,4,5-trifluoroaniline with sodium nitrite in the presence of an inorganic acid and a peracid to obtain 1,2,4-trifluorobenzene as an intermediate.

5. A method for preparing 1-bromo-2,4,5-trifluorobenzene, the method comprising the following steps: a) diazotizing 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid to obtain 2,4,5-trifluorophenyl diazonium salt; and b) brominating 2,4,5-trifluorophenyldiazonium salt using a brominating agent in the presence of a metal bromide or a metal bromide generated in situ to obtain crude 1-bromo-2,4,5-trifluorobenzene, 6. The process of claim 5, comprising purifying crude 1-bromo-2,4,5-trifluorobenzene to obtain 1-bromo-2,4,5-trifluorobenzene with a purity greater than 99%.

7. The process of claim 5, comprising using one or more solvents in step (b), wherein the solvent is selected from the group consisting of acetonitrile, acetic acid, water, dimethyl sulfoxide, and mixtures thereof.

8. The method of claim 5, wherein the molar ratio of 2,4,5-trifluoroaniline or its sulfate to nitrosylsulfuric acid is 1:1 to 1:1.5; and the concentration of nitrosylsulfuric acid in sulfuric acid is 30% to 40% by weight.

9. The method of claim 5, wherein the metal bromide is selected from copper (I) bromide and copper (II) bromide, and the amount of the metal bromide relative to 2,4,5-trifluoroaniline or sulfate is 2.5 to 3.0 wt%.

10. The process of claim 5, wherein the in situ generated metal bromide is formed by reacting copper or copper oxide with a brominating agent.

11. The process of claim 5 or 10, wherein the brominating agent is selected from hydrogen bromide and elemental bromine.

12. The method of claim 1 or 5, wherein the reaction of 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid is carried out at a temperature of 15 to 40°C for 5 seconds to 5 hours, and the bromination reaction is carried out at a temperature of 40 to 110°C for 1 to 7 hours.

13. The process of claim 5, wherein the purity of crude 1-bromo-2,4,5-trifluorobenzene is in the range of 70% to 96%.

14. The process of claim 5, wherein the purity of crude 1-bromo-2,4,5-trifluorobenzene is in the range of 85% to 96%.

15. A method for preparing 1-bromo-2,4,5-trifluorobenzene, the method comprising the following steps: a) deaminating 2,4,5-trifluoroaniline in the presence of sodium nitrite, an inorganic acid and a peracid to obtain 1,2,4-trifluorobenzene; and b) brominating 1,2,4-trifluorobenzene to obtain 1-bromo-2,4,5-trifluorobenzene, 16. The method of claim 15, wherein the inorganic acid is selected from hydrogen chloride and sulfuric acid; and the peracid is selected from hydrogen peroxide, peracetic acid and trifluoroperacetic acid.

17. The method of claim 15, wherein the deamination is carried out at a temperature of 0°C to 10°C for 1 hour to 6 hours.

18. A method for preparing an intermediate for preparing 1-bromo-2,4,5-trifluorobenzene, the method comprising converting 2,4,5-trifluoroaniline or its sulfate into the intermediate, wherein the intermediate is formed by reacting 2,4,5-trifluoroaniline or its sulfate with nitrosylsulfuric acid to form 2,4,5-trifluorophenyl diazonium salt, or reacting 2,4,5-trifluoroaniline with sodium nitrite in the presence of an inorganic acid and a peracid to form 1,2,4-trifluorobenzene.

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