A kind of synthetic method of 4-ethoxy-2,3-difluorophenol

Abstract

The invention discloses a synthetic method of 4-ethoxy-2,3-difluorophenol, belonging to the field of medicine, pesticide and liquid crystal intermediate preparation. It comprises the following steps: adding a first catalyst to 2,3-difluorophenyl ether and carrying out bromination reaction to obtain 4-bromo-2,3-difluorophenyl ether, adding a second catalyst to the obtained 4-bromo-2,3-difluorophenyl ether and carrying out amination reaction to obtain 4-amino-2,3-difluorophenyl ether, diazotizing the obtained 4-amino-2,3-difluorophenyl ether, and stirring with water to the third catalyst, adding the diazo liquid obtained by diazotization, and carrying out catalytic hydrolysis to obtain the final product 4-ethoxy-2,3-difluorophenol. The synthetic method disclosed in the present invention has easy-to-obtain raw materials, short reaction route and stable reaction conditions, and realizes the scale of synthesis of 4-ethoxy-2,3-difluorophenol.

Description

Technical Field

[0001] The invention relates to the fields of medicine, pesticide and liquid crystal intermediate preparation, and more specifically to a method for synthesizing 4-ethoxy-2,3-difluorophenol. Background Art

[0002] 4-Ethoxy-2,3-difluorophenol is an electronic chemical and an important raw material for synthesizing liquid crystal intermediates. Due to the introduction of lateral double fluorine atoms, it has a large negative dielectric anisotropy, a very wide nematic range, moderate birefringence and a low viscoelastic coefficient, thereby improving the display performance of liquid crystal materials.

[0003] With the development of liquid crystal display technology, the demand for research and development of new liquid crystal materials is becoming more and more urgent, but there are only a few reports on the preparation of 4-ethoxy-2,3-difluorophenol. Patent No. CN201510423679.X discloses a one-pot method for preparing 4-ethoxy-2,3-difluorophenol, by using 4-ethoxy-2,3-difluorobromobenzene as a raw material, first preparing a Grignard reagent with magnesium chips, then boration with trimethyl borate, hydrolyzing with hydrochloric acid to obtain 4-ethoxy-2,3-difluorophenylboric acid, and then oxidizing with hydrogen peroxide to obtain 4-ethoxy-2,3-difluorophenol. This method has a long reaction route and the raw materials are not easy to obtain, so it is difficult to be applied in actual production. Summary of the invention

[0004] 1. Technical issues to be solved

[0005] In view of the problems existing in the prior art, the object of the present invention is to provide a synthetic method for preparing 4-ethoxy-2,3-difluorophenol by using simpler 2,3-difluorophenethyl ether as a raw material through bromination, amination and diazo hydrolysis.

[0006] 2. Technical solution

[0007] To solve the above problems, the present invention adopts the following technical solutions.

[0008] A method for synthesizing 4-ethoxy-2,3-difluorophenol comprises the following steps:

[0009] The first step is to add a first catalyst to 2,3-difluorophenethyl ether and perform a bromination reaction to obtain 4-bromo-2,3-difluorophenethyl ether;

[0010] The second step is to add a second catalyst to the 4-bromo-2,3-difluorophenethyl ether obtained in the first step, and perform an amination reaction to obtain 4-amino-2,3-difluorophenethyl ether;

[0011] In the third step, 4-amino-2,3-difluorophenethyl ether is diazotized to obtain a diazo liquid, and the diazo liquid is catalytically hydrolyzed under the action of a third catalyst to obtain the product 4-ethoxy-2,3-difluorophenol.

[0012] Furthermore, in the first step, bromine and hydrogen peroxide are used for bromination reaction, and the molar ratio of bromine to 2,3-difluorophenethyl ether is 0.55:1 to 0.6:1

[0013] Further, the molar ratio of bromine to 2,3-difluorophenethyl ether is 0.55:1;

[0014] In the second step, ammonia water is used for the amination reaction, and the molar ratio of ammonia water to 4-bromo-2,3-difluorophenethyl ether is 8:1 to 12:1;

[0015] Further, the molar ratio of ammonia water to 4-bromo-2,3-difluorophenethyl ether is 10.5:1;

[0016] In the third step, nitrosylsulfuric acid is used for diazotization reaction, and the molar ratio of nitrosylsulfuric acid to 4-amino-2,3-difluorophenyl ether is 1.05:1 to 1.1:1;

[0017] Furthermore, the molar ratio of nitrosylsulfuric acid to 4-amino-2,3-difluorophenyl ether is 1.05:1; the chemical reaction formula of the first step is

[0018]

[0019] The chemical reaction formula of the second step is

[0020]

[0021] The chemical reaction formula of the third step diazotization is:

[0022]

[0023] The chemical reaction formula of the third step catalytic hydrolysis is:

[0024]

[0025] Furthermore, in the first step, the first catalyst is selected from one of Lewis acids, including but not limited to anhydrous aluminum chloride, anhydrous ferric chloride or anhydrous zinc chloride, and the amount of the first catalyst is 2.5% of the weight of 2,3-difluorophenethyl ether.

[0026] Furthermore, in the first step, a promoter is added, and the promoter is sulfur powder.

[0027] Furthermore, in the second step, the second catalyst is selected from one of copper-containing catalysts, including but not limited to cuprous chloride, cuprous bromide or cuprous oxide, and the amount of the second catalyst is 3% of the weight of 4-bromo-2,3-difluorophenethyl ether.

[0028] Furthermore, in the third step, the third catalyst is selected from copper sulfate pentahydrate or copper sulfate, and the amount of the third catalyst is 1.5 equivalents of the substrate molar ratio.

[0029] Furthermore, after adding the first catalyst in the first step, stirring and cooling to 10°C-15°C, and performing bromination reaction, keeping warm and adding 30% hydrogen peroxide, the molar ratio of hydrogen peroxide to 2,3-difluorophenyl ether is 0.7:1, and sampling is performed by GC control. The reaction is considered to be complete when the content of 2,3-difluorophenyl ether is less than 1%;

[0030] After the reaction was completed, 15% sodium sulfite solution was added to remove excess bromine in the reaction system, and the molar ratio of the sodium sulfite solution to 2,3-difluorophenethyl ether was 0.5:1.

[0031] Furthermore, after adding the second catalyst in the second step, during the amination reaction, the temperature is raised to 140°C-180°C with stirring, and the reaction is carried out for 8h-10h. The GC is used for central control sampling. When the content of 4-bromo-2,3-difluorophenyl ether is less than 1%, the reaction is considered to be complete, and the material is transferred out and subjected to steam distillation.

[0032] Furthermore, in the third step, the diazotization reaction is to slowly add the product 4-amino-2,3-difluorophenyl ether obtained in the second step into 50% sulfuric acid, and after solid precipitation occurs, heat it to 40°C-60°C and keep it warm until it is completely clear, cool it to -5°C-5°C, and when conducting the diazotization reaction, control the reaction temperature to 0°C-5°C, keep it warm until the reaction is complete, and obtain a diazo liquid, wherein the molar ratio of sulfuric acid to 4-amino-2,3-difluorophenyl ether is 5:1.

[0033] Furthermore, the catalytic hydrolysis reaction in the third step is that after adding water to the diazo liquid and adding the third catalyst, the temperature is raised to 110°C-140°C, and the steam distillation reaction is carried out for 6h-8h, and the steam distillation is continued until no product is evaporated. After the evaporated phenol-water mixture is extracted and layered, the organic layer is concentrated under reduced pressure to obtain the product 4-ethoxy-2,3-difluorophenol.

[0034] 3. Beneficial effects

[0035] Compared with the prior art, the advantages of the present invention are:

[0036] The invention uses simple 2,3-difluorophenethyl ether as a raw material, and prepares 4-ethoxy-2,3-difluorophenol through bromination, amination and diazo hydrolysis. The raw material is easy to obtain, the reaction route is short, the reaction conditions are stable, the yield and purity of the obtained product are high, and the synthesis of 4-ethoxy-2,3-difluorophenol is more scalable. DETAILED DESCRIPTION

[0037] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0038] Example 1: Synthesis of 4-bromo-2,3-difluorophenyl ether

[0039] 40 g 2,3-difluorophenethyl ether, 1 g anhydrous aluminum chloride, and 0.1 g sulfur powder were added to a 500 mL dry flask, stirring was started, and the temperature was lowered to 10-15° C.; 22.3 g bromine was added dropwise, and the temperature was kept warm for 30 min after the addition was completed. 20 g 30% hydrogen peroxide was added dropwise, and the temperature was kept warm for 1 h after the addition was completed; sampling was controlled in the GC, and the reaction was considered to be over when the 2,3-difluorophenethyl ether content was less than 1%; after the reaction was completed, 100 g of 15% sodium sulfite solution was added dropwise to remove excess bromine in the reaction system, and the reaction was allowed to stand for stratification to obtain 56.4 g of crude 2,3-difluoro-4-bromophenethyl ether with a GC purity of 98.8% (isomer 0.2%) and a yield of 94.1%. The obtained crude 2,3-difluoro-4-bromophenethyl ether was stored for later use.

[0040] Example 2: Synthesis of 4-bromo-2,3-difluorophenyl ether

[0041] 40 g 2,3-difluorophenethyl ether, 1 g anhydrous ferric chloride, and 0.1 g sulfur powder were added to a 500 mL dry flask, and stirring was started. The temperature was lowered to 10-15° C. 22.3 g bromine was added dropwise, and the mixture was kept warm for 30 min. 20 g 30% hydrogen peroxide was added dropwise, and the mixture was kept warm for 1 h. The GC was used for sampling. The reaction was considered to be over if the content of 2,3-difluorophenethyl ether was less than 1%. After the reaction was completed, 100 g of 15% sodium sulfite solution was added dropwise to remove excess bromine in the reaction system, and the mixture was allowed to stand for stratification to obtain 56.0 g of crude 2,3-difluoro-4-bromophenethyl ether with a GC purity of 98.5% (0.25% for isomers) and a yield of 93.4%. The crude 2,3-difluoro-4-bromophenethyl ether was stored for later use.

[0042] Example 3: Synthesis of 4-bromo-2,3-difluorophenyl ether

[0043] 40 g 2,3-difluorophenethyl ether, 1 g anhydrous aluminum chloride, and 0.1 g sulfur powder were added to a 500 mL dry flask, stirring was started, and the temperature was lowered to 10-15° C.; 24.3 g bromine was added dropwise, and after the addition was completed, the temperature was kept warm for 30 min, and 20 g 30% hydrogen peroxide was added dropwise, and after the addition was completed, the temperature was kept warm for 1 h; GC central control sampling was performed, and the reaction was considered to be complete when the 2,3-difluorophenethyl ether content was less than 1%; after the reaction was completed, 100 g of 15% sodium sulfite solution was added dropwise to remove excess bromine in the reaction system, and the reaction was allowed to stand for stratification to obtain 56.2 g of crude 2,3-difluoro-4-bromophenethyl ether with a GC purity of 98.8% (isomer 0.21%) and a yield of 93.8%. The obtained crude 2,3-difluoro-4-bromophenethyl ether was stored for later use.

[0044] Example 4: Synthesis of 4-amino-2,3-difluorophenyl ether

[0045] Take out the crude 2,3-difluoro-4-bromophenethyl ether obtained in Example 1, add 100g of the 2,3-difluoro-4-bromophenethyl ether, 300g of 25% ammonia water, and 3g of cuprous chloride into a 1L autoclave, seal the autoclave, start stirring, stir at a speed of 500r / min, slowly heat to 160°C, react for 8-10h, and the pressure during the reaction reaches a maximum of about 2.5MPa. GC central control sampling, 2,3-difluoro-4-bromophenethyl ether content <1%, transfer the material, steam distill, and obtain 4-amino-2,3-difluorophenethyl ether 62.6g, GC purity 97.6%, yield 85.8%, and the obtained 4-amino-2,3-difluorophenethyl ether is stored for standby use.

[0046] Example 5: Synthesis of 4-amino-2,3-difluorophenyl ether

[0047] Take out the crude 2,3-difluoro-4-bromophenethyl ether obtained in Example 2, add 100g of the 2,3-difluoro-4-bromophenethyl ether, 345g of 25% ammonia water, and 3g of cuprous chloride into a 1L autoclave, seal the autoclave, start stirring, stir at a speed of 500r / min, slowly heat to 160°C, react for 8-10h, and the pressure during the reaction reaches a maximum of about 2.5MPa. GC central control sampling, 2,3-difluoro-4-bromophenethyl ether content <1%, transfer the material, steam distill, and obtain 4-amino-2,3-difluorophenethyl ether 62.8g, GC purity 97.6%, yield 86.1%, and the obtained 4-amino-2,3-difluorophenethyl ether is stored for standby use.

[0048] Example 6: Synthesis of 4-amino-2,3-difluorophenyl ether

[0049] Take out the crude 2,3-difluoro-4-bromophenethyl ether obtained in Example 3, add 100g of the 2,3-difluoro-4-bromophenethyl ether, 300g of 25% ammonia water, and 3g of cuprous oxide into a 1L autoclave, seal the autoclave, start stirring, stir at a speed of 500r / min, slowly heat to 160°C, react for 8-10h, and the pressure during the reaction reaches a maximum of about 2.5MPa. GC central control sampling, 2,3-difluoro-4-bromophenethyl ether content <1%, transfer the material, steam distill, and obtain 62.5g of 4-amino-2,3-difluorophenethyl ether, GC purity 97.5%, yield 85.7%, and the obtained 4-amino-2,3-difluorophenethyl ether is stored for standby use.

[0050] Example 7: Synthesis of 4-ethoxy-2,3-difluorophenol

[0051] Take out the 4-amino-2,3-difluorophenyl ether obtained in Example 4, weigh 392g of 50% sulfuric acid and add it to a 1000mL flask, start stirring, slowly add 69.2g of the 4-amino-2,3-difluorophenyl ether, solid precipitates, heat to 50℃ and keep warm for 0.5h, after complete clarification, cool to 0℃, drop 133g of 40% nitrosylsulfuric acid solution, control the dropping temperature to 0~5℃, keep warm for 1h, obtain diazo liquid, and store at low temperature for standby use. Weigh 150g of copper sulfate pentahydrate, add it to another 2000mL flask, add 40g of water and 80g of concentrated sulfuric acid, start stirring, heat to 125℃, start dropping the above diazo liquid, and steam distill while dropping, the dropping time is about 6~8h, and continue distillation for 1h after the dropping is completed until no product is evaporated. The phenol-water mixture evaporated by water vapor was extracted with dichloromethane and separated into layers. The organic layer was concentrated under reduced pressure to obtain 57.1 g of crude 4-ethoxy-2,3-difluorophenol with a GC purity of 98.2% and a yield of 82.0%.

[0052] Example 8: Synthesis of 4-ethoxy-2,3-difluorophenol

[0053] Take out the 4-amino-2,3-difluorophenyl ether obtained in Example 5, weigh 392g of 50% sulfuric acid and add it to a 1000mL flask, start stirring, slowly add 69.2g of the 4-amino-2,3-difluorophenyl ether, solid precipitates, heat to 50℃ and keep warm for 0.5h, after complete clarification, cool to 0℃, drop 133g of 40% nitrosylsulfuric acid solution, control the dropping temperature at 0~5℃, keep warm for 1h, obtain diazo liquid, and store at low temperature for standby use. Weigh 96g of anhydrous copper sulfate, add it to another 2000mL flask, add 40g of water and 80g of concentrated sulfuric acid, start stirring, heat to 125℃, start dropping the above diazo liquid, and steam distill while dropping, the dropping time is about 6~8h, and continue distillation for 1h after the dropping is completed until no product is evaporated. The phenol-water mixture evaporated by water vapor was extracted with dichloromethane and then separated into layers. The organic layer was concentrated under reduced pressure to obtain 56.8 g of crude 4-ethoxy-2,3-difluorophenol with a GC purity of 98.2% and a yield of 81.6%.

[0054] Example 9: Synthesis of 4-ethoxy-2,3-difluorophenol

[0055] Take out the 4-amino-2,3-difluorophenyl ether obtained in Example 6, weigh 392g of 50% sulfuric acid and add it to a 1000mL flask, start stirring, slowly add 69.2g of the 4-amino-2,3-difluorophenyl ether, solid precipitates, heat to 50℃ and keep warm for 0.5h, after complete clarification, cool to 0℃, drop 139g of 40% nitrosylsulfuric acid solution, control the dropping temperature to 0~5℃, keep warm for 1h, obtain diazo liquid, and store at low temperature for standby use. Weigh 150g of copper sulfate pentahydrate, add it to another 2000mL flask, add 40g of water and 80g of concentrated sulfuric acid, start stirring, heat to 125℃, start dropping the above diazo liquid, and steam distill while dropping, the dropping time is about 6~8h, and continue distillation for 1h after the dropping is completed until no product is evaporated. The phenol-water mixture evaporated by water vapor was extracted with dichloromethane and separated into layers. The organic layer was concentrated under reduced pressure to obtain 57.0 g of crude 4-ethoxy-2,3-difluorophenol with a GC purity of 98.0% and a yield of 81.9%.

[0056] Comparative Example 1:

[0057] In a 1000mL three-necked flask, add 600mL THF and 200g 4-ethoxy-2,3-difluorobromobenzene, stir to make a solution, and set aside. Then, in a 2L three-necked flask, add 25g magnesium, 20mL THF, and 1g iodine. Add 20mL of the prepared THF solution of 4-ethoxy-2,3-difluorobromobenzene dropwise, heat and initiate, and then add the remaining THF solution of 4-ethoxy-2,3-difluorobromobenzene dropwise at 10-20°C. After the addition is complete, heat at 30- Keep warm and stir at 35℃ for 1h, cool the reaction flask to below -30℃ with liquid nitrogen for standby use; slowly dropwise add 110g trimethyl borate in 600mL THF solution, keep below -30℃ during the dropping process, stir and naturally warm to room temperature after dropping, dropwise add 400mL 10% hydrochloric acid, reflux for 1h, distill out THF, add 500mL cold water, stir for 30min, cool, crystallize and separate to obtain 153g 4-ethoxy-2,3-difluorophenylboric acid with a yield of 90%;

[0058] In a 1L three-necked flask, add 50g of 4-ethoxy-2,3-difluorophenylboric acid and 200mL of methanol, stir to dissolve, add 30mL of 50% hydrogen peroxide at 15°C, stir for 30min after the addition, heat to 50°C, desolventize, add 200g of water, cool and centrifuge to obtain crude 4-ethoxy-2,3-difluorophenol; add 100mL of water to mix, add a small amount of sodium sulfite solution until the starch potassium iodide test paper does not change color, centrifuge and add 200mL of toluene to dissolve, desolventize, cool, crystallize, centrifuge and dry to obtain 32g of 4-ethoxy-2,3-difluorophenol product, with a yield of 74%.

Claims

1. A method for synthesizing 4-ethoxy-2,3-difluorophenol, characterized in that: The following steps are involved: The first step is to add a first catalyst to 2,3-difluorophenethyl ether, and use bromine and hydrogen peroxide to carry out bromination reaction to obtain 4-bromo-2,3-difluorophenethyl ether, wherein the first catalyst is anhydrous aluminum chloride, anhydrous ferric chloride or anhydrous zinc chloride, and the molar ratio of hydrogen peroxide to 2,3-difluorophenethyl ether is 0.7:1; The second step is to add a second catalyst to the 4-bromo-2,3-difluorophenethyl ether obtained in the first step, and perform an amination reaction to obtain 4-amino-2,3-difluorophenethyl ether; The third step is to diazotize 4-amino-2,3-difluorophenethyl ether with nitrosylsulfuric acid to obtain a diazo liquid, and catalytically hydrolyze the diazo liquid under the action of a third catalyst to obtain a product 4-ethoxy-2,3-difluorophenol, wherein the molar ratio of nitrosylsulfuric acid to 4-amino-2,3-difluorophenethyl ether is 1.05:1 to 1.1:1; After adding the first catalyst in the first step, stirring and cooling to 10°C-15°C, keeping warm and adding 30% hydrogen peroxide during the bromination reaction, sampling by GC control, the reaction is considered to be complete when the content of 2,3-difluorophenyl ether is less than 1%; After the reaction is completed, 15% sodium sulfite solution is added to remove excess bromine in the reaction system, and the molar ratio of the sodium sulfite solution to 2,3-difluorophenyl ether is 0.5:1; After the second catalyst is added in the second step, the amination reaction is carried out with stirring and the temperature is raised to 140°C-180°C for reaction for 8h-10h. The reaction is sampled by GC control. If the content of 4-bromo-2,3-difluorophenyl ether is less than 1%, the reaction is considered to be complete, and the material is transferred out and subjected to steam distillation; In the third step, the diazotization reaction is to slowly add the product 4-amino-2,3-difluorophenyl ether obtained in the second step to 50% sulfuric acid, and after solid precipitation occurs, heat it to 40°C-60°C and keep it warm until it is completely clear, cool it to -5°C-5°C, and control the reaction temperature to 0°C-5°C during the diazotization reaction, and keep it warm until the reaction is complete to obtain a diazo liquid, wherein the molar ratio of sulfuric acid to 4-amino-2,3-difluorophenyl ether is 5:1; The catalytic hydrolysis reaction in the third step is to add water to the diazo liquid and add the third catalyst, then heat it to 110°C-140°C, and steam distill for 6h-8h, and continue the steam distillation until no product is evaporated, extract and separate the phenol-water mixture, and then reduce the pressure and concentrate the organic layer to obtain the product 4-ethoxy-2,3-difluorophenol; In the second step, the second catalyst is selected from cuprous chloride, cuprous bromide or cuprous oxide; In the third step, the third catalyst is selected from copper sulfate pentahydrate or copper sulfate.

2. A method for synthesizing 4-ethoxy-2,3-difluorophenol according to claim 1, characterized in that: In the first step, the molar ratio of bromine to 2,3-difluorophenethyl ether is 0.55:1 to 0.6:1; In the second step, ammonia water is used for the amination reaction, and the molar ratio of ammonia water to 4-bromo-2,3-difluorophenethyl ether is 8:1 to 12:1; The chemical reaction formula of the first step is ； The chemical reaction formula of the second step is ； The chemical reaction formula of the third step diazotization is: ； The chemical reaction formula of the third step catalytic hydrolysis is: 。 3. A method for synthesizing 4-ethoxy-2,3-difluorophenol according to claim 1, characterized in that: In the first step, the amount of the first catalyst used is 2.5% by weight of 2,3-difluorophenethyl ether.

4. A method for synthesizing 4-ethoxy-2,3-difluorophenol according to claim 3, characterized in that: In the first step, a promoter is also added, and the promoter is sulfur powder.

5. A method for synthesizing 4-ethoxy-2,3-difluorophenol according to claim 1, characterized in that: The amount of the second catalyst used is 3% by weight of 4-bromo-2,3-difluorophenethyl ether.

6. A method for synthesizing 4-ethoxy-2,3-difluorophenol according to claim 1, characterized in that: The amount of the third catalyst used was 1.5 equivalents of the substrate.

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