A method for preparing 1,2,4-trifluorobenzene by cracking diazonium fluoroborate

Abstract

The invention belongs to the technical field of preparation methods of chemical drug intermediates, and is specifically related to a method for preparing 1,2,4-trifluorobenzene by cracking diazonium fluoroborate. The present invention uses 2,4-difluoroaniline, concentrated hydrochloric acid and sodium nitrite as starting materials. After obtaining diazonium fluoroborate intermediate, trifluorobenzene is used as solvent, iron powder is used as catalyst, and cracking obtains trifluorobenzene, nitrogen and boron trifluoride. Compared to other reagents such as toluene, chlorobenzene and acetone, when trifluorobenzene is used as solvent, because the target product is consistent with the solvent, and the remaining two products are gases, it is easier to separate from liquid, therefore there is no need to carry out separation and purification operation, to achieve the goal of reducing process and reducing cost. At the same time, iron powder is used as catalyst for the best inhibitory effect on side reactions, and the target cracking reaction can be carried out smoothly, showing excellent conversion rate and yield (96% and 94%), suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation methods of chemical drug intermediates, and specifically relates to a method for preparing 1,2,4-trifluorobenzene by cracking diazonium fluoroborate. Background Art

[0002] 1,2,4-Trifluorobenzene 1.2.4-Trifluorobenzene is an important intermediate for the preparation of pesticides and medicines. It can be used to produce the hypoglycemic drug sitagliptin phosphate, and can also be used to synthesize key intermediates of fluoroquinolones such as clinafloxacin and sitafloxacin. It can also be used as a raw material for liquid crystal materials. It has a wide range of applications, a large demand, and good application prospects. The synthetic preparation research process of the sitagliptin intermediate 1.2.4-trifluorobenzene in this project is an independently developed product.

[0003] In the prior art, patents CN104844412A and CN101817724A both disclose a method for preparing 1,2,4-trifluorobenzene, but the two by-products of the production of 2,4-dichloro-5-fluoroacetophenone are difficult to separate as reactants, the wastewater generated in the preparation process is difficult to treat, and the steps are relatively complicated, the yield is low, and it is difficult to achieve industrial production. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing 1,2,4-trifluorobenzene by cracking diazonium fluoroborate, which has solved at least one problem in the background technology. The technical solution adopted is:

[0005] A method for preparing 1,2,4-trifluorobenzene by cracking diazonium fluoroborate, comprising the following steps:

[0006] (1) Preparation of diazonium fluoroborate: 2,4-difluoroaniline reacts with concentrated hydrochloric acid to generate hydrochloride, then the temperature is lowered to 0-5°C, sodium nitrite solution is added in an ice bath to carry out diazotization reaction, the reaction temperature is maintained at no more than 5°C, and finally a fluoroboric acid aqueous solution is added dropwise to generate diazonium fluoroborate. The reaction formula is:

[0007]

[0008] (2) Preparation of 1,2,4-trifluorobenzene: Using 1,2,4-trifluorobenzene as solvent and iron powder as catalyst, diazonium fluoroborate is subjected to high temperature cracking reaction at 80°C to 150°C to obtain 1,2,4-trifluorobenzene. The reaction formula is:

[0009]

[0010] Preferably, in step (1), the mass fraction concentration of concentrated hydrochloric acid is 25-35%.

[0011] Preferably, in step (1), the mass fraction concentration of the sodium nitrite solution is 20 to 30%.

[0012] Preferably, in step (1), the molar ratio of 2,4-difluoroaniline, concentrated hydrochloric acid, sodium nitrite and fluoroboric acid is 1:2.2:1.05:1.2.

[0013] Preferably, in step (1), 2,4-difluoroaniline reacts with concentrated hydrochloric acid to generate hydrochloride. If salt is precipitated after ice bathing, a small amount of distilled water may be added to dissolve it.

[0014] Preferably, in the step (1), after the addition of the fluoroboric acid aqueous solution, the temperature is kept below 5° C. for 1 to 2 hours, and the mixture is filtered and the solid is washed to obtain fluoroboric acid diazonium salt.

[0015] Preferably, in the step (2), after the diazonium fluoroborate and 1,2,4-trifluorobenzene solution is heated to 40°C, the temperature is increased by 10°C each time the temperature is gradually increased to 110-150°C, and then heated to decompose for 1-2 hours.

[0016] Preferably, in step (2), the released boron trifluoride gas is absorbed by an organic solvent; wherein the organic solvent is any one of methanol, ether, tetrahydrofuran, ethanol or acetic acid.

[0017] Preferably, in step (2), the mass of the added catalyst iron powder is 2% to 4% of the mass of the diazonium fluoroborate salt.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention uses 2,4-difluoroaniline, concentrated hydrochloric acid and sodium nitrite as starting materials, and after obtaining the diazonium fluoroborate intermediate, uses trifluorobenzene as a solvent and iron powder as a catalyst to crack to obtain trifluorobenzene, nitrogen and boron trifluoride. Compared with other reagents such as toluene, chlorobenzene and acetone, when trifluorobenzene is used as a solvent, since the target product and the solvent are consistent, and the other two products are gases, it is easier to separate them from the liquid, so there is no need to perform separation and purification operations, achieving the goal of reducing the number of steps and reducing costs. At the same time, using iron powder as a catalyst has the best inhibitory effect on side reactions, and the target cracking reaction can proceed smoothly, showing excellent conversion rate and yield (96% and 94%);

[0020] The method of the invention has high yield and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a flow chart of the present invention. DETAILED DESCRIPTION

[0022] The accompanying drawings are only for illustrative purposes; it should be understood that the cases mentioned below are only used to explain the present invention, in order to facilitate the description of the present invention and simplify the description, and therefore, should not be understood as limiting the present invention.

[0023] The principles and features of the present invention are described below in conjunction with the examples, which are only used to explain the present invention and are not intended to limit the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0024] Example 1

[0025] (1) Decomposition of diazonium fluoroborate

[0026] Prepare a 250mL three-necked flask with mechanical stirring, reflux condenser, and thermometer. Connect an air guide tube above the condenser, which is connected to a bubble tester filled with 30% concentrated hydrochloric acid. The bubble tester outlet tube is passed into another 250mL three-necked flask filled with methanol, and the catheter is inserted below the methanol liquid level. Then cool to 0°C, add a 20% sodium nitrite solution under ice bath conditions to carry out diazotization reaction, maintain the reaction temperature not exceeding 5°C, and finally add a 30% fluoroboric acid aqueous solution dropwise, and keep warm for 1.5 hours. Filter the generated fluoroboric acid diazonium salt, and wash the solid to obtain fluoroboric acid diazonium salt.

[0027] (2) Preparation of 1,2,4-trifluorobenzene

[0028] Add 20g of fluoroborate diazonium salt, 80mL of 1,2,4-trifluorobenzene and 0.16g of iron powder to a 250mL three-necked flask. Heat the 250mL three-necked flask to 40°C, increase the temperature by 10°C each time, gradually raise the temperature to 110°C, maintain the temperature, and heat and decompose for 1.5h until no bubbles are generated in the bubbler and the 250mL three-necked flask. Stop heating, the reaction is over, and 1,2,4-trifluorobenzene is obtained.

[0029] The reaction yielded 10.9 g of 1,2,4-trifluorobenzene, with a conversion rate of 96% and a yield of 94% as determined by GC. The technical parameters and yields of statistical changes are shown in Table 1.

[0030] Example 2

[0031] (1) Decomposition of diazonium fluoroborate

[0032] Prepare a 250mL three-necked flask with mechanical stirring, reflux condenser, and thermometer. Connect an air duct above the condenser, which is connected to a bubble tester filled with 30% concentrated hydrochloric acid. The bubble tester outlet pipe is passed into another 250mL three-necked flask filled with methanol, and the catheter is inserted below the tetrahydrofuran liquid level. Then cool to 0°C, add a 20% sodium nitrite solution under ice bath conditions to carry out diazotization reaction, maintain the reaction temperature not exceeding 5°C, and finally add a 30% fluoroboric acid aqueous solution dropwise, and keep warm for 1.5 hours. Filter the generated fluoroboric acid diazonium salt, and wash the solid to obtain fluoroboric acid diazonium salt.

[0033] (2) Preparation of 1,2,4-trifluorobenzene

[0034] Add 20g of fluoroborate diazonium salt, 80mL of toluene and 0.16g of iron powder to a 250mL three-necked flask. Heat the 250mL three-necked flask to 40°C, increase the temperature by 10°C each time, gradually raise the temperature to 120°C, maintain the temperature, and heat and decompose for 1.5h until no bubbles are generated in the bubble tester and the 250mL three-necked flask, stop heating, and the reaction is completed to obtain 1,2,4-trifluorobenzene. The other operations not described are the same as those in Example 1.

[0035] The reaction yielded 10.4 g of 1,2,4-trifluorobenzene, with a conversion rate of 92% and a yield of 90% as determined by GC. The technical parameters and yields of statistical changes are shown in Table 1.

[0036] Example 3

[0037] The same operation as in Example 1 is performed, except that the solvent 1,2,4-trifluorobenzene in Example 1 is replaced by chlorobenzene as the solvent, and the temperature is still increased in a gradient manner to 150° C. during cracking.

[0038] The reaction yielded 9.5 g of 1,2,4-trifluorobenzene, with a conversion rate of 85% and a yield of 82% as determined by GC. The technical parameters and yields of statistical changes are shown in Table 1.

[0039] Example 4

[0040] The same operation as in Example 1 is performed, except that the solvent 1,2,4-trifluorobenzene in Example 1 is replaced by petroleum ether as the solvent, and the temperature is still increased in a gradient manner to 100° C. during cracking.

[0041] The reaction yielded 8.12 g of 1,2,4-trifluorobenzene, with a conversion rate of 75% and a yield of 70% as determined by GC. The technical parameters and yields of statistical changes are shown in Table 1.

[0042] Example 5

[0043] The same operation as in Example 1 is performed, except that the solvent 1,2,4-trifluorobenzene in Example 1 is replaced by acetone as the solvent, and the temperature is still increased in a gradient manner to 60° C. during pyrolysis.

[0044] The reaction yielded 7.5 g of 1,2,4-trifluorobenzene, with a conversion rate of 69% and a yield of 65% as determined by GC. The technical parameters and yields of statistical changes are shown in Table 1.

[0045] The effects of different solvents on the conversion rate and yield of cracking 1,2.4-trifluorobenzene are shown in Table 1. As can be seen from Table 1, when the solvent is 1,2.4-trifluorobenzene, the conversion rate is the highest, which is 96%, and the yield is 94%.

[0046] Table 1 Effect of different solvents on the conversion rate and yield of 1,2.4-trifluorobenzene

[0047] Solvents Cracking temperature (℃) Conversion rate (%) Yield (%) Example 1: 1,2,4-Trifluorobenzene 110 96 94 Example 2: Toluene 120 92 90 Example 3: Chlorobenzene 150 85 82 Example 4: Petroleum ether 100 75 70 Example 5: Acetone 60 69 65

[0048] Example 6

[0049] The same operation as in Example 1 was performed, except that 0.42 g of Fe was added to the 250 mL three-necked flask. 2 O 3 .

[0050] The reaction yielded 10.2 g of 1,2,4-trifluorobenzene, with a conversion rate of 92% and a yield of 88% as determined by GC. The conversion rates and yields under different catalysts are shown in Table 2.

[0051] Example 7

[0052] The same operation as in Example 1 was performed, except that 0.17 g Cu was added to the 250 mL three-necked flask.

[0053] The reaction yielded 9.2 g of 1,2,4-trifluorobenzene, with a conversion rate of 82% and a yield of 79% as determined by GC. The conversion rates and yields under different catalysts are shown in Table 2.

[0054] Example 8

[0055] The same operation as in Example 1 was performed except that 0.41 g of Mn was added to the 250 mL three-necked flask. 2 O 3 .

[0056] The reaction yielded 7.1 g of 1,2,4-trifluorobenzene, with a conversion rate of 64% and a yield of 61% as determined by GC. The conversion rates and yields under different catalysts are shown in Table 2.

[0057] The effects of different catalysts on the conversion rate and yield of cracking 1,2.4-trifluorobenzene are shown in Table 2. As can be seen from Table 2, when the catalyst is Fe powder, the conversion rate and yield are the highest.

[0058] Table 2 Effect of different catalysts on the conversion rate and yield of cracking 1,2.4-trifluorobenzene

[0059] catalyst Conversion rate (%) Yield (%) Example 1: Fe powder 96 94 <![CDATA[Example 6: Fe 2 O 3 > 92 88 Example 7: Cu 82 79 <![CDATA[Example 8: Mn 2 O 3 > 64 61

[0060] For other parts not mentioned in the present invention, conventional methods or modes of the prior art are adopted, and if there is no clear description, the measuring instruments used are standard instruments commonly used in general laboratories.

[0061] Of course, the above description is not a limitation of the present invention, and the present invention is not limited to the above examples. Changes, modifications, additions or substitutions made by technicians in this technical field within the essential scope of the present invention should also fall within the protection scope of the present invention.

Claims

1. A method for preparing 1,2,4-trifluorobenzene by cracking diazonium fluoroborate, characterized in that: The following steps are involved: (1) Preparation of diazonium fluoroborate: 2,4-difluoroaniline reacts with concentrated hydrochloric acid to generate hydrochloride, then the temperature is lowered to 0-5°C, sodium nitrite solution is added in an ice bath to carry out diazotization reaction, the reaction temperature is maintained at no more than 5°C, and finally a fluoroboric acid aqueous solution is added dropwise. After the addition of the fluoroboric acid aqueous solution, the temperature is kept below 5°C for 1-2 hours, filtered, and the solid is washed to obtain diazonium fluoroborate; (2) Preparation of 1,2,4-trifluorobenzene: Using 1,2,4-trifluorobenzene as solvent and iron powder as catalyst, diazonium fluoroborate is subjected to a high temperature cracking reaction at 110°C to obtain 1,2,4-trifluorobenzene; The mass of iron powder added is 2% to 4% of the mass of diazonium fluoroborate; After heating the solution of fluoroborate diazonium salt and 1,2,4-trifluorobenzene to 40°C, increase the temperature by 10°C each time until the temperature gradually rises to 110°C, and then heat to decompose for 1 to 2 hours; The released boron trifluoride gas is absorbed by an organic solvent; wherein the organic solvent is any one of methanol, ether, tetrahydrofuran, ethanol or acetic acid.

2. The method for preparing 1,2,4-trifluorobenzene by decomposing diazonium fluoroborate according to claim 1, characterized in that: In the step (1), the mass fraction concentration of concentrated hydrochloric acid is 25-35%.

3. The method for preparing 1,2,4-trifluorobenzene by decomposing diazonium fluoroborate according to claim 1, characterized in that: In the step (1), the mass fraction concentration of the sodium nitrite solution is 20-30%.

4. The method for preparing 1,2,4-trifluorobenzene by decomposing diazonium fluoroborate according to claim 1, characterized in that: In the step (1), the molar ratio of 2,4-difluoroaniline, concentrated hydrochloric acid, sodium nitrite and fluoroboric acid is 1:2.2:1.05:1.

2.

5. The method for preparing 1,2,4-trifluorobenzene by decomposing diazonium fluoroborate according to claim 1, characterized in that: In the step (1), 2,4-difluoroaniline reacts with concentrated hydrochloric acid to generate hydrochloride. If salt is precipitated after ice bathing, a small amount of distilled water can be added to dissolve it.

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