Preparation method of 3-bromobenzotrifluoride

Abstract

The invention relates to a preparation method of 3-bromobenzotrifluoride, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: taking benzotrifluoride as a raw material, and reacting with liquid bromine under the action of a catalyst and a complexing agent to obtain 3-bromobenzotrifluoride; the catalyst is iron powder, ferric trichloride or ferric tribromide; the complexing agent is at least one of methanol, ethanol, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone or sodium acetate. The compound containing lone pair electrons is added into the reaction liquid to form a complex with ferric iron, so that the activity of the ferric iron catalyst is reduced, and the situation that the bromine substitution selectivity is reduced due to too high activity is avoided; the selectivity of aromatic ring bromine meta-substitution is improved, the generation of para-bromine substituted isomers and polysubstituted impurities is reduced, and the purity and yield of the product are improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of m-bromotrifluorotoluene. BACKGROUND

[0002] M-bromotrifluorotoluene is an important pesticide and pharmaceutical chemical intermediate, which is widely used in synthesis of the intermediate m-trifluoromethylacetophenone of triflumizole, the intermediate methyl m-trifluoromethylbenzoate of nifluramide, and fenfluramine, a weight loss drug.

[0003] In the prior art, there are mainly two methods for preparing m-bromotrifluorotoluene. I. Indirect bromination method: this method uses m-trifluorotoluene as a raw material, and synthesizes the target product through nitration, reduction, and then Sandmeyer reaction. However, this method has obvious defects, such as long synthesis route, high risk due to the involvement of the nitration step in the production process, large amount of three wastes (especially wastewater), and low product yield, which limits its industrial application.

[0004] II. Direct bromination method: US patent US6420608 discloses a method for obtaining m-bromotrifluorotoluene through direct bromination reaction. In this method, m-trifluorotoluene is directly subjected to electrophilic substitution reaction of aromatic ring under the catalysis of iron powder. Compared with the indirect bromination method, this method has higher yield and lower production cost. However, this method still has the following key problems: (1) The conversion rate is extremely fast at the initial stage of the reaction, and the instantaneous conversion rate can reach more than 80%, which leads to the rapid generation of a large amount of hydrogen bromide gas in the reaction system. If the hydrogen bromide is not discharged in time, it is easy to cause a sudden pressure rise and cause safety accidents.

[0005] (2) The fast reaction rate also leads to poor selectivity of the product, and the generated substitution product contains para-position isomer impurities of aromatic ring bromination, and the ratio of meta-position and para-position products is about 96:4. Since the boiling range (154-155℃) of the para-position impurity is very close to the boiling range (151-152℃) of the target product m-bromotrifluorotoluene, it is difficult to realize effective separation by using conventional rectification method, which puts high requirements on the rectification equipment, and it is difficult to obtain a product with a purity higher than 99%, thereby affecting its application in subsequent fine chemical synthesis.

[0006] (3) The fast reaction rate is also easy to cause multi-substitution side reactions, and generate dibromo or multi-bromo impurities, thereby reducing the yield of the target product.

[0007] Therefore, it is of great significance to develop a method for efficiently preparing high-purity m-bromotrifluorotoluene with mild reaction, high selectivity, good safety, and high efficiency, in order to meet the needs of the pesticide and pharmaceutical industries. SUMMARY

[0008] In view of the technical problems of poor substitution selectivity and poor product purity caused by too fast reaction speed in the existing preparation of m-bromotoluene by using bromination method, the application provides a preparation method of m-bromotoluene to solve the above problems.

[0009] The technical scheme of the application is as follows: A preparation method of m-bromotoluene, which uses trifluorotoluene as a raw material, reacts with liquid bromine under the action of a catalyst and a complexing agent to obtain m-bromotoluene; the catalyst is iron powder, ferric chloride or iron tribromide; the complexing agent is at least one of methanol, ethanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone or sodium acetate. The reaction formula is as follows: .

[0010] Further, the specific preparation method is as follows: Trifluorotoluene and a catalyst are put into a reactor; the temperature is controlled at 20-30 DEG C, and a complexing agent is added; after warming, liquid bromine is added; after the feeding is completed, the temperature is controlled and stirring is carried out until the trifluorotoluene is completely reacted; then the reaction liquid is slowly added to 10% sodium sulfite aqueous solution, stirred, and separated; the organic phase is dried and concentrated to obtain m-bromotoluene.

[0011] Further, the molar ratio of the catalyst to trifluorotoluene is 0.45-0.55:1.

[0012] Further, the molar ratio of the complexing agent to the catalyst is 1.5-2.0:1.

[0013] Further, the complexing agent is methyl tert-butyl ether, tetrahydrofuran or 2-methyltetrahydrofuran.

[0014] Further, the reaction temperature is 45-55 DEG C.

[0015] Further, the molar ratio of the liquid bromine to trifluorotoluene is 1:1.4-1.6.

[0016] Further, the temperature of the 10% sodium sulfite aqueous solution is 5-10 DEG C.

[0017] Further, the m-bromotoluene also includes a refining process of reduced pressure rectification.

[0018] The application has the following beneficial effects: The preparation method of m-bromotoluene provided by the application, by adding a compound containing a lone pair of electrons to the reaction solution to form a complex with ferric iron, reduces the activity of the ferric iron catalyst, avoids reducing the selectivity of bromine substitution due to excessively high activity, improves the selectivity of bromine substitution at the meta position of the aromatic ring, reduces the generation of para-bromine substitution isomers and polysubstituted impurities, and improves the purity and yield of the product. Moreover, the reaction rate is stable, and safety accidents caused by the too fast generation of hydrogen bromide gas are avoided. After rectification, the purity of the product can reach more than 99.5%, and the yield can be more than 95%. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or the prior art description. Obviously, for those skilled in the art, other drawings can also be obtained from these drawings without creative labor.

[0020] Figure 1 is the retention time of various components in the high-performance liquid chromatogram of the present application. Among them, RT=4.906 min is trifluorotoluene, RT=6.098 min is o-bromotoluene, RT=6.610 min is p-bromotoluene, RT=6.780 min is m-bromotoluene, RT=7.911 min is 2,5-dibromotoluene, and RT=8.041 min is 1,2-dibromo-4-(trifluoromethyl)benzene.

[0021] Figure 2 is the HPLC spectrum of m-bromotoluene prepared in Example 2 of the present application.

[0022] Figure 3 is the HPLC spectrum of m-bromotoluene prepared in Example 8 of the present application.

[0023] Figure 4 is the HPLC spectrum of m-bromotoluene prepared in the comparative example of the present application. DETAILED DESCRIPTION

[0024] In order to enable those skilled in the art to better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor should belong to the scope of protection of the present application.

[0025] Example 1 Trifluorotoluene (30.00 g, 0.205 mol, 1.0 eq.) and iron powder (5.16 g, 0.0924 mol, 0.45 eq.) were added to the reaction bottle, the temperature was controlled at 20-30°C, and methyl tert-butyl ether (12.20 g, 0.138 mol, 0.675 eq.) was added. The reaction system was heated to 45°C, and liquid bromine (45.94 g, 0.287 mol, 1.4 eq.) was added. The reaction was carried out at 45°C for 4h, and the reaction was completed. The reaction liquid was cooled to 10°C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and separated by standing. The organic phase was dried and concentrated to obtain the crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a purity of 99.7% and a yield of 97.1%.

[0026] Example 2 Trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.43 g, 0.061 mol, 0.45 eq.) were added to the reaction bottle, the temperature was controlled at 20-30°C, and tetrahydrofuran (6.67 g, 0.0924 mol, 0.675 eq.) was added. The reaction system was heated to 45°C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45°C for 4h, and the reaction was completed. The reaction liquid was cooled to 10°C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and separated by standing. The organic phase was dried and concentrated to obtain the crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a purity of 99.8% and a yield of 97.2%. The HPLC spectrum is shown in Figure 2 .

[0027] Example 3 Trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.43 g, 0.061 mol, 0.45 eq.) were added to the reaction bottle, the temperature was controlled at 20-30°C, and 2-methyltetrahydrofuran (7.97 g, 0.0924 mol, 0.675 eq.) was added. The reaction system was heated to 45°C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45°C for 4h, and the reaction was completed. The reaction liquid was cooled to 10°C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and separated by standing. The organic phase was dried and concentrated to obtain the crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a purity of 99.6% and a yield of 96.9%.

[0028] Example 4 Trifluorotoluene (30.00 g, 0.205 mol, 1.0 eq.) and iron powder (6.31 g, 0.1128 mol, 0.55 eq.) were added to a reaction flask, and the temperature was controlled at 20-30 °C. Methyl tert-butyl ether (19.89 g, 0.226 mol, 1.1 eq.) was added. The reaction system was heated to 45 °C, and liquid bromine (45.94 g, 0.287 mol, 1.4 eq.) was added. The reaction was carried out at 45 °C for 4 h, and the reaction was completed. The reaction liquid was cooled to 10 °C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and allowed to stand to separate. The organic phase was dried and concentrated to obtain crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a purity of 99.7% and a yield of 95.5%.

[0029] Example 5 Trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.84 g, 0.0685 mol, 0.50 eq.) were added to a reaction flask, and the temperature was controlled at 20-30 °C. Tetrahydrofuran (9.88 g, 0.137 mol, 1.0 eq.) was added. The reaction system was heated to 45 °C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45 °C for 4 h, and the reaction was completed. The reaction liquid was cooled to 10 °C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and allowed to stand to separate. The organic phase was dried and concentrated to obtain crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a purity of 99.5% and a yield of 96.1%.

[0030] Example 6 Trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.43 g, 0.061 mol, 0.45 eq.) were added to a reaction flask, and the temperature was controlled at 20-30 °C. Methanol (2.93 g, 0.0915 mol, 0.675 eq.) was added. The reaction system was heated to 45 °C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45 °C for 5 h, and the reaction was completed. The reaction liquid was cooled to 5 °C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and allowed to stand to separate. The organic phase was dried and concentrated to obtain crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a purity of 99.6% and a yield of 85.2%.

[0031] Example 7 Into a reaction flask was placed trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (4.20 g, 0.075 mol, 0.55 eq.), temperature was controlled at 20-30 °C, and ethanol (6.91 g, 0.15 mol, 1.1 eq.) was added. The reaction system was heated to 55 °C, and liquid bromine (35.03 g, 0.219 mol, 1.6 eq.) was added. The reaction was carried out at 55 °C for 5 h. The reaction solution was cooled to 5 °C, and then slowly added to 10% sodium sulfite aqueous solution. After stirring, the reaction solution was allowed to stand and separate. The organic phase was dried and concentrated to obtain m-bromotrifluorotoluene, which was purified by distillation to obtain m-bromotrifluorotoluene with a HPLC purity of 99.8% and a yield of 89.2%.

[0032] Example 8 Into a reaction flask was placed trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.43 g, 0.061 mol, 0.45 eq.), temperature was controlled at 20-30 °C, and acetone (5.37 g, 0.0924 mol, 0.675 eq.) was added. The reaction system was heated to 45 °C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45 °C for 5 h. The reaction solution was cooled to 10 °C, and then slowly added to 10% sodium sulfite aqueous solution. After stirring, the reaction solution was allowed to stand and separate. The organic phase was dried and concentrated to obtain m-bromotrifluorotoluene, which was purified by distillation to obtain m-bromotrifluorotoluene with a HPLC purity of 97.5% and a yield of 92.5%. Figure 3 .

[0033] Example 9 Into a reaction flask was placed trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.43 g, 0.061 mol, 0.45 eq.), temperature was controlled at 20-30 °C, and sodium acetate (7.59 g, 0.0924 mol, 0.675 eq.) was added. The reaction system was heated to 45 °C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45 °C for 5 h. The reaction solution was cooled to 10 °C, and then slowly added to 10% sodium sulfite aqueous solution. After stirring, the reaction solution was allowed to stand and separate. The organic phase was dried and concentrated to obtain m-bromotrifluorotoluene, which was purified by distillation to obtain m-bromotrifluorotoluene with a HPLC purity of 99.8% and a yield of 84%.

[0034] Comparative Example Trifluorotoluene (20.00 g, 0.137 mol, 1.0 eq.) and iron powder (3.43 g, 0.061 mol, 0.45 eq.) were added to a reaction bottle, the temperature was controlled at 20-30°C, and sodium acetate (7.59 g, 0.0924 mol, 0.675 eq.) was added. The reaction system was heated to 45°C, and liquid bromine (30.65 g, 0.192 mol, 1.4 eq.) was added. The reaction was carried out at 45°C for 3h, and the reaction was completed. The reaction liquid was cooled to 5°C, and then the reaction liquid was slowly added to 10% aqueous sodium sulfite solution, stirred, and separated. The organic phase was dried and concentrated to obtain the crude m-bromotrifluorotoluene, which was rectified to obtain m-bromotrifluorotoluene with a HPLC purity of 95.3% and a yield of 80.2%. The HPLC spectrum is shown in Figure 4 .

[0035] There are different position substitution impurities (ortho-bromine substitution, para-bromine substitution, 1,3-dibromine substitution, 2,5-dibromine substitution) in the bromine substitution of trifluorotoluene (as shown in Figure 1 . The impurities were positioned by dissolving each impurity in acetonitrile and then detecting by liquid chromatography to position the impurity out-of-phase position), among which the ortho-bromine substitution, 1,2-dibromine substitution and 2,5-dibromine substitution can be removed by rectification because their boiling ranges are quite different from that of m-bromotrifluorotoluene, while the para-bromine substitution is difficult to separate by rectification because its boiling range is close to that of the product, resulting in a product purity of less than 99%.

[0036] Fe 3+ has an empty orbital that can complex with lone pair electrons (1) Methanol, ethanol and sodium acetate have small steric hindrance, and their lone pair electrons have strong complexing ability with Fe 3+ , resulting in the inhibition of the catalytic bromine substitution ability of Fe 3+ , and the final residue of raw materials is more and the yield is low. (2) Methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran have moderate complexing ability with Fe 3+ due to the presence of steric hindrance, which reduces the catalytic ability of Fe 3+ , but has sufficient catalytic effect, resulting in good product purity and yield. (3) Acetone has weakened ability to provide lone pair electrons, which reduces the complexing ability of lone pair electrons, and Fe 3+ retains sufficient catalytic ability, which reduces the selectivity of bromine substitution, resulting in low product purity.

[0037] Although the present application has been described in detail with reference to the preferred embodiments, it should be understood that the application is not limited to those preferred embodiments. Various modifications and equivalents can be made by those skilled in the art without departing from the spirit and scope of the application. Any and all modifications and equivalents are intended to be included within the scope of the present application.

Claims

1. A process for the preparation of m-bromotolyl trifluoride, characterized in that, The m-bromotrifluorotoluene is obtained by reacting trifluorotoluene with liquid bromine under the action of a catalyst and a complexing agent; the catalyst is iron powder, ferric chloride or iron tribromide; and the complexing agent is at least one of methanol, ethanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone or sodium acetate.

2. A process for the preparation of m-bromobenzotrifluoride according to claim 1, characterized in that, The specific preparation method is as follows: trifluorotoluene and a catalyst are put into a reactor; the temperature is controlled at 20-30 DEG C, and a complexing agent is added; after warming, liquid bromine is added; after the feeding is completed, the temperature is controlled and stirring is carried out until the trifluorotoluene is completely reacted; then the reaction liquid is slowly added into 10% sodium sulfite aqueous solution, stirred, and allowed to stand to separate; the organic phase is dried and concentrated to obtain m-bromotrifluorotoluene.

3. A process for the preparation of m-bromobenzotrifluoride according to claim 1 or 2, characterized in that, The molar ratio of the catalyst to trifluorotoluene is 0.45-0.55:

1.

4. The method of claim 1 or 2, wherein the 3-bromo-4-fluorobenzene is prepared by the process comprising:

4. The method of claim 1 or 2, wherein the 3-bromo-4-fluorobenzene is prepared by the process comprising: The molar ratio of the complexing agent to the catalyst is 1.5-2.0:

1. ​ 5. The method for preparing m-bromotrifluorotoluene as described in claim 1 or 2, characterized in that, The complexing agent is methyl tert-butyl ether, tetrahydrofuran or 2-methyltetrahydrofuran.

6. The method for preparing m-bromotrifluorotoluene as described in claim 1 or 2, characterized in that, The reaction temperature is 45-55 DEG C.

7. A process for the preparation of m-bromobenzotrifluoride according to claim 1 or 2, characterized in that, The molar ratio of the liquid bromine to trifluorotoluene is 1:1.4-1.

6.

8. The method for preparing m-bromotrifluorotoluene according to claim 2, characterized in that, The temperature of the 10% sodium sulfite aqueous solution is 5-10 DEG C.

9. The method for preparing m-bromotrifluorotoluene as described in claim 1 or 2, characterized in that, The process further comprises a refining process of reduced pressure rectification.

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