Preparation method of 2, 4, 5-trifluorophenylacetic acid

Abstract

The invention belongs to the field of preparation of fluorine-containing compounds, and particularly relates to a preparation method of 2, 4, 5-trifluorophenylacetic acid. According to the method, 2, 4, 5-trifluoroaniline is taken as a raw material, 2, 4, 5-trifluoro-(2, 2, 2-trichloroethyl) benzene is synthesized through two-step reaction, and then the target product 2, 4, 5-trifluorophenylacetic acid can be obtained through hydrolysis. The method comprises the following steps: firstly, generating a 2, 4, 5-trifluorobenzene diazonium salt intermediate at a relatively high temperature, and adding vinylidene chloride before the diazotization reaction is started; according to the method disclosed by the invention, salt formation is complete, vinylidene chloride can be rapidly subjected to a coupling reaction with 2, 4, 5-trifluoroaniline diazonium salt, and generation of azo compounds is reduced, so that the yield and the content of the obtained intermediate and the product are higher than those of a contrast file, and the hydrolysis step does not generate nitrogen-containing wastewater, so that the method conforms to the concept of green sustainable development.

Description

Technical Field

[0001] The invention belongs to the field of preparation of fluorine-containing compounds, and specifically relates to a method for preparing 2,4,5-trifluorophenylacetic acid. Background Art

[0002] 2,4,5-Trifluorophenylacetic acid is an important intermediate for the treatment of type 2 diabetes, and its synthesis has received widespread attention.

[0003] Chinese patent CN101450895A reports a method in which 2,4,5-trifluorobromobenzene is made into a Grignard reagent and coupled with ethyl bromoacetate to obtain ethyl 2,4,5-trifluorophenylacetic acid, and then hydrolyzed and acidified with dilute sodium hydroxide to obtain 2,4,5-trifluorophenylacetic acid. This route reaction has the disadvantages of low yield, harsh conditions, and high raw material prices. U.S. Patent US20040068141A1 discloses a method in which 2,4,5-trifluorobromobenzene reacts with diethyl malonate and sodium tert-butoxide under cuprous chloride catalysis, and then hydrolyzes to obtain 2,4,5-trifluorophenylacetic acid. This method requires a large amount of cuprous chloride catalysis, and the price of sodium tert-butoxide is relatively high, which is not suitable for industrial production. Chinese patent CN102690166A introduces sulfuric acid saturated with hydrogen chloride into 1,2,4-trifluorobenzene and polyformaldehyde for chloromethylation reaction to prepare 2,4,5-trifluorobenzyl chloride, which is then cyanated with sodium cyanide and hydrolyzed with sulfuric acid or sodium hydroxide to obtain 2,4,5-trifluorophenylacetic acid. The chloromethylation reaction of this route is highly corrosive, sodium cyanide is highly toxic, and there are great production safety risks.

[0004] Chinese patent document CN108794320A discloses a method for preparing 2,4,5-trifluorophenylacetic acid, wherein 2,4,5-trifluoroaniline reacts with hydrochloric acid and sodium nitrite to obtain 2,4,5-trifluorobenzene diazonium salt; 2,4,5-trifluorobenzene diazonium salt undergoes coupling reaction with 2-chloroacrylonitrile; and hydrolyzes to 2,4,5-trifluorophenylacetic acid under the action of strong acid or strong base. However, the patent has the disadvantages of more by-products and low product yield, and the yield of the intermediate product 2,2-dichloro-3-(2,4,5-trifluorophenyl)-propionitrile crude product is only 57%. This is because 2-chloroacrylonitrile has a cyano group, and the carbon adjacent to the cyano group lacks electrons, which makes it very easy to undergo a diazo coupling reaction with a diazonium salt, and the intermediate obtained by this diazo coupling is very active and very easy to produce tar impurities; in addition, the patent also produces nitrogen-containing wastewater when the cyano group is hydrolyzed into a carboxyl group. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing 2,4,5-trifluorophenylacetic acid in view of the defects of the current technology.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for preparing 2,4,5-trifluorophenylacetic acid comprises the following steps:

[0008] (1) 2,4,5-trifluoroaniline is dissolved in a solvent and reacted with hydrochloric acid at 20-100°C to generate a 2,4,5-trifluorobenzene diazonium salt intermediate;

[0009] (2) adding a catalyst and vinylidene chloride to the 2,4,5-trifluorobenzene diazonium salt intermediate obtained in step (1) at -20 to 20° C.; then adding a sodium nitrite solution dropwise at -20 to 20° C. and reacting at the temperature to generate 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene;

[0010] (3) 2,4,5-Trifluoro-(2,2,2-trichloroethyl)benzene reacts in the presence of an acid and a catalyst to produce 2,4,5-trifluorophenylacetic acid.

[0011] The above reaction is achieved through the following route:

[0012]

[0013] As a preferred embodiment of the present invention, the solvent in step (1) is selected from organic solvents, preferably a combination of one or more of acetone, tetrahydrofuran and acetonitrile.

[0014] As a preferred embodiment of the present invention, the molar ratio of hydrochloric acid to 2,4,5-trifluoroaniline in step (1) is 4 to 6:1.

[0015] As a preferred embodiment of the present invention, the concentration of hydrochloric acid in step (1) is 10 wt% to 35 wt%.

[0016] As a preferred embodiment of the present invention, the molar ratio of vinylidene chloride to 2,4,5-trifluoroaniline in step (2) is 1 to 5:1.

[0017] As a preferred embodiment of the present invention, the catalyst in step (2) is a combination of one or more of copper salts or copper oxides, preferably a combination of one or more of cupric chloride, cupric bromide, cupric oxide, cuprous chloride, cuprous bromide, cuprous oxide, and cupric carbonate. More preferably, one or both of cupric carbonate and cupric chloride are used.

[0018] As a preferred embodiment of the present invention, the concentration of the sodium nitrite solution in step (2) is 10-40%, more preferably 20-35%. The molar ratio of sodium nitrite to 2,4,5-trifluoroaniline is 1-1.05:1. The preferred reaction temperature in step (2) is -20-0°C. The temperature of the insulation reaction in step (2) is 24-26h.

[0019] As a preferred embodiment of the present invention, the catalyst in step (3) is a combination of one or more of iron salts, copper salts, mercury salts, and cobalt salts, preferably a combination of one or more of FeCl3, Fe2(SO4)3, Fe(NO3)3, CuCl2, CuBr2, CuCl, CuBr, HgSO4, CoCl2, and Co(NO3)2.

[0020] As a preferred embodiment of the present invention, the reaction temperature in step (3) is 80°C to 120°C.

[0021] As a preferred embodiment of the present invention, in step (3), the molar ratio of the acid to 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene is 1 to 5:1.

[0022] As a preferred embodiment of the present invention, the acid in step (3) is a combination of one or more of hydrochloric acid and sulfuric acid.

[0023] As a preferred embodiment of the present invention, the concentration of hydrochloric acid in step (3) is 10% to 35%.

[0024] As a preferred embodiment of the present invention, the sulfur concentration in step (3) is 10% to 98%.

[0025] Beneficial effects of the present invention:

[0026] The preparation method of 2,4,5-trifluorophenylacetic acid of the present invention uses 2,4,5-trifluoroaniline as a raw material, synthesizes 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene through two-step reaction, and then hydrolyzes to obtain the target product 2,4,5-trifluorophenylacetic acid. The yield and content of the intermediate and product obtained by the present invention are higher than those of the comparative documents, and the hydrolysis step does not generate nitrogen-containing wastewater, which conforms to the concept of green and sustainable development.

[0027] Compared with the prior art, the present invention first generates a 2,4,5-trifluorobenzene diazonium salt intermediate at a relatively high temperature, and then lowers the temperature to carry out a diazotization reaction, so that the salt formation is relatively complete and the generation of azo compounds can be reduced.

[0028] Compared with the prior art, the present invention adds vinylidene chloride before the diazotization reaction begins, so that the vinylidene chloride can react with 2,4,5-trifluoroaniline diazonium salt more quickly.

[0029] Compared with the prior art, the method adopts vinylidene chloride to prepare 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene, and the obtained intermediate 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene has lower activity and is not easy to undergo secondary reaction with diazonium salt, and the hydrolysis step of the method does not produce nitrogen-containing wastewater; while 2-chloroacrylonitrile is very easy to undergo diazo coupling reaction with diazonium salt due to the presence of cyano group and the electron-deficient carbon at the ortho-position of cyano group, and the intermediate obtained by the diazo coupling is very active and is very easy to produce tar impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the mass spectrum of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene obtained in Example 2.

[0031] Figure 2 This is the HPLC chart of 2,4,5-trifluorophenylacetic acid obtained in Example 4.

[0032] Figure 3 This is the HPLC chart of 2,4,5-trifluorophenylacetic acid obtained in Comparative Example 2. Specific implementation methods

[0034] The specific implementation method of the present invention is further described below in conjunction with the examples. These examples are only typical descriptions of the present invention, but the present invention is not limited thereto. The test methods used in the following examples are conventional methods unless otherwise specified, and the raw materials and reagents used are raw materials and reagents that can be obtained from conventional commercial channels unless otherwise specified.

[0035] Example 1

[0036] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene

[0037] Dissolve 625g 2,4,5-trifluoroaniline (4.25mol, 1.0equiv) in 1000g acetone, add 3103g 25% hydrochloric acid (21.3mol, 5.0equiv) dropwise at 20°C, and keep the temperature at 20°C for 1h. Cool to -20°C, add 200g copper chloride, 150g toluene and 412g vinylidene chloride (4.25mol, 1.0equiv), and keep the temperature at 20°C for 1h. Control the temperature at -20°C, add 314g 20% ​​sodium nitrite (98%, 4.46mol, 1.05equiv), and keep the temperature at 24h. The product was extracted with dichloromethane and washed with 500 mL of 10% liquid alkali, followed by desolventizing and distilling to obtain 900 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene with a yield of 78.8% and a content of 98.0% (HPLC area normalization method).

[0038] Example 2

[0039] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene

[0040] Dissolve 3000g 2,4,5-trifluoroaniline (20.4mol, 1.0equiv) in 2000g tetrahydrofuran, add 12509g 30% hydrochloric acid (102.8mol, 5.0equiv) dropwise at 20°C, heat to 100°C and keep warm for 1h. Cool to 0°C, add 500g copper carbonate, 2500g tetrahydrofuran and 9888g vinylidene chloride (102mol, 5.0equiv), keep warm for 1h. Control the temperature at 0°C, then add 4104g 35% sodium nitrite (20.4mol, 1.0equiv), keep warm for 24h. The mixture was extracted with chloroform and washed with 2.5 L of 10% liquid alkali, followed by desolventizing and distilling to obtain 4364 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene with a yield of 80% and a content of 98.5% (HPLC area normalization method).

[0041] Figure 1 Among them, m / z=261.9, 263.9 is 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene.

[0042] Example 3

[0043] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene

[0044] 3000g 2,4,5-trifluoroaniline (20.4mol, 1.0equiv) was dissolved in 2000g tetrahydrofuran, 30% hydrochloric acid 12509g (102.8mol, 5.0equiv) was added dropwise at 65°C, and the mixture was kept at 65°C for 1h. After cooling to 20°C, 500g copper carbonate, 2500g acetonitrile and 3160g vinylidene chloride (32.6mol, 1.6equiv) were added, and the mixture was kept at this temperature for 1h. The temperature was controlled at 0°C, and then 35% sodium nitrite 4104g (20.4mol, 1.0equiv) was added dropwise, and the mixture was kept at this temperature for 24h. The mixture was extracted with chloroform and washed with 2.5 L of 10% liquid alkali, followed by desolventizing and distilling to obtain 4309 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene with a yield of 79% and a content of 98.8% (HPLC area normalization method).

[0045] Example 4

[0046] Preparation of 2,4,5-trifluorophenylacetic acid

[0047] 95 g of 98% sulfuric acid (0.95 mol, 5.0 equiv) and 0.5 g of each of FeCl3, Fe2(SO4)3, Fe(NO3)3, CuCl2, and CuBr2 were added, and the mixture was heated to 120° C. Then, 50 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (content 98.5%, 0.19 mol, 1.0 equiv) obtained in Example 2 was added dropwise, and the mixture was kept warm for 8 h. After the reaction was completed, 30 g of 2,4,5-trifluorophenylacetic acid was obtained by distillation, with a yield of 83% and a content of 99.90% (area normalization method).

[0048] Example 5

[0049] Preparation of 2,4,5-trifluorophenylacetic acid

[0050] 45 g of 30% hydrochloric acid (0.37 mol, 1.0 equiv) and 1 g of CuCl, CuBr, and HgSO4 were added and heated to 80°C. Then 100 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (content 98.5%, 0.37 mol, 1.0 equiv) obtained in Example 2 was added and kept warm for 8 hours to complete the reaction. 65 g of 2,4,5-trifluorophenylacetic acid was obtained by distillation at 5 mmHg and 190°C, with a yield of 90% and a content of 99.91% (area normalization method).

[0051] Comparative Example 1

[0052] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (low salt formation temperature)

[0053] Dissolve 5g of 2,4,5-trifluoroaniline in 10g of chloroform, add 25g of 10% hydrochloric acid at 10°C, and keep warm for 1h. Add 0.2g of cuprous chloride, 15g of chloroform and 6g of vinylidene chloride, and keep warm for 1h. Then add 15g of 10% sodium nitrite, and keep warm for 24h. Extract and desolventize with dichloromethane to obtain 5.8g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene, with a yield of 65% and a content of 90% (HPLC area normalization method).

[0054] Comparative Example 2

[0055] Preparation of 2,4,5-trifluorophenylacetic acid (cobalt as catalyst, low hydrolysis temperature)

[0056] 300 g of 15% hydrochloric acid and 5 g of cobalt chloride were added, and the mixture was heated to 70°C. Then about 100 g of crude 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (the sample obtained in Example 2) was added dropwise, and the mixture was kept warm for 8 hours to complete the reaction. 47.6 g of 2,4,5-trifluorophenylacetic acid was obtained by distillation, with a yield of 63% and a content of 95.46% (HPLC area normalization method).

[0057] Comparative Example 3

[0058] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (vinylidene chloride added later)

[0059] Dissolve 625g 2,4,5-trifluoroaniline (4.25mol, 1.0equiv) in 1000g acetone, add 3103g 25% hydrochloric acid (21.3mol, 5.0equiv) dropwise at 20°C, and keep the mixture at 20°C for 1h. Cool to -20°C, add 200g copper chloride and 1500g toluene, add 412g vinylidene chloride (4.25mol, 1.0equiv) dropwise to the mixture, and keep the mixture at 20°C for 1h. Control the temperature at -20°C, add 314g 20% ​​sodium nitrite (98%, 4.46mol, 1.05equiv), and keep the mixture at 24h. The mixture was extracted with dichloromethane and washed with 500 mL of 10% liquid alkali, followed by desolventizing and distilling to obtain 628 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene with a yield of 55% and a content of 95.3% (HPLC area normalization method).

[0060] Comparative Example 4

[0061] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (with more sodium nitrite)

[0062] Dissolve 625g 2,4,5-trifluoroaniline (4.25mol, 1.0equiv) in 1000g acetone, add 3103g 25% hydrochloric acid (21.3mol, 5.0equiv) dropwise at 20°C, and keep the temperature at 20°C for 1h. Cool to -20°C, add 200g copper chloride, 1500g toluene and 412g vinylidene chloride (4.25mol, 1.0equiv), and keep the temperature at 20°C for 1h. Control the temperature at -20°C, add 329g 20% ​​sodium nitrite (98%, 4.67mol, 1.1equiv), and keep the temperature at 24h. The mixture was extracted with dichloromethane and washed with 500 mL of 10% liquid alkali, followed by desolventizing and distilling to obtain 849 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene with a yield of 74.3% and a content of 96.0% (HPLC area normalization method).

[0063] Comparative Example 5

[0064] Preparation of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene (with a small amount of vinylidene chloride)

[0065] Dissolve 625g 2,4,5-trifluoroaniline (4.25mol, 1.0equiv) in 1000g acetone, add 3103g 25% hydrochloric acid (21.3mol, 5.0equiv) dropwise at 20°C, and keep the temperature at 20°C for 1h. Cool to -20°C, add 200g copper chloride, 1500g toluene and 370g vinylidene chloride (3.83mol, 0.9equiv), and keep the temperature at 20°C for 1h. Control the temperature at -20°C, add 329g 20% ​​sodium nitrite (98%, 4.67mol, 1.1equiv), and keep the temperature at 24h. The mixture was extracted with dichloromethane and washed with 500 mL of 10% liquid alkali, followed by desolventizing and distilling to obtain 733 g of 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene with a yield of 64.1% and a content of 95.3% (HPLC area normalization method).

[0066] Comparative Example 6

[0067] 147g (1 mol) of 2,4,5-trifluoroaniline and 694g (4.56 mol) of 24% hydrochloric acid were mixed and stirred with heating. After the system was dissolved, it was stirred for 1 hour, cooled to 0°C, and a 40% aqueous solution containing sodium nitrite (82.8g) was added dropwise. After the addition was completed, the mixture was kept warm for 1 hour. The diazonium salt was completely prepared. 131.3g of 2-chloroacrylonitrile, 18.57g (0.1 mol) of ferrocene and 200g (2w / w) of acetone were mixed, cooled to 0°C, and the diazonium salt system was slowly added dropwise for 2-3 hours. After the addition was completed, the mixture was kept warm for 6-8 hours. The mixture was filtered, and the organic phase was recrystallized with 50g of ethyl acetate and 200g of n-heptane. The reaction was completed to obtain a crude product of 2,2-dichloro-3-(2,4,5-trifluorophenyl)-propionitrile with a yield of 57%.

[0068] The prepared 2,4,5-trifluorophenylacetic acid was subjected to HPLC test, and the results showed that the HPLC of 2,4,5-trifluorophenylacetic acid in Example 4 was greater than 99% ( Figure 2 , retention time 18.540min), HPLC of 2,4,5-trifluorophenylacetic acid in Comparative Example 2 was greater than 95% ( Figure 3 , retention time 20.075min). The product obtained by the method of the present invention has a higher content.

Claims

1. A method for preparing 2,4,5-trifluorophenylacetic acid, characterized in that: The following steps are involved: (1) 2,4,5-trifluoroaniline is dissolved in a solvent and reacted with hydrochloric acid at 20-100°C to generate a 2,4,5-trifluorobenzene diazonium salt intermediate; (2) adding a catalyst and vinylidene chloride to the 2,4,5-trifluorobenzene diazonium salt intermediate obtained in step (1) at -20 to 20° C.; then adding a sodium nitrite solution dropwise at -20 to 20° C. and reacting at the temperature to generate 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene; (3) 2,4,5-Trifluoro-(2,2,2-trichloroethyl)benzene reacts in the presence of an acid and a catalyst to produce 2,4,5-trifluorophenylacetic acid.

2. The preparation method according to claim 1, characterized in that: The solvent in step (1) is selected from an organic solvent, preferably a combination of one or more of acetone, tetrahydrofuran and acetonitrile.

3. The preparation method according to claim 1, characterized in that: The molar ratio of hydrochloric acid to 2,4,5-trifluoroaniline in step (1) is 4 to 6:1; the concentration of hydrochloric acid in step (1) is 10 wt% to 35 wt%.

4. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of vinylidene chloride to 2,4,5-trifluoroaniline is 1-5:1; the molar ratio of sodium nitrite to 2,4,5-trifluoroaniline is 1-1.05:

1.

5. The preparation method according to claim 1, characterized in that: The catalyst in step (2) is a combination of one or more of copper salts or copper oxides, preferably a combination of one or more of cupric chloride, cupric bromide, cupric oxide, cuprous chloride, cuprous bromide, cuprous oxide and cupric carbonate.

6. The preparation method according to claim 1, characterized in that: The concentration of the sodium nitrite solution in step (2) is 10 to 40%, preferably 20 to 35%; the reaction temperature in step (2) is -20 to 0°C.

7. The preparation method according to claim 1, characterized in that: The catalyst in step (3) is a combination of one or more of iron salts, copper salts, mercury salts, and cobalt salts, preferably a combination of one or more of FeCl3, Fe2(SO4)3, Fe(NO3)3, CuCl2, CuBr2, CuCl, CuBr, HgSO4, CoCl2, and Co(NO3)2.

8. The preparation method according to claim 1, characterized in that: In step (3), the reaction temperature is 80° C. to 120° C.; the molar ratio of the neutral acid to 2,4,5-trifluoro-(2,2,2-trichloroethyl)benzene is 1 to 5:

1.

9. The preparation method according to claim 1, characterized in that: The acid in step (3) is a combination of one or more of hydrochloric acid and sulfuric acid.

10. The preparation method according to claim 1, characterized in that: In step (3), the concentration of hydrochloric acid is 10% to 35%; the concentration of sulfur is 10% to 98%.

Images