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Preparation method of 2-chloro-5-(trifluoromethyl) benzoic acid

A technology of p-chlorobenzotrifluoride and trifluoromethyl, which is applied in the field of preparation of 2-chloro-5-benzoic acid, can solve the problems of low yield, long cycle, and increased cost

Active Publication Date: 2014-01-08
TIANCHANG TIANJIA CHEM TECH
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Problems solved by technology

[0007] For the two routes and reaction conditions of method one, using p-chlorobenzotrifluoride as raw material directly adopts the synthetic route of n-butyllithium. According to literature reports, the highest yield is only 76%, which is relatively low and increases the cost. The treatment process also needs to use organic solvents for extraction again, which increases the steps of the process operation and the cost of raw materials
And take p-chlorobenzotrifluoride as raw material under the effect of antimony pentachloride to make 3-bromo-4-chlorobenzotrifluoride earlier, and then use n-butyllithium and dry ice to make intermediate 3 at subzero 100 degrees -Bromo-4-chlorobenzotrifluoride is made in the technique of 2-chloro-5-(trifluoromethyl)benzoic acid, according to bibliographical reports, yield is 88%, although this route has improved product yield, but process It is complicated, the production conditions are harsh, and antimony pentachloride with stench and strong corrosion is used. The cost of raw materials is expensive, which is not conducive to industrial production
[0008] For the synthesis process of method 2, the raw materials are not easy to obtain, and the highly toxic compound sodium cyanide is used in the synthesis process, the process is complicated, the total yield is low, and it is not conducive to industrialized large-scale production
[0009] For the preparation method of 2-chloro-5-(trifluoromethyl)benzoic acid in this area, there are problems such as low product yield, high raw material cost, harsh production conditions, complex production process, long period, and unfavorable for industrialized production

Method used

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Embodiment 1

[0065] Taking p-chlorobenzotrifluoride as raw material to prepare 2-chloro-5-(trifluoromethyl)benzoic acid under the effect of tert-butyllithium / tetramethylethylenediamine, its chemical reaction equation is as follows:

[0066]

[0067] Weigh 18.1g (0.1mol) of the compound p-chlorotrifluoromethylbenzene and 11.6g (0.1mol) of tetramethylethylenediamine and dissolve it in 150ml of anhydrous tetrahydrofuran, and cool the reaction mixture to -75°C with a dry ice acetone bath The reaction system was vacuumed under nitrogen protection. Under the protection of nitrogen, extract 77.0ml (0.1mol) of tert-butyllithium (1.3M n-hexane solution) into a constant pressure dropping funnel, and then slowly add it to the reaction system. During the dropwise addition, the reaction temperature should not exceed - 70°C. After the dropwise addition, the reaction continued to stir for 1 hour, and the reaction solution was slowly poured on the surface of 50 g of dry ice, and continued to stir for ...

Embodiment 2

[0069] Using p-chlorobenzotrifluoride as raw material to prepare 2-chloro-5-(trifluoromethyl)benzoic acid under the action of tert-butyllithium / N,N-diisopropylethylamine, the chemical reaction equation is as follows:

[0070]

[0071] Weigh 18.1g (0.1mol) of the compound p-chlorotrifluoromethylbenzene and 12.9g (0.1mol) of N,N-diisopropylethylamine and dissolve it in 150ml of anhydrous tetrahydrofuran, and cool down the reaction mixture with a dry ice acetone bath To -75°C, the reaction system was evacuated under nitrogen protection. Under the protection of nitrogen, extract 77.0ml (0.1mol) of tert-butyllithium (1.3M n-hexane solution) into a constant pressure dropping funnel, and then slowly add it to the reaction system. During the dropwise addition, the reaction temperature should not exceed - 70°C. After the dropwise addition was completed, the reaction continued to stir for 1 hour, and the reaction solution was slowly poured on the surface of 50 g of dry ice, and cont...

Embodiment 3

[0073] A kind of preparation method of 2-chloro-5-(trifluoromethyl)benzoic acid, its chemical equation is identical with embodiment 1, specifically comprises the steps:

[0074] (1) Dissolve 0.08mol of p-chlorobenzotrifluoride and 0.1mol of tetramethylethylenediamine in 150mL of anhydrous tetrahydrofuran, cool down to -80°C, fill with nitrogen for protection, and then dropwise add 0.12mol of tert-butyl 88 mL of n-hexane solution of lithium lithium was stirred for reaction, and after the dropwise addition was completed, stirring was continued for 1.2 h to obtain the lithium salt of p-chlorotrifluorotoluene;

[0075] (2) Slowly pour the p-chlorobenzotrifluorotoluene lithium salt obtained in step (1) onto the surface of 50g of dry ice, stir the reaction solution for 60min, and after the dry ice has evaporated, add dropwise the concentration of 8mol / L at 15°C Hydrochloric acid aqueous solution 10mL, adjust the pH value to 3, distill the reaction liquid under reduced pressure, remo...

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Abstract

The invention provides a preparation method of 2-chloro-5-(trifluoromethyl) benzoic acid, which comprises the following steps: (1) taking p-trifluoromethyl chlorobenzene and tertiary amines as raw materials, taking t-butyl lithium as a catalyst, preparing 2-chloro-5-(trifluoromethyl)phenyl lithium salt; and (2) taking reaction between the 2-chloro-5-(trifluoromethyl)phenyl lithium salt which is obtained in the step (1) and solid carbon dioxide, removing the solvent, and at last preparing 2-chloro-5-(trifluoromethyl)benzoic acid. In the method, the raw materials are easily obtained; the yield is high; the technical process is simple; the purification process is simplified; the production cycle is shortened; and the method is beneficial to industrial production.

Description

technical field [0001] The invention relates to a preparation method of 2-chloro-5-(trifluoromethyl)benzoic acid, which belongs to the field of preparation of pharmaceutical intermediates. Background technique [0002] 2-Chloro-5-(trifluoromethyl)benzoic acid is an important intermediate of a new drug for treating diabetes. In addition, it can also be used in the synthesis of heat shock protein inducers and non-steroidal anti-inflammatory drugs. As an important pharmaceutical intermediate, 2-chloro-5-(trifluoromethyl)benzoic acid also has important application prospects in the development of new drugs. [0003] The preparation method of 2-chloro-5-(trifluoromethyl) benzoic acid mainly contains two kinds at present, method one: people such as Mongin adopts in the system of n-butyllithium / tetramethylethylenediamine / tetrahydrofuran, will Chlorotrifluorotoluene is made into 2-chloro-5-(trifluoromethyl)phenyllithium salt, and then synthesized with dry ice into 2-chloro-5-(triflu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C63/70C07C51/15
Inventor 孙郁张春涛纪奉元
Owner TIANCHANG TIANJIA CHEM TECH
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