Preparation method of 2-chloro-4-fluorobenzonitrile

Abstract

The invention relates to a preparation method of 2-chloro-4-fluorobenzonitrile, which is characterized in that 2-chloro-4-fluorobenzoic acid is used as an initial raw material, and after acylating chlorination, amidation and cyanation reactions, the product 2-chloro-4-fluorobenzonitrile is obtained. The method has the advantages that the 2-chloro-4-fluorobenzoic acid is industrially easy to obtain, the reaction conditions of each step are mild, byproducts are few, and the yield is high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of 2-chloro-4-fluorobenzonitrile. Background Art

[0002] The existing preparation methods mainly include the following: 1) 2,4-dichlorobenzonitrile is used as the starting material, potassium fluoride is used as the fluorination agent, and 2,4-difluorobenzonitrile is prepared by fluorination reaction. This process has many by-products and is complicated to separate and purify.

[0003] 2,4-dichlorobenzonitrile is produced as a byproduct of the target product; 2) Using 2-chloro-4-fluoroaniline as the starting material, a diazotization reaction is performed, followed by a reaction with cuprous cyanide to obtain the product 2-chloro-4-fluorobenzonitrile. In this process, diazotization is a high-risk reaction, and the system may be acidic, which easily produces hydrocyanic acid. From a safety perspective, it is not suitable for industrial scale-up production.

[0004] 2-Chloro-4-fluoroaniline cuprous cyanide 2-Chloro-4-fluorobenzonitrile; 3) Using 2-chloro-4-fluorobenzaldehyde as the starting material, 2-chloro-4-fluorobenzonitrile is prepared by reacting with formic acid, hydroxylamine hydrochloride and sodium acetate. However, the raw materials of this process are not easy to obtain, the synthesis purity is not necessarily high, and the yield is low, so it is not suitable for production.

[0005]

[0006] 2-Chloro-4-fluorobenzaldehyde 2-Chloro-4-fluorobenzonitrile; Therefore, the above processes cannot be used to obtain 2-chloro-4-fluorobenzonitrile in industrial production. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides a preparation method of 2-chloro-4-fluorobenzonitrile, which has reasonable design, perfect process, mild reaction conditions in each step, few by-products and high yield.

[0008] The technical solution of the present invention: A method for preparing 2-chloro-4-fluorobenzonitrile, using 2-chloro-4-fluorobenzoic acid as a starting material, and obtaining the product 2-chloro-4-fluorobenzonitrile through acyl chlorination, amidation, and cyanation reactions; the synthetic reaction equation is: CFB-1 CFB-2 CFB-3 CFB.

[0009] Specific steps: 1) Add CFB-1 to a dry reaction bottle, replace with nitrogen, prepare an acidic tail gas absorption device, cool the reaction system to below 20°C, start dripping thionyl chloride into the reaction bottle, start stirring, control the temperature not higher than 40°C, and observe the gas release during the process; after the dripping of thionyl chloride is completed, heat to 60°C and keep warm for 3 hours; after the insulation is completed, remove excess thionyl chloride; weigh the residue CFB-2 and set aside; 2) Add ammonia water to the concentrated solution in the previous step. The ammonia water needs to be added dropwise during the process. The temperature is controlled not to be higher than 30°C. Then stir at room temperature overnight. The process can also be monitored by central control to observe the reaction phenomenon and precipitation of solids. After the reaction is completed, filter, wash the filter cake with water, weigh the wet CFB-3, dry it, and vacuum dry it. 3) Transfer the material CFB-3 into the reaction bottle, add excess thionyl chloride, add slowly, pay attention to heat release and tail gas absorption, the reaction is water-resistant; after adding thionyl chloride, keep warm at 60°C for 3 hours, and control can be performed; recover excess thionyl chloride by post-processing; obtain CFB crude product; the crude product can be recrystallized by solvent to obtain the finished product.

[0010] The method has the advantages that 2-chloro-4-fluorobenzoic acid is easily available in industry, and each step of the reaction has mild reaction conditions, few by-products and high yield. DETAILED DESCRIPTION

[0011] All features disclosed in this specification, or all steps in the methods or processes disclosed, except for mutually exclusive features and / or steps, can be combined in any way. Example 1. Preparation of 2-chloro-4-fluorobenzoyl chloride Add 2-chloro-4-fluorobenzoic acid (1g) to the dry reaction bottle, replace with nitrogen, prepare the acid tail gas absorption device, cool the reaction system to below 20°C, start dripping thionyl chloride (24.5g) into the reaction bottle, start stirring, control the temperature not higher than 40°C, and observe the gas release during the process. After the thionyl chloride is added, heat to 60°C and keep warm for 3 hours. After the insulation is completed, recover the excess thionyl chloride. Weigh 1.1g of the residue and set aside.

[0012] Example 2. Preparation of 2-chloro-4-fluorobenzamide Add 2.7g of ammonia water to the concentrate. The ammonia water needs to be added dropwise. The temperature is controlled not to be higher than 30°C. Then stir at room temperature overnight. The process can also be monitored by central control to observe the reaction phenomenon and precipitate solids. After the reaction is completed, filter, wash the filter cake with water, weigh the wet product, and dry it to 1.0g (vacuum drying). The HPLC purity is about 99.2%.

[0013] Example 3. Preparation of 2-chloro-4-fluorobenzonitrile Transfer the material 2-chloro-4-fluorobenzamide into the reaction bottle, add 8.2g thionyl chloride (add slowly, pay attention to heat release and tail gas absorption), the reaction avoids water. After adding thionyl chloride, keep warm at 60°C for 3 hours, and it can be controlled. Post-process to recover excess thionyl chloride. Obtain crude 2-chloro-4-fluorobenzonitrile. The crude product can be recrystallized from solvent ethanol to obtain the finished product with a purity of 99.6% and a yield of 86%.

[0014] The method of the invention is reasonable, simple, easy to operate, high in yield, and the purity meets the quality research requirements.

[0015]

[0016] 2-Chloro-4-fluorobenzonitrile; 2-Chloro-4-fluorobenzoic acid is an important intermediate for drugs and pesticides. It can also be used in liquid crystal materials. It has the advantages of high value and good market prospects. From a physiological level, compared with general inorganic drugs, fluorine-containing drugs have better biological penetration and better selectivity for acting on target organs, and the dosage usually used is greatly reduced. Therefore, fluorine is widely used in the preparation of fluorine-containing pharmaceuticals with special therapeutic effects.

Claims

1. A method for preparing 2-chloro-4-fluorobenzonitrile, characterized in that: Using 2-chloro-4-fluorobenzoic acid as the starting material, the product 2-chloro-4-fluorobenzonitrile is obtained through acyl chlorination, amidation, and cyanation reactions; the synthetic reaction equation is: CFB-1 CFB-2 CFB-3 CFB.

2. The method for preparing 2-chloro-4-fluorobenzonitrile according to claim 1, characterized in that: Specific steps: 1) Add CFB-1 to a dry reaction bottle, replace with nitrogen, prepare an acidic tail gas absorption device, cool the reaction system to below 20°C, start dripping thionyl chloride into the reaction bottle, start stirring, control the temperature not higher than 40°C, and observe the gas release during the process; after the dripping of thionyl chloride is completed, heat to 60°C and keep warm for 3 hours; after the insulation is completed, remove excess thionyl chloride; weigh the residue CFB-2 and set aside; 2) Add ammonia water to the concentrated solution in the previous step. The ammonia water needs to be added dropwise during the process. The temperature is controlled not to be higher than 30°C. Then stir at room temperature overnight. The process can also be monitored by central control to observe the reaction phenomenon and precipitation of solids. After the reaction is completed, filter, wash the filter cake with water, weigh the wet CFB-3, dry it, and vacuum dry it. 3) Transfer the material CFB-3 into the reaction bottle, add excess thionyl chloride, add slowly, pay attention to heat release and tail gas absorption, the reaction is water-resistant; after adding thionyl chloride, keep warm at 60°C for 3 hours, and control can be performed; recover excess thionyl chloride by post-processing; obtain CFB crude product; the crude product can be recrystallized by solvent to obtain the finished product.

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