Method for preparing halogenated difluorobenzene

Abstract

The present invention relates to a novel process for the preparation of 1-halo-3, 5-difluorobenzene of formula (I).

Description

[0001] The present invention relates to a novel process for the preparation of 1-halo-3,5-difluorobenzene of formula (I).

[0002] The synthesis of 1-bromo-3,5-difluorobenzene of formula (I) has been described in US 5,977,412 starting from 2-bromo-4,6-difluoroaniline. A recently published literature for the synthesis of 1-bromo-3,5-difluorobenzene starting from 2,4-difluoroaniline is CN 105949067.

[0003] IN 2019 1100 3809 discloses a two-step process for the preparation of 1-bromo-3,5-difluorobenzene wherein in the first step 2,4-difluoroaniline is reacted with bromine in the presence of hydrochloric acid and water to form 2-bromo-4,6-difluoroaniline and in the second step 2-bromo-4,6-difluoroaniline is converted to 3,5-difluorobromobenzene in the presence of isopropanol, cuprous oxide and sodium nitrite.

[0004] WO 01 / 14311 A1 discloses a process for the preparation of 2-bromo-4,6-difluoroaniline by reacting 4,6-difluoroaniline with HBr in the presence of sulfuric acid and hydrogen peroxide. It does not mention the conversion of 2-bromo-4,6-difluoroaniline to 1-halo-3,5-difluorobenzene.

[0005] 1-halo-3,5-difluorobenzene of formula (I) is an important precursor for the preparation of agrochemical compounds, for example for the preparation of isoxazoline carboxamide class of chemicals which are very potent herbicides (e.g. WO 2018 / 228985, WO 2018 / 228986).

[0006] In order to prepare 1-bromo-3,5-difluorobenzene according to the process disclosed in US 5,977,412, it is necessary to synthesize 2-bromo-4,6-difluoroaniline using bromine as reagent in highly acidic aqueous medium at high dilution, thereby generating additional stoichiometric amount of hydrobromic acid. It is not possible to isolate the desired material under such conditions due to the need of large amount of base for neutralization of the reaction medium. Moreover, direct workup of the aqueous product solution in the next step leads to reduced yield. In CN 105949067, the reaction is also carried out in aqueous medium. The disadvantage is the need of more than stoichiometric amount of reagent and leads to contamination with water.

[0007] It is an object of the present invention to provide a cost effective process for the preparation of 1-halo-3,5-difluorobenzene which can be used on industrial scale without the above mentioned disadvantages.

[0008] The said object is achieved by a process for the preparation of 1-halo-3,5-difluorobenzene of formula (I) (I), characterized in that in a first step a compound of general formula (II) (II), is reacted in the presence of bromine or chlorine or a source of bromine or chlorine and a combination with an oxidizing agent to form a compound of general formula (III) (III), wherein X is bromine or chlorine, and in a second step is further converted to a compound of formula (I) in the presence of a source of nitrous acid, a copper catalyst and an oxidizable secondary alcohol.

[0009] In one preferably embodiment, the reaction of the present application is carried out with X being bromine.

[0010] In another preferred embodiment embodiment, the reaction of the present application is carried out in the first step with Br2as halogenating agent.

[0011] In another preferred embodiment embodiment, the reaction of the present application is carried out in the first step with Br2 / H2O2, Br2 / Oxone or Br2 / NaOCl as halogenating agent.

[0012] In another preferred embodiment embodiment, the reaction of the present application is carried out in the first step with NaBr or KBr / H2O2, NaBr or KBr / Oxone, NaBr or KBr / NaOCl as halogenating agent.

[0013] In another preferred embodiment embodiment, the reaction of the present application is carried out in the first step with HBr / H2O2, HBr / Oxone or HBr / NaOCl as halogenating agent.

[0014] In another preferred embodiment embodiment, the reaction of the present application is carried out in the second step with HCl, Cu2O or CuO, NaNO2and 2-PrOH as reagents.

[0015] In another preferred embodiment embodiment, the reaction of the present application is carried out in the second step with CuCl or CuCl2, NaNO2and 2-PrOH as reagents.

[0016] In another preferred embodiment embodiment, the reaction of the present application is carried out in the second step with CuSO4, NaNO2and 2-PrOH as reagents.

[0017] The advantage of the present invention is that the halogenation is performed with high atom efficiency and minimal waste generation. It also leads to an improved yield of the deamination step and in addition to a higher catalyst flexibility and process stability.

[0018] description of the method and intermediates The reaction scheme shows a two-step synthesis of the present invention. scheme 1 A process for the preparation of 1-halo-3,5-difluorobenzene of formula (I) characterized in that in a first step a compound of general formula (II) is reacted in the presence of a bromine or chlorine source and an oxidizing agent to a compound of general formula (III) and in a second step is further converted to a compound of formula (I) in the presence of a nitrite source, a copper catalyst and an oxidizable secondary alcohol.

[0019] step 1 In the process of the present invention, 0.45 to 1.5, preferably 0.55 to 1.2 equivalents of a bromine or chlorine source are used.

[0020] for reactions using h 2 O 2 / hbr In the process of the present invention, 0.9 to 1.5, preferably 0.99 to 1.2 equivalents of H2O2 are used.

[0021] In the process of the present invention, 0.9 to 1.5, preferably 0.99 to 1.2 equivalents of HBr are used.

[0022] for reactions using h 2 O 2 / naor kbr In the process of the present invention, 0.9 to 1.5, preferably 0.99 to 1.2 equivalents of H2O2 are used.

[0023] In the process of the present invention, 0.9 to 1.5, preferably 0.99 to 1.2 equivalents of NaBr or KBr are used.

[0024] In a preferred embodiment, stoichiometric amounts of an acid, such as H2SO4, HC1, HBr, H3PO4 or boric acid, are added.

[0025] These stoichiometric amounts can be applied analogously to other oxidizing agents as described above.

[0026] for reactions using br 2 preferably In the process of the present application, 0.90 to 1.5, for reactions using h 0.99 to 1.2 equivalents of Br2.

[0027] preferably 2 O 2 / Br 2 preferably In the process of the present application, 0.40 to 0.6, temperature range for halogenation 0.45 to 0.55 equivalents of Br2.

[0028] In the process of the present application, 0.45 to 0.65, preferably 0.50 to 0.60 equivalents of H2O2.

[0029] particularly preferred The halogenation is usually carried out at a temperature in the range of -10°C to 60°C, solvent for halogenation -5°C to 50°C, preferred 0 to 40°C.

[0030] step 2 Furthermore, the halogenation is carried out in the presence of a solvent or diluent, preferably the solvent is water, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, cyclopentyl methyl ether, methyltetrahydrofuran, tert-amyl methyl ether, dichloromethane, dichloroethane or a mixture of the aforementioned solvents.

[0031] temperature range for reductive deamination In the process of the present application, 0.01 to 0.5 equivalents, preferably 0.05 to 0.1 equivalents of a copper reagent.

[0032] In the process of the present application, 0.95 to 1.2 equivalents, preferably 0.99 to 1.1 equivalents of a nitrite source are used.

[0033] In the process of the present application, sodium nitrite (NaNO2) or potassium nitrite (KNO2) is used as the nitrite source, preferably sodium nitrite is used.

[0034] In the process of the present application, 2-propanol or 2-butanol is used as the oxidizable alcohol, preferably 2-propanol is used.

[0035] particularly preferred The reductive deamination is generally carried out at a temperature ranging from -10°C to 40°C, solvent for reductive deamination -0°C to 50°C, example 0 to 30°C.

[0036] measurement methods Moreover, the reductive deamination is carried out in the presence of a solvent or diluent, the preferred solvents being water, aqueous HBr or HCl or mixtures thereof.

[0037] step 1 The application is illustrated in more detail by the following examples, without limiting the application to the examples.

[0038] step 2 The products are characterized by 1 H spectra and / or HPLC and / or GC-MS (liquid chromatography mass spectrometry) and / or GC.

[0039] The NMR spectra are determined using an ECZL 400 S NMR (JEOL 40 MHz NMR).

[0040] The GC chromatogram is measured on a Shimadzu instrument connected to a mass detector.

[0041] ​ Example 1.1 : Preparation of 5-bromo-2,4-difluoroaniline At a temperature of 28 to 30°C, 300 g of a 47% HBr solution is added to 200 g of 2,4-difluoroaniline in a two-liter reactor over a period of 15 minutes. In addition, 188 g of MTBE (methyl tert-butyl ether) and 240 g of water are added at this temperature. Stirring is continued for a further 15 minutes. Then 125 g of a 48% H2O2 solution is added at 30 to 32°C over a period of 2 hours. Stirring is continued for 4 hours. The reaction mixture is then cooled to 15°C and 296 g of MTBE is added. Stirring is continued for 30 minutes. Then stirring is stopped and phase separation is carried out by standing for 30 minutes. The aqueous phase is extracted with MTBE. The combined organic layers are evaporated to give 320 g of 5-bromo-2,4-difluoroaniline, which is dissolved in 231 g of isopropanol and used directly in the next step without further purification.

[0042] According to Example 1.1 (step 1), the following examples are prepared: a) H2SO4 is added after the addition of H2O2. b) H2SO4 is added and then H2O2.

[0043] ​ Example 2.1 : Preparation of 1 -bromo-3,5-difluorobenzene In a flask was added 936 g 30% HC1, followed by 7.6 g CuCl, 222 g water, then 320 g 5-bromo-2,4-difluoroaniline (step 1 ) dissolved in 231 g isopropanol. Stirring was performed at 25°C for 1 h, then cooled to 0°C. Then 318 g 40% NaNC>2 solution (127.2 g NaNC>2 and 190.8 g water) was added at 0 to 2°C over 4 h. Stirring was continued at 0°C to 2°C for 30 min. Then the temperature was slowly increased to 25°C and stirring was performed for 3 to 4 h. Then 1000 g water was added. Stirring was performed at 25°C for 15 min. Then 888 g MTBE was added, stirring was performed at 25°C for 30 min. The precipitate was allowed to settle for 30 min. Then the phases were separated. The aqueous phase was extracted with MTBE. The organic phases were combined. The solvent was distilled off. The product was distilled off from the crude product to give a colorless liquid (256 g, GC purity > 98%, 86% over two steps).

[0044] GC-MS: 113.05 (192 / 194, M + ) 1 H-NMR (CDCI3): 7.10 - 7.05 (m, 2H), 6.78 (tt, 1 H) ppm.

[0045] The following examples were prepared according to example 1.2 (step 2): a) The reaction mixture from example 1.5 was used directly without intermediate work-up. b) The product from step 1 was extracted with the HC1 required for step 2.

Claims

1. Method for preparing 1-halo-3,5-difluorobenzene of formula (I) (I)， Its features are, In the first step, the compound of formula (II) (II), The reaction occurs in the presence of a combination of a bromine or chlorine source and an oxidant. Compounds of formula (III) (III), in X is bromine or chlorine. In the second step, it is further converted into a compound of formula (I) in the presence of a nitrite source, a copper catalyst and an oxidizable secondary alcohol.

2. The method according to claim 1, Where X is bromine.

3. The method according to claim 1, wherein the reaction of the present invention is carried out in the first step using Br2 as a halogenating agent.

4. The method according to claim 1, wherein the reaction of the present invention is carried out in the first step using Br2 / H2O2, Br2 / Oxone or Br2 / NaOCl as a halogenating agent.

5. The method according to claim 1, wherein the reaction of the present invention is carried out in the first step using NaBr or KBr / H2O2, NaBr or KBr / Oxone, or NaBr or KBr / NaOCl as a halogenating agent.

6. The method according to claim 1, wherein the reaction of the present invention is carried out in the first step using HBr / H2O2, HBr / Oxone or HBr / NaOCl as a halogenating agent.

7. The method according to claim 1, wherein the reaction of the present invention is carried out in the second step using HCl, Cu2O or CuO, NaNO2 and 2-PrOH as reagents.

8. The method according to claim 1, wherein the reaction of the present invention is carried out in the second step using CuCl or CuCl2, NaNO2 and 2-PrOH as reagents.

9. The method according to claim 1, wherein the reaction of the present invention is carried out in the second step using CuSO4, NaNO2 and 2-PrOH as reagents.

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