A preparation method of 3,4-difluorobromobenzene

Abstract

The present invention provides a method for preparing 3,4-difluorobromobenzene, belonging to the technical field of fine chemical industry. Using 1,2-difluorobenzene as the raw material and solvent, and silica gel supported Lewis acid as the catalyst, bromine is added dropwise while heating up to obtain part of 3,4-difluorobromobenzene. Meanwhile, the generated hydrogen bromide is converted into bromine by an oxidant and continues to be added dropwise, and the product is obtained by rectification to get 3,4-difluorobromobenzene. The present invention uses a catalyst to reduce the generation of isomers; by setting the first / second reaction kettle, the inactivation of the catalyst is avoided, and at the same time, the bromine utilization rate is improved; by selecting an oxidant, the oxidation efficiency is improved, the storage risk is reduced, and the possibility of product pollution is reduced. The bromine utilization rate of the present invention can reach 92%, the product purity can reach 99.7%, and the yield can reach 85.5%.

Description

Technical Field

[0001] The present invention relates to a method for preparing 3,4-difluorobromobenzene, belonging to the technical field of fine chemical production. Background Art

[0002] 3,4-Difluorobromobenzene is an important pharmaceutical intermediate, which is mostly used for preparing anti-influenza drugs such as baloxavir. In addition, it is also an important intermediate for liquid crystal materials. So far, the main synthesis methods of 3,4-difluorobromobenzene are as follows:

[0003] 1. Bromination-diazotization method: Using 2,3-difluoronitrobenzene as the raw material, a Lewis acid as the catalyst, adding solvents such as chloroform, and carrying out a bromination reaction at a certain temperature. Then, using ethanol as the solvent and Raney nickel as the catalyst, the product is hydrogenated to form 1-bromo-3,4-difluoroaniline. Finally, in an environment where acids such as HBr, HCl, and H2SO4 are present, sodium nitrite is added for diazotization and deamination to finally obtain 3,4-difluorobromobenzene. The advantages of this scheme are good selectivity, high product purity, and easy availability of raw materials; the disadvantages are complex reactions, difficult operations, large amounts of waste acid and waste water, serious pollution, and the unloaded Lewis acid catalyst may have phenomena such as sublimation, wall sticking, deactivation, and adhesion, resulting in a large amount of reaction isomers.

[0004] 2. Sandmeyer method: Using 3,4-difluoroaniline as the raw material, bromine as the bromination reagent, hydrogen peroxide as the oxidant, and adding cuprous bromide for catalysis under acidic conditions to carry out the Sandmeyer reaction to form 3,4-difluorobromobenzene. The advantages of this scheme are good bromine substitution positioning effect, high purity, and high bromine utilization rate; the disadvantages are that the raw materials and catalysts are expensive and difficult to obtain, and the amounts of waste acid and waste water are large.

[0005] 3. Direct bromination method: Using o-difluorobenzene as the raw material, bromine as the bromination agent, chloroform as the solvent, and ferric chloride as the catalyst, reacting at 20-50 °C to obtain 3,4-difluorobromobenzene. The advantage of this scheme is simple reaction, and the disadvantages are low bromine utilization rate, generation of waste solvents, and low purity.

[0006] In addition, the conventional means for bromination and oxidation of hydrogen are hydrogen peroxide, chlorine, and oxygen. However, the addition of hydrogen peroxide will deactivate the Lewis acid catalyst, and hydrogen peroxide and oxygen are not suitable for long-term storage. Especially at higher temperatures, hydrogen bromide will decompose hydrogen peroxide; the addition of chlorine will increase the by-products of benzene ring halogenation, so neither is suitable for this reaction. Summary of the Invention

[0007] In order to make up for the deficiencies in the existing technology, the present invention provides a new method for preparing 3,4-difluorobromobenzene with high bromine utilization rate, high purity and simple continuous preparation. Since Lewis acid will undergo hydrolysis reaction with water, deactivating the catalyst, it is necessary to control the bromination reaction to be water-free. Therefore, in a nitrogen purge environment, the selection of the silica gel-supported catalyst in the first reaction kettle and the acidic dryer is particularly important. In addition, separating the bromination reaction and the oxidation reaction is also a key step to improve the bromine utilization rate and ensure the smooth progress of the bromination reaction. Secondly, controlling the temperature of the second reaction kettle to be always lower than that of the first reaction kettle creates a pressure difference between the two, which is conducive to the transfer of hydrogen bromide from the first reaction kettle to the second reaction kettle. Thirdly, selenic acid as an oxidant has adjustable concentration, can be stored for a long time, has strong oxidizing property and can be reused, which is also a key part of this experiment. Finally, the connection system of the first reaction kettle, the second reaction kettle and the dropping kettle is the key setting to ensure the continuous and smooth progress of the experiment. In addition, the method provided by the present invention uses silica gel-supported Lewis acid as a catalyst, aiming to increase the specific surface area through silica gel loading, control the reaction rate and reduce the formation of isomers.

[0008] The present invention provides a method for preparing 3,4-difluorobromobenzene, comprising the following steps:

[0009] S1: Place o-difluorobenzene in the first reaction kettle, add silica gel-supported Lewis acid as a catalyst into the first reaction kettle, use nitrogen as a protective gas, raise the temperature and dropwise add bromine for reaction to obtain 3,4-difluorobromobenzene;

[0010] S2: Introduce the hydrogen bromide gas generated by the reaction into the second reaction kettle, and under a temperature lower than that of the first reaction kettle, oxidize it to bromine with an oxidant, and let it flow out through the lower discharge port of the second reaction kettle. After drying and removing water, introduce it into the dropping kettle for continuous dropping;

[0011] S3: When the flowmeter shows that no gas is generated and there is no bromine in the second reaction kettle, the reaction ends. Use gas chromatography to assist in detecting the reaction process, and after rectifying the product, 3,4-difluorobromobenzene is obtained.

[0012] Further, in the above technical solution, o-difluorobenzene itself is used as a solvent, and its mass is 1-10 times the amount of o-difluorobenzene used in the reaction; the preferred amount of the solvent is 3-5 times the reaction amount.

[0013] Further, in the above technical solution, the dropping rate of bromine is 5-70 mL / h. The preferred dropping rate is 15-25 mL / h; the molar ratio of bromine to the reaction amount of o-difluorobenzene is 0.5-0.8:1, and the preferred molar ratio is 0.6:1; the reaction temperature is 20-110 °C, the preferred reaction temperature is 40-60 °C, and the reaction time is 2-4 h.

[0014] Further, in the above technical solution, the silica-supported catalyst is prepared by co-infiltrating, pulping, and drying Lewis acid and silica with one or more of acetone, ethanol, and methanol, and the loading amount is 20-40%; the Lewis acid is one or more of FeCl3, FeBr2, and AlCl3 in a compound. The mass dosage of the silica-supported catalyst is 5-10% of the reaction amount of o-difluorobenzene. After the catalyst is filtered, it can be washed with one or more of ethanol, acetone, and methanol, dried, and reused 4-5 times.

[0015] Further, in the above technical solution, the preparation method of the silica-supported Lewis acid catalyst is as follows: completely dissolve the Lewis acid in a solvent, then add silica under stirring, keep it warm at 20°C, 40°C, 80°C, and 100°C for 2 hours respectively, put the obtained silica into a vacuum drying oven, dry it at 50°C for 10 hours, and dry it at 80°C for 3 hours to obtain the silica-supported Lewis acid catalyst.

[0016] Further, in the above technical solution, nitrogen is introduced into the first reaction kettle and then discharged from the second reaction kettle.

[0017] Further, in the above technical solution, the reaction temperature of the first reaction kettle is 20°C - 110°C; the reaction temperature of the second reaction kettle is 0 - 75°C, preferably 10 - 30°C; the temperature of the second reaction kettle is always lower than the temperature of the first reaction kettle.

[0018] Further, in the above technical solution, the oxidation of hydrogen bromide is carried out in the second reaction kettle, and hydrogen bromide is directly led below the liquid level of the oxidant.

[0019] Further, in the above technical solution, the oxidant in the second reaction kettle is an aqueous solution of selenic acid; the selenic acid can be reused after oxidation; the solution concentration is 10 - 70%; the concentration is preferably 40 - 60%.

[0020] Further, in the above technical solution, acid drying agents are used for drying and water removal, and one or more of silica gel, anhydrous CaCl2, anhydrous MgSO4, and 4A molecular sieve are compounded and filled in the acid dryer.

[0021] Further, in the above technical solution, the gas outlet of the first reaction kettle is directly connected to the gas inlet of the second reaction kettle, the liquid discharge valve of the second reaction kettle is directly connected to the inlet of the acid dryer, and the outlet of the acid dryer is directly connected to the bromine dropping kettle.

[0022] Further, in the above technical solution, the first reaction kettle, the second reaction kettle, and the dropping kettle are an integrated continuous whole, and the total reaction is a continuous process.

[0023] Further, in the above technical solution, when the flowmeter shows that the exhaust gas volume is close to the nitrogen exhaust gas volume, the reaction ends. After quenching, the obtained crude product is rectified to obtain 3,4-difluorobromobenzene.

[0024] Further, in the above technical solution, the rectification is carried out under a vacuum degree of -0.12 Mpa. The fore fraction is mainly o-difluorobenzene and can be recycled; the residue in the kettle is a small amount of tar waste liquid; the outflow at the top temperature of 100-110 °C is 3,4-difluorobromobenzene.

[0025] The preparation method provided by the present invention is continuous and simple. The product purity can reach 99.7%, the bromine utilization rate can reach 92%, the yield can reach 85.5%, both selenic acid and the catalyst can be recycled, the economy is high, the equipment requirements are low, industrial production is easy, there is almost no solid waste and waste gas, and the waste liquid is less. Specific Embodiments

[0026] The following non-limiting embodiments can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The test methods described in the following embodiments are all conventional methods unless otherwise specified; the reagents and materials used are all commercially available unless otherwise specified.

[0027] Description of the Drawings

[0028] Figure 1 It is a schematic diagram of the reaction device in Embodiments 1-3 of the present invention.

[0029] Example 1

[0030] Add 200 g of ethanol to a 1000 mL kettle. While stirring, add 150 g of ferric chloride. After complete dissolution, add 150 g of silica gel particles. Keep warm at room temperature, 40 °C, 80 °C, and 100 °C for 2 h respectively. After filtration, dry in a vacuum drying oven at 50 °C for 10 h and at 80 °C for 3 h to obtain 250 g of ferric chloride supported on silica gel catalyst, and the loading rate is 40%.

[0031] Take a 2000 mL four-necked flask as the first reaction kettle, add 1000 g of o-difluorobenzene, and while stirring, add 50 g of ferric chloride supported on silica gel catalyst. Take another 1000 mL four-necked flask with a liquid discharge port as the second reaction kettle, and add 400 mL of selenic acid and 250 mL of water to it to prepare a solution with a concentration of 61.54%. Put 400 g of silica gel and 600 g of calcium chloride into an acidic dryer, and connect the first reaction kettle, flowmeter, second reaction kettle, acidic dryer, and constant pressure dropping funnel with a catheter.

[0032] In the first reactor, 210 g of bromine was added dropwise while maintaining the temperature at 50 °C, and the dropping rate of bromine was 15 mL / h. The temperature of the second reactor was set at 10 °C. When bromine was generated in the second reactor, it was discharged through the liquid discharge port and flowed naturally through the acidic dryer into the dropping funnel until the flowmeter showed no gas generation and there was no bromine accumulation in the second reactor, and the reaction ended. After rectification, 361.56 g of 3,4-difluorobromobenzene, a colorless liquid, was obtained, with a yield of 85.5%, a purity of 99.7%, and a bromine utilization rate of 92%.

[0033] Example 2

[0034] First, 180 g of acetone was added to a 1000 mL reactor. While stirring, 80 g of ferrous bromide and 80 g of ferric chloride were added. After complete dissolution, 100 g of silica gel particles were added. The mixture was kept warm at room temperature, 40 °C, 80 °C, and 100 °C for 2 h respectively. After filtration, it was dried in a vacuum drying oven at 50 °C for 10 h and at 80 °C for 3 h to obtain 156.25 g of silica gel supported ferrous bromide catalyst with a loading rate of 36%.

[0035] A 2000 mL four-necked flask was taken as the first reactor, and 1000 g of o-difluorobenzene was added. While stirring, 55.6 g of silica gel supported ferrous bromide and ferric chloride catalyst were added. Another 1000 mL four-necked flask with a liquid discharge port was taken as the second reactor, and 300 mL of selenic acid and 300 mL of water were added to it to prepare a 50% solution. 800 g of anhydrous magnesium sulfate was placed in the acidic dryer, and the first reactor, the flowmeter, the second reactor, the acidic dryer, and the constant pressure dropping funnel were connected with pipelines.

[0036] In the first reactor, at 65 °C, 210 g of bromine was added dropwise at a rate of 25 mL / h and the reaction was kept warm. The temperature of the second reactor was set at 30 °C. When bromine was generated in the second reactor, it was discharged through the liquid discharge port and flowed naturally through the acidic dryer into the dropping funnel until the flowmeter showed no gas generation and there was no bromine accumulation in the second reactor, and the reaction ended. After rectification, 339 g of 3,4-difluorobromobenzene, a colorless liquid, was obtained, with a yield of 80.17%, a purity of 99%, and a bromine utilization rate of 90%.

[0037] Example 3

[0038] In a 2000 mL reactor, 250 g of ethanol and 250 g of methanol were added. While stirring, 100 g of ferric chloride and 100 g of aluminum trichloride were added. After complete dissolution, 100 g of silica gel particles were added. The mixture was kept warm at room temperature, 40 °C, 80 °C, and 100 °C for 2 h respectively. After filtration, it was dried in a vacuum drying oven at 50 °C for 10 h and at 80 °C for 3 h to obtain 149.25 g of silica gel supported ferric chloride and aluminum trichloride catalyst with a loading rate of 33%.

[0039] Take a 2000 mL four-necked flask as the first reactor, add 1000 g of o-difluorobenzene, and add 60.6 g of silica-supported ferrous bromide and ferric chloride catalysts under stirring. Take another 1000 mL four-necked flask with a liquid discharge port as the second reactor, add 300 mL of selenic acid and 300 mL of water to it to prepare a 50% solution. Put 500 g of anhydrous magnesium sulfate and 500 g of calcium chloride into an acidic desiccator, and connect the first reactor, flowmeter, second reactor, acidic desiccator, and constant-pressure dropping funnel with a conduit.

[0040] In the first reactor, at 50 °C, 210 g of bromine is added dropwise at a rate of 20 mL / h, and the reaction is carried out while maintaining the temperature. Set the temperature of the second reactor to 25 °C. When bromine is generated in the second reactor, it is discharged through the liquid discharge port, and it naturally flows into the dropping funnel through the acidic desiccator until the flowmeter shows no gas generation and there is no bromine accumulation in the second reactor. The reaction ends, and 3,4-difluorobromobenzene is obtained by rectification. The yield of the colorless liquid is 355.22 g, the yield is 84%, the purity is 99.3%, and the bromine utilization rate is 91%.

[0041] Comparative Example 1

[0042] Take a 500 mL four-necked flask, place 80 g (0.7 mol) of o-difluorobenzene into the flask, add 250 g of chloroform as a solvent, add 4 g of ferric chloride as a catalyst under stirring, add 123.25 g (0.77 mol) of bromine dropwise at 20 °C while maintaining the temperature. After the addition is complete, maintain the temperature for 2 h. After rectification, 94.6 g of 3,4-difluorobromobenzene is obtained, the yield is 64%, the purity is 97%, and the bromine utilization rate is nearly 50%.

[0043] The above is only the preferred embodiment of the present invention. It should be noted that the above preferred embodiment should not be regarded as a limitation of the present invention. The protection scope of the present invention should be subject to the scope defined by the claims. For those of ordinary skill in the art of this technology, without departing from the spirit and scope of the present invention, several improvements and modifications can also be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing 3,4-difluorobromobenzene, characterized in that, The steps are as follows: S1: Place o-difluorobenzene in the first reaction kettle, add a silica-supported Lewis acid as a catalyst to the first reaction kettle, use nitrogen as a protective gas, heat up and dropwise add bromine for reaction to obtain 3,4-difluorobromobenzene; use o-difluorobenzene itself as a solvent, and its mass is 3-5 times the amount of o-difluorobenzene used in the reaction; the dropping rate of bromine is 15-25 mL / h; the molar ratio of the reaction amount of bromine to o-difluorobenzene is 0.6:

1. S2: Introduce the hydrogen bromide gas generated by the reaction into the second reaction kettle. At a temperature lower than that of the first reaction kettle, oxidize it to bromine using an oxidant, and let it flow out through the lower discharge port of the second reaction kettle. After drying to remove water, introduce it into the dropping kettle for continuous dropping; nitrogen is introduced from the first reaction kettle and then discharged from the second reaction kettle; the reaction temperature of the first reaction kettle is 40-60 °C; the reaction temperature of the second reaction kettle is 10-30 °C; the temperature of the second reaction kettle is always lower than that of the first reaction kettle; carry out the oxidation of hydrogen bromide in the second reaction kettle, and directly introduce the hydrogen bromide below the liquid level of the oxidant; the oxidant in the second reaction kettle is an aqueous solution of selenic acid; the dissolution fraction is 40-60%. S3: When the flowmeter shows that no gas is generated and there is no bromine in the second reaction kettle, the reaction ends. Use gas chromatography to assist in detecting the reaction process, and obtain 3,4-difluorobromobenzene after rectifying the product.

2. The preparation method of 3,4-difluorobromobenzene according to claim 1, wherein: The silica-supported catalyst is prepared by co-infiltrating, beating and drying Lewis acid and silica with one or more of acetone, ethanol, and methanol, and the loading amount is 20-40%; the Lewis acid is one or more of FeCl3, FeBr2, and AlCl3 in a compound; the total amount of the Lewis acid used is 5-10% of the reaction amount of o-difluorobenzene.

3. The preparation method of 3,4-difluorobromobenzene according to claim 1, characterized in that: Acidic desiccants are used for drying and water removal, and one or more of silica gel, anhydrous CaCl2, anhydrous MgSO4, and 4A molecular sieve are filled in the acidic dryer for compounding.

4. The preparation method of 3,4-difluorobromobenzene according to any one of claims 1-3, characterized in that: The first reaction kettle, the second reaction kettle, and the dropping kettle form a unified continuous whole, and the total reaction is a continuous process.

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