Preparation method of 2-trifluoromethyl benzamide

Abstract

The invention discloses a preparation method of 2-trifluoromethyl benzamide, and belongs to the technical field of organic synthesis. The method comprises the following steps: reacting 2-cyanophenylboronic acid serving as a raw material with a trifluoromethylation reagent under the action of a copper catalyst and alkali to generate a 2-trifluoromethyl cyanophenyl intermediate; and then hydrolyzing the 2, 2-trifluoromethyl cyanophenyl intermediate under the action of acid to generate 2-trifluoromethyl benzamide. According to the invention, key phenylboronic acid and a trifluoromethylation reagent are directly subjected to a trifluoromethyl substitution reaction under the action of a copper catalyst and alkali, and a simple and effective new path is provided for preparation of 2-trifluoromethyl benzamide.

Description

Technical Field

[0001] The invention relates to a preparation method of 2-trifluoromethylbenzamide, and belongs to the technical field of organic synthesis. Background Art

[0002] 2-Trifluoromethylbenzamide (CAS No: 360-64-5) is widely used in the fields of medicine and pesticides. As an important chemical intermediate, its market demand continues to grow. In the field of medicine: 2-Trifluoromethylbenzamide can be used as an intermediate for the preparation of monkeypox specific drugs such as Tecoviridin, showing its application potential in the antiviral field. In the field of pesticides: 2-Trifluoromethylbenzamide is an important intermediate for pesticides such as fluopyram and cyfluthrin.

[0003]

[0004] Fluopyram is a new type of succinate dehydrogenase inhibitor, a broad-spectrum, systemic fungicide with protective and therapeutic effects. It can be used to control gray mold, powdery mildew, sclerotinia and brown rot on more than 70 crops such as grapes, pears, stone fruits and vegetables. It can also control banana leaf spot disease. It is also a new generation of excellent nematicides. Butyflumetofen is a new type of acyl acetonitrile acaricide, which is effective against both eggs and adult spider mites, and has higher activity against nymph mites. It is mainly used to control harmful mites on crops such as fruit trees, cotton, vegetables and tea.

[0005] There are many methods for synthesizing 2-trifluoromethylbenzamide. Among them, patent [CN113880725A] uses 2-trifluoromethylnitrobenzene as raw material and obtains it through diazotization, fluorination, cyanation and alkaline hydrolysis. The chemical reaction equation is as follows:

[0006]

[0007] Patents and literature [CN114195667A; WO2015193911A; US200886008A; Green Chemistry, 2021, 23, 3595] use 2-trifluoromethylbenzoyl chloride and ammonia to hydrolyze to obtain 2-trifluoromethylbenzamide. The chemical reaction equation is as follows:

[0008]

[0009] The literature [Journal of Organic Chemistry, 2013, 78, 11126; Organic Proce ss Research and Development, 2014, 18, 1020] uses 2-iodobenzamide and trifluoromethylcopper to synthesize 2-trifluoromethylbenzamide; the chemical reaction equation is as follows:

[0010]

[0011] In view of the shortcomings of the above methods, the present invention adopts a preparation method with simple process, mild reaction conditions, low equipment requirements and high total yield, which is suitable for factory production to meet the growing market demand. Summary of the invention

[0012] In order to overcome the above technical defects, the present invention provides a method for preparing 2-trifluoromethylbenzamide. 2-Nitrilophenylboronic acid is used as a raw material and a trifluoromethylating agent is reacted with a copper catalyst and a base to generate a 2-trifluoromethylbenzonitrile intermediate; the 2-trifluoromethylbenzonitrile intermediate is then hydrolyzed under the action of an acid to generate 2-trifluoromethylbenzamide. The route of the present invention is overall reasonable and is carried out in two steps, providing a simple and effective new path for the preparation of 2-trifluoromethylbenzamide.

[0013] The preparation method of 2-trifluoromethylbenzamide described in the present invention is represented by the following reaction equation:

[0014]

[0015] The steps include:

[0016] A. reacting 2-nitrile phenylboronic acid, a trifluoromethylating agent, a copper powder catalyst and a mixed base in an organic solvent at elevated temperature to generate 2-trifluoromethylbenzonitrile;

[0017] B. Mix 2-trifluoromethylbenzonitrile, trifluoroacetic acid and sulfuric acid, react under elevated temperature conditions, and then hydrolyze to obtain the product 2-trifluoromethylbenzamide.

[0018] Furthermore, in step A of the above technical solution, the organic solvent is selected from DMF or DMAc.

[0019] Furthermore, in step A of the above technical scheme, the trifluoromethylating agent is selected from S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate or 5-(trifluoromethyl)-5H-dithioanthene-5-ium trifluoromethanesulfonate; preferably 5-(trifluoromethyl)-5H-dithioanthene-5-ium trifluoromethanesulfonate.

[0020] Furthermore, in step A of the above technical solution, the temperature of the reaction is 40-50°C.

[0021] Furthermore, in step A of the above technical solution, the mixed base is selected from NaHCO3 / CsF, NaHCO3 / t-BuONa or NaHCO3 / DBU, wherein the molar ratio of sodium bicarbonate to the other three different bases (CsF, t-BuONa, DBU) is 1:0.5-1.5.

[0022] During the experiment, it was found that the influence of alkali was very large. After trying a variety of organic and inorganic bases (sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methoxide, potassium acetate, potassium fluoride, DBU, tetramethylguanidine, DMAP, sodium tert-butoxide, sodium tert-amyloxide, etc.), it was finally found that the best effect was achieved when a mixed alkali was used. The above three combinations are the best combinations.

[0023] Furthermore, in the above technical solution, in step A, the molar ratio of the 2-nitrilephenylboronic acid, the trifluoromethylation reagent, the copper powder catalyst and the mixed base is 1:1.1-1.5:1.8-2.2:1.5-2.5.

[0024] Furthermore, in the above technical solution, in step B, the temperature of the reaction is 50-70°C.

[0025] Furthermore, in the above technical solution, in step B, the molar ratio of 2-trifluoromethylbenzonitrile, trifluoroacetic acid and sulfuric acid is 1:13-15:4-6.

[0026] Beneficial effects of the invention:

[0027] A. In the first step of the present invention, 2-nitrilephenylboronic acid and a trifluoromethylating agent are used in the presence of a copper catalyst and a base to directly carry out trifluoromethyl substitution of the boronic acid, and the route is novel and feasible.

[0028] B. In the second step of the present invention, 2-trifluoromethylbenzonitrile is treated with trifluoroacetic acid and sulfuric acid, and then hydrolyzed to directly generate 2-trifluoromethylbenzamide, which has a simple route and provides a route reference for the synthesis of such compounds.

[0029] C. The raw materials for this process are easily available in the market, the process is simple, safe and stable, and is suitable for industrial scale expansion. Specific embodiments

[0030] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0031] Example 1

[0032]

[0033] Under nitrogen protection, 14.7 g (0.1 mol) of 2-nitrilephenylboronic acid, 56.5 g (0.13 mol) of 5-trifluoromethyl-5H-dithioxanthen-5-ium trifluoromethanesulfonate, 12.7 g (0.2 mol) of copper powder and 16.8 g (0.20 mol) of sodium bicarbonate were mixed in 650 mL of DMF, heated to 45-50° C., reacted for 7 hours, cooled to room temperature, filtered, and then 400 mL of water and 600 mL of dichloromethane were added. The layers were separated, and the aqueous layer was extracted twice with 300 mL of dichloromethane. The organic layers were combined and concentrated. The crude product was purified by column chromatography (eluent n-pentane) to obtain 10.8 g of 2-trifluoromethylbenzonitrile with a yield of 63% and an HPLC yield of 99.2%. 1 HNMR(400MHz, CDCl3):7.84(d,1H),7.83-7.74(m,2H),7.71(t,1H).

[0034] Under the same conditions, 8.4 g (0.10 mol) of sodium bicarbonate and 15.2 g (0.10 mol) of cesium fluoride were used as the base to obtain 14.7 g of 2-trifluoromethylbenzonitrile with a yield of 86% and an HPLC purity of 99.3%.

[0035] Example 2

[0036]

[0037] Under nitrogen protection, 14.7 g (0.1 mol) of 2-nitrile phenylboronic acid, 56.3 g (0.14 mol) of S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate, 11.4 g (0.18 mol) of copper powder and 21.8 g (0.26 mol) of sodium bicarbonate were mixed in 650 mL of DMAc, heated to 40-45 ° C, reacted for 9 hours, cooled to room temperature, filtered, and then 400 mL of water and 600 mL of dichloromethane were added. The layers were separated, and the aqueous layer was extracted twice with 300 mL of dichloromethane. The organic layers were combined and concentrated. The crude product was purified by column chromatography (eluent n-pentane) to obtain 10.3 g of 2-trifluoromethylbenzonitrile with a yield of 60% and an HPLC yield of 99.0%.

[0038] Under the same conditions, 12.6 g (0.15 mol) of sodium bicarbonate and 15.2 g (0.10 mol) of DBU were used as the base to obtain 13.9 g of 2-trifluoromethylbenzonitrile with a yield of 81% and an HPLC purity of 99.2%.

[0039] Example 3

[0040]

[0041] Under nitrogen protection, 15 g (0.1 mol) of 2-trifluoromethylbenzonitrile, 160 g (1.4 mol) of trifluoroacetic acid and 49 g (0.5 mol) of sulfuric acid were mixed, heated to 60-65° C., reacted for 3 hours, then poured into 600 mL of ice water, extracted twice with 200 mL of ethyl acetate, the organic layers were combined and concentrated, and then slurried with ethyl acetate / petroleum ether (v / v=1 / 6) to obtain 14.2 g of the product 2-trifluoromethylbenzamide, 75%, and chemical purity 98.8%. 1 HNMR(400MHz, DMSO-d6):7.94(s,1H),7.76(d,1H),7.72(t,1H),7.61(t,1H),7.58(d,1H),7.54(d,1H).

[0042] Example 4

[0043]

[0044] Under nitrogen protection, 15 g (0.1 mol) of 2-trifluoromethylbenzonitrile, 0.075 g (0.5 mmol) of trifluoromethanesulfonic acid, 160 g (1.4 mol) of trifluoroacetic acid and 49 g (0.5 mol) of sulfuric acid were mixed, heated to 50-55° C., reacted for 3 hours, then poured into 600 mL of ice water, extracted twice with 200 mL of ethyl acetate, the organic layers were combined, concentrated, and then slurried with ethyl acetate / petroleum ether (v / v=1 / 6) to obtain 17.2 g of 2-trifluoromethylbenzamide, 91%, and chemical purity 99%.

[0045] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 2-trifluoromethylbenzamide, characterized in that: The steps include: A. reacting 2-nitrile phenylboronic acid, a trifluoromethylating agent, copper powder and a mixed base in an organic solvent at elevated temperature to generate 2-trifluoromethylbenzonitrile; B. Mix 2-trifluoromethylbenzonitrile, trifluoroacetic acid and sulfuric acid, react under elevated temperature conditions, and then hydrolyze to obtain the product 2-trifluoromethylbenzamide.

2. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step A, the organic solvent is selected from DMF or DMAc.

3. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step A, the trifluoromethylating agent is selected from S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate or 5-(trifluoromethyl)-5H-dithioanthen-5-ium trifluoromethanesulfonate.

4. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step A, the temperature of the reaction is 40-50°C.

5. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step A, the mixed base is selected from NaHCO3 / CsF, NaHCO3 / t-BuONa or NaHCO3 / DBU.

6. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step A, the molar ratio of the 2-nitrilephenylboronic acid, the trifluoromethylation reagent, the copper powder and the mixed base is 1:1.1-1.5:1.8-2.2:1.5-2.

5.

7. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step B, the temperature is raised to 50-70°C.

8. The method for preparing 2-trifluoromethylbenzamide according to claim 1, characterized in that: In step B, the molar ratio of 2-trifluoromethylbenzonitrile, trifluoroacetic acid and sulfuric acid is 1:13-15:4-6.

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