EP4702001A1 - Process for the preparation of halodifluorobenzene - Google Patents
Process for the preparation of halodifluorobenzeneInfo
- Publication number
- EP4702001A1 EP4702001A1 EP24722130.2A EP24722130A EP4702001A1 EP 4702001 A1 EP4702001 A1 EP 4702001A1 EP 24722130 A EP24722130 A EP 24722130A EP 4702001 A1 EP4702001 A1 EP 4702001A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- process according
- bromo
- formula
- hbr
- reaction according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/02—Monocyclic aromatic halogenated hydrocarbons
- C07C25/13—Monocyclic aromatic halogenated hydrocarbons containing fluorine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a novel process for preparing 1-halo-3,5-difluorobenzene of the formula (I).
Description
Process for the preparation of Halodifluorobenzene
The present invention relates to a novel process for preparing l-halo-3,5-difluorobenzene of the formula (I).
The synthesis of l-bromo-3,5-difluorobenzene of the formula (I) has already been described in US patent 5,977,412 starting from 2-bromo-4,6-difluoroaniline. A recent publication for the synthesis of l-bromo-3,5-difluorobenzene starting from 2,4-difluoroaniline is CN105949067.
IN 2019 1100 3809 discloses a process for producing l-bromo-3,5-difluorobenzene by a two- step process wherein the first step is reacting 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 converting 2-bromo-4,6-difluoroaniline to 3,5- difluorobromobenzene in the presence of isopropanol, cuprous oxide and sodium nitrite.
WO 01/14311 Al discloses a process for producing 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 l-halo-3,5-difluorobenzene. l-Halo-3,5-difluorobenzene of the formula (I) is an important precursor for the preparation of agrochemical compounds, e.g., for the chemical class of isooxazoline carboxamides which are very potent herbicides (e.g.: WO 2018/228985, WO 2018/228986).
In order to prepare l-bromo-3,5-difluorobenzene according to the procedure disclosed in US patent 5,977,412 2-bromo-4,6-difluoroaniline has to be synthesized in high dilution in a highly acidic aqueous medium employing bromine as reagent, thus, producing additional stoichiometric amounts of hydrobromic acid. An isolation of the desired material is not possible under these conditions since the neutralization of the reaction medium requirs large amounts of base. In addition, a direct processing of the aqueous product solution within the next step results in decreased yields. In CN105949067 the reaction is performed in aqueous medium, too. The disadvantage is that more than stoichiometric amounts of the reagents are need and a pollution of the water is the consequence.
An object of the present invention is providing a cost-effective process for preparing 1 -halo-3, 5- difluorobenzene that can be used on industrial scale without the above-mentioned disadvantages.
The object is achieved by a process for preparing l-halo-3,5-difluorobenzene of the formula (I)
characterized in that compounds of the general formula (II)
(II), react in a first step in the presence of bromine or chlorine or a combination of a bromine or chlorine source and an oxidizing agent to compounds of the general formula (III)
wherein
X is bromo or chloro, and in a second step, is further converted to compounds of the formula (I) in the presence of a nitrite source, a copper catalyst and a secondary alcohol that can be oxidized.
In a preferred embodiment the reaction according to the invention is performed with
X is bromo.
In another preferred embodiment the reaction according to the invention is performed with Bn as halogenating agent in step 1.
In another preferred embodiment the reaction according to the invention is performed with
Bn / H2O2, Bn /Oxone or Bn / NaOCl as halogenating agent in step 1.
In another preferred embodiment the reaction according to the invention is performed with NaBr or KBr/ H2O2, NaBr or KBr/ Oxone, NaBr or KBr/ NaOCl as halogenating agent in step 1. In another preferred embodiment the reaction according to the invention is performed with
HBr/EbCh, HBr /Oxone or HBr/ NaOCl as halogenating agent in step 1.
In another preferred embodiment the reaction according to the invention is performed with HC1, Cu2O or CuO, NaNCh and 2-PrOH as reagent in step 2.
In another preferred embodiment the reaction according to the invention is performed with CuCl or CuCh, NaNCh and 2-PrOH as reagent in step 2.
In another preferred embodiment the reaction according to the invention is performed with CuSO4, NaNCh and 2-PrOH as reagent in step 2.
The present invention has the advantage, that the halogenation is conducted with high atom efficiency and minimum waste production. It also leads to increased yield for the deamination step and in addition higher catalyst flexibility and process robustness.
Elucidation of the processes and intermediates
The reaction scheme shows the two-step synthesis according to the invention.
Process for preparing l-halo-3,5-difluorobenzene of the formula (I), characterized in that compounds of the general formula (II) react in a first step in the presence a bromine or chlorine source and an oxidizing agent to compounds of the general formula (III) and is in a second step is further converted to compounds of the formula (I) in the presence of a nitrite source, a copper catalyst and a secondary alcohol that can be oxidized.
Step 1:
In the process according to the invention 0.45 to 1.5, preferably 0.55 to 1.2 equivalents bromine or chlorine source is used.
For reactions with FhCh/HBr
In the process according to the invention 0.9 to 1.5, preferably 0.99 to 1.2 equivalents IfcCh is used.
In the process according to the invention 0.9 to 1.5, preferably 0.99 to 1.2 equivalents HBr is used.
For reactions with FhCh/NaBr or KBr
In the process according to the invention 0.9 to 1.5, preferably 0.99 to 1.2 equivalents IfcCh is used.
In the process according to the invention 0.9 to 1.5, preferably 0.99 to 1.2 equivalents NaBr or KBr is used.
In a preferred embodiment, stochiometric amounts of acid, for example H2SO4, HC1, HBr, H3PO4 or boric acid are added.
These stoichiometric quantities can be applied analogously for the other oxidizing agents as mentioned above./w reactions with Bn
In the process according to the invention 0.90 to 1.5, preferably 0.99 to 1.2 equivalents Br2 is used.
For reactions with H2O2 Bn
In the process according to the invention 0.40 to 0.6 , preferably 0.45 to 0.55 equivalents Brc is used.
In the process according to the invention 0.45 to 0.65, preferably 0.50 to 0.60 equivalents H2O2 is used.
Temperature range for the halogenation
The halogenation is usually performed in a temperature range from -10°C to 60°C, preferably -5 °C to 50°C, particularly preferably 0 to 40°C.
Solvent for the halogenation
The halogenation is furthermore performed in the presence of a solvent or diluent, preferred solvents being, water, toluene, chlorobenzene, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, cylopentylmethylether, methyl-tetrahydrofuran, tert-amylmethylether, Dichloromethane, Dichloroethane or mixtures of the above mentioned solvents.
Step 2:
In the process according to the invention 0.01 to 0.5 equivalents. , preferably 0.05 to 0.1 equivalents copper reagent is used.
In the process according to the invention 0.95 to 1.2 equivalents , preferably 0.99 to 1.1 equivalents of the nitrite source are used.
In the process according to the invention sodium nitrite (NaNCh) or potassium nitrite (KNO2) is used as nitrite source, preferably sodium nitrite is used.
In the process according to the invention as oxidizable alcohol 2-propanol or 2-butanol is used, preferably 2-propanol is used.
Temperature range for the reductive deamination
The reductive deamination is usually performed in a temperature range from -10°C to 40°C, preferably - 0°C to 50°C, particularly preferably 0 to 30°C.
Solvent for the reductive deamination
The reductive deamination is furthermore performed in the presence of a solvent or dilutent, preferred solvents are water, aqueous solutions of HBr or HC1 or mixtures of those.
Examples
The present invention is elucidated in more detail by the examples that follow, without restriction of the invention thereto.
Measurement methods
The products were characterized by ’H spectroscopy and/or HPLC and/or GC-MS (Liquid Chromatography Mass Spectrometry) and / or GC
The NMR spectra were determined using a ECZL 400S NMR (JEOL 40 MHz NMR).
The GC chromatograms were measured on Shimadzu instrument, connected to a mass detector.
Step 1
Example 1.1: Preparation of 5-Bromo-2,4-difluoroaniline
To 200 g 2,4-difluoroaniline in a two-liter reactor is added 300 g of a 47% HBr solution over a time period of 15 minutes at a temperature of 28 to 30°C. Furthermore 188 g of MTBE (Methylter Ebutyl ether) and 240 g of water is added at that temperature. Stirring is continued for further 15 minutes. Then 125 g of a 48 % H2O2 solution is added at 30 to 32 °C over 2 hours. It is stirred for 4 hours. Then the reaction mixture is cooled to 15°C, 296 g of MTBE is added. It is stirred for 30 minutes. Then stirring is stopped and the separation of phases is awaited for 30 minutes. The aqueous phase is extracted with MTBE. The combined organic layers are evaporated to yield the 320 g of 5-Bromo-2,4-difluoroaniline which is dissolved in 231 g isopropyl alcohol and directly used for the next step without further purification.
In accordance with example 1.1 (Step 1), the following examples have been prepared:
<u H2SO4 added after H2O2 addition. I:i' Addition of H2SO4 followed by H2O2. Step 2
Example 2.1 Preparation of l-Bromo-3,5-difluorobenzene
A flask is charged with 936 g 30% HC1, followed by 7.6 g of CuCl, 222 g of water and then 320 g of 5- Bromo-2,4-difluoroaniline which is dissolved in 231 g isopropyl alcohol (step 1). Stirring for 1 hour at 25°C and then cooling to 0°C. Then 318 g of a 40% NaNCh solution (127.2 g NaNCh and 190.8 g water) at 0 to 2°C is added over 4 hours. Further stirring for 30 minutes at 0°C to 2 °C.
Then raise temperature slowly to 25°C and stir for 3 to 4 hours. Then 1000 g water is added. Stirring for 15 minutes at 25°C. Then 888 g MTBE is added and stirring for 30 minutes at 25°C. Wait for settling for 30 minutes. Then separation of phases. Aqueous phase is extracted with MTBE. Organic phases are combined. The solvent is distilled off. The product is distilled out of the crude to yield a colourless liquid. (256 g , GC purity > 98% 86% over two steps).
GC-MS: 113.05 (192/194, M+)
'H-NMR (CDCh): 7.10 - 7.05 (m, 2H), 6.78 (tt, 1H) ppm.
In accordance with example 1.2 (Step 2), the following examples have been prepared:
a) Direct use of reaction mixture from example 1.5 without intermediate work-up. b) Extraction of product from step 1 with HC1 required for step 2.
Claims
1. Process for preparing l-halo-3,5-difluorobenzene of the formula (I)
characterized in that compound of the formula (II)
(II), reacts in a first step in the presence of bromine or chlorine or a combination of a bromine or chlorine source and an oxidizing agent to compounds of the formula (III)
wherein
X is bromo or chloro, and is, in a second step, further converted to compounds of the formula (I) in the presence of a nitrite source, a copper catalyst and a secondary alcohol that can be oxidized.
2. Process according to Claim 1, wherein X is bromo.
3. Process according to Claim 1, wherein the reaction according to the invention is performed with Bn as halogenating agent in step 1.
4. Process according to Claim 1, wherein the reaction according to the invention is performed with Bn / H2O2, Bn /Oxone or Bn / NaOCl as halogenating agent in step 1.
5. Process according to Claim 1, wherein the reaction according to the invention is performed with
NaBr or KBr/ H2O2,NaBr or KBr/ Oxone, NaBr or KBr/ NaOCl as halogenating agent in step 1.
6. Process according to Claim 1, wherein the reaction according to the invention is performed with HBr/H2O2, HBr /Oxone or HBr/ NaOCl as halogenating agent in step 1.
7. Process according to Claim 1, wherein the reaction according to the invention is performed with HC1, CU2O or CuO, NaNO2 and 2-PrOH as reagent in step 2.
8. Process according to Claim 1, wherein the reaction according to the invention is performed with CuCl or CuCh, NaNO2 and 2-PrOH as reagent in step 2.
9. Process according to Claim 1, wherein the reaction according to the invention is performed with CuSO4, NaNCh and 2-PrOH as reagent in step 2.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP23170073.3A EP4455116A1 (en) | 2023-04-26 | 2023-04-26 | Process for the preparation of halodifluorobenzene |
| PCT/EP2024/060879 WO2024223459A1 (en) | 2023-04-26 | 2024-04-22 | Process for the preparation of halodifluorobenzene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4702001A1 true EP4702001A1 (en) | 2026-03-04 |
Family
ID=86226991
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP23170073.3A Pending EP4455116A1 (en) | 2023-04-26 | 2023-04-26 | Process for the preparation of halodifluorobenzene |
| EP24722130.2A Pending EP4702001A1 (en) | 2023-04-26 | 2024-04-22 | Process for the preparation of halodifluorobenzene |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP23170073.3A Pending EP4455116A1 (en) | 2023-04-26 | 2023-04-26 | Process for the preparation of halodifluorobenzene |
Country Status (7)
| Country | Link |
|---|---|
| EP (2) | EP4455116A1 (en) |
| JP (1) | JP2026513416A (en) |
| KR (1) | KR20260003040A (en) |
| CN (1) | CN121001983A (en) |
| IL (1) | IL324149A (en) |
| TW (1) | TW202506612A (en) |
| WO (1) | WO2024223459A1 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5977412A (en) | 1998-08-14 | 1999-11-02 | Basf Corporation | Process for preparing 3,5-difluoroaniline |
| FR2797871B1 (en) * | 1999-08-24 | 2002-07-12 | Rhodia Chimie Sa | USEFUL PROCESS FOR MONOHALOGENATING AMINOAROMATIC DERIVATIVES |
| CN105949067A (en) | 2016-05-06 | 2016-09-21 | 蚌埠中实化学技术有限公司 | Preparation method of 3,5-difluoroaniline |
| EP3638665B1 (en) | 2017-06-13 | 2021-07-21 | Bayer Aktiengesellschaft | Herbicidal 3-phenylisoxazoline-5-carboxamides of tetrahydro and dihydrofuran carboxylic acids and esters |
| HUE056695T2 (en) | 2017-06-13 | 2022-03-28 | Bayer Ag | Herbicide 3-phenylisoxazoline-5-carboxamides of tetrahydrofuran and dihydrofuran carboxylic acid amides |
| IN201911003809A (en) * | 2019-01-31 | 2020-08-28 | Srf Ltd |
-
2023
- 2023-04-26 EP EP23170073.3A patent/EP4455116A1/en active Pending
-
2024
- 2024-04-22 CN CN202480028015.0A patent/CN121001983A/en active Pending
- 2024-04-22 WO PCT/EP2024/060879 patent/WO2024223459A1/en not_active Ceased
- 2024-04-22 JP JP2025562541A patent/JP2026513416A/en active Pending
- 2024-04-22 KR KR1020257038978A patent/KR20260003040A/en active Pending
- 2024-04-22 EP EP24722130.2A patent/EP4702001A1/en active Pending
- 2024-04-24 TW TW113115196A patent/TW202506612A/en unknown
-
2025
- 2025-10-22 IL IL324149A patent/IL324149A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW202506612A (en) | 2025-02-16 |
| CN121001983A (en) | 2025-11-21 |
| EP4455116A1 (en) | 2024-10-30 |
| KR20260003040A (en) | 2026-01-06 |
| IL324149A (en) | 2025-12-01 |
| JP2026513416A (en) | 2026-04-24 |
| WO2024223459A1 (en) | 2024-10-31 |
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