Synthesis method of 3, 4, 5-trifluorobenzaldehyde
By using the reaction method of decompression and psychology in the synthesis of 3,4,5-trifluorophenylene formaldehyde, the problem of low reaction conversion rate and slow response rate in existing technologies has been solved, and more efficient and environmentally friendly synthesis has process.
Patent Information
- Application Number
- CN202411352994.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-26
- Publication Date
- 2025-01-24
AI Technical Summary
The existing synthesis method of 3,4,5-trifluorobenzaldehyde is carried out under normal pressure, resulting in low reaction conversion, slow reaction rate and long time.
The reaction method of decompression and distillation is used to mix the solvent, catalyst and fluoride reagent, and reduce the pressure to -0.08 ~ -0.09MPa in the freshing device to 150 ~ 170 ° C, add 3,4-diodes -5-fluorophenyldehyde, to increase the conversion rate and rate of reaction.
The reaction conversion rate and speed are improved, the required reaction time is shortened, the generation of by-products is reduced, the yield and purity of the product are improved, and the process is more environmentally friendly and has better economic benefits.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3,4,5-trifluorobenzaldehyde. Background Art
[0002] 3,4,5-Trifluorobenzaldehyde, also known as trifluorobenzoic acid aldehyde. 3,4,5-Trifluorobenzaldehyde is an important organic synthesis intermediate, which is widely used in the fields of pesticides, medicines and chemical synthesis. In the field of pesticides, 3,4,5-trifluorobenzaldehyde can be used to synthesize agricultural chemicals such as pesticides, insecticides and herbicides. In the field of medicine, 3,4,5-trifluorobenzaldehyde can be used as an intermediate and active substance for the synthesis of drugs norfloxacin and sitafloxacin. In chemical synthesis, 3,4,5-trifluorobenzaldehyde can be used as a starting material or catalyst for organic synthesis reactions.
[0003] Norfloxacin, also known as norfloxacin, has the characteristics of strong antibacterial effect, broad antibacterial spectrum, stable pharmacokinetic properties, high bioavailability, good tissue permeability, no cross-resistance with other antibiotics, small side effects and rapid oral absorption. It has a strong antibacterial effect on Escherichia coli, Klebsiella pneumoniae, Cloacae, Proteus, Salmonella, Shigella, Citrobacter and Serratia, etc. It is clinically used for infectious diseases of the urinary system, intestinal tract, respiratory system, surgery, gynecology, ENT and dermatology caused by sensitive bacteria.
[0004] Norfloxacin is one of the outstanding representatives of the third generation of quinolone antibacterial drugs. It was first synthesized by Japan's Kyorin Pharmaceutical Co., Ltd. in 1978 and launched on the market in 1984. In my country, Taiyuan Pharmaceutical Factory put it into production in 1985. Since then, there have been many manufacturers in China, but most of them have problems such as high unit consumption, low yield and poor quality due to low process level. Its synthesis route is an important cause of these problems, and continuous research and improvement is needed.
[0005] Among them, as a raw material for the preparation of norfloxacin intermediates, the preparation method of 3,4,5-trifluorobenzaldehyde usually adopts the fluorination reaction of aromatic carbonyl compounds, which can be achieved by reacting the corresponding aromatic carboxylic acid aldehyde with a fluorination reagent, such as sodium fluoride (NaF) and hydrofluoric acid (HF). Existing fluorination reactions are usually carried out under normal pressure, resulting in low reaction conversion rate, slow reaction rate, and long reaction time. Summary of the invention
[0006] The purpose of the present invention is to provide a method for synthesizing 3,4,5-trifluorobenzaldehyde to improve the reaction conversion rate and reaction rate.
[0007] The present invention is achieved through the following technical solutions: The present invention provides a method for synthesizing 3,4,5-trifluorobenzaldehyde, comprising the following steps: The solvent, catalyst and fluorination agent are mixed and placed in a distillation device, the distillation device is decompressed to -0.08~-0.09MPa, the temperature is raised to 150~170°C, and then 3,4-dichloro-5-fluorobenzaldehyde is added, the reaction is carried out by vacuum distillation, and the product is collected.
[0008] Preferably, the solvent is sulfolane.
[0009] Preferably, the catalyst is tetraphenylphosphonium bromide.
[0010] Preferably, the fluoridation agent is potassium fluoride.
[0011] Preferably, the reaction time is 2 to 4 hours.
[0012] Preferably, during the reaction, the reaction products are collected in stages according to the temperature in the distillation device until the solvent is evaporated to obtain products of different purities.
[0013] Preferably, after collecting the product, the method further comprises: a step of purifying the collected product.
[0014] Furthermore, the purification method adopts column chromatography separation or distillation.
[0015] Preferably, the mass ratio of the solvent, the catalyst and the fluorination agent is (1.3-1.5):0.005:1.
[0016] Preferably, the moisture content of the solvent, the catalyst, the fluorination agent and the 3,4-dichloro-5-fluorobenzaldehyde is controlled within 500 ppm in advance.
[0017] Compared with the prior art, the present invention has the following beneficial effects: The synthesis method of 3,4,5-trifluorobenzaldehyde adopts a vacuum distillation reaction mode, abandons the original normal pressure reaction mode, the vacuum reaction mode improves the reaction conversion rate, accelerates the reaction process, and can timely separate the products of each temperature section during the reaction process, avoiding the problems of further post-processing and purification of the product after the reaction and long-term decomposition of the product in a high-temperature reaction system. The method has a fast reaction rate, a short required reaction time, few by-products, a high product yield and high purity, a green process and environmental protection, and achieves maximum economic benefits.
[0018] Furthermore, the present invention adopts sulfolane with a higher boiling point as a solvent, which is more conducive to separating the products during the product collection process, improves the product purity, reduces the product purification steps, and greatly saves the production cost.
[0019] Furthermore, the catalyst of the present invention uses tetraphenylphosphonium bromide (TPPB), which is not easy to decompose at the reaction temperature, so the stability of the catalyst can be maintained for a long time, the catalytic effect can be continuously exerted, and the yield and purity of 3,4,5-trifluorobenzaldehyde can be improved.
[0020] Furthermore, by controlling the reaction time, the problem of product decomposition caused by long reaction time can be avoided, thereby improving the product yield and purity. DETAILED DESCRIPTION
[0021] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.
[0022] It should be noted that the process equipment or devices not specifically specified in the following embodiments are all conventional equipment or devices in the art.
[0023] It should be noted that the terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusions. For example, a process, method, system, product or device that includes a series of steps or units is not necessarily limited to those steps or units clearly listed, but may include other steps or units that are not clearly listed or inherent to these processes, methods, products or devices. Moreover, unless otherwise specified, the numbering of each method step is only a convenient tool for identifying each method step, and is not intended to limit the order of arrangement of each method step or to define the scope of the present invention. Changes or adjustments in their relative relationships should also be regarded as the scope of the present invention without substantially changing the technical content.
[0024] The synthesis method of 3,4,5-trifluorobenzaldehyde of the present invention comprises the following steps: The solvent, catalyst and fluorination agent are mixed and placed in a distillation device, the distillation device is decompressed to -0.08~-0.09MPa, the temperature is raised to 150~170°C, and then 3,4-dichloro-5-fluorobenzaldehyde is added, the reaction is carried out by vacuum distillation, and the product is collected.
[0025] The chemical reaction formula is: The solvent used in the present invention is preferably sulfolane, the catalyst used is preferably tetraphenylphosphonium bromide, and the fluorination agent used is preferably potassium fluoride.
[0026] In the above-mentioned synthesis method of the present invention, during the reaction process, the reaction products are collected in stages according to the temperature in the distillation device until the solvent is evaporated to obtain products of different purities.
[0027] After collecting the product, the present invention further comprises: a step of purifying the collected product; the purification method can be column or distillation, and distillation is more preferred.
[0028] In the present invention, the mass ratio of the solvent, the catalyst and the fluorination agent is (1.3-1.5):0.005:1. The molar ratio of the fluorination agent to 3,4-dichloro-5-fluorobenzaldehyde is 2.1:1.
[0029] In the present invention, the reaction time is preferably 2 to 4 hours, more preferably 3 hours.
[0030] In the present invention, the vacuum degree of the distillation reaction equipment is 50-200 mmHg, more preferably 100 mmHg.
[0031] Example 1 3,4,5-trifluorobenzaldehyde is prepared by fluorination method, and the specific steps are: Before the reaction, the moisture content of the reaction materials sulfolane, TPPB, KF and 3,4-dichloro-5-fluorobenzaldehyde was strictly controlled below 500ppm. Sulfolane, TPPB and KF were mixed evenly at a weight ratio of 1.4:0.005:1, added to a distillation reaction device with a metal packing column, a condenser, a receiving bottle and a heating device, and the decompression was turned on. The vacuum degree was adjusted to 100mmHg. When the vacuum degree tended to be stable, the temperature began to rise to 160°C, and 1mol of 3,4-dichloro-5-fluorobenzaldehyde (the amount of TPPB added was 0.5% of the mass of 3,4-dichloro-5-fluorobenzaldehyde) was added dropwise. The addition time should not be too fast. After the addition was completed, the reaction lasted for 3h. The reaction product was collected according to the temperature gradient change inside the distillation reaction device, and the collection was continued until the sulfolane was evaporated. The total yield of the product was 93%; the collected crude product was further purified by distillation to obtain a product with an HPLC content of 94.3%.
[0032] Example 2 The method is basically the same as Example 1, except that the weight ratio of sulfolane, TPPB and KF is 1.2:0.005:1, the total yield of the product is 90%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of 90.2%.
[0033] Example 3 The method is basically the same as Example 1, except that the weight ratio of sulfolane, TPPB and KF is 1.5:0.005:1, the total yield of the product is 92%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of 91.8%.
[0034] Example 4 The method is basically the same as Example 1, except that the heating temperature is 150° C., the total yield of the product is 92.2%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of 91.4%.
[0035] Example 5 The method is basically the same as Example 1, except that the heating temperature is 170° C., the total yield of the product is 92.9%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of 94.0%.
[0036] Example 6 The method is basically the same as Example 1, except that the reaction time is 2 h, the total yield of the product is 90.6%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of more than 85.5%.
[0037] Example 7 The method is basically the same as Example 1, except that the reaction time is 4 h, the total yield of the product is 93.3%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of more than 55.2%.
[0038] Example 8 The method is basically the same as Example 1, except that the reaction is carried out at normal pressure, the total yield of the product is 65%, and the collected crude product is further purified by distillation to obtain a product with an HPLC content of more than 94.0%.
[0039] Example 9 The method is basically the same as Example 1, except that the reaction is carried out at normal pressure, and the obtained product is not distilled. The total yield of the product is 65%, and the content of the product is 68.3%.
[0040] Comparative Example 1 It is basically the same as Example 1, except that TPPB is replaced by TMAC.
[0041] Comparative Example 2 It is basically the same as Example 1, except that TPPB is replaced by TEACl.
[0042] Comparative Example 3 It is basically the same as Example 1, except that TPPB is replaced by TEAB.
[0043] Comparative Example 4 The method is substantially the same as Example 1, except that TPPB is replaced by tetrabutylammonium bromide (TBAB).
[0044] Comparative Example 5 The method is substantially the same as Example 1, except that sulfolane is replaced by dimethylformamide (DMF).
[0045] Comparative Example 6 The method is substantially the same as Example 1, except that sulfolane is replaced by N-methylpyrrolidone (NMP).
[0046] Comparative Example 7 The method is basically the same as Example 1, except that the reaction time is 5 h.
[0047] Comparative Example 8 The method is basically the same as Example 1, except that the reaction time is 6 h.
[0048] Comparative Example 9 The method is basically the same as Example 1, except that the reaction time is 12 h.
[0049] Comparative Example 10 The method is basically the same as Example 1, except that the reaction time is 36 h.
[0050] Comparative Example 11 It is basically the same as Example 1, except that the vacuum degree of the distillation reaction equipment is 50 mmHg.
[0051] Comparative Example 12 The method is basically the same as Example 1, except that the vacuum degree of the distillation reaction equipment is 200 mmHg.
[0052] The Example 1 was compared with the Comparative Examples 1-4 to explore the effect of the catalyst on the reaction. The comparison results are shown in Table 1.
[0053] Table 1 Effect of catalyst on reaction
[0054] As can be seen from Table 1, when other reaction conditions are the same, the TPPB catalyst is selected, the reaction is more thorough, the product content is higher, that is, the purity is higher. Due to the high reaction temperature, the above-mentioned TMAC, TEACl, TEAB and TBAB catalysts gradually decompose as the reaction proceeds, and the catalysts are deactivated, so the content of the product obtained by the reaction is low. Therefore, the TPPB catalyst used in the present invention can obtain a better catalytic effect, and the obtained product has a higher purity.
[0055] The effect of the solvent on the product was investigated by comparing Example 1 with Comparative Examples 5-6. The comparison results are shown in Table 2.
[0056] Table 2 Effect of solvent on product
[0057] As can be seen from Table 2, under the same reaction conditions, the product content is higher when sulfolane is used as the solvent. This is because DMF and NMP have lower boiling points and are not easy to separate from the product; while sulfolane has a higher boiling point and is easier to separate from the product, resulting in a higher purity of the product.
[0058] The effects of reaction time on the product were investigated by comparing Example 1, Examples 6-7 and Comparative Examples 7-10. The results are shown in Table 3.
[0059] Table 3 Effect of time on the reaction.
[0060]
[0061] As can be seen from Table 3, as the reaction proceeds, the reaction conversion rate is the highest at 3h, and the product content is the highest at this time. As the reaction time increases, the product content continues to decrease. This is because the reaction product is aldehyde, which is easily hydrolyzed. Therefore, the longer the time, the lower the product content. Finally, the reaction time of 3h is the best.
[0062] The Example 1 and the comparative examples 11-12 were compared and analyzed to explore the effect of vacuum degree on the product. The comparison results are shown in Table 4.
[0063] Table 4 Effect of vacuum degree on reaction
[0064] At the same time, in order to illustrate the advantages of the vacuum distillation method, the present invention also conducts experiments in two ways: atmospheric distillation and atmospheric non-distillation. Comparing Example 1 and Example 8-9, it can be seen that when the reaction is carried out at atmospheric pressure, the total yield of the product is significantly reduced, and when no distillation is carried out, the purity of the product is significantly reduced. Therefore, Example 1 of the present invention adopts the reaction mode of vacuum distillation, replacing the atmospheric pressure reaction mode, so that the reactants are fully contacted and reacted, the reaction conversion rate is improved, the reaction process is accelerated, and the product obtained by the reaction is directly distilled, avoiding material loss in the material conversion process, and greatly improving the reaction yield and production efficiency.
Claims
1. A method for synthesizing 3,4,5-trifluorobenzaldehyde, characterized in that: The following steps are involved: The solvent, catalyst and fluorination agent are mixed and placed in a distillation device, the distillation device is decompressed to -0.08~-0.09MPa, the temperature is raised to 150~170°C, and then 3,4-dichloro-5-fluorobenzaldehyde is added, the reaction is carried out by vacuum distillation, and the product is collected.
2. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: The solvent is sulfolane.
3. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: The catalyst is tetraphenylphosphonium bromide.
4. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: The fluoridation agent is potassium fluoride.
5. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: The reaction time is 2~4h.
6. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: During the reaction, the reaction products are collected in stages according to the temperature in the distillation device until the solvent is evaporated to obtain products of different purities.
7. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: After collecting the product, the method further includes: a step of purifying the collected product.
8. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 7, characterized in that: The purification method adopts column chromatography separation or distillation.
9. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: The mass ratio of solvent, catalyst and fluorination agent is (1.3~1.5):0.005:
1.
10. The method for synthesizing 3,4,5-trifluorobenzaldehyde according to claim 1, characterized in that: The moisture content of the solvent, catalyst, fluorination agent and 3,4-dichloro-5-fluorobenzaldehyde is controlled within 500 ppm in advance.