Method for preparing halodifluorobenzene

Abstract

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

Description

Technical Field

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

Background Art

[0002] The synthesis of 1-bromo-3,5-difluorobenzene of formula (I) starting from 2-bromo-4,6-difluoroaniline has already been described in US Patent No. 5,977,412. A recent publication on the synthesis of 1-bromo-3,5-difluorobenzene starting from 2,4-difluoroaniline is Chinese Patent Application Publication No. 105949067.

[0003] Indian Patent Application Publication No. 2019 1100 3809 discloses a method for producing 1-bromo-3,5-difluorobenzene by a two-step process, in which the first step is to react 2,4-difluoroaniline with bromine in the presence of hydrochloric acid and water to produce 2-bromo-4,6-difluoroaniline, and the second step is to convert 2-bromo-4,6-difluoroaniline to 3,5-difluorobromobenzene in the presence of isopropanol, cuprous oxide, and sodium nitrite.

[0004] International Publication No. 01 / 14311 pamphlet discloses a method for producing 2-bromo-4,6-difluoroaniline by reacting 4,6-difluoroaniline with HBr in the presence of sulfuric acid and hydrogen peroxide. This document 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 a group of compounds of isoxazoline carboxamide, which is a very powerful herbicide (for example, International Publication No. 2018 / 228985 pamphlet, International Publication No. 2018 / 228986 pamphlet).

[0006] To prepare 1-bromo-3,5-difluorobenzene according to the procedure disclosed in U.S. Patent No. 5,977,412, bromine must be used as a reagent to synthesize 2-bromo-4,6-difluoroaniline at high dilution in a highly acidic aqueous medium, thus generating an additional stoichiometric amount of hydrobromic acid. Since a large amount of base is required to neutralize the reaction medium, isolation of the desired material is impossible under these conditions. Furthermore, direct treatment of the aqueous solution of the product during the next step reduces the yield. In Chinese Patent Application Publication No. 105949067, the reaction is also carried out in an aqueous medium. The drawback is the need for more than stoichiometric amounts of reagent, resulting in water contamination. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 5,977,412 [Patent Document 2] Chinese Patent Application Publication No. 105949067 Specification [Patent Document 3] Indian Patent Application Publication No. 2019 1100 3809 Specification [Patent Document 4] International Publication No. 01 / 14311 Pamphlet [Patent Document 5] International Publication No. 2018 / 228985 Brochure [Patent Document 6] International Publication No. 2018 / 228986 Brochure [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide a cost-effective method for preparing 1-halo-3,5-difluorobenzene that can be used on an industrial scale without the aforementioned drawbacks. [Means for solving the problem]

[0009] This objective is achieved by the following method: Equation (I) [ka] A method for preparing 1-halo-3,5-difluorobenzene, wherein in the first step, the general formula (II) [ka] The compound reacts in the presence of bromine or chlorine, or a combination of a bromine source or chlorine source and an oxidizing agent to form general formula (III). [ka] (wherein X is bromo or chloro) the compound becomes In the second step, the compound is further converted to the compound of formula (I) in the presence of a nitrite source, a copper catalyst, and a secondary alcohol that can be oxidized. method.

[0010] In a preferred embodiment, the reaction according to the present invention is carried out with X being bromo.

[0011] In another preferred embodiment, the reaction according to the present invention is carried out using Br2 as the halogenating agent in step 1.

[0012] In another preferred embodiment, the reaction according to the present invention is carried out in step 1 using Br2 / H2O2, Br2 / Oxone®, or Br2 / NaOCl as the halogenating agent.

[0013] In another preferred embodiment, the reaction according to the present invention is carried out in step 1 using NaBr or KBr / H2O2, NaBr or KBr / Oxone®, or NaBr or KBr / NaOCl as the halogenating agent.

[0014] In another preferred embodiment, the reaction according to the present invention is carried out in Step 1 using HBr / H2O2, HBr / Oxone®, or HBr / NaOCl as the halogenating agent.

[0015] In another preferred embodiment, the reaction according to the present invention is carried out in Step 2 using HCl, Cu2O or CuO, NaNO2, and 2-PrOH as reagents.

[0016] In another preferred embodiment, the reaction according to the present invention is carried out in Step 2 using CuCl or CuCl2, NaNO2, and 2-PrOH as reagents.

[0017] In another preferred embodiment, the reaction according to the present invention is carried out in Step 2 using CuSO4, NaNO2, and 2-PrOH as reagents.

[0018] The present invention has the advantage that halogenation is carried out with high atom efficiency while minimizing waste generation. The present invention also results in an increase in the yield of the deamination step, and further an improvement in the flexibility of the catalyst and the robustness of the method.

[0019] Description of the method and intermediate The reaction scheme shows a two-step synthesis according to the present invention.

Chemical formula

[0020] A method for preparing 1-halo-3,5-difluorobenzene of formula (I), comprising in a first step, a compound of general formula (II) reacting in the presence of a bromine source or a chlorine source and an oxidizing agent to form a compound of general formula (III), and in a second step, further converting the compound of formula (I) in the presence of a nitrite source, a copper catalyst, and a secondary alcohol that can be oxidized.

[0021] Step 1: In the method according to the present invention, 0.45 to 1.5 equivalents, preferably 0.55 to 1.2 equivalents, of a bromine source or chlorine source are used.

[0022] In the case of reaction with H2O2 / HBr In the method according to the present invention, 0.9 to 1.5 equivalents, preferably 0.99 to 1.2 equivalents of H2O2 are used.

[0023] In the method according to the present invention, 0.9 to 1.5 equivalents, preferably 0.99 to 1.2 equivalents of HBr are used.

[0024] In the case of reaction with H2O2 / NaBr or KBr In the method according to the present invention, 0.9 to 1.5 equivalents, preferably 0.99 to 1.2 equivalents of H2O2 are used.

[0025] In the method according to the present invention, 0.9 to 1.5 equivalents, preferably 0.99 to 1.2 equivalents, of NaBr or KBr are used.

[0026] In a preferred embodiment, a stoichiometric amount of acid, such as H2SO4, HCl, HBr, H3PO4, or boric acid, is added.

[0027] These stoichiometric quantities can be applied similarly to the other oxidizing agents mentioned above.

[0028] In the case of reaction with Br2 In the method according to the present invention, 0.90 to 1.5 equivalents, preferably 0.99 to 1.2 equivalents of Br2 are used.

[0029] In the case of reaction with H2O2 / Br2 In the method according to the present invention, 0.40 to 0.6 equivalents, preferably 0.45 to 0.55 equivalents of Br2 are used.

[0030] In the method according to the present invention, 0.45 to 0.65 equivalents, preferably 0.50 to 0.60 equivalents of H2O2 are used.

[0031] Halogenation temperature range Halogenation is usually carried out in a temperature range of -10°C to 60°C, preferably -5°C to 50°C, and particularly preferably 0 to 40°C.

[0032] solvent for halogenation The halogenation is further carried out in the presence of a solvent or diluent, and preferred solvents are water, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, cyclopentyl methyl ether, methyl-tetrahydrofuran, tert-amyl methyl ether, dichloromethane, dichloroethane, or a mixture of the above solvents.

[0033] Step 2: In the method according to the present invention, 0.01 to 0.5 equivalents, preferably 0.05 to 0.1 equivalents, of copper reagent are used.

[0034] In the method according to the present invention, a nitrite source in an amount of 0.95 to 1.2 equivalents, preferably 0.99 to 1.1 equivalents, is used.

[0035] In the method according to the present invention, sodium nitrite (NaNO2) or potassium nitrite (KNO2) is used as the nitrite source, and sodium nitrite is preferably used.

[0036] In the method according to the present invention, 2-propanol or 2-butanol is used as the alcohol that can be oxidized, and preferably 2-propanol is used.

[0037] Temperature range of reductive deamination Reductive deamination is usually carried out in a temperature range of -10°C to 40°C, preferably 0°C to 50°C, and particularly preferably 0°C to 30°C.

[0038] Solvents for reductive deamination Reductive deamination is further carried out in the presence of a solvent or diluent, preferred solvents being water, an aqueous solution of HBr or HCl, or a mixture thereof.

[0039] Examples The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0040] Measurement method The product is, 1 Characterized by 1H spectroscopy and / or HPLC and / or GC-MS (liquid chromatography-mass spectrometry) and / or GC.

[0041] The NMR spectrum was determined using ECZL 400S NMR (JEOL 40MHz NMR).

[0042] The GC chromatogram was measured using a Shimadzu instrument connected to a mass detector.

[0043] Step 1 Example 1.1: Preparation of 5-bromo-2,4-difluoroaniline To 200 g of 2,4-difluoroaniline in a 2 liter reactor, 300 g of 47% HBr solution is added over 15 minutes at a temperature of 28-30°C. Then, 188 g of MTBE (methyl tert-butyl ether) and 240 g of water are added at the same temperature. Stirring is continued for another 15 minutes. Next, 125 g of 48% H2O2 solution is added over 2 hours at 30-32°C. This is stirred for 4 hours. The reaction mixture is then cooled to 15°C, and 296 g of MTBE is added. This is stirred for 30 minutes. Then, stirring is stopped, and the phases are allowed to separate for 30 minutes. The aqueous phase is extracted with MTBE. The combined organic layers are evaporated to obtain 320 g of 5-bromo-2,4-difluoroaniline. This is dissolved in 231 g of isopropyl alcohol and used directly in the next step without further purification.

[0044] The following examples were prepared according to Example 1.1 (Step 1).

[0045] [Table 1] Step 2 Example 2.1: Preparation of 1-bromo-3,5-difluorobenzene Step 1: Charge 936g of 30% HCl into a flask, followed by 7.6g of CuCl, 222g of water, and then 320g of 5-bromo-2,4-difluoroaniline dissolved in 231g of isopropyl alcohol. Stir at 25°C for 1 hour, then cool to 0°C. Next, add 318g of 40% NaNO2 solution (127.2g of NaNO2 and 190.8g of water) over 4 hours at 0-2°C. Stir for another 30 minutes at 0-2°C. Then, slowly raise the temperature to 25°C and stir for 3-4 hours. Next, add 1000g of water. Stir at 25°C for 15 minutes. Next, add 888g of MTBE and stir at 25°C for 30 minutes. Let stand for 30 minutes. Then, separate the phases. Extract the aqueous phase with MTBE. Combine with the organic phase. Remove the solvent by distillation. The crude product is distilled to separate the product and obtain a colorless liquid. (256g, GC purity >98%, 86% in the two steps). GC-MS:113.05(192 / 194,M + ) 1 H-NMR(CDCl3):7.10-7.05(m,2H),6.78(tt,1H)ppm

[0046] The following examples were prepared according to Example 1.2 (Step 2).

[0047] [Table 2]

Claims

1. Equation (I) 【Chemistry 1】 A method for preparing 1-halo-3,5-difluorobenzene, wherein in the first step, formula (II) 【Chemistry 2】 The compound reacts in the presence of bromine or chlorine, or a combination of a bromine source or chlorine source and an oxidizing agent, to produce equation (III). 【Transformation 3】 (wherein X is bromo or chloro) the compound becomes In the second step, the compound is further converted to the compound of formula (I) in the presence of a nitrite source, a copper catalyst, and a secondary alcohol that can be oxidized. method.

2. The method according to claim 1, wherein X is bromo.

3. The reaction according to the present invention uses Br as the halogenating agent in step 1. 2 The method according to claim 1, which is carried out using

4. The reaction according to the present invention uses Br as the halogenating agent in step 1. 2 / H 2 O 2 , Br 2 Oxone®, or Br 2 The method according to claim 1, performed using NaOCl.

5. The reaction according to the present invention uses NaBr or KBr / H as the halogenating agent in step 1. 2 O 2 The method according to claim 1, wherein the method is carried out using NaBr or KBr / Oxone (registered trademark), NaBr or KBr / NaOCl.

6. The reaction according to the present invention is carried out in step 1 using HBr / H 2 O 2 , HBr / Oxone (registered trademark), or HBr / NaOCl, the method according to claim 1.

7. The reaction according to the present invention involves HCl and Cu as reagents in step 2. 2 O or CuO, NaNO 2 The method according to claim 1, wherein the method is carried out using 2-PrOH.

8. The reaction according to the present invention uses CuCl or CuCl as the reagent in step 2. 2 , NaNO 2 The method according to claim 1, wherein the method is carried out using 2-PrOH.

9. The reaction according to the present invention uses CuSO4 as the reagent in step 2. 4 , NaNO 2 The method according to claim 1, wherein the method is carried out using 2-PrOH.

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