Method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3, 5-dichloro-4-fluorobenzoyl chloride
By heating and distilling fluorobenzoyl chloride with a chlorine-containing catalyst, the problems of long reaction time, high energy consumption, and large amount of acidic waste gas in the synthesis of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride in the existing technology have been solved, achieving efficient and low-cost green production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HUBEI LIANCHANG NEW MATERIALS CO LTD
- Filing Date
- 2026-01-28
- Publication Date
- 2026-04-17
AI Technical Summary
The synthesis of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride in the existing technology has problems such as long reaction time, high energy consumption, generation of a large amount of acidic waste gas, and difficulty in product purification.
The reaction was carried out by heating a mixture of p-fluorobenzoyl chloride and a chlorine-containing catalyst to control the chlorination reaction depth, and then purified by distillation to obtain 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride.
It has achieved efficient production of two important chemical products, with mild reaction conditions, low acid gas emissions, and compliance with green chemistry requirements. The raw materials are inexpensive and readily available, resulting in significant economic benefits.
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Figure CN121872907A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical technology, specifically relating to a method for the co-production of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. Background Technology
[0002] 3-Chloro-4-fluorobenzoyl chloride is an important organic intermediate primarily used in pharmaceutical and materials chemistry. In pharmaceuticals, it is often used as a key "building block" molecule in the synthesis of drug molecules with specific biological activities. It is frequently used to prepare compounds such as N-(3-chloro-4-fluorobenzoyl)-piperidin-4-one. These compounds are of significant value in drug development and may serve as intermediates in the synthesis of other drugs. 3,5-Dichloro-4-fluorobenzoyl chloride is also a very important fine chemical intermediate. In pesticide synthesis, it is a key intermediate for the synthesis of certain isoxazole or benzoylurea insecticides.
[0003] Currently, there are two main processes for the synthesis of 3-chloro-4-fluorobenzoyl chloride (3,5-dichloro-4-fluorobenzoyl chloride). The first process involves reacting 3-chloro-4-fluorobenzoic acid (3,5-dichloro-4-fluorobenzoic acid) with a chlorinating agent to obtain the target product. Commonly used chlorinating agents include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and oxalyl chloride. Among these, thionyl chloride is the most commonly used acyl chloride reagent due to its mild reaction conditions and volatile byproducts. However, this process still suffers from problems such as long reaction time, high energy consumption, generation of large amounts of acidic waste gas, and difficulty in product purification. The second method uses 3-chloro-4-fluorotoluene (3,5-dichloro-4-fluorotoluene) as a starting material. Under the action of a catalyst, it undergoes side-chain chlorination with chlorine to obtain 3-chloro-4-fluorotrichlorobenzyl (3,5-dichloro-4-fluorotrichlorobenzyl). Then, under the action of a catalyst, it undergoes hydrolysis with water, followed by purification by distillation to obtain 3-chloro-4-fluorobenzoyl chloride (3,5-dichloro-4-fluorobenzoyl chloride). This process has a long reaction time, high raw material costs, and generates a large amount of acidic HCl waste gas. Summary of the Invention
[0004] In view of this, the present invention provides a method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride, which does not require the addition of organic solvents, is simple to operate, has low raw material costs, and produces less acidic waste gas.
[0005] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for the co-production of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride, comprising the following steps: S1. Mix p-fluorobenzoyl chloride with a chlorine-containing catalyst to obtain a mixture; S2. The mixture is heated and reacted under a chlorine atmosphere to obtain the reactants; S3. After distilling the reactants, 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride are obtained.
[0006] Preferably, in step S1, the chlorine-containing catalyst includes zinc chloride, ferric chloride, or aluminum chloride.
[0007] Preferably, in step S1, the mass ratio of p-fluorobenzoyl chloride to the chlorine-containing catalyst is 100:(3-5).
[0008] Preferably, in step S2, the heating temperature is 100-130°C.
[0009] Preferably, in step S2, the reaction is stopped when p-fluorobenzoyl chloride ≤ 1%, and the reactant is obtained.
[0010] Preferably, in step S3, the residual chlorine in the reaction system is removed by nitrogen gas before distillation.
[0011] Preferably, the temperature at which 3-chloro-4-fluorobenzoyl chloride is distilled off is 115-130°C and the pressure is 1.3-2.7 kPa.
[0012] Preferably, the temperature at which 3,5-dichloro-4-fluorobenzoyl chloride is distilled off is 140-160°C and the pressure is 1.3-2.7 kPa.
[0013] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This invention uses p-fluorobenzoyl chloride as raw material, and through a one-step benzene ring chlorination reaction, the depth of the chlorination reaction is controlled. After distillation and purification, two important fine chemical products, 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride, are obtained simultaneously. The reaction efficiency is high and the product market is greatly enriched.
[0014] (2) The process of this invention is simple to operate, the reaction conditions are relatively mild, and the amount of acidic gas produced by the reaction is relatively small, resulting in relatively little pollution, which meets the current development requirements of green chemistry.
[0015] (3) The raw materials of this invention are cheap and readily available, the raw material reaction utilization rate is high, and the product quality and yield are relatively stable. At the same time, the product has high added value, extremely high economic value, and very significant economic benefits, making it suitable for large-scale industrial production. Attached Figure Description
[0016] Figure 1 The 1H NMR spectrum of 3-chloro-4-fluorobenzoyl chloride provided in Example 1 of this invention; Figure 2The 1H NMR spectrum of 3,5-dichloro-4-fluorobenzoyl chloride provided in Example 1 of this invention. Detailed Implementation
[0017] The present invention will now be described in further detail with reference to specific embodiments, so that those skilled in the art can more clearly understand the present invention.
[0018] 3-Chloro-4-fluorobenzoyl chloride is an important organic intermediate primarily used in pharmaceutical and materials chemistry. In pharmaceuticals, it is often used as a key "building block" molecule in the synthesis of drug molecules with specific biological activities. It is frequently used to prepare compounds such as N-(3-chloro-4-fluorobenzoyl)-piperidin-4-one. These compounds are of significant value in drug development and may serve as intermediates in the synthesis of other drugs. 3,5-Dichloro-4-fluorobenzoyl chloride is also a very important fine chemical intermediate. In pesticide synthesis, it is a key intermediate for the synthesis of certain isoxazole or benzoylurea insecticides.
[0019] Currently, there are two main processes for the synthesis of 3-chloro-4-fluorobenzoyl chloride (3,5-dichloro-4-fluorobenzoyl chloride). The first process involves reacting 3-chloro-4-fluorobenzoic acid (3,5-dichloro-4-fluorobenzoic acid) with a chlorinating agent to obtain the target product. Commonly used chlorinating agents include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and oxalyl chloride. Among these, thionyl chloride is the most commonly used acyl chloride reagent due to its mild reaction conditions and volatile byproducts. However, this process still suffers from problems such as long reaction time, high energy consumption, generation of large amounts of acidic waste gas, and difficulty in product purification. The second method uses 3-chloro-4-fluorotoluene (3,5-dichloro-4-fluorotoluene) as a starting material. Under the action of a catalyst, it undergoes side-chain chlorination with chlorine to obtain 3-chloro-4-fluorotrichlorobenzyl (3,5-dichloro-4-fluorotrichlorobenzyl). Then, under the action of a catalyst, it undergoes hydrolysis with water, followed by purification by distillation to obtain 3-chloro-4-fluorobenzoyl chloride (3,5-dichloro-4-fluorobenzoyl chloride). This process has a long reaction time, high raw material costs, and generates a large amount of acidic HCl waste gas.
[0020] To solve the above-mentioned technical problems, the present invention provides a method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride, comprising the following steps: S1. Mix p-fluorobenzoyl chloride with a chlorine-containing catalyst to obtain a mixture; S2. The mixture is heated and reacted under a chlorine atmosphere to obtain the reactants; S3. After distilling the reactants, 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride are obtained.
[0021] Furthermore, in step S1, the chlorine-containing catalyst includes zinc chloride, ferric chloride, or aluminum chloride.
[0022] Further, in step S1, the mass ratio of p-fluorobenzoyl chloride to the chlorine-containing catalyst is 100:(3-5).
[0023] Furthermore, in step S2, the heating temperature is 100-130℃.
[0024] Further, in step S2, the reaction is stopped when p-fluorobenzoyl chloride is ≤1%, and the reactant is obtained.
[0025] Furthermore, in step S3, the residual chlorine in the reaction system is removed by nitrogen gas before distillation.
[0026] Furthermore, the temperature at which 3-chloro-4-fluorobenzoyl chloride is distilled off is 115-130℃, and the pressure is 1.3-2.7 kPa.
[0027] Furthermore, the temperature at which 3,5-dichloro-4-fluorobenzoyl chloride is distilled off is 140-160℃, and the pressure is 1.3-2.7 kPa.
[0028] In some embodiments, 300g of p-fluorobenzoyl chloride is added to a 500mL four-necked flask, stirring is started, and 9-15g of anhydrous ferric chloride is added. The temperature is raised to 110℃ and chlorination is started. The temperature of the flask is controlled between 110-130℃ throughout the chlorination process. Gas chromatography is used to monitor the reaction until p-fluorobenzoyl chloride is ≤1%, at which point the reaction is stopped. The reaction solution contains 80-90% 3-chloro-4-fluorobenzoyl chloride and 5-15% 3,5-dichloro-4-fluorobenzoyl chloride. The residual chlorine in the system is removed with nitrogen, and the mixture is then distilled under reduced pressure to obtain 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride, respectively.
[0029] This invention uses p-fluorobenzoyl chloride as a raw material, and through a one-step benzene ring chlorination reaction, controlling the depth of the chlorination reaction, and after distillation purification, simultaneously yields two important fine chemical products: 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The reaction is highly efficient, greatly enriching the product market. The process of this invention is simple to operate, the reaction conditions are relatively mild, and the amount of acidic gas produced is relatively small, resulting in relatively low pollution, which meets the current requirements for the development of green chemistry.
[0030] The raw materials used in this invention are inexpensive and readily available, with high utilization rates in the reaction process, and stable product quality and yield. At the same time, the products have high added value and extremely high economic value, resulting in significant economic benefits and making them suitable for large-scale industrial production.
[0031] Example 1 This embodiment provides a method for the co-production of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are as follows: 300g of p-fluorobenzoyl chloride is added to a 500mL four-necked flask, stirring is started, and 9g of anhydrous ferric chloride is added. The temperature is raised to 110℃ and chlorination is started. The temperature of the flask is controlled between 110-130℃ throughout the chlorination process. Gas chromatography is used to monitor the reaction until p-fluorobenzoyl chloride is ≤1%, at which point the reaction is terminated. Residual chlorine in the system is removed with nitrogen. 3-chloro-4-fluorobenzoyl chloride is obtained by distillation at 115-130℃ and 1.3-2.7 kPa. Then, 2,5-dichlorobenzoyl chloride is obtained by distillation at 140-160℃ and 1.3-2.7 kPa. The obtained products are analyzed separately, and the results are shown in the figure. Figure 1 and 2 .from Figure 1 It can be seen that the three hydrogen atoms with different chemical environments on the benzene ring correspond to three sets of characteristic signals. The signals near 8.06 ppm and 7.93 ppm are attributed to aromatic protons of neighboring electron-withdrawing groups (-C(=O)Cl, -Cl, -F), while the signal near 7.12 ppm corresponds to protons on the benzene ring that are less affected by the electronic effects of substituents. The predicted chemical shift (Base + Inc.) has a small deviation from the experimental observation (Shift), verifying the matching between the -Cl, -F, and -C(=O)Cl substitution positions and the chemical shifts of the benzene ring protons. The spectral characteristics are consistent with the molecular structure of 3-chloro-4-fluorobenzoyl chloride. Figure 2 It can be seen that the benzene ring protons of this compound exhibit a single peak with a chemical shift of approximately 7.94 ppm, consistent with the chemical shift characteristics of hydrogen atoms on aromatic rings under the influence of strong electron-withdrawing groups (-COCl and halogens). Prediction protocols show that the chemical shift of CH on the benzene ring is due to the superposition of substitution effects from the 1-benzaldehyde core (7.26 ppm) through the chlorine atoms at positions 3 and 5 (+0.81 ppm each), the fluorine atom at position 4 (-0.02 ppm), and the acyl chloride group (+0.81 ppm). The final calculated value is consistent with the measured value, confirming the symmetry of the benzene ring and the rationality of the substituent positions in the structure. The spectral characteristics are consistent with the molecular structure of 3,5-dichloro-4-fluorobenzoyl chloride.
[0032] Example 2 This embodiment provides a method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are the same as in Example 1, except that the amount of catalyst is changed to 12g.
[0033] Example 3 This embodiment provides a method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are the same as in Example 1, except that the amount of catalyst is changed to 15g.
[0034] Example 4 This embodiment provides a method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are the same as in Example 2, except that the catalyst is replaced with zinc chloride.
[0035] Example 5 This embodiment provides a method for co-producing 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are the same as in Example 2, except that the catalyst is replaced with aluminum trichloride.
[0036] Example 6 This embodiment provides a method for the co-production of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are the same as in Example 2, except that the reaction temperature is 115-125℃.
[0037] Example 7 This embodiment provides a method for the co-production of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The steps are the same as in Example 2, except that the reaction temperature is 120-130°C.
[0038] Performance Tests and Results The yield and purity of the products obtained in Examples 1-7 were tested, and the results are shown in Table 1.
[0039] Table 1
[0040] As shown in Table 1, using ferric chloride as a catalyst resulted in the highest total yield and best purity of the products 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride. The best reaction effect was achieved when the amount of ferric chloride catalyst used was 4% of the mass of the raw material p-fluorobenzoyl chloride. The optimal temperature for the chlorination reaction was 115-125℃.
[0041] Unless otherwise specified, all raw materials used in this invention are existing substances that can be purchased directly from the market.
[0042] The above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for the co-production of 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride, characterized in that, Includes the following steps: S1. Mix p-fluorobenzoyl chloride with a chlorine-containing catalyst to obtain a mixture; S2. The mixture is heated and reacted under a chlorine atmosphere to obtain the reactants; S3. After distilling the reactants, 3-chloro-4-fluorobenzoyl chloride and 3,5-dichloro-4-fluorobenzoyl chloride are obtained.
2. The method according to claim 1, characterized in that, In step S1, the chlorine-containing catalyst includes zinc chloride, ferric chloride, or aluminum chloride.
3. The method according to claim 1, characterized in that, In step S1, the mass ratio of p-fluorobenzoyl chloride to the chlorine-containing catalyst is 100:(3-5).
4. The method according to claim 1, characterized in that, In step S2, the heating temperature is 100-130℃.
5. The method according to claim 1, characterized in that, In step S2, the reaction is stopped when p-fluorobenzoyl chloride is ≤1%, and the reactants are obtained.
6. The method according to claim 1, characterized in that, In step S3, the residual chlorine in the reaction system is removed by nitrogen gas before distillation.
7. The method according to claim 1, characterized in that, The temperature at which 3-chloro-4-fluorobenzoyl chloride is distilled off is 115-130℃, and the pressure is 1.3-2.7 kPa.
8. The method according to claim 1, characterized in that, The temperature at which 3,5-dichloro-4-fluorobenzoyl chloride is distilled off is 140-160℃, and the pressure is 1.3-2.7 kPa.