Preparation method of 2, 4-difluoroaniline

Abstract

The invention relates to a preparation method of 2, 4-difluoroaniline, which comprises the following steps: a, setting the reaction temperature and pressure of a continuous tubular reactor loaded with a catalyst, and introducing inert gas into the continuous tubular reactor; b, after reaction conditions in the tubular reactor reach preset conditions, introducing hydrogen into the tubular reactor for at least 5 minutes; c, 2, 4-difluoronitrobenzene is introduced into the tubular reactor, and a hydrogenation reduction reaction is carried out; and d, collecting and purifying the reaction product 2, 4-difluoroaniline. The invention further provides a system for implementing the preparation method. The method is high in production efficiency and high in safety and operability.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing 2,4-difluoroaniline. Background Art

[0002] 2,4-Difluoroaniline is an important organic synthesis intermediate, which is widely used in the pharmaceutical field. In particular, 2,4-difluoroaniline plays a key role in the synthesis of compounds with specific biological activities. In pharmaceutical synthesis, 2,4-difluoroaniline is used to prepare compounds such as difluorophenylsalicylic acid and polyfluorobenzoic acid.

[0003] Diflunisal is a carboxylic acid non-steroidal anti-inflammatory drug with the international non-proprietary name (INN) Diflunisal. Compared with traditional non-steroidal anti-inflammatory drugs, diflunisal has some significant advantages. First, its molecular structure does not contain the acetyl group of aspirin, but contains difluorophenyl. This structural change makes diflunisal have less antiplatelet side effects, making it safer in clinical applications.

[0004] In addition, diflunisal also has mild gastrointestinal reactions, which improves the comfort of patients during use. More importantly, diflunisal has a longer duration of action, which can last for 8 to 12 hours, providing patients with a more lasting therapeutic effect. Therefore, diflunisal is considered to be one of the most promising varieties of salicylic acid drugs.

[0005] In summary, 2,4-difluoroaniline, as an intermediate in organic synthesis, has important application value in the field of medicine. By synthesizing compounds such as difluorophenylsalicylic acid, 2,4-difluoroaniline provides the possibility for the development of new, efficient and safe pharmaceutical products. With the continuous advancement of medical technology, the application prospects of 2,4-difluoroaniline and its derivatives will be broader. Summary of the invention

[0006] In order to solve the problems in the prior art, the present application provides a method for preparing 2,4-difluoroaniline, which has high production efficiency and is safe and operable.

[0007] In order to solve the above technical problems, a technical solution provided by this application is:

[0008] A method for preparing 2,4-difluoroaniline comprises the following steps: a. setting the reaction temperature and pressure of a continuous tubular reactor loaded with a catalyst, and introducing an inert gas therein; b. after the reaction conditions in the tubular reactor reach a preset value, introducing hydrogen therein for at least 5 minutes; c. introducing 2,4-difluoronitrobenzene into the tubular reactor to carry out a hydrogenation reduction reaction; d. collecting and purifying the reaction product 2,4-difluoroaniline.

[0009] Wherein, the catalyst is a palladium-platinum-nickel mixture, and the carrier of the catalyst is a porous material.

[0010] Wherein, the porous material includes: activated carbon, silicon carbide, zeolite molecular sieve, alumina, silicon dioxide or ceramics.

[0011] After the reaction is carried out for 7-10 days, the catalyst is recovered from the tubular reactor and regenerated.

[0012] The regeneration treatment of the catalyst includes filtering, washing, drying and / or heating and reactivation under a protective atmosphere.

[0013] The catalyst maintains at least 90% of its initial activity during continuous use.

[0014] The reaction is carried out at a temperature of 80-200° C. and a pressure of 10-100 atmospheres.

[0015] The reactor is filled with inert materials to enhance the mixing and mass transfer efficiency between the gas, liquid and solid phases.

[0016] Another technical solution provided by the present application is a continuous tubular hydrogenation reaction system for executing any of the methods described above, characterized in that the system comprises: a. a feeding system for conveying inert gas, hydrogen, and 2,4-difluoronitrobenzene; b. a temperature control and pressure control system for controlling reaction conditions; c. a product post-processing system for collecting and purifying 2,4-difluoroaniline.

[0017] The system also includes a system for recovering and regenerating the catalyst to achieve recycling of the catalyst.

[0018] The preparation method of 2,4-difluoroaniline provided in this application and the continuous tubular hydrogenation reaction system provided realize fully automated operation from raw material transportation to product collection, improve production efficiency and safety, simplify the operation process, and facilitate industrial-scale production and process control. The continuous flow reactor has a small volume and a small liquid holding capacity, which reduces potential safety risks, especially the handling of flammable gases such as hydrogen is safer. The use of a palladium-platinum-nickel mixture as a catalyst and a porous carrier increases the specific surface area of ​​the catalyst and improves the catalytic efficiency. DETAILED DESCRIPTION

[0019] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and do not limit the present invention.

[0020] The present application provides a method for preparing 2,4-difluoroaniline, comprising the following steps: a. setting the reaction temperature and pressure of a continuous tubular reactor loaded with a catalyst, and introducing an inert gas therein; b. after the reaction conditions in the tubular reactor reach a preset value, introducing hydrogen therein for at least 5 minutes; c. introducing 2,4-difluoronitrobenzene into the tubular reactor to carry out a hydrogenation reduction reaction; d. collecting and purifying the reaction product 2,4-difluoroaniline.

[0021] The molar ratio of hydrogen to 2,4-difluoronitrobenzene is 2: 1 to 20: 1. The design of the continuous tubular reactor allows for efficient loading of the catalyst, uniform distribution of the reactants, and easy recovery of the catalyst.

[0022] Furthermore, the catalyst is a palladium-platinum-nickel mixture, and the carrier of the catalyst is a porous material.

[0023] Furthermore, the porous material includes activated carbon, silicon carbide, zeolite molecular sieve, alumina, silicon dioxide or ceramics to improve the stability and recyclability of the catalyst.

[0024] The preparation method of the catalyst is as follows: pre-treating the carrier, which may include acid washing, alkali washing, heat treatment or chemical vapor deposition, etc.; then immersing the carrier in a solution containing a platinum precursor, a palladium precursor and a nickel precursor, and then drying, roasting and reducing to obtain a palladium-platinum-nickel mixture.

[0025] Furthermore, after the reaction is carried out for 7-10 days, the catalyst is recovered from the tubular reactor and regenerated. After the regeneration, the catalyst can be reused in multiple reaction cycles, and the activity decay in each cycle does not exceed 10%.

[0026] Furthermore, the regeneration treatment of the catalyst includes filtering, washing, drying and / or heating and reactivation under a protective atmosphere.

[0027] Further, the catalyst retains at least 90% of its initial activity during continuous use. In the case where the catalyst can be reused, waste generation is reduced and process sustainability is improved.

[0028] Furthermore, the reaction is carried out at a temperature of 80-200° C. and a pressure of 10-100 atmospheres.

[0029] Furthermore, the reactor is filled with an inert material to enhance the mixing and mass transfer efficiency between the gas, liquid and solid phases. The inert material can enhance the mixing between the gas, liquid and solid phases, improve the mass transfer efficiency, and thus improve the overall performance of the reaction. The inert material can be a mixture of one or more of the following: quartz sand, ceramic balls, glass beads, carbon molecular sieves, polytetrafluoroethylene, stainless steel balls, alumina balls, zeolite, porous carbon, silicon carbide, silicon nitride, etc.

[0030] Another technical solution provided by the present application is a continuous tubular hydrogenation reaction system for executing any of the methods described above, characterized in that the system comprises: a. a feeding system for conveying inert gas, hydrogen, and 2,4-difluoronitrobenzene; b. a temperature control and pressure control system for controlling reaction conditions; c. a product post-processing system for collecting and purifying 2,4-difluoroaniline.

[0031] The system also includes a system for recovering and regenerating the catalyst to achieve recycling of the catalyst.

[0032] The preparation method of 2,4-difluoroaniline provided in this application and the continuous tubular hydrogenation reaction system provided realize fully automated operation from raw material transportation to product collection, improve production efficiency and safety, simplify the operation process, and facilitate industrial-scale production and process control. The continuous flow reactor has a small volume and a small liquid holding capacity, which reduces potential safety risks, especially the handling of flammable gases such as hydrogen is safer. The use of a palladium-platinum-nickel mixture as a catalyst and a porous carrier increases the specific surface area of ​​the catalyst and improves the catalytic efficiency.

[0033] The preparation method of the present invention is specifically described below through multiple examples.

[0034] Examples 1-3

[0035] A method for preparing 2,4-difluoroaniline comprises the following steps: a. setting the reaction temperature and pressure of a continuous tubular reactor loaded with a catalyst, and introducing an inert gas therein; b. introducing hydrogen therein for at least 5 minutes after the reaction conditions in the tubular reactor reach a preset value; c. introducing 2,4-difluoronitrobenzene into the tubular reactor to perform a hydrogenation reduction reaction; d. collecting and purifying the reaction product 2,4-difluoroaniline. The catalyst is a palladium-platinum-nickel mixture.

[0036] The reaction conditions of Examples 1-3 were set according to the conditions listed in Table 1.

[0037] Table 1

[0038]

[0039] Example 4-6 is based on Example 1-3, but after the reaction is continued for 8 days, the catalyst is regenerated and the preparation reaction is performed again.

[0040] Embodiment 4-6

[0041] A method for preparing 2,4-difluoroaniline comprises the following steps: a. setting the reaction temperature and pressure of a continuous tubular reactor loaded with a catalyst, and introducing an inert gas therein; b. introducing hydrogen therein for at least 5 minutes after the reaction conditions in the tubular reactor reach a preset value; c. introducing 2,4-difluoronitrobenzene into the tubular reactor to perform a hydrogenation reduction reaction; d. collecting and purifying the reaction product 2,4-difluoroaniline. The catalyst is a palladium-platinum-nickel mixture.

[0042] The reaction conditions of Examples 4-6 were set according to the conditions listed in Table 2.

[0043] Table 2

[0044]

[0045] It is known from the test results that the present invention can also make appropriate changes and modifications to the above specific embodiments according to the above principles. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and changes to the present invention should also fall within the scope of protection of the claims of the present invention. In addition, although some specific terms are used in this specification, these terms are only for the convenience of description and do not constitute any limitation to the present invention.

Claims

1. A method for preparing 2,4-difluoroaniline, characterized in that: The following steps are involved: a. setting the reaction temperature and pressure of a continuous tubular reactor loaded with a catalyst, and introducing an inert gas therein; b. After the reaction conditions in the tubular reactor reach the preset conditions, hydrogen is introduced therein for at least 5 min; c. introducing 2,4-difluoronitrobenzene into the tubular reactor to carry out a hydrogenation reduction reaction; d. Collect and purify the reaction product 2,4-difluoroaniline.

2. The method according to claim 1, characterized in that The catalyst is a palladium-platinum-nickel mixture, and the carrier of the catalyst is a porous material.

3. The method according to claim 1, characterized in that The porous material includes: activated carbon, silicon carbide, zeolite molecular sieve, alumina, silicon dioxide or ceramics.

4. The method according to claim 1, characterized in that: After the reaction is carried out for 7-10 days, the catalyst is recovered from the tubular reactor and regenerated.

5. The method according to claim 4, characterized in that The regeneration treatment of the catalyst includes filtering, washing, drying and / or heating and reactivation under a protective atmosphere.

6. The method according to claim 1, characterized in that The catalyst retains at least 90% of its initial activity during continued use.

7. The method according to any one of claims 1 to 6, characterized in that The reaction is carried out at a temperature of 80-200° C. and a pressure of 10-100 atmospheres.

8. The method according to claim 1, characterized in that The reactor is filled with inert materials to enhance the mixing and mass transfer efficiency between the gas, liquid and solid three phases.

9. A continuous tubular hydrogenation reaction system for performing the method according to any one of claims 1 to 6, characterized in that: The system includes: a. A feeding system for conveying inert gas, hydrogen and 2,4-difluoronitrobenzene; b. Temperature and pressure control systems for controlling reaction conditions; c. Product work-up system for collecting and purifying 2,4-difluoroaniline.

10. The reaction system according to claim 9, characterized in that: The system also includes a system for recovering and regenerating the catalyst to achieve recycling of the catalyst.

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