Preparation method of 2-bromo-5-fluorobenzotrifluoride

Abstract

The invention provides a method for preparing 2-bromo-5-fluorobenzotrifluoride, which comprises the following steps: in a solvent, in the presence of a substance X, subjecting m-fluorobenzotrifluoride and bromine to a substitution reaction to obtain 2-bromo-5-fluorobenzotrifluoride; the substance X is Fe and / or FeBr3. The preparation method has high reaction selectivity, high yield and purity of the product, mild conditions, convenient operation, safety and environmental protection.

Description

Technical Field

[0001] The present application relates to a method for preparing 2-bromo-5-fluorotoluene trifluoride. Background Art

[0002] 2-Bromo-5-fluorobenzotrifluoride is an important organic fluoride intermediate, widely used in medicine, pesticides, chemicals, etc. Its molecular formula is C7H3BrF4, and its relative molecular mass is 243.

[0003] According to domestic literature reports, the current synthetic route of 2-bromo-5-fluorobenzotrifluoride is mainly the following methods: ① Patent document CN114163294A uses meta-fluorobenzotrifluoride as raw material, uses quaternary ammonium salt composite catalyst, bromine as bromination reagent, hydrogen peroxide as oxidant, and obtains 2-bromo-5-fluorobenzotrifluoride by bromination and reoxidation. This method has good reaction effect, but the use of a large amount of oxidant may cause explosion danger. ② Patent document CN102951996A uses meta-fluorobenzotrifluoride as raw material, first nitrates and hydrogenates to generate 4-fluoro-2-trifluoromethylaniline, and then performs diazotization and bromination to obtain the product. This route has complicated steps, high cost, large amount of three wastes, and harsh industrial conditions. ③ Patent CN107337576A reports that meta-fluorobenzotrifluoride is used as raw material, uses composite catalyst, sulfuric acid as oxidant, and bromine as bromination reagent to obtain the product. This route produces a large amount of waste acid, and the bottom acid separation step of the post-treatment is difficult to achieve in industry. ④ In patent CN104610015A, bromate is used as a bromination reagent and meta-fluorobenzotrifluoride is used as a raw material to efficiently obtain the product. However, bromate is mostly expensive and not suitable for large-scale production. In addition, patent CN111362775A reports that benzotrifluoride is used as a raw material, first bromination in the presence of potassium bromide, cuprous chloride, sulfuric acid and a catalyst, and then fluorination is performed using potassium fluoride and KCoF4. This process produces a large amount of heavy metal waste liquid and requires the use of expensive Pd catalysts. Summary of the invention

[0004] The technical problem to be solved by the present invention is that the existing preparation method of 2-bromo-5-fluorobenzotrifluoride is complicated in operation, the reagents used are highly polluting, and the yield and purity are low. Therefore, the present invention provides a preparation method of 2-bromo-5-fluorobenzotrifluoride. The preparation method has high reaction selectivity, high product yield and purity, mild conditions, convenient operation, and is safe and environmentally friendly.

[0005] The present invention provides a method for preparing 2-bromo-5-fluorobenzotrifluoride, comprising the following steps: in a solvent, in the presence of a substance X, subjecting m-fluorobenzotrifluoride and bromine to a substitution reaction to obtain 2-bromo-5-fluorobenzotrifluoride;

[0006]

[0007] The substance X is Fe and / or FeBr3.

[0008] In the preparation method, the solvent may be a halogenated hydrocarbon solvent and / or an alkane solvent; the alkane solvent is preferably heptane and / or hexane; the halogenated hydrocarbon solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride.

[0009] The solvent is more preferably dichloromethane and / or 1,2-dichloroethane.

[0010] In the preparation method, the solvent is further preferably the dichloromethane and 1,2-dichloroethane; the volume ratio of the dichloromethane to 1,2-dichloroethane is preferably 1:1.

[0011] In the preparation method, the molar ratio of the substance X to the meta-fluorobenzotrifluoride is preferably (0.01-0.6):1, more preferably (0.05-0.25):1, for example 0.05:1, 0.10:1, 0.18:1, 0.20:1 or 0.25:1.

[0012] In the preparation method, the molar ratio of the meta-fluorobenzotrifluoride to the bromine is preferably 1:(1-5), more preferably 1:(2-4), such as 1:2, 1:2.5 or 1:4.

[0013] In the preparation method, the molar ratio of the meta-fluorobenzotrifluoride to the solvent is preferably 1:(0.5-8), more preferably 1:(0.5-6), such as 1:1, 1:1.5, 1:2, 1:4 or 1:6.

[0014] In the preparation method, the reaction temperature of the substitution reaction is a conventional temperature for substitution reactions in the art, preferably 40-60°C, more preferably 40-45°C or 50-55°C.

[0015] In the preparation method, the progress of the substitution reaction is monitored by conventional detection methods in the art (such as GC), and the end point is preferably when the concentration of the meta-fluorobenzotrifluoride in the reaction solution is less than 0.05%. The reaction time of the substitution reaction is preferably 6-18 hours, such as 7 hours, 10 hours or 16 hours.

[0016] The preparation method preferably comprises the following steps: adding bromine to the mixture; the temperature of the mixture is 40-60° C.; the mixture is a mixture of the solvent, the substance X and meta-fluorotrifluorotoluene; the bromine is preferably added in the form of drops.

[0017] In the preparation method, after the substitution reaction is completed, post-treatment may be included;

[0018] The post-processing may include the following steps:

[0019] A) distilling the reaction solution after the substitution reaction to recover the solvent and unreacted bromine to obtain a crude product;

[0020] B) The crude product is mixed with a reducing agent, distilled, and the fraction at 158-162° C. / 760 mmHg is collected.

[0021] The reducing agent is preferably sodium sulfite.

[0022] The ratio of the amount of the reducing agent to the amount of the bromine substance is preferably 1:(40-160), more preferably 1:(40-80), such as 46.9:1, 60:1, 78:1 or 80:1.

[0023] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0024] The reagents and raw materials used in the present invention are commercially available.

[0025] The positive and progressive effects of the present invention are:

[0026] (1) Mild reaction conditions and simple operation;

[0027] (2) High reaction selectivity, high product yield and purity;

[0028] (3) No diazotizing agent and concentrated sulfuric acid are used, and no organic waste that is difficult to separate is produced, which is safe and environmentally friendly. DETAILED DESCRIPTION

[0029] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0030] The parameters of the GC detection method in the following examples are as follows:

[0031]

[0032]

[0033] Example 1

[0034] The reaction equation is:

[0035] In a 1000mL glass four-necked bottle, add 164g (1mol) of meta-fluorobenzotrifluoride, 336g (4mol) of dichloromethane, and 3g (0.05mol) of iron powder at room temperature. Then heat the reactor to 40-45°C, start to drop 400g (2.5mol) of bromine, and keep warm for 10 hours after the dropwise addition is completed. Then take a sample from the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC ≤0.5%. Distill out the dichloromethane and excess bromine in the system for the next batch of reactions, and then add 4g (0.032mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification to obtain 218g of product. The molecular weight of the product determined by GC-MS is consistent with the target product, and the gas phase peak position is consistent with the standard product. The purity measured by GC is greater than 99%, and the yield is 90%.

[0036] Example 2

[0037] The reaction equation is:

[0038] In a 1000mL glass four-necked bottle, add 164g (1mol) of meta-fluorobenzotrifluoride, 148g (1.5mol) of 1,2-dichloroethane, and 16g (0.25mol) of iron powder at room temperature. Then heat the reactor to 50-55°C, start to drop 320g (2mol) of bromine, and keep warm for 7 hours after the dropwise addition. Then take a sample from the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC to ≤0.5%. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 3.2g (0.025mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification to obtain 206g of product, with a purity of more than 99% measured by GC and a yield of 85%.

[0039] Example 3

[0040] The reaction equation is:

[0041] In a 1000mL glass four-necked bottle, add 164g (1mol) of meta-fluorobenzotrifluoride, 54g (0.5mol) of 1,2-dichloroethane, 43g (0.5mol) of dichloromethane, and 16g (0.25mol) of iron powder at room temperature. Then heat the reactor to 50-55℃, start to drop 240g (1.5mol) of bromine, and keep warm for 7 hours after the dropwise addition. Then take a sample from the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC ≤0.5%. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 4g (0.032mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162℃ / 760mmHg by rectification to obtain 194g of product, with a purity of more than 99% measured by GC and a yield of 80%.

[0042] Example 4

[0043] The reaction equation is:

[0044] In a 1000mL glass four-necked bottle, add 164g (1mol) of meta-fluorobenzotrifluoride, 396g (4mol) of 1,2-dichloroethane, and 10g (0.18mol) of iron powder at room temperature. Then heat the reactor to 50-55°C, start to drop 240g (1.5mol) of bromine, and keep warm for 7 hours after the dropwise addition. Then take a sample from the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC to ≤0.5%. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 3.2g (0.025mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification to obtain 199g of product, with a purity of more than 99% measured by GC and a yield of 82%.

[0045] Example 5

[0046] The reaction equation is:

[0047] In a 1000mL glass four-necked bottle, add 164g (1mol) of meta-fluorobenzotrifluoride, 396g (4mol) of 1,2-dichloroethane, and 14.8g (0.05mol) of ferric bromide at room temperature. Then heat the reactor to 50-55°C, start to drop 240g (1.5mol) of bromine, and keep warm for 7 hours after the dropwise addition. Then take a sample from the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC ≤0.5%. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 3.2g (0.025mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification to obtain 209g of product, with a purity of more than 99% measured by GC and a yield of 86%.

[0048] Example 6

[0049] Distillation of bromine and dichloromethane recovery and re-use experiment,

[0050] The reaction equation is:

[0051] In a 1000mL glass four-necked bottle, the bromine and dichloromethane distilled in the above Example 1 were recovered, bromine was supplemented to 400g, dichloromethane was supplemented to 330g, and put into a 1000mL glass four-necked bottle, 164g of raw materials and 3g of iron powder were added, and the remaining raw materials, catalysts and other operations were the same as in Example 1 to obtain 216g of the final product with a yield of 89% and a purity of more than 99% measured by GC.

[0052] Examples 7-10

[0053] The reaction equation is:

[0054] Take four 1000mL glass four-necked bottles, add 164g (1mol) of meta-fluorobenzotrifluoride, 336g (4mol) of 1,2-dichloroethane, and 0.6g (0.01mol), 3g (0.05mol), 6g (0.10mol), and 12g (0.20mol) of iron powder respectively at room temperature. Then heat the reactor to 50°C, and start to drop 400g (2.5mol) of bromine respectively. After the dropwise addition is completed, keep warm for 16 hours. Then take the sample in the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC ≤0.5%. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 4g (0.032mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification, and the purity and yield of the obtained product are shown in Table 1 below.

[0055] Table 1

[0056] serial number Catalyst dosage (mol) Temperature(℃) Time (h) Yield (%) purity(%) 7 0.01 50 16 53 99.4 8 0.05 50 16 90 99.5 9 0.10 50 16 91 99.2 10 0.20 50 16 87 99.6

[0057] Examples 11-14

[0058] The reaction equation is:

[0059] Take four 1000mL glass four-necked bottles, add 164g (1mol) of meta-fluorobenzotrifluoride, 84g (0.5mol), 168g (2mol), 504g (6mol), 672g (8mol) of 1,2-dichloroethane, and 3g (0.05mol) of iron powder respectively at room temperature. Then heat the reactor to 50°C, start dripping 400g (2.5mol) of bromine, and keep warm for 16 hours after the dripping is completed. Then take the sample in the reactor, monitor the content of meta-fluorobenzotrifluoride by GC ≤0.5% to stop the reaction. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, then add 4g (0.032mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification, and the purity and yield of the obtained product are shown in Table 2 below.

[0060] Table 2

[0061] serial number Solvent dosage (mol) Temperature(℃) Time (h) Yield (%) purity(%) 11 0.5 50 16 73 99.0 12 2.0 50 16 84 99.3 13 6.0 50 16 71 99.1 14 8.0 50 16 62 99.2

[0062] Examples 15-18

[0063] The reaction equation is:

[0064] Take four 1000mL glass four-necked bottles, add 164g (1mol) of meta-fluorobenzotrifluoride, 336g (4mol) of 1,2-dichloroethane, and 3g (0.05mol) of iron powder at room temperature. Then heat the reactor to 50°C, add 160g (1mol), 240g (1.5mol), 320g (2mol), and 640g (4mol) of bromine respectively, and keep warm for 16 hours after the addition is completed. Then take the sample in the reactor, monitor the content of meta-fluorobenzotrifluoride by GC ≤0.5% to stop the reaction. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 4g (0.032mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162°C / 760mmHg by rectification, and the purity and yield of the obtained product are shown in Table 3 below.

[0065] Table 3

[0066] serial number Bromine dosage (mol) Temperature(℃) Time (h) Yield (%) purity(%) 15 1.0 50 16 23 99.5 16 1.5 50 16 45 99.3 17 2.0 50 16 69 99.2 18 4.0 50 16 91 99.4

[0067] Examples 19-20

[0068] The reaction equation is:

[0069] Take two 1000mL glass four-necked bottles, add 164g (1mol) of meta-fluorobenzotrifluoride, 336g (4mol) of 1,2-dichloroethane, and 3g (0.05mol) of iron powder at room temperature. Then heat the reactor to 40℃ and 60℃ respectively, start to add 400g (2.5mol) of bromine, and keep warm for 16 hours after the addition is completed. Then take the sample in the reactor, and stop the reaction by monitoring the content of meta-fluorobenzotrifluoride by GC ≤0.5%. Distill out the dichloroethane and excess bromine in the system for the next batch of reactions, and then add 4g (0.032mol) of sodium sulfite to the reaction solution in the reactor to remove the remaining very small amount of bromine. Then collect the fraction of 158-162℃ / 760mmHg by rectification, and the purity and yield of the obtained product are shown in Table 4 below.

[0070] Table 4

[0071] serial number Temperature(℃) Time (h) Yield (%) purity(%) 19 40 16 79 99.1 20 60 16 82 99.3

[0072] Comparative Example 1

[0073] The method of Example 1 of patent document CN114163294A was repeated, but the target product 2-bromo-5-fluorobenzotrifluoride was not obtained.

[0074] Comparative Example 2

[0075] The Example 1 of the repeated patent CN107337576A failed to obtain the target product 2-bromo-5-fluorotrifluorotoluene.

Claims

1. A method for preparing 2-bromo-5-fluorobenzotrifluoride, characterized in that: The method comprises the following steps: in a solvent, in the presence of a substance X, subjecting m-fluorobenzotrifluoride and bromine to a substitution reaction to obtain 2-bromo-5-fluorobenzotrifluoride; The substance X is Fe and / or FeBr3; The solvent is dichloromethane and / or 1,2-dichloroethane; The molar ratio of the substance X to the meta-fluorobenzotrifluoride is (0.01-0.6):1; The molar ratio of the meta-fluorobenzotrifluoride to the bromine is 1:(1-5); The molar ratio of the meta-fluorobenzotrifluoride to the solvent is 1:(0.5-8).

2. The preparation method according to claim 1, characterized in that The preparation method satisfies one or both of the following: ① The reaction temperature of the substitution reaction is 40-60°C; ② The reaction time of the substitution reaction is 6-18h.

3. The preparation method according to claim 1, characterized in that: The preparation method satisfies one or more of the following: ① The molar ratio of the substance X to the meta-fluorobenzotrifluoride is (0.05-0.25):1; ② The molar ratio of the meta-fluorobenzotrifluoride to the bromine is 1:(2-4); ③ The molar ratio of the meta-fluorobenzotrifluoride to the solvent is 1:(0.5-6); ④ The reaction temperature of the substitution reaction is 40-45°C or 50-55°C; ⑤ The reaction time of the substitution reaction is 7h, 10h or 16h.

4. The preparation method according to claim 3, characterized in that: The preparation method satisfies one or more of the following: ① The molar ratio of the substance X to the meta-fluorobenzotrifluoride is 0.05:1, 0.10:1, 0.18:1, 0.20:1 or 0.25:1; ② The molar ratio of the meta-fluorobenzotrifluoride to the bromine is 1:2, 1:2.5 or 1:4; ③ The molar ratio of the meta-fluorotrifluorotoluene to the solvent is 1:1, 1:1.5, 1:2, 1:4 or 1:

6.

5. The preparation method according to claim 4, characterized in that: The solvent is dichloromethane and 1,2-dichloroethane, and the volume ratio of the dichloromethane to 1,2-dichloroethane is 1:

1.

6. The preparation method according to any one of claims 1 to 5, characterized in that The preparation method comprises the following steps: adding bromine to the mixture; The temperature of the mixture is 40-60°C; The mixture is a mixture of the solvent, the substance X and m-fluorotrifluorotoluene.

7. The preparation method according to claim 6, characterized in that: The bromine is added in a dropwise manner.

8. The preparation method according to any one of claims 1 to 5, characterized in that After the substitution reaction is completed, post-treatment is included; The post-processing comprises the following steps: A) distilling the reaction solution after the substitution reaction to recover the solvent and the unreacted bromine to obtain a crude product; B) The crude product is mixed with a reducing agent, distilled, and the fraction at 158-162° C. / 760 mmHg is collected.

9. The preparation method according to claim 8, characterized in that: The reducing agent is sodium sulfite; And / or, the ratio of the amount of the reducing agent to the amount of the bromine substance is 1:(40-160).

10. The preparation method according to claim 9, characterized in that: The ratio of the amount of the reducing agent to the amount of the bromine substance is 1:(40-80).

11. The preparation method according to claim 10, characterized in that: The ratio of the amount of the reducing agent to the amount of the bromine substance is 46.9:1, 60:1, 78:1 or 80:1.

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