A process for the preparation of 1,2,4-trifluorobenzene

Abstract

The application provides a method for preparing 1,2,4-trifluorobenzene, and belongs to the field of preparation of fluorine-containing intermediates, and comprises the following steps: (1) adding 2,4,5-trifluoroaniline, hypophosphorous acid and a catalyst into a dialkyl carbonate to obtain a mixed solution; (2) adding a nitrosyl sulfuric acid solution into the mixed solution obtained in step (1) and reacting for a certain time; and (3) separating 1,2,4-trifluorobenzene from the reaction solution in step (2). The method has the advantages of simple process, mild reaction condition, no generation of waste water and sodium bisulfate salt, recyclable 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 more than 99%, and the product purity is as high as more than 99.9%.

Description

Technical Field

[0001] This invention relates to a method for preparing 1,2,4-trifluorobenzene, belonging to the field of fluorine-containing intermediate preparation. Background Technology

[0002] 1,2,4-Trifluorobenzene is a widely used fluorinated intermediate used in the synthesis of the hypoglycemic drugs sitagliptin and ensitrelvir. Its preparation methods mainly include the following:

[0003] (1) Using 2,4-difluoroaniline as the starting material [Journal of the American Chemical Society, 78, 2593-6; 1956], it was first reacted with fluoroboric acid to form a fluoroborate, which was then subjected to diazo cracking to produce 1,2,4-trifluorobenzene.

[0004]

[0005] The pyrolysis method using solid direct heating generates a large amount of nitrogen and highly toxic boron trifluoride gas, posing certain safety hazards. The reaction molar yield is low, and a large amount of difficult-to-treat fluorine and nitrogen-containing wastewater is generated 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 was generated through selective defluorination.

[0007]

[0008] Although the process is simple, the 1,2,3,4-tetrafluorobenzene raw material is not readily available and is expensive. In addition, it is easy to generate other trifluorobenzene isomers, so it has little advantage in industrial production.

[0009] (3) Using 1,2,4-trichlorobenzene as the starting material (WO2009122044A3), it is fluorinated with potassium fluoride under strong catalytic conditions to produce 1,2,4-trifluorobenzene.

[0010]

[0011] Although the process is simple, the yield is low, the conditions are harsh, requiring high temperature and high pressure, and there are certain safety hazards.

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

[0013]

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

[0015] (5) CN110498730A describes a method that first reacts 2,4,5-trifluoroaniline with sulfuric acid to form a salt, then reacts it with nitrososulfuric acid to undergo a diazotization reaction, followed by a deamination reduction reaction with sodium hypophosphite under the catalysis of 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, consuming a large amount of sulfuric acid. Furthermore, the method of preparing an aqueous solution with sodium hypophosphite and copper oxide, and then adding diazo solution, inevitably introduces water during this process, resulting in the production of a salt containing sodium bisulfate.

[0016] It is evident that existing methods for preparing 1,2,4-trifluorobenzene all have various shortcomings. Summary of the Invention

[0017] To overcome the problems existing in the above methods, this invention provides a method for preparing 1,2,4-trifluorobenzene. This method does not produce wastewater or sodium bisulfate.

[0018] To achieve the above objectives, the present invention adopts the following technical solution:

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

[0020] (1) 2,4,5-trifluoroaniline, hypophosphoric acid and catalyst were added to dialkyl carbonate to obtain a mixture;

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

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

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

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

[0025] Preferably, in step (1), the dialkyl carbonate is 2 to 10 times the mass of 2,4,5-trifluoroaniline, more preferably 3 to 4 times. The molar ratio of hypophosphoric acid to 2,4,5-trifluoroaniline is greater than or equal to 0.25:1, more preferably 0.5 to 1.5:1, further 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 is recyclable and can be reused from the lower acid phase. Research on this invention shows that the lower acid phase can be reused at least 3 times. Compared with the copper oxide used in patent CN110498730A, the catalyst of this invention is more atom-economical. The reuse refers to the fact that the acid and catalyst in the mixture after the lower acid phase is extracted with dialkyl carbonate can directly participate in the next reaction without adding another catalyst, which can maximize the utilization of cuprous oxide, minimize pollution, and make full use of resources.

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

[0028] Preferably, the reaction temperature in step (2) is 40–50°C. Below 40°C, the reaction is slow and the selectivity is poor; above 50°C, tar-like substances will be generated, affecting selectivity and yield. More preferably, the temperature is 40–45°C. After the reaction is complete, extraction is performed using dialkyl carbonate. The dialkyl carbonate used for extraction can be the same as or different from the dialkyl carbonate used in the reaction; preferably, the same dialkyl carbonate is used.

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

[0030] Preferably, the separation method in step (3) is extraction and distillation. More preferably, the specific separation method in step (3) is as follows: after the reaction solution in step (2) is allowed to stand and separate into layers, the upper organic phase is collected, and the lower acid phase is extracted with dialkyl carbonate to obtain the extract phase; the upper organic phase and the extract phase are mixed and distilled to obtain 1,2,4-trifluorobenzene.

[0031] The beneficial effects of this invention are:

[0032] The conventional method for producing 1,2,4-trifluorobenzene in the industry generally follows the method described in CN110498730A. This method requires first preparing a 2,4,5-trifluoroaniline sulfate solution using sulfuric acid, then reacting it with nitrosylsulfuric acid via a diazotization reaction, followed by a deamination reduction reaction with sodium hypophosphite under copper salt catalysis, and finally obtaining 1,2,4-trifluorobenzene via steam distillation. The inventors surprisingly discovered in their experiments that by salting 2,4,5-trifluoroaniline with hypophosphite in dialkyl carbonate, and then adding nitrosylsulfuric acid under catalytic conditions, 1,2,4-trifluorobenzene could also be obtained under heterogeneous conditions and the aforementioned combination of factors. Compared to the method in patent CN110498730A, the method of this invention does not require the salting of 2,4,5-trifluoroaniline with sulfuric acid; instead, it uses hypophosphite, and it also eliminates the need for an aqueous solution of sodium hypophosphite, thus avoiding the introduction of excess water. Furthermore, the process designed in this invention is simpler. It only requires putting materials other than nitrosylsulfuric acid into the reactor and then adding nitrosylsulfuric acid, instead of requiring two preparation processes as described in CN110498730A.

[0033] The reaction equation of this invention is as follows:

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

[0035] The method of this invention is simple, operates under mild reaction conditions, produces no wastewater or sodium bisulfate, and the catalyst is recyclable. It maximizes the utilization of cuprous oxide, minimizes pollution, and fully utilizes resources. The conversion rate can reach 100%, the selectivity is over 99%, and the product purity can reach 99.99%. Attached Figure Description

[0036] Figure 1 This is the GC spectrum of the upper layer 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 in the upper layer obtained in Example 11. Detailed Implementation

[0039] The technical solution of the present invention will be further described below with reference to specific embodiments and accompanying drawings. All raw materials used in the specific embodiments of the present invention are commercially available products, and nitrosyl sulfuric acid can be prepared in-house.

[0040] Example 1

[0041] Preparation of 1,2,4-trifluorobenzene: 14.7 g (0.1 mol, 1.0 eq) of 2,4,5-trifluoroaniline, 0.147 g of cuprous oxide, 12.4 g (50% content, 0.1 mol, 1.0 eq) of hypophosphite, and 50 g of dimethyl carbonate were added to a reaction flask. The temperature was maintained at 40℃, and 31.8 g (0.1 mol, 1.0 eq) of 40 wt% nitrosylsulfuric acid was added dropwise. The mixture was kept at this temperature for 1 hour after the addition was complete. The reaction solution separated into layers. The lower acidic phase was extracted with diethyl carbonate. The extract was combined with the upper organic phase, and the organic phase was analyzed. The results are shown in [Figure number missing]. Figure 1 In the figure, the peak at 2.9 min is for 1,2,4-trifluorobenzene, the peak at 5 min is for the solvent diethyl carbonate, and the peak at 11–12 min is for coupling impurities. The conversion rate of 2,4,5-trifluoroaniline is 100%, and the selectivity of 1,2,4-trifluorobenzene is 99.4% (rounded).

[0042] The yield of 1,2,4-trifluorobenzene was 99.3% and the purity was 99.90% by organic phase distillation. The mass spectrum of 1,2,4-trifluorobenzene is shown below. 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 according to the method described in Example 1, using 1.04 eq of nitrosylsulfuric acid at a temperature of 45°C. Other conditions were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 100%, and 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 according to the method described in Example 1, using diethyl carbonate as the solvent and at a temperature of 45°C. All other conditions were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 100%, and the selectivity of 1,2,4-trifluorobenzene was 99.3%. The yield of 1,2,4-trifluorobenzene was 99.3%, and its purity was 99.92%.

[0047] Example 4

[0048] 1,2,4-trifluorobenzene was prepared according to the method described in Example 1, using methyl ethyl carbonate as the solvent. All other steps were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 100%, and 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 according to the method described in Example 1, using dipropyl carbonate as the solvent. All other steps were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 100%, and the selectivity of 1,2,4-trifluorobenzene was 99.1%. The yield of 1,2,4-trifluorobenzene was 99.0%, and its purity was 99.91%.

[0051] Example 6

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

[0053] Example 7

[0054] 1,2,4-Trifluorobenzene was prepared according to the method described in Example 1, with 0.24 eq of hypophosphite. Other steps were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 93.3%, and the selectivity of 1,2,4-trifluorobenzene was 99.2%. A hypophosphite equivalent of at least 0.25 eq was required for complete conversion of the feedstock 2,4,5-trifluoroaniline. The yield of 1,2,4-trifluorobenzene was 85.3%, and its purity was 99.91%.

[0055] Example 8

[0056] 1,2,4-Trifluorobenzene was prepared according to the method described in Example 1. The amount of cuprous oxide used was 0.95% of the weight of 2,4,5-trifluoroaniline (0.14 g of cuprous oxide). Other steps were the same as in Example 1. The conversion rate of 2,4,5-trifluoroaniline was 100%, and 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 according to the method described in Example 1, with a reaction temperature of 39°C and other parameters identical to those in Example 1. The conversion rate was 100%, and 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 according to the method described in Example 1, with a reaction temperature of 51°C and other parameters identical to those in Example 1. The conversion rate was 100%, and the selectivity was 92.5%. The yield of 1,2,4-trifluorobenzene was 91.3%, and the purity was 99.99%.

[0061] Example 11

[0062] First reuse of the acid phase: 14.7 g (0.1 mol, 1.0 eq) of 2,4,5-trifluoroaniline was added to the reaction flask, followed by the lower acid phase extracted in Example 1. Then, 12.4 g (50% content, 0.1 mol, 1.0 eq) of hypophosphite and 50 g of dimethyl carbonate were added. The temperature was controlled at 40-50°C, and 31.8 g (0.1 mol, 1.0 eq) of 40% nitrosylsulfonic acid was added dropwise. After the addition was complete, the mixture was kept at this temperature for 1 hour. A sample of the upper layer solution was taken for analysis. The results showed a 100% conversion rate of 2,4,5-trifluoroaniline and a 99.4% selectivity for 1,2,4-trifluorobenzene. See the results below. Figure 3 The lower layer was extracted with dimethyl carbonate, and the extract was combined with the organic phase and distilled to obtain 1,2,4-trifluorobenzene.

[0063] Example 12

[0064] Acidity application for the second time: The above experiment was repeated using the lower acid phase extracted in Example 11.

[0065] Example 13

[0066] Acidity application for the third time: The above experiment was repeated using the lower acid phase extracted in Example 12.

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

[0068] Table 1

[0069] serial number Conversion rate Selective 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％ Example 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, Includes the following steps: (1) 2,4,5-trifluoroaniline, hypophosphoric acid and catalyst are added to dialkyl carbonate or diphenyl carbonate to obtain a mixture, wherein the catalyst is cuprous oxide; (2) Add nitrosyl sulfuric acid solution to the mixture obtained in step (1) and react for a certain period of time; (3) 1,2,4-trifluorobenzene was separated from the reaction solution in step (2).

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

3. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that, In step (1), the dialkyl carbonate or diphenyl carbonate is 2 to 10 times the mass 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 dialkyl carbonate or diphenyl carbonate is 3 to 4 times the mass 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 hypophosphoric acid and 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 hypophosphoric acid and 2,4,5-trifluoroaniline is 0.5~1.5:

1.

7. The method for preparing 1,2,4-trifluorobenzene according to claim 1, characterized in that, The amount of catalyst added in step (1) 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 nitrosylsulfuric 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℃.

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

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