A method for synthesizing 2,4,5-trifluorophenylacetic acid

Abstract

This application discloses a method for synthesizing 2,4,5-trifluorophenylacetic acid, belonging to the field of organic chemical technology. Using 1,2,4-trifluorobenzene as a raw material, it reacts with tetrachloromethane and boehmite-passivated aluminum chloride to generate 2,4,5-trifluoro-(trichloromethyl)benzene. After the reaction, the oil phase is separated and extracted. An aqueous solution of zinc chloride is added dropwise to the oil phase, causing the 2,4,5-trifluoro-(trichloromethyl)benzene to hydrolyze to generate 2,4,5-trifluorobenzoyl chloride. Then, azidomethane and silver oxide are added, and the acyl chloride is converted to a carboxylic acid using the Arndt-Eistert reaction to generate 2,4,5-trifluorophenylacetic acid. This synthetic route is simple to operate and streamlined, reducing the use of highly toxic intermediate raw materials, exhibiting low corrosivity and risk to equipment, reduced byproduct generation, and easier separation. It is a safer, more environmentally friendly, and highly selective route for synthesizing 2,4,5-trifluorophenylacetic acid.

Description

Technical Field

[0001] This application belongs to the field of organic chemical technology, and in particular relates to a method for synthesizing 2,4,5-trifluorophenylacetic acid. Background Technology

[0002] 2,4,5-Trifluorophenylacetic acid is an important pharmaceutical intermediate, mainly used in the synthesis of the oral hypoglycemic drugs sitagliptin and repagliptin. It is also a raw material for the synthesis of novel fluorinated herbicides. Sitagliptin, developed and marketed by Merck & Co., is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It can be used alone or in combination with other drugs to treat type 2 diabetes, and has the advantages of high safety and few side effects.

[0003] The commonly used synthetic route for 2,4,5-trifluorophenylacetic acid in China involves using 1,2,4-trifluorobenzene as a raw material. This involves chloromethylation with paraformaldehyde and a chlorinating agent to obtain 2,4,5-trifluorobenzyl chloride, followed by cyanation with a cyaniding agent to obtain 2,4,5-trifluorophenylacetonitrile. Crude 2,4,5-trifluorophenylacetic acid is then obtained through hydrolysis in a solvent, followed by recrystallization to obtain pure 2,4,5-trifluorophenylacetic acid. This entire route utilizes chloromethylation and cyanation reactions, both of which use highly toxic and carcinogenic raw materials. It also places high demands on the corrosiveness of equipment. Furthermore, chloromethylation is an electrophilic reaction, making it difficult to achieve high yields with 1,2,4-trifluorobenzene. The reaction also generates large quantities of highly toxic and carcinogenic waste liquid, failing to meet the requirements for efficient and environmentally friendly production.

[0004]

[0005] Patent CN102690166A reports a method for preparing 2,4,5-trifluorophenylacetic acid from 1,2,4-trifluorobenzene. This method involves adding sulfuric acid with hydrogen chloride gas to 1,2,4-trifluorobenzene and paraformaldehyde, using an 80-90% sulfuric acid solution as a chlorinating agent to perform a chloromethylation reaction to obtain 2,4,5-trifluorobenzyl chloride. This is followed by cyanation in a cyanation reagent to obtain 2,4,5-trifluorobenzyl cyanide, which is then hydrolyzed by heating in an acidic or alkaline aqueous solution, followed by post-treatment to obtain 2,4,5-trifluorophenylacetic acid.

[0006] Patent CN1749232A reports a method for preparing 2,4,5-trifluorophenylacetic acid from 1,2,4-trifluorobenzene. The method involves reacting 1,2,4-trifluorobenzene and paraformaldehyde under chlorination conditions to obtain 2,4,5-trifluorobenzyl chloride, followed by cyanation in a solvent to obtain 2,4,5-trifluorobenzyl cyanide, and then reflux hydrolysis under acidic or alkaline conditions to obtain crude 2,4,5-trifluorophenylacetic acid. High-purity 2,4,5-trifluorophenylacetic acid is then obtained by recrystallization.

[0007] Patent CN109400459B reports a method for preparing 2,4,5-trifluorophenylacetic acid from 2,4-dichlorofluorobenzene. The method involves reacting 2,4-dichlorofluorobenzene with nitric acid and sulfuric acid to nitrate it, yielding 2,4-dichloro-5-fluoronitrobenzene. This nitration is then reacted with a fluorinating agent to obtain 2,4,5-trifluoronitrobenzene. The obtained 2,4,5-trifluoronitrobenzene is then chlorinated with chlorine gas to obtain 2,4,5-trifluorochlorobenzene. This chlorination is then coupled with ethyl cyanoacetate to obtain ethyl 2-cyano-2-(2,4,5)-trifluorophenylacetate. Finally, the ethyl 2,4,5-trifluorophenylacetic acid is obtained by stirring in an excess sodium hydroxide solution and then acidified.

[0008] Patent CN101659611A reports a method for preparing 2,4,5-trifluorophenylacetic acid from 1,2,4-trifluorobenzene. The method involves adding a chlorinating agent to 1,2,4-trifluorobenzene and paraformaldehyde to perform a chloromethylation reaction. The reaction product is hydrolyzed in ice water to obtain 2,4,5-trifluorobenzyl chloride. The 2,4,5-trifluorobenzyl chloride reacts with a cyanating agent in an ionic solution to obtain 2,4,5-trifluorophenylacetonitrile. Finally, the product is hydrolyzed under acidic or alkaline conditions, and after purification, 2,4,5-trifluorophenylacetic acid is obtained.

[0009] Patent CN100516014C reports a method for preparing 2,4,5-trifluorophenylacetic acid from 1,2,4-trifluorobenzene. The method involves adding a chlorinating agent to 1,2,4-trifluorobenzene and paraformaldehyde to carry out a chloromethylation reaction to obtain 2,4,5-trifluorobenzyl chloride. The 2,4,5-trifluorobenzyl chloride then undergoes a carbonylation reaction with carbon monoxide in the presence of a cobalt tetracarbonyl salt catalyst to obtain 2,4,5-trifluorophenylacetic acid.

[0010] The main disadvantages of the above process are: 1. It involves chloromethylation and cyanation reactions, and the raw materials are highly toxic and carcinogenic, and the equipment is highly corrosive, making industrial production dangerous; 2. During the chloromethylation process, isomer impurities are generated due to the fluorine atom positioning effect, which makes separation more difficult; 3. Strongly acidic waste liquid is generated after the reaction, which requires additional treatment and is not conducive to environmentally friendly production requirements.

[0011] To address the above shortcomings, we hope to create a new synthetic route for 2,4,5-trifluorophenylacetic acid through process improvement. Starting with 1,2,4-trifluorobenzene, we will use the synthesis method of azidomethane and silver oxide to replace the original process and utilize the Arndt-Eistert reaction to convert acyl chloride into carboxylic acid. Summary of the Invention

[0012] The purpose of this application is to provide a method for synthesizing 2,4,5-trifluorophenylacetic acid, in order to solve the technical problems of the existing technology, such as high risk, complex and lengthy synthesis process, use of highly toxic raw materials in intermediate processes, large amount of waste generated, and serious pollution.

[0013] To achieve the above objectives, the technical solution adopted in this application is: to provide a method for synthesizing 2,4,5-trifluorophenylacetic acid, specifically including the following steps:

[0014] (a) Add 1,2,4-trifluorobenzene, tetrachloromethane, and pseudoboehmite to the reaction vessel to passivate aluminum chloride, heat the reaction vessel, and then process it to obtain crude 2,4,5-trifluoro-(trichloromethyl)benzene.

[0015] (ii) Add crude 2,4,5-trifluoro-(trichloromethyl)benzene to the reaction vessel, heat up, add zinc chloride aqueous solution dropwise, keep the temperature at the end of the dropwise addition, and after the reaction is completed, post-process to obtain 2,4,5-trifluorobenzoyl chloride;

[0016] (III) Add 2,4,5-trifluorobenzoyl chloride to the reaction vessel, cool down, add diazomethane dissolved in tetrahydrofuran and silver oxide to react, and after the reaction is completed, post-process to obtain 2,4,5-trifluorophenylacetic acid.

[0017] In one embodiment,

[0018] Step (I) The molar ratio of 1,2,4-trifluorobenzene to tetrachloromethane is 1:3.0-5.0, and the molar ratio of 1,2,4-trifluorobenzene to pseudoboehmite passivated aluminum chloride is 1:0.4; preferably, the molar ratio of 1,2,4-trifluorobenzene to tetrachloromethane is 1:4.0.

[0019] In one embodiment,

[0020] Step (1) The temperature for heating is 50-70 ℃, and the reaction time is 5 h; preferably, the temperature for heating is 60 ℃.

[0021] In one embodiment,

[0022] Step (ii) The molar ratio of 1,2,4-trifluorobenzene to zinc chloride in the aqueous solution of zinc chloride is 1:0.1-0.3; preferably, the molar ratio of 1,2,4-trifluorobenzene to zinc chloride in the aqueous solution of zinc chloride is 1:0.2.

[0023] In one embodiment,

[0024] The concentration of the zinc chloride aqueous solution is 40 wt%.

[0025] In one embodiment,

[0026] Step (ii) involves heating to a temperature of 50-70 ℃, adding zinc chloride aqueous solution dropwise for 60 min, and maintaining the temperature for 60 min; preferably, the heating temperature is 60 ℃.

[0027] In one embodiment,

[0028] Step (3) The molar ratio of 1,2,4-trifluorobenzene to tetrahydrofuran is 1:0.30-0.36; preferably, the molar ratio of 1,2,4-trifluorobenzene to tetrahydrofuran is 1:0.33.

[0029] In one embodiment,

[0030] Step (3) The molar ratio of 1,2,4-trifluorobenzene to diazomethane is 1:1.0-1.2, and the molar ratio of 1,2,4-trifluorobenzene to silver oxide is 1:0.1; preferably, the molar ratio of 1,2,4-trifluorobenzene to diazomethane is 1:1.1.

[0031] In one embodiment,

[0032] Step (3) The cooling temperature is -10~10 ℃; preferably, the cooling temperature is 0 ℃.

[0033] In one embodiment,

[0034] The reaction time for step (iii) is 1-5 h; preferably, the reaction time is 3 h.

[0035] This application provides a method for synthesizing 2,4,5-trifluorophenylacetic acid. Using 1,2,4-trifluorobenzene as a starting material, it undergoes a trichloromethylation reaction with tetrachloromethane under the condition of boehmite passivation of aluminum chloride as a catalyst, yielding 2,4,5-trifluoro-(trichloromethyl)benzene. After the trichloromethylation reaction, a 40 wt% zinc chloride aqueous solution is used for hydrolysis at 60 °C to generate 2,4,5-trifluorobenzoyl chloride, which then reacts with diazomethane and silver oxide to produce 2,4,5-trifluorophenylacetic acid. The reaction equation is as follows:

[0036]

[0037] Compared to existing processes, this method utilizes reactions such as trichloromethylation and Arndt-Eistert reaction to create a new process route for the synthesis of 2,4,5-trifluorophenylacetic acid.

[0038] 1. Compared with the chloromethylating reagent used in the original process, the new process uses a milder trichloromethylating reagent. Furthermore, since tetrachloromethane is used for the trichloromethylation reaction, tetrachloromethane has greater steric hindrance, making it difficult to generate isomer impurities that are easily generated in the traditional process route. This reduces the difficulty of post-processing separation and improves the selectivity of the reaction.

[0039] 2. Compared with the original process that uses cyaniding reagents for cyanidation reactions, the new process does not use the corresponding cyanidation solution, which greatly reduces the harm of cyanidation raw materials to relevant personnel and the environment. Compared with the original process's chloromethylation and cyanation reactions, which are highly toxic and dangerous, the new process only has one similar trichloromethylation reaction, and the degree of toxicity is far lower than that of the original process. This reduces the problem of large amounts of waste acid treatment caused by chloromethylation, greatly enhances the safety of the entire route, and makes the entire route more in line with the concept of green and environmental protection.

[0040] 3. After the Arndt-Eistert reaction is completed, the silver oxide catalyst can be recovered through post-processing and reused in production, which can significantly reduce production costs. Compared with the original process, this synthesis process is a safer, more environmentally friendly, and more selective optimized route. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0042] Figure 1 Here is the gas chromatogram of the product from Example 4;

[0043] Figure 2 This is a gas chromatogram of the product of Example 18. Detailed Implementation

[0044] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, this application will be further described in detail. It should be understood that the specific embodiments described herein are only for explaining this application and are not intended to limit this application.

[0045] Example 1

[0046] 13.20 g of 1,2,4-trifluorobenzene and 46.14 g of tetrachloromethane (calculated as 1,2,4-trifluorobenzene, the same below) were added to a four-necked flask equipped with a thermometer and a mechanical stirrer. 3.51 g of boehmite aluminum chloride was added as a catalyst. The mixture was heated to 50 °C and reacted under mechanical stirring. After the reaction was completed, the mixture was washed with water, filtered, and separated. After vacuum distillation, 22.29 g of crude 2,4,5-trifluoro-(trichloromethyl)benzene was obtained. The purity of the crude product was determined by gas chromatography to be 98.81%, and the yield was 89.35%.

[0047] Example 2

[0048] The difference between this embodiment and Example 1 is that the mass of tetrachloromethane was changed to 61.52 g, while the rest of the operation was the same, and 22.81 g of crude 2,4,5-trifluoro-(trichloromethyl)benzene was obtained. Its purity was determined to be 98.78% by gas chromatography, and the yield was 91.46%.

[0049] Example 3

[0050] The difference between this embodiment and Example 1 is that the mass of tetrachloromethane was changed to 76.9 g, while the rest of the operation was the same, and 22.63 g of crude 2,4,5-trifluoro-(trichloromethyl)benzene was obtained. Its purity was determined to be 98.03% by gas chromatography, and the yield was 90.72%.

[0051] Example 4

[0052] The difference between this embodiment and Example 2 is that the reaction temperature was changed to 60 °C, while the other operations remained the same. 23.00 g of crude 2,4,5-trifluoro-(trichloromethyl)benzene was obtained, and its purity was determined to be 98.78% by gas chromatography, with a yield of 92.19%. The structure of 2,4,5-trifluoro-(trichloromethyl)benzene was characterized as follows: Figure 1 As shown.

[0053] Example 5

[0054] The difference between this embodiment and Example 2 is that the reaction temperature was changed to 70 °C, while the rest of the operation was the same. 22.62 g of crude 2,4,5-trifluoro-(trichloromethyl)benzene was obtained, and its purity was determined to be 99.56% by gas chromatography, with a yield of 90.68%.

[0055] Repeating the optimal conditions in Example 4 above, a total of 376.68 g of crude 2,4,5-trifluoro-(trichloromethyl)benzene was collected and summarized. Its purity was determined to be 98.41% by gas chromatography and used as raw material for Examples 6 to 12 below.

[0056] Example 6

[0057] 48.89 g of 2,4,5-trifluoro-(trichloromethyl)benzene with a concentration of 98.41% (purity determined by gas chromatography) was added to a four-necked flask equipped with a stirrer. The mixture was heated to 50 °C, and 6.82 g of a 40 wt% zinc chloride aqueous solution was added dropwise with stirring. The zinc chloride was added over a period of 60 min, while maintaining the temperature at 50 °C. After the addition was completed, the mixture was kept at this temperature for another 60 min. After the reaction was completed, the mixture was separated by oil phase distillation under reduced pressure to obtain 18.72 g of crude 2,4,5-trifluorobenzoyl chloride. The purity of the crude product was determined to be 98.20% by gas chromatography, and the yield was 96.23%.

[0058] Example 7

[0059] The difference between this embodiment and Example 6 is that the reaction temperature was changed to 60 °C, while the rest of the operation was the same. 19.00 g of crude 2,4,5-trifluorobenzoyl chloride was obtained, and its purity was determined to be 98.37% by gas chromatography, with a yield of 97.68%.

[0060] Example 8

[0061] The difference between this embodiment and Example 6 is that the reaction temperature was changed to 70 °C, while the rest of the operation was the same. 18.53 g of crude 2,4,5-trifluorobenzoyl chloride was obtained, and its purity was determined to be 98.92% by gas chromatography, with a yield of 95.23%.

[0062] Example 9

[0063] The difference between this embodiment and Example 7 is that the mass of the 40 wt% zinc chloride aqueous solution was changed to 13.63 g, while the rest of the operation was the same, and 19.09 g of crude 2,4,5-trifluorobenzoyl chloride was obtained. Its purity was determined to be 99.29% by gas chromatography, and the yield was 98.11%.

[0064] Example 10

[0065] The difference between this embodiment and Example 7 is that the mass of the 40 wt% zinc chloride aqueous solution was changed to 20.45 g, while the rest of the operation was the same, and 19.02 g of crude 2,4,5-trifluorobenzoyl chloride was obtained. Its purity was determined to be 99.43% by gas chromatography, and the yield was 97.78%.

[0066] Example 11

[0067] The difference between this embodiment and Example 9 is that the reaction temperature was changed to 60 °C, while the rest of the operation was the same. 19.24 g of crude 2,4,5-trifluorobenzoyl chloride was obtained, and its purity was determined to be 99.44% by gas chromatography, with a yield of 98.89%.

[0068] Example 12

[0069] The difference between this embodiment and Example 9 is that the reaction temperature was changed to 70 °C, while the rest of the operation was the same. 18.96 g of crude 2,4,5-trifluorobenzoyl chloride was obtained, and its purity was determined to be 99.46% by gas chromatography, with a yield of 97.45%.

[0070] Repeating the optimal conditions in Example 11 above, a total of 154.26 g of crude 2,4,5-trifluorobenzoyl chloride was collected and the purity was determined to be 99.30% using gas chromatography. This crude product was then used as the raw material for Examples 13 to 19 below.

[0071] Example 13

[0072] 19.59 g of 2,4,5-trifluorobenzoyl chloride with a purity of 99.30% (identified by gas chromatography) was added to a four-necked flask equipped with a stirrer and a condenser. The mixture was reacted with 4.20 g of diazomethane dissolved in 21.63 g of THF solvent at -10 °C. 2.32 g of silver oxide was added as a catalyst, and the reaction was carried out for 1 h. After the reaction was complete, the mixture was washed with water, filtered, and separated. The oil phase was then distilled under reduced pressure to obtain 17.34 g of the target product, 2,4,5-trifluorophenylacetic acid. Its purity was determined to be 98.78% by gas chromatography, with a yield of 91.23%.

[0073] Example 14

[0074] The difference between this embodiment and Example 13 is that the reaction temperature was changed to 0 °C, while the rest of the operation was the same, and 17.60 g of 2,4,5-trifluorophenylacetic acid with a purity of 98.79% (identified by gas chromatography) was obtained, with a yield of 92.56%.

[0075] Example 15

[0076] The difference between this embodiment and Example 13 is that the reaction temperature was changed to 10 °C, while the rest of the operation was the same, and 17.38 g of 2,4,5-trifluorophenylacetic acid with a purity of 98.79% (identified by gas chromatography) was obtained, with a yield of 91.42%.

[0077] Example 16

[0078] The difference between this embodiment and Example 14 is that the amount of diazomethane was changed to 4.62 g, and the solvent THF was changed to 23.80 g. The rest of the operation was the same, and 17.73 g of 2,4,5-trifluorophenylacetic acid with a purity of 98.98% (identified by gas chromatography) was obtained, with a yield of 93.28%.

[0079] Example 17

[0080] The difference between this embodiment and Example 14 is that the amount of diazomethane was changed to 5.04 g and the solvent THF was changed to 25.96 g. The rest of the operation was the same, and 17.56 g of 2,4,5-trifluorophenylacetic acid with a purity of 98.71% (identified by gas chromatography) was obtained, with a yield of 92.34%.

[0081] Example 18

[0082] The difference between this example and Example 16 is that the reaction time was changed to 3 hours, while the other operations remained the same. 17.89 g of 2,4,5-trifluorophenylacetic acid with a purity of 99.18% (identified by gas chromatography) was obtained, with a yield of 94.12%. The structural characterization of 2,4,5-trifluorophenylacetic acid is as follows: Figure 2 As shown.

[0083] Example 19

[0084] The difference between this embodiment and Example 16 is that the reaction time was changed to 5 h, while the rest of the operation was the same, and 17.83 g of 2,4,5-trifluorophenylacetic acid with a purity of 98.77% (identified by gas chromatography) was obtained, with a yield of 93.78%.

[0085] This application provides a method for synthesizing 2,4,5-trifluorophenylacetic acid. Using 1,2,4-trifluorobenzene as a starting material, it reacts with tetrachloromethane and boehmite-passivated aluminum chloride to generate 2,4,5-trifluoro-(trichloromethyl)benzene. After the reaction, the oil phase is separated and extracted. An aqueous solution of zinc chloride is added dropwise to the oil phase, causing the 2,4,5-trifluoro-(trichloromethyl)benzene to hydrolyze to generate 2,4,5-trifluorobenzoyl chloride. Then, azidomethane and silver oxide are added, and the acyl chloride is converted to a carboxylic acid using the Arndt-Eistert reaction to generate 2,4,5-trifluorophenylacetic acid. This synthetic route is simple to operate and streamlined, reduces the use of highly toxic intermediate raw materials, has low corrosivity and risk to equipment, reduces the amount of byproducts generated, and is easier to separate. It is a safer, more environmentally friendly, and highly selective route for synthesizing 2,4,5-trifluorophenylacetic acid.

[0086] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for synthesizing 2,4,5-trifluorophenylacetic acid, characterized in that, Specifically, the following steps are included: (a) Add 1,2,4-trifluorobenzene, tetrachloromethane, and pseudoboehmite to the reaction vessel to passivate aluminum chloride, heat the reaction vessel, and then process it to obtain crude 2,4,5-trifluoro-(trichloromethyl)benzene. (ii) Add the crude product 2,4,5-trifluoro-(trichloromethyl)benzene to the reaction vessel, heat up, add zinc chloride aqueous solution dropwise, keep the temperature at the end of the dropwise addition, and after the reaction is completed, post-process to obtain 2,4,5-trifluorobenzoyl chloride; (III) Add the 2,4,5-trifluorobenzoyl chloride to the reaction vessel, cool down, add diazomethane dissolved in tetrahydrofuran and silver oxide to react, and after the reaction is completed, post-process to obtain 2,4,5-trifluorophenylacetic acid; In step (a), the molar ratio of 1,2,4-trifluorobenzene to tetrachloromethane is 1:3.0-5.0, and the molar ratio of 1,2,4-trifluorobenzene to pseudoboehmite passivated aluminum chloride is 1:0.

4. In step (ii), the molar ratio of 1,2,4-trifluorobenzene to zinc chloride in the aqueous solution is 1:0.1-0.3, and the concentration of the aqueous solution is 40 wt%; the heating temperature is 50-70 °C, the time for adding the aqueous solution is 60 min, and the reaction time is 60 min. In step (iii), the molar ratio of 1,2,4-trifluorobenzene to diazomethane is 1:1.0-1.2, the molar ratio of 1,2,4-trifluorobenzene to silver oxide is 1:0.1, and the molar ratio of 1,2,4-trifluorobenzene to tetrahydrofuran is 1:0.30-0.36; the reaction time is 1-5 h.

2. The method for synthesizing 2,4,5-trifluorophenylacetic acid according to claim 1, characterized in that, The temperature for heating in step (1) is 50-70 ℃, and the reaction time is 5 h.

3. The method for synthesizing 2,4,5-trifluorophenylacetic acid according to claim 1, characterized in that, The temperature for cooling in step (iii) is -10~10 ℃.

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