Synthesis method of 2-bromine-5-halogenated benzotrifluoride

Abstract

The invention relates to a synthesis method of 2-bromine-5-halogenated trifluorotoluene, which is characterized in that a bromination reaction is directly carried out by taking a simple and easily available iron or aluminum compound as a catalyst, the reaction selectivity is high, and the steps are simple and short. The new route is good in atom economy, less in investment equipment, simple and convenient to operate, low in cost and beneficial to industrial production, and can be carried out in the absence of a solvent.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a method for synthesizing 2-bromo-5-halotrifluorotoluene. Background Art

[0002] 2-Bromo-5-halotrifluorotoluene is an important intermediate of organic fluorides and is widely used in the fields of medicine, pesticides, chemicals, etc.

[0003] At present, the process route for preparing 2-bromo-5-halotrifluorotoluene has long steps, complex operations, poor atom economy, and a large amount of three wastes. Specifically, it includes:

[0004] 1) CN106905104A records that o-aminotrifluorotoluene is brominated, nitrated, and reduced to obtain 2-amino-5-fluorotrifluorotoluene, and then diazotized and halogenated to obtain the product. The raw materials of this route are expensive, almost the same as the product selling price, and it is not suitable for industrial production.

[0005] 2) CN104447183A discloses that m-aminotrifluorotoluene is first subjected to amino protection, bromination, deprotection, and halogenation to obtain the product. This route requires amino protection, has low atom utilization rate and high cost, and is not suitable for industrial production.

[0006] 3) CN102951996A discloses that m-aminotrifluorotoluene is halogenated, nitrated, reduced, and brominated to obtain the product, and the reaction yield is low, which is not suitable for industrial production.

[0007]

[0008] In summary, the existing technology has problems such as long route steps, high cost, high three wastes, and low yield. There is an urgent need for a new synthesis route that can shorten the reaction steps, improve the atom utilization rate and reaction yield, and is conducive to realizing industrial production and improving the market competitiveness of products. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a method for synthesizing 2-bromo-5-halotrifluorotoluene with short steps, simple and easily available catalysts, and less three wastes. The new route has good atom economy, requires less equipment investment, can be carried out in the absence of a solvent, has simple operation, high reaction yield, and high selectivity.

[0010] The technical solution for the present invention to solve the above technical problems is as follows:

[0011] A method for synthesizing 2-bromo-5-halotrifluorotoluene, comprising the following steps:

[0012] In the absence of a solvent, mix the compound of formula II with liquid bromine, add a catalyst, and obtain the compound of formula I.

[0013] Among them, X is selected from F, Cl, I; the catalyst is selected from Fe(0), Fe(II), Fe(III), Al(III) compounds and their salts or any combination of several of them.

[0014] The specific reaction formula is as follows:

[0015]

[0016] Preferably, the catalyst is selected from one or more of iron powder, ferrous chloride, ferrous sulfate, ferric chloride, ferric bromide, ferric sulfate, aluminum trichloride, and aluminum sulfate.

[0017] Preferably, the catalyst is selected from one or more of iron powder, ferric chloride, ferric bromide, ferric sulfate, aluminum chloride, and aluminum sulfate.

[0018] Among them, the reaction can be carried out at 0 - 1 Mpa, preferably 0 - 0.5 Mpa.

[0019] Among them, the reaction temperature is 0 - 120 °C, preferably 0 - 100 °C, and further preferably 20 - 70 °C.

[0020] Among them, the reaction time is 1 - 48 h, preferably 2 - 24 h, and further preferably 4 - 18 h.

[0021] Among them, the molar ratio of the compound of formula II to liquid bromine is 1:0.95 - 5.0, preferably 1:1.0 - 4.0; further preferably 1:1.2 - 3.0.

[0022] The molar ratio of the compound of formula II to the catalyst is 1:0.001 - 1, preferably 1:0.01 - 0.5; further preferably 1:0.01 - 0.3.

[0023] Preferably, the reaction specifically includes the following steps: mixing the catalyst with the compound of formula II, heating the mixture to 20 - 70 °C for reaction, adding liquid bromine to the mixture, and maintaining the reaction for 2 - 24 h to obtain the target product; wherein the mixture is a mixture of the catalyst and the compound of formula II; liquid bromine is preferably added in a dropwise manner.

[0024] Furthermore, a weak acidic substance can be added during the reaction to promote the reaction.

[0025] Furthermore, all the catalyst can be added at once during the reaction, or the catalyst can be added in batches, preferably, the catalyst can be added in batches.

[0026] Furthermore, after the reaction, a post-treatment method is also involved, including the following steps:

[0027] After the reaction is completed, the reaction solution is subjected to distillation or vacuum rectification to recover the unreacted liquid bromine. The remaining reaction solution is filtered to recover the catalyst, and the filtrate is separated by atmospheric rectification to obtain the target product. Alternatively, the reaction solution after the reaction is completed is dropped with 10% sodium sulfite solution to neutralize the excessive bromine. After standing and separating layers, chlorine gas is introduced into the aqueous layer to recover the unreacted liquid bromine. The organic layer is adjusted to neutral with an alkali solution, the aqueous layer is separated, and the organic layer is separated by atmospheric rectification to obtain the target product.

[0028] Through long-term research, the inventors of the present invention found that when the compound of formula II undergoes a bromination reaction with liquid bromine in the presence of a solvent, a series of side reactions may occur, such as the formation of isomers such as 4-bromo-3-fluorobenzotrifluoride, 2-bromo-3-fluorobenzotrifluoride, 3-bromo-5-fluorobenzotrifluoride, and over-brominated dibromides. When no solvent is added, unexpectedly, the content of by-products is significantly reduced, the reaction selectivity is significantly improved, and the reaction yield is thereby increased.

[0029] The advantages of the present invention are as follows: The synthesis method of the present invention uses simple and easily available iron or aluminum compounds as catalysts, and the bromination reaction can be directly carried out under solvent-free conditions. The reaction has high selectivity and short steps. The new route has good atom economy, requires less equipment investment, is easy to operate, the bromine is easy to recycle and reuse, has low cost, and is conducive to industrial production. Specific Embodiments

[0030] Example 1

[0031] In a 500 ml four-necked flask, 164 g (1 mol, 1 eq) of 3-fluorobenzotrifluoride and 5.6 g (0.1 mol, 0.1 eq) of iron powder were added. The temperature was raised to 40 - 70 °C, and 255 g of liquid bromine (1.6 mol, 1.6 eq) was added dropwise. The addition was completed in about 1 h. The reaction was carried out at 70 °C for 2 - 24 h, and the reaction was monitored by sampling until the raw material content ≤ 1%. The temperature was lowered to 20 - 30 °C, and 10% sodium sulfite solution was added dropwise until the red color of the system faded and the starch potassium iodide test paper just did not turn blue. After separation, the aqueous layer was treated for bromine recovery, the organic layer was neutralized with 10% liquid alkali to pH = 7 - 8, the lower organic layer after separation was sent to rectification, and the bromine-containing waste water in the aqueous layer was sent to recover bromine. 238.51 g of the product was obtained, with a yield of 95.7% and a product purity of 97.5%.

[0032] In Examples 2 - 5, different catalysts were replaced.

[0033] Take 4 four-necked flasks of 500 ml, and respectively add 164 g (1 mol, 1 eq) of 3-fluorobenzotrifluoride. Then add ferric chloride (0.1 mol, 0.1 eq), ferric sulfate (0.1 mol, 0.1 eq), ferrous sulfate (0.1 mol, 0.1 eq), and ferric chloride + ammonium molybdate (3:1, a total of 0.1 mol, 0.1 eq). Heat up to 40 - 70 °C, and slowly add 255 g of liquid bromine (1.6 mol, 1.6 eq). The addition is completed in about 1 h. Keep the temperature at 70 °C and react for 2 - 24 h. Take samples to monitor the reaction until the raw material content ≤ 1%. Cool down to 20 - 30 °C, and slowly add 10% sodium sulfite solution until the red color of the system fades and the starch potassium iodide test paper just stops turning blue. After liquid separation, the aqueous layer is treated for bromine recovery, and the organic layer is neutralized with 10% liquid alkali to pH = 7 - 8. After liquid separation, the lower organic layer goes for rectification, and the bromine-containing wastewater in the aqueous layer goes for bromine recovery. The purity and yield of the obtained product are shown in Table 1 below.

[0034] Table 1

[0035] Number Type and dosage of catalyst (mol) Product mass (g) Yield (%) Purity (%) 2 Ferric chloride (0.1 mol, 0.1 eq) 240.51 96.40％ 97.40％ 3 Ferric sulfate (0.1 mol, 0.1 eq) 238.77 95.90％ 97.60％ 4 Ferrous sulfate (0.1 mol, 0.1 eq) 239.51 96.10％ 97.50％ 5 Ferric chloride + ammonium molybdate (3:1, total 0.1 mol, 0.1 eq) 242.25 97.20％ 97.50％

[0036] In Examples 6 - 10, the raw material is replaced with chloride.

[0037] Take 5 four-necked flasks of 500 ml, and respectively add 180 g (1 mol, 1 eq) of 3-chlorobenzotrifluoride. Then add iron powder (0.13 mol, 0.13 eq), ferric chloride (0.15 mol, 0.15 eq), ferric sulfate (0.17 mol, 0.17 eq), ferrous sulfate (0.19 mol, 0.19 eq), and ferric chloride + ammonium molybdate (3:1, a total of 0.18 mol, 0.18 eq). Heat up to 40 - 70 °C, and slowly add 255 g of liquid bromine (1.6 mol, 1.6 eq). The addition is completed in about 1 h. Keep the temperature at 70 °C and react for 2 - 24 h. Take samples to monitor the reaction until the raw material content ≤ 1%. Cool down to 20 - 30 °C, and slowly add 10% sodium sulfite solution until the red color of the system fades and the starch potassium iodide test paper just stops turning blue. After liquid separation, the aqueous layer is treated for bromine recovery, and the organic layer is neutralized with 10% liquid alkali to pH = 7 - 8. After liquid separation, the lower organic layer goes for rectification, and the bromine-containing wastewater in the aqueous layer goes for bromine recovery. The purity and yield of the obtained product are shown in Table 2 below.

[0038] Table 2

[0039] Number Type and dosage of catalyst (mol) Product mass (g) Yield (%) Purity (%) 6 Iron powder (0.13 mol, 0.13 eq) 240.54 90.30％ 97.40％ 7 Ferric chloride (0.15 mol, 0.15 eq) 242.15 91.04％ 97.50％ 8 Ferric sulfate (0.17 mol, 0.17 eq) 241.85 90.70％ 97.30％ 9 Ferrous sulfate (0.19 mol, 0.19 eq) 242.29 91.05％ 97.50％ 10 Ferric chloride + ammonium molybdate (3:1, total 0.18 mol, 0.18 eq) 243.16 91.38％ 97.50％

[0040] In Examples 11 - 13, the amount of bromine is changed.

[0041] Take 3 four-necked flasks of 500 ml, and respectively add 164 g (1 mol, 1 eq) of 3-fluorobenzotrifluoride and iron(III) chloride (0.10 mol, 0.10 eq). Heat up to 40 - 70 °C, and respectively dropwise add 320 g of liquid bromine (2.0 mol, 2.0 eq), 208 g of liquid bromine (1.3 mol, 1.3 eq), and 255 g of liquid bromine (1.6 mol, 1.6 eq). The dropping is completed in about 1 h. Keep the temperature at 70 °C and react for 2 - 24 h. Take samples to track the reaction until the raw material content ≤ 1%. Cool down to 20 - 30 °C, and dropwise add 10% sodium sulfite solution until the red color of the system fades and the starch potassium iodide test paper just stops turning blue. After liquid separation, the aqueous layer is treated for bromine recovery, and the organic layer is neutralized with 10% liquid alkali to pH = 7 - 8. After liquid separation, the lower-layer organic layer goes for rectification, and the bromine-containing wastewater in the aqueous layer goes for bromine recovery. The purity and yield of the obtained product are shown in Table 3 below.

[0042] Table 3

[0043] Number Bromine dosage (mol) Product mass (g) Yield (%) Purity (%) 11 320 g liquid bromine (2.0 mol, 2.0 eq) 239.76 96.20％ 97.50％ 12 208 g liquid bromine (1.3 mol, 1.3 eq) 236.76 94.90％ 97.40％ 13 255 g liquid bromine (1.6 mol, 1.6 eq) 237.51 95.30％ 97.50％

[0044] Examples 14 - 16 change the amount of bromine

[0045] Take 3 four-necked flasks of 500 ml, and respectively add 180 g (1 mol, 1 eq) of 3-chlorobenzotrifluoride and iron(III) sulfate (0.05 mol, 0.05 eq). Heat up to 40 - 70 °C, and respectively dropwise add 320 g of liquid bromine (2.0 mol, 2.0 eq), 208 g of liquid bromine (1.0 mol, 1.3 eq), and 288 g of liquid bromine (1.8 mol, 1.8 eq). The dropping is completed in about 1 h. Keep the temperature at 70 °C and react for 2 - 24 h. Take samples to track the reaction until the raw material content ≤ 1%. Cool down to 20 - 30 °C, and dropwise add 10% sodium sulfite solution until the red color of the system fades and the starch potassium iodide test paper just stops turning blue. After liquid separation, the aqueous layer is treated for bromine recovery, and the organic layer is neutralized with 10% liquid alkali to pH = 7 - 8. After liquid separation, the lower-layer organic layer goes for rectification, and the bromine-containing wastewater in the aqueous layer goes for bromine recovery. The purity and yield of the obtained product are shown in Table 4 below.

[0046] Table 4

[0047]

[0048]

[0049] Examples 17 - 19 change the reaction pressure

[0050] Take 3 four-necked flasks of 500 ml, and respectively add 164 g (1 mol, 1 eq) of 3-fluorobenzotrifluoride, iron(III) chloride (0.10 mol, 0.10 eq). Heat up to 40 - 70 °C, and dropwise add 255 g of liquid bromine (1.6 mol, 1.6 eq). The addition is completed in about 1 h. Pressurize to 0.1 MPa, 0.3 MPa, and 0.5 MPa respectively, and keep the temperature at 70 °C for reaction for 2 - 24 h. Take samples to track the reaction until the raw material content ≤ 1%. Cool down to 20 - 30 °C, and dropwise add 10% sodium sulfite solution until the red color of the system fades and the starch potassium iodide test paper just does not turn blue. After liquid separation, the aqueous layer is treated for bromine recovery, the organic layer is neutralized with 10% liquid alkali to 7 - 8%, and after liquid separation, the lower-layer organic layer goes to rectification, and the bromine-containing wastewater in the aqueous layer goes to bromine recovery. The purity and yield of the obtained product are shown in Table 5 below.

[0051] Table 5

[0052] Number Reaction pressure (MPa) Product mass (g) Yield (%) Purity (%) 17 0.1 MPa 237.02 95.10％ 97.50％ 18 0.3 MPa 239.26 96.00％ 97.50％ 19 0.5 MPa 240.01 96.30％ 97.50％

[0053] In Example 20, change the feeding method of the catalyst to batch addition

[0054] In a 500 ml four-necked flask, add 164 g (1 mol, 1 eq) of 3-fluorobenzotrifluoride, first add iron powder (0.07 mol, 0.07 eq), heat up to 40 - 70 °C, and dropwise add 255 g of liquid bromine (1.6 mol, 1.6 eq). The addition is completed in about 1 h. After reacting at 70 °C for 6 - 8 h, add iron powder (0.03 mol, 0.03 eq) again, and continue to keep the temperature at 70 °C for 2 - 12 h. Take samples to track the reaction until the raw material content ≤ 1%. Cool down to 20 - 30 °C, and dropwise add 10% sodium sulfite solution until the red color of the system fades and the starch potassium iodide test paper just does not turn blue. After liquid separation, the aqueous layer is treated for bromine recovery, the organic layer is neutralized with 10% liquid alkali to pH = 7 - 8, and after liquid separation, the lower-layer organic layer goes to rectification, and the bromine-containing wastewater in the aqueous layer goes to bromine recovery. 240.26 g of the product is obtained, with a yield of 96.5% and a product purity of 97.6%.

[0055] Comparative Example 1

[0056] Repeat Example 1 of Patent Document CN116143581A. Select iron powder as the catalyst and dichloromethane as the solvent. The mass of the target product 2-bromo-5-fluorobenzotrifluoride is 209.70 g, the yield is 83.10%, and the purity is 96.30%. Excessive bromine and a large amount of organic solvents are used, resulting in a large amount of three wastes.

[0057] Comparative Example 2

[0058] Repeat Example 5 of patent document CN116143581A. Ferric tribromide was selected as the catalyst, and dichloroethane was used as the solvent. The mass of the target product 2-bromo-5-fluorobenzotrifluoride was 215.91 g, the yield was 85.30%, and the purity was 96.00%. Excessive bromine and a large amount of organic solvents were used, resulting in a large amount of three wastes.

[0059] Comparative Example 3

[0060] Repeat Example 1 of patent CN105152853A. The target product 2-bromo-5-fluorobenzotrifluoride was not obtained.

[0061] Comparative Example 4

[0062] Repeat Example 1 of patent CN114163294A. The target product 2-bromo-5-fluorobenzotrifluoride was not obtained.

[0063] Comparative Example 5

[0064] Except for additionally adding 200 g of dichloromethane as the solvent, the rest was the same as in Example 1. The mass of the target product 2-bromo-5-fluorobenzotrifluoride was 203.94 g, the yield was 80.40%, and the purity was 95.80%.

[0065] It can be seen from Examples 1-19 and Comparative Examples 1-5 that the technical solution of the present invention is related to the presence of the solvent, the type and amount of the reaction catalyst, the amount of bromine, and the reaction pressure.

[0066] The inventors of the present invention have found through long-term research that when the compound of formula II undergoes a bromination reaction with liquid bromine in the presence of a solvent, a series of side reactions may occur, such as the formation of isomers such as 4-bromo-3-fluorobenzotrifluoride, 2-bromo-3-fluorobenzotrifluoride, 3-bromo-5-fluorobenzotrifluoride, and over-brominated dibromides. See Comparative Examples 1, 2, and 5. However, when no solvent is added, unexpectedly, the content of by-products is greatly reduced, the reaction selectivity is greatly improved, and thus the reaction yield is increased.

[0067] In addition, the type and amount of the catalyst selected in the reaction also affect the reaction yield and rate. When iron powder, ferric chloride, ferric sulfate, or ferrous sulfate is used as the catalyst, the reaction yield and rate can be greatly improved.

[0068] In addition, the amount of bromine used in the reaction and the reaction pressure will also affect the reaction yield. In the prior art, an excessive amount of bromine is often added to ensure the full progress of the reaction. However, the addition of excessive bromine not only easily leads to waste of raw materials, but also greatly increases the post-treatment operations of the reaction and the discharge of three wastes. Through the optimized reaction scheme of the present invention, the reaction can be completed in the presence of a slightly excessive amount of bromine, and a high reaction yield can be obtained, which is conducive to realizing industrial production. Further, applying a little pressure to the reaction system during the reaction is beneficial to accelerating the reaction rate and improving production efficiency.

[0069] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-bromo-5-halotrifluorotoluene, characterized in that, It includes the following steps: in the absence of a solvent, mix the compound of formula II with liquid bromine, add a catalyst to obtain the compound of formula I. Wherein X is selected from F, Cl, I; the catalyst is selected from one or more of Fe(0), Fe(II), Fe(III), Al(III) compounds and their salts.

2. The synthesis method according to claim 1, characterized in that, The catalyst is selected from one or more of iron powder, ferrous chloride, ferrous sulfate, ferric chloride, ferric bromide, ferric sulfate, aluminum trichloride, and aluminum sulfate.

3. The synthesis method according to claim 1, characterized in that, The catalyst is selected from one or more of iron powder, ferric chloride, ferric bromide, ferric sulfate, aluminum chloride, and aluminum sulfate.

4. The synthesis method according to claims 1-3, characterized in that, The reaction can be carried out at 0 - 1 Mpa, preferably 0 - 0.5 Mpa.

5. The synthesis method according to claims 1-3, characterized in that, The reaction temperature is 0 - 120 °C, preferably 0 - 100 °C; the reaction time is 1 - 48 h, preferably 2 - 24 h.

6. The synthesis method according to claims 1-3, characterized in that, The molar ratio of the compound of formula II to liquid bromine is 1:0.95 - 5.0, further preferably 1:1.0 - 4.0; the molar ratio of the compound of formula II to the catalyst is 1:0.001 - 1, further preferably 1:0.01 - 0.

5.

7. The synthesis method according to claims 4-6, characterized in that, The reaction specifically includes the following steps: mix the catalyst with the compound of formula II, heat the mixture to 20 - 70 °C, add liquid bromine to the mixture, and keep the reaction for 2 - 24 h to obtain the target product; wherein the mixture is a mixture of the catalyst and the compound of formula II; liquid bromine is preferably added dropwise.

8. The synthesis method according to claim 7, wherein After the reaction, a post-treatment method is also involved. It includes the following steps: The reaction solution after the reaction is subjected to distillation or vacuum rectification to recover the unreacted liquid bromine, the remaining reaction solution is filtered to recover the catalyst, and the filtrate is separated by atmospheric rectification to obtain the target product; or the reaction solution after the reaction is added dropwise with a 10% sodium sulfite solution to neutralize the excess bromine, allowed to stand and layer, the water layer is passed through chlorine to recover the unreacted liquid bromine, the organic layer is adjusted to neutral with an alkali solution, the water layer is separated, and the organic layer is separated by atmospheric rectification to obtain the target product.

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