Synthetic method of 4-fluoro-2-trifluoromethyl acetophenone

Abstract

The invention provides a synthesis method of 4-fluoro-2-trifluoromethyl acetophenone, which comprises the following steps: under protective gas, firstly adding a metal palladium catalyst, a ligand, alkali, an organic solvent, 2-bromo-4-fluorine-trifluorotoluene and methylboronic acid into a reactor, then introducing carbon monoxide gas into the reactor, raising the pressure of the reactor, and reacting for 2-4 hours at the temperature of between 20 and 30 DEG C; and heating and stirring until the reaction is complete, and carrying out post-treatment to obtain the product 4-fluoro-2-trifluoromethyl acetophenone. According to the method, the 4-fluoro-2-trifluoromethyl acetophenone is synthesized through the one-pot reaction of the 2-bromo-4-fluoro-trifluorotoluene and the methylboronic acid under the catalysis of the metal palladium catalyst, the reaction method is easy and convenient to operate, the target product can be efficiently synthesized only through one-step reaction, no waste water is generated in treatment after the reaction, and the method is green and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing 4-fluoro-2-trifluoromethylacetophenone. Background Art

[0002] 4-Fluoro-2-trifluoromethylacetophenone is an important raw material for the synthetic fungicide clofoconazole. Clofoconazole is the first new isopropanol triazole fungicide developed and launched by BASF in 2016. It is a new product of BASF with epoch-making significance. The isopropanol group in the molecular structure of clofoconazole enables it to bind more tightly to the enzyme action site, making its biological activity better than traditional triazole fungicides. It has a good therapeutic effect on a variety of fungal diseases that are generally recognized to be difficult to control, such as rust and diseases caused by Septoria. It is suitable for more than 60 crops such as field crops, cash crops and specialty crops, such as field crops such as corn, grains, soybeans, and rice, as well as cash crops such as green peppers and grapes. It can also be used for lawns, ornamental plants and seed treatment. The fungicide has a broad spectrum, high efficiency, selectivity and systemic conductivity, and has the characteristics of protection, treatment and high safety.

[0003] At present, the method for synthesizing 4-fluoro-2-trifluoromethylacetophenone mainly comprises: using 2-bromo-4-fluoro-trifluorotoluene as a starting material, preparing a Grignard reagent by means of an isopropyl magnesium chloride reagent, and then reacting the acetyl chloride or acetic anhydride to produce 4-fluoro-2-trifluoromethylacetophenone. This method has two-step reactions and uses a Grignard reagent. The reaction is harsh and a large amount of magnesium-containing wastewater is generated in the post-reaction treatment. The amount of three wastes is large and difficult to treat. Summary of the invention

[0004] In view of this, the present invention aims to provide a method for synthesizing 4-fluoro-2-trifluoromethylacetophenone, which is simple to operate, can obtain the target product in one step, has a good yield, and does not generate wastewater.

[0005] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0006] The synthesis method of 4-fluoro-2-trifluoromethylacetophenone comprises the following steps:

[0007] Under protective gas, a metal palladium catalyst, a ligand, a base, an organic solvent, 2-bromo-4-fluoro-trifluorotoluene and methylboric acid are first added to the reactor, and then carbon monoxide gas is filled into the reactor. The pressure of the reactor is increased, and the temperature is increased and stirred until the reaction is complete, and post-processed to obtain the product 4-fluoro-2-trifluoromethylacetophenone.

[0008] Furthermore, the molar ratio of the metal palladium catalyst, the ligand, the base, 2-bromo-4-fluoro-trifluorotoluene, and methylboric acid is (0.01-0.1): (0.01-0.2): (1-3): 1: (1-3);

[0009] Preferably, the molar ratio of the metal palladium catalyst, the ligand, the base, 2-bromo-4-fluoro-trifluorotoluene, and methylboric acid is 0.05:0.1:2:1:1.5.

[0010] Furthermore, the ratio of the 2-bromo-4-fluoro-trifluorotoluene to the organic solvent is 1 g: 4 to 10 mL;

[0011] Preferably, the usage ratio of 2-bromo-4-fluoro-trifluorotoluene to the organic solvent is 1 g:8 mL.

[0012] Furthermore, the metal palladium catalyst is one or more of palladium chloride, palladium acetate, di(acetylacetone)palladium, tri(dibenzylideneacetone)dipalladium, and tetrakistriphenylphosphine palladium.

[0013] Furthermore, the ligand is one or more of triphenylphosphine, 1,1'-ferrocenyldiyl-bis(diphenylphosphine), 1,3-bis(diphenylphosphine)propane, bis(diphenylphosphine)methane, 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, bis(2-diphenylphosphinophenyl)ether, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and tricyclohexylphosphine fluoroborate.

[0014] Further, the base is an inorganic base or an organic base; preferably, the cation of the inorganic base is Li + 、Na + , K + Any one of the above, wherein the anion of the inorganic base is F – 、CO3 2– PO4 3– OH – , [OMe] – and [O t Bu] – Any of;

[0015] Preferably, the organic base is any one of triethylamine, diisopropylamine, N,N-diisopropylethylamine, tri-n-propylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0016] Furthermore, the organic solvent is one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, acetone, and acetonitrile.

[0017] Furthermore, the protective gas is an inert gas, and preferably, the inert gas is one of argon or nitrogen.

[0018] Furthermore, the elevated pressure is increased to 1-1.5 MPa, and the elevated stirring reaction temperature is 70-80°C.

[0019] Furthermore, the post-treatment specifically includes the following steps: after the reaction is complete, filtering to remove insoluble matter, distilling to recover the solvent, and distilling to obtain the product 4-fluoro-2-trifluoromethylacetophenone.

[0020] Compared with the prior art, the synthesis method of 4-fluoro-2-trifluoromethylacetophenone described in the present invention has the following advantages:

[0021] The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone of the present invention uses 2-bromo-4-fluoro-trifluorotoluene and methylboric acid to synthesize 4-fluoro-2-trifluoromethylacetophenone through a one-pot reaction under the catalysis of a metal palladium catalyst. The reaction method is simple to operate, and the target product can be efficiently synthesized in one step. No wastewater is generated in the post-reaction treatment, and the method is green and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the accompanying drawings:

[0023] Figure 1 This is the HPLC chart of 4-fluoro-2-trifluoromethylacetophenone described in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0025] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0026] The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with embodiments.

[0027] Example 1

[0028] Under nitrogen protection, palladium acetate (11.3 mg, 0.05 mmol), triphenylphosphine (26.2 mg, 0.1 mmol), potassium carbonate (276.4 mg, 2 mmol), N, N-dimethylformamide (2 mL), 2-bromo-4-fluoro-trifluorotoluene (243 mg, 1 mmol) and methylboric acid (89.8 mg, 1.5 mmol) were added to the reactor in sequence, and then carbon monoxide gas was charged into the reactor, the reactor pressure was raised to 1 MPa, and then the temperature was raised to 75°C and stirred until the reaction was complete. After the reaction was completed, the insoluble matter was filtered out, the solvent was distilled and recovered, and then the product 4-fluoro-2-trifluoromethylacetophenone 187.6 mg was obtained by rectification, with a yield of 91%.

[0029] Embodiment 2-14

[0030] Except that the palladium catalyst and the ligand are different from those in Example 1, everything else is the same as in Example 1. The reaction results are shown in Table 1.

[0031] Table 1

[0032]

[0033]

[0034] Examples 15-26

[0035] Except that the base is different from that in Example 1, everything else is the same as in Example 1. The reaction results are shown in Table 2.

[0036] Table 2

[0037]

[0038] Examples 27-35

[0039] Except that the organic solvent is different from that in Example 1, everything else is the same as in Example 1. The reaction results are shown in Table 3.

[0040] Table 3

[0041]

[0042]

[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 4-fluoro-2-trifluoromethylacetophenone, characterized in that: The steps include: Under protective gas, a metal palladium catalyst, a ligand, a base, an organic solvent, 2-bromo-4-fluoro-trifluorotoluene and methylboric acid are first added to the reactor, and then carbon monoxide gas is filled into the reactor. The pressure of the reactor is increased, and the temperature is increased and stirred until the reaction is complete, and post-processed to obtain the product 4-fluoro-2-trifluoromethylacetophenone.

2. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The molar ratio of the metal palladium catalyst, the ligand, the base, 2-bromo-4-fluoro-trifluorotoluene, and methylboric acid is (0.01-0.1): (0.01-0.2): (1-3): 1: (1-3); Preferably, the molar ratio of the metal palladium catalyst, the ligand, the base, 2-bromo-4-fluoro-trifluorotoluene, and methylboric acid is 0.05:0.1:2:1:1.

5.

3. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The dosage ratio of the 2-bromo-4-fluoro-trifluorotoluene to the organic solvent is 1 g: 4 to 10 mL; Preferably, the usage ratio of 2-bromo-4-fluoro-trifluorotoluene to the organic solvent is 1 g:8 mL.

4. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The metal palladium catalyst is one or more of palladium chloride, palladium acetate, di(acetylacetone)palladium, tri(dibenzylideneacetone)dipalladium, and tetrakistriphenylphosphine palladium.

5. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The ligand is one or more of triphenylphosphine, 1,1'-ferrocenyldiyl-bis(diphenylphosphine), 1,3-bis(diphenylphosphine)propane, bis(diphenylphosphine)methane, 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, bis(2-diphenylphosphinophenyl)ether, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and tricyclohexylphosphine fluoroborate.

6. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The base is an inorganic base or an organic base; preferably, the cation of the inorganic base is Li + 、Na + , K + Any one of the above, wherein the anion of the inorganic base is F – 、CO3 2– PO4 3– OH – , [OMe] – and [O t Bu] – Any of; Preferably, the organic base is any one of triethylamine, diisopropylamine, N,N-diisopropylethylamine, tri-n-propylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

7. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The organic solvent is one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, acetone, and acetonitrile.

8. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The protective gas is an inert gas, and preferably, the inert gas is one of argon or nitrogen.

9. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The elevated pressure is increased to 1-1.5 MPa, and the elevated stirring reaction temperature is 70-80°C.

10. The method for synthesizing 4-fluoro-2-trifluoromethylacetophenone according to claim 1, characterized in that: The post-treatment specifically includes the following steps: after the reaction is complete, filtering to remove insoluble matter, distilling to recover the solvent, and rectifying to obtain the product 4-fluoro-2-trifluoromethylacetophenone.

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