Method for preparing 1, 2, 4-trifluorobenzene

Abstract

The invention provides a method for preparing 1, 2, 4-trifluorobenzene, which belongs to the field of fluorine-containing intermediate preparation, and comprises the following steps: (1) adding 2, 4, 5-trifluoroaniline, hypophosphorous acid and a catalyst into dialkyl carbonate to obtain a mixed solution; (2) adding a nitrosyl sulfuric acid solution into the mixed solution obtained in the step (1), and reacting for a certain time; and (3) separating the reaction liquid in the step (2) to obtain the 1, 2, 4-trifluorobenzene. The method has the advantages of simple process, mild reaction conditions, no generation of waste water and sodium bisulfate, recycling of the catalyst, maximum utilization of cuprous oxide, maximum reduction of pollution and full utilization of resources. The conversion rate is as high as 100%, the selectivity is as high as 99% or above, and the product purity is as high as 99.9% or above.

Description

Technical Field

[0001] The invention relates to a method for preparing 1,2,4-trifluorobenzene, and belongs to the field of preparation of fluorine-containing intermediates. Background Art

[0002] 1,2,4-Trifluorobenzene is a widely used fluorinated intermediate that can be used to synthesize hypoglycemic drugs such as Sitagliptin and Ensitrelvir. There are mainly the following methods for its preparation:

[0003] (1) 2,4-difluoroaniline is used as the starting material [Journal of the American Chemical Society, 78, 2593-6; 1956], and fluoroboric acid is first prepared into fluoroborate, and then diazo cleavage is performed to generate 1,2,4-trifluorobenzene.

[0004]

[0005] This route uses direct solid heating to produce a large amount of nitrogen and highly toxic boron trifluoride gas, which poses certain safety risks. The reaction molar yield is low, and a large amount of difficult-to-treat fluorine- and nitrogen-containing wastewater is produced during the salt formation process using fluoroboric acid.

[0006] (2) Using 1,2,3,4-tetrafluorobenzene as the starting material (Journal of the American Chemical Society, 136(12), 4634-4639; 2014), 1,2,4-trifluorobenzene is produced by selective defluorination.

[0007]

[0008] Although the process is simple, the raw material 1,2,3,4-tetrafluorobenzene is not easy to obtain and is relatively expensive. In addition, other trifluorobenzene isomers are easily produced, so there is little advantage in industrial production.

[0009] (3) 1,2,4-trichlorobenzene is used as the starting material (WO2009122044A3), and fluorinated with potassium fluoride under strong catalyst conditions to generate 1,2,4-trifluorobenzene.

[0010]

[0011] Although the process has a simple route, the yield is not high, the conditions are relatively harsh, it requires high temperature and high pressure, and has certain safety hazards.

[0012] (4) 2,6-dichloro-3-fluoroacetophenone is used as the starting material (Chinese patent document CN104844412A), and 1,2,4-trifluorobenzene is prepared through fluorination, oxidation and decarboxylation.

[0013]

[0014] The raw material 2,6-dichloro-3-fluoroacetophenone used in this process is the isomer of 2,4-dichloro-5-fluoroacetophenone produced by Friedel-Crafts acylation of 2,4-dichlorofluorobenzene and acetyl chloride. It has great advantages in resource utilization and cost, but the fluorination is difficult to carry out and requires a stronger fluorination catalyst, and the overall yield is slightly low.

[0015] (5) CN110498730A first reacts 2,4,5-trifluoroaniline with sulfuric acid to form a salt, then reacts with nitrosylsulfuric acid to undergo a diazotization reaction, then reacts with sodium hypophosphite to undergo a deamination reduction reaction under the catalysis of a copper salt, and finally obtains 1,2,4-trifluorobenzene by steam distillation. This method first uses sulfuric acid to form a salt with 2,4,5-trifluoroaniline, which consumes more sulfuric acid. In addition, sodium hypophosphite and copper oxide are used to prepare an aqueous solution, and then a diazo solution is added to introduce water. In the process, salt containing sodium bisulfate is inevitably produced.

[0016] It can be seen that the existing preparation methods of 1,2,4-trifluorobenzene all have various defects. Summary of the invention

[0017] In order to overcome the problems existing in the above method, the present invention provides a method for preparing 1,2,4-trifluorobenzene, which does not generate waste water and sodium bisulfate salt.

[0018] In order to achieve the above object, the present invention adopts the following technical solutions:

[0019] A method for preparing 1,2,4-trifluorobenzene comprises the following steps:

[0020] (1) adding 2,4,5-trifluoroaniline, hypophosphorous acid and a catalyst into dialkyl carbonate to obtain a mixed solution;

[0021] (2) adding nitrosyl sulfuric acid solution to the mixed solution obtained in step (1) and reacting for a certain period of time;

[0022] (3) Separating 1,2,4-trifluorobenzene from the reaction solution in step (2).

[0023] Preferably, the purity of hypophosphorous acid in step (1) is 50%.

[0024] Preferably, the dialkyl carbonate in step (1) comprises one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, ethyl methyl carbonate and diphenyl carbonate.

[0025] Preferably, in step (1), the mass of dialkyl carbonate is 2 to 10 times that of 2,4,5-trifluoroaniline, preferably 3 to 4 times. The molar ratio of hypophosphorous acid to 2,4,5-trifluoroaniline is greater than or equal to 0.25:1, preferably 0.5 to 1.5:1, more preferably 0.95 to 1.05:1, and even more preferably 1:1.

[0026] Preferably, the catalyst in step (1) is cuprous oxide, and the amount added is greater than or equal to 1% of the weight of 2,4,5-trifluoroaniline, preferably 1-4%. The catalyst can be recycled and introduced from the lower acid phase. The research of the present invention shows that the lower acid phase can be recycled at least 3 times. Compared with the copper oxide used in patent CN110498730A, the catalyst of the present invention is more atom-economical. The above-mentioned recycling reference means that the acid and catalyst in the mixed solution after the lower acid phase is extracted with dialkyl carbonate can be directly used in the next reaction without adding catalyst, which can maximize the utilization of cuprous oxide, minimize pollution and make full use of resources.

[0027] Preferably, the concentration of the nitrosyl sulfuric acid solution in step (2) is 40%. The molar ratio of nitrosyl sulfuric acid to 2,4,5-trifluoroaniline is 1:1 (substance equivalent ratio), and excess nitrosyl sulfuric acid will continue to react with the product, affecting the yield.

[0028] Preferably, the reaction temperature in step (2) is 40-50°C. When the temperature is lower than 40°C, the reaction is slow and the selectivity is poor; when the temperature is higher than 50°C, a tar-like substance will be generated, which affects the selectivity and yield. More preferably, the temperature is 40-45°C. After the reaction is completed, extraction is performed with dialkyl carbonate. The dialkyl carbonate used for extraction may be the same as the dialkyl carbonate used for the reaction, or may be different. It is preferred to use the same dialkyl carbonate.

[0029] Preferably, the reaction time of step (2) is 0.5 to 2 h, and more preferably the reaction time is 1 h.

[0030] Preferably, the separation method in step (3) is preferably extraction and distillation. Further preferably, the specific separation method in step (3) is: after the reaction solution in step (2) is allowed to stand for stratification, the upper organic phase is collected, and the lower acid phase is extracted with dialkyl carbonate to obtain an extraction phase; the upper organic phase and the extraction phase are mixed, and 1,2,4-trifluorobenzene is obtained by distillation.

[0031] Beneficial effects of the present invention:

[0032] Conventional production of 1,2,4-trifluorobenzene in the industry is generally carried out with reference to the method of CN110498730A. It is necessary to first use sulfuric acid to form a salt to prepare a sulfuric acid 2,4,5-trifluoroaniline salt solution, then react with nitrosylsulfuric acid to undergo a diazotization reaction, and then react with sodium hypophosphite under the catalysis of copper salt to undergo a deamination reduction reaction, and finally obtain 1,2,4-trifluorobenzene by steam distillation. The inventor surprisingly found in the experiment that after using hypophosphorous acid to form a salt with 2,4,5-trifluoroaniline in dialkyl carbonate, nitrosylsulfuric acid is added under catalytic conditions, and 1,2,4-trifluorobenzene can actually be obtained under the heterogeneous combination of the above-mentioned various factors. Compared with the method of patent CN110498730A, the method of the present invention does not need to use sulfuric acid to form a salt with 2,4,5-trifluoroaniline, but instead uses hypophosphorous acid to form a salt with 2,4,5-trifluoroaniline, and does not use a sodium hypophosphite aqueous solution, so no excess water is introduced. In addition, the process designed by the present invention is simpler, and only requires placing materials other than nitrosyl sulfuric acid into the reactor and then adding nitrosyl sulfuric acid, instead of requiring two preparation processes as described in CN110498730A.

[0033] Reaction equation of the present invention is as follows:

[0034] 4C6H4NF3+4NOSO3H+H3PO2→4C6H3F3+4H2SO4+H3PO4.

[0035] The method of the present invention has a simple process, mild reaction conditions, no waste water and sodium bisulfate salt are generated, and the catalyst can be recycled, which can maximize the use of cuprous oxide, minimize pollution and fully utilize resources. The conversion rate can reach 100%, the selectivity can reach more than 99%, and the product purity can reach 99.99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the GC spectrum of the upper liquid obtained in Example 1.

[0037] Figure 2 This is the mass spectrum of 1,2,4-trifluorobenzene obtained in Example 1.

[0038] Figure 3 This is the GC spectrum of 1,2,4-trifluorobenzene of the upper liquid obtained in Example 11. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is further described below in conjunction with specific examples and drawings. All raw materials in the specific implementation methods of the present invention are commercially available products, and nitrosylsulfuric acid can be homemade.

[0040] Example 1

[0041] Preparation of 1,2,4-trifluorobenzene: 14.7g (0.1mol, 1.0eq) of 2,4,5-trifluoroaniline, 0.147g of cuprous oxide, 12.4g of hypophosphorous acid (50% content, 0.1mol, 1.0eq) and 50g of dimethyl carbonate were added to the reaction bottle, the temperature was controlled at 40°C, 31.8g (0.1mol, 1.0eq) of nitrosyl sulfuric acid with a concentration of 40wt% was added dropwise, and the temperature was kept for 1 hour after the addition. The reaction solution was separated into layers, and diethyl carbonate was added to the lower acid phase for extraction. The extract was combined with the upper organic phase and the organic phase was taken for detection. The detection results are shown in Figure 1 In the figure, the peak of 1,2,4-trifluorobenzene is at 2.9min, the peak of solvent diethyl carbonate is at 5min, and the peak of coupling impurities is at 11-12min. The conversion rate of 2,4,5-trifluoroaniline is 100%, and the selectivity of 1,2,4-trifluorobenzene is 99.4% (rounded off).

[0042] The yield of 1,2,4-trifluorobenzene from the organic phase was 99.3% and the purity was 99.90%. The mass spectrum of 1,2,4-trifluorobenzene is shown in Figure 2 In the figure, m / z=132.1 is the MS peak of 1,2,4-trifluorobenzene.

[0043] Example 2

[0044] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, 1.04 eq of nitrosyl sulfuric acid was used, the temperature was 45°C, and the other conditions were the same as in Example 1, the conversion rate of 2,4,5-trifluoroaniline was 100%, the selectivity of 1,2,4-trifluorobenzene was 96.4%, the yield of 1,2,4-trifluorobenzene was 93.3%, and the purity was 99.91%.

[0045] Example 3

[0046] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the solvent was diethyl carbonate, the temperature was 45°C, and the other conditions were the same as in Example 1, the conversion rate of 2,4,5-trifluoroaniline was 100%, the selectivity of 1,2,4-trifluorobenzene was 99.3%, the yield of 1,2,4-trifluorobenzene was 99.3%, and the purity was 99.92%.

[0047] Example 4

[0048] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the solvent was ethyl methyl carbonate, and the other conditions were the same as in Example 1, the conversion rate of 2,4,5-trifluoroaniline was 100%, the selectivity of 1,2,4-trifluorobenzene was 99.2%, the yield of 1,2,4-trifluorobenzene was 99.1%, and the purity was 99.92%.

[0049] Example 5

[0050] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the solvent was dipropyl carbonate, and the other conditions were the same as in Example 1, the conversion rate of 2,4,5-trifluoroaniline was 100%, the selectivity of 1,2,4-trifluorobenzene was 99.1%, the yield of 1,2,4-trifluorobenzene was 99.0%, and the purity was 99.91%.

[0051] Example 6

[0052] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the solvent was diphenyl carbonate, and the other conditions were the same as in Example 1, the conversion rate of 2,4,5-trifluoroaniline was 100%, the selectivity of 1,2,4-trifluorobenzene was 99.5%, the yield of 1,2,4-trifluorobenzene was 99.3%, and the purity was 99.93%.

[0053] Example 7

[0054] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the amount of hypophosphorous acid used was 0.24 eq, and the other conditions were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 93.3%, the selectivity of 1,2,4-trifluorobenzene was 99.2%, and the equivalent of hypophosphorous acid was at least 0.25 eq, so that the raw material 2,4,5-trifluoroaniline could be completely converted. The yield of 1,2,4-trifluorobenzene was 85.3%, and the purity was 99.91%.

[0055] Example 8

[0056] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the amount of cuprous oxide used was 0.95% of the weight of 2,4,5-trifluoroaniline (the amount of cuprous oxide used was 0.14 g), and the other aspects were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 100%, the selectivity of 1,2,4-trifluorobenzene was 83.4%, the yield of 1,2,4-trifluorobenzene was 80.3%, and the purity was 99.91%.

[0057] Example 9

[0058] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the reaction temperature was 39°C, and the other conditions were the same as in Example 1, the conversion rate was 100%, the selectivity was 93.6%, the yield of 1,2,4-trifluorobenzene was 92.3%, and the purity was 99.99%.

[0059] Example 10

[0060] 1,2,4-trifluorobenzene was prepared by referring to the method described in Example 1, the reaction temperature was 51°C, and the other conditions were the same as in Example 1, the conversion rate was 100%, the selectivity was 92.5%, the yield of 1,2,4-trifluorobenzene was 91.3%, and the purity was 99.99%.

[0061] Embodiment 11

[0062] Acid phase application for the first time: 14.7g (0.1mol, 1.0eq) of 2,4,5-trifluoroaniline was added to the reaction flask, and the lower acid phase extracted in Example 1 was added, and then 12.4g (50% content, 0.1mol, 1.0eq) of hypophosphorous acid and 50g of dimethyl carbonate were added, and the temperature was controlled at 40-50°C, and 31.8g (0.1mol, 1.0eq) of 40% nitrosyl sulfuric acid was added dropwise, and the temperature was kept for 1 hour after the addition. The upper solution was sampled for testing, and the test results showed that the conversion rate of 2,4,5-trifluoroaniline was 100%, and the selectivity of 1,2,4-trifluorobenzene was 99.4%. The test results are shown in Figure 3 Dimethyl carbonate was added to the lower layer for extraction, and the extract was combined with the organic phase and distilled to obtain 1,2,4-trifluorobenzene.

[0063] Example 12

[0064] Acidic application 2nd time: Repeat the above experiment using the lower acid phase extracted in Example 11.

[0065] Embodiment 13

[0066] Acidic application for the third time: Repeat the above experiment using the lower acid phase extracted in Example 12.

[0067] The results obtained in the above examples are summarized in Table 1.

[0068] Table 1

[0069] serial number Conversion rate Selectivity Yield purity Example 1 100％ 99.4％ 99.3％ 99.90％ Example 2 100％ 96.4％ 93.3％ 99.91％ Example 3 100％ 99.3％ 99.3％ 99.92％ Example 4 100％ 99.2％ 99.1％ 99.92％ Example 5 100％ 99.1％ 99.0％ 99.91％ Example 6 100％ 99.5％ 99.3％ 99.93％ Example 7 93.3％ 99.2％ 85.3％ 99.91％ Example 8 100％ 83.4％ 80.3％ 99.91％ Example 9 100％ 93.6％ 92.3％ 99.99％ Example 10 100％ 92.5％ 91.3％ 99.99％ Embodiment 11 100％ 99.4％ 99.5％ 99.91％ Example 12 100％ 99.4％ 99.3％ 99.92％ Example 13 100％ 99.3％ 99.1％ 99.92％

Claims

1. A method for preparing 1,2,4-trifluorobenzene, characterized in that: The following steps are involved: (1) adding 2,4,5-trifluoroaniline, hypophosphorous acid and a catalyst into dialkyl carbonate to obtain a mixed solution; (2) adding nitrosyl sulfuric acid solution to the mixed solution obtained in step (1) and reacting for a certain period of time; (3) Separating 1,2,4-trifluorobenzene from the reaction solution in step (2).

2. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: The dialkyl carbonate in step (1) includes one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, ethyl methyl carbonate and diphenyl carbonate.

3. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: In step (1), the mass of dialkyl carbonate is 2 to 10 times that of 2,4,5-trifluoroaniline.

4. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: In step (1), the mass of dialkyl carbonate is 3 to 4 times that of 2,4,5-trifluoroaniline.

5. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: In step (1), the molar ratio of hypophosphorous acid to 2,4,5-trifluoroaniline is greater than or equal to 0.25:

1.

6. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: In step (1), the molar ratio of hypophosphorous acid to 2,4,5-trifluoroaniline is 0.5 to 1.5:

1.

7. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: The catalyst in step (1) is cuprous oxide, and the added amount is greater than or equal to 1% of the weight of 2,4,5-trifluoroaniline.

8. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: In step (2), the molar ratio of nitrosyl sulfuric acid to 2,4,5-trifluoroaniline is 1:

1.

9. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: The reaction temperature in step (2) is 40-50°C.

10. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that: The reaction time of step (2) is 0.5 to 2 hours.

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