Preparation method of 2, 3, 5, 6-tetrafluorophenol

Abstract

The invention discloses a preparation method of 2, 3, 5, 6-tetrafluorophenol, and belongs to the technical field of chemical synthesis. The method comprises the following steps: by taking pentafluorobenzonitrile as a raw material, adding inorganic alkali and a catalyst into an organic solvent, reacting to generate salt of 2, 3, 5, 6-tetrafluoro-4-hydroxybenzonitrile, and acidifying to generate 2, 3, 5, 6-tetrafluoro-4-hydroxybenzonitrile; then in the presence of acid and a hydrolysis decarboxylation catalyst, high-temperature catalysis and hydrolysis decarboxylation are completed in one pot, and 2, 3, 5, 6-tetrafluorophenol is generated. The method is simple in process operation, low in cost, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and mainly relates to a method for preparing 2,3,5,6-tetrafluorophenol. Background Art

[0002] 2,3,5,6-Tetrafluorophenol is an important chemical raw material and pharmaceutical intermediate, and is the basic raw material for organic synthesis. Liquid crystal materials; production of degradable functional polymer materials, lubricants, fragrances, coatings, cosmetics, plasticizers and other additives; synthesis of anti-inflammatory drugs such as robencoxib for the treatment of arthritis, etc.

[0003] Patent CN108069832A uses pentafluorobenzoic acid as a raw material, hydrolyzes it at high temperature under alkaline conditions, acidifies it with hydrochloric acid after the reaction is completed, and extracts it with a solvent to obtain a 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid intermediate. Then, it is decarboxylated at high temperature in an N,N-dimethylaniline solvent. The reaction cost is high, and the introduction of two solvents increases the cost and energy consumption.

[0004] Patent CN113214050A uses pentafluorobenzoic acid as a raw material and replaces the fluorine element on the benzene ring with sodium of a short-chain fatty acid. The reaction has large isomerization impurities and a long reaction time, which is not conducive to industrial production.

[0005] Therefore, it is necessary to develop a more economical and practical method for preparing 2,3,5,6-tetrafluorophenol to meet the needs of industrial production and improve product competitiveness. Summary of the invention

[0006] In order to overcome the above technical defects, the present invention provides a method for preparing 2,3,5,6-tetrafluorophenol. The present invention avoids the traditional method of using pentafluorobenzoic acid as a raw material and uses pentafluorobenzonitrile as a raw material, thereby reducing the reaction cost and making the process method simpler. Using pentafluorobenzonitrile as a raw material, para-defluorination hydrolysis and acidification are performed to generate 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile, and the cyano group is then hydrolyzed and decarboxylated, which is completed in one pot. The reaction operation is simple, the yield is high, the isomerization is small, the raw materials are cheap and easy to obtain, the cost is low, and it is suitable for industrial production.

[0007] The present invention discloses a method for preparing 2,3,5,6-tetrafluorophenol, and its synthesis route is expressed as follows using a chemical reaction equation:

[0008]

[0009] The technical solution adopted by the method for preparing 2,3,5,6-tetrafluorophenol of the present invention comprises the following steps:

[0010] A. Pentafluorobenzonitrile is used as raw material, hydrolyzed in the presence of an inorganic base and a phase transfer catalyst, and acidified to generate 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile;

[0011] B. In the presence of acid and hydrolytic decarboxylation catalyst, high temperature catalysis and hydrolytic decarboxylation are completed in one pot to obtain 2,3,5,6-tetrafluorophenol.

[0012] Furthermore, in the above technical solution, in step A, the inorganic base is selected from at least one of potassium hydroxide, sodium hydroxide, calcium hydroxide or sodium carbonate.

[0013] Furthermore, in the above technical solution, in step A, the phase transfer catalyst is tetraphenylphosphonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bromide or tetra(n-butyl)ammonium hydrogen sulfate; and the acidification is carried out using aqueous hydrochloric acid solution.

[0014] Furthermore, in the above technical solution, in step A, the organic solvent is selected from tert-butanol, isopropanol, methanol or ethanol.

[0015] Furthermore, in the above technical solution, in step A, the molar ratio of the inorganic base to pentafluorobenzonitrile is 2-5:1; and the mass ratio of the phase transfer catalyst to pentafluorobenzonitrile is 0.01-0.10:1.

[0016] Furthermore, in the above technical solution, in step A, the reaction temperature is 30-100° C. and the reaction time is 5-10 h.

[0017] Furthermore, in the above technical solution, in step B, the acid is selected from sulfuric acid, and the acid concentration is 50-70%.

[0018] Furthermore, in the above technical solution, in step B, the molar ratio of acid to pentafluorobenzonitrile is 2-10:1.

[0019] Furthermore, in the above technical solution, in step B, the hydrolysis decarboxylation reaction temperature is 100-150° C.; and the reaction time is 3-15 h.

[0020] Furthermore, in the above technical solution, in step B, the hydrolysis decarboxylation catalyst is selected from silver nitrate, copper oxide or lead tetraacetate.

[0021] Furthermore, in the above technical solution, in step B, the weight ratio of the hydrolysis decarboxylation catalyst to pentafluorobenzonitrile is 0.01-0.10:1.

[0022] Advantageous Effects of the Invention

[0023] The invention adopts pentafluorobenzonitrile as a raw material, performs para-defluorination hydrolysis to generate 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile under the condition of inorganic base and catalyst, and then performs cyano group hydrolysis and decarboxylation in one pot under the condition of catalyst catalysis.

[0024] The invention uses pentafluorobenzonitrile as a raw material, reduces the raw material cost and improves the economic benefit, has simple reaction operation, mild reaction conditions, small environmental pollution and is suitable for industrial production; the purity of the obtained product is more than 99%, the by-product is small, the yield is high and is suitable for large-scale workshop preparation. DETAILED DESCRIPTION

[0025] Example 1

[0026] Take a 250mL four-necked bottle, connect it with a stirrer, a condenser, and a thermometer sleeve, add 20g of pentafluorobenzonitrile, 4g of calcium hydroxide, 11.6g of potassium hydroxide, 100g of tert-butyl alcohol, 40g of water, and 1g of tetra(n-butyl)ammonium hydrogen sulfate. Heat to 50°C, keep warm for 3-4h, and the raw materials react completely. Filter, add hydrochloric acid to the filtrate to adjust the pH to 1-2, add chloroform to extract, separate, and concentrate to obtain 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile.

[0027] Prepare 60% sulfuric acid solution, add 0.5g copper oxide, raise the temperature to 110°C, start to drop 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile aqueous solution, and add it in about 2 hours. Keep warm for 2-3 hours, the raw materials react, add 100g toluene for extraction, and concentrate to obtain 14.9g of 2,3,5,6-tetrafluorophenol, with a content of 99.1% and a yield of 87%.

[0028] Example 2

[0029] Take a 1000mL four-necked bottle, connect a stirrer, condenser and thermometer sleeve, add 96.5g pentafluorobenzonitrile, 18.5g calcium hydroxide, 56g potassium hydroxide, 338g isopropanol, 130g water and 1.93g tetrabutylammonium bromide. Heat to 55°C, keep warm for 5-6h, and the raw materials react completely. Filter, add hydrochloric acid to the filtrate to adjust the pH to 1-2, add chloroform to extract, separate and concentrate to obtain 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile.

[0030] Prepare 70% sulfuric acid solution, add 1.0g silver nitrate, raise the temperature to 115°C, start dripping 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile aqueous solution, and complete the dripping in about 2-3 hours. Keep warm for 6 hours, the raw materials react, add 300g toluene for extraction, and concentrate to obtain 70.55g of 2,3,5,6-tetrafluorophenol, with a content of 99.3% and a yield of 85%.

[0031] Example 3

[0032] Take a 1000mL four-necked bottle, connect a stirrer, condenser and thermometer sleeve, add 115.8g pentafluorobenzonitrile, 72g sodium hydroxide, 450g tert-butyl alcohol, 168g water and 3.45g tetra(n-butyl)ammonium hydrogen sulfate. Heat to 65°C, keep warm for 5h, and the raw materials react completely. Filter, add hydrochloric acid to the filtrate to adjust the pH to 1-2, add dichloromethane to extract, separate and concentrate to obtain 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile.

[0033] Prepare 65% sulfuric acid solution, add 1.2g of lead tetraacetate, heat to 140°C, start to drop 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile aqueous solution, and add it after about 4 hours. Keep warm for 4-5 hours, the raw materials react, add 350g of chloroform for extraction, and concentrate to obtain 85.2g of 2,3,5,6-tetrafluorophenol, with a content of 99% and a yield of 85.6%.

[0034] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 2,3,5,6-tetrafluorophenol, characterized in that: The following steps are involved: A. Pentafluorobenzonitrile is used as the raw material, and hydrolyzed in the presence of an inorganic base and a phase transfer catalyst, and acidified to generate 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile; B. In the presence of an acid and a hydrolytic decarboxylation catalyst, high-temperature catalysis and hydrolytic decarboxylation are completed in one pot to obtain 2,3,5,6-tetrafluorophenol.

2. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step A, the inorganic base is selected from at least one of potassium hydroxide, sodium hydroxide, calcium hydroxide or sodium carbonate; the phase transfer catalyst is tetraphenylphosphonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bromide or tetra(n-butyl)ammonium hydrogen sulfate; the organic solvent is selected from tert-butyl alcohol, isopropanol, methanol or ethanol; and the acidification adopts aqueous hydrochloric acid solution.

3. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step A, the molar ratio of the inorganic base to pentafluorobenzonitrile is 2-5:1; and the mass ratio of the phase transfer catalyst to pentafluorobenzonitrile is 0.01-0.10:

1.

4. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step A, the reaction temperature is 30-100° C. and the reaction time is 5-10 h.

5. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step B, the acid is selected from sulfuric acid, and the acid concentration is 50-70%.

6. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step B, the molar ratio of acid to pentafluorobenzonitrile is 2-10:

1.

7. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step B, the hydrolysis decarboxylation reaction temperature is 100-150° C. and the reaction time is 3-15 h.

8. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step B, the hydrolysis decarboxylation catalyst is selected from silver nitrate, copper oxide or lead tetraacetate.

9. The method for preparing 2,3,5,6-tetrafluorophenol according to claim 1, characterized in that: In step B, the weight ratio of the hydrolysis decarboxylation catalyst to pentafluorobenzonitrile is 0.01-0.10:1.

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