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CN116135829A - Industrial preparation method of fluorophenol - Google Patents

Industrial preparation method of fluorophenol Download PDF

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CN116135829A
CN116135829A CN202111358125.8A CN202111358125A CN116135829A CN 116135829 A CN116135829 A CN 116135829A CN 202111358125 A CN202111358125 A CN 202111358125A CN 116135829 A CN116135829 A CN 116135829A
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substituted
cupric
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sodium
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甘建刚
吴明遥
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Zhejiang Zhongke Chuangyue Medicine Co ltd
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Zhejiang Zhongke Chuangyue Medicine Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/02—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of halogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts

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Abstract

The invention discloses an industrial preparation method of fluorophenol, in particular to the method, under the catalysis of copper/oxalic acid diamide ligand, under the alkaline condition, (poly) fluorohalogenobenzene is subjected to coupling reaction under the heating condition to generate (poly) fluorophenol. The method has the advantages of mild reaction conditions, no need of high temperature and high pressure, less three wastes, low cost, high yield and purity, and easy industrial production.

Description

Industrial preparation method of fluorophenol
Technical Field
The invention belongs to the field of organic chemistry, and in particular relates to the chemical field of (poly) fluorophenol synthesis.
Background
The (poly) fluorophenol is an important organic fluorine-containing intermediate and has wide application in the fields of medicines, pesticides, liquid crystal materials and the like. In the medical field, a great deal of research shows that introducing fluorine atoms or fluorine-containing groups at specific positions of drug molecules can cause changes in the physiological activity of the drug molecules, enhance the activity of the drugs and improve the drug efficacy, for example, 2, 4-difluorophenol is an important starting material for a plurality of drugs such as Mivebressib, etamicastat hydrochloride and the like, and 3, 5-difluorophenol is an important starting material for the gastric drug tergore. In the field of materials, liquid crystal materials containing polyfluorophenols tend to exhibit more excellent electronic properties due to the special electronic effects of fluorine atoms. In the field of pesticides, novel antibiotics synthesized by fluorine-containing compounds and fluorine-containing pesticides are widely used due to their unique properties.
The current synthesis of (poly) fluorophenols involves several methods:
1. the method is characterized in that fluoroaniline is taken as a raw material, and diazonium salt generated after diazotization is decomposed in acid water. The method has the advantages that the three wastes are more generated, the reaction condition is very harsh, and especially for polyfluoro-substituted phenol, diazotization hydrolysis can be carried out in concentrated sulfuric acid at high temperature (140-190 ℃). In the reaction process, a large amount of copper salt is required to catalyze, and the yield is not high, so that the difficulty of industrial production is high
2. The (poly) fluorohalogenobenzenes are hydrolyzed in an alkaline medium to give phenols. For example, chinese patent CN105384603A uses Raney Ni, pd/C, pt/C, ru/C and other catalysts, and has a reaction temperature of 100-180 deg.C and a reaction pressure of 0.3-2MPa. In the synthesis method, an expensive catalyst is used, and the reaction is carried out at high temperature and high pressure, so that the method is not suitable for industrial production. The substitution of the fluorine atom on the (poly) fluorohalogenobenzene with a hydroxyl group under strongly basic conditions and at high temperature and high pressure is an unavoidable competitive reaction, resulting in a low yield of the process.
3. Reacting (poly) fluorobromobenzene with strong alkali such as magnesium or butyl lithium, adding boric acid ester to generate (poly) fluorobenzeneboric acid, and oxidizing to obtain (poly) fluorophenol. The reaction conditions of this process are dangerous and costly.
4. The method has good atom economy, but poor selectivity, can generate various fluorophenols, is difficult to purify and has no industrial value.
In view of the above, there is an urgent need in the art to develop a process for preparing (poly) fluorophenol that has mild reaction conditions and high product quality and is suitable for industrial production.
Disclosure of Invention
The invention provides a preparation method of (poly) fluorophenol, which has mild reaction conditions and high product quality and is suitable for industrial production.
In a first aspect of the present invention, there is provided a process for the preparation of a substituted phenol, said process comprising:
in a solvent, under the catalysis of copper salt and oxalic acid diamide ligand, carrying out hydrolysis reaction by using fluorohalogenobenzene to obtain fluorophenol;
Figure BDA0003358066180000021
wherein n is 1, 2,3, 4 or 5;
the oxalic acid diacyl ligand has a structure shown in the following formula I:
Figure BDA0003358066180000022
wherein R is a Selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted 5-7 membered heteroaryl group; wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms as a ring skeleton;
R b selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted 5-7 membered heteroaryl group; wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms as a ring skeleton;
unless otherwise specified, the substituents refer to the substitution of one or more hydrogen atoms on a group with a substituent selected from the group consisting of: halogen, hydroxy, cyano, phenyl, carbonyl, C1-C6 alkylamino, C2-C6 ester, C2-C6 acyl, 5-7 membered heteroaryl, C1-C6 alkyl, C1-C6 alkoxy.
In another preferred embodiment, the ligand is selected from one or more of the ligands shown in formula I;
Figure BDA0003358066180000023
Figure BDA0003358066180000031
Figure BDA0003358066180000041
in another preferred embodiment, the ligand is selected from one or more of the ligands shown in formula I;
Figure BDA0003358066180000042
in another preferred embodiment, the copper salt is selected from the group consisting of: cuprous oxide, cupric sulfate, thiophene-2-carboxylic acid, cupric acetate, cupric nitrate, cupric acetoacetate, cupric bromide, cupric chloride, cupric cyanide, cupric acetylacetonate, cuprous thiocyanate, cupric iodide, cuprous bromide, cuprous chloride, cuprous cyanide, or combinations thereof.
In another preferred embodiment, the copper salt is cuprous iodide.
In another preferred embodiment, the hydrolysis reaction is carried out in the presence of a base, and the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, tetrabutylammonium hydroxide, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU), tetramethylammonium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or combinations thereof.
In another preferred embodiment, the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, or a combination thereof.
In another preferred embodiment, the solvent is selected from the group consisting of: water, alcohol solvents, ether solvents, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetonitrile, alcohol solvents, ketone solvents.
In another preferred embodiment, the ethereal solvent is selected from the group consisting of: tetrahydrofuran, dioxane, methyl tertiary butyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, or combinations thereof.
In another preferred embodiment, the ketone solvent is selected from the group consisting of: acetone, 2-butanone, methyl isopropyl ketone, or a combination thereof.
In another preferred embodiment, the alcoholic solvent is selected from the group consisting of: C1-C8 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or combinations thereof.
In another preferred embodiment, the solvent is water.
In another preferred embodiment, the copper salt is used in an amount of 0.5 to 20mol%, preferably 0.5 to 5mol%, more preferably 1 to 3mol% of the fluorohalogenobenzene.
In another preferred embodiment, the oxalic acid diamide ligand is used in an amount of 0.5 to 20mol%, preferably 0.5 to 5mol%, more preferably 1 to 3mol% of fluorohalogenobenzene.
In another preferred embodiment, the base is used in an amount of 1 to 20 molar equivalents, preferably 1 to 5 equivalents, more preferably 1 to 3 equivalents of fluorohalogenobenzene.
In another preferred embodiment, the solvent of the coupling reaction has a volume of 1 to 20 times, preferably 1 to 10 times, more preferably 2 to 8 times the volume of the fluorohalogenobenzene.
In another preferred embodiment, the reaction temperature is 60-120 ℃.
In another preferred embodiment, the reaction time is from 5 to 24 hours, preferably from 10 to 20 hours.
In another preferred embodiment, the method further comprises, after the reaction is completed, post-treatment purification by:
adding acid into the reaction solution, filtering, extracting with organic solvent, concentrating, and vacuum distilling or recrystallizing to obtain pure product.
In another preferred embodiment, the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, or a combination thereof.
In another preferred embodiment, the extraction solvent is selected from the group consisting of: dichloromethane, toluene, ethyl acetate, or a combination thereof.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have conducted long and intensive studies on a novel process for the preparation of (poly) fluorophenol under copper/oxalic acid diamide catalysis at atmospheric pressure. The reaction condition is mild, the catalytic efficiency is high, the side reaction is less, the product quality is high, and the method is suitable for the preparation method of (poly) fluorophenol in industrial production. The copper salt and oxalic acid diamide ligand used in the method are low in price, the dosage is catalytic amount, the catalytic efficiency is high, byproducts are few, the product is easy to purify, and the yield is high. Based on the above findings, the inventors have completed the present invention.
Process for the preparation of (poly) fluorophenols
In the invention, (poly) substituted fluorobenzene is taken as an initial raw material, hydrolysis reaction is carried out in a solvent at the reaction temperature of 60-120 ℃ under the catalysis of copper salt and oxalic acid diamide ligand to obtain (poly) substituted phenol, and the (poly) substituted phenol is subjected to post-treatment and refining to obtain a high-purity product. The method comprises the following specific steps:
Figure BDA0003358066180000061
wherein the copper salt of the hydrolysis reaction is selected from one or more of cuprous oxide, cupric sulfate, thiophene-2-formic acid cuprous, cupric acetate, cupric nitrate, ethylacetoacetic acid cupric, cupric bromide, cupric chloride, cupric cyanide, cupric acetylacetonate, cuprous thiocyanate, cupric iodide, cuprous bromide, cuprous chloride and cuprous cyanide, preferably cuprous iodide.
The ligand is one or more of ligands shown in a formula I;
Figure BDA0003358066180000062
wherein R is a Selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted 5-7 membered heteroaryl group; wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms as a ring skeleton;
R b selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted 5-7 membered heteroaryl group; wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms as a ring skeleton;
unless otherwise specified, the substituents refer to the substitution of one or more hydrogen atoms on a group with a substituent selected from the group consisting of: halogen, hydroxy, cyano, phenyl, carbonyl, C1-C6 alkylamino, C2-C6 ester, C2-C6 acyl, 5-7 membered heteroaryl, C1-C6 alkyl, C1-C6 alkoxy.
Preferably, the ligand is selected from one or more of the ligands shown in Table 1 (L1-L37);
TABLE 1
Figure BDA0003358066180000071
Figure BDA0003358066180000081
More preferably, the ligand is selected from:
Figure BDA0003358066180000082
wherein the alkali of the hydrolysis reaction is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, tetrabutylammonium hydroxide, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU), tetramethylammonium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and preferably sodium hydroxide and potassium hydroxide.
The solvent for the coupling reaction can be one or more of water, alcohol solvent or ether solvent, N, N-Dimethylformamide (DMF), N, N-Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile, alcohol solvent and ketone solvent. The ether solvent is one or more of tetrahydrofuran, dioxane, methyl tertiary butyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and ethylene glycol diethyl ether; the ketone solvent is preferably one or more of acetone, 2-butanone and methyl isopropyl ketone; the alcohol solvent is preferably one or more of C1-C8 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, etc., and more preferably water.
The amount of copper used in the coupling reaction is preferably 0.5 to 20mol%, for example 2mol%, of the (poly) fluorohalogenobenzene.
The amount of ligand used in the coupling reaction is preferably 0.5 to 20mol%, for example 2mol%, of the (poly) fluorohalogenobenzene.
In the coupling reaction, the equivalent of the base is preferably 1 to 20 times the molar equivalent of the (poly) fluorohalogenobenzene, for example 2 times the equivalent.
Wherein the coupling reaction solvent has a volume of 1 to 20 volumes, for example 5 volumes, of the (poly) fluorohalogenobenzene.
In the reaction, the reaction temperature is preferably 60 to 120 ℃.
In the reaction, the reaction time of the coupling reaction is 5 to 24 hours, preferably 10 to 20 hours.
In the present invention, the method preferably further comprises the step (2) of post-treatment purification: adding acid into the reaction solution, filtering, extracting with an organic solvent, concentrating, and then distilling under reduced pressure or recrystallizing to obtain a pure product. Wherein the acid is hydrochloric acid or sulfuric acid, and the extraction solvent is one or more of dichloromethane, toluene, ethyl acetate and the like.
Compared with the prior art, the invention has the main advantages that:
1. the invention provides a preparation method of copper/oxalic acid diamide catalyzed polyfluorophenol, which has mild reaction conditions, can be carried out under normal pressure, and is suitable for industrial production.
2. The preparation method of the invention has high product quality, the used copper salt and oxalic acid diamide ligand are low in price, the dosage is catalytic amount, the catalytic efficiency is high, the byproducts are few, the product is easy to purify, and the yield is high.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1:
193g of 2, 4-difluorobromobenzene, 80g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added into a reaction bottle, and the mixture is heated to 80-100 ℃ to react for 10 hours until the reaction is complete. The reaction liquid is filtered, hydrochloric acid is added to adjust the pH value to 1-3, dichloromethane is added for extraction and delamination, and the product of 2, 4-difluorophenol is obtained by vacuum distillation, 110g, the yield is 85%, and the purity is 99.5%. 1 H-NMR(CDCl 3 )δ6.74-6.95(3H,m),5.33(1H,s)。
Example 2:
193g of 3, 5-difluorobromobenzene, 80g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added into a reaction bottle, and the mixture is heated to 80-100 ℃ to react for 16 hours until the reaction is complete. The reaction liquid is filtered, hydrochloric acid is added to adjust the pH value to 1-3, dichloromethane is added for extraction and delamination, and the 3, 5-difluorophenol product is obtained by reduced pressure distillation, 115g of the 3, 5-difluorophenol product is obtained, the yield is 88%, and the purity is 99.8%. 1 H-NMR(CDCl 3 )δ6.35-6.41(3H,m),6.56(1H,s)。
Example 3:
200g of p-fluorobromobenzene, 80g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added into a reaction bottle, and the mixture is heated to 80-100 ℃ to react for 10 hours until the reaction is complete. Filtering the reaction solution, adding hydrochloric acid to adjust pH to 1-3, adding dichloromethane for extraction and delamination, and steaming under reduced pressureThe p-fluorophenol product 101g is obtained by distillation, the yield is 90 percent, and the purity is 99.5 percent. 1 H-NMR(CDCl 3 )δ6.90-6.95(2H,m),6.75-6.79(2H,m),4.64(1H,s)。
Example 4:
193g of 2, 6-difluorobromobenzene, 80g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added into a reaction bottle, and the mixture is heated to 80-100 ℃ to react for 16 hours until the reaction is complete. The reaction liquid is filtered, hydrochloric acid is added to adjust the pH value to 1-3, dichloromethane is added for extraction and delamination, and the 2, 6-difluorophenol product 112g is obtained by reduced pressure distillation, the yield is 86%, and the purity is 99.4%. 1 H-NMR(CDCl 3 )δ6.70-6.90(3H,m)。
Example 5:
193g of 2, 3-difluorobromobenzene, 8g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added into a reaction bottle, and the mixture is heated to 80-100 ℃ to react for 16 hours until the reaction is complete. The reaction solution is filtered, added with hydrochloric acid to adjust the pH value to 1-3, added with dichloromethane for extraction and delamination, and distilled under reduced pressure to obtain 118g of 2, 3-difluorophenol product with the yield of 91% and the purity of 99.6%. 1 H-NMR(CDCl 3 )δ6.71-6.93(3H,m),5.81(1H,s)。
Example 6:
into the reaction flask, 193g of 3, 4-difluorobromobenzene, 80g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added, and the mixture is heated to 80-100 ℃ to react for 16 hours until the reaction is complete. The reaction liquid is filtered, hydrochloric acid is added to adjust the pH value to 1-3, dichloromethane is added for extraction and delamination, and the 3, 4-difluorophenol product 116g is obtained by reduced pressure distillation, the yield is 89%, and the purity is 99.2%. 1 H-NMR(CDCl 3 )δ6.53-7.02(3H,m),5.31(1H,s)。
Example 7:
211g of 3,4, 5-trifluoro bromobenzene, 80g of sodium hydroxide, 1000g of water, 7g of cuprous iodide and 10g of ligand are added into a reaction bottle, and the mixture is heated to 80-100 ℃ to react for 16 hours until the reaction is complete. The reaction solution is filtered, added with hydrochloric acid to adjust the pH value to 1-3, added with dichloromethane for extraction and delamination, and distilled under reduced pressure to obtain 130g of 3,4, 5-trifluorophenol product with the yield of 88% and the purity of 99.5%. 1 H-NMR(CDCl 3 )δ6.40-6.54(2H,m),6.96(1H,s)。
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A process for the preparation of a substituted phenol, said process comprising:
in a solvent, under the catalysis of copper salt and oxalic acid diamide ligand, carrying out hydrolysis reaction by using fluorohalogenobenzene to obtain fluorophenol;
Figure FDA0003358066170000011
wherein n is 1, 2,3, 4 or 5;
the oxalic acid diacyl ligand has a structure shown in the following formula I:
Figure FDA0003358066170000012
wherein R is a Selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted 5-7 membered heteroaryl group; wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms as a ring skeleton;
R b selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted 5-7 membered heteroaryl group; wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms as a ring skeleton;
unless otherwise specified, the substituents refer to the substitution of one or more hydrogen atoms on a group with a substituent selected from the group consisting of: halogen, hydroxy, cyano, phenyl, carbonyl, C1-C6 alkylamino, C2-C6 ester, C2-C6 acyl, 5-7 membered heteroaryl, C1-C6 alkyl, C1-C6 alkoxy.
2. The method of claim 1, wherein the ligand is selected from one or more of the ligands of formula I;
Figure FDA0003358066170000013
Figure FDA0003358066170000021
Figure FDA0003358066170000031
3. the method of claim 1, wherein the ligand is selected from one or more of the ligands of formula I;
Figure FDA0003358066170000032
4. the method of claim 1, wherein the copper salt is selected from the group consisting of: cuprous oxide, cupric sulfate, thiophene-2-carboxylic acid, cupric acetate, cupric nitrate, cupric acetoacetate, cupric bromide, cupric chloride, cupric cyanide, cupric acetylacetonate, cuprous thiocyanate, cupric iodide, cuprous bromide, cuprous chloride, cuprous cyanide, or combinations thereof.
5. The method of claim 1, wherein the copper salt is copper iodide.
6. The method of claim 1, wherein the hydrolysis is performed in the presence of a base selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, tetrabutylammonium hydroxide, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU), tetramethylammonium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or combinations thereof.
7. The method of claim 1, wherein the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, or a combination thereof.
8. The method of claim 1, wherein the solvent is selected from the group consisting of: water, alcohol solvents, ether solvents, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dimethylsulfoxide (DMSO), acetonitrile, alcohol solvents, ketone solvents.
9. The process according to claim 1, wherein the copper salt is used in an amount of 0.5 to 20mol%, preferably 0.5 to 5mol%, more preferably 1 to 3mol% of the fluorohalogenobenzene.
10. The method of claim 1, further comprising, after the reaction is completed, post-treatment purification by:
adding acid into the reaction solution, filtering, extracting with organic solvent, concentrating, and vacuum distilling or recrystallizing to obtain pure product.
CN202111358125.8A 2021-11-16 2021-11-16 Industrial preparation method of fluorophenol Pending CN116135829A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116693448A (en) * 2023-06-05 2023-09-05 瑞博(杭州)医药科技有限公司 Application of Indole Amide Ligands in Carbon Nitrogen Coupling Reaction

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116693448A (en) * 2023-06-05 2023-09-05 瑞博(杭州)医药科技有限公司 Application of Indole Amide Ligands in Carbon Nitrogen Coupling Reaction
CN116693448B (en) * 2023-06-05 2025-09-12 九洲药业(杭州)有限公司 Application of indoleamide ligands in carbon-nitrogen coupling reactions

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